3-(1 H-IMIDAZOL-2-YL)-2,3,8,8A-TETRAHYDROINDOLIZIN-5(1 H)-ONE DERIVATIVES USEFUL AS FACTOR XIA INHIBITORS

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/054,826, filed on July 22, 2020, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

The present invention is directed 3-(1H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one derivatives, stereoisomers, isotopologues, 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, pp7425-7447, 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)

(R ² )e·

R ¹

O Q

(I) wherein

R ¹ is selected from the group consisting of halogen, hydroxy, Ci-4alkyl, fluorinated Ci-*alkyl, Ci^alkoxy, fluorinated Ci-4alkoxy, cyano, nitro, -NR ^A R ^B , - C(0)-Ci-*alkyl, Ca-ecycloalkyl, phenyl and 5 to 6 membered heterocyclyl; wherein the Cs^cycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, Ci^alkyl, fluorinated Ci- 4alkyl, C^alkoxy, fluorinated Ci^alkoxy, -C(0)0H, -C(0)0-(CMalkyl), -NR ^A R ^B , -(Ci-4alkyl)-NR ^A R ^B , C3-7cydoalkyl and 5 to 6 membered heterocyclyl; and wherein R ^A and R ^B are each independently selected from the group consisting of hydrogen and Ci-4alkyl; a is an integer from 0 to 3; each R ² is 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 are taken together with the carbon atom to which they are bound to form oxo;

R ^c is selected from the group consisting of hydrogen and Ci-4alkyl;

R ^D is selected from the group consisting of hydrogen, Ci-4alkyl and Ci-

4alkoxy;

R ^E is selected from the group consisting of hydrogen and Ci^alkyl; Q is selected from the group consisting of wherein

R ⁴ is selected from the group consisting of hydrogen and Ci-*alkyl;

R ⁵ is selected from the group consisting of hydrogen, halogen and Ci- «alkyl; selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 9 to 10 membered heterocyclyl; b is an integer from 0 to 1 ;

R ⁶ is selected from the group consisting of Ca-acydoalkyl, -0-(Ci- 2alkylene)-C3-8cycloalkyl, -C(0)-(C3-8cycloalkyl), -NH-(C3-8cycloalkyl), -NH-C(O)- (Ca-acycloalkyl), -C(0)-NH-(C3-ecycloalkyl), 4-6 membered heterocycloalkyl, -O- (Ci-2alkylene)-(4-6 membered heterocycloalkyl), -C(0)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocydoalkyl), -C(0)-NH-(4-6 membered heterocydoalkyl), -NH-C(0)-(4-6 membered heterocydoalkyl), 5-6 membered heteroaryl, -0-(Ci-2alkylene)-(5-6 membered heteroaryl), -C(0)-(5-6 membered heteroaryl), -NH-(5-6 membered heteroaryl), -NH-C(0)-(5-6 membered heteroaryl), -C(0)-NH-(5-6 membered heteroaryl), 2-oxa-6- azaspiro[3.3]hept-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, and 7-oxa-2- azaspiro[3.5]nonan-2-yl; wherein the Ca-acydoalkyl, 4-6 membered heterocydoalkyl, or 5-6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-<alkyl, hydroxy, oxo, cyano and NR ^P R ^Q ; wherein R ^p and R ^Q are each independently selected from the group consisting of hydrogen and Ci-4alkyl; c is an integer from 0 to 3; each R ⁷ is independently selected from the group consisting of halogen, Ci-4alkyl, fluorinated Ci-4alkyl, hydroxy substituted Ci-ealkyl, hydroxy substituted fluorinated Ci-2alkyl, cyano substituted Ci-2alkyl, Ci-4alkoxy, fluorinated Ci- 2alkoxy, hydroxy substituted Ci-4alkoxy, -(Ci-2alkylene)-0-(Ci-4alkyl), oxo, - C(0)0-(Ci-2alkyl), -NR ^K R ^L , -NR ^K -(hydroxy substituted Ci^alkyl), - lkylene)-0-(Ci- ₂ alkyl), -C(0)-NR ^K R ^L , -C(0)-NR ^K -0-(Ci^alkyl), -C(O)- lkylene)-0-(Ci - ₂ alkyl) , -(Ci. ₂ alkylene)-C(0)-NR ^K R ^L , -NR ^K -C(0)-(Ci- ^K -C(0)-(fluorinated Ci. ₂ alkyl), -NR ^K -C(0)0-(Ci-4alkyl), -NR«-C(0)- Cs-ecycloalkyl, -(Ci-2alkylene)-NR^C(0)-(Ci^alkyl), -(Ci- ₂ alkylene)-NR ^K -C(0)0- (Ci-4alkyl), -(Ci-2alkylene)-0-C(0)-(amino substituted Ci-4alkyl), -NR^SC^tCi- 4alkyl), -C(0)-NR ^K -S0 ₂ -(Ci-2alkyl), -(Ci-2alkyene)-0-P(0)(0H)2, and -(Cv 2alkyene)-0-(Ci-2alkylene)-P(0)(0H)2; wherein R ^K and R ^L are each independently selected from hydrogen and Ci-4alkyl; and wherein the heterocyclyl, heteroaryl or heterocydoalkyl present as

(R ⁷ )e any part of the -K5 (R ⁶ )b group contains a nitrogen atom, then said heterocyclyl, heteroaryl or heterocycloalkyl may be further substituted to form an N-oxide; provided that when R ¹ is 1,2,3,4-tetrazoM-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

The present invention is further directed to a compound of formula (II) ci

Ν·

N

ΗΝ.

R

HO (II) 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)-8 a-methyl-2,3,8,8a- tetrahydroindolizin-5(1 H)-one; and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

The present invention is further directed to a compound of formula (III) also known as (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol- 2-yl)-7-(5-chloro-2-(1 H-tetrazol-1-yl)phenyl)hexahydroindolizin-5(1 H)-one; and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

The present invention is further directed to a compound of formula (IV) also known as (3S,7R,8aR)-7-(3-chloro-2-fluoro6-(1H-tetrazol-1- yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H- imidazol-2- yl)hexahydroindolizin-5(1H)-one; and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for the preparation of the compounds of formula (I), compounds of formula (II), compounds of formula (III) and compounds of formula (IV). The present invention is further directed to a compound of formula (I), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) as described herein. An illustration of the invention is a pharmaceutical composition made by mixing a compound of formula (I), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) for use as a medicament. In another embodiment, the present invention is directed to a compound of formula (I), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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), compound of formula (II), compound of formula (III) or compound of formula (IV) 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, 0) peripheral occlusive arterial disease, (k) venous thrombosis, (I) 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, (I) 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.

The present invention is further directed to a compound, composition (e.g. pharmaceutical composition), method of treatment, method of preparation or use, as herein described.

DETAILED DESCRIPTION OF THE INVENTION 1. 3-(1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one Derivatives Factor Xla 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 yield 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 Xla, 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 Vila (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. Vase. Biol., 27:2507-2513 (2007)). The resulting burst of thrombin converts fibrinogen to fibrin that polymerizes to form the structural framework of a blood dot, and activates platelets, which are a key cellular component of coagulation (Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Factor Xla plays a key role in propagating this amplification loop. Epidemiological studies showed that increased drculating FXI levels in humans have been assodated with increased risk for venous and arterial thrombosis, induding stroke (see Quan et al. supra). In contrast, patients with congenital FXI defidency (hemophilia C) are protected from ischemic stroke and venous thromboembolism. Therefore, Factor Xla 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 indude not only surface structures of foreign cells (e.g. bacteria) but also artifidal surfaces such as vascular prostheses, stents and extracorporeal drculation. On the surface, initially Factor XII (FXII) is activated to Factor Xlla which subsequently activates Factor XI, attached to cell surfaces, to Factor Xla. This leads to further activation of the coagulation cascade as described above. In addition, Factor Xlla 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.

The present invention is directed to compounds of formula (I) wherein a, R ¹ , R ² , R ^A , R ^B , R ^c , R ^D , R ^E , Q, etc. are as described herein; and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. The present invention is further directed to compounds of formula (II) r"

N

Cl

F N

O N

HN

F,

HO (II) and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. The present invention is further directed to a compound of formula (III) and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. The present invention is further directed to a compound of formula (IV) and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. The compounds of formula (I), compounds of formula (II), compounds of formula (III) and compounds of formula (IV) 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.

Embodiments

In some embodiments, the present invention is directed to compounds of formula (I) having formula (l-A) wherein

R ¹ is selected from the group consisting of halogen, hydroxy, Ci-4alkyl, fluorinated Ci-*alkyl, Ci-4alkoxy, fluohnated Ci-4alkoxy, cyano, nitro, -NR ^A R ^B , - C(0)-Ci-*alkyi, Ca-ecycloalkyl, phenyl and 5 to 6 membered heterocyclyl; wherein the Ca^cycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, Ci-4alkyl, fluorinated Cv 4alkyl, Ci-*alkoxy, fluorinated Ci-talkoxy, -C(0)0H, -C(0)0-(Ci-*alkyl), -NR ^A R ^B , -(Ci-4alkyl)-NR ^A R ^B , Ca-rcydoalkyl and 5 to 6 membered heterocyclyl; and wherein R ^A and R ^B are each independently selected from the group consisting of hydrogen and Ci-«alkyl; a is an integer from 0 to 3; each R ² is 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 are taken together with the carbon atom to which they are bound to form oxo;

R ^c is selected from the group consisting of hydrogen and Ci-«alkyl;

R ^D is selected from the group consisting of hydrogen, Ci-4alkyl and Ci-

₄ alkoxy;

R ^E is selected from the group consisting of hydrogen and Ci-4alkyl; Q is selected from the group consisting of wherein

R ⁴ is selected from the group consisting of hydrogen and Ci^alkyl;

R ⁵ is selected from the group consisting of hydrogen, halogen and Ci- ₄ alkyl; selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 9 to 10 membered heterocyclyl; b is an integer from 0 to 1 ;

R ⁶ is selected from the group consisting of Ca-acycloalkyl, -0-(Ci- ₂ alkylene)-C3-8cycloalkyl, -C(0)-(C3-8cycloalkyl), -NH-(C ₃ -8cycloalkyl), -NH-C(O)- (Ca-acycloalkyl), -C(0)-NH-(C3-ecycloalkyl), 4-6 membered heterocycloalkyl, -O- (Ci-2alkylene)-(4-6 membered heterocycloalkyl), -C(0)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocydoalkyl), -C(0)-NH-(4-6 membered heterocycloalkyl), -NH-C(0)-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -0-(Ci-2alkylene)-(5-6 membered heteroaryl), -C(0)-(5-6 membered heteroaryl), -NH-(5-6 membered heteroaryl), -NH-C(0)-(5-6 membered heteroaryl), -C(0)-NH-(5-6 membered heteroaryl), 2-oxa-6- azaspiro[3.3]hept-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, and 7-oxa-2- azaspiro[3.5]nonan-2-yl; wherein the Ca-scycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-talkyl, hydroxy, oxo, cyano and NR ^P R ^Q ; wherein R ^p and R ^Q are each independently selected from the group consisting of hydrogen and Ci^alkyl; c is an integer from 0 to 3; each R ⁷ is independently selected from the group consisting of halogen, Ci-4alkyl, fluorinated Ci^alkyl, hydroxy substituted Ci-ealkyl, hydroxy substituted fluorinated Ci-2alkyl, cyano substituted Ci-2alkyl, Ci-4alkoxy, fluorinated Ci- 2alkoxy, hydroxy substituted Ci^alkoxy, -(Ci-2alkylene)-0-(Ci-4alkyl), oxo, - C(0)OH, -C(0)0-(Ci- ₂ alkyl), -NR ^K R ^L , -NR*-(hydroxy substituted NR ^K -(Ci-2alkylene)-0-(Ci- ₂ alkyl), -C(0)-NR ^K R ^L , -C(0)-NR ^K -0-(Ci NRK-iCi^alkylenei-O-iCi^alkyl), -(Ci-2alkylene)-C(0)-NR ^K R ^L , -N olkyl), -NR ^K -C(0)-(fluorinated Ci- ₂ alkyl), -NR ^K -C(0)0-(CMalkyl) Cs-ecycloalkyl, -(Ci- ₂ alkylene)-NR ^K -C(0)-(Ci.*alkyl), -(Ci- ₂ alkylen (Ci-4alkyl), -(Ci-2alkylene)-0-C(0)-(amino substituted Ci-*alkyl), - i. ₂ alkyene)-0-P(0)(0H)2, wherein R ^K and R ^L are each independently selected from hydrogen and Ci-*alkyl; and wherein the heterocyclyl, heteroaryl or heterocydoalkyl present as

(R ⁷ )= any part of the -K5 (R ^e )b group contains a nitrogen atom, then said heterocyclyl, heteroaryl or heterocycloalkyl may be further substituted to form an N-oxide; provided that when R ¹ is 1,2,3,4-tetrazoM-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof. In some embodiments, the present invention is directed to compounds of formula (I) having formula (l-B) wherein

R ¹ is selected from the group consisting of halogen, hydroxy, Ci-4alkyl, fluorinated Ci-*alkyl, Ci^alkoxy, fluorinated Ci-4alkoxy, cyano, nitro, -NR ^A R ^B , - C(0)-Ci-talkyl, Cs-ecycloalkyl, phenyl and 5 to 6 membered heterocyclyl; wherein the Ca-ecycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, Ci-<alkyl, fluorinated Ci- 4alkyl, Ci-4alkoxy, fluorinated Ci-<alkoxy, -C(0)0H, -C(0)0-(Ci-4alkyl), -NR ^A R ^B , -(Ci-4alkyl)-NR ^A R ^B , Cs-ycydoalkyl and 5 to 6 membered heterocyclyl; and wherein R ^A and R ^B are each independently selected from the group consisting of hydrogen and Ci-4alkyl; a is an integer from 0 to 3; each R ² is 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 are taken together with the carbon atom to which they are bound to form oxo;

R ^c is selected from the group consisting of hydrogen and Ci-«alkyl;

R ^D is selected from the group consisting of hydrogen, Ci-4alkyl and Ci-

4alkoxy;

R ^E is selected from the group consisting of hydrogen and Ci-4alkyl; Q is selected from the group consisting of wherein

R ⁴ is selected from the group consisting of hydrogen and Cualkyl;

R ⁵ is selected from the group consisting of hydrogen, halogen and Ci-

4alkyl; selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 9 to 10 membered heterocyclyl; b is an integer from 0 to 1 ;

R ⁶ is selected from the group consisting of Ca-acycloalkyl, -0-(Ci- 2alkylene)-C3-8cycloalkyl, -C(0)-(C3-8cycloalkyl), -NH-(C3-ecydoalkyl), -NH-C(O)- (C3-8cycloalkyl), -C(0)-NH-(C3-scycloalkyl), 4-6 membered heterocycloalkyl, -O- (Ci-2alkylene)-(4-6 membered heterocycloalkyl), -C(0)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocydoalkyl), -C(0)-NH-(4-6 membered heterocydoalkyl), -NH-C(0)-(4-6 membered heterocydoalkyl), 5-6 membered heteroaryl, -0-(Ci-2alkylene)-(5-6 membered heteroaryl), -C(0)-(5-6 membered heteroaryl), -NH-(5-6 membered heteroaryl), -NH-C(0)-(5-6 membered heteroaryl), -C(0)-NH-(5-6 membered heteroaryl), 2-oxa-6- azaspiro[3.3]hept-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl , and 7-oxa-2- azaspiro[3.5]nonan-2-yl; wherein the Cs-acydoalkyl, 4-6 membered heterocydoalkyl, or 5-6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-4alkyl, hydroxy, oxo, cyano and NR ^P R ^Q ; wherein R ^p and R ^Q are each independently selected from the group consisting of hydrogen and Ci^alkyl; c is an integer from 0 to 3; each R ⁷ is independently selected from the group consisting of halogen, Ci-4alkyl, fluorinated Ci^alkyl, hydroxy substituted Ci-ealkyl, hydroxy substituted fluorinated Ci-2alkyl, cyano substituted Ci-2alkyl, Ci-4alkoxy, fluorinated Ci- 2alkoxy, hydroxy substituted Ci^alkoxy, -(Ci-2alkylene)-0-(Ci-4alkyl), oxo, - independently selected from hydrogen and Ci-*alkyl; and wherein the heterocyclyl, heteroaryl or heterocydoalkyl present as

(R ⁷ )C any part of the -K& (R ⁶ )b group contains a nitrogen atom, then said heterocyclyl, heteroaryl or heterocydoalkyl may be further substituted to form an N-oxide; provided that when R ¹ is 1,2,3,4-tetrazol-1-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein

R ¹ is selected from the group consisting of halogen, Cualkyl, fluorinated Ci-4alkyl, Ci-*alkoxy, fluorinated Ci-«alkoxy, phenyl and 5 to 6 membered heterocyclyl; wherein the phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-<alkyl, fluorinated Ci^alkyl, Ci^alkoxy, and fluorinated Ci^alkoxy; a is an integer from 0 to 2; each R ² is 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 are taken together with the carbon atom to which they are bound to form oxo;

R ^c is selected from the group consisting of hydrogen and Ci-4alkyl;

R ^D is selected from the group consisting of hydrogen, Ci-4alkyl and Ci- 4alkoxy;

R ^E is selected from the group consisting of hydrogen and Ci-*alkyl;

Q is selected from the group consisting ; wherein R ⁴ is selected from the group consisting of hydrogen and Ci^alkyl;

R ⁵ is selected from the group consisting of hydrogen, halogen and Ci-

♦alkyl; b is an integer from 0 to 1 ;

R ⁶ is selected from the group consisting of Cs-ecycloalkyl, -0-(Ci- 2alkylene)-Ca-6cycloalkyl, -NH-(C3-ecycloalkyl), -N H-C(0)-(C3-acydoalkyl) , 4-6 membered heterocycloalkyl, -0-(Ci-2alkylene)-(4-6 membered heterocycloalkyl), -C(0)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(0)-NH-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -0-(Ci-2alkylene)-(5-6 membered heteroaryl), -NH-C(0)-(5-6 membered heteroaryl), and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein the Ca- ecycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, Ci-2alkyl, hydroxy, oxo, cyano and NR ^P R ^Q ; wherein R ^p and R ^Q are each independently selected from the group consisting of hydrogen and Ci- ♦alkyl; c is an integer from 0 to 2; each R ⁷ is independently selected from the group consisting of halogen, Ci-2alkyl, fluorinated Ci-2alkyl, hydroxy substituted Ci-ealkyl, hydroxy substituted fluorinated Ci-2alkyl, cyano substituted Ci-2alkyl, Ci-<alkoxy, fluorinated Ci- independently selected from hydrogen and C^alkyl; provided that when R ¹ is 1,2,3,4-tetrazol-1-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein

R ¹ is selected from the group consisting of fluorinated Ci-2alkyl, fluorinated Ci-2alkoxy, and 5-membered nitrogen containing heteroaryl; wherein the 5-membered nitrogen containing heteroaryl is optionally substituted with halogen or fluorinated Ci-2alkyl; a is an integer from 1 to 2; each R ² is 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 are taken together with the carbon atom to which they are bound to form oxo;

R ^c is selected from the group consisting of hydrogen and Ci-2alkyl;

R ^D is selected from the group consisting of hydrogen, Ci-2alkyl and Ci-

2alkoxy;

R ^E is selected from the group consisting of hydrogen and Ci-2alkyl;

Q is selected from the group consisting wherein

R ⁴ is selected from the group consisting of hydrogen and Ci-2alkyl;

R ⁵ is selected from the group consisting of hydrogen, halogen and Cv

2alkyl; is selected from the group consisting of phenyl, 5 to 6 membered heteroaryl, and 9 to 10 membered heterocyclyl; b is an integer from 0 to 1 ;

R ⁶ is selected from the group consisting of Ca-scydoalkyl, -NH-C(0)-C3- scycloalkyl, 4-6 membered heterocycloalkyl, -0-(Ci-2alkylene)-(4-6 membered heterocycloalkyl), -C(0)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(0)-NH-(5-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -0-(Ci-2alkylene)-(5-6 membered heteroaryl), -NH-C(0)-(5-6 membered heteroaryl), and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein the Cs- scycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, Ci-2alkyl, hydroxy, oxo, cyano, and NR ^P R ^Q ; wherein R ^p and R ^Q are each independently selected from the group consisting of hydrogen and Ci- ₄ alkyl; c is an integer from 0 to 2; each R ⁷ is independently selected from the group consisting of halogen, Ci-2alkyl, fluorinated Ci-2alkyl, hydroxy substituted Ci-ealkyl, hydroxy substituted fluorinated Ci-2alkyl, cyano substituted Ci-2alkyl, Ci-4alkoxy, fluorinated Ci- 2alkoxy, hydroxy substituted Ci^alkoxy, -(Ci-2alkylene)-0-(Ci-4alkyl), oxo, - C(0)0H, -C(0)0-(Ci-2alkyl), -NR ^K R ^L , -NR ^K -(hydroxy substituted C^alkyl), - N RK-(Ci - ₂ al kylene)-0-(Ci - ₂ alkyl) , -C(0)-NR ^K R ^L , -C(0)-NR ^K -0-(Ci^alkyl), -C(O)- NRX-iCi^alkylenei-O-tCi^alkyl), -(Ci. ₂ alkylene)-C(0)-NR ^K R ^L , -NR^OHCi- ₄ alkyl), -NR ^K -C(0)-(fluorinated Ci salkyl), -NRX-CiOJCHCi^alkyl), -NRX-CiO)- Cs-scycloalkyl, -(Ci- ₂ alkylene)-NR ^K -C(0)-(Ci^alkyl), -(Ci- ₂ alkylene)-NR ^K -C(0)0- (Ci-4alkyl), -(Ci- ₂ alkylene)-0-C(0)-(amino substituted Ci-*alkyl), -NR^SQz-tCi- ₂ alkyl), -CiOJ-NR^SCfc-iCi^alkyl), -(Ci- ₂ alkyene)-0-R(0)(0H) ₂ , and -(Ci- ₂ alkyene)-0-(Ci- ₂ alkylene)-P(0)(0H) ₂ ; wherein R ^K and R ^L are each independently selected from hydrogen and Ci- ₂ alkyl; and wherein the heterocyclyl, heteroaryl or heterocydoalkyl present as

(R ⁷ )C any part of the -K3 ( ^R6 )b group contains a nitrogen atom, then said heterocyclyl, heteroaryl or heterocycloalkyl may be further substituted to form an N-oxide; provided that when R ¹ is 1,2,3,4-tetrazoM-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein

R ¹ is 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-tetrazoM-yl; a is an integer from 1 to 2; each R ² is 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, and fluoro; alternatively, R ^A and R ^B are taken together with the carbon atom to which they are bound to form oxo; R ^c is selected from the group consisting of hydrogen, deutero and methyl;

R ^D is selected from the group consisting of hydrogen, deutero, 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 ; wherein

R ⁴ is selected from the group consisting of hydrogen and methyl;

R ⁵ is selected from the group consisting of hydrogen, deutero, fluoro, chloro, bromo, and methyl;

(R ⁷ )C

(3 (R ^e )b is selected from the group consisting of 2-methoxy-phenyl, 2-(isopropyloxy)-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-(1 R-(methyl-carbonyl-amino)-ethyl)-phenyl, 2- (cyclopropyl-carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2- (cyclopropyl-carbonyl-amino)-5-methoxy-phenyl, 2-(cydopropyl-carbonyl- amino)-4-methoxy-phenyl, 2-(methyl-sulfonyl-amino)-phenyl, 4-(oxazolidin-3-yl- 2-one)-phenyl;

2-carboxy-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)- thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 2-(amino-carbonyl)-3-fluoro-thien-4-yl,

2-(amino-carbonyl)-3-fluoro-thien-5-yl, 3-(cyclopropyl-carbonyl-amino)-thien-2- yl, 2-(methyl-sulfbnyl-amino-carbonyl)-3-fluoro-thien-5-yl _l 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-(aminocarbonyl)-thiazol-5-yl, 1,2,4-triazol-3-yl, 1 ,2,3-triazol-S-yl, 1-methyl-(1 ,2,4-triazol-3-yl), 1 -methyl-1, 2,3-triazol-5-yl;

3-fluoropyridin-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-fluoropyridin-4-yl, 2-(methoxy-carbonyl)-3-fluoro-pyridin-4-yl, 2- (hydroxy-methyl)-3-fluoropyridin-4-yl, 2-(hydroxy-d2-methyl)-3-fluoro-pyridin-4- yl, 2-(2-hydroxy-ethyloxy)-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-(1 R ^w -hydroxy-ethyl)-3-fluoro- pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R-hydroxy-ethyl)-3- fluoropyridin-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-(trifluoromethyl)-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-f1uorO-pyridin-4-yl _l 2-fluoro4-deutero-6-aminopyridin- 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-fluorc)- pyridin-4-yl, 2-(amino-carbonyl)-pyridin-4-yl, 2-(amino-carbonyl)-pyridin-5-yl, 2- (amino-carbonyl)-3-fluorc)-pyridin-3-yl, 2-chloro-6-(amino-carbonyl)-pyridin-3-yl, 2-(2-methoxy-ethyl-amino-carbonyl)-3-fluoro-pyridin-4-yl _l 2-(methoxy-amino- carbonyl)-3-fluoropyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, S-itrifluoromethyl-carbonykaminoi-pyridin-^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-methyO-d-fluoro-pyridin-^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)-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-cycloprop-1-yl)-pyridin-4-yl,

2-(1 -hydroxy-cydoprop-1 -yl)-3-chloro-pyridin-4-yl, 2-(2-cyano-cydoprop- 1 -yl)-3- fluoro-pyridin-4-yl, 2-(1-hydiOxy-cydoprop-1-yl)-3-fluoro-pyridin-4-yl _l 2-(1- hydroxy-cydoprop-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cydopropyl-carbonyl- amino)-pyridin-4-yl, 4-(cydopiOpyl-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 ^.S-triazoM-yO-pyridin-^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-(dioxan- 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-fluoiO-pyridin-4-yl, 2-(1S-(1 ,3,4-oxadiazol-2- yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoroazetin-1-yl-carbonyl)-3-fluoro- pyridin-4-yl, 2-fluoro-6-(bicydo[1.1.1]pentanyl-amino)-pyridin-3-yl, 2- (bicyclo[1.1.1]pentanyl-amino)-3-fluoro-pyridin-3-yl, 2-(bicyclo[1.1.1]pentanyl- amino-carbonyl)-3-fluoro-pyridin-3-yl, 3-(cydopropyl-carbonyl-amino)-6- (trifluoro-methyl)-pyridin-4-yl , 2-(3-methyl-isoxazol-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, benzimidiazol-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-benzisoxazol-5-yl, benzoxazol-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(1 H)-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, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 1 H-pyrrolo[2,3-b]pyridin-3-yl, 1 H-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-1 H-pyrrolo[2,3-c]pyridin-3-yl, 1 H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy- 1 H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1 H-pyrazolo[3,4- b]pyridin-4-yl, and 1H-pyrazolo[3,4-b]pyridin-5-yl, l,4-dihydro-2H- benzo[d][1 ,3]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, 2,3-dihydro-[1 _l 4]dioxino[2,3-b]pyridin-8-yl _l and 7-methyl-6,7-dihydro- 5H-cydopenta[b]pyridin-4-yl-7-ol; and wherein one or both of (i) the hydrogen atom bound to the phenyl ring at the meta-position to R ¹ and (ii) the hydrogen atom bound to the 8a- position of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one are optionally deuterium; provided that when R ¹ is 1,2,3,4-tetrazol-l-yl, a is 2, and the two R ²

$T f

% OH groups are 2-fluoro and 3-chloro, then Q is other than (a) and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed 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)-l ,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-l-yl; a is an integer from 1 to 2; each R ² is independently selected from the group consisting of 2-fluoro, and 3-chloro;

R ^A and R ^B are each 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, R*-methyl, S-methoxy, and R-methoxy;

R ^E is hydrogen;

Q is selected from the group consisting wherein

R ⁴ is hydrogen;

R ⁵ is selected from the group consisting of hydrogen, deutero, fluoro, chloro, bromo, and methyl; is selected from the group consisting of

2-methoxy-phenyl, 2-fluoro-4-(amino-cartx)nyl)-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-(cydopropyl-carbonyl-amino)-phenyl, 2-(cydopentyl-carbonyl- amino)-phenyl, 2-(cydopropyl-carbonyl-amino)-5-methoxy-phenyl, 2- (cydopropyl-carbonyl-amino)-4-methoxy-phenyl;

2-carboxy-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)- thien-4-yl, 2-(amino-cartx>nyl)-thien-5-yl, 2-(amino-carbonyl)-3-fluoro-thien-4-yl, 3-(cydopropyl-carbonyl-amino)-thien-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-

3-fluoro-thien-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-fluoro-pyrazol-4-yl, 3- chloropyrazol-4-yl, 3-methoxy-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 5- chloro-pyrazol-4-yl, 2-(amino-carbonyl)-thiazol-5-yl;

3-fluoiO-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-cartx>xy-3-fluoro-pyridin-4-yl, 2- (methoxy-cartx)nyl)-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-ethyloxy)-pyridin-4- yl, 2-(2-hydroxy-n-propyl-oxy)-3-fluoro-pyridin-4-yl _l 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-(1 R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro- pyridin-4-yl, 2-(1 R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-( 1 S-hydroxy-ethyl)-3- fluoro-pyridin-4-yl, 2-(1 R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*- hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl _l 2-(1 R*-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- (1 R*-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-deutero-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-fluorc>-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 _l 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-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 _l 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 _l 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-(methyl-carbonyl-amino-methyl)-3-fluoro-pyridin-4-yl _l 2-(ethoxy- carbonyl-amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-amino-methyl)-3-fluoro- pyridin-4-yl, 2-( 1 S-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-oxy-methyl)-3-fluoro-pyridin-4-yl, 2-(phosphono- methoxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cydoprop-1 -yl)-pyridin-4-yl,

2-(1 -hydroxy-cydoprop-1 -yl)-3-chloro-pyridin-4-yl, 2-(1 -hydroxy-cydoprop- 1 -yl)-

3-fluoro-pyridin-4-yl, 2-(1 -hydroxy-cydoprop-1 -yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cydopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cydopropyl-carbonyl-amino)- pyridin-3-yl, 2-(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-(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 _l 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 ,2,4-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-(dioxan-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S*-oxazol-2-yl-ethoxy)-3- fluoro-pyridin-4-yl, 2-(1S-(1.SAoxadiazol^-yO-ethoxyi-S-fluoro-pyridin-^yl, 2- (bicyclo[1.1.1]pentanyl-amino)-3-fluoro-pyridin-3-yl, 3-(cydopropyl-carbonyl- amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxazol-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, benzimidiazol-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-benzisoxazol-5-yl, benzoxazol-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(1 H)-one, 7-methyl-5H- cydopenta[b]pyridin-4-yl, 2,3-dihydrofuro[2,3-b]pyridin-4-yl, thieno[3,2-b]pyridin- 7-yl, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 1 H-pyrrolo[2,3-b]pyridin-3-yl, 1 H-pyrrolo[2,3- c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3yl, 1 H-pyrrolo[3,2-c]pyridin-3-yl, 6- methoxy-1H-pynOlo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl _l 1H- pyrazolo[3,4-b]pyridin-4-yl, 1 H-pyrazolo[3,4-b]pyridin-5-yl, 1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, and 7-methyl-6,7-dihydro- 5H-cydopenta[b]pyridin-4-yl-7-ol; and wherein one or both of (i) the hydrogen atom bound to the phenyl ring at the meta-position to R ¹ and (ii) the hydrogen atom bound to the 8a- position of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one are optionally deuterium; provided that when R ¹ is 1,2,3,4-tetrazol-1-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein

R ¹ is selected from the group consisting of 4-chloro-1 ,2,3-triazol-l-yl, 4- (trifluoromethyl)-l ,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl; a is an integer from 1 to 2; each R ² is independently selected from the group consisting of 2-fluoro, and 3-chloro;

R ^A and R ^B are each 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 wherein

R ⁴ is hydrogen;

R ⁵ is selected from the group consisting of hydrogen, deutero, fluoro, and chloro; is 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-cartx>nyl-amino)-phenyl, 2-(cyclopropyl-cartx>nyl-amino)-phenyl, 2- (cyclopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5- methoxy-phenyl , 2-(cydopropyl-cartx)nyl-amino)-4-methoxy-phenyl ;

2-carboxy-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)- thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 2-(amino-carbonyl)-3-fluoro-thien-4-yl, 3-(cydopropyl-carbonyl-amino)-thien-2-yl, 3-(trifluoiO-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-ethyloxy)-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-(1 R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4- yl, 2-(1 R*-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-deutero-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*-hydiOxy-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- cartx>nyl-amino)-pyridin-4-yl, 5-(methoxy-carbonyl-amino)-pyridin-2-yl, 2-

(methoxy-carbonyl-amino)-pyridin-5-yl, 2-(methoxy-cartx>nyl-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-f1uoro-pyridin-4-yl, 2-(1-hydroxy-cydoprop-1- yl)-pyridin-4-yl, 2-(1-hydroxy-cydoprop-1-yl-methoxy)-3-fluoro-pyridin-4-yl _I 3- (cydopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cydopropyl-carbonyl-amino)- pyridin-3-yl, 2-(3-cyano-azetidin-1-yl)-3-fluoropyridin-4-yl _l 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-(dioxan-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, benzimidiazol-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, benzoxazol-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-cydopenta[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, 1 H-pyrrolo[2,3-c]pyridin-3-yl, 1H- pyrrolo[2,3-c]pyhdin-3yl, 6-methoxy-1 H-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]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, and 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-8-yl; and wherein one or both of (i) the hydrogen atom bound to the phenyl ring at the meta-position to R ¹ and (ii) the hydrogen atom bound to the 8a- position of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one are optionally deuterium; provided that when R ¹ is 1,2,3,4-tetrazoM-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein

R ¹ is selected from the group consisting of 4-chloro-1,2,3-triazol-1-yl, 4- (trifl uoromethyl)- 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 is independently selected from the group consisting of 2-fluoro, and 3-chloro;

R ^A and R ^B are each 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 wherein

R ⁴ is hydrogen;

R ⁵ is selected from the group consisting of hydrogen, deutero, fluoro, and chloro;

(R ⁷ )=

<3 (R ⁶ k is 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- (cydopentyl-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-5- methoxy-phenyl , 2-(cydopropyl-carbonyl-amino)-4-methoxy-phenyl ;

2-carboxy-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)- thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3- chloro-pyrazol-4-yl, 3-(trifluoiOmethyl)-pyrazol-4-yl, 1 -methyl-4-(cydopropyl- 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-(1 R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(2-methyl-2-hydroxy-n- propyl-oxy)-3-fluoropyridin-4-yl, 2-fluoro-6-amino-pyridin-3-yl, 2-amino-3- fluoro-pyridin-4-yl, 2-fluoro-5-deutero-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-fluoropyridin-4-yl, 2-(2-methyl-2-hydroxy-n-propyl-amino)-3- fluoro-pyridin-4-yl, 2-fluoro-4-deuterc>-6-amino-pyridin-3-yl, 2-fluoro4,5- 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- sulfbnyl-amino)-pyridin-4-yl, 2-(methyl-sulfbnyl-amino)-3-fluoro-pyridin-4-yl, 2- (phosphono-oxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1 -hydroxy-cydoprop-1 -yl)- pyridin-4-yl, 2-(1-hydroxy-cydoprop-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3- (cydopiOpyl-carbonyl-amino)-pyridin-4-yl, 4-(cydopropyl-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-aminoindazol-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-cydopenta[b]pyridin-4-yl, 1H- pynOlo[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]oxazin-6-yl-2-one, 5- fluoro-1,4-dihydro-2H-benzo[d][1 _l 3]oxazin-6-yl-2-one, and 2,3-dihydro- [1 ,4]dioxino[2,3-b]pyridin-8-yl; and wherein one or both of (i) the hydrogen atom bound to the phenyl ring at the meta-position to R ¹ and (ii) the hydrogen atom bound to the 8a- position of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one are optionally deuterium; provided that when R ¹ is 1,2,3,4-tetrazol-l-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed 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; a is an integer from 1 to 2; each R ² is independently selected from the group consisting of 2-fluoro, and 3-chloro;

R ^A and R ^B are each hydrogen; R ^c is hydrogen;

R ^D is hydrogen;

R ^E is hydrogen;

Q is selected from the group consisting wherein R ⁴ is hydrogen;

R ⁵ is selected from the group consisting of hydrogen, deutero, fluoro, and chloro;

(R ⁷ )C

(¾ (R ⁶ )b is selected from the group consisting of

4-(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)- phenyl;

2-carboxy-thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)- thien-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- fluoropyridin-4-yl, 2-fluoro-5-deuterc>-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-sulfbnyl-amino)-3- fluoro-pyridin-4-yl 2-(1 -hydroxy-cycloprop-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-dihydiO-2H-quinolin-6-yl-2-one, 1 H-pyrrolo[2,3- b]pyridin-4-yl, 1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl-2-one, and 5-fluoro-1 ,4- dihydro-2H-benzo[d][1,3]oxazin-6-yl-2-one; and wherein one or both of (i) the hydrogen atom bound to the phenyl ring at the meta-position to R ¹ and (ii) the hydrogen atom bound to the 8a- position of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one are optionally deuterium; provided that when R ¹ is 1,2,3,4-tetrazoM-yl, a is 2, and the two R ² groups are 2-fluoro and 3-chloro, then Q is other than ( and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) 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 are each hydrogen; R ^c is hydrogen; R ^D is hydrogen; R ^E is hydrogen; Q is selected from the group consisting of (a) ; wherein R ⁴ is hydrogen; R ⁵ is

(R ⁷ )C selected from the group consisting of hydrogen, and chloro; and (3 (R®)b is selected from the group consisting of 4-(methoxy-carbonyl-amino)-phenyl, 2- (cyclopropyl-carbonyl-amino)-phenyl, 2-(amino-carbonyl)-thien-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, 1 H- pyrrolo[2,3-b]pyridin-4-yl, and 1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6-yl-2-one; and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ¹ is selected from the group consisting of halogen, Ci- 4alkyl, fluorinated Ci-4alkyl, Ci-*alkoxy, fluorinated Ci-«alkoxy, phenyl and 5 to 6 membered heterocyclyl; wherein the phenyl or 5 to 6 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci^alkyl, fluorinated Ci-*alkyl, Ci-*alkoxy, and fluorinated Ci-<alkoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ¹ is selected from the group consisting of fluorinated Cvaalkyl, fluorinated Cvaalkoxy, and 5-membered nitrogen containing heteroaryl; wherein the 5-membered nitrogen containing heteroaryl is optionally substituted with halogen or fluorinated Ci-2alkyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ¹ is 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-triazoH-yl, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazoH-yl.

In some embodiments, the present invention is directed 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-l-yl. In some embodiments, the present invention is directed 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-l-yl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ¹ is 1,2,3,4-tetrazol-l-yl.

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

In some embodiments, the present invention is directed to compounds of formula (I) wherein each R ² is independently selected from the group consisting of chloro, fluoro and methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein each R ² is independently selected from the group consisting of 2-fluoro, 3-chloro, 5-chloro and 3-methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein each R ² is independently selected from the group consisting of 2- fluoro, and 3-chloro. In some embodiments, the present invention is directed to compounds of formula (I) wherein the each R ² is independently selected from the group consisting of 2-fluoro, and 3-chloro.

In some embodiments, the present invention is directed to compounds of formula (I) wherein a is 2, and the two R ² groups are 2-fluoro and 3-chloro.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is selected from the group consisting of hydrogen and halogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is selected from the group consisting of hydrogen and fluoro. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is selected from the group consisting of hydrogen (or deutero), and fluoro. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is hydrogen (or deutero). In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is halogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A is fluoro.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is selected from the group consisting of hydrogen and halogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is selected from the group consisting of hydrogen and fluoro. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is hydrogen (or deutero) and fluoro. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is hydrogen (or deutero). In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is halogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^B is fluoro.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A and R ^B are each hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A and R ^B are each deutero.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A and R ^B are taken together with the carbon atom to which they are bound to form oxo.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is selected from the group consisting of hydrogen and Ci-2alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is selected from the group consisting of hydrogen (or deutero), and methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is hydrogen (or deutero). In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is selected from the group consisting of hydrogen and methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is selected from the group consisting of methyl and ethyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c is methyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is selected from the group consisting of hydrogen, Ci- aalkyl and Cvaalkoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is selected from the group consisting of hydrogen (or deutero), methyl and methoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is hydrogen (or deutero). In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is selected from the group consisting of methyl and methoxy. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is methoxy.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is selected from the group consisting of hydrogen (or deutero), methyl, S*-methyl, R*-methyl, methoxy, S-methoxy, and R-methoxy.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is selected from the group consisting of hydrogen (or deutero), methyl, S*-methyl, R*-methyl, S-methoxy, and R-methoxy. In some embodiments, the present invention is directed 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 is directed 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 is directed 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 is directed to compounds of formula (I) wherein R ^D is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^D is deutero.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^E is selected from the group consisting of hydrogen and Ci-2alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^E is selected from the group consisting of hydrogen and methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^E is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^E is methyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A and R ^B are each hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c and R ^D are each hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A , R ^B and R ^E are each hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^c , R ^D and R ^E are each hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A , R ^B , R ^c and R ^D are each hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A , R ^B , R ^c , R ^D and R ^E are each hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein one of R ^A , R ^B , R ^c , R ^D or R ^E is other than hydrogen.

In some embodiments, the present invention is directed to compounds of formula (I) whereinR ⁴ is selected from the group consisting of hydrogen and Ci- 2alkyl. In some embodiments, the present invention is directed to compounds of formula (I) whereinR ⁴ is selected from the group consisting of hydrogen and methyl. In some embodiments, the present invention is directed to compounds of formula (I) whereinR ⁴ is hydrogen. In some embodiments, the present invention is directed to compounds of formula (I) whereinR ⁴ is methyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is selected from the group consisting of hydrogen, halogen and Cvzalkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is hydrogen or deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is halogen. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is selected from the group consisting of fluoro and chloro. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is chloro. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is Cv 2alkyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is methyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is selected from the group consisting of hydrogen, deutero, fluoro, chloro, bromo, and methyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is selected from the group consisting of hydrogen (or deutero), fluoro, and chloro. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is selected from the group consisting of hydrogen (or deutero), and chloro.

In some embodiments, the present invention is directed to compounds of formula (I) wherein is phenyl. In some embodiments, the present

(A ) invention is directed to compounds of formula (I) wherein ^ is 5-6 membered heteroaryl. In some embodiments, the present invention is directed to compounds of formula (I) wherein G W) is 5 membered heteroaryl. In some embodiments, the present invention is directed to compounds of formula (I) wherein 6 membered heteroaryl. In some embodiments, the present invention is directed to compounds of formula (I) wherein G ^) is 9 to 10 membered heterocyclyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein ( ^v —\ '> is 9 membered heterocyclyl. In some embodiments, the present invention is directed to compounds of

(A ) formula (I) wherein is 10 membered heterocyclyl.

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

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁶ is selected from the group consisting of Ca-ecycloalkyl, - 0-(Ci-2alkylene)-CMcycloalkyl, -NH-(C3-8cycloalkyl), -NH-C(0)-(C3-8cycloalkyl), 4-6 membered heterocycloalkyl, -0-(Ci-2alkylene)-(4-6 membered heterocycloalkyl), -C(0)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(0)-NH-(4-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -0-(Ci-2alkylene)-(5-6 membered heteroaryl), -NH-C(0)-(5-6 membered heteroaryl), and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein the Ca ecycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, Ci-2alkyl, hydroxy, oxo, cyano and NR ^P R ^Q ; wherein R ^p and R ^Q are each independently selected from the group consisting of hydrogen and Ci- 4alkyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁶ is selected from the group consisting of Ca-scycloalkyl, - NH-C(0)-C3-5 cycloalkyl, 4-6 membered heterocycloalkyl, -0-(Ci-2alkylene)-(4-6 membered heterocycloalkyl), -C(0)-(4-6 membered heterocycloalkyl), -NH-(4-6 membered heterocycloalkyl), -C(0)-NH-(5-6 membered heterocycloalkyl), 5-6 membered heteroaryl, -0-(Ci-2alkylene)-(5-6 membered heteroaryl), -NH-C(O)- (5-6 membered heteroaryl), and 2-oxa-6-azaspiro[3.3]hept-6-yl; wherein the Cs- scycloalkyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of halogen, Ci-2alkyl, hydroxy, oxo, cyano, and NR ^P R ^Q ; wherein R ^p and R ^Q are each independently selected from the group consisting of hydrogen and Ci- ₄ alkyl.

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

In some embodiments, the present invention is directed to compounds of formula (I) wherein each R ⁷ is independently selected from the group consisting of halogen, Ci-2alkyl, fluorinated Cvaalkyl, hydroxy substituted Ci-ealkyl, hydroxy substituted fluorinated Cvzalkyl, cyano substituted Ci-2alkyl, Ci-*alkoxy, fluorinated Ci-2alkoxy, hydroxy substituted Cualkoxy, -(Ci-2alkylene)-0-(Ci- «alkyl), oxo, -C(0)OH, -C(0)0-(Ci-2alkyl), -NR ^K R ^L , -NR<-(hydroxy substituted independently selected from hydrogen and Ci-*alkyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherein each R ⁷ is independently selected from the group consisting of halogen, Cvaalkyl, fluorinated Ci-2alkyl, hydroxy substituted Ci-ealkyl, hydroxy substituted fluorinated Ci-2alkyl, cyano substituted Ci-2alkyl, Ci-*alkoxy, fluorinated Ci-2alkoxy, hydroxy substituted Ci-<alkoxy, -(Ci-2alkylene)-0-(Ci- olkyl), oxo, -C(0)0H, -C(0)0-(Ci- ₂ alkyl), -NR ^K R ^L , -NR ^K -(hydroxy substituted RK-(Ci-2alkylene)-0-(Ci- ₂ alkyl), -C(0)-NR ^K R ^L , -CCOi-NR^O-tCi- -NR ^K -(Ci- ₂ alkylene)-0-(Ci- ₂ alkyl), -(Ci- ₂ alkylene)-C(0)-NR ^K R ^L , - i - ₄ alkyl) , -NR ^K -C(0)-(fluorinated Ci. ₂ alkyl), -NR ^K -C(0)0-(Ci- ₄ alkyl), s-scycloalkyl, -(Ci-2alkylene)-NR ^K -C(0)-(Ci-talkyl), -(Ci-2alkylene)- Ci-4alkyl), -(Ci-2alkylene)-0-C(0)-(amino substituted Ci-*alkyl), - - ₂ al kyl) , -C(0)-NR ^K -S02-(Ci. ₂ alkyl), -(Ci. ₂ alkyene)-0-P(0)(0H)2, yene)-0-(Ci-2alkylene)-P(0)(0H)2; wherein R ^K and R ^L are each independently selected from hydrogen and Ci-2alkyl.

In some embodiments, the present invention is directed to compounds of formula (I) wherei is selected from the group consisting of 2- methoxy-phenyl, 2-(isopropyloxy)-phenyl, 3-fluoro-4-cartx)xy-phenyl _l 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-cartx>nyl)-phenyl, 2-(methyl-amino- carbonyl)-phenyl, 2-(dimethyl-amino-cartx)nyl)-phenyl, 2-(ethyl-carbonyl- amino)-phenyl, 2-(methyl-cartx)nyl-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-cartx)nyl-amino)-phenyl, 2-(cydopropyl- 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-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-cartx)nyl)-thien-4-yl _l 2-(amino-carbonyl)-thien-5-yl, 2-(amino-carbonyl)-3-fluoro-thien-4-yl, 2-(amino- carbonyl)-3-fluoro-thien-5-yl, 3-(cyclopropyl-carbonyl-amino)-thien-2-yl, 2- (methyl-sulfbnyl-amino-carbonyl)-3-fluoro-thien-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-fluoropyridin-4-yl, 2-carboxy-3-fluoro-pyridin-4-yl, 2- (methoxy-cartx>nyl)-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-ethyloxy)-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-(1 R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro- pyridin-4-yl, 2-(1 R-hydroxy-ethyl)-3-fluoropyridin-4-yl, 2-(1 S-hydroxy-ethyl)-3- fluoropyridin-4-yl, 2-(1 R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*- hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R*-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-( 1 S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-

(1 R*-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- fluoropyridin-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 ^w -hydroxy-n-propyl)-3-fluoro-pyridin-4-yl, 2-fluoro-4-deutero-6-amino-pyridin-3-yl, 2-fluoro5-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-(ΙπΑιιθΓοητΐ6ΐΐΊνΙ-θ3Γΐ3(>Γ^3ηίΐ ΐηο)- 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-cartx>nyl-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)-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-cydopiOp-1-yl)-pyridin-4-yl, 2-(1-hydroxy-cydoprop-1-yl)-3-chloro- pyridin-4-yl, 2-(2-cyano-cydoprop-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy- cydoprop-1-yl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cycloprop-1-yl-methoxy)-3- fluoro-pyridin-4-yl, 3-(cydopropyl-carbonyl-amino)-pyridin-4-yl, 4-(cydopropyl- 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-tetrahydro1ur ^, an-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-fluoropyridin-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-(dioxan-2S-yl-ethoxy)-3-fluoro- pyridin-4-yl, 2-(1 R*-oxazol-2-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1 S*-oxazol-2-yl- ethoxy)-3-fluoro-pyridin-4-yl, 2-(1S-(1 ,3,4-oxadiazol-2-yl)-ethoxy)-3-fluoro- pyridin-4-yl, 2-(3,3-difluoro-azetin-1-yl-carbonyl)-3-fluoro-pyridin-4-yl, 2-fluoro-6- (bicyclo[1.1.1]pentanyl-amino)-pyridin-3-yl, 2-(bicyclo[1.1.1]pentanyl-amino)-3- fluoro-pyridin-3-yl, 2-(bicyclo[1.1 ,1]pentanyl-amino-carbonyl)-3-fluoro-pyridin-3- yl, 3-(cyclopropyl-carbonyl-amino)-6-(trifluoro-methyl)-pyridin- 4-yl, 2-(3-methyl· isoxazol-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, benzimidiazol-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-benzisoxazol-5-yl, benzoxazol-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(1 H)-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, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 1 H-pyrrolo[2,3-b]pyridin-3-yl, 1 H-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-1 H-pyrrolo[2,3-c]pyridin-3-yl, 1 H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy- 1 H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H-pyrazolo[3,4- b]pyridin-4-yl, and 1 H-pyrazolo[3,4-b]pyridin-5-yl, 1 ,4-di hydro-2 H- benzo[d][1 ,3]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, 2,3-dihydro-[1 _l 4]dioxino[2,3-b]pyridin-8-yl, and 7-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl-7-ol.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C formula (I) wherein (¾ ( ^R ®)b is 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-(cydopentyl-carbonyl-amino)- phenyl, 2-(cydopropyl-carbonyl-amino)-5-methoxy-phenyl _I 2-(cydopropyl- carbonyl-amino)-4-methoxy-phenyl, 2-carboxy-thien-5-yl, 2-carboxy-3-fluoro- thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 2- (amino-carbonyl)-3-fluoro-thien-4-yl, 3-(cyclopropyl-carbonyl-amino)-thien-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3-fluoro-thien-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-ethyloxy)-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 _l 2-(1 R*-hydroxy-ethyl)-3-fluoro pyridin-4-yl, 2-(1S ^w -hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R-hydroxy-ethyl)-3- fluoro-pyridin-4-yl, 2-(1 S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R-(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 _l 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-(1 S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R*-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-deutero-6-amino-pyridin-3-yl, 2-fluoro-6-(methyl-amino)-pyridin-3-yl, 2-amino-pyridin-4-yl, 2-amino-3-chloropyridin-4-yl, 2-amino3-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-fluoro4-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-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 _l 2-(amino- carbonyl-methyl)-3-fluoro-pyridin-4-yl, S-ttrifluoromethyl-carbonykamino)- 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-(methyl-carbonyl-aminomethyl)-3-fluoro-pyridin-4-yl, 2-(ethoxy-carbonyl- amino)-pyridin-3-yl, 2-(ethoxy-carbonyl-aminomethyl)-3-fluoro-pyridin-4-yl, 2- (1 S-amino-isopropyl-carbonyl-oxo-methyO-S-fluoro-pyhdin-^yl, 2-(methyl- sulfbnyl-amino)-pyridin-4-yl, 2-(methyl-sulfbnyl-amino)-3-fluoropyridin-4-yl, 2- (phosphono-oxy-methyl)-3-fluoro-pyridin-4-yl, 2-(phosphono-methoxy-methyl)- 3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cydoprop-1-yl)-pyridin-4-yl, 2-(1-hydroxy- cydoprop-1 -yl)-3-chloro-pyridin-4-yl, 2-(1 -hydroxy-cydoprop-1 -yl)-3-fluoro- pyridin-4-yl, 2-(1-hydroxy-cydoprop-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3- (cydopiOpyl-carbonyl-amino)-pyridin-4-yl, 4-(cydopropyl-carbonyl-amino)- pyridin-3-yl, 2-(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-(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 _l 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-(1,2,4-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-(dioxan-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1 S*-oxazol-2-yl-ethoxy)-3- fluoro-pyridin-4-yl, 2-(1S-(1,3,4-oxadiazol-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2- (bicyclo[1.1.1]pentanyl-amino)-3-fluoro-pyridin-3-yl, 3-(cydopropyl-carbonyl- amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxazol-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, benzimidiazol-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- benzisoxazol-5-yl, benzoxazol-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, 1 H-pyrrolo[2,3-b]pyridin- 4-yl, 1 H-pyrrolo[2,3-b]pyridin-3-yl, 1 H-pyrrolo[2,3-c]pyridin-3-yl, 1H-pyrrolo[2,3- c]pyridin-3yl, 1 H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy-1 H-pyrrolo[3,2-c]pyridin- 3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1 H-pyrazolo[3,4-b]pyridin-4-yl, 1H- pyrazolo[3,4-b]pyridin-5-yl, 1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6-yl-2-one, 5- fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-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 .

In some embodiments, the present invention is directed 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-thien-5-yl, 2- carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)- thien-5-yl, 2-(amino-carbonyl)-3-fluoro-thien-4-yl, 3-(cyclopropyl-carbonyl- amino)-thien-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- ethyloxy)-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- chloropyridin-4-yl, \ 2-(1 R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R*- hydroxy-2,2-difluoiO-ethyl)-3-f1uoro-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-deutero-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-fluoropyridin-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-cydoprop-1-yl)-pyridin-4-yl, 2-(1- hydroxy-cydoprop-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cydopropyl-carbonyl- amino)-pyridin-4-yl, 4-(cydopropyl-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-(dioxan-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, benzimidiazol-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, benzoxazol-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, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 1 H-pyrrolo[2,3-c]pyridin- 3-yl, 1 H-pynOlo[2,3-c]pyridin-3yl, 6-methoxy-1 H-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]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, and 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-8-yl.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )c formula (I) wherein Q ( ^R6 )b is 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-thien-5-yl, 2- carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)- thien-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-deutero-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-fluoro4,5-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-cycloprop-1-yl)-pyridin-4-yl, 2-(1 -hydroxy-cycloprop- 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-cydopenta[b]pyridin-4-yl, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 6- methoxy-1 H-pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1 ,4- dihydro-2H-benzo[d][1 ,3]oxazin-6-yl-2-one, S-fluoro-1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-6-yl-2-one, and 2,3-dihydro-[1 ,4]dioxino[2,3-b]pyridin-8-yl.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C formula (I) wherein <3 ( ^R6 )b is selected from the group consisting of 4-

(methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2- carboxy-thien-5-yl, 2-(amino-cartx)nyl)-thien-4-yl, 2-(amino-carbonyl)-thien-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-deutero-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-cycloprop-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, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6-yl-2- one, and 5-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl-2-one.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C formula (I) wherein <3 ( ^R6 )b is selected from the group consisting of 4- (methoxy-carbonyl-amino)-phenyl, 2-(cyclopropyl-carbonyl-amino)-phenyl, 2- (amino-carbonyl)-thien-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]oxazin-6-yl-2-one.

In some embodiments, the present invention is directed to compounds of formula (I) wherein selected from the group consisting of 2- methoxy-phenyl, 2-(isopropyloxy)-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-(1 R-(methyl-carbonyl-amino)-ethyl)-phenyl, 2-(cyclopropyl- carbonyl-amino)-phenyl, 2-(cyclopentyl-carbonyl-amino)-phenyl, 2-(cydopropyl- 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.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C formula (I) wherein ⁽ 5 ( ^R6 )b is 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-(cydopropyl- carbonyl-amino)-4-methoxy-phenyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein is 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-(cydopentyl-carbonyl-amino)-phenyl, 2-(cydopropyl- carbonyl-amino)-5-methoxy-phenyl, and 2-(cydopropyl-cartx>nyl-amino)-4- methoxy-phenyl. In some embodiments, the present invention is directed to compounds of formula (I) wherein is selected from the group consisting of 4-(methoxy-carbonyl-amino)-phenyl, and 2-(cydopropyl-carbonyl- amino)-phenyl.

In some embodiments, the present invention is directed to compounds of (R ⁷ )C formula (I) wherein <¾ ( ^R6 )b is selected from the group consisting of 2- carboxy-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 2-(amino-carbonyl)-3-fluoro-thien-4-yl, 2-(amino- carbonyl)-3-fluoro-thien-5-yl, 3-(cyclopropyl-carbonyl-amino)-thien-2-yl, 2- (methyl-sulfonyl-amino-carbonyl)-3-fluoro-thien-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), and 1-methyl-1,2,3-triazol-5-yl.

In some embodiments, the present invention is directed to compounds of (R ⁷ )C formula (I) wherein <3 ( ^R6 k is selected from the group consisting of 2- carboxy-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 2-(amino-carbonyl)-3-fluoro-thien-4-yl, 3-

(cydopropyl-carbonyl-amino)-thien-2-yl, 2-(methyl-sulfonyl-amino-carbonyl)-3- fluoro-thien-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

(R ⁷ )C present invention is directed to compounds of formula (I) wherein <3 (R ⁶ )b is selected from the group consisting of 2-carboxy-thien-5-yl, 2-carboxy-3-fluoro- thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 2- (amino-cartx>nyl)-3-fluoro-thien-4-yl, 3-(cyclopropyl-carbonyl-amino)-thien-2-yl,

3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol-4-yl, 3-(trifluoromethyl)-pyrazol-

4-yl, 5-chloropyrazol-4-yl, 1 -methyl-4-(cydopropyl-carbonyl-amino)-pyrazol-5- yl, and 2-(amino-carbonyl)-thiazol-5-yl.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C formula (I) wherein <3 (R ⁶ )b is selected from the group consisting of 2- carboxy-thien-5-yl, 2-carboxy-3-fluoro-thien-5-yl, 2-(amino-carbonyl)-thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 3-(trifluoro-methyl)-pyrrol-4-yl, 3-chloro-pyrazol- 4-yl, 3-(trifluoromethyl)-pyrazol-4-yl, 1-methyl-4-(cydopropyl-carbonyl-amino)- pyrazol-5-yl, and 2-(amino-carbonyl)-thiazol-5-yl. In some embodiments, the

(R ⁷ )C present invention is directed to compounds of formula (I) wherein ⁽ 3 (R ⁶ )b is selected from the group consisting of 2-carboxy-thien-5-yl, 2-(amino-carbonyl)- thien-4-yl, 2-(amino-carbonyl)-thien-5-yl, 3-(trifluoro-methyl)-pyrral-4-yl, and 2- (amino-carbonyl)-thiazol-5-yl.

In some embodiments, the present invention is directed to compounds of (R ⁷ )C formula (I) wherein <3 (R ⁶ )b is 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-ethyloxy)-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-(1 R*-hydroxy-ethyl)-3-fluoro- pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R-hydroxy-ethyl)-3- fluoropyridin-4-yl, 2-(1 S-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R-(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 _l 2- (3 _l 3,3-trifluoro-2S*-hydroxy-n-propyl)-3-fluoro-pyridin-4 -yl _l 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-fluoropyridin-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-cartx)nyl)-3-fluoro-pyridin-4-yl, 2-(methoxy-amino- carbonyl)-3-fluoropyridin-4-yl, 2-(amino-carbonyl-methyl)-3-fluoro-pyridin-4-yl, 3-(trifluoromethyl-rartx>nyl-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-methyO-S-fluoro-pyridin-^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)-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-cydoprop-1-yl)-pyridin-4-yl, 2-(1 -hydroxy-cydoprop-1 -yl)-3-chloro-pyridin-4-yl, 2-(2-cyano-cydoprop- 1 -yl)-3- fluoro-pyridin-4-yl, 2-(1-hydiOxy-cydoprop-1-yl)-3-fluoro-pyridin-4-yl _l 2-(1- hydroxy-cydoprop-1-yl-methoxy)-3-fluoro-pyridin-4-yl, 3-(cyclopropyl-carbonyl- amino)-pyridin-4-yl, 4-(cydopropyl-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-fluoropyridin-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-(dioxan- 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-oxadiazol-2- yl)-ethoxy)-3-fluoro-pyridin-4-yl, 2-(3,3-difluoro-azetin-1-yl-carbonyl)-3-fluoro- pyridin-4-yl, 2-fluoro-6-(bicydo[1.1.1]pentanyl-amino)-pyridin-3-yl, 2- (bicydo[1.1.1]pentanyl-amino)-3-fluoro-pyridin-3-yl, 2-(bicydo[1.1.1]pentanyl- amino-carbonyl)-3-fluoro-pyridin-3-yl, 3-(cydopropyl-carbonyl-amino)-6- (trifluoro-methyl)-pyridin-4-yl , 2-(3-methyl-isoxazol-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.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C formula (I) wherein (¾ ( ^R ®)b is 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-ethyloxy)-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-(1 R*-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1S*-hydroxy-ethyl)-3-fluoro- pyridin-4-yl, 2-(1 R-hydroxy-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 S-hydroxy-ethyl)-3- fluoro-pyridin-4-yl, 2-(1 R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 S*- hydroxy-2,2-difluoro-ethyl)-3-fluoro-pyridin-4-yl, 2-(1 R*-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-fluoropyridin-4-yl, 2-(1S*-cyano-ethyl)-3-fluoro-pyridin-4-yl, 2- (1 R*-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-deutero-6-amino-pyridin-3-yl, 2- fluoro-6-(methyl-amino)-pyridin-3-yl, 2-aminopyridin-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-trifluoiO-2R*-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-(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-cartx)nyl-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, 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-oxy-methyl)-3-fluoro-pyridin-4-yl, 2-(phosphono- methoxy-methyl)-3-fluoiO-pyridin-4-yl, 2-(1-hydroxy-cycloprop-1-yl)-pyridin-4-yl,

2-(1-hydroxy-cycloprop-1-yl)-3-chloro-pyridin-4-yl, 2-(1 -hydroxy-cycloprop- 1-yl)-

3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cycloprop-1-yl-methoxy)-3-f1uorO-pyridin-4-yl _l 3-(cydopropyl-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-(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-f1uoro-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 _l 2-(3-amino- pyrazol- 1 -yl)-pyridin-4-yl , 2-(imidazol-2-yl)-3-f1uorO-pyridin-4-yl _l 1-(1 ,2,5-triazol- 1-yl)-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-(dioxan-2S-yl-ethoxy)-3-fluoro-pyridin-4-yl, 2-(1 S*-oxazol-2-yl-ethoxy)-3- fluoro-pyridin-4-yl, 2-(1S-(1,3,4-oxadiazol-2-yl)-ethoxy)-3-fluoro-pyridin-4-yl _l 2- (bicyclo[1.1.1]pentanyl-amino)-3-fluoro-pyridin-3-yl, 3-(cydopropyl-cartx)nyl- amino)-6-(trifluoro-methyl)-pyridin-4-yl, 2-(3-methyl-isoxazol-5-yl-carbonyl- amino)-3-fluoro-pyridin-4-yl, and pyridin-4-yl-2-one.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C

A formula (I) wherein ( ^r6 )>> is selected from the group consisting of 2- carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(1 R- (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-deutero-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 _l 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-cartx>nyl-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 _l 2-(phosphono-oxy- methyl)-3-fluoro-pyridin-4-yl, 2-(1-hydroxy-cycloprop-1-yl)-pyridin-4-yl, 2-(1- hydroxy-cycloprop-1 -yl-methoxyl-d-fluoro-pyridin-^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.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C

A formula (I) wherein ( ^R6 k is selected from the group consisting of 2- carboxy-3-fluoro-pyridin-4-yl, 2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-(2- hydroxy-ethyloxy)-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-(1 R-(hydroxy-methyl)-ethyl)-3-fluoro-pyridin-4- yl, 2-(1 R*-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-deutero-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-cycloprop-1- yl)-pyridin-4-yl, 2-(1 -hydroxy-cycloprop-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-f1uoro- pyridin-4-yl, 1-(1,2,5-triazol-1-yl)-pyridin-4-yl, 2-(dioxan-2S-yl-ethoxy)-3-fluoro- pyridin-4-yl, and pyridin-4-yl-2-one.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C

A formula (I) wherein ( ^R6 k is 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-deutero-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-cycloprop-1-yl)-pyridin-4-yl, and 3-(cyclopropyl- carbonyl-amino)-pyridin-4-yl.

In some embodiments, the present invention is directed to compounds of (R ⁷ )C formula (I) wherein <a (R ⁶ )b is 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, benzimidiazol-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-benzisoxazol-5-yl, benzoxazol-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(1 H)-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, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 1 H-pyrrolo[2,3-b]pyridin-3-yl, 1 H-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-1 H-pyrrolo[2,3-c]pyridin-3-yl, 1 H-pyrrolo[3,2-c]pyridin-3-yl, 6-methoxy- 1 H-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]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, 2,3-dihydro-[1 _l 4]dioxino[2,3-b]pyridin-8-yl, and 7-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl-7-ol.

In some embodiments, the present invention is directed to compounds of

(R ⁷ )C formula (I) wherein (¾ ( ^R6 )b is 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, benzimidiazol-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-benzisoxazol-5-yl, benzoxazol-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(1 H)-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, 1 H-pyrrolo[2,3-b]pyridin-4-yl, 1 H-pyrrolo[2,3-b]pyridin-3-yl, 1 H-pyrrolo[2,3- c]pyridin-3-yl, 1H-pyrrolo[2,3-c]pyridin-3yl, 1 H-pyrrolo[3,2-c]pyridin-3-yl, 6- methoxy-1H-pynOlo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1H- pyrazolo[3,4-b]pyridin-4-yl, 1 H-pyrazolo[3,4-b]pyridin-5-yl, 1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-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. In some embodiments, the present invention is directed to compounds of (R ⁷ )= formula (I) wherein <¾ (R ⁶ )b is 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, benzimidiazol-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, benzoxazol-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, 1 H-pyrrolo[2,3-c]pyridin-3-yl, 1H- pyrrolo[2,3-c]pyridin-3yl, 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]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl. In some embodiments,

(R ⁷ )C the present invention is directed to compounds of formula (I) wherein ⁽ ¾ (R®)b is 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-1 H- pyrrolo[3,2-c]pyridin-3-yl, 7H-pyrrolo[2,3-d]pyrimidin-5-yl, 1,4-dihydro-2H- benzo[d][1 ,3]oxazin-6-yl-2-one, 5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl-2-one, and 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl. In some embodiments, the present invention is directed to compounds of formula (I)

(R ⁷ )C

A wherein ( ^R6 k is 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-pynOlo[2,3-b]pyridin-4-yl, 1,4- dihydro-2H-benzo[d][1,3]oxazin-6-yl-2-one, and 5-fluoro-1,4-dihydro-2H- benzo[d][1 ,3]oxazin-6-yl-2-one. In some embodiments, the present invention is directed to compounds of formula (I) wherein one or more, preferably one to two, more preferably one heterocyclyl, heteroaryl or heterocydoalkyl (present as any part of a substituent group, preferably an R ⁵ substituent group) contains a nitrogen atom is further substituted to form an N-oxide. In some embodiments, the present invention is directed to compounds of formula (I) wherein any one or more (preferably one to two, more preferably one) heterocydyl, heteroaryl or heterocydoalkyl present as any part of the group contains a nitrogen atom, then said heterocyclyl, heteroaryl or heterocydoalkyl may be further substituted to form an N-oxide.

In some embodiments, the present invention is directed to compounds of formula (I) wherein one or more, (for example, one, two, three, four, five, six, seven, eight, nine, ten, eleven, etc.) hydrogen atoms are replaced with deuterium.

In some embodiments, the present invention is directed to compounds of formula (I) wherein a hydrogen atom on the R ¹ portion of the compound of formula (I) is replaced with deuterium. In some embodiments, the present invention is directed to compounds of formula (I) wherein the hydrogen

2 atom at the 4-position of the R ¹ portion of the compound of formula (I) (i.e. in the meta- position to R ¹ ) is replace with deuterium. In some embodiments, the present invention is directed to compounds of formula (I)

(R ² )» wherein the R ¹ portion of the compound of formula (I) is selected Cl Cl

D. F D. from the group consisting of R ¹ , and R ¹

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A and R ^B are each deutero. In some embodiments, the present invention is directed to compounds of formula

(I) wherein R ^c and R ^D are each deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ^A , R ^B , R ^c and R ^D are each deutero.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the hydrogen atom at the 8a position of the 2,3,8,8a- tetrahydroindolizin-5(1 H)-one is replaced with deuterium. In some embodiments, the present invention is directed to compounds of formula (I) wherein one or more of R ^A , R ^B , R ^c and R ^D is deutero and wherein the hydrogen atom at the 8a position of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one is replaced with deuterium.

In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is deutero. In some embodiments, the present invention is directed to compounds of formula (I) wherein R ⁵ is deutero and the hydrogen atom at the 8a position of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one is replaced with deuterium.

In some embodiments, the present invention is directed to compounds of

(R ² )

^• v* formula (I) wherein the hydrogen atom at the 4-position of the R ¹ portion of the compound of formula (I) (i.e. in the meta- position to R ¹ ) and the hydrogen atom at the 8a position of the 2,3,8,8a-tetrahydroindolizin-5(1H)-one are each replaced with deuterium. In some embodiments, the present

2'

"a invention is directed to compounds of formula (I) wherein the R ¹ portion of the compound of formula (I) is selected from the group consisting of

Cl Cl

D. F D.

R ¹ and R ¹ , and wherein the hydrogen atom at the 8a position of the 2,3,8, 8a-tetrahydroindolizin-5(1H)-one are each replaced with deuterium.

In some embodiments, the present invention is directed to compounds of formula (I) wherein one or more (for example 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) is replaced with deuterium.

In some embodiments, the present invention is directed to a compound of formula (I) selected from the group consisting of

Cmpd # Compound lUPAC name

(3S,8aR)-3-[5-(6-amino-2-fluoro-3-pyridyl)-1H- imidazol-2-yi]-7-[3-chloro-2-fluoro-6-(tetrazol-1-

358 yOphenyn^.d.e.Sa-tetrahydro-IH-indolizin-S-one;

(3S,8aR)-3-[5-(6-amino-2-chloro-3-pyridyl)-1H- imidazol-2-yi>7-[3-chloro-2-f1uoro-6-(tetrazol-1-

354 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-pyridyl]-1H-imidazol-2-yl]-2, 3,8,8a-

166 tetrahydro-1 H-indolizin-5-one;

(3S _l 8aR)-7-[3-chloro-2-fluoro6-(tetrazol-1- yl)phenyl]-3-[5-[3-fluoro-2-(1-hydroxycyclopropyl)-4- pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-

162 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-

126 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-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H-

107 indolizin-5-one;

(3S,8aR)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-3-[4- fluoro-5-[3-fluoro-2-(hydroxymethyl)-4-pyridyl]-1H-

80 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-[5-chloro-2-(tetrazol-1-yl)phenyl]-

90 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-

44 pyridyllcarbamate;

(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-

361 1H-indolizin-5-one and isotopologues and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to a compound of formula (lx) and tautomers, stereoisomers, isotopologues, and pharmaceutically acceptable salts or solvates thereof. In some embodiments, the present invention is directed to a compound of formula (ly) also known as (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-y l)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one and tautomers, isotopologues, and pharmaceutically acceptable salts or solvates thereof. In some embodiments, the present invention is directed to a compound of formula (Iz)

( i H

Cl w U

Γ

M

(Iz) also known as (3S,8aS)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one, and tautomers, isotopologues, and pharmaceutically acceptable salts or solvates thereof.

One skilled in the art will recognize that, depending on substituent groups, the compounds of the present invention may contain one or more stereo-centers, including for example, the stereo-centers denoted by the symbols in the structure of formula (I) shown below

Unless otherwise noted, the starred (“*”) stereo-center at the bridge carbon atom of the 2,3,8,8a-tetrahydroindolizin-5(1H)-one structure shall be referred to as the “Ring” stereo-center. One skilled in the art will further recognize that wherein the compound of formula (I) is present in a stereo- isomeric excess of one of the corresponding Ring stereo-isomers, then said compound may alternatively be referred to as the corresponding atropisomer.

Unless otherwise noted, the starred (“*”) stereo-center at the carbon atom of the 2,3,8,8a-tetrahydroindolizin-5(1H)-one structure bound to R ^A and R ^B shall be referred to as the “R ^A /R ^B " stereo-center; the starred (“*”) stereo- center at the carbon atom of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one structure bound to R ^c and R ^D shall be referred to as the “R ^C /R ^D ” stereo-center; the starred (“*”) stereo-center at the carbon atom of the 2,3,8,8a- tetrahydroindolizin-5(1H)-one structure bound to R ^E shall be referred to as the “R ^E ” stereo-center; and the starred (“*”) stereo-center at the carbon atom of the 2,3,8,8a-tetrahydroindolizin-5(1 H)-one structure bound to the Q substituent group shall be referred to as the “Q” stereo-center.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the Ring stereo-center is present as a racemic mixture. In some embodiments, the present invention is directed to compounds of formula (I) wherein the Ring stereo-center is present in an enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention is directed to compounds of formula (I) wherein the Ring stereocenter is present in an enantiomeric excess of the corresponding S-enantiomer.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the Ring stereo-center is present in a stereo-isomeric excess of either the R- or S- enantiomer 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) is present in a stereo- isomeric excess at the Ring stereo-center 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%.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^A /R ^B stereo-center is present as a racemic mixture. In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^A /R ^B stereo-center is present in an enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^A /R ^B stereocenter is present in an enantiomeric excess of the corresponding S-enantiomer.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^A /R ^B stereo-center is present in a stereo-isomeric excess of either the R- or S- enantiomer 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) is present in a stereo- isomeric excess at the R ^A /R ^B stereo-center 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%.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^C /R ^D stereo-center is present as a racemic mixture. In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^C /R ^D stereo-center is present in an enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^C /R ^D stereocenter is present in an enantiomeric excess of the corresponding S-enantiomer.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^C /R ^D stereo-center is present in a stereo-isomeric excess of either the R- or S- enantiomer 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) is present in a stereo- isomeric excess at the R ^C /R ^D stereo-center 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%.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^E stereo-center is present as a racemic mixture. In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^E stereo-center is present in an enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^E stereocenter is present in an enantiomeric excess of the corresponding S-enantiomer.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the R ^E stereo-center is present in a stereo-isomeric excess of either the R- or S- enantiomer 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) is present in a stereo- isomeric excess at the R ^E stereo-center 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%.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the Q stereo-center is present as a racemic mixture. In some embodiments, the present invention is directed to compounds of formula (I) wherein the Q stereo-center is present in an enantiomeric excess of the corresponding R-enantiomer. In some embodiments, the present invention is directed to compounds of formula (I) wherein the Q stereocenter is present in an enantiomeric excess of the corresponding S-enantiomer.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the Q stereo-center is present in an stereo-isomeric excess of either the R- or S- enantiomer 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) is present in a stereo- isomeric excess at the Ring stereo-center 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%.

In some embodiments, the present invention is directed to compounds of formula (I) wherein the Ring stereo-center is present in a stereo-isomeric excess of the R- configuration and the Q- stereo-center is present in a stereo- isomeric excess of the S- configuration.

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 starred (“*") stereo-centers (i.e. Ring, R ^A /R ^B , R ^C /R ^D , R ^E , Q, etc.) are each independently present in a racemic mixture or in a stereo-isomeric excess of either the corresponding R- or S- stereo- orientation. One skilled in the art will recognize that as such, 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 starred (“*”) stereo-centers (i.e. Ring, R ^A /R ^B , R ^C /R ^D ,

R ^E , Q, etc.) are present in any combination of stereo-configurations and any combination of stereo-isomeric excess.

Additional embodiments of the present invention include those wherein 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 to be any individual substituent or any subset of substituents selected from the complete list as defined herein. Additional embodiments of the present invention include those wherein the substituents selected for one or more of the variables defined herein (a, R ¹ , R ² , R ^A , R ^B , R ^c , R ^D , R ^E , Q, etc.) are independently selected to correspond to any of the embodiments as defined herein.

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.

Representative compounds of formula (I) of the present invention are as listed in Tables 1 and 2, below. Unless otherwise noted, the position of the R ² group(s) as listed in the Table below using the following numbering scheme: such that the R ¹ substituent is bound at the 6-position and the R ² substituents are bound at the 2-, 3-, 4~ and / or 5-positions of the phenyl group.

In the Tables which follow hereinafter, wherein a column lists the stereo- orientation of a particular stereo-center (as indicated by the heading of the column), “RAC" shall indicate that the compound was prepared as a racemic mixture at the designated stereo-center. The S* and R* designations shall indicate that although the compound was prepared in a stereo-isomeric excess of one of the corresponding stereoisomers at the designated stereo-center, the exact stereo-configuration was not determined. The S and R designations indicate that the compound was prepared in a stereo-isomeric excess of the corresponding S or R stereoisomer at the designated stereo-center, with the exact stereo-configuration as noted.

Table 1 : Representative Compounds of Formula ill

Q

Ring Store No. R ¹ (R ² ), Stereo R\ R ^B R ⁶ , R ^p o R ⁵

1, 2,3,4- 2-fluoro, 3-chloro-6-amino-

1 tetrazol-l-yl 3-chloro R H, H H, H S fluoro pyridin-4-yl

1,2, 3, 4- 2-fluoro, 2-(imidazol-2-yl>3-

2 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl

1,2, 3,4- 2-fluoro, 4-ch k>ro-pyrazol-3-

4 tetrazol-l-yl 3-chloro R H, H H, H RAC H yl

2-(3-methyl- isoxazol-5-yl-

1, 2,3,4- 2-fluoro, carbonyl-amino>3-

5 tetrazol-l-yl 3-chloro R H, H H. H S H fluoro-pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(methyl-sulfonyl-

6 tetrazol-l-yl 3-chloro RAC H, H H, H RAC fluoro amino)-pvridin-4-yl

1, 2,3,4- 2-fluoro, 2-(methyl-sulfonyl-

7 tetrazol-l-yl 3-chloro RAC H, H H, H RAC H amino>pyridin-4-yl

1,2, 3,4- 2-fluoro,

8 tetrazol-l-yl 3-chloro R H, H H, H S H indol-6-yl 4-(lR-(methyl-

1, 2,3,4- 2-fluoro, cartjonyl-amino)- 1 tetrazol-l-yl 3-chloro RAC H. H H, H S fluoro ethyl)-Dhenyl

2-(ethoxy-carbonyl-

1, 2,3,4- 2-fluoro, amino-methyl>3- 2 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl

2-(methyl-carbonyl-

1, 2,3,4- 2-fluoro, amino-methyl>3- 3 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl

1,2, 3,4- 2-fluoro, 4 tetrazol-l-yl 3-chloro R H, H H, H S H indol-5-yl

1,2, 3,4- 2-fluoro, 3-chloro-6-amino- 5 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

4-(lR-(methyl-

1, 2,3,4- 2-fluoro, carbonyl-amino)- 6 tetrazol-l-yl 3-chloro RAC H. H H, H S H ethyl)-phenyl

1,2, 3,4- 2-fluoro, 7 tetrazol-l-yl 3-chloro R H, H H, H S H 3-fluoro-pyridin-4-yl

3-chloro-6-(methyl-

1, 2,3,4- 2-fluoro, cabonyl-amino)- 8 tetrazol-l-yl 3-chloro RAC H, H H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro, lH-pyrrok)[2,3- 9 tetrazol-l-yl 3-chloro R* H, H H, H S H clpyridin-3-yl

1, 2,3,4- 2-fluoro, lH-pyiroto[2,3-

20 tetrazol-l-yl 3-chloro R* H, H H, H S H clpyridin-3-yl

1,2, 3,4- 2-fluoro, 2-amino-3-methyl-

21 tetrazol-l-yl 3-chloro RAC H, H H. H S H oyridin-4-yl difluoro- 2-fluoro, 2-(hydroxy-methyl)-

23 methoxy 3-chloro R H, H H, H S fluoro 3-fluoro-pyridin-4-yl

1, 2,3,4- 2-fluoro, lH-pyrrolo[2,3-

24 tetrazol-l-yl 3-chloro R H, H H, H S H blpyridin-5-yl difluoro- 2-fluoro, 2-(hydroxy-methyl)-

25 methyl 3-chloro R H, H H, H S H 3-fluoro-pyridin-4-yl difluoro- 2-fluoro, 2-(hydroxy-nnethyl)-

26 methyl 3-chloro R H, H H. H S H 3-fluoro-pyridin-4-yl difluoro- 2-fluoro, 2-(hydroxy-methyl)-

27 methyl 3-chloro R H, H H, H S fluoro 3-fluoro-pyridin-4-yl

2-(2-hydraxy-n-

1, 2,3,4- 2-fluoro, propyl-oxy)-3-

28 tetrazol-l-yl 3-chloro S* H, H H, H S* H fluoro-oyridin-4-yl

2-(2-hydroxy-n-

1,2, 3,4- 2-fluoro, propyl-oxy)-3-

29 tetrazol-l-yl 3-chloro S* H, H H, H S* H fluoro-pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-methyl-

30 tetrazol-l-yl 3-chloro R H, H H. H S H benzimidazol-6-γΙ

1, 2,3,4- 2-fluoro, 2-(pyrazol-5-yl)-

31 tetrazol-l-yl 3-chloro R* H, H H, H S* fluoro pyridin-4-yl 4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 2-carboxy-3-fluoro-

34 1-yl 3-chloro R H, H H. H S fluoro □yridin-4-yl

1, 2,3,4- 2-fluoro, methy 2-(hydroy-methyl)-

35 tetrazol-l-yl 3-chloro R H, H H, H S* I 3-fluoro-pyridin-4-yl

2-(phosphono-

1, 2,3,4- 2-fluoro, methoxy-methyl)-3-

37 tetrazol-l-yl 3-chloro R H, H H, H R* H fluoro-pyridin-4-yl

2-(methoxy-

1,2, 3,4- 2-fluoro, carbonyl-amino>3-

40 tetrazol-l-yl 3-chloro R H, H H. H S fluoro fluoro-pyridin-4-yl

2-(methoxy-

1,2, 3,4- 2-fluoro, cart)onyl-amino>3-

44 tietrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl

2-(lR-hydroxy-

1, 2,3,4- ethyl)-3-fluoro-

45 tetrazol-l-yl 3-chloro R H, H H. H S fluoro pyridin-4-yl

2-(lS-hydroxy-

1,2, 3,4- ethyl)-3-fluoro-

46 tetrazol-l-yl 3-chloro R H, H H, H S fluoro pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(5-amino-pyrazol-

49 tetrazol-l-yl 3-chloro R H, H H, H R* H l-yl)-pyridin-4-yl

4-chloro- 2-(methoxy-

1,2,3-triazol- 2-fluoro, carbonyl>3-fluoro-

50 1-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-(methoxy-

1, 2,3,4- 2-fluoro, carbonyl>3-fluoro-

52 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

1,2, 3,4- 2-fluoro, 2-(pyrazol-5-yl)-

53 tetrazol-l-yl 3-chloro RAC H, H H, H RAC H pyridin-4-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-carboxy-3-fluoro-

54 1-yl 3-chloro R H, H H, H S* H pyridin-4-yl

1, 2,3,4- fluoro, 2-(hydroxy-methyl)-

56 tetrazol-l-yl 3-chloro RAC fluoro H, H S H 3-fluoro-pyridin-4-yl

1, 2,3,4- 2-fluoro- 2-(hydroxy-methyl)-

57 tetrazol-l-yl 3-methyl R H, H H, H S H 3-fluoro-pyridin-4-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 2-carboxy-3-fluoro-

58 1-yl 3-chloro R H. H H, H S H pyridin-4-yl

4-(trifluoro- methyl)- 6-methyl-

1,2,3-triazol- quinoxalin-5-yl-

59 1-yl 3-chloro R* H. H H, H S* H 2(lH>one 2-(phosphono-oxy-

1, 2,3,4- 2-fluoro, methyl>3-fluoro-

61 tetrazol-l-yl 3-chloro R H, H H. H S H pyridin-4-yl

2-(3-amino-pyrazol-

1, 2,3,4- 2-fluoro, l-yl)-3-fluoro-

63 tetrazol-l-yl 3-chloro R H, H H, H R* H pyridin-4-yl

4-(trifluoro- methyl)- l,2,34riazol- 2-(hydroxy-methyl)-

64 1-yl 3-chloro R H, H H, H S H 3-fluoro-pyridin-4-yl

2-(hydroxy-methyl)-

1,2, 3,4- 2-fluoro, 3-fluoro-pyridin-4-

65 tetrazol-l-yl 3-chloro R H, H H. H S H yl-N-oxide

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 2-(hydraxy-methyl)-

67 1-yl 3-chloro R H, H H, H S H 3-fluoro-pyridin-4-yl

2-(5-amino-pyrazol-

1, 2,3,4- 2-fluoro, l-yl)-3-fluoro-

68 tetrazol-l-yl 3-chloro R H. H H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro-6-amino-

69 tetrazol-l-yl 3-chloro R H, H H, H S fluoro pyridin-3-yl

1, 2,3,4- 2-amino-3-fluoro-

70 tetrazol-l-yl 3-chloro R H, H H, H S* fluoro pyridin-4-yl

2-{l,2,3-triazol-l-

1, 2,3,4- 2-fluoro, yl>3-fluoro-pyridin-

71 tetrazol-l-yl 3-chloro R H, H H, H R* H 4-yl

1, 2,3,4- 2-fluoro, 2-(3-amino-pyrazol-

72 tetrazol-l-yl 3-chloro R H, H H, H R* H l-yl)-pyridin-4-yl

2<S- tetrahydrofuran-3-

1,2, 3,4- 2-fluoro, yl-amino)-3-fluoro-

73 tetrazol-l-yl 3-chloro R* H, H H, H S H pyridin-4-yl

2<S- t3etrahydrofuran-3-

1,2, 3,4- 2-fluoro, yl-amino)-3-fluoro-

74 tetrazol-l-yl 3-chloro S* H, H H, H S H pyridin-4-yl

2-(lS-amino- isopropyl-carbonyl-

1, 2,3,4- 2-fluoro, oxo-methyl)-3-

75 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl

2<S- tetrahydrofuran-3-

1, 2,3,4- 2-fluoro, yl-amino)-3-fluoro-

76 tetrazol-l-yl 3-chloro RAC H, H H, H S* fluoro pyridin-4-yl

2-(S- tKtrahydrofuran-3-

1,2, 3,4- 2-fluoro, yl-amino)-3-fluoro-

77 tetrazol-l-yl 3<hloro RAC H, H H. H R* fluoro pyridin-4-yl 2-(l,3,4-triazol-l-

1, 2,3,4- 2-fluoro, yl>3-fluoro-pyridin-

78 tetrazol-l-yl 3-chloro R* H. H H, H R* H 4-yl

2-{l,l-dimethyl-2- hydroxy-ethyl-

1, 2,3,4- amino)-3-fluoro-

79 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

1, 2,3,4- 2-(hydroxy-methyl)-

80 tetrazol-l-yl 3-chloro R H, H H, H S fluoro 3-fluoro-pyridin-4-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 3,4-dihydro-2H-

81 1-yl 3-chloro R H, H H. H S fluoro quinolin-6-yl-2-one

2-fluoro-6-

(bicyclo[l.l.l]penta

1,2, 3,4- nyl-amino)-pyridin-

83 tetrazol-l-yl 3-chloro R H. H H, H S H 3-yl

2-(2-methyl-2- hydroxy-n-propyl-

1, 2,3,4- amino)-3-fluoro-

84 tetrazol-l-yl 3-chloro R H. H H, H S fluoro pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-{l,2,3-triazol-l-

85 tetrazol-l-yl 3-chloro R H, H H, H S H yl)-pyridin-4-yl

1, 2,3,4- 2-fluoro, Hl,2,5-triazol-l-

86 tetrazol-l-yl 3-chloro R H, H H, H S H yl)-pyridin-4-yl

1, 2,3,4- 2-fluoro, Hl,2,5-triazol-l-

87 tetrazol-l-yl 3-chloro R H, H H, H S fluoro yl)-pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(pyrazol-l-yl)-

88 tetrazol-l-yl 3-chloro R H, H H, H S fluoro oyridin-4-yl

2-(l,l-dimethyl-2- hydroxy-ethyl-

1,2, 3,4- 2-fluoro, amino)-3-fiuoro-

89 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

1,2, 3,4- 2-amino-3-fluoro-

90 tetrazol-l-yl 3-chloro R H, H H, H S* H pyridin-4-yl

2-(l,2,4-triazol-l-

1, 2,3,4- 2-fluoro, yl>3-fluoro-pyridin-

92 tetrazol-l-yl 3-chloro R H, H H, H R* fluoro 4-yl

1, 2,3,4- 2-fluoro, 2-(pyrazol-l-yl)-

93 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-(3,3-difluoro- azetin-l-yl-

1,2, 3,4- 2-fluoro, carbonyl>3-fluoro-

94 tetrazol-l-yl 3-chloro R H, H H. H S H pyridin-4-yl

7-methyl-6,7- dihydro-5H-

1,2, 3,4- 2-fluoro, cyclopenta[b]pyridi

95 tetrazol-l-yl 3-chloro RAC H. H H, H RAC H n-4-yl-7-ol 2-

(bicyck)[l.l.l]penta

1, 2,3,4- nyl-amino>3-fluoro-

96 tetrazol-l-yl 3-chloro R H. H H, H S H pyridin-3-yl

4-(tnfluoro- methyl)-

1,2,3-triazol- 3,4-dihydro-2H-

97 1-yl 3-chloro R H, H H, H S H quinolin-6-yl-2-one

1, 2,3,4- 2-fluoro-6-amino-

98 tetrazol-l-yl 3-chloro R H, H H, H S* H pyridin-3-yl

2-(methoxy-

1,2, 3,4- 2-fluoro, carbonyl-amino)-

99 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-(3-cyanonazetidin-

1,2, 3,4- 2-fluoro, l-yl)-3-fluoro-00 tetrazol-l-yl 3-chloro R H, H H, H S* H oyridin-4-yl

4-(trifluoro- methyl)-

1,2,3-triazol-01 1-yl 3-chloro R H, H H, H S H quinolin-5-yl-2-one

2-(3-cyano-azetidin-

1, 2,3,4- 2-fluoro, l-yl)-3-fluoro-02 tetrazol-l-yl 3-chloro R H, H H, H R* H pyridin-4-yl

2-{methoxy-amino-

1, 2,3,4- 2-fluoro, cart»nyl>3-fluoro-03 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-

(bicyclo[l.l.l]penta nyl-amino-

1, 2,3,4- 2-fluoro, carbonyl>3-fluoro-04 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-3-yl

2-(pyrrolidin-l-yl-2-

1, 2,3,4- 2-fluoro, one>3-fluoro-05 tetrazol-l-yl 3-chloro S H, H H, H S H pyridin-4-yl

2-(pyrrolidin-l-yl-2-

1,2, 3,4- 2-fluoro, one>3-fluoro-06 tetrazol-l-yl 3-chloro R H, H H. H S H pyridin-4-yl

1,2, 3,4- 2-fluoro, 2-(hydroxy-methyl)-07 tetrazol-l-yl 3-chloro R H, H H, H S fluoro 3-fluoro-pyridin-4-yl

2-(2-oxa-6- azaspiro[3.3]hept-

1, 2,3,4- 2-fluoro, 6-yl)-3-fluoro-08 tetrazol-l-yl 3-chloro R H, H H. H S* H pyridin-4-yl

2-(l-hydroxy-

1, 2,3,4- 2-fluoro, cycloprop-l-yl>3-09 tetrazol-l-yl 3-chloro R H, H H. H R* fluoro fluoro-pyridin-4-yl

1,2, 3,4- 2-fluoro, 2-(azetidin-l-yl)-3-10 tetrazol-l-yl 3-chloro R H, H H. H R* H fluoro-pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(azetidin-l-yl)-3-11 tetrazol-l-yl 3-chloro R H, H H, H S* H fluoro-pyridin-4-yl 2-(l,2,4-triazol-l-

1, 2,3,4- 2-fluoro, yiy-3-fluoro-pyridin-12 tetrazol-l-yl 3-chloro R H. H H, H R* H 4-yl

2-(hydroxy-d2-

1, 2,3,4- 2-fluoro, deuter methyl>3-fluoro-13 tetrazol-l-yl 3-chloro R H, H H, H S 0 pyridin-4-yl

2-(oxazolidin-3-yl-2-

1, 2,3,4- 2-fluoro, one>3-fluoro-14 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-(l-hydroxy-

1,2, 3,4- 2-fluoro, deuter cycloprop-l-yl>3-16 tetrazol-l-yl 3-chloro R H, H H. H R* O fluoro-pyridin-4-yl

1,2, 3,4- 2-fluoro, deuter 2-(hydraxy-methyl)-17 tetrazol-l-yl 3-chloro R H, H H, H S o 3-fluoro-pyridin-4-yl

5-fluoro-l,4- dihydro-2H-

1, 2,3,4- 2-fluoro, benzo[d][l,3]oxazin18 tetrazol-l-yl 3-chloro R* H. H H, H S* H -6-yl-2-one

3-ch loro- 2-fluoro-5-deutero-

1,2, 3,4- 4- 6-amino-pyridin-3-19 tetrazol-l-yl deutero R H, H H. H R* H yl

3-ch loro- 2-fluoro-5-deutero-

1, 2,3,4- 4- 6-amino-pyridin-3-20 tetrazol-l-yl deutero R H. H H, H S* H yl

3-chloro-

1, 2,3,4- 4- 2-fluoro-6-amino-21 tetrazol-l-yl deutero R H, H H, H R* H pyridin-3-yl

3-chloro-

1, 2,3,4- 4- 2-fluoro-6-amino-22 tetrazol-l-yl deutero R H, H H, H S* H pyridin-3-yl

1,2, 3,4- 2-fluoro-6-amino-23 tetrazol-l-yl 3-chloro R H, H H. H S H pyridin-3-yl

2-fluoro-5-deutero-

1, 2,3,4- 6-amino-pyridin-3-24 tetrazol-l-yl 3-chloro R H, H H, H S H yl

1, 2,3,4- 2-fluoro, 2-amino-3-fluoro-26 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-( lS-( 1,3,4- oxadiazol-2-yl>

1,2, 3,4- 2-fluoro, ethoxy )-3-fluoro-27 tetrazol-l-yl 3-chloro S* H, H H. H S* H pyridin-4-yl

2-(lS-(l,3,4- oxadiazol-2-yl>

1,2, 3,4- 2-fluoro, ethoxy)-3-fluoro-28 tetrazol-l-yl 3-chloro R* H, H H, H S* H pyridin-4-yl

2-fluoro,

3-chloro,

1,2, 3,4- 4- deuter 2-fluoro-6-amino-29 tetrazol-l-yl deutero R H. H H, H S o pyridin-3-yl

1,2, 3,4- 2-fluoro, 2-(oxetan-3-yl)-3-30 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl 2-fluoro-4,5- dideutero-6-

1,2, 3, 4- 2-fluoro, (methyl-amino)-33 tetrazol-1-γΙ 3-chloro R H, H H, H S H oyridin-3-yl

1,2, 3, 4- 2-fluoro, 2-(metiiyl-amino>34 tetrazol-l-yl 3-chloro R H, H H, H S H 3-fluoro-pyridin-4-yl

2-(N-ethyl-N-2- hydnoxy-ethyl-

1,2, 3,4- 2-fluoro, amino)-3-fluoro-35 tetrazol-l-yl 3-chloro S* H, H H, H S H pyridin-4-yl

2-(N-ethyl-N-2- hydroxy-ethyl-

1, 2,3,4- 2-fluoro, amino)-3-fiuoro-36 tetrazol-l-yl 3-chloro R* H. H H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro, 37 tetrazol-l-yl 3-chloro R H, H H. H R* H indol-3-yl

2-(3-cyano-oxetan-

1,2, 3,4- 2-fluoro, 3-yl)-3-fluoro-38 tetrazol-l-yl 3-chloro R* H. H H, H S H pyridin-4-yl

2-(2-cyano-

1,2, 3,4- 2-fluoro, cycloprop-l-yl>3-39 tietrazol-l-yl 3-chloro R* H, H H, H S H fluoro-pyridin-4-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, lH-pyrrok)[2,3-40 1-yl 3-chloro S H, H H, H R* H blpyridin-3-yl

2-{lR*-oxazol-2-yl-

1,2, 3,4- 2-fluoro, ethoxy)-3-fluoro-41 tetrazol-l-yl 3-chloro R* H, H H, H S* H pyridin-4-yl

2-(lS*-oxazol-2-yl-

1, 2,3,4- 2-fluoro, ethoxy)-3-fluoro-42 tetrazol-l-yl 3-chloro R* H, H H. H S* H pyridin-4-yl

2-(3,3,3-trifluoro-

2S*-hydroxy-n-

1, 2,3,4- 2-fluoro, propyl)-3-fluoro-43 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-(3,3,3-trifluoro-

2R*-hydroxy-n-

1, 2,3,4- 2-fluoro, propyl>3-fluoro-44 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

2-fluoro-5-deutero-

1, 2,3,4- 2-fluoro, deuter 6-amino-pyridin-3-45 tetrazol-l-yl 3-chloro R H, H H, H S 0 yl

2-fluoro-5-deutero-

1, 2,3,4- 2-fluoro, 6-amino-pyridin-3-47 tetrazol-l-yl 3-chloro R H, H H, H S H yl

2-fluoro-4KleutEro-

1,2, 3,4- 2-fluoro, deuter 6-amino-pyridin-3-48 tetrazol-l-yl 3-chloro R H, H H, H S 0 yl

2-fiuoro-4,5-

1, 2,3,4- 2-fluoro, deuter dideutero-6-amino-49 tetrazol-l-yl 3-chloro R H, H H, H S o pyridin-3-yl 2-fluoro-4-deutero-

1, 2,3,4- 2-fluoro, 6-amino-pyridin-3-50 tetrazol-l-yl 3-chloro R H, H H, H S H yl

2-fiuoro-4,5-

1, 2,3,4- 2-fluoro, dideutero-6-amino-51 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-3-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 52 1-yl 3-chloro R H, H H, H S H ouinolin-6-yl-2-one

1,2, 3,4- 2-fluoro, deuter 2-fluoro-6-amino-54 tietrazol-l-yl 3-chloro R H, H H, H S o pyridin-3-yl

2-(l-hydroxy-

1, 2,3,4- 2-fluoro, cycloprop-l-yl>3-55 tetrazol-l-yl 3-chloro R H. H H, H S* H chbro-pyridin-4-yl

2-(dioxan-2S-yl-

1, 2,3,4- 2-fluoro, ethoxy)-3-fluoro-56 tetrazol-l-yl 3-chloro R H, H H. H R* H pyridin-4-yl

2-(dioxan-2S-yl-

1,2, 3,4- 2-fluoro, ethoxy)-3-fluoro-57 tetrazol-l-yl 3-chloro R H, H H, H S* H pyridin-4-γΙ

2-(3-hydraxy-3-

1, 2,3,4- 2-fluoro, methyl-n-butyl)-3-58 tietrazol-l-yl 3-chloro R* H, H H, H S* H fluoro-pyridin-3-yl

2-(3-hydroxy-3-

1, 2,3,4- 2-fluoro, methyl-n-butyl)-3-59 tetrazol-l-yl 3-chloro S* H, H H, H S* H fluoro-pyridin-3-yl

2-(l,l-difiuoro-2-

1,2, 3,4- 2-fluoro, hydroxy-ethyl)-3-60 tetrazol-l-yl 3-chloro R H, H H, H S* H fluoro-pyridin-4-yl

2-(methoxy-ethyl-

1, 2,3,4- 2-fluoro, amino)-3-fiuoro-61 tetrazol-l-yl 3-chloro RAC H, H H, H S H pyridin-4-yl

2-(l-hydroxy-

1, 2,3,4- 2-fluoro, cycloprop-l-yl>3-62 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl

2-(lS*-cyano-

1,2, 3,4- 2-fluoro, ethyl)-3-fluoro-63 tetrazol-l-yl 3-chloro RAC H, H H, H S H pyridin-4-γΙ

2-(lR*-cyano-

1, 2,3,4- 2-fluoro, ethyl)-3-fluoro-64 tetrazol-1-γΙ 3-chloro RAC H, H H, H S H pyridin-4-yl

4-(trifluoro- methyl)- 2-(amino-cart>onyl- l,2,34riazol- 2-fluoro, methyl>3-fluoro-65 1-yl 3-chloro R* H, H H, H S* H pyridin-4-yl

2-(2-methyl-2- hydraxy-n-propyl-

1,2, 3,4- 2-fluoro, oxy)-3-fluoro-66 tetrazol-l-yl 3-chloro R H. H H, H S H pyridin-4-γΙ 2-amino-6-

1, 2,3,4- 2-fluoro, (trifluoro-methyl)-67 tetrazol-l-yl 3-chloro R* H, H H, H S* H pyridin-5-yl

2-{lR-

(hydroxymethyl>

1, 2,3,4- 2-fluoro, ethyl)-3-fluoro-68 tetrazol-l-yl 3-chloro R* H, H H, H S H pyridin-4-yl

2-(lR-

(hydroxymethyl)-

1,2, 3,4- 2-fluoro, ethyl)-3-fluoro-69 tetrazol-l-yl 3-chloro S* H, H H. H S H pyridin-4-yl

2-(lS*-hydroxy-2,2-

1,2, 3,4- 2-fluoro, difluoro-ethyl>3-70 tetrazol-l-yl 3-chloro S* H, H H, H S* H fluoro-pyridin-4-yl

2-(lR*-hydroxy-

1, 2,3,4- 2-fluoro, 2,2-difluoro-ethyl>71 tetrazol-l-yl 3-chloro R* H, H H, H S* H 3-fluoro-pyridin-4-yl

2-(lS*-hydraxy-2,2-

1, 2,3,4- 2-fluoro, difluoro-ethyl>3-72 tetrazol-l-yl 3-chloro S* H, H H, H S* chloro fluoro-pyridin-4-yl

2-(lR*-hydroxy-

1,2, 3,4- 2-fluoro, 2,2-difluoro-ethyl>73 tetrazol-l-yl 3-chloro R* H, H H, H S* chloro 3-fluoro-pyridin-4-yl

2-(lS*-hydraxy-2,2-

1,2, 3,4- 2-fluoro, difluoro-ethyl>3-74 tetrazol-l-yl 3-chloro S* H. H H, H S* H fluoro-pyridin-4-yl

2-(lR*-hydroxy-

1, 2,3,4- 2-fluoro, 2,2-difluoro-ethyl>75 tetrazol-l-yl 3-chloro R* H, H H, H S* H 3-fluoro-pyridin-4-yl

2-(l-hydroxy-

1,2, 3,4- 2-fluoro, cycloprop-l-yl>78 tetrazol-l-yl 3-chloro R H, H H, H R* chloro pyridin-4-yl

2-(l-hydroxy-

1, 2,3,4- 2-fluoro, cycloprop-l-yl>79 tetrazol-l-yl 3-chloro R H, H H. H R fluoro □yridin-4-yl

2-(2-methoxy-ethyl-

1, 2,3,4- 2-fluoro, amino-carbonyl>3-80 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(amino-carbonyl>81 tetrazol-l-yl 3-chloro R H, H H, H S H 3-fluoro-pyridin-3-yl

1,2, 3,4- 2-fluoro, 2-carboxy-3-fluoro-82 tetrazol-l-yl 3-chloro R H. H H, H S H pyridin-4-yl

2-(l-hydroxy- cycloprop-l-yl-

1,2, 3,4- 2-fluoro, methoxy)-3-fluoro-83 tetrazol-l-yl 3-chloro R* H, H H, H S H oyridin-4-yl

2-(hydraxy-d2-

1, 2,3,4- methyl>3-fluoro-84 tetrazol-l-yl 3-chloro R H, H H, H S bromo pyridin-4-yl 2-(lR*-hydroxy-

1, 2,3,4- 2-fluoro, ethyl)-3-fluoro-85 tetrazol-l-yl 3-chloro R* H, H H. H S H □yridin-4-yl

2-(lS*-hydroxy-

1, 2,3,4- 2-fluoro, ethyl)-3-fluoro-86 tetrazol-l-yl 3-chloro R* H, H H, H S H pyridin-4-yl

2-(3S-hydraxy-

1, 2,3,4- 2-fluoro, piperidin-l-yl>3-87 tetrazol-l-yl 3-chloro R H, H H, H R* H fluoro-pyridin-4-yl

2-(3S-hydroxy-

1,2, 3,4- 2-fluoro, piperidin-l-yl)-3-88 tetrazol-l-yl 3-chloro R H, H H, H S* H fluoro-pyridin-4-yl

2-(hydraxy-d2-

1,2, 3,4- 2-fluoro, methyl)-3-fchloro-89 tetrazol-l-yl 3-chloro RAC H, H H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro, 99 tetrazol-l-yl 3-chloro RAC H, H H. H S chloro pyrklin-4-yl-2-one

1, 2,3,4- 2-fluoro, 3-amino-01 tetrazol-l-yl 3-chloro R H, H H, H S H benzisoxazol-5-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 2-(amino-cartx>nyl>04 1-yl 3-chloro R* H, H H. H S* H pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(amino-carbonyl>06 tetrazol-l-yl 3-chloro R* H, H H, H S* H pyridin-4-yl

4-chloro-

1,2,3-triazol- 2-fluoro, 2-(amino-carbonyl)-07 1-yl 3-chloro R H, H H, H S H thien-5-yl

4-chloro-

1,2,3-triazol- 2-fluoro, 2-(amino-carbonyl>08 1-yl 3-chloro R H, H H, H S H thiazol-5-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 2-(amino-cart)onyl>12 1-yl 3-chloro R* H, H H, H S* H pyridin-5-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 2-(amino-cart)onyl>13 1-yl 3-chloro S* H. H H, H S* H pyridin-5-yl

1, 2,3,4- 2-fluoro, 3-fluoro-pyrazol-4-17 tetrazol-l-yl 3-chloro R H, H H, H S H yl

1,2, 3,4- 2-fluoro, 2-(hydraxy-methyl)-22 tetrazol-l-yl 3-chloro R H, H H. H S H 3-fluoro-pyridin-4-yl

4-(trifluoro- methyl)- 2-chk)ro-6-

1,2,3-triazol- 2-fluoro, (hydroxy-methyl)-23 1-yl 3-chloro R H, H H, H S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 3-chtoro-pyrazol-4-24 tetrazol-l-yl 3-chloro R* H, H H, H S H yl

1,2, 3,4- 2-fluoro, 2-(amino-carbonyl>25 tetrazol-l-yl 3-chloro R* H, H H, H S* H pyridin-5-yl 1, 2,3,4- 2-fluoro, 2-(amino-cartx)nyl>26 tetrazol-l-yl 3-chloro R* H, H H. H R* H pyridin-5-yl

1, 2,3,4- 2-fluoro, 3-methoxy-pyrazol-27 tetrazol-l-yl 3-chloro R H, H H, H S H 4-yl

2-chloro-6-(amino-

1, 2,3,4- 2-fluoro, carbonyl>pyridin-3-28 tetrazol-l-yl 3-chloro R H, H H, H S H yl

2-chloro-6-(amino-

1,2, 3,4- 2-fluoro, carbonyl>pyridin-3-29 tetrazol-l-yl 3-chloro S H, H H, H S H yl

1,2, 3,4- 2-fluoro, 3-(trifiuoro-methyl)-30 tietrazol-l-yl 3-chloro R H. H H, H S H Pvrrol-4-yl

1, 2,3,4- 2-fluoro, 2-(trifluoro-methyl)-31 tetrazol-l-yl 3-chloro R H, H H, H S H imidazol-4-yl

1,2, 3,4- 2-fluoro, 3-(amino-carbonyl>32 tetrazol-l-yl 3-chloro S H, H H, H S H 4-fluoro-phenyl

1, 2,3,4- 2-fluoro, 3-(amino-cartx)nyl>33 tetrazol-l-yl 3-chloro R H, H H, H S H 4-fluoro-phenyl

1, 2,3,4- 2-fluoro, 2-(amino-carbonyl>34 tetrazol-l-yl 3-chloro R H, H H, H S H thien-4-yl

2-fluoro-6-

1,2, 3,4- 2-fluoro, (hydroxy-methyl)-35 tetrazol-l-yl 3-chloro R* H, H H. H S* H oyridin-3-yl

2-chloro-6-

1, 2,3,4- 2-fluoro, (hydroxy-methyl)-36 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-fluoro-3-(amino-37 tetrazol-l-yl 3-chloro R H, H H, H S H carbonyl)-phenyl

1,2, 3,4- 2-fluoro, 2-(amino-cart)onyl>38 tetrazol-l-yl 3-chloro R H, H H, H S* H thien-5-yl

1,2, 3,4- 2-fluoro, 3-(trifluoro-methyl)-39 tetrazol-l-yl 3-chloro R* H, H H, H R* H oyrazol-4-yl

1, 2,3,4- 2-fluoro, 3-(trifluoro-methyl)-40 tetrazol-l-yl 3-chloro R* H. H H, H S* H pyrazol-4-yl

3-(cytiopropyl- carbonyl-amino)-6-

1,2, 3,4- 2-fluoro, (trifluoro-methyl)-41 tetrazol-l-yl 3-chloro R H, H H, H S H oyridin-4-yl

3-{cyctopropyl- carbonyl-amino)-6-

1, 2,3,4- 2-fluoro, (trifluoro-methyl)-42 tetrazol-l-yl 3-chloro S H, H H, H S H pyridin-4-yl

3-(d3-methyl- carbonyl-amino>6-

1, 2,3,4- 2-fluoro, (trifluoro-methyl)-43 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

3-(methyl-carbonyl-

1, 2,3,4- 2-fluoro, amino)-6-(trifluoro-44 tetrazol-l-yl 3-chloro S H, H H, H S H methyl)-pyridin-4-yl 3-( methyl -carbon yl-

1, 2,3,4- 2-fluoro, aminoj-e-itrifluoro-45 tetrazol-l-yl 3-chloro R H, H H. H S H methyl>pyridin-4-yl

1, 2,3,4- 2-fluoro, 3-(methyl-amino>58 tetrazol-l-yl 3-chloro RAC H, H H, H S H indazol-6-yl

1, 2,3,4- 2-fluoro, 61 tetrazol-l-yl 3-chloro RAC H, H H, H S H quinolin-6-yl-2-one

1,2, 3,4- 2-fluoro, 3-(metiiyl-amino>65 tetrazol-l-yl 3-chloro S H, H H, H S H indazol-6-yl

1,2, 3,4- 2-fluoro, 2-(methyl-amino>69 tetrazol-l-yl 3-chloro S H, H H, H S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 70 tetrazol-l-yl 3-chloro S H. H H, H S H quinolin-6-yl-2-one

1,2, 3,4- 2-fluoro, quinazolin-6-yl-2-73 tetrazol-l-yl 3-chloro RAC H, H H. H S H one l,4-dihydro-2H-

1, 2,3,4- 2-fluoro, benzo[d][l,3]oxazin77 tetrazol-l-yl 3-chloro R* H, H H, H S H -6-yl-2-one l,4-dihydro-2H-

1, 2,3,4- 2-fluoro, benzo[d][l,3]oxazin78 tetrazol-l-yl 3-chloro S* H, H H, H S H -6-yl-2-one

1, 2,3,4- 2-fluoro, 3,4-dihydroquinolin-80 tetrazol-l-yl 3-chloro S* H, H H, H S H 6-yl-2-one

1,2, 3,4- 2-fluoro, 3,4-dihydroquinolin-81 tetrazol-l-yl 3-chloro R* H, H H, H S H 6-yl-2-one

1,2, 3,4- 2-fluoro, 2-fluoro-6-(methyl-82 tetrazol-l-yl 3-chloro R* H, H H, H S H amino>pyridin-3-yl

1, 2,3,4- 2-fluoro, 83 tetrazol-l-yl 3-chloro S* H. H H, H S H indol-5-yl-2-one

1, 2,3,4- 2-fluoro, 84 tetrazol-l-yl 3-chloro R* H, H H, H S H indol-5-yl-2-one

1,2, 3,4- 2-fluoro, benzimidazol-5-yl-86 tetrazol-l-yl 3-chloro R* H. H H, H S H 2-one

1, 2,3,4- 2-fluoro, 2-(dimethyl-amino>89 tetrazol-l-yl 3-chloro RAC H, H H, H S H phenyl

1, 2,3,4- 2-fluoro, 2-fluoro-6-(methyl-91 tetrazol-l-yl 3-chloro S* H, H H, H S H amino)-pyridin-3-yl

1,2, 3,4- 2-fluoro, benzimidazol-5-yl-92 tetrazol-l-yl 3-chloro S* H, H H. H S H 2-one l,4-dihydro-2H-

1, 2,3,4- 2-fluoro, benzo[d][l,3]oxazin97 tetrazol-l-yl 3-chloro RAC H, H H, H S H -6-yl-2-one

1-methyl-

1, 2,3,4- 2-fluoro, benzimidazol-6-yl-99 tetrazol-l-yl 3-chloro S* H, H H, H S H 2-one

1-methyl-

1, 2,3,4- 2-fluoro, benzimidazol-6-yl-00 tetrazol-l-yl 3-chloro R* H, H H, H S H 2-one 1-methyl-

1, 2,3,4- 2-fluoro, benzimidazol-5-yl-03 tetrazol-l-yl 3-chloro R H, H H. H S H 2-one

1, 2,3,4- 2-fluoro, 3,4-dihydro-2H-11 tetrazol-l-yl 3-chloro RAC H, H H, H S H quinolin-6-yl-2-one

1, 2,3,4- 2-fluoro, benzimidazol-5-yl-12 tetrazol-l-yl 3-chloro RAC H, H H, H S H 2-one

1,2, 3,4- 2-fluoro, 3-amino-indazol-6-13 tetrazol-l-yl 3-chloro RAC H. H H, H S H yl

1,2, 3,4- 2-fluoro, 14 tetrazol-l-yl 3-chloro RAC H. H H, H S H ΙηΰοΙίη-5·Ύΐ-2-οηβ

2-fluoro-6-

1, 2,3,4- 2-fluoro, (dimethyl-amino)-15 tetrazol-l-yl 3-chloro RAC H, H H, H S H pyridin-3-yl

5-(methoxy-

1,2, 3,4- 2-fluoro, carbonyl-amino)-16 tetrazol-l-yl 3-chloro R* H. H H, H S H pyridin-2-yl

1, 2,3,4- 2-fluoro, 4-(oxazolidin-3-yl-2-18 tetrazol-l-yl 3-chloro RAC H, H H, H S H one)-phenyl

4-(methoxy- difluoro- 2-fluoro, carbonyl-amino)-19 methoxy 5-chloro S* H, H H, H S H phenyl

4-(methoxy- difluoro- 2-fluoro, cartwnyl-amino)-20 methoxy 3-chloro S* H, H H. H S H phenyl

1, 2,3,4- 2-fluoro, 21 tetrazol-l-yl 3-chloro S* H, H H, H S H pyridin-4-yl-N-oxide

5-(methoxy-

1, 2,3,4- 2-fluoro, cartionyl-amino)-22 tetrazol-l-yl 3-chloro S* H, H H, H S H pyridin-2-yl

4-(methoxy- difluoro- 2-fluoro, carbonyl-amino)-23 methoxy 3-chloro R* H, H H, H S H phenyl

2,2,2- 4-(methoxy- trifluoro- 2-fluoro, carbonyl-amino)-24 ethoxy 3-chloro RAC H, H H. H S H phenyl

2-(methoxy-

1,2, 3,4- 2-fluoro, cartfonyl-amino)-25 tetrazol-l-yl 3-chloro RAC H. H H, H S H pyridin-5-yl

5-(methoxy-

1, 2,3,4- 2-fluoro, cartionyl-amino)-26 tetrazol-l-yl 3-chloro RAC H, H H, H S H pyridin-2-yl

1,2, 3,4- 2-fluoro, methyl, 2-chloro-6-amino-35 tetrazol-l-yl 3-chloro R* H, H methyl S H pyridin-3-yl

1, 2,3,4- 2-fluoro, methyl, 2-fluoro-6-amino-36 tetrazol-l-yl 3-chloro R* H, H methyl S H pyridin-3-yl

1, 2,3,4- 2-fluoro, methyl, 2-fluoro-6-amino-37 tetrazol-l-yl 3-chloro S* H, H methyl S H pyridin-3-yl

1, 2,3,4- 2-fluoro, methyl, 2-chloro-6-amino-38 tetrazol-l-yl 3-chloro S* H, H methyl S H pyridin-3-yl 4-(methoxy-

1, 2,3,4- 2-fluoro, carbonyl-amino)-40 tetrazol-l-yl 3-chloro S H, H H. H S H phenyl

4-(methoxy-

1, 2,3,4- 2-fluoro, carbonyl-amino)-41 tetrazol-l-yl 3-chloro R H, H H, H S H phenyl

1, 2,3,4- 2-fluoro, H, 5*- 2-fluoro-6-amino-44 tetrazol-l-yl 3-chloro R* H, H methyl S H pyridin-3-yl

1,2, 3, 4- 2-fluoro, H, R*- 2-fluoro-6-amino-45 tetrazol-l-yl 3-chloro R* H, H methyl S H pyridin-3-yl

1,2, 3,4- 2-fluoro, H, S*- 2-fluoro-6-amino-46 tetrazol-l-yl 3-chloro S* H. H methyl S H pyridin-3-yl

1, 2,3,4- 2-fluoro, H, 2-chloro-6-amino-47 tetrazol-l-yl 3-chloro RAC H. H methyl S H pyridin-3-yl

1,2, 3,4- 2-fluoro, H, 2-fluoro-6-amino-48 tetrazol-l-yl 3-chloro RAC H, H methyl S H pyridin-3-yl

1, 2,3,4- 2-fluoro, methyl, 2-chloro-6-amino-49 tetrazol-l-yl 3-chloro RAC H, H methyl S H pyridin-3-yl

1, 2,3,4- 2-fluoro, methyl, 2-fluoro-6-amino-50 tetrazol-l-yl 3-chloro RAC H, H methyl S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-(trifluoro-methyl)-51 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

1,2, 3,4- 2-fluoro, 2-chloro-6-amino-52 tetrazol-l-yl 3-chloro S H, H H. H S H pyridin-3-yl

1,2, 3,4- 2-fluoro, 2-(trifluoro-methyl)-53 tetrazol-l-yl 3-chloro S H. H H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-chlono-6-amino-54 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-3-yl

4-(methoxy-

1, 2,3,4- 2-fluoro, carbonyl-amino)-55 tetrazol-l-yl 3-chloro RAC H, H H, H S H phenyl

1,2, 3,4- 2-fluoro, 2-fluoro-6-amino-56 tetrazol-l-yl 3-chloro R H, H H, H R H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-fluoro-6-amino-57 tetrazol-l-yl 3-chloro S H, H H, H R H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-fluoro-6-amino-58 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-3-yl

1,2, 3,4- 2-fluoro, 2-fluoro-6-amino-59 tetrazol-l-yl 3-chloro S H, H H, H S H pyridin-3-yl

2,3-dihydro-

1, 2,3,4- 2-fluoro, [l,4]dioxino[2,3-61 tetrazol-l-yl 3-chloro R H, H H. H S H b]pyridin-8-yl

1, 2,3,4- 2-fluoro, lH-pyrrolo[2,3-62 tetrazol-l-yl 3-chloro R* H, H H, H S H blpyridin-4-yl

2-fluoro, 2-fluoro-6-amino-63 pyrazol-5-yl 3-chloro RAC H, H H, H S H pyridin-3-yl

4-(trifluoro- methyl)-

1,2,3-triazol- 2-fluoro, 7H-pyrrok)[2,3-65 1-yl 3-chloro RAC H, H H. H S H dlpyrimidin-5-yl 1, 2,3,4- 2-fluoro, 5-chloro-pyrazol-4-66 tetrazol-l-yl 3-chloro RAC H. H H, H S H yl

2-(methyl-suHonyl-

1, 2,3,4- 2-fluoro, amino)-3-fluoro-67 tetrazol-l-yl 3-chloro R* H, H H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-f1uora-6-(methyl-68 tetrazol-l-yl 3-chloro RAC H, H H, H S H amino)-pyridin-3-yl

1,2, 3,4- 2-fluoro, 2-fluoro-5-chloro-71 tetrazol-l-yl 3-chloro R H, H H. H S H pyridin-4-yl

1,2, 3,4- 2-fluoro, 2-amino-pyridin-4-72 tietrazol-l-yl 3-chloro R H. H H, H S chloro yl

7-methyl-5H-

1, 2,3,4- 2-fluoro, cyclopenta[b]pyridi74 tetrazol-l-yl 3-chloro RAC H. H H, H RAC H n-4-yl

1,2, 3,4- 2-fluoro, 7H-pyrrok)[2,3-79 tetrazol-l-yl 3-chloro R* H, H H. H S H d]pyrimidin-5-yl

1, 2,3,4- 2-fluoro, 2-amino-3-chk>ro-80 tetrazol-l-yl 3-chloro R H, H H, H S H pyridin-4-yl

5-methyl-lH-

1, 2,3,4- 2-fluoro, pyrrok)[2,3-81 tetrazol-l-yl 3-chloro RAC H, H H, H S H c]pyridin-3-yl

2-amino-3-

1,2, 3,4- 2-fluoro, methoxy-pyridin-4-82 tetrazol-l-yl 3-chloro S H, H H, H R* H yl

1, 2,3,4- 2-fluoro, 6-methyl-indolin-7-83 tetrazol-l-yl 3-chloro RAC H, H H, H S H yl-2-one

1, 2,3,4- 2-fluoro, 84 tetrazol-l-yl 3-chloro R H, H H, H S H 7-fluoro-indol-6-yl

4-(trifluoro- methyl)- l,2,34riazol- 2-fluoro, lH-pyrrolo[3,2-85 1-yl 3-chloro R* H, H H, H S H clpyridin-3-yl

2,3-

1,2, 3,4- 2-fluoro, dihydrofuro[2,3-86 tetrazol-l-yl 3-chloro R H, H H, H S H b]pyridin-4-yl

1, 2,3,4- 2-fluoro, thieno[3,2-87 tetrazol-l-yl 3-chloro R H. H H, H S H blpyridin-7-yl

6-methoxy-lH-

1,2, 3,4- 2-fluoro, pyrrok>[3,2-88 tetrazol-l-yl 3-chloro R H, H H, H S H c]pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-amino-pyridin-4-89 tetrazol-l-yl 3-chloro R H, H H, H S H yl

1, 2,3,4- 2-fluoro, 2-(ethyl-amino)-3-90 tetrazol-l-yl 3-chloro R H, H H, H S H fluoro-pyridin-4-yl eutero)

(R ⁷ )C

Ring Q No. R ¹ (R ² )» Stereo R ^A , R ^B RF, R ^D Stereo R ⁵ (R ⁶ )b

1, 2,3,4- 2-(hydroxy- tetrazol-1- 241uoro, deutero, deutero, methyl)-3-fluoro-

33 yl 3-chloro R deutero deutero S H pyridin-4-yl

1, 2,3,4- 2-(hydroxy-d2- tetrazol-1- 2-fluoro, methyl>3-fluoro-

36 yl 3-chloro R* H, H H, H S H pyridin-4-yl

1, 2,3,4- 2-(hydroxy- tetrazol-1- 241uoro, methyl)-3-fluoro-

47 yl 3-chloro R H, H H. H S H pyridin-4-yl

1, 2,3,4- 2-(hydroxy- tetrazol-1- 2-fluoro, methyl>3-fluoro-

48 yl 3-chloro S H, H H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro-4,5- tetrazol-1- 241uoro, dideutero-6- 31 yl 3-chloro R* H. H H, H R* deutero amino-pyridin-3-yl

1, 2,3,4- 2-fiuoro-4,5- tetrazol-1- 2-fluoro, dideutero-6- 32 yl 3-chloro R* H. H H, H S* deutero amino-pyridin-3-yl

1, 2,3,4- tetrazol-1- 241uoro, 2-fluoro-6-amino- 46 yl 3-chloro R H, H H. H S H pyridin-3-yl

O 2 R

(R )a ^c

R ^D

R ¹

O y 'NH

N.

R ⁵ ( A4— (R ⁷ ) _C

(R ⁶ )b (R ^A +R ^B = OXO)

© (R ⁷ )= No. R ¹ (R ² ). R ^C , R ^P Q Stereo R ⁵ (R ⁶ )b

1, 2,3,4- 2-fluoro, 3- 60 tetrazol-l-yl chloro H, H S* H 2-fluoro-6-amino-pyridin-3-yl No. R ¹ (R ² ), Stereo R* R ^B R ^C , R ^D Stereo R ⁵ (R ⁶ )b

1, 2,3,4- 2-fluoro, 2-fluoro-6-amino- 28 tetrazol-l-yl 3-chloro RAC H, H H, H RAC H □yridin-3-yl

(R ² ), CH ₃

R ^{1 0} /T

R ⁵ ( A4-(R ⁷ )C

(R®)b (Bridge methyl)

(R ⁷ )C

ID No. R ¹ (R ² )a Q Stereo R ⁵ (R ⁶ )b

1 ,2,3,4-tetrazol- 2-(hydroxy-methyl)-3-

391 1-yl 2-fluoro, 3-chloro S H fluoro-pyridin-4-yl

Table 2: Representative Compounds of Formula (I) (R ⁷ )e

Ring Q

ID No. R ¹ (R*k Stereo R ^c , R ^D Stereo R* (R ^e )b

1, 2,3,4- 2-fluoro, 2-(difluoro-methoxy>

3 tetrazol-1-yl 3-chloro RAC H, H S* fluoro pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(2-hydroxy-ethyl·

9 tetrazol-1-yl 3-chloro RAC H, H S* H oxy)-pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(difluoro-methoxy>-

10 tetrazol-1-yl 3-chloro RAC H, H S* H pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(hydroxy-methyl>

22 tetrazol-1-yl 3-chloro S H, H S H thiazol-4-yl

1, 2,3,4- 2-fluoro, 1H-pyrrolo[2,3-

32 tetrazol-1-yl 3-chloro R H, H S H blpyridin-4-yl

1, 2,3,4- 2-fluoro, 1H-pyrazolo[3,4-

38 tetrazol-1-yl 3-chloro R H, H S H blpyridin-4-vl

1, 2,3,4- 2-fluoro, 4-(hydroxy-methyl>

39 tetrazol-1-yl 3-chloro R H, H S H thiazol-2-yl

1, 2,3,4- 2-fluoro, 1H-pyrazolo[3,4-

41 tetrazol-1-yl 3-chloro R H, H S H blpyridin-5-yl

1, 2,3,4- 2-fluoro,

42 tetrazol-1-yl 3-chloro R H, H S H benzimidiazol-5-yl

1, 2,3,4- 2-fluoro,

43 tetrazol-1-yl 3-chloro R H, H S H indazol-5-yl

1, 2,3,4- 2-fluoro,

51 tetrazol-1-yl 3-chloro R H. H S H indazol-4-yl

1, 2,3,4- 2-fluoro, 2-(pyrazol-5-yl)-

66 tetrazol-1-yl 3-chloro RAC H, H S* fluoro pyridin-2-yl

1, 2,3,4- 2-fluoro, 2-(pyrazol-5-yl)-3-

115 tetrazol-1-yl 3-chloro R* H. H S H fluoro-pyridin-4-vl

2-fluoro,

1, 2,3,4- 3-chloro, 2-fluoro-5-deutero-6-

125 tetrazol-1-yl 4-deutero R H, H S H amino-pyridin-3-yl

2-fluoro,

1, 2,3,4- 3-chloro, 2-fluoro-6-amino-

153 tetrazol-1-yl 4-deutero R H, H S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-(cyano-methyl)-3-

176 tetrazol-1-yl 3-chloro R H, H S H fluoro-pyridin-4-yl

1, 2,3,4- 2-fluoro, 2-(methoxy-methyl)-

177 tetrazol-1-yl 3-chloro RAC H, H S H 3-fluoro-pyridin-4-vl

2-(2-hydroxy-2-

1, 2,3,4- 2-fluoro, methykn-propyl-oxy)-

190 tetrazol-1-yl 3-chloro R* H, H S* H 3-fluoro-pyridin-4-yl

4-(trifluoro- methyl> 2-(2-hydroxy-2-

1 ,2,3-triazol- 2-fluoro, methykn-propyl-oxy)-

191 1-yl 3-chloro R* H, H S* H 3-fluoro-pyridin-4-yl

4-(trifluoro- methyl> 2-(methyl-sulfbnyl-

1 ,2,3-triazol- 2-fluoro, amino-carbonyl)-3-

192 1-yl 3-chloro R H, H RAC H fluoro-thien-5-yl

4-chloro- 1 ,2,3-triazol- 2-fluoro,

193 1-yl 3-chloro RAC H, H S H 2-carboxy-th ien-5-yl 2-(hydroxy-d2-

1, 2,3,4- 2-fluoro, methyl)-3-fluoro-

194 tetrazol-1-yl 3-chloro R* H, H S* H pyridin-4-yl

4-(trifluoro- methyl>

1 ,2,3-triazol- 2-fluoro, 2-carboxy-3-fluoro-

195 1-yl 3-chloro R H, H S* H thien-5-yl

1, 2,3,4- 2-fluoro, 2-fluoro-4-(amino-

196 tetrazol-1-yl 3-chloro R H, H S H carbonvD-phenyl

1.2.3.4- 2-fluoro, 3-fluoro-4-(amino-

197 tetrazol-1-yl 3-chloro R H, H S H carbonyQ-phenyl

1, 2,3,4- 2-fluoro, 3-fluoro-4-(amino-

198 tetrazol-1-yl 3-chloro S H, H S H carbonyQ-phenyl

4-chloro- 1 ,2,3-triazol- 2-fluoro, 3-fluoro-pyridin-4-yl-

200 1-vl 3-chloro R H, H S H 2-one

4-(trifluoro- methyl>

1 ,2,3-triazol- 2-fluoro, 2-(amino-cartx)nyl>

202 1-yl 3-chloro S* H, H S chloro thien-5-yl

4-(trifluoro- methyl>

1 ,2,3-triazol- 2-fluoro, 2-(amino-cart»nyl>

203 1-vl 3-chloro R* H, H S chloro thien-5-yl

1, 2,3,4- 2-fluoro, 2-(amino-carbonyl)-

205 tetrazol-1-yl 3-chloro R* H, H S* H thiazol-5-yl

4-(trifluoro- methyl>

1 ,2,3-triazol- 2-fluoro, 2-(amino-carbonyl>

209 1-yl 3-chloro S* H, H S H thiazokS-yl

4-(trifluoro- methyl)- 1 ,2,3-triazol- 2-fluoro, 2-(amino-carbonyl>

210 1-vl 3-chloro R* H, H S H thiazoj-5-yl

1, 2,3,4- 2-fluoro, 2-(amino-cart)onyl)-

211 tetrazol-1-yl 3-chloro R* H, H S chloro thiazol-5-yl

1.2.3.4- 2-fluoro, 2-(amino-cartoonyl>3-

214 tetrazol-1-yl 3-chloro R H, H S H fluoro-thien-4-yl

1.2,3,4- 2-fluoro, 2-(amino-carbonyl>3-

215 tetrazol-1-yl 3-chloro S H, H S H fluoro-thien-5-yl

1.2,3,4- 2-fluoro, 2-(amino-carbonyl)-3-

216 tetrazol-1-yl 3-chloro R H. H S H fluoro-thien-5-yl

1.2,3,4- 2-fluoro, 2-(amino-cart)onyl>

218 tetrazol-1-yl 3-chloro RAC H, H S chloro thien-4-yl

1.2,3,4- 2-fluoro, 2-(amino-cait)onyl)-

219 tetrazol-1-yl 3-chloro RAC H, H S H thien-4-yl

4-(trifluoro- methyl>

1 ,2,3-triazol- 2-fluoro, 2-(amino-cartx)nyl>

220 1-yl 3-chloro R* H, H S H thien-4-yl

4-(trifluoro- methyO- 1 ,2,3-triazol- 2-fluoro, 2-(amino-cart»nyl>

221 1-yl 3-chloro S* H, H S H thien-4-yl

3-(trifluoro-methyl-

1, 2,3,4- 2-fluoro, carbonyl-amino)-

246 tetrazol-1-yl 3-chloro RAC H, H S H pyridin-4-yl 1-methyl-4-

(cyclopropyl-

1, 2,3,4- 2-fluoro, carbonyl-amino)-

247 tetrazol-1-yl 3-chloro S H, H S H pyrazol-5-yl

3-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino}-

248 tetrazol-1-yl 3-chloro RAC H, H S H thien-2-yl

3-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino)-

249 tetrazol-1-yl 3-chloro R* H, H S H pyridin-4-yl

3-(cyclopropyl-

1, 2,3,4- 2-fluoro, carbonyl-amino)-

250 tetrazol-1-yl 3-chloro S* H, H S H pyridin-4-yl

1, 2,3,4- 2-fluoro, 4-(ethoxy-carbonyl-

251 tetrazol-1-yl 3-chloro RAC H, H S H amino)-pyridin-3-yl

4-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino)-

252 tetrazol-1-yl 3-chloro RAC H, H S H pyridin-3-yl

1.2.3.4- 2-fluoro,

253 tetrazol-1-yl 3-chloro RAC H, H S H 4-amino-pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-(ethoxy-carbonyl-

254 tetrazol-1-yl 3-chloro R H, H S H amino)-pyridin-3-yl

1, 2,3,4- 2-fluoro, 1-methyl-(1,2,4-

255 tetrazol-1-yl 3-chloro RAC H, H S H triazol-3-yl)

3-(d3-methyl-

1.2.3.4- 2-fluoro, cart>onyl-amino)-

256 tetrazol-1-yl 3-chloro RAC H, H s H pyridin-4-yl

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonykaminol-S-

257 tetrazol-1-yl 3-chloro R H, H S H methoxy-phenyl

1-methyl-3-

(cyclopropyl-

1, 2,3,4- 2-fluoro, caibonyl-amino)-

259 tetrazol-1-yl 3-chloro RAC H, H S H pyrazol-4-yl

1.2.3.4- 2-fluoro, 2-(methy^amino>

260 tetrazol-1-yl 3-chloro RAC H, H S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-(ethoxy-carbonyl-

262 tetrazol-1-yl 3-chloro S H, H S H amino)-pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-(ethoxy-carbonyl-

263 tetrazol-1-yl 3-chloro s H, H S H amino)-pyridin-3-yl

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbony^amino)-4-

264 tetrazol-1-yl 3-chloro S H, H S H methoxy-phenyl

2-(cyclopropyl-

1, 2,3,4- 2-fluoro, carbonykamino)^

266 tetrazol-1-yl 3-chloro R* H, H S H methoxy-phenyl

4-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino}-

267 tetrazol-1-yl 3-chloro S H, H S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 4-(ethoxy-carbonyl-

268 tetrazol-1-yl 3-chloro S H, H S H amino)-pyridin-3-yl

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino)-5-

271 tetrazol-1-yl 3-chloro S H, H S H methoxy-phenyl

1, 2,3,4- 2-fluoro,

272 tetrazol-1-yl 3-chloro S H, H S H 4-amino-pyridin-3-yl 1, 2,3,4- 2-fluoro, 1-methyl-(1 ,2,4-

274 tetrazol-1-yl 3-chloro S H, H S H triazol-3-yl)

1-methyl-4-

(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino)-

275 tetrazol-1-yl 3-chloro S H, H S H pyrazol-5-yl

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino)-4-

276 tetrazol-1-yl 3-chloro RAC H, H S H methoxy-phenyl

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino)-5-

279 tetrazol-1-yl 3-chloro RAC H, H S H methoxy-phenyl

1, 2,3,4- 2-fluoro, H. S- 2-fluoro-6-amino-

285 tetrazol-1-yl 3-chloro RAC methoxy S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-(methyl-amino-

287 tetrazol-1-yl 3-chloro RAC H, H S H carbonyl)-phenyl

1.2.3.4- 2-fluoro, 2-(dimethyl-amino-

288 tetrazol-1-yl 3-chloro RAC H, H S H carbonyD-phenyl

1.2,3,4- 2-fluoro, 2-(amino-carbonyl)-

290 tetrazol-1-yl 3-chloro RAC H, H S H phenyl

1.2,3,4- 2-fluoro, 2-(methy^sulfonyl-

293 tetrazol-1-yl 3-chloro RAC H, H S H aminol-phenyl

1.2,3,4- 2-fluoro, 2-(isopropyloxy)-

294 tetrazol-1-yl 3-chloro RAC H, H S H phenyl

1.2,3,4- 2-fluoro, 2-(ethyl-carbonyl·

295 tetrazol-1-yl 3-chloro R* H, H S H amino)-phenyl

1.2.3.4- 2-fluoro, 2-(ethy^carbony^

296 tetrazol-1-yl 3-chloro S* H, H S H amino)-phenyl

1, 2,3,4- 2-fluoro, 2-(methoxy-carbonyl·

301 tetrazol-1-yl 3-chloro R* H, H S H amino)-phenyl

1.2,3,4- 2-fluoro, 2-(methoxy-carbonyl-

302 tetrazol-1-yl 3-chloro S* H, H S H aminol-phenyl

1, 2,3,4- 2-fluoro, 2-(isopropyl-cartoonyl·

305 tetrazol-1-yl 3-chloro R H, H S H amino)-phenyl

1, 2,3,4- 2-fluoro, 2-(methyl-carbonyl-

306 tetrazol-1-yl 3-chloro R H, H S H amino)-phenyl

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, cartwnyl-amino)-

307 tetrazol-1-yl 3-chloro R H, H S H phenyl

1, 2,3,4- 2-fluoro,

308 tetrazol-1-yl 3-chloro S* H, H S H 2-amino-phenyl

1, 2,3,4- 2-fluoro, benzoxazol-6-y^2-

309 tetrazol-1-yl 3-chloro S H, H S H one

1.2.3.4- 2-fluoro,

310 tetrazol-1-yl 3-chloro R* H, H S H 2-amino-phenyl

1, 2,3,4- 2-fluoro,

317 tetrazol-1-yl 3-chloro RAC H, H S H 2-methoxy-phenyl

1, 2,3,4- 2-fluoro, H, R- 2-fluoro-6-amino-

327 tetrazol-1-yl 3-chloro RAC methoxy S H pyridin-3-yl

1, 2,3,4- 2-fluoro, 2-(isopropyl-cartoonyl·

329 tetrazol-1-yl 3-chloro RAC H, H S H aminoj-phenyl

2-(cyclopentyl·

1, 2,3,4- 2-fluoro, carbonyl-amino)-

330 tetrazol-1-yl 3-chloro RAC H, H S H phenyl

1, 2,3,4- 2-fluoro,

331 tetrazol-1-yl 3-chloro RAC H. H S H 1 ,2,4-triazol-3-yl 1, 2,3,4- 2-fluoro,

332 tetrazol-1-yl 3-chloro RAC H, H S H I^.S-triazokS-yl

1, 2,3,4- 2-fluoro,

333 tetrazol-1-yl 3-chloro RAC H, H S H imidazol-2-yl

1, 2,3,4- 2-fluoro, 1 -methyl-imidazol-2-

334 tetrazol-1-yl 3-chloro RAC H, H S H yl

1, 2,3,4- 2-fluoro, 1 -methyl-1 ,2,3-

339 tetrazol-1-yl 3-chloro RAC H, H S H triazol-5-yl

1, 2,3,4- 2-fluoro, 3-fluoro-4-carboxy-

342 tetrazol-1-yl 3-chloro RAC H, H S H phenyl

2-fluoro, 2-fluoro-6-amino-

364 imidazol-5-yl 3-chloro RAC H, H S H pyridin-3-yl

2-(cyclopropyl·

1.2,3,4- 2-fluoro, carbonyl-amino)-

369 tetrazol-1-yl 3-chloro R* H, H S H phenyl

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino}-

370 tetrazol-1-yl 3-chloro RAC H, H S H phenyl

4-(trifluoro- methyl)- 1 ,2,3-triazol-

373 1-yl 2-chloro RAC H. H RAC H 2-carboxy-th ien-5-y I methyl)

(R ⁷ )C

Ring Q

ID No. R ¹ (R ³ )» Stereo R ^c , R ^D Stereo R® (R ^e )b

2-(cyclopropyl·

1, 2,3,4- 2-fluoro, carbonyl-amino}-

298 tetrazol-1-yl 3-chloro R* H, H s H phenyl

2-(cyclopropyl·

1.2.3.4- 2-fluoro, cart>onyl-amino)-

304 tetrazol-1-yl 3-chloro S* H, H S H phenyl

As used herein, the symbol or notation shall denote the presence of a stereogenic center.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. It is further understood that atropisomers (a specific type of stereoisomer resulting from steric or other hinderances to rotation) are also encompassed within the scope of the present invention.

Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer or stereoisomer, the diastereomer or stereoisomer is present at a diastereomeric or stereoisomeric excess of greater than or equal to about 80%, more preferably, at a diastereomeric or stereoisomeric excess of greater than or equal to about 90%, more preferably still, at a diastereomeric or stereoisomeric excess of greater than or equal to about 95%, more preferably still, at a diastereomeric or stereoisomeric excess of greater than or equal to about 98%, most preferably, at a diastereomeric or stereoisomeric excess of greater than or equal to about 99%.

In some embodiments, the present invention is directed to compounds of formula (I), compounds of formula (II), compounds of formula (III) and / or compounds of formula (IV) in an enantiomeric excess of one of the R- or S- enantiomers (at the R ³ stereocenter denoted with the “*”). In some embodiments of the present invention, the compound of formula (I) is present in an enantiomeric excess of one of the R- or S- enantiomers (at the R ³ stereocenter denoted with the “*”) 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), compounds of formula (II), compounds of formula (III) and / or compounds of formula (IV) is present in an enantiomeric excess of one of the R- or S- enantiomers (at the R ³ stereocenter denoted with the 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%.

In some embodiments, the present invention is directed to compounds of formula (I), compounds of formula (II), compounds of formula (III) and / or compounds of formula (IV) in a diastereomeric or stereoisomeric excess of one of the possible diastereomers or stereoisomers. In some embodiments of the present invention, the compound of formula (I), compounds of formula (II), compounds of formula (III) and / or compounds of formula (IV) is present in a diastereomeric or stereoisomeric 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), compounds of formula (II), compounds of formula (III) and / or compounds of formula (IV) is present in a diastereomeric or stereoisomeric 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%.

Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

As used herein, unless otherwise noted, the term “isotopologues” shall mean molecules that differ only in their isotopic composition. More particularly, an isotopologue of a molecule differs from the parent molecule in that it contains at least one atom which is an isotope (i.e. has a different number of neutrons from its parent atom). For example, isotopologues of water include, but are not limited to, "light water" (HOH or HaO), "semi-heavy water" with the deuterium isotope in equal proportion to protium (HEX) or ¹ H ² HO), “heavy water” with two deuterium isotopes of hydrogen per molecule (cfe O or ² H20), "super-heavy water' ¹ or tritiated water (T2O or ³ H20), where the hydrogen atoms are replaced with tritium ( ³ H) isotopes, two heavy-oxygen water isotopologues (H2 ¹⁸ 0 and H2 ¹⁷ 0) and isotopologues where the hydrogen and oxygen atoms may each independently be replaced by isotopes, for example the doubly labeled water isotopologue cfe ¹⁸ 0.

It is intended that within the scope of the present invention, any one or more element(s), in particular when mentioned in relation to a compound of formula (I), shall comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an 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 respectively ¹² C, ¹³ C and ¹⁴ C and ¹⁶ 0 and ¹⁸ 0. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise one or more radioactive isotope(s) selected from the group of ³ H, ¹¹ C, ¹⁸ F, ¹²² l, ¹²³ l, ¹²⁵ l, ¹³¹ l, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br and ⁸² Br. Preferably, the radioactive isotope is selected from the group of ³ H, ¹¹ C and ¹⁸ F.

As used herein, unless otherwise noted, the term “isotopomer” shall mean isomers with isotopic atoms, having the same number of each isotope of each element but differing in their position. Isotopomers include both constitutional isomers and stereoisomers solely based on isotopic location. For example, CHsCHDCHsand CH3CH2CH2D are a pair of constitutional isotopomers of n-propane; whereas (R)-CH3CHDOH and (^-CHsCHDOH or (Z)-CH3CH=CHD and (£)-CH3CH=CHD are examples of isotopic stereoisomers of ethanol and n-propene, respectively.

One skilled in the art will recognize that wherein the compound of formula (I) R ⁴ and R ⁵ are each hydrogen, then the compound of formula (I) may exist as any one or any mixture of its corresponding tautomers (i.e. structural isomers of that may readily interconvert), as shown below

One 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 of or any mixture of its corresponding tautomers. The present invention is intended to encompass any compound described herein, present in any of its corresponding tautomeric forms, or as a mixture of its tautomeric forms.

It is intended that the present invention includes the compounds described herein, including all isomers thereof (including, but not limited to stereoisomers, enantiomers, diastereomers, tautomers, isotopologues, atropisomers, and the like).

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-(Ci- Cealkylene)-amino-carbonyl-(Ci-Cealkylene)-" substituent refers to a group of the formula

Jl^^Cr-Ce alkylene)— / ^™" S

-|-(Ci-C _e alkylene H

As used herein, unless otherwise noted, the term “isolated form” shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment. In an embodiment of the present invention, the compound of formula (I), compound of formula (II), compound of formula (III) or compound of formula (IV) is present in an isolated form.

As used herein, unless otherwise noted, the term “substantially pure form” shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment of the present invention, the compound of formula (I), compound of formula (II), compound of formula (III) or compound of formula (IV) is present as a substantially pure form.

As used herein, unless otherwise noted, the term “substantially free of a corresponding salt form(s)” when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt fbrm(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent In an embodiment of the present invention, the compound of formula (I), compound of formula (II), compound of formula (III) or compound of formula (IV) is present in a form which is substantially free of corresponding salt form(s). 2. General Synthesis Schemes

Compounds of formula (I) of the present invention may be prepared as described in the general synthesis schemes and Examples herein, selecting and substituting suitable reagents and conditions, as would be well within the skill of persons versed in the art. Additionally, the preparation of any starting materials used in the schemes and synthesis examples which follow herein is well within the skill of persons versed in the art.

One skilled in the art will further recognize that by selecting and substituting suitable starting reagent(s) (and then following or applying the processes described in the General Synthesis Schemes and Examples which follow herein) the compound of formula (I) (and any intermediates, such as the compound of formula (M1)) may be prepared as a racemate, may be prepared as a racemate and then separated into its corresponding stereo-isomers (according to known methods, for example, chiral separation or SFC), or may be prepared as a stereo-isomerically enriched or pure stereo-isomer.

Intermediates in the synthesis of the compounds of formula (I) of the present invention include compounds of formula (M1)

R ^A R ^B RC

O, R ^D rT A ¹ (M1). wherein A ¹ is selected from Ci-<alkyl, preferably methyl or ethyl. Some compounds of formula (M1) are known or may be prepared according to known methods, as would be recognized by those skilled in the art.

Compounds of formula (M1) may be prepared for example, as described in Scheme 1, below.

Scheme 1

Accordingly, a suitably substituted compound of formula (V), wherein A ¹ is Ci-*alkyl, preferably methyl or ethyl, and wherein PG ¹ is a suitably selected nitrogen protecting group such as Boc, Benzyl, PMB, and the like, a known compound or compound prepared by known methods (for example, as described in the Examples which follow herein), is reacted with SUPER- HYDRIDE® (1.0M Lithium triethylborohydride in THF), a known solution; in a suitably selected solvent such as THF, 1,4-dioxane, and the like; at a reduced temperature, for example at about -78°C; and then reacted with a suitably selected catalyst such as p-TsOH, and the like; in a suitably selected solvent such as MeOH, and the like; to yield the corresponding compound of formula

(VI).

The compound of formula (VI) is reacted with a suitably substituted compound of formula (VII) (for example wherein R ^A and R ^B are each hydrogen then the compound of formula (VII) is allyltrimethylsilane), a known compound; in the presence of a suitably selected Lewis acid such as BF3*EbO, TiCL, and the like; in a suitably selected solvent such as diethyl ether, THF, DCM, and the like; at a reduced temperature, for example at about -40°C; to yield the corresponding compound of formula (VIII).

The compound of formula (VIII) is de-protected according to known methods; to yield the corresponding compound of formula (IX). For example, the compound of formula (VIII) may be reacted with a suitably selected acid such as HCI; in a suitably selected solvent such as 1,4-dioxane.

The compound of formula (IX) is reacted with acryloyl chloride, a known compound; in the presence of a suitably selected organic amine base such as TEA, pyridine, DIEA, and the like; in a suitably selected solvent such as THF, DCM, DMF, and the like; at a reduced temperature, for example at about - 78°C; to yield the corresponding compound of formula (X).

The compound of formula (X) is reacted with a suitably selected catalyst such as Grubb’s 2 ^nd Generation Catalyst, Grubb’s 3 ^rd Generation Catalyst, and the like; in a suitably selected solvent such a DCM, THF, toluene, and the like; at an elevated temperature, for example at about 45°C; to yield the corresponding compound of formula (XI).

The compound of formula (XI) is reacted with a suitably selected hydroboronating agent such as bis(pinacolato)diboron, and the like; in the presence of a suitably selected copper reagent such as CuCI, and the like; in the presence of a suitably selected ligand such as BINAP, and the like; in the presence of a suitably selected base such a NaOt-Bu, and the like; in a suitably selected solvent or mixture of solvents, such as a mixture of THF and methanol, and the like; and then reacted with peroxide such as 30% H2O2, to yield the corresponding compound of formula (XII).

The compound of formula (XII) is reacted with a suitably selected oxidizing agent such as PCC, Dess-Martin periodonane (DMP), and the like; in a suitably selected solvent such as DCM, EtOAc, and the like; to yield the corresponding compound of formula (M1).

Compounds of formula (M1) may alternatively be prepared as described in Scheme 2, below.

Scheme 2

Accordingly, a suitably substituted compound of formula (VIII), prepared for example as described in Scheme 1 above, is reacted with a suitably selected oxidizing agent or system such as a mixture of OsO< and NalO*, O3, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF and water, DCM, and the like; at about room temperature; to yield the corresponding compound of formula (XIII).

The compound of formula (XIII) is reacted with ethyl acetate, a known compound; in the presence of a suitably selected base such as LiHMDS, UN(Pr-i)2, NaOEt, and the like; in a suitably selected solvent such as THF, toluene, EtOAc, and the like; at a reduced temperature, for example at about - 78°C; to yield the corresponding compound of formula (XIV).

The compound of formula (XIV) is reacted with a suitably selected oxidizing agent such as Dess-Martin periodonane (DMP), PCC, a mixture of DMSO/(COCI)2, and the like; in a suitably selected solvent such as DCM, EtOAc, and the like; at about room temperature; to yield the corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably selected add such as HCI, TFA, and the like; in a suitably selected solvent such as 1,4- dioxane, THF, DCM, and the like; and then reacted with a suitably selected base such as NaHCOa, NazCOa, K2CO3, and the like; in a suitably selected solvent such as toluene, xylene and the like; at an elevated temperature, for example, at about 110°C; to yield the corresponding compound of formula

(M1).

One skilled in the art will recognize that although the processes of Scheme 1 and 2 above describe the preparation of racemic mixtures of the compound of formula (M1), said processes may also be used to prepared spedfic stereo-isomer(s), by either using a stereo-isomerically enriched starting material, or by separating the prepared racemic mixture of the compound of formula (M1) and isolating the corresponding stereo-isomers, according to known methods, for example by chiral separation, SFC, and the like.

Some compounds of formula (M1), for example compounds of formula (M1) wherein R ^A , R ^B , R ^c , R ^D and R ^E are each hydrogen, may alternatively be prepared as described in Scheme 3, below. Scheme 3

Accordingly, a suitably substituted compound of formula (V), a known compound or compound prepared by known methods is reacted with ethyl acetate, a known compound; in the presence of a suitably selected base such as LiHMDS, UN(Pr-i)2, NaOEt, and the like; in a suitably selected solvent such as THF, PhMe, EtOH, and the like; at a reduced temperature, for example at about -78°C; to yield the corresponding compound of formula (XVI).

The compound of formula (XVI) is reacted with a suitably selected organic base such as TFA, HCI and the like; to effect de-protection and ring closure; to yield the corresponding compound of formula (XVII).

The compound of formula (XVII) is reacted with H2; in the presence of a suitably selected catalyst such as Pt02, Pd, Ni, Pd(OH)2, and the like; in a suitably selected solvent such as HOAc, EtOH, DCM, and the like; to yield the corresponding compound of formula (XVIII).

The compound of formula (XVIII) is reacted with ethyl 3-chloro-3- oxopropanoate, a known compound; in the presence of a suitably selected organic amine base such as DIPEA, TEA, pyridine, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (XIX).

The compound of formula (XIX) is reacted with a suitably selected base such as NaOEt, NaOMe, NaH, and the like; in a suitably selected solvent such as EtOH, MeOH, DMF, and the like; to yield the corresponding compound of formula (XX).

The compound of formula (XX) is reacted with a suitably selected reagent such as oxalic acid in water, 10% water in AcOH, HCI in water (at pH~2) or a mixture of ACN/water; at an elevated temperature, for example, at about 110°C; to yield the corresponding compound of formula (M1a).

One skilled in the art will recognize that although the process of Scheme 3 above describes the preparation of a particular stereo-isomer of the compound of formula (M1), the process of Scheme 3 may also be used to prepared racemic mixtures and alternate specific stereo-isomer(s) of the compound of formula (M1), by either using a suitably selected racemic or stereo-isomerically enriched starting material, or by preparing a racemate of the compound of formula (M1) and then isolating the corresponding stereo-isomers according to known methods, for example by chiral separation, SFC, and the like.

Suitably substituted compounds of formula (M1) may be reacted as described in the Schemes and Examples which follow herein, to yield the compounds of formula (I) of the present invention.

Some compounds of formula (I) wherein R ⁴ is hydrogen, and R ⁵ is hydrogen may be prepared as described in Scheme 4, below.

Scheme 4

Accordingly, a suitably substituted compound of formula (M1b), wherein A ¹ is Ci-talkyl, preferably methyl or ethyl, prepared for example as described herein, is reacted with a suitably selected oxygen protecting reagent such as 1,1,1 -trifluoro-N-phenyl-N-((trifluoromethyl)sulfony I) methanesulfonamide, trifluoromethanesulfonic anhydride, and the like; in the presence of a suitably selected organic amine base such as TEA, pyridine, DIEA, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (XXI), wherein PG ² is the corresponding oxygen protecting group.

The compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXII), and wherein -B(OR)2 is for example, -B(OH)2, - O

B(OCH ₃ )2, , and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as Pd(dppf)Cb, Pd(PPh3)4, Pd(OAc)z, and the like; in the presence of a suitably selected base such as K2CO3, CS2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of 1 ,4-dioxane and water, DMF, toluene/water, and the like; at an elevated temperature, such as about 80°C; to yield the corresponding compound of formula (XXIII).

The compound of formula (XXII) is reacted with a suitably substituted compound of formula (XXIII), wherein LG ¹ is a suitably selected leaving group such as Cl, Br, I, and the like, a known compound, compound prepared by known methods, or compound prepared as described in the Examples which follow herein; in the presence of a suitably selected base such as CS2CO3, K2CO3, NaaCOs, and the like; in a suitably selected solvent such as DMF, ACN, 1 ,4-dioxane, and the like; at about room temperature; to yield the corresponding compound of formula (XXIV).

The compound of formula (XXIV) is reacted with a suitably selected reagent such as NhUOAc and the like; in the presence of a suitably selected acid such as AcOH, and the like; in a suitably selected solvent such as toluene, xylene, and the like; at an elevated temperature, for example at about 110°C; to yield the corresponding compound of formula (la).

Compounds of formula (I) wherein R ⁵ is halogen may be prepared from the corresponding compound of formula (la), by reacting with a suitably selected halogenating agent such as NCS (for chloro), NBS (for bromo), NIS (for iodo), Selectfluor (for fluoro), and the like, in a suitably selected solvent such as DCM, DCE, ACN, THF, Et20, and the like.

Compounds of formula (I) wherein R ⁵ is Ci^alkyl may be similarly prepared as described in Scheme 4 above, by reacting the compound of formula (XXII) with a suitably substituted analog of the compound of formula (XXIII), such as a compound of formula (XXIII-ALT) and then reacting the resulting intermediate to effect ring closure as described in Scheme 4.

One skilled in the art will recognize that although Scheme 4 describes the preparation of a specific stereoisomer of the compound of formula (I), the processes describe therein may be applied to the preparation of racemic mixtures and alternate stereo-isomers of the compounds of formula (I). Said racemates and / or alternate stereoisomers may be prepared by either using a suitably selected racemic or stereo-isomerically enriched starting material, or by preparing a racemate of the desired compound of formula (I) and then isolating the corresponding stereo-isomers according to known methods, for example by chiral separation, SFC, and the like.

Compounds of formula (I) wherein R ¹ is 1,2,3,4-tetrazoM-yl may alternatively be prepared from the corresponding compound of formula (la) where R ¹ is Nhb, as described in Scheme 5, below.

(R ² )a

(R ² )a· L > ^RB UR ^D

NH ₂ Li R

< , ^N N ^E

O z ~NH N-N

(R ⁷ )C

(R ⁷ )=

(lb) A

(R ⁶ )b (lc)

(R®)b

Scheme 5

Accordingly, a suitably substituted compound of formula (lb), prepared for example as described in Scheme 4 above, is reacted with a suitably selected reagent such as TMSNs, NaNa, and the like; in the presence of trimethoxymethane, and the like; in a suitably selected solvent such as AcOH, and the like; at an elevated temperature, for example at about 80°C; to yield the corresponding compound of formula (lc).

Compounds of formula (I) wherein R ¹ is 1,2,3,4-tetrazol-1-yl may alternatively be prepared by reacting a compound of formula (XXII) wherein R ¹ is NH2, a compound of formula (XXIIa)

(R ² )a R°

NH ₂

(XXI la) with a suitably reagent such as TMSNa, NaNa, and the like; in the presence of trimethoxymethane and the like; in a suitably selected solvent such as AcOH and the like; at an elevated temperature, for example at about 80°C; as described Scheme 5, above; to yield the corresponding compound of formula (XXV) (xxv); which compound of formula (XXV) is then substituted for the compound of formula (XXII) in Scheme 4 above, and reacted as described therein; to yield the corresponding compound of formula (lc).

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

Scheme s

Accordingly, a suitably substituted compound of formula (M1b), wherein A ¹ is Ci-*alkyl, preferably methyl or ethyl, a known compound or compound prepared as described in the Schemes and Examples herein, is reacted with a suitably selected oxygen protecting reagent such as 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide, trifluoromethanesulfonic anhydride, and the like; in the presence of a suitably selected organic amine base such as TEA, pyridine, DIEA, and the like; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula (XXI), wherein PG ² is the corresponding oxygen protecting group.

The compound of formula (XXI) is reacted with bis(pinacolato)diboron, a known compound; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2, Pd(PPha)4, Pd(OAc)2, and the like; in the presence of a suitably selected base such as KOAc, potassium ethylhexanoate (n-BuCH(Et)C02K), and the like; in a suitably selected solvent or mixture of solvents such as a mixture of 1 ,4-dioxane and water, DMF, toluene/water, and the like; at an elevated temperature, such as about reflux temperature; to yield the corresponding compound of formula (XXVI).

The compound of formula (XXVI) is reacted with a suitably substituted compound of formula (XXVII), wherein LG ² is a suitably selected leaving group such as I, Br, Cl, OTf, and the like, a known compound, compound prepared by known methods, or compound prepared as described in the Examples which follow herein; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2, Pd(PPh3)4, Pd(OAc)2, and the like; in the presence of a suitably selected base such as K2CO3, CS2CO3, K3PO4, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of 1,4-dioxane and water, DMF, toluene/water, and the like; at an elevated temperature, for example reflux temperature; to yield the corresponding compound of formula (XXII).

One skilled in the art will recognize that although Scheme 6 describes the preparation of a specific stereoisomer of the compound of formula (XXII), the processes describe therein may be applied to the preparation of racemic mixtures and alternate stereo-isomers of the compounds of formula (XXII). Said racemates and / or alternate stereoisomers may be prepared by either using a suitably selected racemic or stereo-isomerically enriched starting material, or by preparing a racemate of the compound of formula (XXII) and then isolating the corresponding stereo-isomers according to known methods, for example by chiral separation.

Compounds of formula (XXII) wherein R ¹ is 4-trifluoromethyl-1 ,2,3- triazol-1-yl may alternatively be prepared as described in Scheme 7, below.

Scheme 7

Accordingly, a suitably substituted compound of formula (XXIIa) wherein R ¹ is NH2, prepared for example as described in the Schemes and Examples herein, is reacted with a suitably selected agent such as TMSNa, NaNs, and the like; in the presence of a suitably selected agent such as t-butyl nitrite, NaNOa/HCI, and the like; in a suitably selected solvent such as acetonitrile, EtOH, heptane, and the like; at about 0 °C to room temperature; to yield the corresponding compound of formula (XXVIII).

The compound of formula (XXVIII) is reacted with 4,4,4-trifluorobut-2- ynoic add, a known compound; in the presence of a suitably selected agent such as CU2O, CuCI, and the like; in a suitably selected solvent such as acetonitrile, DCM, and the like; at an elevated temperature, for example at about reflux temperature; to yield the corresponding compound of formula (XXIIb).

One skilled in the art will recognize that the compound of formula (XXI lb) may then be further substituted for the compound of formula (XXII) in Scheme 4 above, and reacted as described therein, to yield the corresponding compound of formula (I) wherein R ¹ is 4-trifluoromethyl-1 ,2,3-triazol-1-yl. One skilled in the art will further recognize that compounds of formula (I) wherein R ¹ is 4-trifluoromethyl-1 ,2,3-triazol-1-yl may alternatively be prepared by substituting a suitably substituted compound of formula (la) wherein R ¹ is NH2, for the compound of formula (XXII) in Scheme 7 above, and reacting as described therein.

One skilled in the art will further recognize that although Scheme 7 describes the preparation of a racemate of the compound of formula (XXIIb), the processes describe therein may be applied to the preparation of specific stereo-isomers of the compounds of formula (XXIIb). Said alternate stereoisomers may be prepared by either using a suitably selected stereo- isomerically enriched starting material, or by preparing the racemic compound and then isolating the corresponding stereo-isomers according to known methods, for example by chiral separation, SFC, and the like.

Some compounds of formula (I) may alteratively be prepared as describe in Scheme 8, below.

Scheme 8

Accordingly, a suitably substituted compound of formula (XXII), prepared for example as described in the Schemes and Examples herein, is reacted with a suitably selected agent such as DABAL, BH3*Me2S, and the like; in a suitably selected solvent such as DCM, THF, and the like; at a reduced temperature, for example at -78°C; to yield the corresponding compound of formula (XXIX).

The compound of formula (XXIX) is reacted with a suitably selected agent such as ΝΗ3·Η2θ, and the like; in the presence of a suitably selected agent such as glyoxal, and the like; in a suitably selected solvent such as methanol and the like; at about room temperature; to yield the corresponding compound of formula (XXX).

The compound of formula (XXX) is reacted with a suitably selected source of iodine such as NIS, la, and the like; in a suitably selected solvent such as DCM, and the like; at about room temperature; and then reacted with a suitably selected agent such as NaaSOs, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of ethanol/water, and the like; at an elevated temperature, for example at about 95°C; to yield the corresponding compound of formula (XXXI).

The compound of formula (XXXI) is reacted with a suitably substituted compound of formula (XXXII), a known compound, compound prepared by known methods, or compound prepared as described herein, where BPin is bis(pinacolate)diboron; in the presence of a suitably selected palladium catalyst such as Pd(dppf)Cl2, Pd(PPh3>4, and the like; in the presence of a suitably selected base such as K2CO3, CsaCOs, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of 1 ,4-dioxane/water, toluene/water, and the like; at an elevated temperature, for example at reflux temperature; to yield the corresponding compound of formula (la).

One skilled in the art will recognize that in the process as described in Scheme 8 above, wherein the compound of formula (XXII) R ¹ is NHa, said NHa group is preferably protected with a suitably selected nitrogen protecting group (for example, BOC, and the like), and subsequently, at the appropriate point in the synthesis, de-protected. One skilled in the art will further recognize that the synthesis as described in Scheme 8 may be modified at any appropriate step to effect conversion of any (intermediate or final) compound wherein R ¹ is NHa to the corresponding compound wherein R ¹ is for example a 1 ,2,3,4-tetrazol-1-yl, 4-trifluoromethyl-1,2,3-trazol-1-yl, etc. applying reaction steps and conditions as described in the Schemes and Examples herein. One skilled in the art will forther recognize that although Scheme 8 describes the preparation of a specific stereoisomer of the compound of formula (la), the processes describe therein may be applied to the preparation of racemic mixtures and alternate stereo-isomers of the compounds of formula (la). Said racemates and / or alternate stereoisomers may be prepared by either using a suitably selected racemic or stereo-isomerically enriched starting material, or by preparing a racemate of the compound of formula (la) and then isolating the corresponding stereo-isomers according to known methods, for example by chiral separation, SFC, and the like.

Compounds of formula (XXIII) are known compounds, compound which may be prepared by known methods, and / or compounds which may be prepared as described herein. Compounds of formula (XXIII) wherein LG ² is for example bromo, may be prepared as described in Scheme 9, below.

Scheme 9

Accordingly, a suitably substituted compound of formula (XXXIII), wherein LG ³ is a suitably selected leaving group such as Br, I, OTf, and the like, a known compound or compound prepared by known methods is reacted with dibutyl(1-ethoxyvinyl)(pentyl)stannane, a known compound; in the presence of a suitably selected coupling agent such as Pd(dppf)Cl2,

Pd(PPh3)Cl2, Pd(PPhs)4, and the like; in a suitably selected solvent such as 1,4-dioxane, toluene, and the like; at an elevated temperature, for example at about 90-100°C; to yield the corresponding compound of formula (XXXIV). The compound of formula (XXXIV) is reacted with a suitably selected source of bromine such as NBS, HBr, ΒΓ2, pyridine-HBr, and the like; in a suitably selected solvent or mixture of solvents such as a mixture of THF/water, DCM, 1,4-dioxane/water, and the like; at about room temperature; to yield the corresponding compound of formula (XXIIIa). One skilled in the art will recognize that wherein the source of bromine is for example a mixture of HBr and Brc, pyridine· HBr, and the like; then the reaction of the compound of formula (XXXIV) with the source of bromine is completed in the presence of a suitably selected acid such as AcOH, and the like. Compounds of formula (XXIII) wherein LG ¹ is I, may be similarly prepared by reacting a suitably substituted compound of formula (XXXIV) with a suitably selected source of iodine, according to known methods.

Alternatively, the compound of formula (XXXIII), wherein LG ³ is -C(0)CI, a known compound or compound prepared by known methods, is reacted with a suitably selected agent such as trimethylsilyldiazomethane (TMSCHN2), and the like; in a suitably selected solvent such as acetonitrile, and the like; and then reacted with a suitably selected source of bromine such a HBr/water, Bra, MBS, and the like; at about room temperature; to yield the corresponding compound of formula (XXIIIa).

One skilled in the art will recognize that any substituent group(s) and / or

(R ² )a -Q* any portion(s) of a substitution group(s) (for example, R ¹ , R ¹ , Q, , etc.) may be incorporated into the desired compound of formula (I) in any order, by applying the appropriate reaction steps in the desired order (for example, reaction steps under reaction conditions described in the Schemes and Examples herein).

One skilled in the art will further recognize that various substituent groups and / or functional groups on said substituent groups (for example -OH, -NHz, etc.) may be protected prior to any reaction step described above, and then de-protected at a later step in the synthesis, as would be desirable or necessary, according to methods well known to those skilled in the art. One 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 may be prepared as a racemate or a stereo-isomerically enriched compound, by selecting and substituting suitable stereoisomers into the processes described herein, or by preparing a racemic mixture and then isolating the stereoisomers according to known methods, for example by chiral separation, SFC, and the like.

As more extensively provided in this written description, terms such as “reacting” and “reacted” are used herein in reference to a chemical entity that is any one of: (a) the actually recited form of such chemical entity, and (b) any of the forms of such chemical entity in the medium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product. One skilled in the art will further recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class/tvoe (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same of different from each other. For example, wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.

Further, one skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

One skilled in the art will further recognize that the reaction or process step(s) as herein described are allowed to proceed for a sufficient period of time until the reaction is complete, as determined by any method known to one skilled in the art, for example, chromatography (e.g. HPLC). In this context a “completed reaction or process step” shall mean that the reaction mixture contains a significantly diminished amount of the starting material(s) / reagent(s) and a significantly reduced amount of the desired product(s), as compared to the amounts of each present at the beginning of the reaction.

To provide a more concise description, some of the quantitative expressions found herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity found herein is meant to refer to the actual value, and it is also meant to refer to the approximation to such value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such value.

To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.

Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided in the detailed descriptions which follow herein. One skilled in the art will recognize that the listing of said examples is not intended, and should not be construed, as limiting in any way the invention set forth in the claims which follow thereafter.

As used herein, unless otherwise noted, the term “leaving group” shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

As used herein, unless otherwise noted, the term “nitrogen protecting group” shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates - groups of the formula -C(0)0-R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, Chi2=CH- CH2-, and the like; amides - groups of the formula -C(0)-R’ wherein R’ is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives - groups of the formula -SGz-R” wherein R” is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4- methoxybenzene, and the like. Other suitable nitrogen protecting groups may be measured in texts such as T.W. Greene & P.G.M. Wilts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protecting group” shall mean a group which may be attached to an oxygen atom to protect said oxygen atom from participating in a reaction and which may be readily removed following the reaction. Suitable oxygen protecting groups include, but are not limited to, acetyl, benzoyl, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like. Other suitable oxygen protecting groups may be measured in texts such as T.W. Greene & P.G.M. Wilts, Protective Groups in Organic Synthesis. John Wiley & Sons, 1991.

Where the processes for the preparation of the compounds according to the invention yield rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active add, such as (-)-di-p-toluoyl-D-tartaric add and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alteratively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determine percent enantiomeric excess (%ee). The enantiomeric excess may be calculated as follows

[ (Rmoles-Smoles)/(Rmoles+Smoles) ] X 100% where Rmoles and Smoles are the R and S mole fractions in the mixture such that Rmoles+Smoles = 1. The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows: ee = ([a-obs] / [a-max]) X 100.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

3. Utility

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 factor Xla and / or plasma kallikrein activity is implicated.

In some embodiments, the present invention is directed to methods for the treatment and/or prophylaxis of a thromboembolic disorder comprising administering to a patient in need of such treatment and / or prophylaxis a therapeutically effective amount of a least one of the compounds as described herein, or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.

As used herein, the term “thromboembolic disorders” includes arterial cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation. The term “thromboembolic disorders” as used herein also includes specific disorders selected from, but not limited to, unstable angina or other acute coronary syndromes, atrial fibrillation, first or 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. The 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, and vessel grafts. The procedures include, but are not limited to: cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In some embodiments, the term “thromboembolic disorders” includes acute coronary syndrome, stroke, deep vein thrombosis, and pulmonary embolism. In some embodiments, the “thromboembolic disorders” include hereditary angioedema (HAE) and diabetic macular edema (DME).

In some embodiments, the present invention is directed to methods for the treatment and/or prophylaxis of an inflammatory disorder comprising: administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof. Examples of the inflammatory disorders include, but are not limited to, sepsis, acute respiratory distress syndrome, and systemic inflammatory response syndrome.

In some embodiments, the present invention is directed to methods for the treatment and / or prophylaxis of a disease or condition in which plasma kallikrein activity is implicated, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof. The diseases or conditions in which plasma kallikrein activity is implicated include, but are not limited to, impaired visual acuity, 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.

In some embodiments, the present invention provides a method for treating the primary prophylaxis of a thromboembolic disorder. In some embodiments, the present invention provides a method for the primary prophylaxis of a thromboembolic disorder wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, 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 provides a method for the primary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, venous thrombosis, and thrombosis resulting from medical implants and devices.

In some embodiments, the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder. In some embodiments, the present invention provides a method for the secondary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable angina, an 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 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 provides a method for the secondary prophylaxis of a thromboembolic disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome, stroke, atrial fibrillation and venous thrombosis.

One skilled in the art will recognize that wherein the present invention is directed to methods of prophylaxis, the subject in need thereof (i.e. a subject in need of prophylaxis) 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. Further, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prophylaxis or prophylactic treatment) as a consequence of the subject’s medical history, including, but not limited to, family history, pre-disposition, coexisting (comorbid) disorders or conditions, genetic testing, and the like.

The compounds of the present invention are preferably administered alone to a mammal in a therapeutically effective amount. However, the compounds of the invention can also be administered in combination with an additional therapeutic agent, as defined below, to a mammal in a therapeutically effective amount. When administered in a combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. Synergy, for example, may occur when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared with the individual components. Possible favorable outcomes of treatment with a synergistic combination include, but are not limited to, (a) increased efficacy of the therapeutic effect, (b) ability to administer decreased dosage while increasing or maintaining efficacy (which in turn may also result in decreased toxicity and / or adverse side effects), (c) minimized or slowed development of drug resistance, (d) selective synergism against the biological target (or efficacy synergism) versus host (toxicity antagonism).

In some embodiments of the present invention, the compound of formula (I), compound of formula (II), compound of formula (III) and / or compound of formula (IV) may be administered in combination with one or more anticoagulant, anti-thrombin agent, anti-platelet agent, fibrinolytic, hypolipidemic agent, antihypertensive agent, and /or anti-ischemic agent. Suitable examples include, but are not limited to warfarin, heparin, aprotinin, a synthetic pentasaccharide, a boroarginine derivative, a boropeptide, heparin, hirudin, argatroban, a thromboxane- A2-receptor antagonist, a thromboxane- A2-synthetase inhibitor, a PDE-III inhibitor, a PDE V inhibitor, an ADP receptor antagonist, an antagonist of the purinergic receptor P2Y1 , an antagonist of the purinergic receptor P2Y12, tissue plasminogen activator and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase, lanoteplase, a PAI-I inhibitor, an alpha-2-antiplasmin inhibitor, an anisoylated plasminogen streptokinase activator complex, a HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a fibrate, a bile add sequestrant, an ACAT inhibitor, a MTP inhibitor, a lipooxygenase inhibitor, a cholesterol absorption inhibitor, a cholesterol ester transfer protein inhibitor, an alpha adrenergic blocker, a beta adrenergic blocker, a calcium channel blocker, a diuretic, a renin inhibitor, an angiotensin-converting enzyme inhibitor, an angiotensin-ll-receptor antagonist, an ET receptor antagonist, a Dual ET/A11 antagonist, a neutral endopeptidase inhibitor, a vasopeptidase inhibitor, a Class I agent, a Class II agent, a Class III agent, a Class IV agent, an lach inhibitor, an Ikur inhibitor and a cardiac glycoside.

By “administered in combination" or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently or consecutively to the subject (preferably mammal, more preferably human) being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as 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, 621-681.

4. Pharmaceutical Compositions

The present invention further comprises pharmaceutical compositions containing a compound of formula (I), compound of formula (II), compound of formula (III) and / or compound of formula (IV) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.

Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 1000 mg or any amount or range therein, and may be administered at a dosage of from about 0.05 mg/day to about 1000 mg/day, or any amount or range therein, about 0.1 mg/day to about 500 mg/day, or any amount or range therein, preferably from about 1 mg/day to about 300 mg/day, or any amount or range therein.

The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alteratively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid pre-formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid pre-formulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 1,000 mg, or any amount or range therein, of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form yielding the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of the treatment and / or prophylaxis of thromboembolic disorders described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and about 1000 mg of the compound, or any amount or range therein, preferably from about 0.05 mg to about 300 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 100 mg of the compound, or any amount or range therein, more preferably from about 0.1 mg to about 50 mg of the compound, or any amount or range therein; and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

To prepare a pharmaceutical composition of the present invention, a compound of formula (I), compound of formula (II), compound of formula (III) and / or compound of formula (IV) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be measured in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous 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.

Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment or prophylaxis of thromboembolic disorders, inflammatory disorders or diseases or conditions in which plasma kallikrein activity is implicated is required.

The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 1 ,000 mg per adult human per day, or any amount or range therein. For oral administration, the compositions are preferably provided in the form of tablets 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 the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug may be ordinarily supplied at a dosage level of from about 0.005 mg/kg to about 10 mg/kg of body weight per day, or any amount or range therein. Preferably, the range is from about 0.01 to about 5.0 mg/kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 1.0 mg/kg of body weight per day, or any amount or range therein, more preferably, from about 0.1 to about 0.5 mg/kg of body weight per day, or any amount or range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a disorder.

One 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 a disorder, may be completed according to methods well known in the clinical and medical arts.

5. Combination Therapy

One or more additional pharmacologically active agents may be administered in combination with the compounds of the invention. The additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which is different from the compound of formula (I), and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents when such forms are sold commercially or are otherwise chemically possible. Generally, any suitable additional active agent or agents, including but not limited to antihypertensive agents, additional diuretics, anti-atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and/or anti-obesity agents may be used in any combination with the compound of formula (I), compound of formula (II), compound of formula (III) and / or compound of formula (IV) in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (coadministration of the separate active agents).

Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril); angiotensin II receptor antagonists also known as angiotensin receptor blockers or ARBs (e.g., losartan i.e.,

COZAAR®, valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartan and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR®); diuretics, e.g. hydrochlorothiazide (HCTZ); potassium sparing diuretics such as amiloride HCI, spironolactone, epleranone, triamterene, each with or without HCTZ; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon); aldosterone antagonists; aldosterone synthase inhibitors; renin inhibitors (e.g. urea derivatives of di- and tri-peptides (See U.S. Pat No. 5,116,835), amino acids and derivatives (U.S. Patents 5,095,119 and 5,104,869), amino acid chains linked by non-peptidic bonds (U.S. Patent 5,114,937), di- and tri- peptide derivatives (U.S. Patent 5,106,835), peptidyl amino diols (U.S. Patents 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiol carbamates (U.S. Patent 5,089,471); also, a variety of other peptide analogs as 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 (including diol sulfonamides and sulfinyls (U.S. Patent 5,098,924), N-morpholino derivatives (U.S. Patent 5,055,466), N-heterocyclic alcohols (U.S. Patent 4,885,292) and pyrrolimidazolones (U.S. Patent 5,075,451); also, pepstatin derivatives (U.S. Patent 4,980,283) and fluoro- and chloro-derivatives of statone-containing peptides (U.S. Patent 5,066,643); enalkrein; RO 42-5892 (CAS Registry Number 126222-34-2, also known as Remikiren); A 65317 (CAS Registry Number 119625-78-4),; CP 80794 (CAS Registry Number 119625-78-4, also known as Terlakiren)); ES 1005 (CAS Registry Number 115404-79-0); ES 8891 (CAS Registry Number 129445-88-1); SQ 34017 (CAS Registry Number 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, cromakalim, minoxidil, aprilkalim, loprazolam); sympatholitics; beta- adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, metoprolol, metoprolol tartate, nadolol, propranolol, sotalol, timolol); alpha adrenergic blocking drugs (e.g., doxazocin, prazocin or alpha methyldopa); central alpha adrenergic agonists; peripheral vasodilators (e.g. hydralazine); lipid lowering agents, e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), and fluvastatin (particularly the sodium salt sold in LESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niadn in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist such as laropiprant (TREDAPTIVE®) and/or with an HMG- CoA reductase inhibitor; niadn in immediate-release or controlled release forms, and particularly niadn in combination with a DP antagonist such as laropiprant (TREDAPTIVE®) and/or with an HMG-CoA reductase inhibitor; niadn receptor agonists such as adpimox and acifran, as well as niacin receptor partial agonists; metabolic altering agents induding insulin sensitizing agents and related compounds for the treatment of diabetes such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also referred to as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g., sitagliptin

(JAN U VI A®), alogliptin, vildagliptin, saxagliptin, linagliptin, dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine), combination medications such as JANUMET® (sitagliptin with metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; or with other drugs beneficial for the prevention or the treatment of the above-mentioned 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 possible. Compounds which can be alternatively or additionally administered in combination with the compounds of the present invention include, but are not limited to, anticoagulants, anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemic agents, antihypertensive agents, and anti- ischemic agents.

Anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin, heparin (either unfractionated heparin or any commercially available low molecular weight heparin, for example enoxaparin and dalteparin), aprotinin, synthetic pentasaccharide inhibitors of Factor Xa such as fondaparinux and idraparinux, direct Factor Xa inhibitors such as rivaroxaban, apixaban, betrixaban, edoxaban, otamixaban, direct acting thrombin inhibitors including hirudin, dabigatran, argatroban, ximelagatran, melagatran, lepirudin, desirudin, and bivalirudin, as well as other factor Vila inhibitors, Villa inhibitors, Dca inhibitors, Xa inhibitors, Xla inhibitors, fibrinogen receptor antagonists (including abciximab, eptifibatide and tirofiban), TAFI inibitors, and others known in the art. Factor Dca inhibitors include synthetic active-site blocked competitive inhibitors, oral inhibitors and RNA aptamers. These are described in Howard, EL, Becker KC, Rusconi, CP, Becker RC. Factor Ixa Inhibitors as Novel Anticoagulents. Arterioscler Thromb Vase Biol, 2007; 27: 722- 727.

The term “anti-platelet agents” or “platelet inhibitory agents", as used herein, denotes agents that inhibit platelet function, for example, by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti- inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred. Other suitable platelet inhibitory agents include llb/llla antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, phosphodiesterase-ill (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE V inhibitors (such as sildenafil), and pharmaceutically acceptable salts or prodrugs thereof.

The term “anti-platelet agents” or “platelet inhibitory agents”, as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferable antagonists of the purinergic receptors P2Y1 and P2Y12 with P2Y12 being even more preferred. Preferred P2Y12 receptor antagonists include ticlopidine, prasugrel, clopidogrel, elinogrel, ticagrelor and cangrelor, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro- intestinal tract in use. The compounds of the present invention may also be dosed in combination with aprotinin.

The term “thrombin inhibitors” or “anti-thrombin agents”, as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-l and/or serotonin), endothelial cell activation, inflammatory reactions, and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, 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 alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term “hirudin”, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.

The term “thrombin receptor antagonists”, also known as protease activated receptor (PAR) antagonists or PAR-1 antagonists, are useful in the treatment of 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 substitutions of amino acids on thrombin receptors. In Bematowicz et al, J Med. Chem., vol. 39, pp. 4879-4887 (1996), tetra-and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p- guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p- guanidinoPhe-Leu-Arg-Arg-Nhh. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479. Substituted tricyclic thrombin receptor antagonists are disclosed in U.S. Pat. Nos. 6,063,847, 6,326,380 and WO

01/96330. Other thrombin receptor antagonists include those disclosed in U.S. Pat. Nos. 7,304,078; 7,235,567; 7,037,920; 6,645,987; and EP Patent Nos. EP1495018 and EP1294714.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (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 pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complexes. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase. Examples of suitable anti- arrhythmic agents for use in combination with the present compounds include: Class I agents (such as propafenone); Class II agents (such as carvedilol and propranolol); Class III agents (such as sotalol, dofetilide, aminodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); lach inhibitors, and Ikur inhibitors (e.g., compounds such as those disclosed in W001/40231). 6. Definitions

As used herein, unless otherwise noted, “halogen” shall mean chloro, bromo, fiuoro and iodo, preferably bromo, fluoro or chloro, more preferably fluoro or chloro.

As used herein, unless otherwise noted, the term “oxo" shall mean a functional group of the structure =0 (i.e. a substituent oxygen atom connected to another atom by a double bond).

As used herein, unless otherwise noted, the term “Cx-valkyr wherein X and Y are integers, whether used alone or as part of a substituent group, include straight and branched chains containing between X and Y carbon atoms. For example, Ci-*alkyl radicals include straight and branched chains of between 1 and 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

As used herein, unless otherwise noted, the terms “-(Cx-valkylene)- and -Cx-valkylene-” wherein X and Y are integers, shall denote any Cx-valkyl carbon chain as herein defined, wherein said Cx-valkyl chain is divalent and is further bound through two points of attachment, preferably through two terminal carbon atoms.

As used herein, unless otherwise noted, the term “fluorinated Ci-*alkyl” shall mean any Ci-4alkyl group as defined above substituted with one or more fluoro groups, preferably one to three fluoro group. Suitably examples include, but are not limited to -CH ₂ F, -CHF ₂ , -CF ₃ , -CH^CFa, -CF^CHs, -CH^CH^ CH ₂ F, -CH^CH^CFa, -C(CH ₃ ) ₂ CF3, -C(CF ₃ )3, and the like.

As used herein, unless otherwise noted, the term “hydroxy substituted Ci-4alkyl” shall mean any Ci-<alkyl group as defined above substituted with at one or more hydroxy (-OH) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to - CH2OH, -CH2CH2OH, -CH(0H)CH ₃ , -CH(OH)CH ₂ OH, -CH2CH2CH2OH, - C(CH ₂ OH) ₃ , and the like.

As used herein, unless otherwise noted, the term “hydroxy substituted fluorinated Ci-talkyl” shall mean any fluorinated Ci-*alkyl group as defined above which is further substituted with at one or more hydroxy (-OH) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to -CF2OH, -CF2CH2OH, -CH(OH)CF ₃ , and the like.

As used herein, unless otherwise noted, the term “amino substituted Ci-talkyl” shall mean any Ci^alkyl group as defined above substituted with one or more amino group, preferably one to two amino groups, more preferably one amino group. Suitably examples include, but are not limited to -CHF-Nhfo, - CF2-NH2, -CH2-CF2-NH2, -CF2-CH2-NH2, -CH2-CH(-NH ₂ ) -CH2F, -CH2-CH2- CH2-NH2, -CH(-NH2)-CH(CH ₃ )2, and the like.

As used herein, unless otherwise noted, the term “cyano substituted Ci-4alkyl” shall mean any Ci-4alkyl group as defined above substituted with one or more cyano group, preferably one to two cyano groups, more preferably one cyano group. Suitably examples include, but are not limited to -CHF-CN, -CF2- CN, -CH2-CF2-CN, -CF2-CH2-CN, -CH2-CH(-CN)-CH ₂ F, -CH2-CH2-CH2-CN, - CH(-CN)-CH(CH ₃ )2. and the like.

As used herein, unless otherwise noted, “Cx-valkoxy” wherein X and Y are integers, shall mean an oxygen ether radical of the above described straight or branched chain Cx-valkyl groups containing between X and Y carbon atoms. For example, Cualkoxy shall include methoxy, ethoxy, n-propoxy, isopropoxy, n- butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy.

As used herein, unless otherwise noted, the term “fluorinated Ci- talkoxy” shall mean any Ci-4alkoxy group as defined above substituted with one or more fluoro groups, preferably one to three fluoro group. Suitably examples include, but are not limited to -OCH2F, -OCHF2, -OCF ₃ , -OCH2-CF ₃ , - OCF2-CH ₃ , -OCH2-CH2-CH2F, -0CH2-CH ₂ -CF ₃ , -OC(CH ₃ ) ₂ CF ₃ , -0C(CF ₃ ) ₃ , and the like. As used herein, unless otherwise noted, the term “hydroxy substituted Ci-4alkoxy” shall mean any Ci-4alkoxy group as defined above which is further substituted with one or more hydroxy (-OH) groups, preferably one to three, more preferably one to two hydroxy groups. Suitable examples include but are not limited to -OCF2OH, -OCF2CH2OH, -OCH(OH)CF ₃ , and the like.

As used herein, unless otherwise noted, the term “Cx-vcycloalkyr, wherein X and Y are integers, shall mean any stable X- to Y-membered monocyclic, bicyclic, polycyclic, bridged or spiro-cyclic saturated ring system, preferably a monocyclic, bicyclic, bridged or spiro-cyclic saturated ring system. For example, the term “Cs-ecycloalkyl” includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, cyclooctyl, bicyclo[2.2.2]octan-2-yl, and the like.

As used herein, unless otherwise noted, the term “heteroaryl” shall denote 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; or nine 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 may be bound through any ring atom which results in a stable structure. Suitable examples include, but are not limited to, furanyl, thienyl, furazanyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyrazyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, indolizinyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, 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.

As used herein, unless otherwise noted, the term “5 to 6 membered heteroaryl” shall denote 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. Suitably examples include, but are not limited to furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl, tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, dioxinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, and the like

The term “5 to 6 membered nitrogen containing heteroaryl” shall denote 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. Suitably examples include, but are not limited to pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, and the like.

Unless otherwise noted, any heteroaryl (regardless of the number of ring atoms, the number and identity of ring heteroatoms, etc.) may be bound through any ring atom which results in a stable structure.

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

As used herein, unless otherwise noted, the term “heterocyclyl” shall denote 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 spiro- cydic 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, thientanyl, pyrrolyl, ftiryl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl ) ) thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, dnnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 2,3-dihydrobenzofUryl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, and the like.

As used herein, unless otherwise noted, the term “5 to 6 membened heterocyclyl” shall denote 5 to 6 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. Unless otherwise noted, the 5 to 6 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 furyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, isothiazolyl, dioxolanyl, pyrazolidinyl, thiadiazolyl, pyranyl, pyridinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, and the like.

As used herein, unless otherwise noted, the term “5 membered heterocyclyl” shall denote 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 noted, the 5 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 furyl, thiophenyl, pyrrdyl, pyrrdidinyl, oxazolyl, thiazolyl, isoxazolyl, pyrazdyl, imidazdyl, triazolyl, isothiazolyl, dioxolanyl, pyrazolidinyl, thiadiazolyl, and the like.

As used herein, unless otherwise noted, the term “6 membered heterocyclyl” shall denote shall denote 5 membered monocydic, 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 noted, the 6 membered heterocyclyl may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Suitable examples indude, but are not limited to pyranyl, pyridinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, and the like.

As used herein, unless otherwise noted, the term “9 to 10 mem be red heterocyclyl” shall denote 9 to 10 membered monocyclic, bicydic, bridged, spire, 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 noted, 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 stmcture.Suitable examples indude, but are not limited to indolenyl, indolyl, isoindolyl, indolizinyl, indolinyl, benzofuryl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquindinyl, quinolizinyl, quinazolinyl, dnnolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pteridinyl, quinudidinyl, thionaphthenyl, isobenzazolyl, pyrano[3,4- b]pyrrdyl, anthranyl, benzopyranyl, chromenyl, coumarinyl, benzopyronyl, and the like.

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 noted, the 4 to 6 membered saturated heterocyclyl may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Suitable examples indude, but are not limited to azetidinyl, oxetanyl, thientanyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, trithianyl, and the like.

When a particular group is “substituted” (e.g. Cx-valkyl, heteroaryl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents. With reference to substituents, the term “independently” means that when more than one of such substituents is possible, such substituents may be the same or different from each other.

Abbreviations used in the spedfication, particularly the Schemes and Examples, are as listed in the Table A, below:

Table A: Abbreviations

Ac — Acetyl (i.e. -C(0)CH ₃ )

AC2O r: Acetic anhydride

AcOH Acetic Add

ACN or MeCN Acetonitrile aq. Aqueous

BFs^EbO Boron trifluoride diethyl etherate

BH ₃ *Me ₂ S _■ Borane Dimethyl Sulfide

BINAP (2,2'-Bis(diphenylphosphino)-1 , 1 -binaphthyl)

Boc or BOC te/Y-Butoxyloxy carbonyl (i.e. -C(0)-0-C(CH3)3)

B(0-iPr) ₃ Tri(isopropyl) Borate

BPin — Bis(pinacolate)diboron

BSA r: Bovine Serum Albumin

CHAPS = 3-[(3-Cholamidopropyl)dimethylammonio]-1- propanesulfonate

DABAL r: Bis(trimethylaluminum)-1 ,4- diazabicydo2.2. octane adduct

DBU s: 1 ,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1 ,2-Dichloroethane

DCM r: Dichloromethane

DEA Diethanolamine

DIEA or DIPEA Diisopropylethyl Amine

DME Diabetic Macular Edema

DMF _■ N,N-Dimethylformamide

DMP or Dess Martin _■ 3-Oxo-1A ⁵ ,2-benziodoxole-1 , 1 , 1 (3H)-triyl triacetate

Periodinane

DMSO _■ Dimethylsulfoxide dppf = 1 , T-Bis(diphenylphosphino)ferrocene

EA or EtOAc Ethyl Acetate

EDCI 1 -Ethyl-3-(3-dimethylaminopropyl) carbodiimide

Ee Enantiomeric Excess

ER r: End Point Read (assay) equiv. Equivalents

ES or ESI Electrospray ionization

Et Ethyl

EtOH Ethanol

EteO _■ Diethyl Ether

EtaN or TEA Triethylamine

Eb*3HF Triethylamine Trihydrofluoride

FA Formic Add

FXIa Factor Xla

Grubbs Catalyst 1 ^st Benzylidene- generation bis(tricydohexylphosphine)dichlororuthenium

Grubbs Catalyst 2 ^nd r: (1 ,3-Bis(2,4,6-trimethylphenyl)-2- generation imidazolidinylidene)dichloro(phenylmethylene)

(tricyclohexylphosphine)ruthenium

Grubb's Catalyst 3 ^rt Dichlorol ,3-bis(2,4,6-trimethylphenyl)-2- generation imidazolidinylidene(benzylidene)bis(3- bromopyridine)rutheniunXII) HAE — Hereditary Angioedema

HATU r: (1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

Hex Hexanes

HOAc r: Acetic Acid

HOBt or HOBT r: Hydroxy benzotri azole

HPLC High Performance Liquid Chromatography

IBX — 2-lodoxybenzoic acid

KIN Kinetic Read (assay)

KOAc 5; Potassium Acetate

KOt-Bu or f-BuOK or _■ Potassium terf-Butoxide tert-BuOK

LC-MS or LC/MS _■ Liquid chromatography-mass spectrometry

LDA or UN(Pr-i)2 Lithium Diisopropylamide

LiHMDS Lithium bis(trimethylsilyl)amide

Me Methyl

Mel — Methyl Iodine

MeOH r: Methanol

MOM Methoxy methyl

Ms or mesyl Methylsulfonyl (i.e. -SO2-CH3)

MTBE Methyl terf-Butyl Ether

NaOEt Sodium Ethoxide

NaOMe 5; Sodium Methoxide

NaOt-Bu or t-BuONa Sodium tert-Butoxide or tort- BuONa

NBS N-Bromosuccinimide n-BuLi n-Butyl Lithium n-BuCH(Et)C0 ₂ K Potassium ethylhexanoate

NCS N-Chlorosuccinimide

NFSI r: N-Fluorobenzenesulfonimide NH4OAC — Ammonium Acetate

NIS r: N-lodosuccinimide

NMR = Nuclear Magnetic Resonance

Oms or mesylate Methanesulfonate (i.e. -0-S0 ₂ -CH ₃ )

Otf or triflate Trifluoromethanesulfbnyl (i.e. -0-S0=-CF3)

Ots or tosylate =2 p-Toluenesulfonate (i.e. -0-S02-(p-methylphenyl))

PCC 5; Pyridinium chlorochromate

Pd(dppf)Cl2 or = [1,1 ’-Bis(diphenylphosphino)ferrocene] Palladium PdCI ₂ (dppf) (II) Dichloride

Pd(dtbpf)CI ₂ 1 , 1 -Bis(di-terf-butylphosphino)fenOcenedichloro palladium (II)

PdCI ₂ (PPh ₃ ) ₂ or _■ Bis(triphenylphosphine)palladium (II) Dichloride Pd(PPh ₃ ) ₂ CI ₂

Pd(PPh3)4 _■ Tetrakis(triphenylphosphine)palladium(0)

PE Petroleum ether

Ph Phenyl

Phl(Oac) ₂ (Diacetoxyiodo)benzene

PhMe Toluene

PK r: Plasma Kallikrein

PMB = pa/a-Methoxybenzyl

PMBCI para-Methoxybenzyl Chloride

PPhs T riphenylphosphine

PPTS Pyridinium p-toluenesulfonate

Py*HBr _{3 ■} Pyridinium Perbromide

RFU Relative Fluorescence Unit

Selectfluor or F-TEDA 1 -Chloromethyl-4-fluoro-1 ,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)

SEMCI 2-(Trimethylsilyl)ethoxymethyl Chloride

SFC (purification) = Supercritical Fluid Chromatography (purification)

TBAF Tetra-n-butylammonium fluoride

TBSCI or TBDMS-CI r: terf-Butyldimethylsilyl chloride TBSOTf terf-Butyldimethylsilyl triflate

TEA or EfeN s: Triethylamine

Tf or triflyl = Trifluoromethylsulfonyl (i.e. -SO2-CF3)

TFA Trifluoroacetic acid

TFAA Trifluoroacetic anhydride

THF — Tetrahydrofuran

THP — Tetrahydropyranyl

TMS = Trimethysilyl

TMSCHN2 = T rimethylsilyldiazomethane

TMSCI Trimethylsilyl Chloride

TMSCN Cyanotrimethylsilane

TMSNa s: Trimethylsilyl azide

Tris (buffer) = 2-Amino-2-(hydroxymethyl)-1,3-propanediol

Ts or tosyl -S02-(p-methylphenyl) p-TsOH para-Toluenesulfonic Acid wt% or wt % _■ Weight Percent

X-Phos _■ Dicyclohexyl[2 ^, ,4',6'-tris(propan-2-yl)[1 , 1 biphenyl]-2-yl]phosphane

X-Phos-Pd G2 [2-(2-aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane

X-Phos-Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 - biphenyl) [2-(2'-amino-1 , 1 '-biphenyl)]palladium(l I) methanesulfonate

For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts”. Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed 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 add, acetic add, benzoic add, dtric add, tartaric add, carbonic add or phosphoric acid. Furthermore, where the compounds of the invention carry an addic moiety, suitable pharmaceutically acceptable salts thereof may indude alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., caldum or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts indude, but are not limited to, the following: acetate, benzenesulfbnate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, caldum edetate, camsylate, carbonate, chloride, davulanate, titrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, sucdnate, tannate, tartrate, teodate, tosylate, triethiodide and valerate.

Representative adds which may be used in the preparation of pharmaceutically acceptable salts indude, but are not limited to, the following: adds induding acetic add, 2,2-dichloroacetic add, acylated amino adds, adipic add, alginic add, ascorbic add, L-aspartic add, benzenesulfonic add, benzoic add, 4-acetamidobenzoic acid, (+)-camphoric add, camphorsulfonic add, (+)- (1S)-camphor-10-sulfonic add, capric add, caproic acid, caprylic add, cinnamic add, dtric add, cyclamic add, dodecylsulfuric acid, ethane-1 ,2-disulfonic add, ethanesulfonic add, 2-hydroxy-ethanesulfonic add, formic add, fumaric add, galactaric add, gentisic acid, glucoheptonic add, D-gluconic add, D-glucoronic add, L-glutamic add, a-oxo-glutaric add, glycolic add, hippuric acid, hydrobromic add, hydrochloric add, (+)-L-lactic add, (±)-DL-lactic add, lactobionic add, maleic add, (±)-L-malic add, malonic add, (±)-DL-mandelic add, methanesulfonic add, naphthalene-2-sulfonic add, naphthalene-1 ,5- disulfonic acid, 1-hydroxy-2-naphthoic add, nicotinic add, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L- pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic add, stearic add, sucdnic add, sulfuric add, tannic add, (+)-L-tartaric acid, thiocyanic add, p-toluenesulfonic add and undecylenic add.

Representative bases which may be used in the preparation of pharmaceutically acceptable salts indude, but are not limited to, the following: bases induding ammonia, L-arginine, benethamine, benzathine, caldum hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who 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.

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 combinations of the specified ingredients in the specified amounts.

As used herein, unless otherwise noted, the terms “treating”, “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 includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, slow the progression of the disease or disorder, or eliminate the disease, condition, or disorder. The terms "treating" or "treatment" further include: (a) inhibiting the disease-state, i.e., arresting its development; and/or (b) relieving the disease-state, i.e., causing regression of the disease state.

As used herein, "prevention” covers the preventive treatment of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population.

As used herein, "prophylaxis" is the protective treatment of a disease state to reduce and/or minimize the risk and/or reduction in the risk of recurrence of a disease state by administering to a patient a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, isotopologue, a pharmaceutically acceptable salt, thereof. Patients may be selected for prophylaxis therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. For prophylaxis treatment, conditions of the clinical disease state may or may not be presented yet. "Prophylaxis" treatment can be divided into (a) primary prophylaxis and (b) secondary prophylaxis. Primary prophylaxis is defined as treatment to reduce or minimize the risk of a disease state in a patient that has not yet presented with a clinical disease state, whereas secondary prophylaxis is defined as minimizing or reducing the risk of a recurrence or second occurrence of the same or similar clinical disease state.

As used herein, "risk reduction" covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.

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

The term “therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. Examples

The following Examples are set forth to aid in the understanding of the invention and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

Where an Example which follow hereinafter lists only analytical measurements such as LC/MS, ¹ H NMR, ¹⁹ F NMR, etc. (rather than reaction step details), it will be understood that the title compound was prepared according to the procedures as described in the synthesis schemes and Examples herein, selecting and substituting suitable reagents and reactants, as would be readily recognized by those skilled in the art.

Unless otherwise indicated in the examples, all temperature is expressed in Centigrade (°C). All reactions were conducted under an inert atmosphere at ambient temperature unless otherwise noted. Unless otherwise specified, reaction solutions were stirred at room temperature under a ½¾) or Ar<g) atmosphere. Reagents employed without synthetic details are commercially available or made according to known methods, for example according to literature procedures. When solutions were “concentrated to dryness”, they were concentrated using a rotary evaporator under reduced pressure, when solutions were dried, they were typically dried over a drying agent such as MgSO* or Na2S04. Where a synthesis product is listed as having been isolated as a residue, it will be understood by those skilled in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

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

LC-MS: Unless otherwise indicated, the analytical LC-MS system used consisted of a Shimadzu LCMS-2020 with electrospray ionization(ESI) in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. The column was a HALO a C1830*5.0 mm, 2.7 pm. The mobile phase A was water containing 0.05% TFA and mobile phase B was acetonitrile containing 0.05% TFA. The gradient was from 5% mobile phase B to 100% (95%) in 2.0 min, hold 0.7 min, then revert to 5% mobile phase B over 0.05 min and maintain for 0.25 min. The Column Oven (CTO-20AC) was operated at a 40.0 °C. The flow rate was 1.5 mL/min, and the injection volume was 1 pi. PDA

(SPD-M20A) detection was in the range 190-400 nm. The MS detector, which was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow:1.5 L/min; Drying Gas Flow:15 L/min; Detector Voltage: Tuning Voltage ± 0.2 kv; DL Temperature: 250 °C; Heat Block Temperature: 250 °C; Scan Range: 90.00 - 900.00 m/z. ELSD (Alltech 3300) detector Parameters: Drift Tube Temperature:60 ± 5 °C; N2 Flow-Rate: 1.8 ± 0.2 L/min. Mobile phase gradients were optimized for the individual compounds. Calculated mass corresponds to the exact mass.

Preparative HPLC: Unless otherwise noted, preparative HPLC purifications were performed with Waters Auto purification system (2545-2767) with a 2489 UV detector. The column was selected from one of the following: Waters C18, 19 x150 mm, 5 pm; XBridge Prep OBD C18 Column, 30x150mm 5pm; XSelect CSH Prep C18 OBD Column, 5pm,19*150mm; XBridge Shield RP18 OBD Column, 30x150mm, 5pm; Xselect CSH Fluoro Phenyl, 30 x 150 mm, 5 pm; or YMC-Actus Triart C18, 30 x 150 mm, 5 pm. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.1% FA or 10 mmol/L NH4HCO3. Flow rates were maintained at 25 mL/min, the injection volume was 1200 pL, and the UV detector used two channels 254 nm and 220 nm. Mobile phase gradients were optimized for the individual compounds.

Chiral chromatography: Chiral analytical chromatography was performed on one of ChiralpakAS, AD, Chiralcel OD.OJ Chiralpak IA,IB,IC,ID,IE,IF,IG,IH columns (Daicel Chemical Industries, Ltd.) (R,R)-Whelk-01, (S,S)-Whelk-01 columns (Regis technologies, Inc. ) CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.) as noted, at different column size (50x4.6mm, 100x4.6mm, 150x4.6mm, 250x4.6mm, 50x3.0mm, 100x3.0mm), with percentage of either ethanol in hexane (%Et/Hex) or isopropanol in hexane (%IPA/Hex) as isocratic solvent systems, or using supercritical fluid (SFC) conditions. Normal phase flash chromatography: Unless otherwise noted, normal phase flash column chromatography (FCC) was performed on silica gel with pre-packaged silica gel columns (such as RediSep®), using ethyl acetate (EtOAc)/hexanes, ethyl acetate (EtOAc)/ Petroleum ether (b.p. 60-90 °C), CtaCb/MeOH, or CH ₂ Cl2/10% 2N NHa in MeOH, as eluent.

¹ H NMR: Unless otherwise noted, ¹ H NMR spectra were acquired using 400 MHz spectrometers (or 300 MHz spectrometers) in DMSO-de solutions. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (6) are expressed in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in DMSO-de solutions, and residual CHaOH peak or TMS was used as internal reference in CDaOD solutions. Coupling constants (J) are reported in hertz (Hz). The nature of the shifts as to multiplicity is reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

Synthesis Examples: Intermediates Intermediate 1 : (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid Step 1: l-(Tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicartx>xylate To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2- dicarboxylate (2.1 g, 8.63 mmol, 1.0 equiv) in THF (40 mL), was added lithium triethylborhydride (13 mL, 13 mmol, 1.5 equiv, 1M in THF) drop-wise at -78 °C under N2. The reaction mixture was stirred for 40 min at -78 °C, then NaaCOs (aq., 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 for 30 min at room temperature. THF was removed under vacuum, and the resulting mixture was extracted with diethyl ether, washed with brine, dried, and concentrated under vacuum to yield a colorless oil. The oil was dissolved in methanol (40 mL), and p-toluenesulfonic acid (149 mg, 0.86 mmol, 0.1 equiv) was added. The resulting solution was stirred overnight at room temperature. The reaction was quenched with water and the resulting mixture was extracted with diethyl ether. The combined organic layer was washed with brine, dried over N32SO4 and concentrated to yield 1-(tert-butyl) 2-methyl (2S)-5- methoxypyrrolidine-1 ,2-dicarboxylate as a colorless oil.

Step 2: 1-(Tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1 ,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1 ,2- dicarboxylate (10.0 g, 38.60 mmol, 1.0 equiv) in EbO (200 mL), were added allyltrimethylsilane (27 mL, 169.70 mmol, 4.4 equiv) and boron trifluoride etherate (6.6 g, 46.30 mmol, 1.2 equiv) at -40 °C in a N2 atmosphere. The reaction mixture was stirred for 30 min at -40 °C, and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na2COa (aq.) and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography (0-20%

EtOAc/petroleum ether) to yield l-(tert-butyl) 2-methyl (2S)-5-allylpyrrolidine- 1 ,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C14H23NO4: 269.16, measured: 270.20 [M+H]*.

Step 3: 1-(Tert-butyl) 2-methyl (2S)-5-(2-oxoethyl)pyrrolidine-1,2-dicarboxylate 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 Os04 (347 mg, 1.36 mmol, 0.05 equiv). The reaction mixture was stirred for 5 min at room temperature in the dark, and sodium periodate (14.5 g, 67.80 mmol, 2.5 equiv) was added. The reaction mixture was stirred for 4 h at room temperature. The reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0-40% EA/PE) to yield l-(tert-butyl) 2-methyl (2S)-5-(2- oxoethyl)pyrrolidine-1,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C13H21NO5: 271.14, measured: 272.15 [M+H] ⁺ .

Step 4: 1-(Tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2-hydroxy-4- oxobutyl)pyrrolidine-1 ,2-dicarboxylate

To a solution of tert-butyl acetate (3.9 g, 44.23 mmol, 2.0 equiv) in tetrahydrofuran (60 mL), was added lithium bis(trimethylsilyl)amide (44 mL, 44 mmol, 1.2 equiv) at -78 °C in a N2 atmosphere. The resulting solution was stirred for 30 min at -78 °C, then 1 -(tert-butyl) 2-methyl (2S)-5-(2- oxoethyl)pyrrolidine-1,2-dicarboxylate (6 g, 22.1 mmol, 1.0 equiv) was added. The reaction mixture was stirred for 2 h at -78 °C. The reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04. The solids were filtered out. The filtrate was concentrated under vacuum and concentrated. The residue was purified by silica gel chromatography (0-80% EA/PE) to yield 1 -(tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2-hydroxy-4- oxobutyl)pyrrolidine-1 ,2-dicarboxylate as a yellow oil. LC/MS: mass calculated For C17H29NO7: 359.19, measured: 360.10 [M+H] ⁺ . Step 5: 1 -(Tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2- dicarboxylate

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 overnight at 50 °C. The residue was purified by silica gel chromatography (0-80% EtOAc/petroleum ether) to yield 1-(tert-butyl) 2-methyl (2S)-5-(4-ethoxy-2,4-dioxobutyl)pyrrolidine-1,2-dicarboxylat e as a yellow oil. LC/MS: mass calculated for C17H27NO7: 357.18, measured: 380.15 [M+Na] ⁺ . Step 6: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of l-(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 HCI (in 1,4-dioxane, 4 M)/dichloromethane (5 mL, 1/1) and the reaction mixture was stirred for 1h at room temperature. The solvent was removed under vacuum to yield yellow oil. The oil was dissolved in toluene (5 mL), and sodium bicarbonate (2.1 g, 25.20 mmol, 10.0 equiv) was added. The reaction mixture was stirred over night at 110 °C. The reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over NazSO* and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc/petroleum ether) to yield methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C10H13NO4: 211.08, measured: 212.10 [Μ+ΗΓ.

Step 7: Methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate (370 mg, 1.75 mmol, 1.0 equiv) in dichloromethane (5 ml_), were 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 over night at room temperature. The mixture was then concentrated. The residue was purified by silica gel chromatography (0-80% EA/PE) to yield methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-

1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for CuHuFaNOeS: 343.03, measured: 344.05 [M+H] ⁺ .

Step 8: Methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of ethyl methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-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) in 1,4-dioxane/H20 (5 mL, 10/1), was added [1,T-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (37 mg, 0.05 mmol, 0.1 equiv). The reaction mixture was stirred for 2 h at 80 °C under N2. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to yield methyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate as a yellow solid. LC/MS: mass calculated for CieHieCIFN203: 338.08, measured: 339.10 [Μ+ΗΓ-

Step 9: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid

To a solution of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (210 mg, 0.62 mmol, 1.0 equiv) in THF/hteO/MeOH (5 mL, 3/1/1), was added lithium hydroxide (124 mg, 3.10 mmol, 5.0 equiv). The reaction mixture was stirred for 1 h at room temperature. The residue was adjusted to pH 4 with HCI, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylic acid as a yellow solid. LC/MS: mass calculated for C15H14CIFN2O3: 324.07, measured: 325.05 [M+HJ\

Intermediate 2: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate Step 1: Methyl (2S)-5-allylpyrrolidine-2-carboxylate l-(tert-Butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate (10 g, 37.13 mmol, 1.0 eq) was dissolved in HCI solution (90 mL, 10.00 eq) (4 M in 1 ,4-dioxane). The resulting mixture was maintained at room temperature for 2 h. The solvent was removed under reduced pressure to yield methyl (2S)-5- allylpyrrolidine-2-carboxylate, which was used in the next step without further purification. LC/MS: mass calculated for CeHi5N02: 169.11, measured: 170.20 [M+H]*.

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

At -78 °C, to a solution of methyl (2S)-5-allylpyrrolidine-2-carboxylate (6.0 g, 35.46 mmol, 1.0 eq) in THF (200 mL) was added TEA (23 mL, 177.28 mmol, 5.0 eq) followed by acryloyl chloride (3.2 g, 35.46 mmol, 1.0 eq). The resulting mixture was maintained at room temperature for 40 min. The reaction was then quenched with NH4CI (aq.). The aqueous phase was extracted with EA. The organic layer was combined, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (EA/PE) to yield methyl (2S)-1-acryloyl-5-allylpyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C12H17NO3: 223.12, measured: 224.20 [M+H]*. Step 3: Methyl (3S)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate Under N2, to a solution of methyl (2S)-1-acryloyl-5-allylpyrrolidine-2- carboxylate (7.2 g, 32.25 mmol, 1.0 eq) in DCM (100 mL) was added Grubbs’ 2nd catalyst (2.7 g, 3.23 mmol, 0.1 eq). The resulting mixture was heated at 45 °C for 10 h and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE) to yield methyl (3S)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as brown oil. LC/MS: mass calculated for C10H13NO3: 195.09, measured: 196.10 [M+H]*. Step 4: Methyl (3S)-7-hydroxy-5-oxooctahydroindolizine-3-carboxylate

Under N2, to a solution of CuCI (0.102 g, 1.03 mmol, 0.2 eq) in THF (100 mL) was added BINAP (638 mg, 1.03 mmol, 0.2 eq). The mixture was maintained at room temperature for 15 min. Then t-BuONa (98 mg, 1.03 mmol, 0.2 eq) was added. 4,4,4 ^, ,4 ^, ,5,5,5',5 ^, -Octamethyl-2,2 ^, -bi(1 ,3,2-dioxaborolane)

(1.6 g, 6.15 mmol, 1.2 eq) was added 30 min later, followed by addition of (3S)- methyl 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.0 g, 5.12 mmol, 1.0 eq). MeOH (328 mg, 10.25 mmol, 2.0 eq) was then added dropwise. The resulting mixture was stirred for 16 h, then cooled to 0 °C. H2O2 (6 mL, 51.23 mmol, 10.0 eq) was added and the reaction mixture was stirred for another 1 h. The solvent was removed under reduced pressure and the residue was purified through silica gel (DCM/MeOH) to yield methyl (3S)-7-hydroxy-5- oxooctahydroindolizine-3-carboxylate as a brown oil, which was used in the next step without further purification. Step 5: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of (3S)-methyl 7-hydroxy-5-oxo-octahydroindolizine-3- carboxylate (1.0 g) in DCM (100 mL) was added pyridinium chlorochromate (2.0 g, 9.38 mmol, 2.0 eq). The resulting mixture was stirred for 16 h. The solvent was removed under reduced pressure and the residue was purified through silica gel (EA/PE) to yield (3S)-methyl 5,7-dioxo-octahydroindolizine-3- carboxylate as a yellow oil. LC/MS: mass calculated for C10H13NO4: 211.08, measured: 212.10 [M+H]*. Intermediate 3: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate

0 _;

N

° <J °\

Step 1: Diethyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanedioate

Into a 3-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tetrahydrofuran (1.0 L), LDA (253 mL, 2 M in THF, 1.00 equiv). This was followed by the addition a solution of ethyl acetate (44.5 g, 505.2 mmol, 1.00 equiv) in THF (100 mL), dropwise with stirring at -78 °C and stirred for 30 min. To the resulting mixture was added a solution of 1-tert-butyl 2-ethyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (130 g, 505.2 mmol, 1.00 equiv) in THF (300 mL) with stirring at -78 °C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of NH4CI (aq., 50 mL). The resulting solution was extracted with DCM (3 x 1 L) and the organic layer was combined. The resulting mixture was washed with brine (2 x 500 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate to yield diethyl (S)-2-((tert- butoxycarbonyl)amino)-5-oxoheptanedioate as a yellow oil. ¹ HNMR: (300 MHz, CDCb, ppm) 65.21-5.09 (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). Step 2: Ethyl (S,Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylate

Into a 3-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,7-diethyl (2S)-2-[(tert- butoxycarbonyl)amino]-5-oxoheptanedioate (105.0 g, 304.0mmol, 1.00 equiv), and trifluoroacetic acid (59.6 g, 608.0 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25 °C. 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 N32C03. The resulting solution was extracted with DCM (3 x 500 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :4) to yield ethyl (S,Z)-5-(2-ethoxy-2- oxoethylidene)pynOlidine-2-carboxylate as a light yellow oil. LC/MS: mass calculated for C11H17NO4: 227.12, measured: 228.00 [M+H]*.

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

Into a 500 ml round-bottom flask, was placed acetic acid (280 mL), ethyl (2S,5Z)-5-(2-ethoxy-2-oxoethylidene)pyrrolidine-2-carboxylat e (35.0 g, 154.0 mmol, 1.00 equiv), RO2 (4.2 g, 18.5 mmol, 0.12 equiv). The mixture was stirred for 3 h under hydrogen atmosphere at room temperature. The mixture was concentrated and diluted with EA (3 L). NaHCOa aqueous solution added to adjust the pH of the mixture to pH 7. The resulting solution was extracted with ethyl acetate (3 x 2 L) acetate, dried over anhydrous sodium sulfate and concentrated to yield ethyl (2S.5R) 5-(2-ethoxy-2-oxoethyl)pyrrolidine-2- carboxylate as a yellow oil. ¹ HNMR (300 MHz, CDCh, ppm) 64.19 (dq, J =11.5, 7.1 Hz, 4H), 3.87 (dd, J=9.0, 5.5 Hz, 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, 7.1 Hz, 6H).

Step 4: Ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3-ethoxy-3- oxopropanoyl)pyrrolidine-2-carboxylate

Into a 2-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DCM (700 mL), DIPEA (39.4 g, 305.3 mmol, 2.00 equiv), ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)pyrrolidine-2- carboxylate (35.0 g, 152.6 mmol, 1.00 equiv). 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) dropwise with stirring at 0 °C. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with water (2 x 200 mL). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate/ petroleum ether (1:20-1:2) to yield ethyl (2S,5R)-5-(2-ethoxy-2-oxoethyl)-1-(3- ethoxy-3 -oxopropanoyl)pyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for CietesNO: 343.16, measured: 334.00 [M+H]*. Step 5: Diethyl (3S,8aR)-5,7-dioxooctahydroindolizine-3,6-dicarboxylate Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl alcohol (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), sodium ethoxide (8.0 g, 118.0 mmol, 1.05 equiv). The resulting solution was stirred for 50 min at 60 °C. The reaction mixture was cooled with a water/ice bath and concentrated. The mixture was poured into HCI (1 N, 300 mL). The resulting solution was extracted with ethyl acetate (2 x 200 mL) acetate, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20-1:3) to yield diethyl (3S,8aR)-5,7-dioxooctahydroindolizine-3,6- dicarboxylate as a yellow oil. LC/MS: mass calculated for CuHigNOe: 297.12, measured: 298.00 [M+H] ⁺ .

Step 6: Ethyl (3S,8aR)-5,7-dioxooctahydroindolizine-3-carboxylate

Into a 2-L 3-necked round-bottom flask, was placed 3,6-diethyl (3S,8aR)- 5,7-dioxo-hexahydroindolizine-3,6-dicarboxylate (28.0 g, 94.1 mmol, 1.00 equiv), and acetic acid (196 mL), H2O (20 mL). The resulting solution was stirred for 2 h at 110 °C. The reaction mixture was cooled with a water/ice bath. The resulting mixture was concentrated to yield ethyl (3S,8aR)-5,7-dioxo- hexahydroindolizine-3-carboxylate as a yellow oil.

¹ HNMR (300 MHz, CDCIa, ppm) δ 4.63 (d, J=8.0 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 4.08-3.90 (m, 1H), 3.32 (s, 2H), 2.88 (dd, J=16.6, 3.2 Hz, 1H), 2.65- 2.54 (m, 1H), 2.41-2.09 (m, 3H), 1.99-1.79 (m, 1H), 1.31 (t, J=7.1 Hz, 3H).

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-hexahydroindolizine-3-carbo xylic acid

Step 1: 1-Azido-4-chloro-3-fluoro-2-iodobenzene

To a solution of 4-chloro-3-fluoro-2-iodoaniline (10 g, 36.83 mmol, 1.0 eq.) in CHsCN (100 mL) and azidotrimethylsilane (10 mL) was added tert-butyl nitrite (5.7 g, 55.25 mmol, 1.5 eq.) dropwise. The resulting mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was applied onto a silica gel column to yield of 1-azido-4-chloro-3-fluoro-2- iodobenzene as a yellow solid. LC/MS: mass calculated for CeHaCIFINa: 296.90, measured: 297.00 [M+HJ\

Step 2: 1-(4-Chloro-3-fluoro-2-iodophenyl)-4-(tri-tert-butylstannyl) -1 H-1 ,2,3- triazole

To 1 -azido-4-chloro-3-fluoro-2-iodobenzene (5 g, 16.81 mmol, 1.0 eq.) in toluene (50 mL) was added tributyl(ethynyl)stannane (5.3 g, 16.81 mmol, 1 eq.). The resulting mixture was stirred at 100°C for overnight. The mixture was concentrated. The residue was applied onto a silica gel column to yield 1-(4- chloro-3-fluoro-2-iodophenyl)-4-(tributylstannyl)-1 H-1 ,2,3-triazole as a yellow solid. LC/MS: mass calculated for CaoHaoCIFINsSn: 613.02, measured: 614.00 [Μ+ΗΓ.

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

To 1-(4-chloro-3-fluoro-2-iodophenyl)-4-(tributylstannyl)-1 H-1 ,2,3-triazole (10 g, 16.33 mmol, 1.0 eq.) in CHaCN (100 mL) was added NCS (2.2 g, 16.33 mmol, 1 eq.). The resulting mixture was stirred at 80°C for 4 h, then concentrated. The residue was applied onto a silica gel column to yield 4- chloro1-(4-chloro-3-fluoro-2-iodophenyl)-1 H-1 ,2,3-triazole. LC/MS: mass calculated for CeHaCfcFINa: 356.87, measured: 358.10 [M+H] ⁺ . Step 4: Methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of methyl (3S)-7-hydroxy-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (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 overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with EA/PE (0-100%) to yield methyl (3S)- 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate as a yellow solid. LC/MS: mass calculated for CnHizFaNOe:

343.03, measured: 344.10 [M+H] ⁺ . Step 5: Methyl (3S)-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

Under an inert atmosphere of nitrogen, to a solution of methyl (3S)-5- oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5 _l 8,8a-hexahydroindolizine-3- carboxylate (800 mg, 2.33 mmol, 1.0 equiv) in 1,4-dioxane (10 mL), were added 4,4,4 ^, ,4 ^, ,5,5,5 ^, ,5 ^, -octamethyl-2,2 ^, -bi(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). The reaction mixture was stirred for 2 h at 90 °C. The solids were filtered out by CELITE. The filtrate was concentrated under vacuum to yield methyl (3S)-5-oxo-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C16H24BNO5: 321.17, measured: 322.10 [M+H] ⁺ .

Step 6: Methyl (3S)-7-(3-chloro-6-(4-chloro-1 H-1 ,2,3-triazol-1-yl)-2- fluorophenyl) -5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

Under an inert atmosphere of nitrogen, to a solution of methyl (3S)-5- oxo-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,5,8,8a- hexahydroindolizine-3-cartx)xylate (500 mg, 1.56 mmol, 1.0 equiv) in 1,4- dioxane (10 mL) with H2O (1.0 mL), were added 4-chloro-1-(4-chloro-3-fluoro-2- iodophenyl)-1 H-1, 2, 3-triazole (613 mg, 1.71 mmol, 1.1 equiv), Pd(PPh3)4 (180 mg, 0.156 mmol, 0.1 equiv), K2CO3 (430 mg, 3.11 mmol, 2.0 equiv). The reaction mixture was stirred for 2 h at 90 °C, then concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield methyl (3S)-7- (3-chloro6-(4-chloro-1 H-1 ,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C18H15CI2FN4O3: 424.05, measured: 425.05 [M+H] ⁺ .

Step 7: (3S)-7-(3-Chloro-6-(4-chloro-1 H-1 ,2,3-triazol-1-yl)-2-fluorophenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add

To a solution of methyl (3S)-7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1- yl)-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3 -carboxylate (300 mg, 0.70 mmol, 1.0 equiv) in THF (6 mL), MeOH (2 mL), and H2O (2 mL) was added LiOH (84 mg, 3.51 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 3 h. The pH was adjusted to 5~6 by HCI (2 M) at 0 °C and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated to yield (3S)-7-(3-chloro-6-(4-chloro-1 H-1 ,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a yellow solid. LC/MS: mass calculated for C17H13CI2FN4O3: 410.03, measured: 411.05 [M+H] ⁺ . 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-hexahydroindolizine- 3-carboxylic acid

Step 1: Methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a - hexahydroindolizine-3-carboxylate.

To a mixture of methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-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.) in 1,4-dioxane (50 mL) and water (10 mL) was 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 flushed three times with nitrogen. The solution was stirred at 100°C for 1 h under N2. To the solution was added water and the resulting mixture was extracted with EA twice. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (0→80% EA/PE) to yield methyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for CieHieCIFN ₂ 03: 338.08, measured (ES, m/z): 339.10 [M+H] ⁺ .

Step 2: Methyl (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate. To a mixture of methyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (3.4 g, 10.04 mmol, 1.0 equiv.) and azidotrimethylsilane (2.6 mL, 20.07 mmol, 2.0 equiv.) in acetonitrile (35 mL) was added tert-butyl nitrite (2.4 mL, 20.07 mmol, 2.0 equiv.) at 0 °C. The solution was stirred at room temperature for 1 h. To the mixture was added water and the resulting mixture was extracted with EA twice. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (0→80% EA/PE) to yield methyl 7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for CieHi4CIFN403: 364.07, measured (ES, m/z): 365.10 [M+H] ⁺ .

Step 3: Methyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol- 1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbox ylate.

To a mixture of methyl 7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a -hexahydroindolizine-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 flushed three times with nitrogen. The solution was stirred at 80 °C for 2 h under N2. The solution was concentrated under vacuum and purified by silica gel chromatography (0→60% EA/PE) to yield methyl 7-(3- chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a white solid. LC/MS: mass calculated for C19H15CIF4N4O3: 458.08, measured (ES, m/z): 459.05 [M+H] ⁺ . Step 4: (3S)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ic acid.

To a mixture of methyl 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H- 1 ,2,3- triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-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 h. The mixture was concentrated under vacuum. The resulting residue was purified by reverse phase chromatography on C18 (330 g, ACN/H2O (0.05%CF3COOH): 0→30%) to yield 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ic add as a yellow solid. LC/MS: mass calculated for CieHiaCIFtlsUOa: 444.06, measured (ES, m/z): 445.15 [M+H] ⁺ . Intermediate 6: 7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2-methyl-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

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

To a solution of glycine ethyl ester hydrochloride (50.0 g, 358.22 mmol, 1.0 equiv.) in dichloroethane (500 mL), were added pivaldehyde (33.9 g, 394.04 mmol, 1.1 equiv.), EtsN (39.9 g, 394.04 mmol, 1.1 equiv.), MgSO* (43.1 g, 358.22 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction was filtrated and concentrated to yield ethyl (E)-2-((2,2- dimethylpropylidene)amino)acetate as a white solid. Step 2: 1-Ethyl 5-methyl (E)-2-((2,2-dimethylpropylidene)amino)-3- methylpentanedioate

To a solution of ethyl (E)-2-((2,2-dimethylpropylidene)amino)acetate (55.0 g, 321.19 mmol, 1.0 equiv.) in THF (450 mL) was added UBr (30.7 g, 353.31 mmol, 1.1 equiv.). The reaction mixture was stirred for 10 minutes at room temperature. trans-Methyl crotonate (32.2 g, 321.19 mmol, 1.0 equiv) in THF (100mL) and DBU (48.9 g, 321.19 mmol, 1.0 equiv.) were added to the reaction mixture. The reaction mixture was stirred for 10 minutes at room temperature. The reaction was quenched with water and extracted with EA.

The combined organic layer was washed with brine, dried over NaaSO* and concentrated. The residue was purified by silica gel chromatography (0-30% DCM/MeOH) to yield 1 -ethyl 5-methyl (E)-2-((2,2-dimethylpropylidene)amino)- 3-methylpentanedioate as a yellow oil.

Step 3: Ethyl 3-methyl-5-oxopyrrolidine-2-carboxylate To a solution of 1 -ethyl 5-methyl (E)-2-((2,2-dimethylpropylidene)amino)- 3-methylpentanedioate (55.0 g, 202.69 mmol, 1.0 equiv.) in MeOH (400 mL) with H2O (100 mL) was added CHaCOOH (5mL). The reaction mixture was stirred overnight at 80 °C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0-30% DCM/MeOH) to yield ethyl 3-methyl-5-oxopyrrolidine- 2-carboxylate as a yellow oil.

Step 4: l-(Tert-butyl) 2-ethyl 3-methyl-5-oxopyrrolidine-1,2-dicarboxylate

To a solution of ethyl 3-methyl-5-oxopyrrolidine-2-carboxylate (27.0 g, 157.72 mmol, 1.0 equiv.) and di-tert-butyl dicarbonate (86.1 g, 394.29 mmol,

2.5 equiv.) in dichloromethane (500 mL), were added 4-dimethylaminopyridine (3.9 g, 31.54 mmol, 0.2 equiv.) and triethylamine (43.8 mL, 315.43 mmol, 2.0 equiv.). The reaction mixture was stirred over night at room temperature. The mixture was concentrated. The residue was purified by silica gel chromatography (0-30% EA/PE) to yield 1-(tert-butyl) 2-ethyl 3-methyl-5- oxopyrrolidine-1 ,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C13H21 NO5: 271.14, measured: 565.40 [2M+Na] ⁺ .

Step 5: l-(Tert-butyl) 2-ethyl 5-methoxy-3-methylpyrrolidine-1 ,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl 3-methyl-5-oxopyrrolidine-1 ,2- dicarboxylate (20.0 g, 73.72 mmol, 1.0 equiv.) in THF (300 mL) was added lithium triethylborhydride (110.6 mL, 110.58 mmol, 1.5 equiv, 1M in THF) at - 78 °C. The reaction mixture was stirred for 40 min at -78 °C, then NaHCOa (120 mL) was added at -78 °C and the mixture was warmed to 0 °C. Hydrogen peroxide (15 mL, 30%) was then added. The mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and the resulting mixture was extracted with diethyl ether, washed with brine, dried and concentrated under vacuum to yield a colorless oil. The oil was dissolved in methanol (300 mL), and p-toluenesulfonic acid (1.3 g, 7.37 mmol, 0.1 equiv.) was added. The solution was stirred over night at room temperature. The reaction was quenched with NaHCOa and extracted with diethyl ether. The combined organic layer was washed with brine, dried over Na2S04 and concentrated to yield 1- (tert-butyl) 2-ethyl 5-methoxy-3-methylpyrTOlidine-1,2-dicarboxylateas a colorless oil.

Step 6: 1 -(Tert-butyl) 2-ethyl 5-allyl-3-methylpyrrolidine-1,2-dicarboxylate

To a solution of 1 -(tert-butyl) 2-ethyl 5-methoxy-3-methylpyrrolidine-1,2- dicarboxylate (20.0 g, 69.60 mmol, 1.0 equiv.) in diethyl ether (300 mL), were added allyltrimethylsilane (48.7 ml, 306.25 mmol, 4.4 equiv.) and boron trifluoride etherate (11.9 g, 83.5 mmol, 1.2 equiv.) at -40°C. The reaction mixture was stirred for 30 min at -40 °C, and then warmed to room temperature and stirred for 40 min. The reaction was quenched with N32C03 and extracted with ethoxyethane. The combined organic layer was washed with brine, dried over Na2SO< and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1 -(tert-butyl) 2-ethyl 5- allyl-3-methylpyrrolidine-1 ,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for CiehtoNO*: 297.19, measured: 298.10 [M+H]*. Step 7: Ethyl 5-allyl-3-methylpyrrolidine-2-carboxylate

To a solution of 1 -(tert-butyl) 2-ethyl 5-allyl-3-methylpyrrolidine-1,2- dicarboxylate (15.0 g, 50.44 mmol, 1.0 equiv.) in dichloromethane (200 mL), was added HCI in 1,4-dioxane (150 mL, 4N). The reaction mixture was stirred for 2 h at room temperature. The resulting solution was concentrated under vacuum to yield ethyl 5-allyl-3-methylpyrrolidine-2-carboxylate as a white solid. LC/MS: mass calculated for C11H19NO2: 197.14, measured: 198.05 [M+H] ⁺ .

Step 8: Ethyl 1-acryloyl-5-allyl-3-methylpyrrolidine-2-carboxylate

To a solution of ethyl 5-allyl-3-methylpyrrolidine-2-carboxylate (9.6 g, 41.07 mmol, 1.0 equiv.) in tetrahydrofuran (200 mL) was added triethylamine (28.5 mL, 205.36 mmol, 5.0 equiv.). The reaction mixture was stirred for -78°C and acryloyl chloride (3.7 mL, 45.18 mmol, 1.1 equiv.) was drop-wise under N2. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by water (100 mL) and extracted with ethyl acetate (2 x 100 mL), and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield ethyl 1-acryloyl-5-allyl-3-methylpyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C14H21NO3: 251.15, measured: 252.10 [Μ+ΗΓ.

Step 9: Ethyl 2-methyl-5-oxo-1,2,3 _l 5,8 _l 8a-hexahydroindolizine-3-carboxylate To a solution of ethyl 1-acryloyl-5-allyl-3-methylpyrrolidine-2-carboxylate (12.5 g, 49.74 mmol, 1.0 equiv.) in dichloromethane (400 mL) was added Grubbs catalyst 2nd generation (2.1 g, 2.49 mmol, 0.05 equiv.). The reaction mixture was stirred over night at 45°C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield ethyl 2-methyl-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C12H17NO3: 223.12, measured: 224.05 [M+H] ⁺ . Step 10: Ethyl 7-hydroxy-2-methyl-5-oxooctahydroindolizine-3-carboxylate A flask was charged with copper(l) chloride (0.53 g, 5.38 mmol, 0.2 equiv.) and BINAP (3.3 g, 5.38 mmol, 0.2 equiv.) under nitrogen. Freshly degassed (freeze-pump-thaw) THF (50 mL) was added, and the yellow reaction mixture was stirred for 15 min. Then sodium tert-butoxide (0.52 g, 5.38 mmol, 0.2 equiv.) was added in one portion and stirring was continued for 30 min.

Bis(pinacolato)diboron (8.2 g, 32.25 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 10 min, then a solution of ethyl 2-methyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (6.0 g, 26.87 mmol, 1.0 equiv.) in THF (10 mL) was added, followed by addition of MeOH (1.7 g, 53.75 mmol, 2.0 equiv.). After stirring overnight, 30% hydrogen peroxide (30.5 mL, 268.74 mmol, 10.0 equiv.) was added at 0 °C. The resulting solution was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0-10% MeOH/DCM) to yield ethyl 7-hydroxy-2-methyl-5-oxooctahydroindolizine-3-carboxylate as a yellow oil LC/MS: mass calculated for C12H19NO4: 241.13, measured: 242.25 [M+H]+, and ethyl 2-methyl- 5-oxo-7-(4, 4,5, 5-tetramethyM, 3, 2-dioxaborolan-2- yl)octahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for CieH3oBN05: 351.22, measured: 352.30 [M+H] ⁺ .

Step 11: Ethyl 7-hydroxy-2-methyl-5-oxooctahydroindolizine-3-carboxylate To a solution of ethyl 2-methyl-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)octahydroindolizine-3-carboxylate (4.8 g, 13.67 mmol, 1.0 equiv. in THF/H2O (50 mL, 4/1), was added sodium perborate trihydrate (5.59 g, 68.33 mmol, 5.0 equiv.). The reaction mixture was stirred over night at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0-10% MeOH/DCM) to yield ethyl 7-hydroxy-2- methyl-5-oxooctahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C12H19NO4: 241.13, measured: 242.25 [M+H]*.

Step 12: Ethyl 2-methyl-5,7-dioxooctahydroindolizine-3-carboxylate

To a solution of ethyl 7-hydroxy-2-methyl-5-oxooctahydroindolizine-3- carboxylate (5.9 g, 24.45 mmol, 1.0 equiv.) in dichloromethane (200 mL), was added pyridinium chlorochromate (10.5 g, 48.91 mmol, 2.0 equiv.). The reaction mixture was stirred over night at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0- 10% MeOH/DCM) to yield ethyl 2-methyl-5,7-dioxooctahydroindolizine-3- carboxylate as a brown oil. LC/MS: mass calculated for C12H17NO4: 239.12, measured: 240.25 [M+H]*. Step 13: Ethyl 2-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8, 8a- hexahydroindolizine-3-carboxylate

To a solution of ethyl 2-methyl-5,7-dioxooctahydroindolizine-3- carboxylate (4.0 g, 16.72 mmol, 1.0 equiv.) in dichloromethane (50 mL), were added triethylamine (3.4 g, 33.44 mmol, 2.0 equiv.) and 1,1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (7.2 g, 20.06 mmol, 1.2 equiv.). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-60% EA/PE) to yield ethyl 2-methyl-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate as a yellow oil. LC/MS: mass calculated for CiaHieFaNOeS: 371.07, measured: 372.15 [M+H]*.

Step 14: Ethyl 7-(6-amino-3-chloro-2-fluorophenyl)-2-methyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of ethyl 2-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (6.0 g, 16.16 mmol, 1.0 equiv.), were added (6-amino-3-chloro-2-fluorophenyl)boronic acid (3.7 g, 19.39 mmol, 1.2 equiv.), potassium carbonate (4.5 g, 32.32 mmol 2.0 equiv.) in 1,4- dioxane/H20 (100 mL, 10/1), and [1 , 1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (0.59 g, 0.81 mmol, 0.1 equiv.). The reaction mixture was stirred for 2 h at 80 °C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield ethyl 7-(6-amino-3-chloro-2- fluorophenyl)-2-methyl-5-oxo-1,2,3 _l 5,8,8a-hexahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C18H20CIFN2O3: 366.11, measured: 367.20 [M+H]*. Step 15: 7-(6-Amino-3-chloro-2-fluorophenyl)-2-methyl-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid

To a solution of ethyl 7-(6-amino-3-chloro-2-fluorophenyl)-2-methyl-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (5.0 g, 13.63 mmol, 1.0 equiv.) in THF/H20/MeOH (100 mL, 3/1/1), was added lithium hydroxide (2.7 g, 68.15 mmol, 5.0 equiv.) The reaction mixture was stirred for 1h at room temperature. The residue was adjusted to pH 4 with HCI, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield 7-(6-amino-3-chloro-2-fluorophenyl)-2-methyl-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid as a brown solid. Step 16: 7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2-methyl-5- oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of 7-(6-amino-3-chloro-2-fluorophenyl)-2-methyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (2.1 g, 6.20 mmol, 1.0 equiv.) in acetic acid (30 mL) were added azidotrimethylsilane (7.1 g, 61.99 mmol, 10.0 equiv.), and trimethoxymethane (6.6 g, 61.99 mmol, 10.0 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted with EA. The combined extracts were washed with water, dried over Na2SO*, filtered and purified by silica gel chromatography (0 - 20 % DCM/methanol) to yield 7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2-methyl-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylic acid as a yellow solid. LC/MS: mass calculated for C17H15CIFN5O3: 391.08, measured 392.10 [M+H] ⁺ . Intermediate 7: (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,1- dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

Step 1: 1-(Tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2- dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2- dicarboxylate (20.0 g, 82.20 mmol, 1.0 equiv.) in tetrahydrofuran (300 mL), was added lithium bis(trimethylsilyl)amide (86.0 mL, 86.30 mmol, 1.05 equiv.) at - 78°C. The reaction mixture was stirred for 1h at -78 °C, then iodomethane (7.7 mL, 123.30 mmol, 1.5 equiv.) was added at -78°C. The reaction mixture was warmed to room temperature, then stirred for anther 1h. The reaction was quenched by water (200 mL), extracted with ethyl acetate (2 x 200 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to yield l-(tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine-1 ,2-dicarboxylate as a white solid. LC/MS: mass calculated for C13H21NO5: 271.14, measured: 565.25 [2M+Na] ⁺ .

Step 2: 1-(Tert-butyl) 2-methyl (2S)-5-methoxy-4,4-dimethylpyrrolidine-1,2- dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S)-4,4-dimethyl-5-oxopyrrolidine- 1 ,2-dicarboxylate (10.0 g, 36.86 mmol, 1.0 equiv.) in THF (200 mL), was added lithium triethyl borhydride (55.3 mL, 55.3 mmol, 1.5 equiv., 1M in THF) drop- wise at -78 °C. The reaction mixture was stirred for 40 min at -78 °C, then Na2COa (50 mL) was added at -78 °C and the mixture was warmed to 0 °C. Hydrogen peroxide (10 mL, 30%) was added. The mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and the resulting mixture was extracted with ethyl acetate, washed with brine, dried and concentrated under vacuum to yield a colorless oil. The oil was dissolved in methanol (200 mL), and p-toluenesulfonic acid (0.60 g, 3.69 mmol, 0.1 equiv.) was added. The resulting solution was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated to yield 1 -(tert-butyl) 2-methyl (2S)-5-methoxy-4,4- dimethylpyrrolidine-1 ,2-dicarboxylate as a colorless oil.

Step 3: 1 -(Tert-butyl) 2-methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-1 ,2- dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2S)-5-methoxy-4,4- dimethylpyrrolidine-1 ,2-dicarboxylate (9.3 g, 32.36 mmol, 1.0 equiv.) in ethoxyethane (200 mL), were added allyltrimethylsilane (22.6 ml, 142.40 mmol, 4.4 equiv.) and boron trifluoride etherate (5.5 g, 38.80 mmol, 1.2 equiv.) at - 40°C. The reaction mixture was stirred for 30 min at -40 °C, and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na2COa and extracted with ethoxyethane. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1- (tert-butyl) 2-methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-1 ,2-dicarboxylate as a colorless oil. Step 4: Methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate To a solution of 1 -(tert-butyl) 2-methyl (2S)-5-allyl-4,4- dimethylpyrrolidine-1,2-dicarboxylate (5.2 g, 17.49 mmol, 1.0 equiv.) in dichloromethane (50 mL), was added HCI in 1,4-dioxane (50 mL, 4N). The reaction mixture was stirred for 2 h at room temperature. The solution was concentrated under vacuum to yield methyl (2S)-5-allyl-4,4-dimethylpyrrolidine- 2-carboxylate as a white solid.

Step 5: Methyl (2S)-1-acryloyl-5-allyl-4,4-dimethylpyrrolidine-2-carboxylat e

To a solution of methyl (2S)-5-allyl-4,4-dimethylpyrrolidine-2-carboxylate (3.2 g, 0.96 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL), was added triethylamine (11.3 mL, 81.1 mmol, 5.0 equiv.). The reaction mixture was stirred for -78 °C and acryloyl chloride (1.5 mL, 17.80 mmol, 1.1 equiv.) was added drop-wise under N2. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by water and extracted with ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (2S)-1-acryloyl-5-allyl-4,4-dimethylpyrrolidine-2- carboxylate as a yellow oil. LC/MS: mass calculated for C14H21NO3: 251.15, measured: 252.20 [M+H]*.

Step 6: Methyl (3S)-1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3- carboxylate

To a solution of methyl (2S)-1-acryloyl-5-allyl-4,4-dimethylpyrrolidine-2- carboxylate (3.6 g, 14.30 mmol, 1.0 equiv.) in dichloromethane (100 mL), was added Grubbs Catalyst 2 ^nd generation (609 mg, 0.70 mmol, 0.05 equiv.). The reaction mixture was stirred over night at 45°C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (3S)- 1,1-dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbox ylate as a brown oil. LC/MS: mass calculated for C12H17NO3: 223.12, measured: 224.20 [M+H]*. Step 7: Methyl (3S)-7-hydroxy-1,1-dimethyl-5-oxooctahydroindolizine-3- carboxylate

A flask was charged with copper (I) chloride (0.24 g, 2.42 mmol, 0.2 equiv.) and BINAP (1.5 g, 2.42 mmol, 0.2 equiv.) under nitrogen. Freshly degassed (freeze-pump-thaw) THF (40 mL) was added, and the yellow reaction mixture was stirred for 15 min. Then sodium tert-butoxide (0.23 g, 2.42 mmol, 0.2 equiv.) was added in one portion and stirring was continued for 30 min. Bis(pinacolato)diboron (3.7 g, 14.50 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 10 min, then a solution of methyl (3S)-1,1- dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylat e (2.7 g, 12.10 mmol, 1.00 equiv.) in THF (10 mL) was added, followed by addition of MeOH (0.78 g, 24.20 mmol, 2 equiv.). After stirring overnight, 30% hydrogen peroxide (13.7 mL, 120.9 mmol, 10 eq) was added at 0 °C. The resulting solution was stirred 1 h at room temperature. The mixture was concentrated under vacuum. The residue as purified by C18 (0-40% H2O/CH3CN) to yield methyl (3S)-7- hydroxy-1,1-dimethyl-5-oxooctahydroindolizine-3-carboxylate as a colorless oil. LC/MS: mass calculated for C12H19NO4: 241.13, measured: 242.20 [M+H]*. Step 8: Methyl (3S)-1 , 1-dimethyl-5,7-dioxooctahydroindolizine-3-carboxylate To a solution of methyl (3S)-7-hydroxy-1 , 1-dimethyl-5- oxooctahydroindolizine-3-carboxylate (2.2 g, 9.12 mmol, 1.0 equiv.) in dichloromethane (100 mL), was added pyridinium chlorochromate (3.9 g, 18.20 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at room temperature. The residue was applied onto a silica gel column with DCM/MeOH (10:1) to yield methyl (3S)-1,1-dimethyl-5,7-dioxooctahydroindolizine-3- carboxylate as a brown oil. LC/MS: mass calculated for C12H17NO4: 239.12, measured: 240.20 [M+H]*. Step 9: Methyl (3S)-1,1-dimethyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (3S)-1,1-dimethyl-5,7-dioxooctahydroindolizine-3- carboxylate (2.2 g, 9.20 mmol, 1.0 equiv.) in dichloromethane (50 mL), were added triethylamine (1.9 g, 18.40 mmol, 2.0 equiv.) and 1,1,1-trifluoroN- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.9 g, 11.0 mmol, 1.2 equiv.). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by silica gel chromatography (0-80% EA/PE) to yield methyl (3S)-1,1-dimethyl-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate as a yellow oil. LC/MS: mass calculated for CiaHieFaNOeS: 371.07, measured: 372.10 [M+H] ⁺ .

Step 10: Methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (3S)-1,1-dimethyl-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate (2.0 g, 5.40 mmol, 1.0 equiv.), (6-amino-3-chloro-2-fluorophenyl) boronic add (1.2 g, 6.50 mmol, 1.2 equiv.) and potassium carbonate (1.5 g, 10.77 mmol 2.0 equiv.) in 1,4-dioxane/H20 (50 mL, 10/1), was added [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (197 mg, 0.27 mmol, 0.05 equiv.). The reaction mixture was stirred for 2 h at 80 °C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over NaaSO* and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield methyl (3S)- 7-(6-amino-3-chloro-2-fluorophenyl)-1 , 1-dimethyl-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C18H20CIFN2O3: 366.11, measured: 367.05 [M+H] ⁺ . Step 11: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1- dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylat e (1.8 g, 4.90 mmol, 1.0 equiv.) in THF/H ₂ 0/MeOH (20 mL, 3/1/1), was added lithium hydroxide (0.98 g, 24.5 mmol, 5.0 equiv.). The reaction mixture was stirred for 1h at room temperature. The residue was adjusted to pH 4 with HCI, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid. LC/MS: mass calculated for C17H18CIFN2O3: 352.10, measured: 353.15 [M+H] ⁺ . Step 12: (3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-1 ,1-dimethyl-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add

To a solution of (3S)-7-(6-amino3-chloro-2-fluorophenyl)-1,1-dimethyl-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.85 mmol, 1.0 equiv.) in acetic add (5 mL), were added azidotrimethylsilane (0.56 mL,

4.25 mmol, 5.0 equiv) and trimethoxymethane (0.46 mL, 4.25 mmol, 5.0 equiv.). The reaction mixture was stirred over night at room temperature. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to yield (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 , 1 -dimethyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add as a brown solid. LC/MS: mass calculated for C18H17CIFN5O3: 405.10, measured: 406.20 [M+H] ⁺ .

Intermediate 8: (1 S,3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 - methyl-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

Step 1: 1-(Tert-butyl) 2-methyl (S,E)-4-((dimethylamino)methylene)-5- oxopyrrolidine-1 ,2-dicarboxylate

To a solution of l-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1 ,2- dicarboxylate (20.0 g, 82.22 mmol, 1.0 equiv.) in 1 ,2-dimethoxyethane (100 mL), was added l-tert-butoxy-N.N.N'.N'-tetramethylmethanediamine (21.49 g, 123.33 mmol, 1.5 equiv.). The reaction mixture was stirred overnight at 70 °C. The residue was applied onto a silica gel column with ethyl acetate/DCM (2:3) to yield 1-(tert-butyl) 2-methyl (S,E)-4-((dimethylamino)methylene)-5- oxopyrrolidine-1 ,2-dicarboxylate as a white solid.

¹ H NMR (300 MHz, Chloroform-d) 6 7.15 (t, J = 1.7 Hz, 1H), 4.57 (dd, J = 10.7, 3.7 Hz, 1H), 3.77 (s, 3H), 3.19 - 3.34 (m, 1H), 3.03 (s, 6H), 2.91 (ddd, J = 14.7, 4.1, 1.5 Hz, 1H), 1.51 (s, 9H).

Step 2: 1-(Tert-butyl) 2-methyl (2S,4S)-4-methyl-5-oxopyrrolidine-1,2- dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (S,E)-4- ((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylat e (10.0 g, 33.50 mmol, 1.0 equivO) in isopropanol (1000 mL), was added Pd/C (2.0 g, 10%). The reaction mixture was stirred overnight at room temperature under an atmosphere of hydrogen. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (0-45%) to yield 1-(tert-butyl) 2-methyl (2S,4S)-4-methyl-5- oxopyrrolidine-1,2-dicarboxylate as a white solid. LC/MS: mass calculated for C12H19NO5: 257.13, measured: 537.25 [2M+Na] ⁺ . Step 3: 1-(Tert-butyl) 2-methyl (2S,4S)-5-methoxy-4-methylpyrrolidine-1,2- dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-4-methyl-5-oxopyrrolidine- 1 ,2-dicarboxylate (15.0 g, 58.30 mmol, 1.0 equiv.) in THF (300 mL), was added lithium triethylborhydride (87.5 mL, 87.50 mmol, 1.5 equiv., 1M in THF) drop- wise at -78 °C. The reaction mixture was stirred for 40 min at -78 °C, then NaaCOa (100 mL) was added at -78 °C and the mixture was warmed to 0 °C. Hydrogen peroxide (8 mL, 30%) was then added. The mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and the resulting mixture was extracted with ethyl acetate, washed with brine, dried and concentrated under vacuum to yield a colorless oil. The oil was re-dissolved by methanol (300 mL), followed by the addition of p-toluenesulfonic add (1.0 g, 5.83 mmol, 0.1 equiv.). The resulting solution was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated to yield 1 -(tert-butyl) 2-methyl (2S,4S)-5-methoxy-4- methylpyrrolidine-1 ,2-dicarboxylate as a yellow oil.

Step 4: 1 -(Tert-butyl) 2-methyl (2S,4S)-5-allyl-4-methylpyrrolidine-1,2- dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl (2S,4S)-5-methoxy-4- methylpyrrolidine-1,2-dicarboxylate (13.0 g, 47.60 mmol, 1.0 equiv.) in ethoxyethane (200 mL), were added allyltrimethylsilane (33.3 ml, 209.30 mmol, 4.4 equiv.) and boron trifluoride etherate (8.1 g, 57.10 mmol, 1.2 equiv.) at - 40°C. The reaction mixture was stirred for 30 min at -40 °C, and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na2COa and extracted with ethoxyethane. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1- (tert-butyl) 2-methyl (2S,4S)-5-allyl-4-methylpyrrolidine-1 ,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C15H25NO4: 283.18, measured: 306.10 [M+Na] ⁺ .

Step 5: Methyl (2S,4S)-5-allyl-4-methylpyrrolidine-2-carboxylate To a solution of 1 -(tert-butyl) 2-methyl (2S,4S)-5-allyl-4- methylpyrrolidine-1,2-dicarboxylate (9.6 g, 33.90 mmol, 1.0 equiv.) in dichloromethane (100 mL) was added HCI in 1,4-dioxane (100 mL, 4 N). The reaction mixture was stirred for 1h at room temperature, then concentrated under vacuum to yield methyl (2S,4S)-5-allyl-4-methylpyrrolidine-2-carboxylate as a white solid. LC/MS: mass calculated for C10H17NO2: 183.13, measured: 184.05 [M+H]*.

Step 6: Methyl (2S,4S)-1-acryloyl-5-allyl-4-methylpyrrolidine-2-carboxylate

To a solution of methyl (2S,4S)-5-allyl-4-methylpyrrolidine-2-carboxylate (3.9 g, 21.10 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL) was added triethylamine (14.6 mL, 105.30 mmol, 5.0 equiv.). The reaction mixture was stirred for -78 °C and acryloyl chloride (1.9 mL, 23.20 mmol, 1.1 equiv.) was added under N2. The reaction mixture was stirred for 2 h at room temperature, quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL), the organic layers were combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (2S,4S)-1-acryloyl-5-allyl-4-methylpyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C12H18N2O3: 237.14, measured: 238.10 [M+H]*.

Step 7: Methyl (1S,3S)-1-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3- carboxylate

To a solution of methyl (2S,4S)-1-acryloyl-5-allyl-4-methylpyrrolidine-2- carboxylate (3.0 g, 12.64 mmol, 1.0 equiv.) in dichloromethane (50 mL), was added Grubbs Catalyst 2 ^nd generation (538 mg, 0.63 mmol, 0.05 equiv.). The reaction mixture was stirred overnight at 45 °C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (3S)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C11H15NO3: 209.11, measured: 210.10 [M+H]*. Step 8: Methyl (1S,3S)-7-hydroxy-1-methyl-5-oxooctahydroindolizine-3- carboxylate

A flask was charged with copper (I) chloride (242 mg, 2.40 mmol, 0.2 equiv.) and BINAP (1.5 g, 2.40 mmol, 0.2 equiv.) under nitrogen. Freshly degassed (freeze-pump-thaw) THF (40 mL) was added, and the yellow reaction mixture was stirred for 15 min. Then sodium tert-butoxide (235 mg, 2.40 mmol, 0.2 equiv.) was added in one portion and the stirring was continued for 30 min. Bis(pinacolato)diboron (3.7 g, 14.70 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 10 min, then a solution of methyl (1S,3S)-1- methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-cartx)xylate (2.6 g, 12.24 mmol, 1.0 equiv.) in THF (10 mL) was added, followed by addition of MeOH (784 mg, 24.5 Ommol, 2.0 equiv.). After 16h, 30% hydrogen peroxide (13.9 g, 122.30 mmol, 10.0 equiv.) was added at 0 °C. The resulting solution was stirred

1 h at room temperature. The mixture was concentrated under vacuum. The residue was purified by C18 (0-40% H2O/CH3CN) to yield methyl (1S,3S)-7- hydroxy-1-methyl-5-oxooctahydroindolizine-3-carboxylate as a colorless oil. LC/MS: mass calculated for C11H17NO4: 227.12, measured: 228.10 [M+H]*. Step 9: Methyl (1S,3S)-1-methyl-5,7-dioxooctahydroindolizine-3-carboxylate To a solution of methyl (1S,3S)-7-hydroxy-1-methyl-5- oxooctahydroindolizine-3-carboxylate (2.6 g, 11.44 mmol, 1.0 equiv.) in dichloromethane (250 mL), was added pyridinium chlorochromate (4.9 g, 22.88 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at room temperature. The residue was applied onto a silica gel column with DCM/MeOH (10:1) to yield methyl (1S,3S)-1-methyl-5,7-dioxooctahydroindolizine-3- carboxylate as a yellow oil. LC/MS: mass calculated for C11H15NO4: 225.10, measured: 226.05 [M+H]*.

Step 10: Methyl (1S,3S)-1-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (1S,3S)-1 -methyl-5, 7-dioxooctahydroindolizine-3- carboxylate (1.3 g, 5.80 mmol, 1.0 equiv.) in dichloromethane (30 mL), were added triethylamine (1.2 g, 11.50 mmol, 2.0 equiv.) and 1,1,1-trifluoro-N-phenyl- N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.5 g, 6.90 mmol, 1.2 equiv.). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated. The residue was purified by silica gel chromatography (0- 40% EA/PE) to yield methyl (1S,3S)-1-methyl-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate as a yellow oil. LC/MS: mass calculated for CiaHuFsNOeS: 357.05, measured: 358.00 [M+H]*.

Step 11: Methyl (1S,3S)-7-(6-amino-3-chloro-2-fiuorophenyl)-1-methyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate To a solution of methyl (1S,3S)-1-methyl-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1 _l 2 _l 3 _l 5,8,8a-hexahydroindolizine-3-carboxylate (1.5 g, 4.20 mmol, 1.0 equiv.), (6-amino-3-chloro-2-fluorophenyl) boronic add (0.95 g, 5.00 mmol, 1.2 equiv.) and potassium carbonate (1.2 g, 8.40 mmol 2.0 equiv.) in 1,4-dioxane/H20 (20 mL, 10/1), was added [1,1 -

Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (154 mg, 0.21 mmol,

0.1 equiv.). The reaction mixture was stirred for 2 h at 80 °C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO< and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield methyl (1S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C17H18CIFN2O3: 352.10, measured: 353.10 [M+H] ⁺ .

Step 12: (1S,3S)-7-(6-Amino-3-chloro2-fluorophenyl)-1-methyl-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of methyl ( 1 S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 1 - methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.3 g, 3.69 mmol, 1.0 equiv.) in THF/hkO/MeOH (15 mL, 3/1/1), was added lithium hydroxide (737 mg, 18.40 mmol, 5.0 equiv.). The reaction mixture was stirred for 1 h at room temperature. The residue was adjusted to pH 4 with HCI, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (1S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl- 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a yellow solid. LC/MS: mass calculated for CieHieCIFlskOa: 338.08, measured: 339.05 [M+H]*. Step 13: (1S,3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1-m ethyl-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add

To a solution of (1S,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methyl-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (500 mg, 1.50 mmol,

1.0 equiv) in acetic acid (10 mL), were added azidotrimethylsilane (0.97 mL, 7.38 mmol, 5.0 equiv.) and trimethoxymethane (0.8 mL, 7.38 mmol, 5.0 equiv.).

The reaction mixture was stirred over night at room temperature. The residue was purified by silica gel chromatography (0-100% EtOAc/petroleum ether) to yield (1 S,3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 1 -methyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid. LC/MS: mass calculated for C17H15CIFN5O3: 391.08, measured: 392.15 [M+H] ⁺ . Intermediate 9: (1 R,3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -y l)phenyl)-1 - methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

Step 1: 1-(Tert-butyl) 2-methyl (2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate To a solution of 1 -(tert-butyl) 2-methyl 4-hydroxypyrrolidine-1 ,2- dicarboxylate (10.0 g, 40.77 mmol, 1.0 equiv.) in N,N-dimethylformamide (150 mL), was added sodium hydride (1.8 g, 44.85 mmol, 1.1 equiv.) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. lodomethane (11.6 g, 81. mmol, 2.0 equiv.) was added. The reaction mixture was stirred over night at room temperature. The reaction was quenched with water extracted with ethoxyethane. The combined organic layer was washed with brine, dried over NaaSO* and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1 -(tert-butyl) 2-methyl 4-methoxypyrrolidine- 1 ,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for C12H21NO5: 259.14, measured: 160.20 [M-Boc] ⁺

Step 2: 1 -(Tert-butyl) 2-methyl (2S,4R)-4-methoxy-5-oxopyrrolidine-1,2- dicarboxylate

To a solution of sodium periodate (20.6 g, 96.41 mmol, 2.5 equiv.) in H2O (160 mL) was added ruthenium trichloride (1.6 g, 7.71 mmol, 0.2 equiv.) under nitrogen. The resulting solution was stirred for 5 minutes followed by addition of 1 -(tert-butyl) 2-methyl 4-methoxypyrrolidine-1 ,2-dicarboxylate (10.0 g, 38.57 mmol, 1.0 equiv.) in EtOAc (88 mL) in one portion. The mixture was stirred overnight at room temperature. The reaction was extracted with ethyl acetate (2 x 100 mL) and washed with Na2SOa solution (100 mL), the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to yield 1 -(tert- butyl) 2-methyl (2S,4R)-4-methoxy-5-oxopyrrolidine-1 ,2-dicarboxylate as a yellow oil. LC/MS: mass calculated for Ci2HigNOe: 273.12, measured: 569.30 [2M+Na] ⁺ . Step 3: 1 -(Tert-butyl) 2-methyl (2S,4R)-4,5-dimethoxypyrrolidine-1 ,2- dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2S,4R)-4-methoxy-5- oxopyrrolidine-1 ,2-dicarboxylate (6.5 g, 23.79 mmol, 1.0 equiv.) in THF (100 mL), was added lithium triethylborhydride (35.7 mL, 35.7 mmol, 1.5 equiv., 1M in THF) at -78 °C. The reaction mixture was stirred for 40 min at -78 °C, then NaHCOs (40 mL) was added at -78 °C and the mixture was warmed to 0 °C. Hydrogen peroxide (4 mL, 30%) was then added. The mixture was stirred for 30 min at room temperature. THF was removed under vacuum, and the residue was extracted with diethyl ether, washed with brine, dried and concentrated under vacuum to yield a colorless oil. The oil was re-dissolved in methanol (100 mL) followed by the addition of p-toluenesulfonic acid (410 mg, 2.38 mmol, 0.1 equiv.). The solution was stirred overnight at room temperature, quenched with NaHCOa and extracted with diethyl ether. The combined organic layer was washed with brine, dried over NaaSO* and concentrated to yield 1 -(tert-butyl) 2- methyl (2S,4R)-4,5-dimethoxypyrrolidine-1 ,2-dicarboxylate as a colorless oil. Step 4: 1 -(Tert-butyl) 2-methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-1,2- dicarboxylate

To a solution of 1 -(tert-butyl) 2-methyl (2S,4R)-4,5-dimethoxypyrrolidine- 1 ,2-dicarboxylate (5.0 g, 17.28 mmol, 1.0 equiv.) in diethyl ether (100 mL), were added allyltrimethylsilane (12.1 ml, 76.04 mmol, 4.4 equiv.) and boron trifluoride etherate (2.9 g, 20.74 mmol, 1.2 equiv.) at -40°C. The reaction mixture was stirred for 30 min at -40 °C, and then warmed to room temperature and stirred for 40 min. The reaction was quenched with Na2COa and extracted with ethoxyethane. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0-30% EtOAc/petroleum ether) to yield 1 -(tert-butyl) 2-methyl (2S)-5-allylpyrrolidine-1,2-dicarboxylate as a yellow oil. Step 5: Methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-2-carboxylate

To a solution of 1-(tert-butyl) 2-ethyl 5-allyl-3-methylpyrrolidine-1 ,2- dicarboxylate (12.6 g, 42.09 mmol, 1.0 equiv.) in dichloromethane (200 mL), was added HCI in 1,4-dioxane (120 mL, 4N). The reaction mixture was stirred for 2 h at room temperature. The solution was concentrated under vacuum to yield methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-2-carboxylate as a white solid. LC/MS: mass calculated for C10H17NO3: 199.12, measured: 200.05 [M+H]*.

Step 6: Methyl (2S,4R)-1-acryloyl-5-allyl-4-methoxypyrrolidine-2-carboxylat e To a solution of methyl (2S,4R)-5-allyl-4-methoxypyrrolidine-2- carboxylate (9.6 g, 40.73 mmol, 1.0 equiv.) in tetrahydrofuran (200 mL), was added triethylamine (28.3 mL, 203.64 mmol, 5.0 equiv.) added. The reaction mixture was stirred for -78°C and acryloyl chloride (3.6 mL, 44.80 mmol, 1.1 equiv.) was added under N2. The reaction mixture was stirred for 2 h at room temperature. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 x 100 mL) and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (2S,4R)-1- acryloyl-5-allyl-4-methoxypyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C13H19NO4: 253.13, measured: 254.10 [M+H]*.

Step 7: Methyl (1R,3S)-1-methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3- carboxylate

To a solution of methyl (2S,4R)-1-acryloyl-5-allyl-4-methoxypyrrolidine-2- carboxylate (8.5 g, 33.56 mmol, 1.0 equiv.) in dichloromethane (200 mL), was added Grubbs Catalyst 2 ^nd generation (1.4 g, 1.68 mmol, 0.05 equiv.). The reaction mixture was stirred over night at 45°C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3) to yield methyl (1 R,3S)-1-methoxy-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C11H15NO4: 223.12, measured: 226.10 [M+H]*.

Step 8: Methyl (1R,3S)-7-hydroxy-1-methoxy-5-oxooctahydroindolizine-3- carboxylate A flask was charged with copper(l) chloride (264 mg, 2.66 mmol, 0.2 equiv.) and BINAP (1.7 g, 2.66 mmol, 0.2 equiv.) under nitrogen. Freshly degassed (freeze-pump-thaw) THF (200 mL) was added, and the yellow reaction mixture was stirred for 15 min. Then sodium tert-butoxide (256 mg, 2.66 mmol, 0.2 equiv.) was added in one portion and stirring was continued for

30 min. bis(pinacolato)diboron (4.1 g, 15.98 mmol, 1.2 equiv.) was added and the reaction mixture was stirred for 10 min, then a solution of methyl (1R,3S)-1- methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (3.0 g, 13.32 mmol, 1.0 equiv.) in THF (40 mL) was added, followed by addition of MeOH (0.85 g, 26.64 mmol, 2.0 equiv.). After stirring overnight, 30% hydrogen peroxide (15.1 mL, 133.19 mmol, 10.0 equiv.) was added at 0 °C. The resulting solution was stirred over night at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0- 10% MeOH/DCM) to yield methyl (1R,3S)-7-hydroxy-1-methoxy-5- oxooctahydroindolizine-3-carboxylate as a yellow oil and LC/MS: mass calculated for C11H17NO5: 243.11, measured: 244.10 [M+H] ⁺ , methyl (1R,3S)-1- methoxy-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)octahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for Ci7H ₂ 8BNOe: 353.20, measured: 354.20 [M+H] ⁺ . Step 9: Methyl (1R,3S)-7-hydroxy-1-methoxy-5-oxooctahydroindolizine-3- carboxylate

To a solution of methyl (1R,3S)-1-methoxy-5-oxo-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)octahydroindolizine-3-carboxylate (3.8 g, 10.76mmol, 1.0 equiv.) in THF/H2O (40 mL, 3/1), was added sodium perborate trihydrate (4.4 g, 53.79 mmol, 5.0 equiv.). The reaction mixture was stirred over night at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0-10% MeOH/DCM) to yield methyl (1R,3S)- 7-hydroxy-1-methoxy-5-oxooctahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C11H17NO5: 243.11, measured: 244.20 [M+H]*. Step 10: Methyl (1R,3S)-1-methoxy-5,7-dioxooctahydroindolizine-3-carboxylate To a solution of methyl (1R,3S)-7-hydroxy-1-methoxy-5- oxooctahydroindolizine-3-carboxylate (3.4 g, 13.98 mmol, 1.0 equiv.) in dichloromethane (150 mL), was added pyridinium chlorochromate (6.0 g, 27.95 mmol, 2.0 equiv.). The reaction mixture was stirred over night at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column (0-10% MeOH/DCM) to yield methyl (1R,3S)-1- methoxy-5,7-dioxooctahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C11H15NO5: 241.10, measured: 242.20 [M+H]*.

Step 11: Methyl (1R,3S)-1-methoxy-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (1R,3S)-1-methoxy-5,7-dioxooctahydroindolizine- 3-carboxylate (2.3 g, 9.53 mmol, 1.0 equiv.) in dichloromethane (30 mL), were added triethylamine (1.9 g, 19.07 mmol, 2.0 equiv.) and 1,1,1 -trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (4.1 g, 11.44 mmol, 1.2 equiv.). The reaction mixture was stirred over night at room temperature. The mixture was concentrated. The residue was purified by silica gel chromatography (0-60% EA/PE) to yield methyl (1R,3S)-1-methoxy-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C12H14F3NO7S: 373.04, measured: 374.05 [M+H]*.

Step 12: Methyl (1R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of methyl (1R,3S)-1-methoxy-5-oxo7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate (3.0 g, 8.04 mmol, 1.0 equiv.), (6-amino-3-chloro-2-fluorophenyl)boronic acid (1.8 g, 9.64 mmol, 1.2 equiv.) and potassium carbonate (2.2 g, 16.07 mmol, 2.0 equiv.) in 1,4-dioxane/H20 (50 mL, 10/1), was added [1,T- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (294 mg, 0.40 mmol, 0.1 equiv.). The reaction mixture was stirred for 2 h at 80 °C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over NaaSO* and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield methyl (1 R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C17H18CIFN2O4: 368.09, measured: 369.10 [M+H] ⁺ .

Step 13: (1R,3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-1-methoxy-5-oxo- 1 ^.d.S.e.ea-hexahydroindolizine-S-carboxylic acid

To a solution of methyl (1R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1- methoxy-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-cartx)xylate (2.2 g, 5.97 mmol, 1.0 equiv.) in THF/hkO/MeOH (50 mL, 3/1/1), was added lithium hydroxide (1.2 g, 29.83 mmol, 5.0 equiv.). The reaction mixture was stirred for 1 h at room temperature. The residue was adjusted to pH 4 with HCI, then extracted with ethyl acetate and washed with brine, dried and concentrated under vacuum to yield (1 R,3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1-methoxy- 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid.

Step 14: (1 R,3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-1-methoxy-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add

To a mixture of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1- methoxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (1.0 g, 2.82 mmol, 1.0 equiv.) in acetic add (15 mL) were added trimethoxymethane (3.0 g, 28.19 mmol, 10.0 equiv.) and azidotrimethylsilane (3.2 g, 28.19 mmol, 10.0 equiv.). The reaction mixture was stirred at room temperature, overnight. The resulting mixture was then washed with water (3x20 mL), dried over Na2SC>4, and concentrated. The residue was applied onto a silica gel column (MeOH/DCM: 1/10) to yield of methyl (3S)-5-oxo-7-

(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroin dolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C17H15CIFN5O4: 407.08, measured: 408.10 [M+H] ⁺ .

Intermediate 10: (6-amino-3-chloro-2-fluorophenyl)boronic acid

„OH

Cl

F OH

Step 1: N-(4-Chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

To a mixture of 4-chloro-3-fluorobenzenamine (20 g, 137.398 mmol, 1.00 equiv) and NazCOs (24.7 g, 233.58 mmol, 1.70 equiv) in EbO (400 mL) was added TFAA (34.6 g, 164.88 mmol, 1.20 equiv) dropwise with stirring at -10°C. The mixture was slowly warmed to room temperature overnight. The mixture was then diluted with hexane (400 mL) and filtered. The filtrate was washed with saturated sodium bicarbonate solution (2 x 200 mL), brine (2 x 200 mL), dried over NaaSO*, and filtered. The filtrate was concentrated to yield N-(4- chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide as a white solid.

Step 2: (6-Amino-3-chloro-2-fluorophenyl)boronic acid

Under an inert atmosphere of nitrogen, to a mixture of N-(4-chloro-3- fluorophenyl)-2,2,2-trifluoroacetamide (30 g, 124.19 mmol, 1.00 equiv) in THF (500 mL) was added n-BuLi (99 mL, 248.38 mmol, 2.00 equiv, 2.5 M in hexane) dropwise with stirring at -78 °C, and the resulting mixture was then stirred at - 78 °C for 15 min. The reaction mixture was slowly warmed to -50 °C. The resulting clear brown solution was cooled to -78 °C and then B(0-iPr)3 (51.3 g, 273.21 mmol, 2.20 equiv) was added dropwise. The reaction mixture was stirred at -78 °C for 10 mm and the reaction mixture was slowly allowed to warm to room temperature. The resulting orange suspension was stirred at room temperature for 4 h, then cooled in an ice bath and quenched with 1M HC1 (300 mL). The resulting mixture was stirred at room temperature overnight, extracted with EtOAc (300 mL x 3), dried over Na2S04, and filtered. The filtrate was concentrated under reduced pressure. 6-Amino-3-chloro-2- fluorophenylboronic acid was recrystallized in EtOAc/PE (v/v 1/10) as a white solid.

Intermediate 11: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-cl]pyrimidine Step 1: 5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo [2,3- djpyrimidine

To a solution of 5-bromo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.52 mmol, 1.0 equiv.) in Ν,Ν-dimethylformamide (10 mL) was added sodium hydride (131 mg, 3.28 mmol, 1.3 equiv.) at 0 °C. The reaction mixture was stirred for 0.5 h. Then 2-(trimethylsilyl)ethoxymethyl chloride (505 mg, 3.03 mmol, 1.2 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. Water was added, the mixture was extracted with EA. The combined extracts were washed with brine and dried over anhydrous N32S04, then concentrated under reduced pressure. The residue was purified by column chromatography (0→20% EA/PE) to yield 5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow oil. LC/MS (ES, m/z): mass calculated for C^HieBrNsOSi: 327.04, measured: 327.95 [M+H]÷, 329.95 [M+H+2]*.

Step 2: 5-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl) ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine (530 mg, 1.61 mmol, 1.0 equiv.) and 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (820 mg, 3.23 mmol, 2.0 equiv.) in 1,4- dioxane (10 mL) were added potassium acetate (475 mg, 4.84 mmol, 3.0 equiv.) and 1,T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (132 mg, 0.16 mmol, 0.1 equiv.). The reaction mixture was stirred at 100 °C for 3 h under Nz, then cooled to room temperature. Water was added, the resulting mixture was extracted with EA. The combined extracts were washed with brine and dried over anhydrous NazSO*. The resulting mixture was concentrated under vacuum to yield 5- (4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)- 7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a black oil (unpurified). LC/MS (ES, m/z): mass calculated for CiaHMBNaOaSi: 375.21, measured: 376.20 [M+H] ⁺ .

Intermediate 12: 2-Bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin -4-yl) ethan-1-one

Br. Step 1: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-fluoropyridine To a solution of (3-fluoropyridin-2-yl)methanol (15.0 g, 118.002 mmol, 1.0 eq.) in DMF (200 mL) was added imidazole (16.1 g, 236.496 mmol, 2.0 eq.), followed by tert-butylchlorodimethylsilane (21.3 g, 141.32 mmol, 1.2 eq.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 x 400 mL), then washed with water (3 x 200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-30% PE/EA) to yield the 2- (((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridine as a yellow oil. LC/MS: mass calculated for C12H20FNOS1: 241.13, measured: 242.10 [M+H]*.

Step 2: 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4-iodopyri dine

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridine (24.0 g, 99.43 mmol, 1.0 eq.) in THF (400 mL) was added LDA (59.7 mL, 119.4 mmol, 1.2 eq.) at -78 °C. The resulting mixture was stirred at -78 °C for 0.5 h. A solution of iodine (30.3 g, 119.38 mmol, 1.2 eq.) in THF (60 mL) was then added to the mixture at -78 °C. The resulting mixture was stirred at -78 °C for 3 h. The reaction was quenched with NH4CI solution (200 mL), extracted with ethyl acetate (3 x 400 mL). The combined extracts were washed with water, dried over Na2S04, filtered and concentrated. The resulting residue was purified by silica gel chromatography (0-30% EA/PE) to yield 2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoro-4-iodopyridine as a white solid. LC/MS: mass calculated for Ci2HieFINOSi: 367.03, measured: 368.20 [M+H]*.

Step 3: 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)-3 -fluoro- pyridine

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4- iodopyridine (20.0 g, 54.45 mmol, 1.0 eq.) and bis(triphenylphosphine)palladium(ll) chloride (3.8 g, 5.414 mmol, 0.1 eq.) in 1,4-dioxane (200 mL) was added tributyl(1-ethoxyvinyl)stannane (29.5 g, 81.68 mmol, 1.5 eq.). The mixture was stirred at 90 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (200 mL), extracted with ethyl acetate (3 x 300 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by AI2O3 chromatography (0-50% ethyl acetate/petroleum ether) to yield the 2-(((tert- butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)-3-fluoropyr idine as a yellow oil. LC/MS: mass calculated for CieH^FNC^Si: 311.17, measured 312.15 [M+H]*. Step 4: 2-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4- yl)ethan-1-one

To a mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)- 3- fluoropyridine (15 g, 48.159 mmol, 1.0 equiv) in THF (120 ml_) and H2O (30 mL) was added NBS (8.6 g, 48.319 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2h. The resulting mixture was then diluted with EtOAc (700 mL), washed with brine (3 x 200 mL), dried over NasSO*, concentrated to yield 2-bromo-1- (2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)ethan-1-one as an off-white solid. LC/MS: mass calculated for Ci4H ₂ iBrFN0 ₂ Si: 361.05, measured: 362.00 [M+H]*

Intermediate 13: Methyl 4-(1-ethoxyvinyl)-2-fluorobenzoate

Step 1: Methyl 4-(1-ethoxyvinyl)-2-fluorobenzoate

To a mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)- 3- fluoropyridine (15 g, 48.16 mmol, 1.0 equiv) in THF (120 mL) and H ₂ 0 (30 mL) was added NBS (8.6 g, 48.32 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was then diluted with EtOAc (700 mL), washed with brine (3x200 mL), dried over Na ₂ S04, filtered and concentrated to yield 2-bromo-1- (2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)ethan-1-one as an off-white solid. LC/MS: mass calculated for Ci4H ₂ iBrFN0 ₂ Si: 361.05, measured: 362.00 [M+H]* Step 2: Methyl 4-(2-bromoacetyl)-2-fluorobenzoate

To a solution of methyl 4-(1-ethoxyvinyl)-2-fluorobenzoate (4.5 g, 20.06 mmol, 1.0 equiv) in THF (50 mL) with H ₂ 0 (10 mL) was added NBS (3.9 g, 22.07 mmol, 1.1 equiv) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched with brine, extracted with EA three times. The organic layer was washed with brine three times, concentrated under reduced pressure, and the residue purified on flash column chromatography on silica gel (EA/PE:0%-20%) to yield methyl 4-(2- bromoacetyl)-2-fluorobenzoate as a yellow solid. LC/MS: mass calculated for CioHeBrFOa: 275.071.

Intermediate 14: 2-Bromo-1 -(2-(1 -((tert- butyldimethylsilyl)oxy)cyclopropyl)-3-fluoropyridin-4-yl)eth an-1-one

Step 1: 2-(1-((Tert-butyldimethylsilyl)oxy)vinyl)-3-fluoropyridine.

To a solution of 1-(3-fluoropyridin-2-yl)ethan-1-one (6.0 g, 43.12 mmol, 1.0 equiv.) and triethylamine (13.1 g, 129.37 mmol, 3.0 equiv.) in DCM (60 mL) was added TBSOTf (14.8 g, 56.06 mmol, 1.3 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h, then quenched with water (20 mL). The resulting mixture was extracted with DCM (3x 50 mL) and combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→20% ethyl acetate/petroleum ether) to yield the 2-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-fluoropyridine as a yellow oil.

Step 2: 2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)-3-fluoropyri dine.

To a solution of diethylzinc (52.6 mL, 78.93 mmol, 1.5 M in toluene, 4.0 equiv.) in DCM (80 mL) was added chloroiodomethane (20.9 g, 118.39 mmol, 6.0 equiv.) under nitrogen at 0 °C. After 0.5 h, 2-(1-((tert- butyldimethylsilyl)oxy)vinyl)-3-fluoropyridine (5.0 g, 19.73 mmol, 1.0 equiv.) in DCM (10 mL) was added at 0°C . The resulting mixture was maintained under nitrogen and stirred at room temperature for 1 h, then quenched with saturated ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→20% ethyl acetate/petroleum ether) to yield the 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-fluoropyri dine as a yellow oil.

Step 3: 2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)-3-fluoro-4-i odopyridine.

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3- fluoropyridine (1.4 g, 5.24 mmol, 1.0 equiv.) in THF (20 mL) was added lithium diisopropylamide (3.4 mL, 6.81 mmol, 2.0 M in THF/Hexane, 1.1 equiv.) at - 78 °C. After 0.5 h, a solution of b (1.5 g, 5.76 mmol, 1.3 equiv.) in THF (4 mL) was added at -78°C. The resulting mixture was maintained under nitrogen and stirred at -78 °C for 1 h. The reaction was quenched with saturated ammonium chloride solution (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→30% ethyl acetate/petroleum ether) to yield the 2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)-3-fluoro-4-iodopyridine as a yellow oil.

Step 4: 2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)-4-(1-ethoxyv inyl)-3- fluoropyridine.

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-fluoro-4- iodopyridine (1.0 g, 2.54 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.8 g, 5.09 mmol, 2.0 equiv.) and Pd(PPh3)4 (294 mg, 0.25 mmol, 0.1 equiv.). The resulting mixture was stirred at 100 °C for 4 h under nitrogen. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→50% ethyl acetate/petroleum ether) to yield the 2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)-4-(1-ethoxyvinyl)-3-fluo ropyridine as a yellow oil.

Step 5: 2-Bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3 - fluoropyridi n-4-y l)ethan- 1 -one.

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-4-(1- ethoxyvinyl)-3-fluoropyridine (1.0 g, 2.96 mmol, 1.0 equiv.) in THF (8 mL) was added H2O (2 mL) and MBS (422 mg, 2.37 mmol, 0.8 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the 2-bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3 - fluoropyridin-4-yl)ethan-1-one as a yellow oil. Intermediate 15: 1-(4-(2-Bromoacetyl)-3-fluoropyridin-2-yl)cyclopropane-1- carbonitrile

Step 1: 1-(3-Fluoro-4-iodopyridin-2-yl)cyclopropane-1-carbonitrile.

To a solution of 2,3-difluoro-4-iodopyridine (0.50 g, 0.83 mmol, 1.0 equiv.) in toluene (10 mL) was added lithium bis(trimethylsilyl)amide solution 1.0 M in THF (3.1 mL, 3.10 mmol, 1.5 equiv.) dropwise under N2 at -10 °C. After stirring for 40 min at -10 °C, cyclopropane carbonitrile (0.17 g, 2.49 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was warmed to room temperature slowly and stirred for 2 h, then quenched with saturated NhUCI, extracted with EA, dried over Na2SO< and concentrated under vacuum. The residue was purified by silica gel chromatography with EA/PE (0→40%) to yield 1-(3-fluoro-4-iodopyridin-2-yl)cyclopropane-1-carbonitrile as a white solid. LC/MS (ES, m/z): mass calculated for CgHeFIta: 287.96, measured: 280.95 [Μ+ΗΓ. Step 2: 1-(4-(1-Ethoxyvinyl)-3-fluoropyridin-2-yl)cyclopropane-1-car bonitrile.

To a solution of 1-(3-fluoro-4-iodopyridin-2-yl)cyclopropane-1 -carbonitrile (0.50 g, 1.74 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) was added tributyl(1- ethoxyvinyl)tin (0.94 g, 2.60 mmol, 2.0 equiv.), bis(triphenylphosphine)palladium(ll) chloride (90 mg, 0.13 mmol, 0.075 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 5 h, then cooled to room temperature and quenched with water. The reaction mixture was extracted with EA. The organic layers were combined, washed with brine, dried and concentrated under vacuum. The residue was purified by silica gel chromatography (0→20% ethyl acetate/petroleum ether) to yield 1-(4- (1 -ethoxyvinyl)-3-fluoropyridin-2-yl)cyclopropane-1 -carbonitrile as a yellow solid. LC/MS (ES, m/z): mass calculated for C13H13FN2O: 232.10, measured: 233.10 [M+H]*.

Step 3: 1-(4-(2-Bromoacetyl)-3-fluoropyridin-2-yl)cyclopropane-1-car bonitrile.

To a solution of 1-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)cyclopropane-1- carbonitrile (0.47 g, 2.02 mmol, 1.0 equiv.) in THF(10 ml_) and water (0.3 mL) was added NBS (0.32 g, 1.82 mmol, 0.9 equiv.). The reaction mixture was stirred at room temperature for 0.5 h, then quenched with water. The reaction mixture was extracted with EA. The organic layers were combined, washed with brine, dried and concentrated under vacuum. The residue was purified by silica gel chromatography (0→20% ethyl acetate/petroleum ether) to yield 1-(4- (2-bromoacetyl)-3-fluoropyridin-2-yl)cyclopropane-1-carbonit rile as a yellow oil. LC/MS (ES, m/z): mass calculated for CnHeBrFN20: 281.98, measured: 282.95 [M+H]*.

Intermediate 16: 2-Bromo-1 -(3-fluoro-2-(2-hydroxy-2- methylpropoxy)pyridin-4-yl)ethan-1 -one

Step 1: 1-((3-Fluoro-4-iodopyridin-2-yl)oxy)-2-methylpropan-2-ol.

To a solution of 2-methylpropane-1,2-diol (1.3 g, 14.94 mmol, 1.2 equiv.) in DMF (40 mL) was added sodium hydride (359 mg, 14.94 mmol, 60%, 1.2 equiv.) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. Then a solution of 2,3-difluoro-4-iodopyridine (3.0 g, 12.45 mmol, 1.0 equiv.) was added dropwise. The mixture was stirred at room temperature for 1 h, then quenched with saturated ammonium solution (50 mL), extracted with EA (3 x 100 mL) and washed with brine (2 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→40% PE/EA) to yield 1- ((3-fluoro-4-iodopyridin-2-yl)oxy)-2-methylpropan-2-ol. LC/MS (ES, m/z): mass calculated for C9H11FINO2: 310.98, measured: 312.00 [M+H]*.

Step 2: 1-((4-(1-Ethoxyvinyl)-3-fluoropyridin-2-yl)oxy)-2-methylprop an-2-ol. Under an inert atmosphere of nitrogen, to a solution of 1-((3-fluoro-4- iodopyridin-2-yl)oxy)-2-methylpropan-2-ol (2.4 g, 7.72 mmol, 1.0 equiv.) in 1,4- dioxane (30 mL) were added tributyl(1-ethoxyvinyl)stannane (3.6 g, 10.03 mmol, 1.3 equiv.) and Pd(PPh3)2Cl2 (542 mg, 0.77 mmol, 0.1 equiv.). The reaction mixture was stirred for 8 h at 100 °C, then concentrated. The residue was applied onto a silica gel column (EA/PE: 0→10%) to yield 1-((4-(1- ethoxyvinyl)-3-fluoropyridin-2-yl)oxy)-2-methylpropan-2-ol as a yellow oil.

LC/MS (ES, m/z): mass calculated for C13H18FNO3: 255.13, measured: 256.10 [M+H] ⁺ . Step 3: 2-Bromo-1 -(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)ethan-1 - one.

To a solution of 1-((4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)oxy)-2- methylpropan-2-ol (750 mg, 2.94 mmol, 1.0 equiv.) in THF (8 ml_) and water (4 ml_) at 0 °C was added NBS (523 mg, 2.94 mmol, 1.0 equiv.) in portions. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with brine, extracted with EA for three times. The combined organic layer was washed with brine, concentrated under vacuum. The residue was purified on flash column chromatography on silica gel (EA/PE: 0→100%) to yield 2-bromo-1 -(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)ethan-1 - one as a yellow solid. LC/MS (ES, m/z): mass calculated for CnHuBrFNCh: 305.01, measured: 306.05 [M+HJ*.

Intermediate 17: 2-Bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2- trifluoroethyl)-3-fluoropyridin-4-yl)ethan-1-one o

Br<

F

F ₃ C OTBS Step 1: 2,2,2-Trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-one.

To a solution of 2-bromo-3-fluoropyridine (5.0 g, 28.41 mmol, 1.0 equiv.) in toluene (40 mL) was dropwise added n-butyllithium (14.78 mL, 36.94 mmol, 1.3 equiv.) under -65 °C under N2. After 30 min, 2,2,2-trifluoro-n-methoxy-n- methylacetamide (6.7 g, 42.62 mmol, 1.5 equiv.) was added to the resulting mixture under -65 °C and the resulting mixture was kept stirring for 1h. The resulting mixture was quenched with NhUCI (aq.), diluted with EA (40 mL) and extracted with EA (2 ^χ 40 mL). The organic layers were combined, washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel column (0→50%, EA/PE) to yield 2,2,2-trifluoro-1-(3-fluoropyridin-2- yl)ethan-1-one as a yellow oil. LC/MS (ES, m/z): mass calculated for C7H3F4NO: 193.02, measured: 212.00 [M+H ₂ 0+H] ⁺ .

Step 2: 2,2,2-Trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-ol.

To a solution of 2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-one (3.9 g, 20.04 mmol, 1.0 equiv.) in DCE (40 mL) was added sodium triacetoxyborohydride (5.5 g, 26.05 mmol, 1.3 equiv.) in several portions. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (50 mL), extracted with EA (3 ^χ 30 mL). The organic layers were combined, washed with brine, dried over Na2S04 and concentrated to yield 2,2,2-trifluoro-1-(5-nitroisoquinolin-1-yl)ethan-1-ol as a light yellow oil. LC/MS (ES, m/z): mass calculated for C7H5F4NO: 195.03, measured: 196.05 [M+H] ⁺ .

Step 3: 2-(1-((Tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoropyridine.

To a solution of 2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-ol (3.9 g, 19.84 mmol, 1.0 equiv.) in DCM (40 mL) were added 2,6-dimethylpyridine (6.9 mL, 59.50 mmol, 3.0 equiv.) and TBSOTf (13.7 mL, 59.50 mmol, 3.0 equiv.). The resulting mixture was stirred at 60 °C overnight. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 ^χ 20 mL). The organic layers were combined, washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel column (EA/PE, 0→50%) to yield 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoropyridine as a light yellow oil. LC/MS (ES, m/z): mass calculated for Ci3HigF4NOSi: 309.12, measured: 310.00 [M+H]*.

Step 4: 2-(1-((Tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoro-5- iodopyridine.

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoropyridine (1.0 g, 3.23 mmol, 1.0 equiv.) in THF (15 mL) was added LDA (2.4 mL, 4.85 mmol, 1.5 equiv.) dropwise at -55 °C under N2. The resulting mixture was stirred at -55°C for 30 min. I2 (1.6 g, 6.47 mmol, 2.0 equiv.) in THF was then added dropwise. The resulting mixture was stirred at -55 °C for 1h, then diluted with aqueous N32S03 (20 mL), extracted with EA (3 ^χ 20 mL). The organic layers were combined, washed with brine, dried over Na2SC>4 and concentrated to yield 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoro-4-iodopyridine as a dark red oil. LC/MS (ES, m/z): mass calculated for Ci3HieF4lNOSi: 435.01, measured: 435.95 [M+H]÷.

Step 5: 2-(1-((Tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4- (1-ethoxyvinyl)- 3-fluoropyridine.

A mixture of 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoro-4-iodopyridine (1.7 g, 3.91 mmol, 1.0 equiv.), tributyl(1- ethoxyvinyl)stannane (2.1 g, 5.86 mmol, 1.5 equiv.) and Pd(PPh3)4 (451 mg, 0.39 mmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was heated at 90 °C under N2 for 1.5 h. The resulting mixture was evaporated and the residue diluted with DCM.

Neutral AI2O3 was added and the resulting mixture was concentrated. The residue was purified by neutral AI2O3 column (EA/PE, 0→15%) to yield 2-(1- ((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4-(1-et hoxyvinyl)-3- fluoropyridine as a light yellow oil. LC/MS (ES, m/z): mass calculated for Ci7H2sF4N02Si: 379.16, measured: 380.15 [M+H] ⁺ .

Step 6: 2-Bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluo roethyl)-3- fluoropyridi n-4-yl)ethan- 1 -one.

A mixture of 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4- (1- ethoxyvinyl)-3-fluoropyridine (850 mg, 2.24 mmol, 1.0 equiv.) and 1- bromopyrrolidine-2,5-dione (399 mg, 2.24 mmol, 1.0 equiv.) in THF/H2O (8 mL) was stirred at room temperature for 2 h. The reaction was diluted with water, then extracted with DCM (3 ^χ 10 mL). The organic layers were combined, washed with brine, dried over N32S04 and added CH3CN to remove DCM. The residue - 2-bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluo roethyl)-3- fluoropyridin-4-yl)ethan-1-one - was used in the next step without further concentration or purification. LC/MS (ES, m/z): mass calculated for Ci5H2oBrF4N02Si: 429.04, measured: 431.95 [M+H] ⁺ . Intermediate 18: 2-Bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3- fluoropyridin-4-yl)ethan-1 -one

Step 1 : (3-Fluoropyridin-2-yl)methan-d2-ol.

To a solution of methyl 3-fluoropicolinate (1.9 g, 12.25 mmol, 1.0 equiv.) in methanol-D (10 mL) was added NaBD4 (767 mg, 18.37 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with D2O (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the (3-fluoropyridin-2-yl)methan-d2-ol as a yellow oil.

Step 2: 2-(((Tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoropyridine .

To a solution of (3-fluoropyridin-2-yl)methan-d2-ol (1.2 g, 9.29 mmol, 1.0 equiv.) and 2,6-lutidine (1.5 g, 13.94 mmol, 1.5 equiv.) in DCM (15 mL) was added TBSOTf (3.2 g, 12.08 mmol, 1.3 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (1 x 50 mL) and washed with water and brine (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→20% ethyl acetate/petroleum ether) to yield the 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoropyridine as a yellow oil. Step 3: 2-(((Tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoro-4-iodop yridine.

To a solution of diisopropylamine (798 mg, 7.89 mmol, 1.2 equiv.) in tetrahydrofuran (20 mL) was added n-butyllithium (3.2 mL, 7.89 mmol, 2.5 M, 1.2 equiv.) at -20 °C. After 0.5 h of stirring, 2-(((tert- butyldimethylsilyl)oxy)methyl-d2)-3-fluoropyridine (1.6 g, 6.57 mmol, 1.0 equiv.) was added at -78 °C and the mixture was maintained stirring at -78 °C for 1h, then I2 (1.8 g, 7.23 mmol, 1.1 equiv.) in tetrahydrofuran (2 mL) was added. The resulting mixture was maintained under nitrogen and stirred at room temperature for 2 h. The reaction was then quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→10% ethyl acetate/petroleum ether) to yield the 2-(((tert- butyldimethylsilyl)oxy)methyl-d2)-3-fluoro-4-iodopyridine as a white solid.

Step 4: 2-(((Tert-butyldimethylsilyl)oxy)methyl-d2)-4-(1-ethoxyvinyl )-3- fluoropyridine.

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoro-4- iodopyridine (1.8 g, 4.87 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) were added tributyl(1-ethoxyvinyl)stannane (2.6 g, 7.31 mmol, 1.5 equiv.), and Pd(PPh3)2Cl2 (342 mg, 0.48 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 90 °C for 2 h. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by silica gel column with EA/PE (0→50%) to yield the 2-(((tert-butyl- dimethylsilyl)oxy)methyl-d2)-4-(1-ethoxyvinyl)-3-fluoropyrid ine as a yellow oil. Step 5: 2-Bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-flu oropyridin-4- yl)ethan-1-one.

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-4-(1- ethoxyvinyl)-3-fluoropyridine (550 mg, 1.76 mmol, 1.0 equiv.) in THF (8 mL) and H2O (2 mL) was added NBS (281 mg, 1.58 mmol, 0.9 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the 2-bromo-1 -(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoropyridi n- 4-yl)ethan-1-one as a yellow oil.

Intermediate 19: 2-Bromo-1-(4-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrrol-3-yl)ethan-1 -one

F ₃ C

O.

SEM

Br

Step 1: Ethyl 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrole- 3-carboxylate To a solution of ethyl 4-(trifluoromethyl)-1H-pyrrole-3-carboxylate (0.50 g, 2.41 mmol, 1.0 equiv.) in THF (20 mL) were added NaH (0.12 g, 2.90 mmol, 1.2 equiv.) and SEMCI (0.60 g, 3.62 mmol, 1.5 equiv.). The resulting mixture was stirred for 3 h at 25 °C. The reaction was quenched with H2O, extracted with EtOAc. The organic layers were combined, dried over NazSO*. filtered and concentrated. The residue was purified by silica gel chromatography (0→20% EA/PE) to yield ethyl 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrole-3-carboxylate as a yellow oil.

Step 2: 4-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrrole-3- carboxylic acid.

To a solution of ethyl 4-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carboxylate (0.70 g, 2.08 mmol, 1.0 equiv.) in MeOH (10 ml_) were added THF (10 ml_) and LiOH (10.4 ml_, 10.37 mmol, 1 M, 5.0 equiv.). The resulting mixture was stirred at 25 °C overnight. The resulting mixture was concentrated. The mixture was then poured onto HCI (2 N) adjusting to pH 2~3. The resulting mixture was extracted with EA. The organic layers were combined, dried over NazSO*. filtered and concentrated to yield 4-(trifluoromethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrrole-3- carboxylic acid as a yellow oil. Step 3: 4-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrole-3- carbonyl chloride.

To a solution of 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrole-3-carboxylic acid (0.30 g, 0.97 mmol, 1.0 equiv.) in DCM (50 mL) was added oxalyl chloride (0.19 g, 1.46 mmol, 1.5 equiv.), followed by DMF (7 mg, 0.097 mmol, 0.1 equiv.). The resulting mixture was stirred for 1 h at 25 °C, concentrated under vacuum to yield 4-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-3-carbonyl chloride as a yellow oil. Step 4: 2-Bromo-1-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1 H- pyrrol-3-yl)ethan- 1 -one.

To a solution of 4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrole-3-carbonyl chloride (0.31 g, 0.95 mmol, 1.0 equiv.) in MeCN (30 mL) was added TMSCHNa (1.4 mL, 2.84 mmol, 3.0 equiv.). The resulting mixture was stirred for 6 h at 25 °C. Then HBr (0.80 g, 4.73 mmol, 5.0 equiv.) was added. The reaction mixture was stirred for 1 h at 25 °C. The reaction was quenched with HaO. The resulting mixture was extracted with EA. The organic layers were combined, dried over Na2S04, filtered and concentrated to yield 2- bromo-1-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)me thyl)-1H-pyrrol-3- yl)ethanone as a yellow oil.

Intermediate 20: 2-Bromo-1-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H- imidazol-4-yl)ethan-1 -one

O. ,PMB

Γ N

Br N CF ₃ Step 1 : Ethyl 1 -(4-methoxybenzyl)-2-(trifluoromethyl)- 1 H-imidazole-4- carboxylate.

To a solution of ethyl 2-(trifluoromethyl)-1H-imidazole-4-carboxylate (2.1 g, 10.23 mmol, 1.0 equiv.) in DMF (30 mL) was added PMBCI (3.2 g, 20.47 mmol, 2.0 equiv.) and K2CO3 (4.2 g, 30.70 mmol, 3.0 equiv.). The resulting mixture stirred at room temperature for 9 h. The reaction progress was monitored by LCMS. LCMS showed the desired product was generated and the reaction was partitioned between H2O and EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→26% ethyl acetate/petroleum ether) to yield the ethyl 1-(4-methoxybenzyl)-2-

(trifluoromethyl)-1H-imidazole-4-carboxylate as a white oil. LC/MS (ES, m/z): mass calculated for C15H15F3N2O3: 328.10, measured: 329.05 [M+H]*.

Step 2: 1-(4-Methoxybenzyl)-2-(trifluoromethyl)-1H-imidazole-4-carbo xylic acid.

To a solution of ethyl 1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H- imidazole-4-carboxylate (2.1 g, 6.45 mmol, 1.0 equiv.) in THF/hteO/EtOH

(10/10/10 mL) was added LiOH (0.62 g, 25.95 mmol, 4.0 equiv.). The resulting mixture stirred at room temperature for 4 h. The reaction was quenched with HCI (2 M) solution and extract with EA to yield the 1-(4-methoxybenzyl)-2- (trifluoromethyl)-1H-imidazole-4-carboxylic acid as a white solid. LC/MS (ES, m/z): mass calculated for C13H11F3N2O3: 300.07, measured: 301.25 [M+H]*.

Step 3: 1-(4-Methoxybenzyl)-2-(trifluoromethyl)-1H-imidazole-4-carbo nyl chloride.

To a solution of 1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H-imidazole-4- carboxylic acid (600 mg, 2.00 mmol, 1.0 equiv.) in DCM (5 ml_) was added oxalyl chloride (507 mg, 4.00 mmol, 2.0 equiv.) and DMF (0.001 mL). The resulting mixture was maintained under nitrogen and stirred at room temperature for 2 h. LCMS showed the desired product was generated and the mixture was used in the next step without any purifications.

Step 4: 2-Bromo-1-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H-imidaz ol-4- yl)ethanone.

To a solution of 1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H-imidazole-4- carbonyl chloride (600 mg, 1.88 mmol, 1.0 equiv.) in ACN (5 mL) was added (trimethylsilyl) diazomethane (860 mg, 7.53 mmol, 4.0 equiv.) slowly at 0 °C. The resulting mixture was maintained under nitrogen and stirred at room temperature for 2 h. LCMS showed the desired product was generated and the mixture was used in the next step without any purifications.

Step 5. 2-bromo-1-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1 H-imidazol-4- yl)ethanone

To a solution of 2-diazo-1-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H- imidazol-4-yl)ethanone (600 mg, 1.85 mmol, 1.0 equiv.) in ACN (5 mL) was added ΗΒΓ/Η2Ο (1.0 g, 12.95 mmol, 7.0 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. LCMS showed the desired product was generated and after the reaction mixture was cooled to room temperature, and the reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the 2- bromo-1-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H-imidazol -4-yl)ethanone.

Intermediate 21 : 4-(2-Bromoacetyl)thiophene-2-carboxamide o Br.

H ₂ N

Step 1: 4-Acetylthiophene-2-carboxamide.

4-Bromothiophene-2-carboxamide (1.0 g, 4.85 mmol, 1.0 equiv.) and tributyl(1-ethoxyvinyl)stannane (1.9 g, 5.34 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (30 mL). Pd(PPha)4 (561 mg, 0.49 mmol, 0.1 equiv.) was then added. The reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layers were separated and combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→80% ethyl acetate/petroleum ether) to yield the 4-acetylthiophene-2-carboxamide as a yellowish oil. LC/MS (ES, m/z): mass calculated for C7H7NO2S: 169.02, measured: 170.05 [M+H]*. Step 2: 4-(2-Bromoacetyl)thiophene-2-carboxamide.

4-Acetylthiophene-2-carboxamide (600 mg, 3.55 mmol, 1.0 equiv.) and pyridinium tribromide (1.0 g, 3.19 mmol, 0.9 equiv.) were dissolved in dichloromethane (15 mL). HBr/HOAc (0.05 mL) was then added. The reaction mixture was stirred at room temperature for 5 h. LCMS showed the desired product was generated and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→80% ethyl acetate/petroleum ether) to yield the 4-(2- bromoacetyl)thiophene-2-carboxamide as a white solid. LC/MS (ES, m/z): mass calculated for C7HeBrN02S: 246.93, measured: 247.95, 249.95 [M+H, M+H+2]*.

Intermediate 22: 5-(2-Bromoacetyl)thiophene-2-carboxamide

Br

O:

H ₂ N— V o

Step 1: 5-(1-Ethoxyvinyl)thiophene-2-carboxamide.

To a solution of 5-bromothiophene-2-cartx>xamide (5.0 g, 24.27 mmol, 1.0 equiv.) in 1,4-dioxane (50 mL) were added tributyl(1-ethoxyvinyl)stannane (13.1 g, 36.40 mmol, 1.5 equiv.) and Pd(PPh3)4 (2.8 g, 2.43 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3h. After cooling to room temperature, the reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL).

The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the 5-(1-ethoxyvinyl)thiophene-2-carboxamide as a green oil. Step 2: 5-(2-Bromoacetyl)thiophene-2-carboxamide.

To a solution of 5-(1-ethoxyvinyl)thiophene-2-carboxamide (2.1 g, 10.65 mmol, 1.0 equiv.) in THF (12 mL) and HaO (4 mL) was added NBS (2.1 g, 11.71 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the 5-(2-bromoacetyl)thiophene-2-carboxamide as a white solid. LC/MS (ES, m/z): mass calculated for CrHeBrNOaS: 246.93, measured: 248.00 [Μ+ΗΓ.

Intermediate 23: 5-(2-Bromoacetyl)-3-fluorothiophene-2-carboxamide

Step 1: 5-Bromo-3-fluorothiophene-2-carboxamide.

To a solution of 5-bromo-3-fluorothiophene-2-carboxylic acid (900 mg, 3.99 mmol, 1.0 equiv.) in DMF (10 ml_) were added HATU (1.8 g, 4.79 mmol,

1.2 equiv.), DIEA (1.5 g, 11.99 mmol, 3.0 equiv.) and ammonium chloride (256 mg, 4.79 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL ^χ 3). The organic layers were combined, washed with brine three times, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by gel chromatography (0→30% MeOH/DCM) to yield the 5-bromo-3-fluorothiophene-2-carboxamide.

LC/MS (ES, m/z): mass calculated for CsHsBrFNOS: 222.91, measured: 223.90 [M+H] ⁺ .

Step 2: 5-(1-Ethoxyvinyl)-3-fluorothiophene-2-carboxamide.

A mixture of 5-bromo-3-fluorothiophene-2-carboxamide (360 mg, 1.67 mmol, 1.0 equiv.), tributyl (l-ethoxyvinyl)tin (724 mg, 2.00 mmol, 1.2 equiv.) and Pd(PPh3)4 (193 mg, 0.16 mmol, 0.1 equiv.) in 1,4-dioxane (10 mL) was degassed and then heated at 100 °C under N2 for 4 hours before being cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was purified by chromatography (AI2O3, EA/PE: 0→30%) to yield the desired compound 5-(1-ethoxyvinyl)-3-fluorothiophene-2-carboxamide as a yellow oil.

Step 3: 5-(2-Bromoacetyl)-3-fluorothiophene-2-carboxamide.

To a solution of 5-(1-ethoxyvinyl)-3-fluorothiophene-2-carboxamide (350 mg, 1.62 mmol, 1.0 equiv.) in THF/H2O (9 mL/3 mL) was added NBS (347 mg, 1.95 mmol, 1.2 equiv.). The resulting mixture was stirred for 1 h, quenched the reaction with water and extracted with EA. The solvent was removed under reduced pressure. The residue was purified through silica gel. The residue was purified by gel chromatography (0→30% EA/PE) to yield the 5-(2-bromoacetyl)- 3-fluorothiophene-2-carboxamide.

Intermediate 24: 2-Bromo-1-(3-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-4-yl)ethan-1 -one

Step 1: Ethyl 3-(trifiuoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazole-4-carboxylate.

To a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate(4.0 g, 19.22 mmol, 1.0 equiv.) in DMF (40 mL) was added NaH (0.51 g, 21.14 mmol, 1.1 equiv.) at 0 °C for 15 min, then SEMCI (3.2 g, 19.22 mmol ,1.0 equiv.) was added. The resulting mixture was maintained under nitrogen and stirred at 25 °C for 3 h, then quenched with HCI (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Yield 4-(4-bromophenyl)- 1-(4-(trifluoromethoxy) phenyl) butane- 1 ,3-dione as a yellow oil. LC/MS (ES, m/z): mass calculated for C13H21F3N2O3S1: 338.13, measured: 339.20 [M+H] ⁺ . Step 2: 3-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazole-4- carboxylic acid. To a solution of ethyl 3-(trifluoromethyl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate(3.3 g, 0.010 mol, 1.0 equiv.) in THF (10 ml_), MeOH (10 mL), and H2O (10 mL) was added LiOH (1.2 g, 0.049 mol, 5.0 equiv.) at room temperature for 1 h. The reaction was quenched with HCI (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 3-(trifluoromethyl)-1-((2-(trimethylsilyl) ethoxy) methyl)- 1H-pyrazole-4-carboxylic acid as a white solid. LC/MS (ES, m/z): mass calculated for C11H17F3N2O3S1: 310.10, measured: 311.20 [M+H]*. Step 3: 3-(Trifluoromethyl)-1-((2-(trimethylsilyl) ethoxy) methyl)- 1 H-pyrazole-4- carbonyl chloride.

To a solution of 3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- IH-pyrazole-4-carboxylicacid (100 mg, 0.32 mmol, 1.0 equiv.) in DCM (5 mL), was added (COCI)2 (61 mg, 0.48 mmol, 1.5 equiv.). The resulting mixture was maintained under nitrogen and stirred at 25 °C for 2 h. The reaction mixture containing the product was used in the next step reaction directly, without further purification or isolation.

Step 4: 2-Bromo-1-(3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1 H- pyrazol-4-yl)ethanone.

To a solution of 3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-4-carbonyl chloride (20 mg, 0.061 mmol, 1.0 equiv.) in acetonitrile (3 mL) was added TMSCHN2 (0.1 mL) at 0 °C. The resulting mixture was maintained under nitrogen and stirred at 25 °C for 16 h, then concentrated under reduced pressure. The residue (300 mg, 0.89 mmol) was re-dissolved in ACN (3 mL). To the resulting solution was then added ΗΒΓ/Η2Ο (0.7 mL) at 0 °C, and the resulting mixture was maintained under nitrogen and stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure and the residue - 2-bromo-1-(3-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethanone -was used in the next step without further purification or isolation.

Intermediate 25: 6-(2-Bromoacetyl)-5-fluoro-1,4-dihydro-2H- benzo[d][1 ,3]oxazin-2-one

Step 1: 6-Amino-3-bromo-2-fluorobenzoic acid.

To a mixture of 2-amino-6-fluorobenzoic acid (5.0 g, 32.23 mmol, 1.0 equiv.) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (6.3 g, 35.45 mmol, 1.1 equiv.) at 0 °C. The reaction mixture was stirred at room temperature overnight, then partitioned between EtOAc and water. The organic layer was separated, and the combined organic layers were washed with brine, dried over Na2S04 and concentrated under vacuum to yield 6-amino-3-bromo- 2-fluorobenzoic acid as a yellow solid. LC/MS (ES, m/z): mass calculated for CyHsBrFNCfc: 232.95, measured: 233.90, 235.90 [M+H, M+H+2]*.

Step 2: (6-Amino-3-bromo-2-fluorophenyl)methanol.

To a mixture of 6-amino-3-bromo-2-fluorobenzoic acid (7.0 g, 29.91 mmol, 1.0 equiv.) in THF (70 mL) was added borane-tetrahydrofuran complex (239 mL, 239.29 mmol, 1 M in THF, 8.0 equiv.) at room temperature. The reaction mixture was stirred at 50 °C for 4 h. The reaction was quenched with water and extracted with EA twice. The combined organic layers were washed with brine, dried over NaaSO*. concentrated under vacuum and the residue purified by silica gel chromatography (0→60% EA/PE) to yield (6-amino-3- bromo-2-fluorophenyl)methanol as a white solid. LC/MS (ES, m/z): mass calculated for CyHyBrFNO: 218.97, measured: 220.15, 222.15 [M+H, M+H+2]*. Step 3: 6-Bromo-5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-2-one.

To a mixture of (6-amino-3-bromo-2-fluorophenyl)methanol (6.0 g, 27.27 mmol, 1.0 equiv.) in THF (70 mL) was added triphosgene (16.2 g, 54.54 mmol, 2.0 equiv.). The reaction mixture was stirred at 60 °C for 1.5 h. The reaction was quenched with saturated NaHCOa and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (0→60% EA/PE) to yield 6-bromo-5-fluoro-1 ,4-dihydro-2H- benzo[d][1,3]oxazin-2-one as a yellow solid. LC/MS (ES, m/z): mass calculated for CeHsBrFNCfc: 244.95, measured: 246.10, 248.15 [M+H, M+H+2]*. Step 4: 6-(1-Ethoxyvinyl)-5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-2-one.

To a mixture of 6-bromo-5-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2- one (2 g, 8.13 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) were added tributyl(1- ethoxyvinyl)stannane (3.3 mL, 9.75 mmol, 1.2 equiv.) and Pd(PPh3)2Cl2 (0.60 g, 0.81 mmol, 0.1 equiv.). The resulting solution was stirred at 100 °C for 6 h under nitrogen. To the reaction mixture was then added water, and the mixture was extracted with EA twice. The combined organic layers were washed with brine, dried over N32S04 and concentrated under vacuum to yield 6-(1- ethoxyvinyl)-5-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-o ne as a yellow solid. LC/MS (ES, m/z): mass calculated for C12H12FNO3: 237.08, measured: 238.15 [M+H]*.

Step 5: 6-(2-Bromoacetyl)-5-fluoro-1,4-dihydro-2H-benzo[d][1,3]oxazi n-2-one.

To a mixture of 6-(1-ethoxyvinyl)-5-fluoro-1,4-dihydro-2H- benzo[d][1 ,3]oxazin-2-one (900 mg, 3.79 mmol, 1.0 equiv.) in THF (9 mL) and water (3 mL) was added N-bromosuccinimide (675 mg, 3.79 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 1.0 h. The mixture was diluted with H2O, extracted with EA twice. The combined organic layers were washed with brine, dried over N32S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (0→50% EA/PE) to yield 6-(2-bromoacetyl)-5-fluoro-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-2-one as a yellow solid. LC/MS (ES, m/z): mass calculated for CioHyBrFNOs: 286.96, measured: 287.95, 289.95 [M+H, M+H+2] ⁺ .

Intermediate 26: 2-Bromo-1-(2-fluoro-6-(methylamino)pyridin-3-yl)ethan-1- one

Br

F

Step 1: 6-Fluoro-5-iodo-n-methylpyridin-2-amine.

To a solution of 6-fluoro-5-iodopyridin-2-amine (4.0 g, 16.81 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL) was added sodium hydride (807 mg, 20.17 mmol, 60%, 1.2 equiv.) at 0 °C. After 30 min, CHal (3.6 g, 25.21 mmol, 1.5 equiv.) was added to the above solution. The resulting mixture was stirred at 0 °C for 2 h, then quenched with ice water, extracted with EA twice, the organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (0→100% ethyl acetate/petroleum ether) to yield the(3S)-7-(6-amino-3-chloro-2-fluorophenyl)- ^(^(S-nitropyridin-^yO-IH-imidazol^-yli^.S.S.Sa-tetrahydroin dolizin-SilH)- one as a yellow solid. LC/MS (ES, m/z): mass calculated for CeHeFIto: 251.96, measured: 253.03 [M+H]*.

Step 2: 1-(2-Fluoro-6-(methylamino)pyridin-3-yl)ethan-1-one.

To a solution of the 6-fluoro-5-iodopyridin-2-amine (1.5 g, 5.95 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL) was added tributyl(1-ethoxyvinyl)stannane (4.30 g, 11.90 mmol, 2.0 equiv.), followed by tetrakis(triphenylphosphine) palladium(O) (688 mg, 0.60 mmol, 0.1 equiv.). The resulting mixture was stirred at 100 °C overnight. The residue was purified by silica gel chromatography (0→100% ethyl acetate/petroleum ether) to yield the 1-(2-fluoro-6- (methylamino)pyridin-3-yl)ethan-1-one as a yellow solid. LC/MS (ES, m/z): mass calculated for CeHeFNaO: 168.07, measured: 169.10 [M+H]*.

Step 3: 2-Bromo-1-(2-fluoro-6-(methylamino)pyridin-3-yl)ethan-1-one.

To a solution of the 1-(2-fluoro-6-(methylamino)pyridin-3-yl)ethan-1-one (800 mg, 4.76 mmol, 1.0 equiv.) in glacial acetic add (20 mL) and HBr (2 mL) was added Br2 (380 mg, 2.38 mmol, 0.5 equiv.). The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to yield 1-(2- fluoro-6-(methylamino)pyridin-3-yl)ethan-1-one as a yellow solid. LC/MS (ES, m/z): mass calculated for CeHeBrFlNfcO: 245.98, measured: 247.10 [M+H]*.

Intermediate 27: Methyl (6-(2-bromoacetyl)pyridin-3-yl)carbamate

Β >ΟΪ Step 1: Methyl n-(6-acetylpyridin-3-yl)carbamate.

To a stirred solution of 1-(5-aminopyridin-2-yl)ethanone (680 mg, 4.99 mmol, 1.0 equiv.) in methylene chloride (20 mL) and pyridine (592 mg, 7.49 mmol, 1.5 equiv.) was added methyl chloroformate (566 mg, 5.99 mmol, 1.2 equiv.) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure to yield methyl n-(6-acetylpyridin-3-yl)carbamate as a yellow solid. Step 2: Methyl (6-(2-bromoacetyl)pyridin-3-yl)carbamate.

To a mixture of methyl (6-acetylpyridin-3-yl)carbamate (300 mg, 1.54 mmol, 1.0 equiv.) in AcOH (5 mL) were added HBr (3 mL) and Br2 (246 mg,

1.54 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 2 h, washed with water (3 x 20 mL), dried over N32S04, concentrated. The residue was applied onto a silica gel column (MeOH/DCM: 0→10%) to yield methyl (6-(2-bromoacetyl)pyridin-3-yl)carbamate as a yellow solid. LC/MS (ES, m/z): mass calculated for CsHgBrtoOs: 271.98, measured: 273.10, 275.10 [M+H, Μ+Η+2Γ.

Intermediate 28: N-(5-(2-bromoacetyl)-6-chloropyridin-2-yl)acetamide o

Br· o

Cl N N Step 1: N-(6-chloro-5-iodopyridin-2-yl)acetamide.

6-Chloro-5-iodopyridin-2-amine (3.0 g, 11.79 mmol, 1.0 equiv.) was added in acetic anhydride (60 mL) at room temperature. The reaction was then stirred overnight at 40 °C. After cooling to room temperature, the solid was collected by filtering to yield N-(6-chloro-5-iodopyridin-2-yl)acetamide as a yellow solid.

Step 2: N-(6-chloro-5-(1-ethoxyvinyl)pyridin-2-yl)acetamide.

N-(6-chloro-5-iodopyridin-2-yl)acetamide (2.3 g, 7.58 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (2.8 mL, 8.35 mmol. 1.1 equiv.), Pd(PPh3)4 (876 mg, 0.75 mmol. 0.1 equiv.) were placed in an oven-dried Schlenk tube under nitrogen and 1,4-dioxane (40 mL) was added. The reaction mixture was stirred for overnight at 100 °C. After cooling to room temperature, the reaction was quenched by water (10 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to yield the N-(6-chloro5-(1-ethoxyvinyl)pyridin-2- yl)acetamide as a yellow solid. Step 3: N-(5-(2-bromoacetyl)-6-chloropyridin-2-yl)acetamide.

To a solution of N-(6-chloro-5-(1-ethoxyvinyl)pyridin-2-yl)acetamide (1.8 g, 7.56 mmol, 1.0 equiv.) in tetrahydrofuran/water (60 mL/20 mL) was added N- bromosucdnimide (2.0 g, 11.34 mmol, 1.5 equiv.) at room temperature. The reaction mixture was then stirred at room temperature for 3 h. The reaction was then concentrated and purified by silica gel chromatography (0→40% ethyl acetate/petroleum ether) to yield the n-(5-(2-bromoacetyl)-6-chloropyridin-2- yl)acetamide as a yellow solid.

Intermediate 29: N-(5-(2-bromoacetyl)-6-fluoropyridin-2-yl)acetamide

H

Step 1: N-(6-fluoro-5-iodopyridin-2-yl)acetamide.

A suspension of 6-fluoro-5-iodopyridin-2-amine (10.0 g, 42.01 mmol, 1.0 equiv.) in acetic anhydride (20 mL) was stirred for 8 h. The resulting mixture was filtered to yield N-(6-fluoro-5-iodopyridin-2-yl)acetamide) as a white solid. LC/MS (ES, m/z): mass calculated for CyHeFItaO: 279.95, measured: 281.00 [Μ+ΗΓ.

Step 2: N-(5-(1-Ethoxyvinyl)-6-fluoropyridin-2-yl)acetamide.

To a solution of N-(6-fluoro-5-iodopyridin-2-yl)acetamide (5.0 g, 17.85 mmol, 1.0 equiv.) and tributyl(1-ethoxyvinyl)stannane (7.7 g, 21.42 mmol, 1.2 equiv.) in 1,4-dioxane (100 mL) was added Pd(PPh3)4 (1.0 g, 0.89 mmol, 0.05 equiv.). The resulting mixture was maintained under nitrogen and stirred at 90 °C for 36 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (EA:PE, 10→50%) to yield n-(5-(1- ethoxyvinyl)-6-fluoropyridin-2-yl)acetamide as a yellow solid. LC/MS (ES, m/z): mass calculated for C11H13FN2O2: 224.10, measured: 225.15 [M+H]*.

Step 3: N-(5-(2-bromoacetyl)-6-fluoropyridin-2-yl)acetamide.

To a solution of N-(5-(1-ethoxyvinyl)-6-fluoropyridin-2-yl)acetamide (3.0 g, 13.39 mmol, 1.0 equiv.) in THF/H2O (90/30 mL) was added NBS (2.9 g, 16.07 mmol, 1.2 equiv.) at 0 °C. The resulting mixture was stirred for 20 min. The mixture was diluted with H2O (50 mL), then extracted with EA (50 mL ^χ 3). The organic layers were combined, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromotography (EA:PE, 10→50%) to yield n-(5-(2-bromoacetyl) -6-fluoropyridin-2-yl)acetamide as a brown solid.

Intermediate 30: 5-(2-Bromoacetyl)picolinamide

ΒΓ·

Ν' NH ₂ o

Step 1: 5-(1-Ethoxyvinyl)picolinamide.

To a solution of 5-bromopicolinamide (1.5 g, 7.46 mmol, 1.0 equiv.) in 1,4-dioxane (15 mL) were added tributyl(1-ethoxyvinyl)stannane (4.0 g, 11.19 mmol, 1.5 equiv.), and tetrakis(triphenylphosphine)palladium (0.86 g, 0.75 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C overnight. After cooling to room temperature, the organic layers were filtered and concentrated. The residue was purified by AI2O3 gel chromatography (0→60% EA/PE) to yield the 5-(1-ethoxyvinyl)picolinamide as a yellow oil.

Step 2: 5-(2-Bromoacetyl)picolinamide.

To a solution of 5-(1-ethoxyvinyl)picolinamide (1.4 g,7.28 mmol 1.0 equiv.) in THF/H20=3:1 (28 mL) was added N-bromosuccinimide (2.6 g, 14.57 mmol, 2.0 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature fori h. The reaction was quenched with aq. sodium hyposulfite (50 mL), The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→60% ethyl acetate/petroleum ether) to yield the 5-(2- bromoacetyl)picolinamide as a white solid.

Intermediate 31: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-iodo-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: Ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a - hexahydroindolizine-3-carboxylate

To a mixture of ethyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (5.0 g, 13.99 mmol, 1.0 equiv.) and (6-amino-3-chloro-2-fluorophenyl)boronic acid (4.770 g, 25.189 mmol, 1.8 equiv.) in 1,4-dioxane (50 mL) and water (10 mL) were added potassium phosphate (7.4 g, 34.98 mmol, 2.5 equiv.) and 1,T- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (1.1 g, 1.40 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 1 h. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EA. The combined extracts were dried over anhydrous Na2S04 and concentrated. The residue was purified by silica gel chromatography (0→15% MeOH/DCM) to yield ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for C17H18CIFN2O3: 352.10, measured: 353.05 [M+Hf.

Step 2: Ethyl (3S)-7-(6-((tert-butoxycarbonyl)amino)-3-chloro-2-fluorophen yl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo - 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (4.7 g, 13.32 mmol, 1.0 equiv.) in toluene (100 mL) was added di-tert-butyl dicarbonate (17.45 g, 79.94 mmol, 6.0 equiv.). The reaction mixture was stirred at 100 °C for 48 h. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (0→55% EA/PE) to yield ethyl (3S)-7-(6-((tert-butoxycarbonyl)amino)-3-chloro-2-fluorophen yl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C^HajCIFtoOs: 452.15, measured: 453.10 [M+H] ⁺ .

Step 3: tert-Butyl (4-chloro-3-fluoro-2-((3S)-3-formyl-5-oxo-1, 2,3,5,8,8a- hexahydroindolizin-7-yl)phenyl)carbamate

To a solution of ethyl (3S)-7-(6-((tert-butoxycarbonyl)amino)-3-chloro-2- fluorophenyl) -5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (4.0 g,

8.83 mmol, 1.0 equiv.) in dichloromethane (40 mL) was added diisobutylaluminium hydride (19.4 mL, 1.0 M in DCM, 19.43 mmol, 2.2 equiv.) slowly at -78 °C under N2. The reaction mixture was stirred for 2.5 h. Potassium sodium tartrate solution was added, and the mixture was extracted with EA.

The combined extracts were dried over anhydrous NaaSO*. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with (0→55% EA/PE) to yield tert-butyl (4-chloro-3-fluoro-2- ((3S)-3-formyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-7-yl)ph enyl)carbamate as a yellow solid. LC/MS: mass calculated for C20H22CIFN2O4: 408.13, measured: 409.10 [Μ+ΗΓ.

Step 4: tert-Butyl (2-((3S)-3-(1 H-imidazol-2-yl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-7-yl)-4-chloro-3-fluorophenyl)carbamate

To a solution of tert-butyl (4-chloro-3-fluoro-2-((3S)-3-formyl-5-oxo- 1,2,3,5,8,8a- hexahydroindolizin-7-yl)phenyl)carbamate (1.0 g, 2.45 mmol, 1.0 equiv.) in methanol (10 mL) and ammonium hydroxide (10 mL) was added glyoxal (1.8 g, 12.23 mmol, 5.0 equiv., 40% in water). The mixture was stirred at room temperature for 48 h, then concentrated under reduced pressure, extracted with EA, washed with brine and dried over anhydrous N32S04. The residue was purified by column chromatography (0→15% MeOH/DCM) to yield tert-butyl (2-((3S)-3-(1 H-imidazol-2-yl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin- 7-yl)-4-chloro-3-fluorophenyl)carbamate as a yellow solid. LC/MS: mass calculated for C22H24CIFN4O3: 446.15, measured: 447.10 [M+H] ⁺ .

Step 5: tert- Butyl (4-chloro-3-fluoro-2-((3S)-3-(5-iodo-1 H-imidazol-2-yl)-5 -oxo- 1,2,3,5,8,8a-hexahydroindolizin-7-yl)phenyl)carbamate

To a solution of tert-butyl (2-((3S)-3-(1H-imidazol-2-yl)-5-oxo- 1 ,2,3,5,8,8a- hexahydroindolizin-7-yl)-4-chloro-3-fluorophenyl)carbamate (450 mg, 1.01 mmol, 1.0 equiv) in DCM (10 mL) was added N-iodosuccinimide (453 mg, 2.01 mmol, 2.0 equiv). The reaction mixture was stirred at room temperature for 10 min. Water was added, and the mixture was extracted with EA. The combined extracts were washed with water, dried over anhydrous NasSO*, then concentrated. EtOH (10 mL), H2O (10 mL) and sodium sulfite (1.0 g, 8.23 mmol, 10.0 equiv.) were added to residue. The mixture was stirred overnight at 95 °C, then cooled to room temperature. Water was added, and the mixture was extracted with EA. The combined extracts were dried over anhydrous NazSO*, filtered and concentrated to yield tert-butyl (4-chloro-3- fluoro-2-((3S)-3-(5-iodo-1 H-imidazol-2-yl)-5 -oxo-1,2,3,5,8,8a- hexahydroindolizin-7-yl)phenyl)carbamate as a brown solid, which was used in the next step without further purification. LC/MS (ES, m/z): mass calculated for C22H23CIFIN4O3: 572.05, measured: 573.00 [M+H] ⁺ .

Step 6: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-iodo-1 H-imidazol-2-yl) - 2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of tert-butyl (4-chloro-3-fluoro-2-((3S)-3-(5-iodo-1H- imidazol-2-yl) -5-oxo-1,2,3,5,8,8a-hexahydroindolizin-7-yl)phenyl)carbamate (580 mg,) in dichloromethane (8 mL) was added trifluoroacetic add (2 mL). The reaction mixture was stirred at room temperature, for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (0→10% MeOH/DCM) to yield (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-3-(5-iodo- 1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one as a yellow solid. LC/MS (ES, m/z): mass calculated for C17H15CIFIN4O: 472.00, measured: 472.90 [M+HJ*.

Synthesis Examples: Compounds of Formula (I)

Example 1: (3S,8aR)-3-[5-(2-Amino-5-chloro-4-pyridyl)-4-fluoro-1H- imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl] -2,3,8,8a- tetrahydro-1 H-indolizin-5-one

Step 1. To a mixture of N-(5-chloro-4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin- 3-yl)-1H-imidazol-5- yl)pyridin-2-yl)acetamide 2,2,2-trifluoroacetate (400 mg, 0.501 mmol, 1.0 equiv) in DMF (9 mL) and H2O (0.9 mL) was added Selectfluor (142 mg, 0.401 mmol, 0.8 equiv) at 0°C. The resulting mixture was warmed to room temperature and then stirred at room temperature for 1 h. The mixture was then partitioned between EtOAc and water. The organic layer was separated, dried, and concentrated under reduced pressure. The residue was purified by C18 reverse column chromatography (330 g, ACN/H2O (0.05%NmHC03): 5%»>40%»>45%) to yield N-(5-chloro-4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-4-fluoro-1 H- imidazol-5-yl)pyridin-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H19CI2F2N9O2: 585.10, measured: 586.05 [M+H] ⁺ .

Step 2. A mixture of N-(5-chloro-4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin- 3-yl)-4-fluoro-1H- imidazol-5-yl)pyridin-2-yl)acetamide (60 mg, 0.102 mmol, 1.0 equiv) in THF (6 mL) and HCI (3 mL, 4N) was stirred at 50°C for 1h, then concentrated. The residue was applied onto a C18 reverse column (120g, ACN/H2O (0.05%NH4HC03): 5%»>45%»>50%) to yield (3S)-3-(5-(2-amino-5- chloropyridin-4-yl)-4-fluoro-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

The isolated solid was further purified by prep-Chiral-HPLC(Column: (R,R)- WHELK-01-Kromasil, 5*25cm,5pm ; Mobile Phase A:MeOH(0.5% 2M NHa- MeOH)— HPLC, Mobile Phase B:EtOH~HPLC; Flow rate:20 mL/min;) to yield (3S,8aR)-3-(5-(2-amino-5-chloropyridin-4-yl)-4-fluoro-1H-imi dazol-2-yl)-7-(3- chloro2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 Hi- one as a white solid.

LC/MS: mass calculated for C23H17CI2F2N9O: 543.09, measured (ES, m/z): 544.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.33 (s, 1 H), 9.85 (s, 1 H), 7.86 - 8.07 (m, 2 H), 7.70 - 7.75 (m, 1 H), 6.51 (s, 1 H), 6.25 (s, 2 H), 5.68 (s, 1 H), 4.97 (d, J = 8.6 Hz, 1 H), 3.59 - 3.82 (m, 1 H), 2.55 - 2.79 (m, 2 H),

2.05 - 2.32 (m, 2 H), 1.82 - 2.04 (m, 2 H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 - 112.93, -128.84. Example 2: (3S,8aR)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-3-[5-[3- fluoro-2-(1H-imidazol-2-yl)-4-pyridyl]-1H-imidazol-2-yl]-2,3 ,8,8a-tetrahydro-

1H-indolizin-5-one

Step 1. A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5, 8, 8a-hexahydroindolizine-3-carboxylic acid (330 mg, 1.016 mmol, 1.0 equiv) and CS2CO3 (199 mg, 0.611 mmol, 0.6 equiv) in DMF (8 mL) was stirred at room temperature for 30 min. 2-Bromo-1-(3-fluoro-2-(1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2-yl)pyridin-4-yl)ethanone (463 mg, 1.117 mmol, 1.1 equiv) was then added to the mixture. The reaction mixture was stirred at room temperature for 4h. The resulting mixture was then diluted with EtOAc (120 mL), washed with water (3 x 20 mL), brine (2 x 20 mL), dried over N 3280*, and concentrated under reduced pressure. The residue was applied onto a silica gel column (40 g, MeOH/DCM: 1/20) to yield (3S)-2-(3- fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2-yl)pyridin-4-yl)-2- oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C3iH34CIF2N ₅ 0 ₅ Si: 657.20, measured: 658.15 [M+H] ⁺ .

Step 2. To a mixture of (3S)-2-(3-fluoro-2-(1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2-yl)pyridin-4-yl)-2-oxoethyl 7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate (350 mg, 0.532 mmol, 1.0 equiv) and NhUOAc (410 mg, 5.319 mmol, 10.0 equiv) were added AcOH (5 mL) and toluene (50 mL). The reaction mixture was stirred at 110°C for 1h, then concentrated under reduced pressure. The residue was applied onto a silica gel column (40g, MeOH/DCM: 1/15) to yield \ (3S)-7-(6-amino-3-chloro-2-fiuorophenyl)-3-(5-(3-fiuoro-2-(1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridin-4-yl )-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid.

Step 3. A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3- fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2 -yl)pyridin-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (180 mg, 0.282 mmol, 1.0 equiv), TMSNa (325 mg, 2.821 mmol, 10.0 equiv) and trimethoxymethane (300 mg, 2.827 mmol, 10.0 equiv) in AcOH (8 mL) was stirred at 65°C for 2h, then concentrated. The residue was applied onto a silica gel column (40g,

MeOH/DCM: 1/20) to yield (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3-(5-(3-fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-im idazol-2-yl)pyridin-4- yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C32H33CIF2Nio02Si: 690.22, measured: 691.20 [M+H]÷.

Step 4. To a mixture of (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-3-(5-(3-fluoro-2-(1-((2-(trimethylsilyl)ethoxy)me thyl)-1H-imidazol-2- yl)pyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (130 mg, 0.188 mmol, 1.0 equiv) in DCM (8 rriL) was added TFA (3 ml_). The reaction mixture was stirred at room temperature for 4h, then concentrated. The residue was applied onto a C18 reverse column (120g, ACN/HzO (0.05%NhUHC03): 5%»>40%>»45%) to yield (3S)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(1 H-imidazol-2-yl)pyridin-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid. The solid was further purified by Prep-Chiral-HPLC(Column: CHIRALPAK IA,

2*25cm,5um; Mobile Phase A:Hex:DCM=3: 1(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B:EtOH~HPLC; Flow rate:18 mL/min;) to yield (3S,8aR)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2 -(1H-imidazol-2- y I) py ridi n-4-y I)- 1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C2eHieCIF2NioO: 560.14, measured (ES, m/z): 561.15[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.77 (s, 1 H), 12.31 (s, 1 H), 9.85 (s, 1 H), 8.44 (d, J = 5.0 Hz, 1 H), 7.92 - 8.01 (m, 2 H), 7.65 - 7.75 (m, 2 H), 7.28 (s, 1 H), 7.14 (s, 1 H), 5.71 (d, J = 2.7 Hz, 1 H), 5.06 (d, J = 8.7 Hz, 1 H), 3.64 - 3.85 (m, 1 H), 2.64 - 2.80 (m, 1 H), 2.54 - 2.59 (m, 1 H), 2.16 - 2.35

(m, 1 H), 2.06 - 2.15 (m, 1 H), 1.91 - 2.05 (m, 2 H). ¹⁸ F NMR (376 MHz, DMSO- de) δ -112.82, -124.37. Example 3: (S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4-[2- (difluoromethoxy)-4-pyridyl]-5-fluoro-1H-imidazol-2-yl]-2,3, 8,8a- tetrahydro-1 H-indolizin-5-one

LC/MS: mass calculated for C24H17CIF4N8O2: 560.11, measured (ES, m/z): 561.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.94 (s, 1 H), 9.82 (s, 1 H), 8.24 (d, J = 5.5 Hz, 1 H), 7.92 - 8.00 (m, 1 H), 7.67 - 7.73 (m, 1 H), 7.70 (t, J =72.6 Hz, 1 H), 7.36 (dd, J = 5.3, 1.5 Hz, 1 H), 7.12 (d, J = 1.5 Hz, 1 H), 5.65 (s, 1 H), 4.91 (d, J = 8.4 Hz, 1 H), 3.63 - 3.76 (m, 1 H), 2.51 - 2.61 (m, 2 H), 1.81 -2.31 (m, 4 H). ¹⁹ F NMR (282 MHz, DMSO-d6) δ - 87.05, - 112.95, - 125.18.

Example 4: (8aR)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5-(4- chloro-1 H-pyrazol-3-yl)-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H-indolizin-

5-one

Step 1: 4-Chloro-1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5 _l 5-tetramethyl-1,3,2 - dioxaborolan-2-yl)-1 H-pyrazole.

To a solution of 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-1 H-pyrazole (1.0 g, 3.60 mmol, 1.0 equiv.) in THF (10 mL) was added NCS (0.58 g, 4.31 mmol, 1.2 equiv.) at room temperature and the mixture was stirred for 2 h at 70 °C. The reaction was diluted with H2O and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2S04, concentrated and purified by silica gel chromatography (0→40% EA/PE) to yield 4-chloro-1-(tetrahydro-2H-pyran-2- yl)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole as a light yellow oil. LC/MS: mass calculated for C14H22BCIN2O3: 312.14, measured (ES, m/z): 313.10 [Μ+ΗΓ.

Step 2: (8aR)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(4-chloro-1H- pyrazol-3- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one.

A mixture of (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-iodo-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (0.10 g, 0.21 mmol, 1.0 equiv.), 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl -1,3,2- dioxaborolan-2-yl)-1 H-pyrazole (0.20 g, 0.64 mmol, 3.0 equiv.), Pd(dtbpf)Cl2 (0.028 g, 0.042 mmol, 0.2 equiv.) and K2CO3 (0.088 g, 0.64 mmol, 3.0 equiv.) in 1 ,4-dioxane (2 mL) and water (0.4 mL) was refluxed at 100 °C under Nz for 2 h. The mixture was diluted with HzO and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over NazSO*, concentrated and the residue was purified by silica gel chromatography (0→8%, MeOH/DCM) to yield (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5- (4-chloro-1 H-pyrazol-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one as a yellow solid. LC/MS: mass calculated for CzoHvCIzFNeO: 446.08, measured (ES, m/z): 447.00 [M+H] ⁺ .

Step 3: (8aR)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5-(4- chloro-1 H- pyrazol-3-yl)-1H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-indol izin-5-one.

A mixture of (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(4-chloro-1- (tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (25 mg, 0.047 mmol, 1.0 equiv.), trimethoxymethane (0.2 mL), azidotrimethylsilane (0.2 mL) and acetic acid (0.5 mL) was stirred overnight at room temperature. The solution was concentrated and the residue was purified by reverse phase chromatography on C18 (0→50% ACN/H2O) to yield (8aR)-3-(5-(4-chloro-1 H-pyrazol-3-yl)-1 H-imidazol-

2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1 -yl)phenyl)-2 , 3, 8, 8a- tetrahydroindolizin-5(1 H)-one as a brown solid.

LC/MS: mass calculated for CziHieCIzFNeO: 499.08, measured (ES, m/z): 500.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.79 - 9.90 (m, 1 H), 7.90 - 8.04 (m, 2 H), 7.68 - 7.77 (m, 2 H), 5.62 - 5.74 (m, 1 H), 5.05 - 5.17 (m, 1 H),

3.59 - 3.80 (m, 1 H), 2.52 - 2.60 (m, 2 H), 1.92 - 2.18 (m, 4 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.54, -112.86. Example 5: 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-y l]-3-fluoro-2- pyndyl]-3-methyl-isoxazole-5-carboxamide

LC/MS: mass calculated for C28H21CIF2N10O3: 618.15, measured (ES, m/z): 619.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.33 (d, J = 2.2 Hz, 1 H), 11.17 (s, 1 H), 9.85 (s, 1 H), 8.31 (d, J = 5.1 Hz, 1 H), 7.92 - 8.02 (m, 2 H), 7.70 - 7.75 (m, 1 H), 7.58 - 7.62 (m, 1 H), 7.19 (s, 1 H), 5.72 (d, J = 2.7 Hz, 1 H), 5.06 (d, J = 8.7 Hz, 1 H), 3.71 - 3.82 (m, 1 H), 2.67 - 2.78 (m, 1 H), 2.50 - 2.60 (m, 1 H), 2.36 (s, 3 H), 2.16 -2.29 (m, 1 H), 2.06 -2.16 (m, 1 H), 1.92 -

2.02 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.82, -126.71.

Example 6: N-[4-[2-[7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo - 2,3,8, 8a-tetrahydro-1 H-indolizin-3-yl]-4-fluoro-1 H-imidazol-5-yl]-2- pyridyl]methanesulfonamide

LC/MS: mass calculated for C24H2oCIF2Ne03S: 587.11, measured (ES, m/z): 588.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.84 (s, 1 H), 8.06 - 8.26 (m, 1 H), 7.89 - 8.05 (m, 1 H), 7.63 - 7.80 (m, 1 H), 7.17 (s, 1 H), 7.04 - 7.12 (m, 1 H), 5.67 (s, 1 H), 4.94 (d, J = 8.4 Hz, 1 H), 3.59 - 3.82 (m, 1 H), 3.20 (s, 3 H), 2.55 - 2.62 (m, 2 H), 1.82 - 2.38 (m, 4 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ - 112.95.

Example 7: N-[4-[2-[7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-oxo - 2,3,8, 8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-5-yl]-2- pyridyl]methanesulfonamide

LC/MS: mass calculated for C24H21CIFN9O3S: 569.12, measured (ES, m/z): 570.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 (300 MHz, DMSO-d6) 6 12.04 - 12.41 (m, 1 H), 9.74 - 9.93 (m, 1 H), 7.87 - 8.14 (m, 2 H), 7.64 - 7.80

(m, 2 H), 7.33 - 7.52 (m, 1 H), 7.08 - 7.30 (m, 1 H), 5.56 - 5.75 (m, 1 H), 4.88 - 5.11 (m, 1 H), 3.59 - 3.81 (m, 1 H), 3.15 (s, 3 H), 2.65 - 2.90 (m, 1 H), 2.53 - 2.63 (m, 1 H), 1.80 - 2.40 (m, 4 H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -112.99.

Example 8: (3S,8aR)-3-(5-(1H-indol-6-yl)-1H-imidazol-2-yl)-7-(3-chloro- 2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindoli zin-5(1H)-one

LC/MS: mass calculated for C2eH2oCIFNeO: 514.1, measured (ES, m/z): 515.3 [M+HJ\ ¹ H NMR (400 MHz, ACETONITRILE-da) δ ppm 9.42 (br s, 1H), 9.16 (s, 1H), 7.78 (s, 1H), 7.76 - 7.70 (m, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.44 (dd, J=1.5, 8.8 Hz, 1H), 7.39 (dd, J=1.3, 8.3 Hz, 1H), 7.26 - 7.22 (m, 2H), 6.44 (br s, 1H), 5.73 (s, 1H), 5.09 (d, J=8.5 Hz, 1H), 3.86 - 3.77 (m, 1H), 2.60 - 2.49 (m, 2H), 2.22 - 2.10 (m, 2H), 1.92 - 1.84 (m, 2H).

Example 9: (S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4-[2-(2 - hydroxyethoxy)-4-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one ^• S

If

^• N-X

H

LC/MS: mass calculated for C25H22CIFN8O3: 536.15, measured (ES, m/z): 537.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.07 (s, 1 H), 9.83 (s, 1 H), 8.06 (d, J = 5.4 Hz, 1 H), 7.96 (t, J = 8.2 Hz, 1 H), 7.66 - 7.76 (m, 2 H), 7.31 (d, J = 5.5 Hz, 1 H), 7.06 - 7.12 (m, 1 H), 5.65 - 5.68 (m, 1 H), 4.99 (d, J = 8.6

Hz, 1 H), 4.82 (t, J = 5.5 Hz, 1 H), 4.27 (t, J = 5.2 Hz, 2 H), 3.44 - 3.77 (m, 3H), 2.71 - 2.84 (m, 1 H), 2.50 - 2.54 (m, 1 H), 2.14 - 2.16 (m, 1 H), 2.05 - 2.13 (m, 1 H), 1.87 - 2.04 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.78.

Example 10: (S)-7-[3-Chloro-2-fluoro-6-(tetrazoM-yl)phenyl]-3-[4-[2- (difluoromethoxy)-4-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one

LC/MS: mass calculated for C24H18CIF3N8O2: 542.12, measured (ES, m/z): 543.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.61 (s, 1 H), 8.26 (d, J = 5.4 Hz, 1 H), 8.00 (s, 1 H), 7.78 - 7.83 (m, 1 H), 7.55 (t, J = 72.6 Hz, 1 H), 7.48

- 7.53 (m, 2 H), 7.30 - 7.31 (m, 1 H), 5.61 (d, J = 2.8 Hz, 1 H), 5.15 (dd, J = 9.8, 1.6 Hz, 1 H), 3.68 - 3.80 (m, 1 H), 2.87 (t, J = 15.6 Hz, 1 H), 2.53 - 2.59 (m, 1 H), 2.25 - 2.42 (m, 1 H), 2.12 - 2.20 (m, 1 H), 2.00 - 2.10 (m, 1 H), 1.75- 1.91 (m, 1 H). ¹⁹ FNMR (376 MHz, DMSO-de) δ - 87.10, -112.77.

Example 11: N-[(1R)-1-[4-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-4-f1uoro-1 H- imidazol-5-yl]phenyl]ethyl]acetamide

LC/MS: mass calculated for C28H25CIF2N8O2: 578.18, measured (ES, m/z): 579.20 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d*) δ 9.57 (s, 1 H), 7.78 - 7.85 (m, 1 H), 7.47 - 7.59 (m, 3 H), 7.34 - 7.38 (m, 2 H), 5.67 (d, J = 2.7 Hz, 1 H), 4.94 - 5.03 (m, 2 H), 3.79 - 3.93 (m, 1 H), 2.91 - 3.02 (m, 1 H), 2.52 - 2.62

(m, 1 H), 2.18 -2.30 (m, 2 H), 2.02 - 2.14 (m, 2 H), 1.97 (s, 3 H), 1.44 (d, J = 7.0 Hz, 3 H). ¹⁸ F NMR (282 MHz, Methanol-d*) δ -113.30, -136.81.

Example 12: Ethyl-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-i midazol-5-yl]-3- fluoro-2-pyridyl]methyl]carbamate

Cl'

NH F

Step 1: (3-Fluoro-4-iodopyridin-2-yl)methanamine.

A solution of 3-fluoro-4-iodopicolinonitrile (3.0 g, 12.10 mmol, 1.0 equiv.) in DCM (50 mL) was cooled to -78 °C, and diisobutylaluminium hydride (24.2 mL, 24.20 mmol, 2.0 equiv.) was then added slowly. The mixture was stirred at -78 °C for 2 h under N2. The reaction was quenched with potassium sodium tartrate solution (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the (3-fluoro-4-iodopyridin-2- yl)methanamine as a yellow solid. LC/MS: mass calculated for CeHeFINa: 251.96, measured (ES, m/z): 252.95 [M+H] ⁺ .

Step 2: Tert-butyl ((3-fluoro-4-iodopyridin-2-yl)methyl)carbamate.

A solution of (3-fluoro-4-iodopyridin-2-yl)methanamine (2.4 g, 9.52 mmol, 1.0 equiv.) in THF (30 mL) was cooled to 0°C, and then di-tert-butyl dicarbonate (2.5 g, 11.46 mmol, 1.2 equiv.) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0→50% EA/PE) to yield the tert-butyl ((3-fluoro-4-iodopyridin-2-yl)methyl)carbamate as a yellow solid. LC/MS: mass calculated for C11H14FIN2O2: 352.01, measured (ES, m/z): 353.10 [M+H] ⁺ . Step 3: Tert-butyl ((4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)methyl)carbamate.

To a solution of tert-butyl ((3-fluoro-4-iodopyridin-2-yl)methyl)carbamate (3.0 g, 8.52 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(ll) chloride (0.60 g, 0.86 mmol, 0.1 equiv.) in 1,4-dioxane (30 mL) was added tributyl(1- ethoxyvinyl)stannane (4.6 g, 12.74 mmol, 1.5 equiv.). The mixture was stirred at 95 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (50 mL), then extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, dried over N32S04, filtered and purified by silica gel chromatography (0→30% EA/PE) to yield 1- (difluoromethyl)-5-(1-ethoxyvinyl)-1H-1,2,4-triazoleas a yellow oil. LC/MS: mass calculated for C15H21FN2O3: 296.15, measured (ES, m/z): 297.25 [M+H]*.

Step 4: Tert-butyl ((4-(2-bromoacetyl)-3-fluoropyridin-2-yl)methyl)carbamate. tert-Butyl ((4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)methyl)carbamate (3.0 g, 10.12 mmol, 1.0 equiv.) was dissolved in THF (40 mL) and H2O (10 mL).

After cooling to 0 °C, 1-bromopyrrolidine-2,5-dione (1.8 g, 10.12 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at room temperature for 1 h, then diluted with water and extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield tert-butyl ((4-(2-bromoacetyl)-3-fluoropyridin-2-yl)methyl)carbamate as a yellow oil. LC/MS: mass calculated for Ci3HieBrFN203: 346.03, measured (ES, m/z): 347.10, 349.10 [M+H, M+H+2]*.

Step 5: 2-(2-(((Tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4- yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3, 5,8, 8a-hexahydroindolizine-3-carboxylic acid (812 mg, 2.50 mmol, 1.0 equiv.) in DMF (15 mL) was added cesium carbonate (489 mg, 1.50 mmol, 0.6 equiv.). The mixture was stirred at room temperature for 0.5 h. Then tert-butyl ((4-(2-bromoacetyl)-3-fluoropyridin-2-yl)methyl)carbamate (1042 mg, 3.00 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with water (50 mL), and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, dried over istaSO*. filtered and purified by silica gel chromatography (0→10%

MeOH/DCM) to yield 2-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin- 4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C28H2eCIF ₂ N40e: 590.17, measured (ES, m/z): 591.35 [M+H]*. Step 6: Tert-butyl ((4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fl uoropyridin-2- yl)methyl)carbamate.

To a solution of 2-(2-(((tert-butoxycarbonyl)amino)methyl)-3- fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.1 g, 1.86 mmol, 1.0 equiv.) in toluene (20 mL) and acetic acid (2 mL) was added ammonium acetate (1.4 g, 18.16 mmol, 10.0 equiv.). The mixture was stirred at 90 °C for 4 h. After cooling to room temperature, the reaction was quenched with water (50 mL), extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0→10% methanol/DCM) to yield the tert-butyl ((4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3 ,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 - yl)methyl)carbamate as a yellow solid. LC/MS: mass calculated for C28H29CIF ₂ Ne03: 570.20, measured (ES, m/z): 571.40 [M+H]*.

Step 7: Tert-butyl ((4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl )-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridi n-2- yl)methyl)carbamate.

To a solution of tert-butyl ((4-(2-((3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5-yl)-3- fluoropyridin-2-yl)methyl)carbamate (872 mg, 1.53 mmol, 1.0 equiv.) in acetic acid (10 mL) was added azidotrimethylsilane (1759 mg, 15.27 mmol, 10.0 equiv.), followed by addition of trimethoxymethane (1621 mg, 15.27 mmol, 10.0 equiv.). The reaction mixture was stirred at 60 °C for 2 h. After cooling to room temperature, the reaction was quenched with water (50 mL), extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the tert-butyl ((4-(2-((3S)-7- (3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 - yl)methyl)carbamate as a yellow solid. LC/MS: mass calculated for C29H28CIF2N8O3: 623.20, measured (ES, m/z): 624.40 [M+H] ⁺ .

Step 8: (3S)-3-(5-(3-(Aminomethyl)-2-fluorophenyl)-1H-imidazol-2-yl) -7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 Hi- one.

To a solution of tert-butyl ((4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol- 1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3- fluoropyridin-2-yl)methyl)carbamate (700 mg, 1.12 mmol) in DCM (4 ml_) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with water and extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield (3S)-3-(5-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1 H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured (ES, m/z): 524.10 [M+H] ⁺ .

Step 9: Ethyl ((4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)ph enyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)methyl)carbamate.

To a solution of (3S)-3-(5-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (220 mg, 0.42 mmol, 1.0 equiv.) in DCM (5 mL) were added TEA (212 mg, 2.10 mmol, 5.0 equiv.) and ethyl carbonochloridate (137 mg, 1.26 mmol, 3.0 equiv.). The reaction mixture was stirred at 25 °C for 2h. The reaction mixture was then diluted with water and extracted with EA.

The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield a residue. To the residue was added MeOH (5 mL) and ΝΗ3·Η2θ (0.5 mL). The mixture was stirred at 35 °C for 0.5 h and concentrated to dryness under reduced pressure. The resulting residue was purified by C18 column chromatography (CH3CN/H2O) & chiral-HPLC (Column: (R,R)-WHELK-01-Kromasil , 2.ir25cm,5pm ; Mobile Phase A:MTBE(0.5% 2M NH ₃ -MeOH)-HPLC, Mobile Phase B:EtOH-HPLC; Flow rate:20 mLZmin) to yield ethyl ((4-(2-((3S,8aR)-7- (3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)methyl)carbamate as a white solid.

LC/MS: mass calculated for C27H24CIF2N9O3: 595.17, measured (ES, m/z): 596.20 [M+H] *. ¹ H NMR (400 MHz, DMSO-de) δ 12.27 (s, 1 H), 9.84 (s, 1 H), 8.32 (d, J = 5.0 Hz, 1 H), 7.93 - 8.02 (m, 1 H), 7.86 (t, J = 5.4 Hz, 1 H), 7.69 - 7.72 (m, 1 H), 7.55 - 7.58 (m, 1 H), 7.47 - 7.52 (m, 1 H), 5.70 (d, J = 2.7 Hz,

1 H), 5.04 (d, J = 8.8 Hz, 1 H), 4.32 - 4.42 (m, 2 H), 4.00 (q, J = 7.1 Hz, 2 H), 3.69 - 3.78 (m, 1 H), 2.67 - 2.77 (m, 1 H), 2.52 - 2.55 (m, 1 H), 2.15 - 2.24 (m, 1 H), 2.07 -2.14 (m, 1 H), 1.90 - 1.99 (m, 2 H), 1.16 (t, J = 7.1 Hz, 3 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.85, -130.28

Example 13: 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-i midazol-5-yl]-3- fluoro-2-pyridyl]methyl]acetamide

LC/MS: mass calculated for C2eH22CIF2Ne02: 565.16, measured (ES, m/z): 566.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.26 (s, 1 H), 9.82 (s, 1 H), 8.29 - 8.32 (m, 2 H), 7.95 (t, J = 8.7 Hz, 1 H), 7.86 (t, J = 5.4 Hz, 1 H), 7.65 - 7.75 (m, 1 H), 7.56 (d, J = 4.2 Hz, 1 H), 5.68 (d, J = 2.5 Hz, 1 H), 5.02 (d, J = 8.6 Hz, 1 H), 4.43 - 4.46 (m, 2 H), 3.67 - 3.77 (m, 1 H), 2.66 - 2.76 (m, 1 H), 2.50 - 2.55 (m, 1 H), 2.04 - 2.26 (m, 2 H), 1.89 -1.97 (m, 2 H), 1.85 (s, 3 H). ¹⁸ F

NMR (282 MHz, DMSO-de) δ -112.58, -129.79.

Example 14: (3S,8aR)-3-(5-(1 H-indol-5-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3 _> 8,8a-tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eH2oCIFNeO: 514.1, measured (ES, m/z): 515.2 [M+H] ⁺ . ¹ H NMR (400 MHz, METHANOL-d*) δ ppm 9.57 (s, 1H), 8.33 (s, 1H), 7.85 - 7.78 (m, 2H), 7.54 (dd, J=1.5, 8.8 Hz, 1H), 7.43 - 7.38 (m, 2H), 7.28 - 7.24 (m, 2H), 6.48 (d, J=3.0 Hz, 1H), 5.72 (d, J=2.8 Hz, 1H), 5.19 (d, J=8.8 Hz, 1H), 3.93 - 3.83 (m, 1H), 3.04 - 2.92 (m, 1H), 2.60 (dd, J=4.3, 16.8 Hz, 1H), 2.42 - 2.30 (m, 1H), 2.27 - 2.18 (m, 2H), 2.12 - 2.00 (m, 1H).

Example 15: (3S,8aR)-3-[5-(2-Amino-5-chloro _* 4-pyridyl)-1 H-imidazol-2-yl]- 7-[3-chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one cr

NH

LC/MS: mass calculated for C23H18CI2FN9O: 525.10, measured (ES, m/z): 526.00 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.09 (s, 1 H), 9.85 (s, 1 H), 7.97 (t, J = 7.9 Hz, 1 H), 7.89 (s, 1 H), 7.68 - 7.75 (m, 2 H), 7.19 (s, 1H),

6.05 (s, 2 H), 5.70 (d, J = 2.6 Hz, 1 H), 5.01 (d, J = 8.8 Hz, 1 H), 3.65 - 3.78 (m, 1 H), 2.59 - 2.79 (m, 1 H), 2.52 - 2.56 (m, 1H), 2.15 - 2.26 (m, 1 H), 2.05 - 2.14 (m, 1 H), 1.88 - 2.04 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.61. Example 16: N-[(1R)-1-[4-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5~oxo~2,3 _l 8,8a-tetrahydro-1H~indolizin-3-yl]-1H~imidazol-5- yl]phenyl]ethyl]acetamide

LC/MS: mass calculated for C28H26CIFN8O2: 560.19, measured (ES, m/z): 561.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.76 - 11.92 (m, 1 H), 9.84 (s, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 7.98 (t, J = 8.2 Hz, 1 H), 7.60 - 7.75 (m, 3 H), 7.42 (s, 1 H), 7.25 - 7.30 (m, 2 H), 5.68 (d, J = 9.1 Hz, 1 H), 5.00 (d, J =

6.6 Hz, 1 H), 4.86 - 4.92 (m, 1 H), 3.65 - 4.13 (m, 1 H), 2.70 - 2.87 (m, 1 H), 2.29 - 2.44 (m, 1 H), 2.16 - 2.27 (m, 1 H), 1.90 - 2.05 (m, 2 H), 1.84 (s, 3 H), 1.64 - 1.74 (m, 1 H), 1.33 - 1.38 (m, 3 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ - 112.82, -113.06. Example 17: (3S,8aR)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-3-[5-(3- fluoro-4-pyridyl)-1H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1H-i ndolizin-5-one

To a mixture of 2-(3-fluoropyridin-4-yl)-2-oxoethyl (3R,8aS)-7-(3-chloro- 2-fluoro-6-(1H-tetrazoM-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate (43 mg, 0.07 mmol) and ammonium acetate (193.1 mg, 2.5 mmol) in a 20 ml scintillation vial was added HOAc (3.0 mL). The reaction mixture was stirred at 90 °C for 4 h, and the excess solvent was removed under reduced pressure. The residue was purified by HPLC to yield a white solid. LC/MS calculated for C23H17CIF2N8O: 494.1, measured 495.1 (MH ⁺ ). ¹ H NMR (400 MHz, METHANOL-d4) δ 9.61 (s, 1H), 8.69 (d, J=3.91 Hz, 1H), 8.57 (d, J=5.87 Hz, 1H), 8.27 (t, J=6.36 Hz, 1H), 7.91 (d, J=3.42 Hz, 1H), 7.81-7.88 (m, 1H), 7.58 (dd, J=1.47, 8.80 Hz, 1H), 5.78-5.81 (m, 1H), 5.25 (d, J=8.80 Hz, 1H), 3.93-4.06 (m, 1H), 2.81-2.92 (m, 1H), 2.74 (s, 1H), 2.36-2.47 (m, 1H),

2.20-2.34 (m, 2H), 2.01-2.13 (m, 1H).

Example 18: N-[5-Chloro-4-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-i midazol-5-yl]-2- pyridyljacetamide

LC/MS: mass calculated for C25H20CI2FN9O2: 567.11, measured (ES, m/z): 568.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.82 (s, 1 H), 8.64 (s, 1 H), 8.44 (s, 1 H), 7.90 - 8.04 (m, 2 H), 7.71 (d, J = 8.7 Hz, 1 H), 5.70 (d, J = 2.7 Hz, 1 H), 5.16 (d, J = 9.2 Hz, 1 H), 3.33 - 3.83 (m, 1 H), 2.84 - 3.02 (m, 1 H), 2.55 - 2.61 (m, 1 H), 2.25 - 2.39 (m, 1 H), 2.11 - 2.20 (m, 4 H), 2.03 - 2.10 (m, 1 H), 1.91 - 2.01 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -74.59, -112.42.

Example 19: (R)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5-(1H- pyrrolo[2,3-c]pyridin-3-yl)-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one

LC/MS: mass calculated for C25H19CIFN9O: 515.14, measured (ES, m/z): 516.10 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d<) δ 9.58 (s, 1 H), 8.71 (d, J =

1.1 Hz, 1 H), 8.14 (d, J = 5.7 Hz, 1 H), 7.75 - 7.93 (m, 3 H), 7.52 - 7.59 (m, 1 H), 7.26 (s, 1 H), 5.72 (d, J = 2.9 Hz, 1 H), 5.10 - 5.21 (m, 1 H), 3.82 - 3.95 (m, 1 H), 2.91 - 3.03 (m, 1 H), 2.55 - 2.64 (m, 1 H), 2.27 - 2.39 (m, 1 H), 2.18 - 2.27 (m, 2 H), 2.02 - 2.16 (m, 1 H). ¹⁹ F NMR (376 MHz, Methanol-d*) 6 -113.30. Example 20: (3S,8aR*)-3-{5-(1 H-Pyrrolo[3,2-c]pyridin-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one ci, ^♦ R j)

0 HN.

N-N

¼ ,'N N

N

N'

Step 1: tert-Butyl 3-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H-pyrrolo[3,2- c]pyridine-1-carboxylate.

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-iodo-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one (150 mg, 0.32 mmol, 1.0 equiv.) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrrolo[3,2-c]pyridine-1-carboxylate (218 mg, 0.63 mmol, 2.0 equiv.) in 1,4- dioxane (10 mL) and water (1 mL) were added potassium carbonate (132 mg, 0.95 mmol, 3.0 equiv.) and 1,T-bis (di-t-butylphosphino)ferrocene palladium dichloride (21 mg, 0.03 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EA. The combined extracts were dried over anhydrous Na2S04, concentrated. The residue was purified by silica gel column chromatography (0→8% MeOH/DCM) to yield tert-butyl 3-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H-pyrrolo[3,2- c]pyridine-1-carboxylate as a brown solid. LC/MS (ES, m/z): mass calculated for C29H2aCIFNe03:562.19, measured: 563.15 [M+H]÷. Step 2: tert-Butyl 3-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)- 5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H-pyrrolo[3,2- c]pyridine-1-carboxylate

To a mixture of tert-butyl 3-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H-pyrrolo[3,2- c]pyridine-1-carboxylate (120 mg, 0.21 mmol, 1.0 equiv.) in acetic acid (5 mL) were added azidotrimethylsilane (2.5 mL) and trimethoxymethane (2.5 mL). The reaction mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum to yield tert-butyl 3-(2-((3S)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-1 H-pyrrolo[3,2-c]pyridine-1-carboxylate as a brown solid, which was used in the next step without further purification. LC/MS (ES, m/z): mass calculated for C30H27CIFN9O3: 615.19, measured: 616.25 [M+H]*.

Step 3: (3S,8a*R)-3-(5-(1 H-Pynrolo[3,2-c]pyridin-3-yl)-1 H-imidazol-2-yl)-7- (3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one

A solution of tert-butyl 3-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)- 5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H- pyrrolo[3,2-c]pyridine-1-carboxylate (157 mg,) in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved into EA, washed with NaHCOa solution, dried over anhydrous N32S04, and concentrated. The residue was purified by chiral HPLC with MtBE (0.1%DEA):EtOH=70:30 to yield (3S,8a*R)-3-(5-(1H-pyrrolo[3,2-c]pyridin-3-yl)- 1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)p henyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a brown solid.

LC/MS: mass calculated for C25H19CIFN9O: 515.14, measured (ES, m/z): 516.10 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d<) 69.58 (s, 1 H), 9.05 (s, 1 H), 8.14 - 8.21 (m, 1 H), 7.78 - 7.84 (m, 1 H), 7.68 (s, 1 H), 7.50 - 7.62 (m, 1 H), 7.45 (dd, J = 5.9, 1.1 Hz, 1 H), 7.28 (s, 1 H), 5.72 (d, J = 2.8 Hz, 1 H), 5.17 (d, J = 8.8 Hz, 1 H), 3.82 - 3.97 (m, 1 H), 2.91 - 3.05 (m, 1 H), 2.55 - 2.64 (m, 1 H),

2.28 - 2.40 (m, 1 H), 2.19 - 2.27 (m, 2 H), 2.03 - 2.17 (m, 1 H). ¹⁸ F-NMR (376 MHz, Methanol-d*) 6 -113.25.

Example 21 : (3S)-3-(5-(2-Amino-3-methylpyridin-4-yl)-1H-imidazol-2-yl)-7 - (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin-

5(1H)-one

Step 1: 4-lodo-3-methylpyridin-2-amine.

To a solution of 2-fluoro-4-iodo-3-methylpyridine (500 mg, 2.11 mmol) in DMSO (5 mL) was added ammonium hydroxide (6 ml_). The resulting mixture was stirred at 100 °C for 2 days. After cooling to room temperature, the resulting mixture was diluted with EA and washed with water three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0→50% ethyl acetate/petroleum ether) to yield the 4-iodo-3-methylpyridin-2- amine as a white solid. LC/MS: mass calculated for CeHyINz: 233.97, measured (ES, m/z): 234.95 [M+H] ⁺ .

Step 2: N-(4-iodo-3-methylpyridin-2-yl)acetamide.

A mixture of 4-iodo-3-methylpyridin-2-amine (540 mg, 2.31 mmol) and AC2O (15 mL) was stirred at room temperature overnight. The resulting mixture was concentrated to yield the N-(4-iodo-3-methylpyridin-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for CeHelteO: 275.98, measured (ES, m/z): 276.95 [M+H] ⁺ .

Step 3: N-(4-(1-ethoxyvinyl)-3-methylpyridin-2-yl)acetamide.

To a solution of N-(4-iodo-3-methylpyridin-2-yl)acetamide (510 mg, 1.85 mmol, 1.0 equiv.) in 1 ,4-dioxane (35 mL) was added tributyl(1-ethoxyvinyl)tin (733 mg, 2.03 mmol, 1.1 equiv.), followed by addition of Pd(dppf)Cl2 (75 mg, 0.092 mmol, 0.05 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C overnight After cooling to room temperature, the reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by alumina gel chromatography (0→80% ethyl acetate/petroleum ether) to yield the N-(4-(1- ethoxyvinyl)-3-methylpyridin-2-yl)acetamide as a yellow oil. LC/MS: mass calculated for Ci2HieN2C>2: 220.12, measured (ES, m/z): 221.15 [M+H]÷. Step 4: N-(4-(2-bromoacetyl)-3-methylpyridin-2-yl)acetamide.

To a solution of N-(4-(1-ethoxyvinyl)-3-methylpyridin-2-yl)acetamide (270 mg, 1.23 mmol, 1.0 equiv.) in THF (6 ml_) and H2O (2 mL) was added NBS (218 mg, 1.23 mmol, 1.0 equiv.). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0→90% ethyl acetate/petroleum ether) to yield n-(4-(2-bromoacetyl)-3-methylpyridin-2-yl)acetamide as a yellow oil. LC/MS: mass calculated for CioHuBrtaOz: 270.00, measured (ES, m/z):

271.00, 273.00 [M+H, M+H+2]*.

Step 5: 2-(2-Acetamido-3-methylpyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate.

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (140 mg, 0.43 mmol, 1.0 equiv.) in ACN (4 mL) was added K2CO3 (119 mg, 0.86 mmol, 2.0 equiv.) at room temperature. After stirring for 30 min, N-(4-(2-bromoacetyl)-3- methylpyridin-2-yl)acetamide (175 mg, 0.65 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the 2-(2-acetamido-3-methylpyridin-4-yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a brown oil. LC/MS: mass calculated for C25H24CIFN4O5: 514.14, measured (ES, m/z): 515.15 [M+H]*. Step 6: N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-methylpyridin-2 -yl)acetamide.

To a solution of 2-(2-acetamido-3-methylpyridin-4-yl)-2-oxoethyl (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate (120 mg, 0.23 mmol, 1.0 equiv.) in toluene (8 mL) and HOAc (0.2 mL) was added NH4OAC (359 mg, 4.66 mmol, 20.0 equiv.). The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0→15% MeOH/DCM) to yield N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-methylpyridin-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H24CIFN6O2: 494.16, measured (ES, m/z): 495.30 [M+H] ⁺ . Step 7: N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-me thylpyridin-2- yl)acetamide.

To a solution of N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-me thylpyridin-2- yl)acetamide (73 mg, 0.15 mmol, 1.0 equiv.) in AcOH (8 mL) were added azidotrimethylsilane (340 mg, 2.95 mmol, 20.0 equiv.) and trimethoxymethane (313 mg, 2.95 mmol, 20.0 equiv.). The resulting mixture was stirred at 50 °C overnight. The resulting mixture was concentrated to yield N-(4-(2-((3S)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-methylpyridin-2-yl)acetamide as a yellow oil, which was used in the next step without further purification. LC/MS: mass calculated for CtthtaCIFNgOa: 547.16, measured (ES, m/z): 548.35 [M+H]÷.

Step 8: (3S)-3-(5-(2-Amino-3-methylpyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro- 2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one.

To a solution of N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- methylpyridin-2-yl)acetamide (75 mg, 0.14 mmol) in THF (3 mL) was added HCI (3 mL, 2 M in H2O). The resulting mixture was stirred at 60 °C overnight After cooling to room temperature, the resulting mixture was concentrated. The residue was purified by prep-HPLC to yield the (3S)-3-(5-(2-amino-3- methylpyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6 -(1H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C24H21CIFN9O: 505.15, measured (ES, m/z): 506.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.95 - 12.18 (m, 1 H), 9.84 (s,

1 H), 7.93 - 8.02 (m, 1 H), 7.56 - 7.85 (m, 2 H), 7.31 (s, 1 H), 6.87 (d, J = 5.4 Hz, 1 H), 5.54 - 5.73 (m, 2 H), 5.01 (d, J = 8.4 Hz, 1 H), 3.60 - 3.82 (m, 2 H), 2.65 - 2.80 (m, 1 H), 2.24 (s, 3 H), 2.07 - 2.16 (m, 2 H), 1.91 - 2.04 (m, 3 H). ¹⁹ F-NMR: (376 MHz, DMSO-de) δ -112.86.

Example 22: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(4- (2-(hydroxymethyl)thiazol-4-yl)-1H-imidazol-2-yl)~2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for: C22H18CIFN8O2S: 512.1, measured (ES, m/z): 513.2 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-di) 69.58 (s, 1H),7.89 (s, 1H), 7.84-7.75 (m, 1H), 7.79 (s, 1H), 7.58 (dd, J = 8.8, 1.7 Hz, 1H), 5.76 (d, J = 2.8 Hz, 1H), 5.28 (dd, J = 10.2, 1.9 Hz, 1H), 4.90 (s, 2H), 2.98 (t, J = 15.3 Hz,

1H), 2.71 (dd, J = 17.0, 4.3 Hz, 1H), 2.57- 2.47 (bm, 1H), 2.36-2.29 (bm, 1H), 2.26-2.19 (bm, 1H), 2.08-1.93 (bm, 1H), 190-1.80 (m, 1H). ¹⁹ F NMR (400 MHz, methanol-d*) δ -113.5.

Example 23: (3S,8aR)-7-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3- (4-f1uoro-5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imid azol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one s li o r

U

Step 1: 2-Bromo-4-chloro-3-fluorophenol.

To a solution of 2-bromo-3-fluorophenol (5.0 g, 26.18 mmol, 1.0 equiv.) in ACN (200 mL) were added NCS (3.5 g, 26.21 mmol, 1.0 equiv.) and TFA (3.3 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature.

The reaction mixture was concentrated. The residue was purified by silica gel chromatography (0→20% EA/PE) to yield 2-bromo-4-chloro-3-fluorophenol as a yellow oil. LC/MS: mass calculated for CeHaBrCIFO: 223.90, measured (ES, m/z): 222.90 [M-H]\

Step 2: 2-Bromo-4-chloro-1-(difluoromethoxy)-3-fluorobenzene.

To a solution of 2-bromo-4-chloro-3-fluorophenol (3.7 g, 16.41 mmol, 1.0 equiv.) in DMF (60 mL) were added CS2CO3 (10.7 g, 32.84 mmol, 2.0 equiv.) and sodium 2-chloro-2,2-difluoroacetate (5.0 g, 32.80 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at 90 °C. After cooling to room temperature, the reaction mixture was poured into water (100mL), then extracted with EA (3 x 100 mL). The organic layers were combined, washed with water (100 mL) and brine (100 mL), dried over NaaSO*. filtered and concentrated. The residue was purified by silica gel chromatography (0→20% EA/PE) to yield 2-bromo-4-chloro-1-(difluoromethoxy)-3-fluorobenzene as a colorless oil. ¹ H NMR (300 MHz, Chloroform-d) δ 7.38 (dd, J = 9.0, 7.8 Hz, 1 H), 6.99 - 7.05 (m, 1 H), 6.55 (t, J = 72.5 Hz, 1 H).

Step 3: Ethyl (3S)-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

Under an inert atmosphere of nitrogen, to a solution of ethyl (3S)-5-oxo- 7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroind olizine-3- carboxylate (1.5 g, 4.20 mmol, 1.0 equiv.) in 1 ,4-dioxane (20 mL) were added 4,4,4 ^, ,4',5 _I 5 _I 5 ^, ,5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (1.6 g, 6.30 mmol, 1.5 equiv.), Pd(dppf)Cl2 (307 mg, 0.42 mmol, 0.1 equiv.), and KOAc (824 mg, 8.40 mmol, 2.0 equiv.). The reaction mixture was stirred for 2 h at 90 °C, then concentrated to dryness under reduced pressure to yield ethyl (3S)-5-oxo-7- (4,4,5,5-tetramethyM ,3,2-dioxaborolan-2-yl)-1 ,2,3,5,8,8a-hexahydroindolizine- 3-carboxylate as a yellow solid. LC/MS: mass calculated for CiyHaBNOs: 335.19, measured (ES, m/z): 336.15 [M+H]*.

Step 4: Ethyl (3S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

Under an inert atmosphere of nitrogen, to a solution of ethyl (3S)-5-oxo- 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (1.2 g, 3.58 mmol, 1.0 equiv.) in 1 ,4-dioxane (15 mL) with H2O (1.5 mL) were added 2-bromo-4-chloro-1-(difluoromethoxy)- 3-fluorobenzene (1.1 g, 3.99 mmol, 1.1 equiv.), Pd(dppf)Cl2 (262 mg, 0.36 mmol, 0.1 equiv.), and K2CO3 (990 mg, 7.16 mmol, 2.0 equiv.). The reaction mixture was stirred for 2 h at 90 °C, then concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0→15%) to yield ethyl (3S)-7- (3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-1,2,3,5, 8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C18H17CIF3NO4: 403.08, measured (ES, m/z): 404.10 [M+H] ⁺ . Step 5: (3S)-7-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid.

To a solution of ethyl (3S)-7-(3-chloro-6-(difluoromethoxy)-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate (1.0 g, 2.48 mmol, 1.0 equiv.) in THF (10 mL), H2O (3 mL) was added UOH (296 mg, 12.36 mmol, 5.0 equiv.). The reaction mixture was stirred overnight at room temperature, then adjusted to pH = 5~6 by using HCI (2 M) at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated to yield (3S)-7-(3-chloro-6- (difluoromethoxy)-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylic add as a yellow solid. LC/MS: mass calculated for C16H13CIF3NO4: 375.05, measured (ES, m/z): 376.10 [M+H] ⁺ .

Step 6: 2-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fiuoropyridin- 4-yl)-2- oxoethyl (3S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

To a mixture of (3S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (800 mg, 2.13 mmol,

1.0 equiv.) in DMF (15 mL) was added CS2CO3 (416 mg, 1.28 mmol, 0.6 equiv.) and the mixture was stirred at room temperature for 30 min. 2-Bromo-1-(2- (((tert-butyldimethylsilyl)oxy)methyl)-3-fiuoropyridin-4-yl) ethan-1-one (1.2 g, 3.31 mmol, 1.5 equiv.) was then added, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (300 mLx 3). The combined organic layer was washed with brine, dried over Na2SO< and concentrated. The residue was purified by silica gel chromatography (0→20% MeOH/DCM) to yield 2-(2- (((tert-butyldimethylsilyl)oxy)methyl)-3-fiuoropyridin-4-yl) -2-oxoethyl (3S)-7-(3- chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-1,2,3,5,8,8 a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C3oH ₃ 3CIF4N20eSi: 656.17, measured (ES, m/z): 657.20 [M+H]*.

Step 7: (3S)-3-(5-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4-yl)- 1H-imidazol-2-yl)-7-(3-chloro-6-(difluoromethoxy)-2-fluoroph enyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2-oxoethyl (3S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (900 mg, 1.37 mmol, 1.0 equiv.) in toluene (15.0 ml_) and CHsCOOH (1.5 mL) was added NH ₄ OAc (1.0 g, 12.97 mmol, 10.0 equiv.). The reaction mixture was stirred for 2 h at 110 °C, then concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0→15%) to yield (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4-yl)-1H- imidazol-2-yl)-7-(3-chloro-6-(difluoromethoxy)-2-fluoropheny l)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C3oH33CIF4N40 ₃ Si: 636.19, measured (ES, m/z): 637.25 [M+H]*.

Step 8: (3S,8aR)-7-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-( 5-(3- fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3, 8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-6-(difluoromethoxy)-2- fluorophenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (700 mg, 1.10 mmol, 1.0 equiv.) in THF (10 mL) was added triethylamine trihydrofluoride (2.5 mL).The reaction mixture was stirred for 2 h at 70 °C, then concentrated under vacuum and the residue was purified by C18 column (eluent: 5% to 50% (v/v) CHsCN and H ₂ 0 with 0.05% NH4HCO3) to yield (3S)-7-(3-chloro-6-(difluoromethoxy)-2- fluorophenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)- 1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid, which was further separated by preparative HPLC (Column: CHIRALPAK IG, 2*25cm,5pm ;

Mobile Phase A: undefined, Mobile Phase B:undefined; Flow rate:20 mL/min;) to yield (3S,8aR)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-( 5-(3-fluoro-2- (hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin- 5(1 H)-one as a white solid. LC/MS: mass calculated for C24H19CIF4N4O3:

522.11, measured (ES, m/z): 523.15 [M+H] ⁺ .

Step 9: (3S,8aR)-7-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-( 4-fluoro-5- (3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of (3S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-3- (5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl )-2,3,8,8a- tetrahydroindolizin-5(1H)-one (200 mg, 0.38 mmol, 1.0 equiv.) in DMF (5 ml_) with H2O (0.5 mL) was added Selectfluor (95 mg, 0.27 mmol, 0.7 equiv.). The reaction mixture was stirred 1 h at room temperature, then concentrated under reduced pressure. The residue was purified by preparative HPLC using a (Column: XBridge Prep OBD C18 Column, 19*250mm,5um; Mobile Phase A:Water (10MMOL7L NH4HCO3), Mobile Phase B:MeOH. Flow rate:25 mL/min;) to yield the (3S,8aR)-7-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3-( 4- fluoro-5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazo l-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C24H18CIF5N4O3: 540.10, measured (ES, m/z): 541.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.67 (s, 1 H), 8.39 (d, J = 5.1 Hz, 1 H), 7.72 (t, J = 8.7 Hz, 1 H), 7.00 - 7.61 (m, 3 H), 5.97 (d, J = 1.9 Hz, 1 H), 5.35 (brs, 1 H), 5.12 (d, J = 8.5 Hz, 1 H), 4.64 (d, J = 2.4 Hz, 2 H), 3.88 - 4.01 (m, 1 H), 2.65 - 2.74 (m, 2 H), 2.14 - 2.29 (m, 2 H), 1.95 - 2.07 (m, 2 H).

¹⁹ F-NMR: (282 MHz, DMSO-de) 6 -82.38, -113.36, -125.75, -130.36.

Example 24: (3S,8aR)-3-(5-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H19CIFN9O: 515.1, measured (ES, m/z): 516.0 [M+H]*. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.89 (s, 1 H), 2.25 (s, 2 H), 2.35 - 2.55 (m, 1 H), 2.63 (dd, J=17.1, 4.4 Hz, 1 H), 2.89 (br s, 1 H), 3.76 - 3.97 (m, 1 H), 5.17 - 5.26 (m, 1 H), 5.27 - 5.34 (m, 1 H), 5.67 (d, J=2.9 Hz, 1 H),

5.84 - 5.92 (m, 1 H), 6.52 (d, J=3.4 Hz, 1 H), 7.42 (d, J=3.4 Hz, 2 H), 7.66 - 7.81 (m, 2 H), 8.12 - 8.15 (m, 1 H), 8.23 (d, J=2.0 Hz, 1 H), 8.45 (d, J=2.0 Hz, 1 H), 9.49 (s, 1 H).

Example 25: (3S,8aR)-7-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)-3- (5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl )-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

. _ N—

E r

Cl— IH

LC/MS: mass calculated for C24H19CIF4N4O3: 522.11, measured (ES, m/z): 523.15 [M+H] *. ¹ H NMR (300 MHz, DMSO-de) δ 12.32 (s, 1 H), 8.30 (d, J = 5.0 Hz, 1 H), 7.90 (t, J = 5.4 Hz, 1 H), 7.72 (t, J = 8.7 Hz, 1 H), 7.05 - 7.65 (m, 3 H), 5.98 (d, J = 2.5 Hz, 1 H), 5.28 (t, J = 5.9 Hz, 1 H), 5.13 (d, J = 8.5 Hz, 1 H), 4.59 - 4.68 (m, 2 H), 3.92 - 4.03 (m, 1 H), 2.85 - 2.96 (m, 1 H), 2.62 - 2.70 (m, 1 H), 2.13 - 2.28 (m, 2 H), 2.01 - 2.08 (m, 2 H). ¹⁸ F-NMR: (282 MHz, DMSO-de) δ -82.38, -113.35, -130.06.

Example 26: (3S,8aR)-7-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(5 - (3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H19CIF4N4O2: 506.11, measured (ES, m/z): 507.15 [M+H] ^♦ . ¹ H NMR (300 MHz, DMSO-de) 6 12.26 (s, 1 H), 8.32 (d, J = 5.0 Hz, 1 H), 7.91 (t, J = 5.4 Hz, 1 H), 7.75 - 7.85 (m, 1 H), 7.54 - 7.65 (m, 2 H), 7.09 (t, J = 54.0 Hz, 1 H), 5.91 (d, J = 2.5 Hz, 1 H), 5.29 (t, J = 5.9 Hz, 1 H),

5.14 (d, J = 8.5 Hz, 1 H), 4.64 (dd, J = 5.9, 2.4 Hz, 2 H), 4.00 - 4.13 (m, 1 H), 2.65 - 2.98 (m, 1 H), 2.62 - 2.73 (m, 1 H), 2.16 - 2.32 (m, 2 H), 1.96 - 2.10 (m, 2 H). ¹⁶ F-NMR: (282 MHz, DMSO-de) 6 -109.38, -115.57, -130.01.

Example 27: (3S,8aR)-7-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)-3-(4 - fluoro-5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazo l-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C24H18CIF5N4O2: 524.12, measured (ES, m/z): 525.05 [M+H] ^♦ . ¹ H NMR (300 MHz, DMSO-de) (300 MHz, DMSO-de) 6 12.65 (s, 1 H), 8.35 - 8.43 (m, 1 H), 7.75 - 7.85 (m, 1 H), 7.45 - 7.65 (m, 2 H),

7.07 (t, J = 54.0 Hz, 1 H), 5.88 - 5.95 (m, 1 H), 5.37 (t, J = 5.8 Hz, 1 H), 5.13 (d, J = 8.5 Hz, 1 H), 4.60 - 4.69 (m, 2 H), 4.01 - 4.11 (m, 1 H), 2.63 - 2.82 (m, 2 H), 2.15 - 2.28 (m, 2 H), 1.99 - 2.08 (m, 2 H). ¹⁹ F-NMR: (282 MHz, DMSO-de) δ - 109.75, -115.57, -125.74, -130.35. Example 28: (3S,8aR)-7-(3-Chloro-2-fluoiO-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-(2-hydroxypropoxy)pyridin-4-yl)-1H-imidazol-2-yl )-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eH23CIF2Ne03: 568.15, measured (ES, m/z): 569.15 [M+H] ^♦ . ¹ H NMR (300 MHz, DMSO-de) (300 MHz, DMSO-d6) δ 12.26 (s, 1 H), 9.84 (s, 1 H), 7.86 - 8.06 (m, 2 H), 7.66 -7.76 (m, 1 H), 7.47 - 7.64 (m, 2 H), 5.70 (d, J = 2.6 Hz, 1 H), 5.04 (d, J = 8.5 Hz, 1 H), 4.89 (d, J =

4.9 Hz, 1 H), 4.19 - 4.29 (m, 1 H), 4.09 - 4.19 (m, 1 H), 3.93 - 4.07 (m, 1 H), 3.63 - 3.85 (m, 1 H), 2.63 - 2.84 (m, 1 H), 2.53 - 2.62 (m, 1 H), 2.05 - 2.32 (m, 2 H), 1.89 - 2.04 (m, 2 H), 1.16 (d, J = 6.3 Hz, 3 H). ¹⁹ F-NMR: (282 MHz, DMSO- de) δ -112.22, -142.53. Example 29: (3S,8aS)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-

(3-fluoro-2-(2-hydroxypropoxy)pyridin-4-yl)-1H-imidazol-2 -yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eH23CIF2Ne03: 568.15, measured (ES, m/z): 569.25 [M+H] ^♦ . ¹ H NMR (300 MHz, DMSO-de) (300 MHz, DMSO-d6) δ 12.40 (s, 1 H), 9.84 (s, 1 H), 7.93 - 8.00 (m, 1 H), 7.85 - 7.91 (m, 1 H), 7.75 - 7.85 (m, 1 H), 7.49 - 7.57 (m, 2 H), 5.66 - 5.74 (m, 1 H), 5.02 (t, J = 7.4 Hz, 1 H), 4.90 (d, J = 4.9 Hz, 1 H), 4.19 - 4.30 (m, 1 H), 4.07 - 4.18 (m, 2 H), 3.91 - 4.06 (m, 1 H), 2.53 - 2.61 (m, 1 H), 2.17 - 2.45 (m, 2 H), 1.82 - 2.15 (m, 2 H), 1.58 - 1.81 (m, 1 H), 1.16 (d, J = 6.3 Hz, 3 H). ¹⁸ F-NMR: (282 MHz, DMSO-de) δ -113.06, -143.10.

Example 30: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2-methyl-1 H-benzo[d]imidazol-6-yl)-1 H-imidazol-2-yl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for CaeHaiCIFNgO: 529.1, measured (ES, m/z): 530.1 [Μ+ΗΓ- ¹ H NMR (400 MHz, DMSO-de) δ ppm 1.95 - 2.22 (m, 4 H) 2.47 - 2.49 (m, 2 H) 2.53 - 2.59 (m, 1 H) 2.77 (br t, >14.43 Hz, 1 H) 3.17 (br s, 1 H)

3.65 - 3.75 (m, 1 H) 5.00 (d, >8.31 Hz, 1 H) 5.67 (d, >2.45 Hz, 1 H) 7.29 - 7.46 (m, 2 H) 7.51 (br d, >7.83 Hz, 1 H) 7.64 - 7.82 (m, 2 H) 7.97 (t, >8.31 Hz, 1 H) 9.84 (s, 1 H) 11.91 (br s, 1 H) 12.03 (br s, 1 H).

Example 31: (3S,8aR)-3-(5-(2-(1 H-Pyrazol-5-yl)pyridin-4-yl)-4-fluoro-1 H- imidazol-2-yl)-7-(3-chloro-2-fluoiO-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for CMHieCIFaNioO: 560.14, measured (ES, m/z): 561.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 13.09 (s, 1 H), 13.03 - 13.08 (m, 1 H), 9.84 (s, 1 H), 8.50 - 8.61 (m, 1 H), 8.18 (s, 1 H), 7.90 - 8.00 (m,

1 H), 7.81 - 7.86 (m, 1 H), 7.70 - 7.80 (m, 1 H), 7.37 - 7.44 (m, 1 H), 6.81 - 6.86(m, 1 H), 5.67 (s, 1 H), 4.95 (d, J = 8.6 Hz, 1 H), 3.70 - 3.75 (m, 1 H), 2.54 - 2.69 (m, 2 H), 2.19 - 2.24 (m, 1 H), 2.08 - 2.15 (m, 1 H), 1.98 - 2.05 (m, 1 H), 1.88 - 1.97 (m, 1 H). ¹⁸ F-NMR: (282 MHz, DMSO-de) δ -112.92, -126.88. Example 32: (3S,8aR)-3-(4-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H19CIFN9O: 515.1, measured (ES, m/z): 516.0 [Μ+ΗΓ· ¹ H NMR (400 MHz, METHANOL-d*) δ ppm 1.91 - 2.89 (m, 7 H), 3.80 - 3.99 (m, 1 H), 5.13 - 5.21 (m, 1 H), 5.23 - 5.30 (m, 1 H), 5.68 (d, J=2.4 Hz, 1 H), 5.86 - 5.91 (m, 1 H), 7.09 (d, J=3.4 Hz, 1 H), 7.40 - 7.81 (m, 4 H),

8.02 (s, 1 H), 8.10 - 8.16 (m, 1 H), 8.22 (d, J=5.9 Hz, 1 H), 9.49 (s, 1 H). Example 33: (3S,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)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one-1 , 1 ,8,8,8a-d5

N

PQS D cr u s

Step 1 : 2-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate-1 , 1 ,8,8,8a-d5.

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic-1,1,8,8,8a-d5 acid (120 mg, 0.36 mmol, 1.0 equiv.) and CS2CO3 (71 mg, 0.22 mmol, 0.6 equiv.) in DMF (8 ml_) was stirred at room temperature for 30 min. 2-Bromo-1-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)ethan-1- one (185 mg, 0.51 mmol, 1.4 equiv.) was then added to the mixture. The reaction mixture was stirred at room temperature for 4h. The resulting mixture was then diluted with EtOAc (120 mL), washed with water (3 x 20 mL), brine (2 x 20 mL), dried over N32S04, and concentrated. The residue was purified by flash column chromatography on silica gel (40 g, MeOH/DCM: 1/20) to yield of 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate- 1,1,8,8,8a-d5 as a yellow solid. LC/MS: mass calculated for C28H2eCID ₅ F2N305Si: 610.22, measured (ES, m/z): 611.15 [M+H] ⁺ . Step 2: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2 _l 3 _l 8,8a- tetrahydroindolizin-5(1 H)-one-1 ,1 ,8,8,8a-d5.

Under an inert atmosphere of nitrogen, a mixture of 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate- 1,1,8,8,8a-d5 (130 mg, 0.21 mmol, 1.0 equiv.) and NhUOAc (164 mg, 2.13 mmol, 10.0 equiv.) in AcOH (2 mL) and toluene (20 mL) was stirred at 110 °C for 30 min and then concentrated. The residue was purified by flash column chromatography on silica gel (40 g, MeOH/DCM: 1/15) to yield (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert-butyldimethyl silyl)oxy)methyl)-3- fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroind olizin-5(1H)-one- 1,1,8,8,8a-d5 as a yellow solid. LC/MS: mass calculated for C29H29D5CIF2N ₅ 02Si: 590.25, measured (ES, m/z): 591.30 [M+H] ⁺ .

Step 3: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro- 2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-te trahydroindolizin- 5(1H)-one-1,1,8,8,8a-d5.

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one-1,1,8,8,8a-d5 (80 mg, 0.14 mmol, 1.0 equiv.), TMSN3 (156 mg, 1.35 mmol, 10.0 equiv.) and trimethoxymethane (143 mg,

1.35 mmol, 10.0 equiv.) in AcOH (8 mL) was stirred at 55 °C overnight. The solvent was removed under reduced pressure and the residue was applied onto a C18 reverse column (330 g, ACN/H2O (0.05%NH4HC03): 5→50%) to yield (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2- (hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin- 5(1 H)-one-1 ,1 ,8,8,8a-d5 as a white solid, which was further purified by prep- chiral-HPLC to yield (3S,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)-2,3,8,8a- tetrahydroindolizin-5(1H)-one-1,1,8,8,8a-d5 as a white solid.

LC/MS: mass calculated for C24H14D5CIF2N8O2: 529.16, measured (ES, m/z): 530.10 [M+H] ^♦ . ¹ H NMR (400 MHz, DMSO-de) (400 MHz, DMSO-de) 6 12.26 (s, 1 H), 9.84 (s, 1 H), 8.34 (d, J = 5.0 Hz, 1 H), 7.90 - 8.00 (m, 1 H), 7.90

(t, J = 5.4 Hz, 1 H), 7.75 - 7.85 (m, 1 H), 7.51 - 7.62 (m, 1 H), 5.70 (s, 1 H), 5.27 (t, J = 6.0 Hz, 1 H), 5.04 (d, J = 8.7 Hz, 1 H), 4.58 - 4.69 (m, 2 H), 2.13 - 2.30 (m, 1 H), 1.84 - 2.00 (m, 1 H). ¹⁹ F-NMR: (376 MHz, DMSO-de) 6 -112.86, - 130.15. Example 34: 4-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-4- fluoro-1 H-imidazol-5-yl)-3-fluoropicolinic acid

LC/MS: mass calculated for QyeHieCIFeNyOa: 623.09, measured (ES, m/z): 624.05 [M+H] ^♦ . ¹ H NMR (400 MHz, DMSO-de) (400 MHz, DMSO-de) 6 9.34 (s, 1 H), 8.32 (d, J = 4.9 Hz, 1 H), 7.90 - 8.00 (m, 1 H), 7.69 - 7.76 (m, 1 H), 7.37 - 7.52 (m, 1 H), 5.69 (s, 1 H), 5.04 (d, J = 8.6 Hz, 1 H), 3.64 - 3.81 (m,

1 H), 2.51 - 2.58 (m, 2 H), 2.04 - 2.27 (m, 2 H), 1.86 - 2.03 (m, 2 H). ¹⁹ F-NMR: (376 MHz, DMSO-de) 6 -59.66, -112.99.

Example 35: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-4-methyl-1H-imidazo l-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1 : 1-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)propan-1- one.

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridine (5.0 g, 20.71 mmol, 1.0 equiv.) in THF (50 mL) was added lithium diisopropylamide (13 mL, 26.93 mmol, 2 M, 1.3 equiv.) at -78 °C. After 0.5 h, a solution of N-methoxy-N-methylpropionamide (2.9 g, 24.86 mmol, 1.2 equiv.) in THF (10 mL) was added at -78 °C. The resulting mixture was maintained under nitrogen and stirred at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→30% ethyl acetate/petroleum ether) to yield the 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)- 3-fluoropyridin-4-yl)propan-1-one as a yellow oil. LC/MS: mass calculated for C15H24FNO2S1: 297.16, measured (ES, m/z): 298.30 [M+H] ⁺ .

Step 2: (4-(2-Bromopropanoyl)-3-fluoropyridin-2-yl)methyl acetate.

To a solution of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)propan-1-one (1.4 g, 4.71 mmol, 1.0 equiv.) and HBr (2.3 g, 9.41 mmol, 2.0 equiv.) in AcOH (10 mL) was added pyridinium tribromide (1.2 g, 3.77 mmol,

0.8 equiv.). The mixture stirred at room temperature for 1 h. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the (4-(2-bromopropanoyl)-3-fluoropyridin-2-yl)methyl acetate as a yellow oil. LC/MS: mass calculated for CnHnBrFNOa: 302.99, measured (ES, m/z): 304.00, 306.00 [M+H, Μ+Η+2Γ.

Step 3: 1-(2-(Acetoxymethyl)-3-fluoropyridin-4-yl)-1-oxopropan-2-yl (8aR)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.53 mmol,

1.0 equiv.) in CHaCN (8 mL) was added K2CO3 (109 mg, 0.80 mmol, 1.5 equiv.). After stirring at room temperature for 0.5 h, (4-(2-bromopropanoyl)-3- fluoropyridin-2-yl)methyl acetate (241 mg, 0.80 mmol, 1.5 equiv.) was added. The mixture was stirred at room temperature for 1 h. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the 1-(2- (acetoxymethyl)-3-fluoropyridin-4-yl)-1 -oxopropan-2-yl (8aR)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate as a yellow oil. LC/MS: mass calculated for C27H23CIF2NeOe: 600.13, measured (ES, m/z): 601.30 [M+H] ⁺ . Step 4: (4-(2-((8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl )-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-4-methyl-1 H-imidazol-5-yl)-3- fluoropyridin-2-yl)methyl acetate.

To a solution of 1-(2-(acetoxymethyl)-3-fluoropyridin-4-yl)-1-oxopropan- 2-yl (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (140 mg, 0.23 mmol, 1.0 equiv.) in toluene (10 mL) and glacial acetic acid (1 ml_) was added ammonium acetate (269 mg, 3.50 mmol, 15.0 equiv.). The mixture was stirred at 100 °C for 1 h. The solvent was removed under vacuum and the residue was purified by silica gel column with MeOH/DCM (0→10%) to yield (4-(2-((8aR)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-4-methyl-1 H- imidazol-5-yl)-3-fluoropyridin-2-yl)methyl acetate as a yellow solid. LC/MS: mass calculated for C27H23CIF2N8O3: 580.15, measured (ES, m/z): 581.10 [M+H]*.

Step 5: (3*S,8aR)-7-(3-Chforo-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 -(5- (3- fluoro-2-(hydroxymethyl)pyridin-4-yl)-4-methyl-1H-imidazol-2 -yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of (4-(2-((8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-4-methyl-1 H-imidazol-5- yl)-3-fluoropyridin-2-yl)methyl acetate (90 mg, 0.16 mmol) in THF (3 mL) was added HCI (3 mL, 12.00 mmol, 4 M). The mixture was stirred at 60 °C for 1 h. The solvent was removed under vacuum and the residue was purified by C18 column [condition: ACN-water-6.5 mM NH4HCO3+NH3H2O (5%→50%)] to yield a residue. The residue was purified by chiral HPLC to yield (3*S,8aR)-7-(3- chloro-2-fluoro-6-( 1 H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-2- (hydroxymethyl)pyridin-4-yl)-4-methyl-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as an off-white solid.

LC/MS: mass calculated for C25H21CIF2N8O2: 538.14, measured (ES, m/z): 539.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) (400 MHz, DMSO-de) δ 11.98 (s, 1 H), 9.83 (s, 1 H), 8.30 - 8.40 (m, 1 H), 7.91 - 8.03 (m, 1 H), 7.68 - 7.75 (m, 1 H), 7.49 - 7.59 (m, 1 H), 5.68 (d, J = 2.7 Hz, 1 H), 5.17 - 5.40 (m, 1 H), 4.96 (d, J = 8.3 Hz, 1 H), 4.60 - 4.67 (m, 2 H), 3.64 - 3.79 (m, 1 H), 2.61 - 2.77 (m, 1 H), 2.53 - 2.57 (m, 1 H), 2.21 - 2.37 (m, 3 H), 2.14 - 2.20 (m, 1 H),

2.03 - 2.12 (m, 1 H), 1.89 - 2.03 (m, 2 H). ¹⁹ F-NMR: (376 MHz, DMSO-de) δ - 112.81, -129.35.

Example 36: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-(hydroxymethyl-d2)pyridin-4-yl)-1H-imidazol-2-yl )-2,3,8,8a- tetrahydroindolizin-5(1 H)-one-8a-d a ^' 1 Tt

⁰ i5 »Γ _s Ψ ^F o

LC/MS: mass calculated for C24HieD3CIF2Ne02: 527.15, measured (ES, m/z): 642.20 [M+H] *. ¹ H NMR (400 MHz, DMSO-de) (400 MHz, DMSO-de) δ 12.29 (s, 1 H), 9.84 (s, 1 H), 8.34 (d, J = 5.1 Hz, 1 H), 7.93 - 8.02 (m, 1 H), 7.84 - 7.92 (m, 1 H), 7.70 - 7.75 (m, 1 H), 7.58 (d, J = 4.0 Hz, 1 H), 5.69 (d, J = 2.7

Hz, 1 H), 5.12 - 5.32 (m, 1 H), 5.04 (d, J = 8.7 Hz, 1 H), 2.63 - 2.80 (m, 1 H), 2.50 - 2.56 (m, 1 H), 2.17 - 2.31 (m, 1 H), 2.05 - 2.15 (m, 1 H), 1.90 - 2.01 (m, 2 H). ¹⁹ F-NMR: (376 MHz, DMSO-de) δ -112.86, -130.13.

Example 37: (((4-(2-((3R*,8aR)-7-(3-chloro-2-fluoiO-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)methoxy)methyl)phosphonic acid

LC/MS: mass calculated for C25H22CIF2N8O5P: 618.11, measured (ES, m/z): 619.05 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 12.27 (s, 1 H), 9.82 (s, 1 Η), 8.33 (d, J = 5.1 Hz, 1 Η), 7.90-7.98 (m, 2 Η), 7.68 (d, J = 8.7 Hz, 1 H), 7.55 (s, 1 H), 5.67 (s, 1 H), 5.01 (d, J = 8.6 Hz, 1 H), 4.68- 4.72 (m, 2 H), 3.61- 3.87 (m, 5 H), 2.62- 2.73 (m, 2 H), 1.83- 2.24 (m, 4 H). ¹⁸ F NMR (376 MHz, DMSO- de) δ -112.82.

Example 38: (3S,8aR)-3-(4-(1 H-pyrazolo[3,4-b]pyridin-4-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H18CIFN10O: 516.1, measured (ES, m/z): 517.1 [M+HJ*. ¹ H NMR (400 MHz, METHANOL-d*) δ ppm 1.93 - 2.95 (m, 7 H),

3.73 - 4.00 (m, 1 H), 5.01 - 5.32 (m, 1 H), 5.58 - 5.75 (m, 1 H), 5.75 - 5.95 (m, 1 H), 7.30 - 7.86 (m, 3 H), 8.10 - 8.20 (m, 1 H), 8.48 - 8.59 (m, 1 H), 8.58 - 8.75 (m, 1 H), 9.38 - 9.66 (m, 1 H).

Example 39: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (4- (5-(hydroxymethyl)thiazol-2-yl)-1H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

^HN U

^T cM R

ΛΛ.

Stepl : 2-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole.

To a solution of (2-bromothiazol-5-yl)methanol (1.70g, 8.76mmol) in DMF (20m L), were added TBDMS-CI (1.584g, 10.51 mmol) and imidazole

(1.193g, 17.52mmol) under N2. The reaction was heated at 50°C overnight. The reaction mixture was partitioned with water and EA at room temperature. The organic was separated, washed with brine, and dried over Na2S04. The solid was filtered and washed with EA. The filtrated was concentrated to yield a yellow solid. The yellow solid was purified by silica gel with heptane and EA as eluent (0% to 30% EA) to yield 2-bromo-5-(((tert- butyldimethylsilyl)oxy)methyl)thiazole as an off white oil. LC/MS: mass calculated for: CioHieBrNOSSi: 307.0, measured (ES, m/z): 308.1 [M+H]*.

Step 2: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(1-ethoxyvinyl)th iazole.

To a solution of 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)thiazole and tributyl(1-ethoxyvinyl)tin (0.843g, 2.335 mmol) in 1,4-dioxane (12 mL), was added Pd(PPh3)4 (0.18g, 0.156 mmol) under N2. The reaction mixture was purged with N2 for 10 minutes and heated at 100°C overnight. The reaction was cooled to room temperature. The solid was filtered through CELITE and washed with EA. The filtrate was concentrated under vacuum. The residue was purified by silica gel with heptane and EA as eluent (0 to 20% EA) to yield 5- (((tert-butyldimethylsilyl)oxy)methyl)-2-(1-ethoxyvinyl)thia zole as a clear oil. LC/MS: mass calculated for C14H25NO2SS1: 299.1, measured (ES, m/z): 300.1 [M+H]*.

Step 3: 2-Bromo-1-(5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2 -yl)ethan-1- one.

To a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(1- ethoxyvinyl)thiazole (0.152 g, 0.507mmol) in THF (10 mL) and water (1 mL), was added NBS (99 mg, 0.558 mmol) at room temperature and the resulting mixture was stirred for one hour. The reaction was partitioned with water and EA. The organic was separated, washed with brine, and dried over N32S04. The solid was filtered and washed with EA. The filtrated was concentrated to yield 2-bromo-1-(5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2 -yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for: Ci2H2oBrN02SSi: 349.0, measured (ES, m/z): 350.1 [M+H]*.

Step 4: 2-(5-(((tert-Butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2-o xoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ic acid (0.08 g, 0.21 mmol) in ACN (6 ml_), was added CS2CO3 (0.207 g, 0.64mmol) and the mixture was stirred at room temperature for 10 minutes. 2-Bromo-1-(5-(((tert- butyldimethylsilyl)oxy)methyl)thiazol-2-yl)ethan-1-one (0.089 g, 0.254 mmol) was then added. The reaction was heated at 50°C for 2 hours. The solid was filtered through CELITE and washed with EA. The filtrate was concentrated to yield 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2-o xoethyl (3S,8aR)- 7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid, which was used in the next step without further purification. LC/MS: mass calculated for: C28H32CIFNe05SSi: 646.2, measured (ES, m/z): 647.3 [M+H] ⁺ .

Step 5: (3S,8aR)-3-(4-(5-(((tert-butyldimethylsilyl)oxy)methyl)thiaz ol-2-yl)-1 H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

Into a microwave vial, 2-(5-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2- yl)-2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-( 1 H-tetrazol- 1 -yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (0.106g, 0.164mmol) in toluene (3mL) and AcOH (0.188ml), was added ammonium acetate (0.252 g, 3.3 mmol). The reaction was heated at 100°C for 2.5 hours. The solvent was removed under vacuum to yield (3S,8aR)-3-(4-(5-(((tert- butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-1H-imidazol-2-yl )-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a red residue, which was used in the next step without further purification.

LC/MS: mass calculated for C28H32CIFNs02SSi: 626.2, measured (ES, m/z): 627.3 [Μ+ΗΓ·

Step 6: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (4-(5-

(hydroxymethyl)thiazol-2-yl)-1H-imidazol-2-yl)-2,3,8,8a-t etrahydroindolizin-

5(1H)-one.

To solution of (3S,8aR)-3-(4-(5-(((tert- butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-1H-imidazol-2-yl )-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (100mg, 0.159mmol) in THF (3mL), was added 1M TBAF in THF (0.3mL, 0.3mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned with water and EA. The organic was separated, washed with brine, and dried over Na2S04. The solid was filtered and washed with EA. The filtrated was concentrated to yield a brown solid. The brown solid was purified via prep-HPLC with 0.1 %TFA in water and 0.1 % TFA in ACN as eluent (10% to 45% 0.1% TFA in ACN) to yield (3S,8aR)-7-(3-chloro- 2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(4-(5-(hydroxymethyl)thiazol-2-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one TFA adduct as an off white solid.

LC/MS: mass calculated for: C22H18CIFN8O2S: 512.1, measured (ES, m/z): 513.2 [M+Hf. ¹ H NMR (400 MHz, methanol-d*) δ 9.58 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.56 (dd, J = 8.7, 1.7 Hz, 1H), 5.75 (d, J = 2.9 Hz, 1H), 5.22 (d, J = 9.3 Hz, 1H), 4.70 (bs, 2H), 3.88-3.98 (m, 1H), 2.95 (t, J = 15.3 Hz, 1H), 2.67 (dd, J = 16.9, 4.3 Hz, 1H), 2.50- 2.40 (bm, 1H), 2.33-2.19 (bm, 2H), 2.08-1.96 (bm, 1H). ^ig F NMR (376 MHz, methanol-dt) δ - 113.4.

Example 40: Methyl N-[4-[2-[(3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-4-fluoro-1 H- imidazol-5-yl]-3-fluoro-2-pyridyl]carbamate

LC/MS: mass calculated for C25H18CIF3N9O3: 585.13, measured (ES, m/z): 586.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) δ 9.57 (s, 1 H), 8.14 (d, J = 5.3 Hz, 1 H), 7.75 - 7.87 (m, 1 H), 7.49 - 7.62 (m, 1 H), 7.39 - 7.43 (m, 1 H), 5.69 (d, J = 2.8 Hz, 1 H), 5.11 (d, J = 8.7 Hz, 1 H), 3.83 - 4.01 (m, 1 H), 3.79 (s, 3 H), 2.80 - 2.92 (m, 1 H), 2.53 - 2.68 (m, 1 H), 1.99 - 2.39 (m, 4 H). ¹⁹ F NMR (376 MHz, Methanol-d*) -113.42, -127.70.

Example 41 : (3S,8aR)-3-(4-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-imidazol-2 - yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

\J rtf

Cl

LC/MS: mass calculated for C24H18CIFN10O: 516.1, measured (ES, m/z): 517.1 [Μ+ΗΓ· ¹ H NMR (400 MHz, METHANOL-d*) δ ppm 1.95 - 2.13 (m, 1 H), 2.20 - 2.42 (m, 2 H), 2.43 - 2.65 (m, 1 H), 2.75 (s, 1 H), 2.88 - 3.09 (m, 1 H),

3.85 - 4.11 (m, 1 H), 5.32 (dd, J=9.8, 1.5 Hz, 1 H), 5.77 (d, J=2.9 Hz, 1 H), 7.58 (dd, J=8.6, 1.7 Hz, 1 H), 7.72 - 7.95 (m, 2 H), 8.23 (s, 1 H), 8.56 (d, J=2.4 Hz, 1 H), 8.87 (d, J=2.0 Hz, 1 H), 9.59 (s, 1 H).

Example 42: (3S,8aR)-3-(4-(1 H-benzo[d]imidazol-5-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin-

5(1H)-one

H rjj

N

H

Cl'

LC/MS: mass calculated for C25H19CIFN9O: 515.1, measured (ES, m/z): 516.0 [Μ+ΗΓ· ¹ H NMR (400 MHz, METHANOLS) δ ppm 1.95 - 2.16 (m, 1 H), 2.16 - 2.45 (m, 2 H), 2.45 - 2.66 (m, 1 H), 2.66 - 2.87 (m, 1 H), 2.88 - 3.08 (m, 1 H), 3.78 - 4.06 (m, 1 H), 5.18 - 5.41 (m, 1 H), 5.69 - 5.81 (m, 1 H), 7.52 - 7.62 (m, 1 H), 7.88 (s, 4 H), 8.07 - 8.24 (m, 1 H), 9.03 - 9.18 (m, 1 H), 9.59 (s, 1 H). Example 43: (3S,8aR)-3-(4-(1 H-indazoi-5-yl)-1 H-imidazol-2-yl)-7-(3-chloro- 2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindo lizin-5(1H)-one l r Xs _:

,Ν·

Cl

LC/MS: mass calculated for C25H19CIFN9O: 515.1, measured (ES, m/z): 516.1 [Μ+ΗΓ. ¹ H NMR (400 MHz, METHANOL-d ₄ ) 6 ppm 1.94 - 2.09 (m, 1 H), 2.21 - 2.43 (m, 2 H), 2.48 - 2.63 (m, 1 H), 2.68 - 2.79 (m, 1 H), 2.92 - 3.06 (m, 1 H), 3.89 - 4.04 (m, 1 H), 5.26 - 5.35 (m, 1 H), 5.74 - 5.79 (m, 1 H), 7.51 - 7.61

(m, 1 H), 7.66 - 7.75 (m, 2 H), 7.77 - 7.79 (m, 1 H), 7.81 - 7.88 (m, 1 H), 8.11 - 8.19 (m, 2 H), 9.55 - 9.66 (m, 1 H).

Example 44: Methy!(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)carbamate

Step 1: 3-Fluoro-4-iodopyridin-2-amine.

To a solution of 2,3-difluoro-4-iodopyridine (5.0 g, 20.75 mmol) in DMSO (50 mL) was added ammonium hydroxide (60 mL). The resulting mixture was stirred at 80 °C overnight. After cooling to room temperature, the resulting mixture was diluted with EA (800 mL) and washed with water three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to yield the 3-fluoro-4-iodopyridin-2-amine as a yellow solid. LC/MS: mass calculated for C5H4FIN2: 237.94, measured (ES, m/z): 239.00 [Μ+ΗΓ.

Step 2: Methyl (3-fluoro-4-iodopyridin-2-yl)carbamate.

To a solution of 3-fluoro-4-iodopyridin-2-amine (2.0 g, 8.40 mmol 1.0 equiv.) in pyridine (30 mL) was added methyl chloroformate (4.0 g, 42.02 mmol, 5.0 equiv.) at 0 °C. The reaction mixture was stirred 2 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and dried over anhydrous N32S04 and concentrated. The residue was purified by silica gel chromatography with EA/PE (0→55%) to yield methyl (3-fluoro-4-iodopyridin-2- yl)carbamate as a yellow solid. LC/MS: mass calculated for C7HeFIN202: 295.95, measured (ES, m/z): 296.95 [M+H]*.

Step 3: Methyl (4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)carbamate.

To a mixture of methyl (3-fluoro-4-iodopyridin-2-yl)carbamate (1.1 g, 3.72 mmol, 1.0 equiv.) and tributyl(1-ethoxyvinyl)stannane (1.6 g, 4.46 mmol, 1.2 equiv.) in 1,4-dioxane (15 mL) was added bis(triphenylphosphine)palladium dichloride (0.26 g, 0.37 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and dried over anhydrous N32S04 and concentrated. The residue was purified by silica gel chromatography with EA/PE (0→45%) to yield methyl (4-(1- ethoxyvinyl)-3-fluoropyridin-2-yl)carbamate as a yellow solid. LC/MS: mass calculated for C11H13FN2O3: 240.09, measured (ES, m/z): 241.10 [M+H] ⁺ .

Step 4: Methyl (4-(2-bromoacetyl)-3-fluoropyridin-2-yl)carbamate.

To a mixture of methyl (4-(1-ethoxyvinyl)-3-fiuoropyridin-2-yl)carbamate (870 mg, 3.62 mmol, 1.0 equiv.) in THF (9 mL) and H2O (3 mL) was added N- bromosuccinimide (645 mg, 3.62 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O. The resulting mixture was extracted with EA. The organic layers were combined, dried over Na2S04. The resulting mixture was concentrated under vacuum to yield methyl (4-(2-bromoacetyl)-3-fluoropyridin-2-yl)carbamate as a yellow solid. LC/MS: mass calculated for CgHeBrFtoCte: 289.97, measured (ES, m/z): 290.95, 292.95 [M+H, M+H+2]*.

Step 5: 2-(3-Fluoro-2-((methoxycarbonyl)amino)pyridin-4-yl)-2-oxoeth yl (3S)-7- (6-amino3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydr oindolizine-3- carboxylate.

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- I^.S.S.e.ea-hexahydroindolizine-S-carboxylic acid (0.45 g, 1.39 mmol, 1.0 equiv.) in acetonitrile (10 mL) was added potassium carbonate (0.25 g, 1.80 mmol, 1.3 equiv.). The reaction mixture was stirred 0.5 h. Methyl (4-(2- bromoacetyl)-3-fluoropyridin-2-yl)carbamate (1.0 g, 3.46 mmol, 2.5 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified silica gel chromatography with MeOH/DCM (0→6%) to yield 2-(3-fluoro-2- ((methoxycarbonyl)amino)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a yellow solid. LC/MS: mass calculated for C24H2iCIF2N40e: 534.11, measured (ES, m/z): 535.25 [M+H] ⁺ .

Step 6: Methyl(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)carbamate.

To a solution of 2-(3-fluoro-2-((methoxycarbonyl)amino)pyridin-4-yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (0.63 g, 0.82 mmol, 1.0 equiv.) and ammonium acetate (1.3 g, 16.49 mmol, 20.0 equiv.) in toluene (10 mL) was added acetic add (0.5 mL). The reaction mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with MeOH/DCM (0→7%) to yield methyl (4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2-yl)carbamate as a yellow solid. LC/MS: mass calculated for C24H21CIF2N6O3: 514.13, measured (ES, m/z): 515.20 [M+H] ⁺ .

Step 7: Methyl(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl )-3-fluoropyridin-2- yl)carbamate.

To a solution of (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(5-chloro-2-(4-(trifluoromethyl)-1 H-1 ,2,3- triazol-1-yl)phenyl)-1 ,2,3,8,9,9a-hexahydro-5H-pyrrolo[1 ,2-a]azepin-5-one (300 mg, 0.42 mmol, 1.0 equiv.) in THF (5 mL) was added triethylamine trihydrofluoride (335 mg, 2.08 mmol, 5.0 equiv.). The reaction mixture was stirred at 70 °C for 1 h, then purified by reverse phase chromatography with CHsCN/water (5→55%) to yield (3S,9aS)-7-(5-chloro-2-(4-(trifluoromethyl)-1 H- 1,2,3-triazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)p yridin-4-yl)-1H- imidazol-2-yl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepi n-5-one as a white solid.

LC/MS: mass calculated for C25H20CIF2N9O3: 567.13, measured (ES, m/z): 568.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) δ 9.57 (s, 1 H), 8.14 (d,

J = 5.3 Hz, 1 H), 7.75 - 7.91 (m, 2 H), 7.45 - 7.63 (m, 2 H), 5.73 (d, J = 2.8 Hz,

1 H), 5.12 - 5.21 (m, 1 H), 3.86 - 3.98 (m, 1 H), 3.78 (s, 3 H), 2.82 - 2.95 (m, 1 H), 2.57 - 2.67 (m, 1 H), 2.16 - 2.40 (m, 3 H), 1.96 - 2.12 (m, 1 H). ¹⁹ F NMR (376 MHz, Methanol-d*) δ -113.49, -133.63. Example 45: (3S,8aR)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)-3-(4-fluoro-5- (3-fluoro-2-((R*)-1-hydroxyethyl)pyridin-4-yl)-1H-imidazol-2 -yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H21CIF2N8O2: 538.14, measured (ES, m/z): 539.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) δ 9.56 (s, 1 H), 8.35 (d,

J = 5.2 Hz, 1 H), 7.61 - 7.72 (m, 3 H), 7.55 (t, J = 5.5 Hz, 1 H), 5.70 (d, J = 2.8 Hz, 1 H), 5.08 - 5.26 (m, 2 H), 3.75 - 3.91 (m, 1 H), 2.59 - 2.73 (m, 1 H), 2.34 - 2.43 (m, 1 H), 2.12 - 2.33 (m, 3 H), 1.93 - 2.08 (m, 1 H), 1.53 (d, J = 6.6 Hz, 3 H). ¹⁸ F NMR (376 MHz, Methanol-cU) δ -127.79, -133.77.

Example 46: (3S,8aR)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)-3-(4-fluoro-5- (3-fluoro-2-((S*)-1-hydroxyethyl)pyridin-4-yl)-1H-imidazol-2 -yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H21CIF2N8O2: 538.14, measured (ES, m/z): 539.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) 69.56 (s, 1 H), 8.34 (d, J = 5.2 Hz, 1 H), 7.61 - 7.74 (m, 3 H), 7.54 (t, J = 5.5 Hz, 1 H), 5.70 (d, J = 2.8 Hz, 1 H), 5.18 - 5.25 (m, 1 H), 5.12 (d, J = 8.8 Hz, 1 H), 3.75 - 3.89 (m, 1 H), 2.61 - 2.74 (m, 1 H), 2.35 - 2.43 (m, 1 H), 2.12 - 2.33 (m, 3 H), 1.93 - 2.09 (m, 1 H), 1.50 - 1.55 (m, 3 H). ¹⁹ F NMR (376 MHz, Methanol-d ₄ ) δ -128.08, -133.95. Example 47: (3S,8aR ^w )-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl )-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one-8a-d

Step 1 : 2-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2- oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1 -yl) phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate-8a-d.

To a solution of (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic-8a-d acid (300 mg, 0.80 mmol, 1.0 equiv.) in CHaCN (10 mL) was added K2CO3 (142 mg, 1.03 mmol, 1.3 equiv.). After stirring at room temperature for 0.5 h, 2-bromo-1-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)ethan-1- one (430 mg, 1.20 mmol, 1.5 equiv.) was added. The mixture was stirred at room temperature for 1 h. The resulting mixture was purified by silica gel column with MeOH/DCM (0→7%) to yield the 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4- yl)-2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate-8a-d as a yellow oil. LC/MS: mass calculated for C3oH32DCIF2Ne05Si: 659.20, measured (ES, m/z): 660.15 [M+H]*.

Step 2: (3S)-3-(5-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4-yl)- 1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)p henyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one-8a-d.

To a solution of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate-8a-d (380 mg, 0.58 mmol, 1.0 equiv.) in toluene (10 mL) and acetic acid (1 mL) was added ammonium acetate (665 mg, 8.63 mmol, 15.0 equiv.). The mixture was stirred at 100 °C for 1 h. The solvent was removed under vacuum and the residue was purified by silica gel column with MeOH/DCM (0→10%) to yield (3S)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1H)- one-8a-d as a yellow oil. LC/MS: mass calculated for C3oH32DCIF2Ne02Si: 639.22, measured (ES, m/z): 640.20 [M+H]*.

Step 3: (3S,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)-2,3, 8,8a- tetrahydroindolizin-5(1 H)-one-8a-d.

To a solution of (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one-8a-d (280 mg, 0.44 mmol, 1.0 equiv.) in THF (5 mL) was added triethylamine trihydrofluoride (1.3 mL). The mixture was stirred at 70 °C for 1 h. The solvent was removed under vacuum and the residue was purified by C18 column [condition: ACN-water-6.5 mM NH4HCO3+NH3H2O (5→50%)] to yield a second residue. The second residue was purified by chiral HPLC [column: (R,R) WHELK-01, 4.6*50mm,3.5um; mobile phase A: Hex ( 0.1% DEA): EtOH=55:45 , mobile phase B:; flow rate:1 mL/min] to yield (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 -(5- (3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one-8a-d as an off-white solid.

LC/MS: mass calculated for C24H18CIDF2N8O2: 525.14, measured (ES, m/z): 526.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.25 (s, 1H), 9.84 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.94 - 8.00 (m, 1H), 7.86 - 7.90 (m, 1H), 7.71 (dd, J = 8.6, 1.5 Hz, 1H), 7.57 (d, J = 3.8 Hz, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.23 - 5.29 (m, 1H), 5.04 (d, J = 8.7 Hz, 1H), 4.63 (dd, J = 6.0, 2.3 Hz, 2H), 2.65 - 2.77 (d, J = 16.7 Hz, 1H), 2.52 - 2.58 (m, 1H), 2.16 - 2.29 (m, 1H), 2.06 - 2.14

(m, 1H), 2.90 - 2.02 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.85, -130.16. Example 48: (3S*,8aS)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one-8a-d

LC/MS: mass calculated for C24H18DCIF2N8O2: 525.14, measured (ES, m/z): 526.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.52 (s, 1H), 9.84 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.94 - 8.01 (m, 1H), 7.85 - 7.92 (m, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.62 (d, J = 3.7 Hz, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.00 - 5.08 (m, 1H), 4.64 (d, J = 2.2 Hz, 2H), 2.42 - 2.46 (m, 1H), 2.31 - 2.41 (m, 1H),

2.20 - 2.30 (m, 1H), 1.95 - 2.08 (m, 1H), 1.64 - 1.78 (m, 1H), 1.14 - 1.28 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -113.06, -129.81.

Example 49: (3R*,8aR)-3-(5-(2-(5-amino-1H-pyrazol-1-yl)pyridin-4-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoiO-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eH2iCIFNnO: 557.16, measured (ES, m/z): 558.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.10 - 12.14 (m, 1 H), 9.81 (s, 1 H), 8.29 (d, J = 5.3 Hz, 1 H), 8.17 (d, J = 1.8 Hz, 1 H), 7.90 - 7.98 (m, 1 H), 7.84 (d, J = 2.2 Hz, 1 H), 7.65 - 7.72 (m, 1 H), 7.51 - 7.59 (m, 1 H), 7.31 - 7.39 (m, 1 H), 6.76 - 6.83 (m, 2 H), 5.61 - 5.67 (m, 1 H), 5.36 - 5.40 (m, 1 H), 4.96 - 5.03 (m, 1 H), 2.72 - 2.84 (m, 1 H), 2.51 - 2.55 (m, 1 H), 2.46 - 2.50 (m, 1 H), 2.13 - 2.23 (m, 1 H), 2.06 - 2.12 (m, 1 H), 1.87 - 2.02 (m, 2 H). ^ig F NMR (376 MHz, DMSO-de) δ -112.57.

Example 50: Methyl 4-[2-[(3S,8aR)-7-[3-chloro-6-(4-chlorotriazol-1-yl)-2- fluoro-phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]- 1H-imidazol-5- yl]-3-fluoro-pyridine-2-carboxylate

2-(3-Fluoro-2-(methoxycarbonyl)pyridin-4-yl)-2-oxoethyl (3R,8aS)-7-(3- chloro-6-(4-chloro-1 H-1 ,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (55 mg, 0.091 mmol) was dissolved in HOAc. To the resulting solution was then added ammonium acetate (69.9 mg, 0.91 mmol) and the reaction mixture was stirred at 80 °C for 75 mins. The solvent was removed under reduced pressure and the residue was purified by

HPLC to yield methyl 4-[2-[(3S,8aR)-7-[3-chloro-6-(4-chlorotriazol-1-yl)-2- fluoro-phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]- 1H-imidazol-5-yl]-3- fluoro-pyridine-2-carboxylate as a white solid.

LC/MS calculated for C^eHieCbFaNyOa: 585.1, measured 586.2 (MH ⁺ ). ¹ H NMR (400 MHz, METHANOL-d4) δ 8.42-8.44 (m, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.73 (d, J=3.42 Hz, 1H), 7.69 (dd, J=7.83, 8.80 Hz, 1H), 7.41 (dd, J=1.71, 8.56 Hz, 1H), 5.65 (d, J=2.45 Hz, 1H), 5.14-5.18 (m, 1H), 3.91 (s, 3H), 2.77- 2.87 (m, 1H), 2.53-2.60 (m, 1H), 2.26-2.37 (m, 1H), 2.13-2.23 (m, 2H), 1.93- 2.02 (m, 1H). Example 51 : (3S,8aR)-3-(4-(1 H-indazol-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro- 2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindo lizin-5(1H)-one

LC/MS: mass calculated for C25H19CIFN9O: 515.1, measured (ES, m/z): 516.1 [M+HJ*. ¹ H NMR (400 MHz, METHANOL-d*) δ ppm 1.91 - 2.12 (m, 1 H), 2.24 - 2.42 (m, 2 H), 2.48 - 2.67 (m, 1 H), 2.67 - 2.80 (m, 1 H), 2.93 - 3.08 (m, 1 H), 3.88 - 4.09 (m, 1 H), 5.25 - 5.44 (m, 1 H), 5.74 - 5.81 (m, 1 H), 7.42 - 7.61

(m, 3 H), 7.65 - 7.74 (m, 1 H), 7.78 - 7.91 (m, 1 H), 7.99 (s, 1 H), 8.28 - 8.40 (m, 1 H), 9.59 (s, 1 H).

Example 52: Methyl 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-i midazol-5-yl]-3- fluoro-pyridine-2-carboxylate

2-(3-Fluoro-2-(methoxycarbonyl)pyridin-4-yl)-2-oxoethyl (3R,8aS)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (44 mg, 0.077 mmol) was dissolved in HOAc. To the resulting solution was added ammonium acetate (59.2 mg, 0.77 mmol) and the reaction mixture was stirred at 80 °C for 75 mins. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield methyl 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-f luoro-pyridine-2- carboxylate as an off-white solid.

LC/MS calculated for C25H19CIF2N8O3: 552.1, measured 553.2 (MH ⁺ ). ¹ H NMR (400 MHz, METHANOL-d4) δ 9.60 (s, 1H), 8.55 (d, J=4.89 Hz, 1H), 8.20 (t, J=5.38 Hz, 1H), 7.81-7.89 (m, 2H), 7.58 (dd, J=1.47, 8.80 Hz, 1H), 5.76-5.80 (m, 1H), 5.23 (s, 1H), 4.02-4.05 (m, 3H), 3.94-4.01 (m, 1H), 2.86-2.98 (m, 1H), 2.65-2.74 (m, 1H), 2.37-2.51 (m, 1H), 2.21-2.34 (m, 2H), 2.02-2.14 (m, 1H). Example 53: 3-(5-(2-(1H-pyrazol-5-yl)pyridin-4-yl)-1H-imidazol-2-yl)-7-( 3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-

5(1H)-one

LC/MS: mass calculated for C2eH2oCIFNioO: 542.15, measured (ES, m/z): 543.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) 6 12.99-13.04 (m, 1H), 12.10 (s, 1H), 9.83 (s, 1H), 8.47-8.52 (m, 1H), 8.26 (s, 1H), 7.92-8.01 (m, 1H),

7.54-7.91 (m, 4H), 6.85 (s, 1H), 5.67 (d, J = 2.7 Hz, 1H), 5.02 (d, J = 8.8 Hz, 1H), 3.63-3.75 (m, 1H), 2.74-2.86 (m,2H), 2.18-2.24 (m, 1H), 2.08-2.14 (m, 1H), 1.92-2.04 (m, 2H)

Example 54: 4-(2-{(3S*,8aR)-7-{5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3 -yl)-1H- imidazol-5-yl)-3-fluoropicolinic acid

LC/MS: mass calculated for C2eHieCIF4N703: 587.11, measured (ES, m/z): 588.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) 69.00 (s, 1H), 8.18 - 8.55 (m, 2H), 7.62 - 7.73 (m, 4H), 5.80 (d, J = 2.4 Hz, 1 H), 5.20 (d, J = 8.6 Hz,

1H), 3.78 - 3.98 (m, 1H), 2.57 - 2.74 (m, 1H), 2.13 - 2.45 (m, 4H), 1.97 - 2.10 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-d*) 6 -62.52.

Example 56: (3S)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)-8,8-difluoro-3-(5- (3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2 , 3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 1-(Tert-butyl) 2-methyl (2R)-5-(2-ethoxy-1 , 1 -difluoro-2- oxoethyl)pyrrolidine-1 ,2-dicarboxylate.

Zinc dust (6.4 g, 97.85 mmol, 2.0 equiv.) was placed in a bottle and heated to 100 °C under vacuum. After being cooled to room temperature, the reaction bottle was filled with N2. Then, CHaCN (8 ml_), TMSCI (0.4 g), and 1,2- dibromoethane (56 mg) were successively added, and the mixture was stirred for 30 min. The mixture was cooled to -10 °C, and a solution of ethyl bromodifluoroacetate (10 g, 49.27 mmol, 1.0 equiv.) in MeCN (16 mL) was added over 40 min. After the completion of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then, the mixture was cooled to 0 °C, TMSCI (8.5 g, 78.27 mmol, 1.6 equiv.) was added dropwise, and the mixture was allowed to warm to room temperature over 45 min. Under N2, the mixture was extracted with pentane (4 * 12 mL, pentane phase was decanted using a cannula). To the above mixture was added a solution of 1- (tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1 ,2-dicarboxylate (3.2 g, 12.34 mmol, 0.50 equiv.) in tert-butyl methyl ether (100 mL) followed by the addition of solution of ((1 -ethoxy-2, 2-difluorovinyl)oxy)trimethylsilane at -40 °C. Boron trifluoride etherate (4.1 g, 28.89 mmol, 0.60 equiv.) was added to the solution at -40 °C under N2 and the mixture was stirred for 40 min, then allowed to warm to ambient temperature over 40 min. The reaction was quenched with Na2COa (aq.). The resulting solution was extracted with ethyl acetate and the organic layers were combined and dried with Na2S04. The solids were filtered out. The resulting organic phase was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EA=3:1) to yield 1- (tert-butyl) 2-methyl (2S)-5-(2-ethoxy-1 , 1-difluoro-2-oxoethyl)pyrrolidine-1 ,2- dicarboxylate as a yellow oil. LC/MS: mass calculated for Ci5H23F2NOe: 351.15, measured (ES, m/z): 252.10 [M-Boc+ΗΓ. Step 2: Methyl (2R)-5-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyrrolidine-2- carboxylate.

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-(2-ethoxy-1,1-difluoro-2- oxoethyl)pyrrolidine-1 ,2-dicarboxylate (2.2 g, 6.26 mmol, 1.0 equiv.) in DCM (30 mL) was added TFA (10 mL). The reaction mixture was stirred for 3 h. The mixture was concentrated under vacuum to yield methyl (2S)-5-(2-ethoxy-1,1- difluoro-2-oxoethyl)pyrrolidine-2-carboxylate (TFA salt) as a yellow oil. LC/MS: mass calculated for C10H15F2NO4: 251.10, measured (ES, m/z): 252.15 [M+H] ⁺ . Step 3: Methyl (2R)-5-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-(3-ethoxy-3- oxopropanoyl)pyrrolidine-2-carboxylate.

To a solution of methyl (2S)-5-(2-ethoxy-1,1-difluoro-2- oxoethyl)pyrrolidine-2-carboxylate (TFA salt) (2.3 g, 6.30 mmol, 1.0 equiv.) in DCM (30 mL) was added TEA (3.5 g, 34.59 mmol, 5.5 equiv.) followed by slow addition of ethyl 3-chloro-3-oxopropanoate (1.0 g, 6.64 mmol, 1.0 equiv.) with stirring at 0 °C. The reaction mixture was stirred for 1.5 h at 0°C. Another portion of ethyl 3-chloro-3-oxopropanoate (1.8 g, 11.96 mmol, 1.9 equiv.) was added to the mixture at 0 °C. The reaction mixture was stirred for 1.5 h, then was quenched with water (60 mL) and extracted with EA (100 mL X 3). The combined organic layer was washed with brine, dried over NaaSO*. The solids were filtered out. The resulting organic phase was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EA=2:1) to yield methyl (2S)-5-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-(3- ethoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate as a yellow oil. LC/MS: mass calculated for C15H21F2NO7: 365.13, measured (ES, m/z): 366.30 [M+H] ⁺ . Step 4: 6-Ethyl 3-methyl (3R)-8,8-difiuoro-7-hydroxy-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3,6-dicarboxylate.

To a solution of methyl (2S)-5-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1-(3- ethoxy-3-oxopropanoyl)pyrrolidine-2-carboxylate (1.4 g, 3.832 mmol, 1.0 equiv.) in EtOH (30 mL) was added NaH (60% in mineral oil, 200 mg, 5.00 mmol, 1.3 equiv.) with stirring at 0 °C. The reaction was then stirred at room temperature for 1.5 h. The mixture was quenched with water (50 mL) and extracted with EA (100 mL X 3). The combined organic layer was washed with brine, dried over N&SO*. The solids were filtered out. The resulting organic phase was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EA=1:1) to yield 6-ethyl 3-methyl (SSi-e^difluoro-T-hydroxy-S-oxo-l^^^^^a-hexahydroindolizine- S^ dicarboxylate (containing diethyl (3S)-8,8-difluoro-7-hydroxy-5-oxo-

1,2,3,5,8,8a-hexahydroindolizine-3,6-dicarboxylate) as a yellow oil. LC/MS: mass calculated for Ci3Hi5F2NOe: 319.09, measured (ES, m/z): 320.20 [M+H]*. Step 5: Methyl (3R)-8,8-difluoro-7-hydroxy-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of 6-ethyl 3-methyl (3S)-8,8-difluoro-7-hydroxy-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3,6-dicarboxylate (0.80 g, 2.51 mmol, 1.0 equiv.) in HOAc (20 mL) was added H2O (4 ml_). The reaction mixture was stirred for 5 h at 90 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a C18 column for purification (CH3CN/H2O) to yield methyl (3S)-8,8-difluoro-7-hydroxy-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow oil (containing ethyl (3S)-8,8- difluoro-7-hydroxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3- carboxylate). LC/MS: mass calculated for C10H11F2NO4: 247.07, measured (ES, m/z): 248.25 [M+H]*. Step 6: Methyl (3R)-8,8-difluoro-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

To a solution of methyl (3S)-8,8-difluoro-7-hydroxy-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (containing ethyl (3S)-8,8-difluoro-7- hydroxy-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate ) (0.50 g, 2.02 mmol, 1.0 equiv.) in DCM (10 mL) were added 1,1,1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (0.80 g, 2.24 mmol, 1.1 equiv.) and TEA (0.5 g, 4.94 mmol, 2.4 equiv.). The reaction mixture was stirred for 16 h at 25 °C. The reaction was quenched with water (20 mL) and extracted with EA (30 mL X 3). The combined organic layer was washed with brine, dried over N32S04. The solids were filtered out. The resulting organic phase was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EA=2:1) to yield methyl (3S)-8,8-difluoro-5- oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydr oindolizine-3- carboxylate (containing ethyl (3S)-8,8-difluoro-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate) as a yellow oil. LC/MS: mass calculated for CuHioFsNOeS: 379.01, measured (ES, m/z): 380.10 [Μ+ΗΓ.

Step 7: Methyl (3S)-7-(5-chloro-2-nitrophenyl)-8,8-difluoro-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-cartx)xylate.

To a solution of methyl (3S)-8,8-difluoro-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate (0.30 g, 0.79 mmol, 1.0 equiv.) in 1,4-dioxane (5 mL) and H2O (1 mL) were added (5-chloro-2-nitrophenyl)boronic acid (175 mg, 0.87 mmol, 1.1 equiv.) and Pd(dppf)Cl2 (38 mg, 0.052 mmol, 0.06 equiv.). The reaction mixture was stirred for 2.5 h at 90 °C under N2. The reaction was quenched with water (10 mL) and extracted with EA (20 mLX 3). The combined organic layer was washed with brine, dried over N32S04. The solids were filtered out. The resulting organic phase was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE/EA=2:1) to yield methyl (3S)-7-(5- chloro2-nitrophenyl)-8, 8-difluoro-5-oxo-1,2, 3,5,8, 8a-hexahydroindolizine-3- carboxylate as a yellow oil. LC/MS: mass calculated for C16H13CIF2N2O5: 386.05, measured (ES, m/z): 387.20 [M+H] ⁺ .

Step 8: (3S)-7-(5-Chloro-2-nitrophenyl)-8,8-difluoro-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic add.

To a mixture of (3S)-methyl 7-(5-chloro-2-nitrophenyl)-8,8-difluoro-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (65 mg, 0.17 mmol, 1.0 equiv.) in MeOH (2 mL) and THF (2 mL) was added a solution of UOH (20 mg, 0.84 mmol, 5.0 equiv.) in H2O (2 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL), the pH value of the aqueous phase was adjusted to 6 with HCI solution (1 M). The mixture was extracted with EtOAc (3 x 30 mL), dried over Na2SO<, and concentrated to yield (3S)-7-(5-chloro-2-nitrophenyl)-8,8-difluoro-5-oxo-

1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add as a yellow solid. LC/MS: mass calculated for C15H11CIF2N2O5: 372.03, measured (ES, m/z): 373.00 [Μ+ΗΓ.

Step 9: 2-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2- oxoethyl (3S)-7-(5-chloro-2-nitrophenyl)-8,8-difluoro-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

A mixture of (3S)-7-(5-chloro-2-nitrophenyl)-8,8-difluoiO-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (55 mg, 0.15 mmol, 1.0 equiv.) and CS2CO3 (29 mg, 0.089 mmol, 0.6 equiv.) in DMF (6 mL) was stirred at room temperature for 30 min. 2-Bromo-1-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)ethan-1- one (80 mg, 0.22 mmol, 1.5 equiv.) was then added to the mixture. The reaction mixture was stirred at room temperature for 4h. The resulting mixture was then diluted with EtOAc (110 mL), washed with water (3 x 20 mL), brine (2 x 20 mL), dried over Na2S04, and concentrated to yield (3S)-2-(2-((tert- butyldimethylsilyloxy)methyl)-3-fluoropyridin-4-yl)-2-oxoeth yl 7-(5-chloro-2- nitrophenyl)-8,8-difluoro-5-oxo-1,2,3,5,8,8a-hexahydroindoli zine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C2gH3iCIF3N307Si: 653.16, measured (ES, m/z): 654.05 [M+H]\

Step 10: (3S)-3-(5-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4-yl)- 1H-imidazol-2-yl)-7-(5-chloro-2-nitrophenyl)-8,8-difluoro-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one.

A mixture of NhUOAc (77 mg, 1.00 mmol, 10.0 equiv.) and (3S)-2-(2- ((tert-butyldimethylsilyloxy)methyl)-3-fluoropyridin-4-yl)-2 -oxoethyl 7-(5-chloro- 2-nitrophenyl)-8,8-difluoro-5-oxo-1,2,3,5,8,8a-hexahydroindo lizine-3- carboxylate (65 mg, 0.099 mmol, 1.0 equiv.) in AcOH (2 mL) and toluene (20 mL) was stirred at 110 °C for 30 min, then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40 g, MeOH/DCM: 1/15) to yield (3S)-3-(5-(2-((tert- butyldimethylsilyloxy)methyl)-3-fluoropyridin-4-yl)-1H-imida zol-2-yl)-7-(5-chloro- 2-nitrophenyl)-8,8-difluoro-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C29H3iCIF3Ns04Si: 633.18, measured (ES, m/z): 634.10 [M+H] ⁺ .

Step 11: (3S)-7-(2-Amino-5-chlorophenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-8,8- difluoro-2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a mixture of (3S)-3-(5-(2-((tert-butyldimethylsilyloxy)methyl)-3- fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(5-chloro-2-nitrophe nyl)-8,8-difluoro- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one (55 mg, 0.087 mmol, 1.0 equiv.) in MeOH (2 ml_), THF (2 mL) and H ₂ 0 (2 ml_) was added sodium dithionite (76 mg, 0.44 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 1h. The resulting mixture was diluted with EtOAc (100 mL), then washed with brine (3 x 20 mL), dried over N32S04, and concentrated. The residue was purified by flash column chromatography on silica gel (40 g, MeOH/DCM: 1/15) to yield (3S)-7-(2-amino-5-chlorophenyl)-3-(5-(2-((tert- butyldimethylsilyloxy)methyl)-3-fluoiOpyridin-4-yl)-1H-imida zol-2-yl)-8,8-difluoro- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C2eH33CIF3Ns02Si: 603.20, measured (ES, m/z): 604.15 [M+H]÷. Step 12: (3S)-3-(5-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4-yl)- 1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-8, 8-difluoro-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

A mixture of (3S)-7-(2-amino-5-chlorophenyl)-3-(5-(2-((tert- butyldimethylsilyloxy)methyl)-3-fluoiOpyridin-4-yl)-1H-imida zol-2-yl)-8,8-difluoro- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one (45 mg, 0.074 mmol, 1.0 equiv.), TMSN3 (85 mg, 0.75 mmol, 10.0 equiv.) and trimethoxymethane (79 mg, 0.75 mmol, 10.0 equiv.) in AcOH (5 mL) was stirred at 65 °C for 2 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40 g, MeOH/DCM: 1/15) to yield (3S)-3-(5-(2- ((tert-butyldimethylsilyloxy)methyl)-3-fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(5- chloro-2-(1H-tetrazol-1-yl)phenyl)-8,8-difluoro-2,3,8,8a-tet rahydroindolizin- 5(1H)-one as a yellow solid. LC/MS: mass calculated for C3oH32CIF3Ne02Si: 656.21, measured (ES, m/z): 657.20 [M+H] ⁺ .

Step 13: (3S)-7-(5-Chloro-2-(1 H-tetrazol-1-yl)phenyl)-8,8-difluoro-3-(5-(3-fluoro- 2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-te trahydroindolizin- 5(1H)-one.

A mixture of (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetr azol-1-yl)phenyl)-8,8- difluoro-2,3,8,8a-tetrahydroindolizin-5(1H)-one (40 mg, 0.061 mmol, 1.0 equiv.) in THF (6 ml_) and HCI (2 mL, 4 M) was stirred at 55 °C for 1 h. The solvent was removed under reduced pressure and the residue was applied onto a C18 reverse column (330 g, ACN/hhO (0.05%NH4HC0 ₃ ): 5%»>40%»>45%, 40 min) to yield (3S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-8,8-difluoro-3- (5-(3- fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3, 8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C24H18CIF3N8O2: 542.12, measured (ES, m/z): 543.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.55 (s, 1H), 9.80 (s,

1H), 8.33 (d, J = 5.1 Hz, 1H), 7.81 - 7.95 (m, 3H), 7.76 (d, J = 2.2 Hz, 1H), 7.54 - 7.68 (m, 1H), 6.38 (d, J = 3.9 Hz, 1H), 5.23 - 5.38 (m, 1H), 5.02 - 5.22 (m,

1H), 4.59 - 4.62 (m, 2H), 4.40 - 4.57 (m, 1H), 2.31 - 2.44 (m, 1H), 2.19 - 2.31 (m, 1H), 2.09 - 2.18 (m, 2H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -103.81, -115.32, -130.15.

Example 57: (3S,8aR)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1 H- imidazol-2-yl)-7-(2-fluoro-3-methyl-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one Step 1: Methyl (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a mixture of methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (600 mg, 1.77 mmol, 1.0 equiv.) and methylboronic acid (530 mg, 8.86 mmol, 5.0 equiv.) in 1,4-dioxane (10 mL) was added potassium phosphate (1128 mg, 5.31 mmol, 3.0 equiv.), palladium (II) acetate (80 mg, 0.35 mmol, 0.1 equiv.) and tricyclohexylphosphonium tetrafluoroborate (130 mg, 0.35 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 5 h. Water was added, the mixture was extracted with EA. The combined extracts were washed with water, saturated brine, dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0→8%) to yield methyl (3S)-7-(6-amino-2-fluoro-3- methylphenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate a brown solid. LC/MS: mass calculated for C17H19FN2O3: 318.14, measured (ES, m/z): 319.10 [M+H] ⁺ .

Step 2: (3S)-7-(6-Amino-2-fluoro-3-methylphenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid.

To a solution of methyl (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-5-oxo- 1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (500 mg, 1.57 mmol, 1.0 equiv.) in acetic acid (9 ml_) was added hydrochloric acid (3 ml_). The reaction mixture was stirred at 90 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography with CH3CN/H2O (5— >45%) to yield (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add as a yellow solid. LC/MS: mass calculated for CieHi7FN203: 304.12, measured (ES, m/z): 305.10 [M+H]÷.

Step 3: 2-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-2- oxoethyl (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-5 -oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-5-oxo- 1,2,3,5,8,8a -hexahydroindolizine-3-carboxylic acid (250 mg, 0.82 mmol, 1.0 equiv.) in N,N-dimethylformamide (5 mL) was added potassium carbonate (148 mg, 1.07 mmol, 1.3 equiv.). The reaction mixture was stirred for 0.5 h. 2-(((tert- Butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)-3-fluoropyr idine (595 mg, 1.64 mmol, 2.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. Water was added, the mixture was extracted with EA. The combined extracts were washed with water, saturated brine, dried over N32S04, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0→6%) to yield 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (3S)-7-(6-amino- 2-fluoro-3-methylphenyl)-5-oxo-1,2,3,5,8,8a-hexahydrOindoliz ine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C30H37F2N3O5S1: 585.25, measured (ES, m/z): 586.45 [M+H]÷.

Step 4: (3S)-7-(6-Amino-2-fluoro-3-methylphenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl) -2-oxoethyl (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (160 mg, 0.27 mmol, 1.0 equiv.) and ammonium acetate (421 mg, 5.46 mmol, 20.0 equiv.) in toluene (10 mL) was added acetic add (0.5 mL). The reaction mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0→6%) to yield (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C3oH37F ₂ N ₅ 02Si: 565.27, measured (ES, m/z): 566.45 [M+H]\

Step 5: (3S)-3-(5-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4-yl)- 1H-imidazol-2-yl)-7-(2-fluoro-3-methyl-6-(1H-tetrazol-1-yl)p henyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a mixture of (3S)-7-(6-amino-2-fluoro-3-methylphenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (50 mg, 0.088 mmol, 1.0 equiv.) in acetic add (3 mL) were added azidotrimethylsilane (102 mg, 0.88 mmol, 10.0 equiv.) and trimethoxymethane (98 mg, 0.88 mmol, 10.0 equiv.). The reaction mixture was stirred overnight at 60 °C. The resulting mixture was concentrated under vacuum to yield (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(2-fluoro-3-methyl-6-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a brown solid. LC/MS: mass calculated for C3iH3eF2Ne02Si: 618.27, measured (ES, m/z): 619.20 [M+H]*.

Step 6: (3S,8aR)-3-(5-(3-Fluoro-2-(hydroxymethyl)pyridin-4-yl)- 1H-imidazol-2- yl)-7-(2-fluoro-3-methyl-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a-tetrahydroindolizin-

5(1H)-one.

To a solution of (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(2-fluoro-3-methyl-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (70 mg) in THF (5 mL) was added triethylamine trihydrofluoride (64 mg, 0.40 mmol, 5.0 equiv.). The reaction mixture was stirred at 70 °C for 1 h, then purified by reverse phase chromatography with CHaCN/water (5→25%) to yield racemic product, which was purified by HPLC to yield (3S,8aR)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin- 4-yl)-1 H-imidazol-2-yl)-7-(2-fluoro-3-methyl-6-(1 H-tetrazol-1 -yl)phenyl)-

2,3,8, 8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25H22F2N8O2: 504.18, measured (ES, m/z): 505.20 [Μ+ΗΓ. ¹ H NMR (400 MHz, Methanol-d*) 69.44 (s, 1 H), 8.24 (dd, J = 5.1, 0.6 Hz, 1 H), 7.91 (s, 1 H), 7.51 (d, J = 4.0 Hz, 1 H), 7.42 - 7.48 (m, 1 H), 7.27 - 7.32 (m, 1 H), 5.56 (d, J = 2.7 Hz, 1 H), 5.02 - 5.11 (m, 1 H), 4.69 (d, J =

2.3 Hz, 2 H), 3.74 - 3.88 (m, 1 H), 2.72 - 2.88 (m, 1 H), 2.46 - 2.56 (m, 1 H),

2.31 - 2.36 (m, 3 H), 2.07 - 2.29 (m, 3 H), 1.89 - 2.03 (m, 1 H). ¹⁹ F NMR (376 MHz, Methanol·^) 6 -116.25, -131.26.

Example 58: 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H- 1 ,2,3-triazoM -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-3-fluoropicolinic acid

Step 1: Methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a - hexahydroindolizine-3-carboxylate.

To a mixture of methyl 5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-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.) in 1,4-dioxane (50 mL) and water (10 mL) was 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 flushed three times with nitrogen. The solution was stirred at 100°C for 1 h under Na, then diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over NaaSO*, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→80% EA/PE) to yield methyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexah ydroindolizine-3- carboxylate as a yellow solid. LC/MS: mass calculated for CieHieCIFNaOa: 338.08, measured (ES, m/z): 339.10 [M+H]*. Step 2: Methyl (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a mixture of methyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (3.4 g, 10.04 mmol, 1.0 equiv.) and azidotrimethylsilane (2.6 mL, 20.07 mmol, 2.0 equiv.) in acetonitrile (35 mL) was added tert-butyl nitrite (2.4 mL, 20.07 mmol, 2.0 equiv.) at 0 °C. The solution was stirred at room temperature for 1 h, diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over NaaSO*. and concentrated under vacuum. The residue was purified by silica gel chromatography (0→80% EA/PE) to yield methyl 7-(6-azido-3- chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for CieHuCIFN^a: 364.07, measured (ES, m/z): 365.10 [M+H] ⁺ .

Step 3: Methyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-tr iazol- 1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

To a mixture of methyl 7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a -hexahydroindolizine-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 flushed three times with nitrogen. The solution was stirred at 80 °C for 2 h under Na. The solution was concentrated under vacuum and purified by silica gel chromatography (0→60% EA/PE) to yield methyl 7-(3- chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a white solid. LC/MS: mass calculated for C19H15CIF4N4O3: 458.08, measured (ES, m/z): 459.05 [M+H]*. Step 4: (3S)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-tr iazol-1 - yl)phenyl)-5-oxo-1 ,2,3,5, 8,8a-hexahydroindolizine-3-carboxylic acid.

To a mixture of methyl 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H- 1 ,2,3- triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-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 h, then concentrated under vacuum. The residue was purified by reverse phase chromatography on C18 column (ACN/H2O (0.05%CF3COOH): 0→30%) to yield 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a yellow solid. LC/MS: mass calculated for C18H13CIF4N4O3: 444.06, measured (ES, m/z): 445.15 [M+H] ⁺ .

Step 5: 2-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl) -2- oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl) phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate .

To a solution of (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-hexahydroindolizine-3-carboxylic acid (500 mg, 1.12 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added potassium carbonate (202 mg, 1.46 mmol, 1.3 equiv.). The reaction mixture was stirred for 0.5 h. 2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)-3 - fluoropyridine (815 mg, 2.25 mmol, 2.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. Water was added, the mixture was extracted with EA. The combined extracts were washed with water, saturated brine, dried over N32S04, filtered and concentrated. The residue was purified by silica gel chromatography with EA/PE (0→70%) to yield 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (3S)-7-(3-chloro- 2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C32H33CIF5N ₅ 05Si: 725.19, measured (ES, m/z): 726.35 [M+H] ⁺ . Step 6: (3S)-3-(5-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4-yl) - 1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl) -1 H-1 ,2,3-triazoM- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin- 4-yl)-2-oxoethyl (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-hexahydroindolizine-3-carbox ylate (0.60 g, 0.83 mmol, 1.0 equiv.) and ammonium acetate (1.3 g, 16.53 mmol, 20.0 equiv.) in toluene (10 mL) was added acetic acid (0.5 mL). The reaction mixture was stirred at 100 °C for 1.5 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with

MeOH/DCM (0—7%) to yield (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)- 3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro -6-(4-(trifluoromethyl)- 1H-1,2,3-triazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5 (1H)-one as a yellow solid. LC/MS: mass calculated for C32H33CIF5N7O2S1: 705.21, measured (ES, m/z): 706.20 [M+H] ⁺ .

Step 7: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2, 3- triazol-1- yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8, 8a-tetrahydroindolizin-5(1H)-one.

To a solution of (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6 -(4-(trifluoromethyl)- 1 H-1 ,2,3-triazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (0.49 g,

0.69 mmol, 1.0 equiv.) in THF (5 mL) was added triethylamine trihydrofluoride (0.56 g, 3.47 mmol, 5.0 equiv.). The reaction mixture was stirred at 70 °C for 1 h, then diluted with water and the organic layer was separated and concentrated. The residue was purified by reverse phase chromatography with CHsCN/water (5—55%) to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(4- (trifluoromethyl)-l H- 1 ,2,3-triazol-1-yl)phenyl)-3-(5-(3-fluoro-2- (hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one as a yellow solid. LC/MS: mass calculated for C26H19CIF5N7O2: 591.12, measured (ES, m/z): 592.10 [M+H] ⁺ .

Step 8: 4-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H- 1,2,3- triazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)-3-fluoropicolinic acid.

To a mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H- 1,2,3-triazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)p yridin-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (80 mg, 0.14 mmol, 1.0 equiv.) in DCM (5 mL) and H2O (0.25 mL) was added TEMPO (21 mg, 0.14 mmol, 1.0 equiv.) and Phl(OAc)2 (2.2 g, 6.83 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was applied onto a C18 reverse column (ACN/H2O (0.05%NH4HC03): 5—35%) to yield 4-(2-((3S,8aR)-7-(3-chloro-2- fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropicolinic acid as a white solid.

LC/MS: mass calculated for CizeHiyCIFsNyOa: 605.10, measured (ES, m/z): 606.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) 68.99 (d, J = 1.0 Hz, 1 H), 8.38 (d, J = 5.1 Hz, 1 H), 8.18 (t, J = 5.4 Hz, 1 H), 7.74 - 7.85 (m, 1 H), 7.67

(d, J = 4.1 Hz, 1 H), 7.48 - 7.58 (m, 1 H), 5.72 (d, J = 2.7 Hz, 1 H), 5.19 (d, J = 8.6 Hz, 1 H), 3.85 - 4.02 (m, 1 H), 2.86 - 2.99 (m, 1 H), 2.57- 2.70 (m, 1 H), 2.16 - 2.39 (m, 3 H), 1.98 - 2.16 (m, 1 H). ¹⁹ F NMR (376 MHz, Methanol-d*) δ - 62.53, -113.68, -124.91. Example 59: 6-{2-((3S*,8aR*)-7-{5-chloro-2-{4-{trifluoromethyl)-1 H-1 ,2,3- triazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-5-fluoroquinoxalin-2(1H)-one

LC/MS: mass calculated for C28H18CIF4N8O2: 610.13, measured (ES, m/z): 611.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.59 (s, 1H), 11.97 (s, 1H), 9.35 (s, 1H), 8.15 - 8.24 (m, 2H), 7.71 - 7.81 (m, 3H), 7.38 (d, J = 3.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 5.70 (d, J = 2.4 Hz, 1H), 5.03 (d, J = 8.4 Hz, 1H), 3.61 - 3.76 (m, 1H), 2.32 - 2.49 (m, 1H), 2.11 -2.30 (m, 2H), 1.87 - 2.07 (m, 3H). ¹⁸ F NMR (282 MHz, DMSO-de) δ - 59.56, - 126.68. Example 61: (4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)methyl dihydrogen phosphate

LC/MS: mass calculated for C24H20CIF2N8O5P: 604.10, measured (ES, m/z): 605.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.87 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.08 - 8.19 (m, 2H), 8.00 (t, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.7, 1.5 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 5.30 (d, J = 9.6 Hz, 1H), 5.09 (dd, J = 6.6, 2.0 Hz, 2H), 3.73 - 3.87 (m, 1H), 3.01 - 3.19 (m, 1H), 2.54 - 2.66 (m, 1H), 2.25 - 2.46 (m, 1H), 1.91 - 2.23 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.48, - 126.39.

Example 63: (3R*,8aR)-3-(5-(2-(3-amino-1H-pyrazol-1-yl)-3-fluoropyridin- 4- yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2eH2oCIF2NiiO: 575.15, measured (ES, m/z): 576.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.29 (s, 1 H), 9.82 (s, 1 H), 8.08 - 8.20 (m, 2 H), 7.91 - 7.99 (m, 1 H), 7.75 - 7.82 (m, 1 H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.60 (d, J = 3.6 Hz, 1H), 5.81 (d, J = 2.7 Hz, 1H), 5.68 (d, J = 2.7 Hz, 1 H), 5.11 - 5.20 (m, 2 H), 5.03 (d, J = 8.8 Hz, 1 H), 3.66 - 3.79 (m, 1 H),

2.64 - 2.78 (m, 1 H), 2.50 - 2.56 (m, 1 H), 2.03 - 2.28 (m, 2 H), 1.87 - 2.01 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.84, -131.49.

Example 64: (3S,8aR*)-7-(5-chloro-2-(4-(trifluoiOmethy l)-1 H-1 ,2,3-triazoM - yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8 _| 8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2eH2oCIF4N702: 573.13, measured (ES, m/z): 574.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) δ 9.00 (s, 1H), 8.34 (d, J = 5.3 Hz, 1 H), 8.03 (t, J = 5.7 Hz, 1 H), 7.65 - 7.75 (m, 4H), 5.79 (d, J = 2.7 Hz,

1H), 5.19 (d, J = 8.7 Hz, 1H), 4.79 - 4.82 (m, 2H). 3.79 - 3.95 (m, 1H), 2.58 - 2.73 (m, 1H), 2.25-2.40 (m, 2H), 2.11 - 2.25 (m, 2 H), 1.91- 2.07 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -62.52, -76.94, -130.74.

Example 65: 4-(2-((3S,8aR)-7-(3-chloiO-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl )-3-fluoro-2- (hydroxymethyl)pyridine 1 -oxide

LC/MS: mass calculated for C24H19CIF2N8O3: 540.12, measured (ES, m/z): 541.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d ₄ ): δ 9.57 (s, 1H), 8.29 (d,

J = 6.9 Hz, 1H), 8.10 (t, J = 7.9 Hz, 1H), 7.77 - 7.85 (m, 1H), 7.60 (d, J = 4.1 Hz, 1H), 7.55 (dd, J = 8.7, 1.6 Hz, 1H), 5.76 (d, J = 2.7 Hz, 1H), 5.16 (d, J = 8.6 Hz, 1H), 4.94 (d, J = 3.2 Hz, 2H), 3.88 - 4.01 (m, 1H), 2.72 - 2.89 (m, 1H), 2.56 - 2.69 (m, 1H), 2.14 - 2.39 (m, 3H), 1.97 - 2.12 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-d ₄ ): 6 -113.62, -124.02.

Example 66: (3S*)-3-(4-(6-(1H-pyrazol-5-yl)pyridin-2-yl)-5-fluoro-1H- imidazol-2-yl)-7-{3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eHi9CIF2NioO: 560.14, measured (ES, m/z): 561.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.96 - 13.61 (m, 1H), 12.35 - 12.67 (m, 1H), 9.83 (s, 1H), 7.92 - 7.99 (m, 1H), 7.75 - 7.91 (m, 2H), 7.68 - 7.72 (m, 1 H), 7.61 (s, 1 H), 7.34 - 7.41 (m, 1 H), 6.91 - 7.21 (m, 1 H), 5.67

(s, 1H), 4.91 - 5.17 (m, 1H), 3.65 - 3.80 (m, 1H), 2.51 - 2.63 (m, 2H), 1.88 - 2.29 (m, 4H). ¹⁸ F NMR (376 MHz, DMSO-de) 6 -112.92, -128.21.

Example 67: (3S,8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1,2,3- triazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin -4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

1 a·

.N-

,s

Step 1: 2-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2 - oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazoM-yl) phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate .

To a solution of (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-hexahydroindolizine-3-carboxylic acid (500 mg, 1.12 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added potassium carbonate (202 mg, 1.46 mmol, 1.3 equiv.). The reaction mixture was stirred for 0.5 h, then 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1- ethoxyvinyl)-3-fluoropyridine (815 mg, 2.25 mmol, 2.0 equiv.) was added and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EA. The combined extracts were washed with water, saturated brine, dried over N32S04, filtered and concentrated. The residue was purified by flash column chromatography on silica gel with EA/PE (0-→70%) to yield 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (3S)-7-(3-chloro-

2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for CaaHsaCIFsNsOsSi: 725.19, measured (ES, m/z): 726.35 [M+H] ⁺ . Step 2: (3S)-3-(5-(2-(((Tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin- 4-yl)- 1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl) -1 H-1 ,2,3-triazol-l- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin - 4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol - 1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbox ylate (0.60 g, 0.83 mmol 1.0 equiv.) and ammonium acetate (1.3 g, 16.53 mmol, 20.0 equiv.) in toluene (10 mL) was added acetic acid (0.5 mL). The reaction mixture was stirred at 100 °C for 1.5 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with MeOH/DCM (0→7%) to yield (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-

3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-flu oiO-6-(4-(trifluoromethyl)- 1H-1,2,3-triazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5 (1H)-one as a yellow solid. LC/MS: mass calculated for C32H33CIFsN702Si: 705.21, measured (ES, m/z): 706.20 [M+H] ⁺ . Step 3: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2, 3-triazol-1- yl) phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1 H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of (3S)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6 -(4-(trifluoromethyl)- 1 H-1 ,2,3-triazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (0.49 g,

0.69 mmol, 1.0 equiv.) in THF (5 mL) was added triethylamine trihydrofluoride (0.56 g, 3.47 mmol, 5.0 equiv.). The reaction mixture was stirred at 70 °C for 1 h, then purified by reverse phase chromatography with CHsCN/water (5→55%) to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H- 1,2,3-triazoM- yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid.

LC/MS: mass calculated for C2eHi8CIFsN702: 591.12, measured (ES, m/z): 592.10 [Μ+Η] ⁺ . ¹ Η NMR (400 MHz, Methanol-cU) δ 8.97 - 9.01 (m, 1 Η), 8.33 (d, J = 5.2 Hz, 1Η), 8.01 (t, J = 5.6 Hz, 1 H), 7.76 - 7.83 (m, 1 H), 7.63 (d,

J = 3.9 Hz, 1 H), 7.54 (dd, J = 8.7, 1.6 Hz, 1 H), 5.72 (d, J = 2.8 Hz, 1 H), 5.16 - 5.21 (m, 1 H), 4.80 (d, J = 2.3 Hz, 2 H), 3.87 - 3.99 (m, 1 H), 2.84 - 2.98 (m, 1 H), 2.58 - 2.68 (m, 1 H), 2.18 - 2.40 (m, 3 H), 1.99 - 2.14 (m, 1 H). ¹⁹ F NMR

(376 MHz, methanol-d*) δ -62.58, -113.68, -130.98.

Example 68: (3S,8aR)-3-(4-(2-(5-amino-1H-pyrazol-1-yl)-3-fluoropyridin-4 - yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -y l)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2eH2oCIF2NnO: 575.15, measured (ES, m/z): 576.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.33 (s, 1H), 9.82 (s, 1H), 8.29 (d, J = 5.1 Hz, 1H), 7.90 - 8.00 (m, 2H), 7.60 - 7.73 (m, 2H), 7.33 (d, J = 1.8 Hz, 1H), 5.64 - 5.77 (m, 3H), 5.44 (d, J = 1.8 Hz, 1H), 5.04 (d, J = 8.8 Hz, 1H), 3.66 - 3.82 (m, 1H), 2.64 - 2.79 (m, 1H), 2.50 - 2.60 (m, 1H), 2.04 - 2.25 (m, 2H), 1.88 -2.02 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.82, - 128.53.

Example 69: (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-4-fluoro-1H- imidazol-2-yl)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H18CIF2N8O: 509.13, measured (ES, m/z): 510.15 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 11.95 (s, 1H), 9.84 (s, 1H), 7.74 - 7.85 (m, 3H), 7.50 - 7.61 (m, 1H), 6.52 (s, 2H), 6.40 (dd, J = 8.3, 2.0 Hz, 1 Η), 5.55 (d, J = 2.6 Hz, 1H), 4.93 (d, J = 8.6 Hz, 1H), 3.56 - 3.76 (m, 1H), 2.40 - 2.50 (m, 1 H), 2.24 - 2.38 (m, 1 H), 2.07 - 2.21 (m, 1 H), 1.98 - 2.06 (m, 1H), 1.80 - 1.96 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -71.32, -136.14. Example 70: (3S*,8aR)-3-(5-(2-amino-3-fluoropyridin-4-yl)-4-fluoro-1H- imidazol-2-yl)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 2-(2-Acetamido-3-fluoropyridin-4-yl)-2-oxoethyl (8aR)-7-(5-chloro-2- (1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoli zine-3-carboxylate.

To a solution of (8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (2.0 g, 5.56 mmol, 1.0 equiv.) in CHaCN (20 mL) was added K2CO3 (1.2 g, 8.34 mmol, 1.5 equiv.). After stirring at room temperature for 0.5 h, N-(4-(2-bromoacetyl)-3- fluoropyridin-2-yl)acetamide (2.3 g, 8.34 mmol, 1.5 equiv.) was added. The mixture was stirred at room temperature for 1 h. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the 2-(2-acetamido-3- fluoropyridin-4-yl)-2-oxoethyl (8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C25H21CIFN7O5: 553.13, measured (ES, m/z): 554.05 [M+H]*.

Step 2: N-(4-(2-((8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo -

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3 -fluoropyridin-2- yl)acetamide.

To a solution of 2-(2-acetamido-3-fluoropyridin-4-yl)-2-oxoethyl (8aR)-7- (5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizi ne-3- carboxylate (2.5 g, 4.51 mmol, 1.0 equiv.) in toluene (30 mL) and acetic acid (3 mL) was added ammonium acetate (5.2 g, 67.70 mmol, 15.0 equiv.). The mixture was stirred at 100 °C for 1 h. The solvent was removed under vacuum and the residue was purified by silica gel column with MeOH/DCM (0→10%) to yield N-(4-(2-((8aR)-7-(5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H21CIFN9O2: 533.13, measured (ES, m/z): 534.40 [M+H]*.

Step 3: N-(4-(2-((8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo -

1,2, 3,5,8, 8a-hexahydroindolizin-3-yl)-4-fluoro-1H-imidazol-5-yl)-3-flu oropyridin-

2-yl)acetamide.

To a solution of n-(4-(2-((8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)acetamide (120 mg, 0.23 mmol, 1.0 equiv.) in DCM (5 mL) and acetone (5 mL) were added NFSI (637 mg, 2.02 mmol, 9.0 equiv.), and NaHCOs (283 mg, 3.37 mmol, 15.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at 60 °C for 3 days. The residue was purified by C18 column with CH ₃ CN/0.05% TFA water (5→50%) to yield the N-(4-(2-((8aR)-7-(5-chloro-2-

(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroind olizin-3-yl)-4-fluoro- 1H-imidazol-5-yl)-3-fluoropyridirv2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H20CIF2N9O2: 551.14, measured (ES, m/z): 552.35 [M+H]*. Step 4: (3S*,8aR)-3-(5-(2-Amino-3-fluoropyridin-4-yl)-4-fluoro-1 H- imidazol-2- yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-5(1H)- one.

To a solution of N-(4-(2-((8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-4-fluoro-1 H-imidazol-5-yl)-3- fluoropyridin-2-yl)acetamide (45 mg, 0.08 mmol) in THF (2 ml_) was added HCI (2 mL, 2 M). The mixture was stirred at 50 °C for 2 h. The solvent was removed under vacuum and the residue was purified by C18 column [condition: ACN- water-6.5 mM NH4HCO3+NH3H2O (5→50%)] to yield a residue. The residue was purified by chiral HPLC [Column: CHIRALART cellulose-SB, 4.6*1 OOmm.Sum; mobile phase A:MtBE (0.1%DEA): EtOH=50:50, mobile phase B:; flow rate:1 ml-Zmin] to yield (3*S,8aR)-3-(5-(2-amino-3-fluoropyridin- 4-yl)-4-fluoro-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol- 1-yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as an off-white solid.

LC/MS: mass calculated for C23H18CIF2N9O: 509.13, measured (ES, m/z): 510.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.36 (s, 1H), 9.84 (s, 1H), 7.81 - 7.84 (m, 1H), 7.71 - 7.80 (m, 3H), 6.62- 6.66 m, 1H), 6.28 (s, 2H), 5.55 (d, J = 2.7 Hz, 1H), 5.01 (d, J = 8.7 Hz, 1H), 3.64 - 3.76 (m, 1H), 2.41 -

2.48 (m, 1H), 2.29 - 2.39 (m, 1H), 2.10 - 2.22 (m, 1H), 2.00 - 2.08 (m, 1H), 1.82 - 1.99 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -127.18, -143.05.

Example 71: (3R*,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 - (5-(3-fluoro-2-(1H-1,2,3-triazol-1-yl)pyridin^-yl)-1H-imidaz ol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 3-Fluoro-4-iodo-2-(1 H-1 ,2,3-triazol-1-yl)pyridine.

To a solution of 2,3-difluoro-4-iodopyridine (2.0 g, 8.30 mmol, 1.0 equiv.) in DMSO (20 mL) was added 2 H-1 ,2,3-triazole (573 mg, 8.30 mmol, 1.0 equiv.) and CS2CO3 (4.1 g, 12.45 mmol, 1.5 equiv.). The resulting mixture was stirred at 25 °C for 1 h. The mixture was extracted with EA (60 mL) and H2O (40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10→30% EA/PE) to yield 3-fluoro-4-iodo-2-(1H-1,2,3-triazol- 1-yl)pyridine as a white solid. LC/MS: mass calculated for C7H4FIN4: 289.95, measured (ES, m/z): 291.10 [M+H]*.

Step 2: 4-(1-Ethoxyvinyl)-3-fluoro-2-(1H-1,2,3-triazol-1-yl)pyridine .

To a solution of 3-fluoro-4-iodo-2-(1H-1,2,3-triazol-1-yl)pyridine (900 mg, 3.10 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) was added tributyl(1- ethoxyvinyl)stannane (2.2 g, 6.20 mmol, 2.0 equiv.) and Pd(PPh3)4 (359 mg, 0.31 mmol, 0.1 equiv.). The resulting mixture was stirred at 100 °C for 6 h. The mixture was extracted with EA (50 mL) and H2O (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (30→50% ethyl acetate/petroleum ether) to yield 4-(1-ethoxyvinyl)-3-fluoiO-2-(1H-1,2,3-triazol- 1-yl)pyridine as a yellow oil. LC/MS: mass calculated for C11H11FN4O: 234.09, measured (ES, m/z): 235.25 [M+H] ⁺ . Step 3: 2-Bromo-1-(3-fluoro-2-(1 H-1 _l 2,3-triazol-1-yl)pyridin-4-yl)ethan-1-one.

To a solution of 4-(1-ethoxyvinyl)-3-fluoro-2-(1H-1,2,3-triazol-1- yl)pyridine (700 mg, 2.90 mmol, 1.0 equiv.) in THF (8 ml_) and H2O (2 ml_) was added NBS (479 mg, 2.61 mmol, 0.9 equiv.). The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was extracted with ethyl acetate (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 2-bromo1-(3-fluoro-2-(1H-1,2,3-triazol-1- yl)pyridin-4-yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for CgHeBrFN40: 283.97, measured (ES, m/z): 284.95 [M+H] ⁺ .

Step 4: 2-(3-Fluoro-2-(1H-1,2,3-triazol-1-yl)pyridin-4-yl)-2-oxoethy l (8aR)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1, 2,3,5, 8, 8a-hexahydroindolizine-3-carboxylic acid (186 mg, 0.49 mmol,

1.0 equiv.) in ACN (5 mL) was added K2CO3 (145 mg, 1.05 mmol, 2.1 equiv.). The resulting mixture was stirred at 25 °C for 0.5 h. 2-Bromo-1-(3-fluoro-2-(1 H- 1,2,3-triazol-1-yl)pyridin-4-yl)ethan-1-one (200 mg, 0.70 mmol, 1.4 equiv.) was then added to the mixture. The resulting mixture was stirred at 25 °C for 1 h, then concentrated under vacuum. The residue was purified by silica gel chromatography (0→20% MeOH/DCM) to yield 2-(3-fluoro-2-(1H-1,2,3-triazol- 1-yl)pyridin-4-yl)-2-oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylateas a yellow solid. LC/MS: mass calculated for C25H18CIF2N9O4: 581.11, measured (ES, m/z): 582.30 [M+H] ⁺ .

Step 5: (3R,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro- 2-(1 H-1 ,2,3-triazol-1-yl)pyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of 2-(3-fluoro2-(1H-1,2,3-triazol-1-yl)pyridin-4-yl)-2- oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (290 mg, 0.50 mmol, 1.0 equiv.) in AcOH (0.3 mL) and toluene (3 mL) was added ammonium acetate (576 mg, 7.50 mmol, 15.0 equiv.). The resulting mixture was stirred at 90 °C for 1 h, concentrated under vacuum. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) and chiral-HPLC with [Column: (R,R)- WHELK-01-Kromasil, 2.12*25cm,5um; Mobile Phase A:MTBE(0.5% 2M NHs- MeOH)— HPLC, Mobile Phase B:EtOH-HPLC; Flow rate:20 mL/min; Gradient:50 B to 50 B in 16 min; 220/254 nm; RT1:9.558; RT2:14.518; Injection Volumn:1.5 ml; Number Of Runs:7] to yield (3R*,8aR)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(1 H-1 ,2,3-triazol-1-yl)pyridin-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25H18CIF2N11O: 561.14, measured (ES, m/z): 562.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.42 (s, 1H), 9.83 (s, 1H), 8.73 - 8.75 (m, 1H), 8.43 (d, J = 5.0 Hz, 1H), 8.11- 8.18 (m, 1H), 7.91 -

8.03 (m, 2H), 7.66 - 7.76 (m, 2H), 5.69 (d, J = 2.7 Hz, 1H), 5.05 (d, J = 8.7 Hz, 1H), 3.67- 3.82 (m, 1H), 2.63- 2.81 (m, 1H), 2.49-2.58 (m, 1H), 2.11- 2.32 (m, 2H), 1.88 -2.03(m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.83, -131.19.

Example 72: (3R*,8aR)-3-(5-(2-(3-amino-1 H-pyrazol-1 -yl)pyridin-4-yl)-1 H- imidazol-2-yl)-7-(3-chloro-2-fluoro~6~(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eH2iCIFNiiO: 557.16, measured (ES, m/z): 558.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.05 (s, 1 H), 9.80 - 9.84 (m, 1 H), 8.18 - 8.28 (m, 2 H), 7.91 - 8.01 (m, 2 H), 7.76 (d, J = 2.2 Hz, 1

H), 7.65 - 7.73 (m, 1 H), 7.38 - 7.52 (m, 1 H), 5.77 (d, J = 2.6 Hz, 1 H), 5.62 -

5.70 (m, 1 H), 5.15 - 5.26 (m, 2 H), 4.97 - 5.02 (m, 1 H), 3.61 - 3.73 (m, 1 H),

2.71 - 2.83 (m, 1 H), 2.50 - 2.55 (m, 1 H), 2.03- 2.34 (m, 2 H), 1.85 - 2.04 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.40, -112.67.

Example 73: (3S,8aR*)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (3-fluoro-2-(((S)-tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1 H-imidazol-2-yl)- 2 _l 3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: (S)-3-Fluoro-4-iodo-n-(tetrahydrofuran-3-yl)pyridin-2-amine.

To a solution of 2,3-difluoro-4-iodopyridine (1.0 g, 4.15 mmol, 1.0 equiv.) in DMSO (15 mL) was added (S)-tetrahydrofuran-3-amine hydrochloride (1.5 g, 12.45 mmol, 3.0 equiv.) and EtaN (2.5 g, 24.90 mmol, 6.0 equiv.). The resulting mixture was stirred at 100 °C overnight. After cooling to room temperature, the reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0→30% ethyl acetate/petroleum ether) to yield the (S)-3- fluoro-4-iodo-n-(tetrahydrofuran-3-yl)pyridin-2-amine as a yellow oil. LC/MS: mass calculated for C9H10FIN2O: 307.98, measured (ES, m/z): 308.90 [M+H] ⁺ . Step 2: (S)-4-(1-Ethoxyvinyl)-3-fluoro-n-(tetrahydrofuran-3-yl)pyrid in-2-amine.

To a solution of (S)-3-fluoro-4-iodo-n-(tetrahydrofuran-3-yl)pyridin-2- amine (550 mg, 1.79 mmol, 1.0 equiv.) in 1 ,4-dioxane (10 mL) were added tributyl(1 -ethoxyvinyl)tin (1.0 g, 2.86 mmol, 1.6 equiv.), Pd(PPh3)4 (103 mg,

0.089 mmol, 0.05 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C overnight After cooling to room temperature, the reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0→30% ethyl acetate/petroleum ether) to yield the (S)-4-(1- ethoxyvinyl)-3-fluoro-N-(tetrahydrofuran-3-yl)pyridin-2-amin e as a red oil. LC/MS: mass calculated for C13H17FN2O2: 252.13, measured (ES, m/z): 253.25 [Μ+ΗΓ.

Step 3: (S)-2-Bromo1-(3-fluoro-2-((tetrahydrofuran-3-yl)amino)pyridi n-4- yl)ethan-1-one

To a solution of (S)-4-(1-ethoxyvinyl)-3-fluoro-n-(tetrahydrofuran-3- yl)pyridin-2-amine (420 mg, 1.67 mmol, 1.0 equiv.) in THF (3 ml_) and h½0 (1 mL) was added NBS (296 mg, 1.67 mmol, 1.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at room temperature for 1 h. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0→40% ethyl acetate/petroleum ether) to yield the (S)-2- bromo-1-(3-fluoro-2-((tetrahydrofuran-3-yl)amino)pyridin-4-y l)ethan-1-one as a yellow oil. LC/MS: mass calculated for CnHi2BrFN202: 302.01, measured (ES, m/z): 303.00, 305.00 [M+H, M+H+2]*. Step 4: 2-(3-Fluoro-2-(((S)-tetrahydrofuran-3-yl)amino)pyridin-4-yl) -2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a- hexahydroindolizine-3-carboxylate.

To a solution of (3S,8aR)-7-(6-amino3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (357 mg, 1.10 mmol, 1.0 equiv.) in ACN (13 mL) was added K2CO3 (304 mg, 2.20 mmol, 2.0 equiv.) at room temperature. After stirring for 30 min, (S)-2-bromo-1-(3-fluoro-2- ((tetrahydrofuran-3-yl)amino)pyridin-4-yl)ethan-1-one (400 mg, 1.32 mmol, 1.2 equiv.) was added. The resulting mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→5% MeOH/DCM) to yield the 2-(3-fluoro-2- (((S)-tetrahydrofuran-3-yl)amino)pyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C2eH25CIF2N405: 546.15, measured (ES, m/z): 547.35 [M+H] ⁺ . Step 5: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro-2-(( (S)- tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one. To a solution of 2-(3-fluoro-2-(((S)-tetrahydrofuran-3-yl)amino)pyridin-4- yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fiuorophenyl)-5-oxo-1,2,3,5,8 ,8a- hexahydroindolizine-3-carboxylate (20 mg, 0.037 mmol, 1.0 equiv.) in toluene (1 ml_) and HOAc (0.05 mL) was added NH4OAC (56 mg, 0.73 mmol, 20.0 equiv.). The resulting mixture was stirred at 100 °C for 2 h, then concentrated. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro-2-(( (S)- tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C2eH25CIF2Ne02: 526.17, measured (ES, m/z): 527.35 [M+H]*.

Step 6: (3S,8aR*)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 -(5-(3- fluoro-2-(((S)-tetrahydro1uran-3-yl)amino)pyridin-4-yl)-1H-i midazol-2-yl)- 2,3,8, 8a-tetrahydroindolizin-5(1H)-one.

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro- 2-(((S)-tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-imidazol -2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (413 mg, 0.78 mmol, 1.0 equiv.) in AcOH (15 mL) was added azidotrimethylsilane (1.8 g, 15.68 mmol, 20.0 equiv.), followed by addition of trimethoxymethane (1.7 g, 15.68 mmol, 20.0 equiv.). The resulting mixture was stirred at 80 °C for 3 h, then concentrated. The residue was purified by reversed phase chromatography on C18 column (MeCN/hbO

(0.05%NH4HC03): 0→45%) and prep-chiral HPLC to yield the (3S,8aR*)-7-(3- chloro-2-fluoro-6-( 1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(((S)- tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C27H24CIF2N9O2: 579.17, measured: 580.20 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 6 12.11 (s, 1H), 9.81 (s, 1H), 7.95 (dd, J = 8.7, 7.8 Hz, 1H), 7.78 (d, J = 5.3 Hz, 1H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.41 (dd, J = 3.9, 1.9 Hz, 1H), 7.11- 7.13 (m, 1H), 6.55 (dd, J = 6.1, 1.6 Hz, 1H), 5.66 (d, J = 2.7 Hz, 1H), 5.01 (d, J = 8.6 Hz, 1H), 4.37 - 4.52 (m, 1H), 3.77 - 3.94 (m, 2H), 3.62 - 3.77 (m, 3H), 3.55 (dd, J = 8.7, 4.6 Hz, 1H), 2.71- 2.73 (m, 1H), 2.02

- 2.27 (m, 3H), 1.82 - 2.01 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.86, - 142.49. Example 74: (3S,8aS*)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (3-fluoro-2-(((S)-tetrahydrofuran-3-yl)amino)pyridin-4-yl)-1 H-imidazol-2-yl)- 2,3,8, 8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C27H24CIF2N9O2: 597.17, measured: 598.20 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 12.11 (s, 1H), 9.81 (s, 1H), 7.95 (dd, J = 8.7, 7.8 Hz, 1H), 7.78 (d, J = 5.3 Hz, 1H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.41 (dd, J = 3.9, 1.9 Hz, 1H), 7.11- 7.13 (m, 1H), 6.55 (dd, J = 6.1, 1.6 Hz, 1H), 5.66 (d, J = 2.7 Hz, 1H), 5.01 (d, J = 8.6 Hz, 1H), 4.37 - 4.52 (m, 1H), 4.11- 4.18 (m, 1H), 3.77 - 3.94 (m, 3H), 3.62 - 3.76 (m, 1H), 3.55 (dd, J = 8.7, 4.6 Hz, 1H),

2.71- 2.73 (m, 1H), 2.42 - 2.49 (m, 1H), 2.18- 2.34 (m, 2H), 1.82 - 2.01 (m, 2H), 1.73- 1.79 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -113.05, -142.51.

Example 75: [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- pyridyQmethyl (2S)-2-amino-3-methyl-butanoate

LC/MS: mass calculated for C2SH28CIF2N9O3: 623.20, measured: 624.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.32 (brs, 1H), 9.84 (s, 1H), 8.37 (d, J = 5.0 Hz, 1H), 7.88 - 8.03 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 3.9 Hz, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.19 - 5.39 (m, 2H), 5.04 (d, J = 8.8 Hz, 1H), 3.64 - 3.81 (m, 1H), 3.19 (d, J = 5.2 Hz, 1H), 2.63 - 2.82 (m, 1H), 2.53 - 2.61 (m, 1H), 2.05 - 2.30 (m, 3H), 1.78 - 2.05 (m, 4H), 0.87 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -112.87, -128.90.

Example 76: (3S*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(4- fluoro-5-(3-fluoro-2-(((S)-tetrahydrofuran-3-yl)amino)pyridi n-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C27H23CIF3N9O2: 597.16, measured: 598.15 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 6 12.39 (s, 1H), 9.82 (s, 1H), 7.95 (dd, J

= 8.7, 7.8 Hz, 1H), 7.82 (d, J = 5.4 Hz, 1H), 7.70 (dd, J = 8.7, 1.5 Hz, 1H), 6.77 - 6.86 (m, 1H), 6.65- 6.69 (m, 1H), 5.65 (d, J = 2.2 Hz, 1H), 4.98 (d, J = 8.6 Hz, 1H), 4.41 - 4.52 (m, 1H), 3.78 - 3.94 (m, 2H), 3.62 - 3.75 (m, 2H), 3.56 (dd, J = 8.8, 4.6 Hz, 1H), 2.53 (d, J = 5.3 Hz, 2H), 2.03 - 2.23 (m, 3H), 1.84 - 2.00 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.88, -127.01, -142.75.

Example 77: (3R*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(4- fluoro-5-(3-fluoro-2-(((S)-tetrahydrofuran-3-yl)amino)pyridi n-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C27H23CIF3N9O2: 597.16, measured: 598.20 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 12.48 (s, 1H), 9.82 (s, 1H), 7.95 (dd, J = 8.7, 7.8 Hz, 1H), 7.82 (d, J = 5.3 Hz, 1H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 6.82 (dd, J = 6.1, 1.7 Hz, 1H), 6.64- 6.66 (m, 1H), 5.67 (d, J = 2.7 Hz, 1H), 4.94- 4.97 (m, 1H), 4.38 - 4.52 (m, 1H), 3.94 - 4.07 (m, 1H), 3.77 - 3.92 (m, 2H), 3.63 - 3.74 (m, 1H), 3.55 (dd, J = 8.8, 4.6 Hz, 1H), 2.50 - 2.55 (m, 1H), 2.26 - 2.38 (m, 2H), 2.07 - 2.25 (m, 2H), 1.84 - 2.00 (m, 2H), 1.59 - 1.75 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -113.06, -127.13, -142.57.

Example 78: (3R*,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 - ( 5-(3-fluoro-2-(4H-1, 2, 4-triazol-4-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H18CIF2N11O: 561.14, measured: 562.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.42 (s, 1 H), 9.83 (s, 1 H), 9.12 (d, J = 1.5 Hz, 2 H), 8.37 (d, J = 5.1 Hz, 1 H), 8.00 - 8.07 (m, 1 H), 7.91 - 8.00 (m, 1

H), 7.64 - 7.74 (m, 2 H), 5.65 - 5.71 (m, 1 H), 4.99 - 5.08 (m, 1 H), 3.70 - 3.90 (m, 1 H), 2.60 - 2.70 (m, 1 H), 2.52 - 2.57 (m, 1 H), 2.15 - 2.26 (m, 1 H), 2.06 - 2.14 (m, 1 H), 1.89 - 1.99 (m, 2 H). ¹⁸ F NMR: (376 MHz, DMSO-de) δ -112.84, - 132.82. Example 79: (3S,8aR)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-3-[5-[3-fluoro -2- [(2-hydroxy-1,1-dimethyl-ethyl)amino]-4-pyridyl]-1H-imidazol -2-yl]- 2,3,8,8a-tetrahydro-1H-indolizin-5-one

LC/MS: mass calculated for C27H27CIFN9O2: 563.20, measured: 564.25 [Μ+ΗΓ. ¹ H NMR: (400 MHz, Methanol-cU) 69.59 (s, 1H), 7.85 - 7.99 (m, 1H), 7.79 - 7.84 (m, 1H), 7.45 - 7.78 (m, 3H), 7.50 - 7.60 (m, 1H), 5.85 (d, J = 2.5 Hz, 1H), 5.22 (d, J = 8.9 Hz, 1H), 3.90 - 4.00 (m, 1H), 3.78 (s, 2H), 2.35 - 2.59 (m, 3H), 2.15 - 2.29 (m, 2H), 1.92 - 2.05 (m, 1H), 1.49 (s, 6H). ¹⁹ F NMR: (376 MHz, Methanol-d ₄ ) 6 -77.25.

Example 80: (3S,8aR)-7-[5-chloro-2-(tetrazol-1 -yl)phenyl]-3-[4-fluoro-5-[3- fluoro-2-(hydroxymethyl)-4-pyridyl]-1H-imidazol-2-yl]-2,3,8, 8a-tetrahydro-

1H-indolizin-5-one

LC/MS: mass calculated for C24H19CIF2N8O2: 524.13, measured: 525.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.59 (brs., 1H), 9.85 (s, 1H), 8.38 (d, J = 5.1 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 1.6 Hz, 2H), 7.49 - 7.51 (m, 1H), 5.56 (d, J = 2.4 Hz, 1 H), 5.36 - 5.41 (m, 1 H), 5.03 (d, J = 8.6 Hz, 1 H), 4.64 (dd, J =

5.7, 2.4 Hz, 2H), 3.60 - 3.80 (m, 1H), 2.31 - 2.46 (m, 1H), 1.79 - 2.31 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -125.71, -130.38.

Example 81: 6-[2-[(3S,8aR)-7-[5-chloro-2-[4-(trifluoromethyl)triazol-1- yl]phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-4-fluoro-1 H- imidazol-5-yl]-3,4-dihydro-1H-quinolin-2-one

LC/MS: mass calculated for C2SH22CIF4N7O2: 611.15, measured: 612.10

[M+H] ⁺ . ¹ H-NMR: (400 MHz, Methanol-cU) 69.00 (d, J = 1.0 Hz, 1 H), 7.63 -

7.72 (m, 3H), 7.32 - 7.42 (m, 2 H), 6.92 (d, J = 8.2 Hz, 1 H), 5.71 (d, J = 2.7 Hz, 1 H), 5.06 (d, J = 8.9 Hz, 1H), 3.76 - 3.89 (m, 1 H), 3.01- 3.03 (m, 2 H), 2.69 -

2.84 (m, 1 H), 2.57 - 2.66 (m, 2 H), 2.21 - 2.38 (m, 2 H), 1.97 - 2.20 (m, 3 H).

¹⁹ F NMR: (376 MHz, Methanol-d*) 6 -62.34, -77.00, -137.84.

Example 83: (3S,8aR)-3-[5-[6-(3-bicyclo[1.1.1]pentanylamino)-2-fluoro-3- pyridyl]-1H-imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phen yl]-2, 3,8,8a- tetrahydro-1 H-indolizin-5-one LC/MS: mass calculated for C28H2sCIFNsO: 557.19, measured: 558.20 [M+H]*. ¹ H NMR: (400 MHz, Methanol-cU): δ 9.56 (s, 1H), 8.05 (s, 1H), 7.61 - 7.71 (m, 3H), 7.11 (s, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.74 (s, 1H), 5.14 (d, J = 8.9 Hz, 1 H), 3.75 - 3.87 (m, 1 H), 2.62 - 2.75 (m, 1 H), 2.45 (s, 1 H), 2.33 - 2.42 (m, 1 H), 2.21 - 2.32 (m, 1 H), 2.09 - 2.21 (m, 8H), 1.85 - 2.03 (m, 1 H). ¹⁸ F NMR:

(376 MHz, Methanol-d ₄ ): δ -71.58.

Example 84: (3S,8aR)-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-3-[4-fluoro-5- [3- fluoro-2-[(2-hydroxy-2-methyl-propyl)amino]-4-pyridyl]-1H-im idazol-2-yl]- 2,3,8,8a-tetrahydro-1H-indolizin-5-one

LC/MS: mass calculated for C27H26CIF2N8O2: 581.19, measured: 582.25 [M+H] ⁺ . ¹ H-NMR: (400 MHz, Methanol-cU) δ 9.46 (s, 1 H), 7.51 - 7.68 (m, 4 H), 6.62 - 6.71 (m, 1 H), 5.60 (d, J = 2.8 Hz, 1 H), 5.02 (d, J = 8.5 Hz, 1 H), 3.66 - 3.79 (m, 1 H), 3.36 (s, 2 H), 2.52 - 2.63 (m, 1 H), 2.24 - 2.32 (m, 1 H), 2.02 - 2.22 (m, 3 H), 1.82 - 1.96 (m, 1 H), 1.14 (s, 6 H). ¹⁸ F NMR (376 MHz, Methanol- cU) δ -129.59, -147.43.

Example 85: (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-3-[5-[2- (triazol-1 -yl)-4-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H-indolizin-

5-one

LC/MS: mass calculated for C25H18CIFN11O: 543.14, measured: 544.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.25 (s, 1H), 9.83 (s, 1H), 8.86 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.42 (d, J = 1.5 Hz, 1H), 7.95-8.01 (m, 3H), 7.85 (d, J = 5.2 Hz, 1H), 7.68 - 7.79 (m, 1H), 5.68 (d, J = 2.7 Hz, 1H), 5.03 (d, J = 8.9 Hz, 1H), 3.67-3.75 (m, 1H), 2.75-2.85 (m, 1H), 2.52-2.56 (m, 1H), 2.18-2.27 (m, 1H), 2.08-2.13 (m, 1H), 1.92-2.00 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.71.

Example 86: (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-3-[5-[2- (triazol-2-yl)-4-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H-indolizin-

5-one

LC/MS: mass calculated for C25H19CIFN11O: 543.14, measured: 544.10 [M+H]÷. ¹ H NMR (400 MHz, DMSO-de) δ 12.22 (s, 1H), 9.83 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 8.17 (s, 2H), 7.93 - 8.01 (m, 2H), 7.80 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 5.67 (d, J = 2.7 Hz, 1H), 5.02 (d, J = 8.8 Hz, 1H), 3.67 - 3.78 (m, 1H), 2.77 - 2.85 (m, 1H), 2.52 - 2.57 (m, 1H), 2.17 -2.27 (m, 1H), 2.10 -2.15 (m, 1H), 1.92 - 2.02 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO- de) δ -112.66.

Example 87: (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4- fluoro-5-[2-(triazol-2-yl)-4-pyridyl]-1H-imidazol-2-yl]-2,3, 8,8a-tetrahydro-

1H-indolizin-5-one

LC/MS: mass calculated for C25H18CIF2N11O: 561.14, measured:562.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 13.21 (s, 1H), 9.85 (s, 1H), 8.55 (d, J = 5.3 Hz, 1H), 8.19 - 8.24 (m, 3H), 7.98 - 8.02 (m, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 5.3 Hz, 1H), 5.68 (d, J = 1.4 Hz, 1H), 4.95 (d, J = 8.4 Hz, 1H), 3.66 - 3.80 (m, 1H), 2.52 - 2.58 (m, 2H), 2.20 - 2.28 (m, 1H), 2.10 - 2.17 (m, 1H), 1.99 - 2.08 (m, 1H), 1.90 - 1.96 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 - 112.93, -124.95.

Example 88: (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4- fluoro-5-(2-pyrazol-1 -yl-4-pyridyl)-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one

LC/MS: mass calculated for C2eHieCIF2NioO: 560.14, measured: 561.15 [Μ+ΗΓ. ¹ H NMR (300 MHz, DMSO-de) 6 13.19 (s, 1H), 9.85 (s, 1H), 8.64 (d, J = 2.6 Hz, 1H), 8.46 (d, J = 5.4 Hz, 1H), 8.15 (s, 1H), 7.98 - 8.03 (m, 1H), 7.86 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 5.2 Hz, 1H), 6.60 (dd, J = 2.6, 1.7 Hz, 1H), 5.68 (s, 1H), 4.91 - 5.00 (m, 1H), 3.67 - 3.78 (m, 1H), 2.52 - 2.58 (m, 2H), 2.19 - 2.27 (m, 1H), 2.10 - 2.16 (m, 1H), 2.00 - 2.07 (m, 1H), 1.90 - 1.99 (m, 1H). ¹⁸ F NMR (282 MHz, DMSO-de) 6 -112.93, -125.31.

Example 89: (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-3-[5-[3- fluoro-2-[(2-hydroxy-1,1-dimethyl-ethyl)amino]-4-pyridyl]-1H -imidazol-2- yl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one

Step 1: 2-(3-Fluoro-2-(n-(1-hydroxy-2-methylpropan-2-yl)acetamido)py ridin-4- yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (0.25 g, 0.77 mmol, 1.0 equiv.) in ACN (10 mL) was added potassium carbonate (0.14 g, 1.00 mmol,

2.0 equiv.). After the reaction mixture was stirred at room temperature for 0.5 h, N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N-(1-((tert-butyl dimethylsilyl)oxy)-2- methylpropan-2-yl)acetamide (0.50 g, 1.08 mmol, 1.4 equiv.) was added. The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by silica gel chromatography with MeOH/DCM (0→10%) to yield 2-(3-fluoro-2-(n-(1-hydroxy-2-methylpropan- 2-yl)acetamido)pyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate. LC/MS: mass calculated for C28H29CIF2N40e: 590.17, measured (ES, m/z): 591.15 [M+H] ⁺ . Step 2: N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2, 3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 -yl)-n-(1-hydroxy-2- methylpropan-2-yl)acetamide.

To a solution of 2-(2-(n-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan- 2-yl)acetamido)-3-fluoropyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro- 2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-car boxylate (0.22 g, 0.38 mmol, 1.0 equiv.) in toluene (5 ml_) and acetic acid (0.25 mL) was added ammonium acetate (0.58 g, 7.57 mmol, 20.0 equiv.). The reaction mixture was stirred at 100 °C for 1 h, concentrated under vacuum. The residue was purified by silica gel chromatography (0→10% DCM/MeOH) to yield N-(4-(2-((3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-3-fluoropyridin-2-yl)-N-(1-hydroxy-2-methylpr opan-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C2eH2eCIF2NeC>3: 570.20, measured (ES, m/z): 571.25 [M+H] ⁺ .

Step 3: N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2-yl)-n-

(1-hydroxy-2-methylpropan-2-yl)acetamide.

To a solution of N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fl uoropyridin-2-yl)-n- (1-hydroxy-2-methylpropan-2-yl)acetamide (0.10 g, 0.18 mmol, 1.0 equiv.) in acetic acid (5 mL) was added azidotrimethylsilane (0.20 g, 1.75 mmol, 10.0 equiv.), then, tert-butyl nitrite (0.18 g, 1.75 mmol, 10.0 equiv.) was slowly added. The reaction mixture was stirred at 40 °C overnight. The solvent was removed under reduced pressure and the residue was diluted with DCM, washed with NaHCOa water, filtered and concentrated to yield N-(4-(2-((3S)-7- (3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 -yl)-n-(1-hydroxy-2- methylpropan-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for CagHaaCIFaNgOa: 623.20, measured (ES, m/z): 624.30 [M+H] ⁺ .

Step 4: N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fl uoropyridin-2-yl)-n- (1-hydroxy-2-methylpropan-2-yl)acetamide.

To a solution of N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)-n-(1-hydroxy-2-methylpropan-2-yl)acetami de (0.12 g, 0.19 mmol, 1.0 equiv.) in THF (3 mL) was added 2 M HCI (3 ml_). The reaction mixture was stirred at 60 °C for 1 h. The pH value of the solution was adjusted to 7 ~ 8 with NaHCOa solution, extracted with EA, the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse column chromatography on C18 column (CHaCN/water (0.05% TFA): 5→70%) to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-((1-hydroxy-2-methylpropan-2-yl)amino)pyridin-4- yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for Ca7HaeCIFaNgOa: 581.19, measured: 582.25 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-dt) 69.48 (s, 1H), 7.67 - 7.85 (m, 3H), 7.38 - 7.50 (m, 2H), 5.67 (d, J = 2.7 Hz, 1H), 5.11 (d, J = 8.6 Hz, 1H), 3.76 - 3.89 (m, 1H), 3.66 (s, 2H), 2.47 - 2.79 (m, 2H), 2.01 - 2.33 (m, 3H), 1.81 - 1.98 (m, 1H), 1.38 (s, 6H). ¹⁸ F NMR (282 MHz, Methanol-cU) 6 -77.34, -113.67, -

137.09.

Example 90: (3S*,8aR)-3-(5-(2-amino-3-fluoropyridin-4-yl)-1 H-imidazol-2- yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-

5(1H)-one

Step 1: 2-(2-Acetamido-3-fluoropyridin-4-yl)-2-oxoethyl (8aR)-7-(5-chloro-2- (1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoli zine-3-carboxylate.

To a solution of (8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (2.0 g, 5.56 mmol, 1.0 equiv.) in ChkCN (20 mL) was added K2CO3 (1.2 g, 8.34 mmol, 1.5 equiv.). After stirring at room temperature for 0.5 h, N-(4-(2-bromoacetyl)-3- fluoropyridin-2-yl)acetamide (2.3 g, 8.34 mmol, 1.5 equiv.) was added to the mixture. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the 2-(2-acetamido-3- fluoropyridin-4-yl)-2-oxoethyl (8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C25H21CIFN7O5: 553.13, measured (ES, m/z): 554.05 [M+H] ⁺ .

Step 2: N-(4-(2-((8aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo -

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3 -fluoropyridin-2- yl)acetamide.

To a solution of 2-(2-acetamido-3-fluoropyridin-4-yl)-2-oxoethyl (8aR)-7- (5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5, 8,8a-hexahydroindolizine-3- carboxylate (2.5 g, 4.51 mmol, 1.0 equiv.) in toluene (30 mL) and acetic acid (3 mL) was added ammonium acetate (5.2 g, 67.70 mmol, 15.0 equiv.). The mixture was stirred at 100 °C for 1 h. The solvent was removed under vacuum and the residue was purified by silica gel column with MeOH/DCM (0→10%) to yield n-(4-(2-((8aR)-7-(5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H21CIFN9O2: 533.15, measured (ES, m/z): 534.40 [M+H] ⁺ .

Step 3: (3S*,8aR)-3-(5-(2-Amino-3-fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(5- chloro-2-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one.

To a solution of n-(4-(2-((8aR)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)acetamide (1.3 g, 2.44 mmol, 1.0 equiv.) in THF (10 mL) was added HCI (10 mL, 20 mmol, 2 M, 8.2 equiv.). The mixture was stirred at 50 °C for 2 h. The solvent was removed under vacuum and the residue was purified by C18 column [condition: ACN-water-6.5 mM NH4HCO3+NH3H2O (5→50%)] to yield a residue. The residue was purified by chiral HPLC [column: CHIRALART cellulose-SB, 4.6*100mm, 3um,; mobile phase A:MtBE ( 0.1%DEA): EtOH=70:30 , mobile phase B:; flow rate:1 mL/min] to yield (3*S,8aR)-3-(5-(2- amino-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(5-chloro-2- (1H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as an off-white solid.

LC/MS: mass calculated for C23H19CIFN9O: 491.14, measured: 492.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.05 (s, 1H), 9.84 (s, 1H), 7.74 - 7.83 (m, 4H), 7.43 (d, J = 3.6 Hz, 1H), 7.12- 7.16 (m, 1H), 6.03 (s, 2H), 5.61 (d, J = 2.6 Hz, 1 H), 5.01 (d, J = 8.6 Hz, 1 H), 3.64 - 3.78 (m, 1 H), 2.54 - 2.59 (m, 1 H), 2.28 - 2.39 (m, 1H), 2.11 - 2.23 (m, 1H), 1.83 - 2.09 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -142.41.

Example 92: 7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4-fluoro-5- [3- fluoro-2-(1 ,2,4-triazol-1 -yl)-4-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-

1H-indolizin-5-one

LC/MS: mass calculated for C25H17CIF3N11O: 579.13, measured: 580.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.81 (s, 1 H), 9.81 (s, 1 H), 9.20 (s, 1 H), 8.41 (d, J = 5.2 Hz, 1 H), 8.34 (s, 1 H), 7.90 - 7.99 (m, 1 H), 7.65 - 7.73 (m, 2 H), 5.66 (d, J = 1.8 Hz, 1 H), 5.03 (d, J = 8.7 Hz, 1 H), 3.64 - 3.76 (m, 1 H),

2.50 - 2.58 (m, 2 H), 2.26 - 2.03 (m, 2 H), 1.88 - 2.01 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.89, -123.46, -131.53.

Example 93: (3S,8aR)-3-(5-(2-(1H-pyrazol-1-yl)pyridin4-yl)-1H-imidazol-2 - yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for CaehfeoCIFNioO: 542.15, measured (ES, m/z): 543.20 [M+H]* ¹ H NMR (300 MHz, DMSO-de) δ 12.19 (s, 1H), 9.84 (s, 1H), 8.59 - 8.65 (m, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.26 (s, 1H), 7.94 - 8.02 (m, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.80 - 7.87 (m, 1H), 7.63 - 7.77 (m, 2H), 6.54 - 6.61 (m, 1H), 5.68 (d, J = 2.6 Hz, 1H), 5.03 (d, J = 8.6 Hz, 1H), 3.66 - 3.77 (m,

1H), 2.71 - 2.88 (m, 1H), 2.53 - 2.58 (m, 1H), 2.19 - 2.28 (m, 1H), 2.08 - 2.14 (m, 1H), 1.94 - 2.03 (m, 2H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -112.60. Example 94 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2-(3,3-difluoroazetidine-1-carbonyl)-3-fluoropyridin-4-yl)- 1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C27H20CIF4N9O2: 613.14, measured (ES, m/z): 614.10 [M+H]* ¹ H NMR (400 MHz, DMSO-de) δ 12.37 (s, 1H), 9.84 (s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 8.10 (t, J = 5.3 Hz, 1H), 7.98 (t, J = 8.2 Hz, 1H), 7.68 - 7.75 (m, 1H), 7.62 - 7.68 (m, 1H), 5.71 (d, J = 2.6 Hz, 1H), 5.04 (d, J = 8.8 Hz, 1H), 4.69 - 4.80 (m, 2H), 4.49 - 4.60 (m, 2H), 3.70 - 3.79 (m, 1H), 2.67 - 2.74 (m, 1H), 2.53 - 2.56 (m, 1H), 2.17 - 2.25 (m, 1H), 2.08 - 2.13 (m, 1H), 1.90 - 2.00 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -100.09, -112.87, -125.46. Example 957-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(7- hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-1 H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one ΰ

F

.NH

LC/MS: mass calculated for C27H24CIFN8O2: 546.17, measured (ES, m/z): 547.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.72 - 9.80 (m, 1H), 8.36 (d, J = 5.3 Hz, 1H), 7.88 - 7.92 (m, 1H), 7.53 - 7.70 (m, 3H), 5.61 - 5.66 (m,

1H), 4.98 - 5.03 (m, 1H), 3.78 - 3.82 (m, 1H), 3.27 - 3.36 (m, 1H), 3.04 - 3.15 (m, 1H), 2.88 - 2.96 (m, 1H), 2.64 - 2.73 (m, 1H), 2.07 - 2.22 (m, 4H), 1.87 - 1.98 (m, 2H), 1.45 (d, J = 4.2 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.43, -112.95.

Example 96: (3S,8aR)-3-(5-(2-(Bicyclo[1.1.1]pentan-1-ylamino)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(5-chloro-2-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1 : 2-(2-(N-(bicyclo[1.1.1]pentan-1-yl)acetamido)-3-fluoropyridi n-4-yl)-2- oxoethyl (3S,8aR)-7-(2-amino-5-chlorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (3S)-7-(2-amino-5-chlorophenyl)-5-oxo1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid (0.22 g, 0.72 mmol, 1.0 equiv.) in MeCN (10 mL) was added potassium carbonate (0.20 g, 1.43 mmol, 2.0 equiv.). After the mixture was stirred for 30 min, N-(bicyclo[1.1.1]pentan-1-yl)-n-(4-(2- bromoacetyl)-3-fluoropyridin-2-yl)acetamide (0.37 g, 1.08 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at room temperature for 2 h, then concentrated under vacuum. The residue was purified by silica gel chromatography with MeOH/DCM (0→10%) to yield 2-(2-(n- (bicyclo[1.1.1]pentan-1-yl)acetamido)-3-fluoropyridin-4-yl)- 2-oxoethyl (3S)-7-(2- amino-5-chlorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine -3-carboxylate as a light yellow solid. LC/MS: mass calculated for C28H28CIFN4O5: 566.17, measured (ES, m/z): 567.15 [M+H] ⁺ .

Step 2: N-(4-(2-((3S)-7-(2-amino-5-chlorophenyl)-5-oxo-1 ,2,3,5, 8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 -yl)-n- (bicyclo[1.1.1]pentan-1-yl)acetamide.

To a solution of 2-(2-(n-(bicyclo[1.1.1]pentan-1-yl)acetamido)-3- fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(2-amino-5-chlorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (0.27 g, 0.48 mmol, 1.0 equiv.) in toluene (15 mL) was added ammonium acetate (0.73 g, 9.52 mmol, 20.0 equiv.) followed by the addition of acetic acid (0.5 mL) under N2. The reaction mixture was stirred for 1.5 h at 100 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography with MeOH/DCM (0—10%) to yield N-(4-(2-((3S)-7-(2-amino- 5-chlorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)- 1H-imidazol-5-yl)- 3-fluoropyridin-2-yl)-n-(bicyclo[1.1.1]pentan-1-yl)acetamide as a light yellow solid. LC/MS: mass calculated for C29H28CIFN6O2: 546.19, measured (ES, m/z): 547.35 [M+H] ⁺ .

Step 3: N-(bicyclo[1.1.1]pentan-1-yl)-n-(4-(2-((3S)-7-(5-chloro-2-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-3- fluoropyridin-2-yl)acetamide.

To a solution of N-(4-(2-((3S)-7-(2-amino-5-chlorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fl uoropyridin-2-yl)-n- (bicyclo[1.1.1]pentan-1-yl)acetamide (0.15 g, 0.27 mmol, 1.0 equiv.) in acetic acid (10 mL) were added trimethoxymethane (0.29 g, 2.74 mmol, 10.0 equiv.), and TMSNs (0.32 g, 2.74 mmol, 10.0 equiv.). The resulting mixture was stirred overnight at 50 °C, then concentrated under vacuum to yield N-

(bicyclo[1.1.1]pentan-1-yl)-n-(4-(2-((3S)-7-(5-chloro-2-( 1 H-tetrazol-1-yl)phenyl)- 5-oxo-1,2 _l 3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-3- fluoropyridin-2- yl)acetamide as a light yellow solid. LC/MS: mass calculated for C30H27CIFN9O2: 599.20, measured (ES, m/z): 600.25 [M+H] ⁺ .

Step 4: (3S,8aR)-3-(5-(2-(Bicydo[1.1.1]pentan-1-ylamino)-3-fluoropyr idin-4-yl)- 1 H-imidazol-2-yl)-7-(5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of N-(bicydo[1.1.1]pentan-1-yl)-n-(4-(2-((3S)-7-(5-chloro-2- (1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-4-yl)-3-fluoropyridin-2-yl)acetamide (0.15 g, 0.25 mmol, 1.0 equiv.) in THF (5mL) was added 2M HCI (5 mL). The mixture was stirred for 5 h at 70 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by reverse column chromatography with ACN-Water-5 mM NH4HCO3 (5— >60%) to yield (3S,8aR)-3-(5-(2-(bicydo[1.1.1]pentan-1-ylamino)- 3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-te trazol-1-yl)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C28H25CIFN9O: 557.19, measured (ES, m/z): 558.15 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*): δ 9.46 (s, 1H), 7.71 (d, J =

5.4 Hz, 1H), 7.52 - 7.62 (m, 3H), 7.35 (s, 1H), 7.07 (s, 1H), 5.66 (s, 1H), 5.07 (d, J = 8.8 Hz, 1H), 3.67 - 3.80 (m, 1H), 2.48 - 2.68 (m, 1H), 2.34 (s, 1H), 2.20 - 2.29 (m, 1H), 2.13 - 2.23 (m, 1H), 2.00 - 2.13 (m, 8H), 1.77 - 1.94 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-cU): δ -144.42.

Example 97: 6-(2-((3S,8aR)-7-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3- triazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5, 8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-3,4-dihydroquinolin-2(1H)-one

LC/MS: mass calculated for C28H23CIF3N7O2: 593.16, measured (ES, m/z): 594.20 [M+H]* ¹ H NMR (400 MHz, Methanol-d*) 68.86 - 9.00 (m, 1 H), 7.61 - 7.70 (m, 3 H), 7.37 - 7.41 (m, 2 H), 7.19 (s, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 5.73 (d, J = 2.7 Hz, 1 H), 5.02 - 5.09 (m, 1 H), 3.56 - 3.78 (m, 1 H), 2.84 -

2.93 (m, 2 H), 2.58 - 2.71 (m, 1 H), 2.44 - 2.52 (m, 2 H), 2.17 - 2.27 (m, 2 H), 1.98 - 2.13 (m, 2 H), 1.85 - 1.92 (m, 1 H). ¹⁹ FNMR: (376 MHz, Methanol-d*) δ - 62.48.

Example 98: (3S*,8aR)-7-(5-chloro-2-(1 H-tetrazol-1 -y l)phenyl)-3-(5-(2- fluoro-6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8, 8a- tetrahydroindolizin-5(1 H)-one

•N ^/

LC/MS: mass calculated for C24H21CIFN8O: 505.15, measured (ES, m/z): 506.15 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) δ 11.70 (s, 1H), 9.84 (s, 1H), 8.06 (s, 1H), 7.74 - 7.80 (m, 3H), 6.99 - 7.06 (m, 1H), 6.83 (s, 1H), 6.42 (dd, J = 8.4, 2.1 Hz, 1H), 5.62 (d, J = 2.6 Hz, 1H), 4.98 (d, J = 8.5 Hz, 1H), 3.62 - 3.77 (m,

1H), 2.75 (d, J = 4.8 Hz, 3H), 2.42 - 2.53 (m, 1H), 2.26 - 2.37 (m, 1H), 2.08 - 2.21 (m, 1H), 1.82 - 2.06 (m, 3H). ¹⁶ F NMR (376 MHz, DMSO-de) δ -70.44. Example 99: Methyl (4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)pyridin-2-yl)carbamate

LC/MS: mass calculated for C25H21CIFN9O3: 549.14, measured (ES, m/z): 550.15 [M+H] ^{+ 1} H NMR (300 MHz, DMSO-de) δ 12.03 (s, 1H), 10.01 (s, 1H), 9.81 (s, 1H), 8.11 - 8.21 (m, 2H), 7.89 - 8.00 (m, 1H), 7.61 -7.79 (m, 2H), 7.35 (d, J = 5.3 Hz, 1 H), 5.65 (d, J = 2.5 Hz, 1 H), 4.99 (d, J = 8.6 Hz, 1 H), 3.66

(s, 4H), 2.70 - 2.85 (m, 1 H), 2.51 - 2.54 (m, 1 H), 2.04 - 2.23 (m, 2H), 1.90 -1.99 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.50.

Example 100 1-(4-(2-((3S*,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)azetidine-3-carbonitrile

LC/MS: mass calculated for C27H21CIF2N10O: 574.16, measured (ES, m/z): 575.15 [M+H] ^{+ 1} H NMR (300 MHz, DMSO-de) δ 12.21 (s, 1H), 9.84 (s, 1H), 7.91- 8.02 (m, 2H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H), 7.49 (d, J = 3.5 Hz, 1H),

7.25 - 7.39 (m, 1H), 5.69 (d, J = 2.7 Hz, 1H), 5.03 (d, J = 8.5 Hz, 1H), 4.31 - 4.42 (m, 2H), 4.15 - 4.27 (m, 2H), 3.82 - 3.93 (m, 1H),3.69 - 3.79 (m, 1H), 2.66 - 2.82 (m, 1H), 2.52 - 2.56 (m, 1H), 2.05 - 2.26 (m, 2H),1.87 - 2.05 (m, 2H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -112.85, -142.54.

Example 101 6-(2-((3S,8aR)-7-(5-chloro-2-(4-(trifluoiOmethyl)-1H-1,2,3- triazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5, 8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)quinolin-2(1 H)-one

LC/MS: mass calculated for C28H21CIF3N7O2: 591.14, measured (ES, m/z): 592.20 [M+H] ^{+ 1} H NMR (300 MHz, Methanol-d*) δ 9.02 (d, J = 1.0 Hz, 1 H), 7.97 - 8.07 (m, 2 H), 7.91 (dd, J = 8.6, 1.9 Hz, 1 H), 7.65 - 7.72 (m, 3 H), 7.35 - 7.44 (m, 2 H), 6.65 (d, J = 9.5 Hz, 1 H), 5.78 (d, J = 2.7 Hz, 1 H), 5.20 (d, J = 8.7 Hz, 1 H), 3.78 - 3.97 (m, 1 H), 2.68 - 2.86 (m, 1 H), 2.30 - 2.44 (m, 2 H), 2.12 - 2.39 (m, 2 H), 1.95 - 2.09 (m, 1 H). ¹⁹ FNMR: (282 MHz, Methanol-ck) δ - 62.54.

Example 102 l-(4-(2-((3R*,8aR)-7-(3-chloro-2-fluoiO-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)azetidine-3-carbonitrile

LC/MS: mass calculated for C27H21CIF2N10O: 574.16, measured (ES, m/z): 575.15 [M+H] ^{+ 1} H NMR (300 MHz, DMSO-de) 6 12.36 (s, 1H), 9.84 (s,

1H), 7.86 - 8.03 (m, 2H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.50 (d, J = 3.9 Hz, 1H), 7.29 - 7.36 (m, 1 H), 5.70 (d, J = 2.5 Hz, 1 H), 4.95 - 5.05 (m, 1 H), 4.31 - 4.42

(m, 2H), 4.15 - 4.26 (m, 2H), 4.03 - 4.14 (m, 1H), 3.82 - 3.96 (m, 1H), 2.41 - 2.46 (m, 1H), 2.15 - 2.49 (m, 3H), 1.92 - 2.11(m, 1H), 1.61 - 1.79 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -113.05, -142.49.

Example 103: 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- N- methoxy-pyridine-2-carboxamide

To a mixture of 4-(2-((3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropicolinic acid (37 mg, 0.07 mmol), O-methylhydroxyamine hydrochloride (8.5 mg, 0.1 mmol), and EDCI (19.5 mg, 0.1 mmol) was added pyridine (3 ml). The resulting mixture was maintained stirring at room temperature for 3 h. The solvent was removed under reduced pressure and the residue was purified by HPLC to yield 4-[2-[(3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl] -5-oxo- 2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-5-yl]-3-fluoro-N-methoxy- pyridine-2-carboxamide as a white solid.

¹ H NMR (400 MHz, METHANOL-d4) δ 9.50 (s, 1H), 8.40-8.48 (m, 1H), 7.97 (t, J=5.14 Hz, 1H), 7.82 (d, J=2.93 Hz, 1H), 7.74 (t, J=8.31 Hz, 1H), 7.47 (d, J=8.31 Hz, 1H), 5.64-5.69 (m, 1H), 5.14-5.21 (m, 1H), 3.81-3.95 (m, 1H), 3.75 (s, 3H), 2.77-2.90 (m, 1H), 2.55-2.64 (m, 1H), 2.30-2.43 (m, 1H), 2.10-2.25 (m, 2H), 1.86-2.01 (m, 1H). LC/MS calculated for C25H20CIF2N9O3567.14, measured 568.2 (MH ⁺ ).

Example 104 N-(bicyclo[1.1.1]pentan-1-yl)-4-(2-((3S,8aR)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizin-3- yl)-1H-imidazol-5-yl)-3-fluoropicolinamide

LC/MS: mass calculated for C29H24CIF2N9O2: 603.17, measured (ES, m/z): 604.10 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) δ 12.33 (s, 1H), 9.84 (s, 1H), 9.10 (s, 1H), 8.39 (d, J = 5.0 Hz, 1H), 8.04 - 8.11 (m, 1H), 7.93 - 8.01 (m,

1H), 7.71 (d, J = 8.7 Hz, 1H), 7.60 - 7.66 (m, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.04 (d, J = 8.8 Hz, 1H), 3.72 - 3.78 (m, 1H), 2.66 - 2.75 (m, 1H), 2.54 - 2.56 (m,

1H), 2.46 (s, 1H), 2.16 - 2.26 (m, 1H), 2.07 - 2.13 (m, 7H), 1.91 - 1.99 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.84, -126.53. Example 105 (3S,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-(2-oxopyrrolidiri-1-yl)pyridin-4-yl)-1H-imidazol -2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

N cr

N·

LC/MS: mass calculated for C27H22CIF2N9O2: 577.16, measured (ES, m/z): 578.15 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) δ 12.43 (s, 1H), 9.83 (s, 1H), 8.23 (d, J = 5.1 Hz, 1H), 7.94 - 8.01 (m, 1H), 7.86 (t, J = 5.2 Hz, 1H), 7.70 (dd, J = 8.7, 1.5 Hz, 1H), 7.58 (d, J = 4.0 Hz, 1H), 5.70 (d, J = 2.6 Hz, 1H), 5.02 (t, J = 7.5 Hz, 1H), 4.08 - 4.19 (m, 1H), 3.90 (t, J = 7.0 Hz, 2H), 2.52 - 2.55 (m, 1H), 2.46 - 2.49 (m, 2H), 2.32 - 2.44 (m, 2H), 2.21 - 2.28 (m, 1H), 2.10 - 2.19 (m, 2H), 1.96 - 2.06 (m, 1H), 1.67 - 1.75 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO- de) δ -113.05, -126.03.

Example 106 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-(2-oxopyiTolidin-1-yl)pyridin-4-yl)-1H-imidazol- 2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 1-(3-Fluoro-4-iodopyridin-2-yl)pyrrolidin-2-one.

To a mixture of methyl 4-((3-fluoro-4-iodopyridin-2-yl)amino)butanoate (720 mg, 2.13 mmol, 1.0 equiv.) in THF (120 mL) was added NaHMDS (2.6 mL, 2.60 mmol, 1.2 equiv.) at -78 °C under N2. The reaction mixture was stirred at room temperature for 2 h. The reaction was then quenched by the addition of NH4CI, extracted with EtOAc (3 x 300 mL), dried over NaaSO*. concentrated. The residue was applied onto a silica gel column (EtOAc/PE:0→70%) to yield 1-(3-fluoro-4-iodopyridin-2-yl)pyrrolidin-2-one as a light yellow oil. LC/MS: mass calculated for C9H8FIN2O: 305.97, measured (ES, m/z): 306.90 [M+H]*.

Step 2: 1-(4-(1-Ethoxyvinyl)-3-fluoropyridin-2-yl)pyrrolidin-2-one.

To a solution of 1-(3-fluoro-4-iodopyridin-2-yl)pyrrolidin-2-one (530 mg, 1.73 mmol, 1.0 equiv.) in 1,4-dioxane (8 mL) were added tributyl(1- ethoxyvinyl)stannane (938 mg, 2.60 mmol, 1.5 equiv.) and Pd(dppf)Ch (121 mg, 0.17 mmol, 0.1 equiv.) The mixture was stirred 2 h at 95 °C under an atmosphere of N2 (balloon). The reaction mixture was cooled to room temperature. The resulting solution was extracted with water (5 mL) and ethyl acetate (20 x 3 mL). The organic layers were combined, washed with sodium carbonate (aq.) and brine, dried and concentrated under vacuum. The residue was applied on a AI2O3 column and eluted with ethyl acetate/hexane (1/3) to yield 1-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)pyrrolidin-2-one. LC/MS: mass calculated for C13H15FN2O2: 250.11, measured (ES, m/z): 251.10 [M+H]*.

Step 3: 1-(4-(2-BiOmoacetyl)-3-fluoiOpyridin-2-yl)pyrrolidin-2-one. To a solution of 1-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)pyrrolidin-2-one (427 mg, 1.70 mmol, 1.0 equiv.) in THF/H2O 4 mL (3:1) was slowly added NBS (455 mg, 2.56 mmol, 1.5 equiv.) and the resulting mixture was stirred at 0 °C for 30 min. The mixture was concentrated under vacuum. The resulting residue was dissolved by the addition of H2O. The resulting solution was extracted with of ethyl acetate (3 x 15mL). The organic layers were combined, washed with brine, dried and concentrated under vacuum to yield 1-(4-(2-bromoacetyl)-3- fluoropyridin-2-yl)pyrrolidin-2-one as a yellow oil. LC/MS: mass calculated for CiiHioBrFN ₂ 02: 299.99, measured (ES, m/z):301.10, 303.10 [M+H, M+H+2]*. Step 4: 2-(3-Fluoro-2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate.

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.92 mmol, 1.0 equiv.) in DMF (5 mL) was added 1-(4-(2-bromoacetyl)-3-fluoropyridin-2- yl)pyrrolidin-2-one (417 mg, 1.39 mmol, 1.5 equiv.), followed by addition of CS2CO3 (180 mg, 0.55 mmol, 0.6 equiv.). The reaction mixture was stirred at room temperature overnight, then partitioned between water and ethyl acetate (3 x 15 mL). The organic layers were combined, washed with sodium carbonate (aq.) and brine, dried and concentrated under vacuum. The residue was applied on a silica gel column and eluted with MeOH/DCM (0→10%) to yield of 2-(3-fluoro-2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate as an off-white solid. LC/MS: mass calculated for CtthtaCIFalvUOs: 544.13, measured (ES, m/z):545.30 [M+H] ⁺ .

Step 5: (3S,8aR)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro- 2-(2- oxopynOlidin-1-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-t etrahydroindolizin-

5(1H)-one.

To a solution of 2-(3-fluoro-2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (260 mg, 0.48 mmol, 1.0 equiv.) in AcOH/toluene 6 mL (5:1) was added CH3COONH4 (735 mg, 9.54 mmol, 20.0 equiv.). The reaction mixture was stirred 2 h at 110 °C. The excess solvent was removed under reduced pressure. The residue was applied on a silica gel column and eluted with MeOH/DCM (0→10%) to yield (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-3-(5-(3-fluoro-2-(2-oxopyrrolidin-1-y l)pyridin-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C26H23CIF2N4O5: 524.15, measured (ES, m/z):525.30 [M+H] ⁺ .

Step 6: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro- 2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3, 8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro- 2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3, 8,8a- tetrahydroindolizin-5(1H)-one (200 mg, 0.38 mmol, 1.0 equiv.) in AcOH (2 ml_) was added trimethoxymethane (2 mL) followed by TMSN3 (2 mL). The resulting solution was stirred at room temperature overnight. The residue was applied onto a prep-HPLC (80 g, MeOH/H ₂ 0 (0.05%NH4HC0 ₃ ): 0→55%) to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3-fluoro-2-(2- oxopyrrolidin-1-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin- 5(1H)-one as a white solid.

LC/MS: mass calculated for C27H22CIF2N9O2: 577.16, measured (ES, m/z): 578.15 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) 6 12.29 (s, 1H), 9.84 (s, 1H), 8.25 (d, J = 5.1 Hz, 1H), 7.97 (t, J = 8.2 Hz, 1H), 7.88 (t, J = 5.3 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.57 (s, 1H), 5.70 (s, 1H), 5.04 (d, J = 8.5 Hz, 1H),

3.80 - 3.92 (m, 2H), 3.70 - 3.79 (m, 1H), 2.66 - 2.76 (m, 1H), 2.51 - 2.56 (m, 3H), 2.09 - 2.24 (m, 4H), 1.91 - 2.00 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -

112.83, -126.08.

Example 107: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3- (4-fluoro-5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imid azol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a mixture of (3S,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)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one (250 mg, 0.48 mmol, 1.0 equiv.) and pyridine (377 mg, 4.77 mmol, 10.0 equiv.) in THF (7 ml_) and ACN (21 mL) under N ₂ was added F-TEDA (236 mg, 0.67 mmol, 1.4 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then quenched with water (30 mL), extracted with EtOAc (3 x 30 mL), dried over NaaSO*. concentrated. The residue was applied onto a C18 reverse column (ACN/H2O (0.05%NhUHC03): 5%→42%→45%) to (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yljphenyl)-

3-(4-fluoro-5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H -imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a light yellow solid.

LC/MS: mass calculated for C24H18CIF3N8O2: 542.12, measured (ES, m/z): 543.10 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) δ 12.60 (s, 1H), 9.83 (s, 1H), 8.38 (d, J = 5.1 Hz, 1H), 7.92 - 8.00 (m, 1H), 7.71 (dd, J = 8.7 Hz, 1.5Hz,

1H), 7.44 - 7.52 (m, 1H), 5.68 (d, J = 2.1 Hz, 1H), 5.34 (t, J = 6.0 Hz, 1H), 5.03 (d, J = 8.6 Hz, 1H), 4.63 (dd, J = 6.0, 2.3 Hz, 2H), 3.63 - 3.82 (m, 1H), 2.53 - 2.66 (m, 2H), 2.16 - 2.28 (m, 1H), 2.04 - 2.16 (m, 1H), 1.88 - 2.03 (m, 2H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -112.89, -125.70, -130.37. Example 108 (3S*,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-

(5-(3-fluoro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin- 4-yl)-1H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1 : 2-(3-Fluoro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl )-2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1, 2,3,5, 8, 8a-hexahydroindolizine-3-carboxylic acid (180 mg, 0.47 mmol, 1.0 equiv.) in DMF (5 ml_) was added K2CO3 (131 mg, 0.95 mmol, 2.0 equiv.).

After stirring at room temperature for 0.5 h, 2-bromo-1-(3-fluoro-2-(2-oxa-6- azaspiro[3.3]heptan-6-yl)pyridin-4-yl)ethan-1-one (450 mg, 1.43 mmol, 3.0 equiv.) was added. The mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→7% MeOH/DCM) to yield the 2-(3-fluoro-2-(2-oxa-6-azaspiro[3.3]heptan-6- yl)pyridin-4-yl)-2-oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate as a yellow oil. LC/MS: mass calculated for C28H24CIF2N7O5: 611.15, measured (ES, m/z):612.35 [M+H] ⁺ .

Step 2: (3S*,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 -(5-(3- fluoro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of 2-(3-fluoro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4- yl)-2-oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (150 mg, 0.25 mmol, 1.0 equiv.) in toluene (10 mL) and acetic acid (1 mL) was added ammonium acetate (378 mg, 4.90 mmol, 20.0 equiv.). The mixture was stirred at 100 °C for 1 h. The residue was purified by reverse phase chromatography on C18 column with CH3CN/0.05% TFA water (5→50%) to yield a second residue, which was purified by Chiral-HPLC with MtBE (0.1%DEA):EtOH=70:30 to yield (3*S,8aR)- 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-flu oro-2-(2-oxa-6- azaspiro[3.3]heptan-6-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one as an off-white solid.

LC/MS: mass calculated for C28H24CIF2N9O2: 591.17, measured (ES, m/z): 592.15 [M+H] ^{+ 1} H NMR (400 MHz, DMSOde) 6 12.17 (s, 1H), 9.83 (s, 1 H), 7.93 - 8.00 (m, 1H), 7.86 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.44 - 7.47 (m, 1H), 7.22 - 7.29 (m, 1H), 5.68 (d, J = 2.7 Hz, 1H), 5.01 (d, J = 8.7 Hz, 1H), 4.73 (s, 4H), 4.21 - 4.27 (m, 4H), 3.65 - 3.78 (m, 1H), 2.64 - 2.83 (m, 1H), 2.53 - 2.57 (m, 1H), 2.14 - 2.29 (m, 1H), 2.04 - 2.13 (m, 1H), 1.88 - 2.01 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.85, -142.71.

Example 109 (3*R,8aR)-3-(5-(2-(1 -((tert- butyldimethylsilyl)oxy)cyclopropyl)-3~fluoropyridin-4-yl)~4- fluoro~1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

*R

F

Cl·

R

N

>

LC/MS: mass calculated for C26H20CIF3N8O2: 568.13, measured (ES, m/z): 569.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.59 (s., 1H), 9.83 (s, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.92 - 8.00 (m, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.40 - 7.44 (m, 1H), 6.15 (s, 1H), 5.67 (d, J = 2.1 Hz, 1H), 5.00 - 5.08 (m, 1H), 3.65 - 3.79 (m, 1H), 2.07 - 2.28 (m, 2H), 1.87 - 2.03 (m, 2H), 1.20 - 1.25 (m,

2H), 1.08 - 1.17 (m, 2H), 0.97 - 1.06 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -112.88, 125.91, -126.75.

Example 110 (3*R,8aR)-3-(5-(2-(azetidin-1-yl)-3-fluoropyridm-4-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eH22CIF2NgO: 549.16, measured (ES, m/z): 550.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.33 (s, 1H), 9.84 (s, 1 H), 7.93 - 8.03 (m, 1H), 7.85 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.47 (d, J = 3.9 Hz, 1H), 7.22 (s, 1H), 5.70 (d, J = 2.5 Hz, 1H), 4.93 - 5.05 (m, 1H), 4.01 - 4.18 (m, 5H), 2.52 - 2.56 (m, 1H), 2.23 -2.49 (m, 5H), 1.98 - 2.09 (m, 1H), 1.61 - 1.72 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -113.05, -142.65. Example 111 (3*S,8aR)-3-(5-(2-(azetidin-1-yl)-3-fluoropyridin-4-yl)-1H- imidazol-2-yl)-7-(3-chloiO-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 2-(2-(Azetidin- 1 -yl)-3-fluoropyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate.

7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic add (300 mg, 0.92 mmol, 1.0 equiv.) and potassium carbonate (192 mg, 1.39 mmol, 1.5 equiv.) were added to acetonitrile (20 mL). The mixture was stirred at room temperature for 0.5 h and then 1-(2-(azetidin-1-yl)-3-fluoropyridin-4-yl)-2-bromoethan-1-on e (378 mg,

1.39 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at room temperature for 4 h, diluted with water (50 mL), then extracted with EA (10.0 mL x 3). The organic layers were combined, washed with brine (50 mL), dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→20% MeOH/DCM) to yield the 2-(2-(azetidin- 1 -yl)-3- fluoropyridin-4-yl)-2-oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. C/MS: mass calculated for C25H23CIF2N4O4: 516.14, measured (ES, m/z):517.20 [M+H] ⁺ . Step 2: (3S,8aR)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(2-(azetid in-1-yl)-3- fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroind olizin-5(1H)-one.

2-(2-(Azetidin-1-yl)-3-fluoropyridin-4-yl)-2-oxoethyl 7-(6-amino-3-chloro- 2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (300 mg, 0.58 mmol, 1.0 equiv.), ammonium acetate (447 mg, 5.80 mmol, 10.0 equiv.) were dissolved in toluene (10 mL) and acetic acid (1 mL). The resulting mixture was stirred at 90 °C for 1 h, then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→20% MeOH/DCM) to yield 7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(azetidin-1-yl)- 3-fluoropyridin- 4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-o ne as a yellow oil. LC/MS: mass calculated for C2sH23CIF2NeO: 496.94, measured (ES, m/z):497.30 [M+H]*.

Step 3: (3*S,8aR)-3-(5-(2-(Azetidin-1-yl)-3-fluoropyridin-4-yl)-1 H-imidazol-2-yl)- 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-te trahydroindolizin- 5(1H)-one.

To a solution of 7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(azetidin-1- yl)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahy droindolizin-5(1H)-one (300 mg, 0.60 mmol, 1.0 equiv.) in acetic acid (4 ml_) was added azidotrimethylsilane (2 mL) and trimethoxymethane (2 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 column with (MeCN/HaO (0.05%): 0→40%) to yield a yellow solid, which was further purified by Chiral HPLC with MeOH:ACN:DCM=1:1:1(0.1% DBA) to yield (3S*,8aR)-3-(5-(2-(azetidin-1-yl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one.

LC/MS: mass calculated for CaeHaaCIFaNgO: 549.16, measured (ES, m/z): 550.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.17 (s, 1H), 9.83 (s, 1H), 7.92 - 8.02 (m, 1H), 7.86 (d, J = 5.2 Hz, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H),

7.40 - 7.50 (m, 1H), 7.25 (s, 1H), 5.69 (d, J = 2.5 Hz, 1H), 5.03 (d, J = 8.4 Hz, 1H), 4.03 - 4.14 (m, 4H), 3.62 - 3.81 (m, 1H), 2.65 - 2.81 (m, 1H), 2.50 - 2.52 (m, 1H), 2.29 - 2.39 (m, 2H), 2.05 - 2.26 (m, 2H), 1.88 -2.02 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -112.85, -142.72. Example 112 (3*R,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(3-fluoro-2-(1H-1,2,4-triazol-1-yl)pyridin-4-yl)-1H-imida zol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H18CIF2N11O: 561.14, measured (ES, m/z): 562.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.41 (s, 1 H), 9.83 (s, 1 H), 9.19 (s, 1 H), 8.37 - 8.45 (m, 1 H), 8.33 (s, 1 H), 8.06 - 8.12 (m, 1 H), 7.91 - 7.99 (m, 1 H), 7.67 - 7.74 (m, 2 H), 5.69 (d, J = 2.7 Hz, 1 H), 5.04 (d, J = 8.8

Hz, 1 H), 3.69 - 3.80 (m, 1 H), 2.65 - 2.77 (m, 1 H), 2.49 - 2.58 (m, 1 H), 2.14 -2.28 (m, 1 H), 2.03 -2.13 (m, 1 H), 1.87 - 2.02 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.83, -131.41.

Example 113: (3S,8aR)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-3-[4- deuterio-5-[2-[dideuterio(hydroxy)methyl]-3-fluoro-4-pyridyl ]-1H-imidazol-

2-yl]-2,3,8,8a-tetrahydro-1H-indolizin-5-one

To a mixture of (3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3-(5-(3-fluoro-2-(hydroxymethyl-d2)pyridin-4-yl)-4-iodo-1H-i midazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one (25 mg, 0.038 mmol) and Zn dust (25 mg, 0.38 mmol) was added CDaCOOD (1.5 g) and the mixture was stirred at room temperature for 2 h. The mixture was stirred for another 2 h and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by Gilson HPLC to yield (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4- deuterio-5-[2- [dideuterio(hydroxy)methyl]-3-fluoro-4-pyridyl]-1H-imidazol- 2-yl]-2,3,8,8a- tetrahydro-1H-indolizin-5-one as a light yellow solid.

LC/MS calculated for C24H19CIF2N8O2: 527.1, measured 528.3 (MH ⁺ ). ¹ H

NMR (400 MHz, METHANOL-d4) 69.62 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 7.85 (dd, J=7.83, 8.80 Hz, 1H), 7.58 (dd, J=1.71, 8.56 Hz, 1H), 5.77-5.85 (m, 1H), 5.21-5.30 (m, 1H), 3.96-4.13 (m, 1H), 2.75-2.88 (m, 1H), 2.66-2.73 (m, 1H), 2.35-2.45 (m, 1H), 2.27-2.33 (m, 1H), 2.16-2.24 (m, 1H), 2.02-2.12 (m, 1H). Example 1143-[4-[2-[(3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)p henyl]- 5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-imidazol-5-y l]-3-fluoro-2- pyridyl]oxazolidin-2-one

Step 1: 2-(3-Fluoro-2-(2-oxooxazolidin-3-yl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate.

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) in DMF (5 ml_), 3-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)oxazolidin-2- one (300 mg, 0.99 mmol, 1.5 equiv.), and K2CO3 (51 mg, 0.37 mmol, 0.6 equiv.) was stirred at room temperature overnight. The resulting solution was partitioned between water and ethyl acetate (3 x 15 mL). The organic layers were combined, washed with sodium carbonate (aq.) and brine, dried and concentrated under vacuum. The residue was applied on a silica gel column and eluted with MeOH/DCM (0→10%) to yield 2-(3-fluoro-2-(2-oxooxazolidin-3- yl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as an off-white solid. LC/MS: mass calculated for C2sH2iCIF2N40e: 546.11, measured (ES, m/z):547.30 [M+H]*.

Step 2: 3-(4-(2-((3S,8aR)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)oxazolidin-2-one.

A mixture of 2-(3-fluoro-2-(2-oxooxazolidin-3-yl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1, 2,3,5,8,8a- hexahydroindolizine-3-carboxylate (360 mg, 0.66 mmol, 1.0 equiv.) in AcOH/toluene (6 mL, 5:1) and CHaCOONH* (1.0 g, 12.99 mmol, 20.0 equiv.) was stirred 2 h at 110 °C. The reaction mixture was concentrated under vacuum. The residue was applied on a silica gel column and eluted with MeOH/DCM (1/10) to yield 3-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridi n-2- yl)oxazolidin-2-one as a yellow solid. LC/MS: mass calculated for C25H2iCIF ₂ Ne03: 526.13, measured (ES, m/z):527.30 [M+H] ⁺ .

Step 3: 3-[4-[2-[(3S,8aR)-7-[3-ChloiO-2-fluoro-6-(tetrazol-1-yl)phen yl]-5-oxo- 2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-5-yl]-3-fluoro-2- pyridyl]oxazolidin-2-one.

To a solution of 3-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridi n-2- yl)oxazolidin-2-one (130 mg, 0.25 mmol, 1.0 equiv.) in AcOH (2 mL) was added trimethoxymethane (2 mL) and TMSNs (2 mL). The resulting solution was stirred at room temperature overnight. The residue was purified by prep-HPLC on C18 column (MeOH/H ₂ 0 (0.05%ΝΗ ₄ Η003): 0→55%) to yield 3-(4-(2- ((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5 -oxo-1,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 -yl)oxazolidin-2-one as a white solid.

LC/MS: mass calculated for C2eH2oCIF2Ng03: 579.13, measured (ES, m/z): 580.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.32 (s, 1H), 9.84 (s, 1H), 8.25 (d, J = 5.1 Hz, 1H), 7.94 - 8.00 (m, 1H), 7.90 (t, J = 5.2 Hz, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.58 - 7.63 (m, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.05 (d,

J = 8.7 Hz, 1H), 4.55 (t, J = 7.7 Hz, 2H), 4.16 (t, J = 7.7 Hz, 2H), 3.71 - 3.78 (m, 1H), 2.67 - 2.76 (m, 1H), 2.54 - 2.56 (m, 1H), 2.16 - 2.25 (m, 1H), 2.07 - 2.14 (m, 1H), 1.94 - 1.99 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.84, -127.74.

Example 115 (3S,8a*R)-7-(3-chloiO-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 - (4-(3-fluoro-2-(1H-pyrazol-5-yl)pyridin-4-yl)-1H-imidazol-2- yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for CMHieCIFaNioO: 560.14, measured (ES, m/z): 561.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 13.10 - 13.69 (m, 1 H), 12.22 - 12.43 (m, 1 H), 9.85 (s, 1 H), 8.45 (s, 1 H), 7.79 - 8.04 (m, 2 H), 7.58 - 7.76 (m, 3 H), 6.85 (s, 1 H), 5.71 (d, J = 2.7 Hz, 1 H), 5.06 (d, J = 8.7 Hz, 1 H),

3.69 - 3.83 (m, 1 H), 2.64 - 2.83 (m, 1 H), 2.54 - 2.59 (m, 1 H), 2.07 - 2.29 (m, 2 H), 1.90 - 2.04 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.83, -124.93, - 126.03.

Example 116 (3*R,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(3-fluoro-2-(1-hydroxycyclopiOpyl)pyridin-4-yl)-1H-imidaz ol-2-yl-4-d)-

2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for CtthkoCIDFaNeCk: 551.15, measured (ES, m/z): 552.10 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 9.59 (s, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.99 (s, 1H), 7.80 - 7.87 (m, 1H), 7.56 (dd, J = 8.7, 1.6 Hz, 1H),

5.76 (s, 1H), 5.19 (d, J = 8.7 Hz, 1H), 3.87 - 4.00 (m, 1H), 2.82 - 2.95 (m, 1H), 2.55 - 2.70 (m, 1H), 2.31 - 2.40 (m, 1H), 2.16 - 2.30 (m, 2H), 2.00 - 2.15 (m,

1H), 1.20 - 1.26 (m, 2H), 1.13 - 1.19 (m, 2H). ¹⁹ F NMR (376 MHz, Methanol-d*) 6 -113.49, -127.60. Example 117 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-

(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl -4-d)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H18CIDF2N8O2: 525.14, measured (ES, m/z): 526.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.30 (brs, 1H), 9.84 (s, 1H), 8.30 - 8.40 (m, 1H), 7.95 - 8.01 (m, 1H), 7.89 (t, J = 5.4 Hz, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.13 - 5.50 (m, 1H), 5.05 (d, J = 8.7 Hz, 1H), 4.64 (d, J = 2.3 Hz, 2H), 3.65 - 3.83 (m, 1H), 2.62 - 2.83 (m, 1H), 2.53 - 2.60 (m, 1H), 2.05 - 2.30 (m, 2H), 1.83 - 2.04 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.51, -130.07.

Example 1186-(2-((3 ^w S,8a ^w R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-5- fluoro-1,4~dihydro-2H-benzo[d][1,3]oxazin-2-one

Step 1 : 2-(5-Fluoro-2-oxo-1,4-dihydro-2H-benzo[d][1 ,3]oxazin-6-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic add (200 mg, 0.62 mmol, 1.0 equiv.) in N,N- dimethylformamide (5 mL) was added cesium carbonate (220 mg, 0.68 mmol, 1.1 equiv.). To the resulting solution was added 6-(2-bromoacetyl)-5-fluoro-1 ,4- dihydro-2H-benzo[d][1 ,3]oxazin-2-one (267 mg, 0.92 mmol, 1.5 equiv.), and the resulting mixture was stirred at room temperature for 1.5 h, then diluted with water and extracted with ethyl acetate twice. The combined organic layers was washed with brine, dried over Na2S(X concentrated to yield 2-(5-fluoro-2-oxo- 1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6-yl)-2-oxoethyl 7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a yellow oil. LC/MS: mass calculated for C2sH2oCIF2N30e: 531.10, measured (ES, m/z): 532.15 [M+H]*. Step 2: 6-(2-((3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5 ,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-5-fluoro-1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-2-one

To a mixture of 2-(5-fluoro-2-oxo-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-6- yl)-2-oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (200 mg, 0.38 mmol, 1.0 equiv.) in toluene (3 ml_) and acetic acid (0.3 mL) was added ammonium acetate (290 mg, 3.76 mmol, 10.0 equiv.). The reaction mixture was stirred at 100 °C for 1.0 h and concentrated under vacuum. The residue was purified by reverse phase chromatography on C18 (ACN/H2O (0.05%CF ₃ COOH): 0→28%) to yield 6-(2- (7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexa hydroindolizin-3- yl)-1H-imidazol-5-yl)-5-fluoro-1,4-dihydro-2H-benzo[d][1,3]o xazin-2-one as a yellow solid. LC/MS: mass calculated for C25H20CIF2N5O3: 511.12, measured (ES, m/z): 512.25 [M+H]*.

Step 3: 6-(2-((3*S,8a*R)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-5-fluoro-1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-2-one.

To a mixture of 6-(2-(7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-5-fluoro-1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-2-one (140 mg, 0.27 mmol) in acetic acid (1.5 mL) were added trimethoxymethane (1.5 mL) and azidotrimethylsilane (1.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the resulting residue was purified by reverse phase chromatography on C18 (120 g, ACN/H2O (0.05%CF3COOH): 0→35%) to yield 100 a residue, which was further purified with prep-chiral-HPLC. This resulted in 6-(2-((3S,8aR)-7-(3-chloro-2-fiuoro-6-(1H-tetrazol-1-yl)phen yl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-5-fluoro-1 ,4- dihydro-2H-benzo[d][1,3]oxazin-2-one as a white solid. LC/MS: mass calculated for C2eHi9CIF2Ne03: 564.12, measured (ES, m/z): 565.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.92 (s, 1 H), 10.38 (s,

1 H), 9.84 (s, 1 H), 7.94 - 8.01 (m, 1 H), 7.86 - 7.93 (m, 1 H), 7.68 - 7.75 (m, 1 H), 7.21 - 7.26 (m, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 5.69 (d, J = 2.6 Hz, 1H), 5.43 (s, 2 H), 5.01 (d, J = 8.6 Hz, 1 H), 3.66 - 3.80 (m, 1 H),2.64 - 2.78 (m, 1 H), 2.51

- 2.56 (m, 1 H), 2.05 - 2.24 (m, 2 H), 1.87 - 2.04 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.87, -122.02.

Example 119 (3*R,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl-5-d)-1H- imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl-3-d)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H17CID2FN9O: 493.15, measured (ES, m/z): 494.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.71 (s, 1H), 9.84 (s, 1H), 7.95 - 8.10 (m, 1H), 7.65 - 7.82 (m, 2H), 7.03 (d, J = 3.8 Hz, 1H), 6.25 (s, 2H), 5.62 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 8.5 Hz, 1H), 3.63 - 3.78 (m, 1H), 2.41

- 2.47 (m, 1H), 2.24 - 2.37 (m, 1H), 2.07 - 2.20 (m, 1H), 1.83 - 2.06 (m, 3H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -70.83.

Example 120 (3*S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl-5-d)-1H- imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl-3-d)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H17CID2FN9O: 493.15, measured (ES, m/z): 494.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.83 (s, 1H), 7.94 (d, J = 10.4 Hz, 1H), 7.74 - 7.83 (m, 2H), 7.20 (s, 1H), 6.41 (s, 2H), 5.61 (d, J = 2.6 Hz, 1H), 5.00 (t, J = 7.5 Hz, 1H), 4.01 - 4.14 (m, 1H), 2.29 - 2.40 (m, 2H), 2.16 - 2.28 (m, 2H), 1.96 - 2.12 (m, 1H), 1.54 - 1.72 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) 6 -70.26, -73.44.

Example 121: (3*R,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl-3-d)-2,3,8,8a-tet rahydroindolizin-

5(1H)-one

LC/MS: mass calculated for C23H18CIDFN9O: 492.14, measured (ES, m/z): 493.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 11.69 (s, 1H), 9.84 (s, 1H), 8.00 - 8.11 (m, 1H), 7.72 - 7.81 (m, 2H), 6.90 - 7.07 (m 1H), 6.35 - 6.47 (m, 1H), 6.23 (s, 2H), 5.63 (d, J = 2.6 Hz, 1H), 4.98 (d, J = 8.5 Hz, 1H), 3.63 - 3.79 (m, 1H), 2.23 - 2.39 (m, 1H), 2.08 - 2.19 (m, 1H), 1.81 - 2.07 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -70.84.

Example 122 (3*S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl-3-d)-2,3,8,8a-tet rahydroindolizin-

5(1H)-one

LC/MS: mass calculated for C23H18CIDFN9O: 492.14, measured (ES, m/z): 493.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 11.91 (s, 1H), 9.83 (s, 1H), 7.95 - 8.05 (m, 1H), 7.64 - 7.86 (m, 2H), 7.04 (s, 1H), 6.37 (dd, J = 8.3, 2.1 Hz, 1H), 6.25 (s, 2H), 5.59 (d, J = 2.7 Hz, 1H), 4.97 (t, J = 7.1 Hz, 1H), 3.97 - 4.15 (m, 1H), 2.16 - 2.41 (m, 4H), 1.92 - 2.13 (m, 1H), 1.52 - 1.70 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -70.75.

Example 123 (3S,8aR)-3-[5-(6-amino-2-fluoro-3-pyridyl)-1 H-imidazol-2-yl]- 7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H- indolizin-5-one Step 1: Methyl (3S)-7-(2-amino-5-chlorophenyl)-5-oxo-1 ,2, 3,5,8,8a- hexahydroindolizine-3-carboxylate.

Under an inert atmosphere of nitrogen, a mixture of (3S)-methyl 5-oxo-7- (trifluoromethylsulfonyloxy)-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate (14.0 g, 40.78 mmol, 1.0 equiv.), 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzenamine (12.4 g, 48.91 mmol, 1.2 equiv.), K2CO3 (11.3 g, 81.76 mmol, 2.0 equiv.) and Pd(dppf)Ch (3.0 g, 4.10 mmol, 0.1 equiv.) in 1,4- dioxane (350 mL) and H2O (35 mL) was stirred at 90 °C for 2 h. After cooling to room temperature, the resulting mixture was diluted with EtOAc (800 mL), washed with water (3 x 200 mL), brine (2 x 200 mL), dried over N32S04, and concentrated under reduced pressure. The residue was applied onto a silica gel column (120g, MeOH/DCM: 0→5%) to yield (3S)-methyl 7-(2-amino-5- chlorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a brown solid. LC/MS: mass calculated for C16H17CIN2O3: 320.09, measured (ES, m/z): 321.05 [M+H]*. Step 2: (3S)-7-(2-Amino-5-chlorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic add.

To a solution of methyl (3S)-7-(2-amino-5-chlorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.5 g, 4.68 mmol, 1.0 equiv.) in THF/H2O (20 ml_/4 mL) was added LiOH (374 mg, 18.71 mmol, 4.0 equiv.). The reaction mixture was stirred at room temperature for 2 h, adjusted to pH 5 with HCI solution (2 N), then extracted by EA. The organic layer was concentrated under vacuum to yield (3S)-7-(2-amino-5-chlorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic add as a colorless oil. LC/MS: mass calculated for C15H15CIN2O3: 306.08, measured (ES, m/z): 307.05 [M+H]*. Step 3: 2-(6-Acetamido2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7-(2-amino-5- chlorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate.

To a solution of (3S)-7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic add (937 mg, 3.05 mmol, 1.2 equiv.) in CHaCN (10 mL) was added K2CO3 (351 mg, 2.55 mmol, 1.0 equiv.) followed by addition of N-(5-(2-bromoacetyl)-6-fluoropyridin-2-yl)acetamide (700 mg, 2.55 mmol, 1.0 equiv.). The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography to yield 2-(6-acetamido-2-fluoropyridin-3-yl)- 2-oxoethyl (3S)-7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C24H22CIFN4O5: 500.13, measured (ES, m/z): 501.10 [M+H] ⁺ .

Step 4: N-(5-(2-((3S)-7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2 -yl)acetamide.

Under an inert atmosphere of nitrogen, a mixture of (3S)-2-(6- acetamido-2-fiuoropyridin-3-yl)-2-oxoethyl 7-(2-amino-5-chlorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (7.0 g, 13.98 mmol, 1.0 equiv.) and NhUOAc (10.7 g, 138.81 mmol, 10.0 equiv.) in AcOH (30 mL) and toluene (300 mL) was heated at 110 °C with stirring for 1 h, then concentrated under reduced pressure. The residue was applied onto a silica gel column (120 g, MeOH/DCM: 1/15) to yield N-(5-(2-((3S)-7-(2-amino-5-chlorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2- yl)acetamide as a yellow solid. LC/MS: mass calculated for C24H22CIFNe02: 480.15, measured (ES, m/z): 481.15 [M+H] ⁺ . Step 5: N-(5-(2-((3S)-7-(5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2 -yl)acetamide.

To a solution of N-(5-(2-((3S)-7-(2-amino-5-chlorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2- yl)acetamide (365 mg, 0.76 mmol, 1.0 equiv.) in AcOH (4 mL) was added trimethoxymethane (2 mL), followed by addition of TMSN3 (2.0 mL). The resulting solution was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM/MeOH v/v 10:1) to yield N-(5-(2-((3S)-7-(5- chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizin-3-yl)- 1H-imidazol-5-yl)-6-fluoropyridirv2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H21CIFN9O2: 533.15, measured (ES, m/z): 534.05 [M+H]*.

Step 6: (3S,8aR)-3-[5-(6-Amino-2-fluoro-3-pyridyl)-1H-imidazol-2-yl] -7-[5- chloro-2-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indol izin-5-one.

A mixture of N-(5-(2-((3S)-7-(5-chloro-2-(2H-tetrazol-2-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2- yl)acetamide (345 mg, 0.65 mmol, 1.0 equiv.) in THF (8 mL) and 4 N HCI (8 mL) was stirred at 53 °C for 1.5 h. The mixture was concentrated under vacuum. The resulting residue was purified by prep-HPLC followed by chiral- HPLC to yield (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-y l)-7- (5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as an off-white solid.

LC/MS: mass calculated for C23H19CIFN9O: 491.14, measured (ES, m/z): 492.10 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 69.85 (s, 1H), 7.95 - 8.05 (m, 1H), 7.76-7.78 (m, 3H), 7.00-7.32 (m, 2H), 6.30 - 6.54 (m, 2H), 5.62 (s, 1H), 5.06 (d, J = 8.9 Hz, 1H), 3.66-3.75 (m, 1H), 2.58-2.66 (m, 1H), 2.29-2.36 (m, 1H), 2.15-2.26 (m, 1H), 1.97-2.06 (m, 2H), 1.85-1.94 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -70.37.

Example 124 (3S,8aR)-3-[5-(6-amino-5-deiiterio-2-fluoro-3-pyridyl)-1H- imidazol-2-yl]-7-[5-chloro-2-(tetrazol-1-yl)phenyl]-2,3,8,8a -tetrahydro-1H- indolizin-5-one

LC/MS: mass calculated for C23H18CIDFN9O: 492.14, measured (ES, m/z): 493.15 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 6 11.65 - 11.95 (m, 1H), 9.84 (s, 1H), 8.05 (d, J = 10.5 Hz, 1H), 7.75 - 7.78 (m, 3H), 7.00 - 7.08 (m, 1H), 6.23 (s, 2H), 5.63 (d, J = 2.6 Hz, 1H), 4.98 (d, J = 8.6 Hz, 1H), 3.65 - 3.74 (m, 1H), 2.43 - 2.48 (m, 1H), 2.28 - 2.33 (m, 1H), 1.85 - 2.18 (m, 4H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -70.85.

Example 125 (3S,8aR)-3-(4-(6-amino-2-fluoropyridin-3-yl-5-d)-1H-imidazol - 2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl-5-d)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23HieCID2F2NgO: 511.14, measured (ES, m/z): 512.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 11.77 (s, 1H), 9.84 (s, 1 H), 8.04 (d, J = 10.4 Hz, 1 H), 7.97 (d, J = 7.7 Hz, 1 H), 6.90 - 7.08 (m, 1 H),

6.15 - 6.50 (m, 2 H), 5.60 - 5.77 (m, 1 H), 4.98 (d, J = 8.6 Hz, 1 H), 3.57 - 3.86 (m, 1 H), 2.58 - 2.77 (m, 1 H), 2.40 - 2.45 (m, 1 H), 2.01 - 2.29 (m, 2 H), 1.85 - 2.02 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -70.81, -112.92.

Example 126 (3S,8aR)-3-(5-(2-amino-3-fluoropyridin-4-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

Step 1: 3-Fluoro-4-iodopyridin-2-amine.

To a solution of 2,3-difluoro-4-iodopyridine (1.8 g, 7.47 mmol, 1.0 equiv.) in DMSO (10 mL) was added ammonia hydrate (5 ml_). The resulting mixture was stirred at 80 °C overnight, diluted with water, and extracted with EA (3 * 20 mL). The organic layers were combined, washed with brine, dried over Na2S04 and concentrated under vacuum to yield 3-fluoro-4-iodopyridin-2-amine as a brown solid. LC/MS: mass calculated for C5H4FIN2: 237.94, measured (ES, m/z): 238.90 [M+H] ⁺ . Step 2: N-acetyl-n-(3-fluoro-4-iodopyridin-2-yl)acetamide.

A solution of 3-fluoro-4-iodopyridin-2-amine (2.0 g, 8.40 mmol, 1.0 equiv.) in AC2O (20 mL) was stirred at 60 °C for 36 h. The resulting mixture was diluted with water (20 mL) extracted with EA (3 ^χ 20 mL). The organic layers were combined, washed with brine, dried over NaaSO* and concentrated. The residue was purified by silica gel column chromatography (EA/PE 0-→100%) to yield N-acetyl-n-(3-fluoro-4-iodopyridin-2-yl)acetamide as a white solid. LC/MS: mass calculated for CyHeFINaO: 321.96, measured (ES, m/z): 322.85 [M+H] ⁺ . Step 3: N-(4-( 1 -ethoxy vinyl)-3-fluoropyridin-2-yl)acetamide.

A mixture of N-acetyl-N-(3-fluoro-4-iodopyridin-2-yl)acetamide (1.6 g, 4.88 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (2.6 g, 7.31 mmol, 1.5 equiv.) and Pd(PPh3)4 (563 mg, 0.49 mmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was heated at 90 °C with stirring under N2 overnight. The resulting mixture was concentrated and the residue was purified on neutral AI2O3 column (EA/PE, 0→15 %) to yield N-(5-(1 -ethoxyvinyl)-6-fluoropyridin-2-yl-4-d)acetamide as a light yellow solid. LC/MS: mass calculated for C11H13FN2O2: 224.10, measured (ES, m/z): 225.05 [M+H]*.

Step 4: N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)acetamide.

A mixture of N-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)acetamide (750 mg, 3.35 mmol, 1 equiv.) and NBS (298 mg, 1.67 mmol, 0.5 equiv.) in THF/H2O

(V/V=3:1, 6 mL) was stirred at room temperature for 30 min. The resulting mixture was diluted with water (10 mL), extracted with EA (3 ^χ 10 mL). The organic layers were combined, dried over N32S04 and concentrated to yield a light yellow liquid of N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)acetamide. LC/MS: mass calculated for CeHeBrFteC^: 273.98, measured (ES, m/z): 274.90, 276.90 [M+H, M+H+2]*.

Step 5: 2-(2-Acetamido-3-fluoropyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate.

A mixture of (3S,8aR)-7-(6-amino-3-chloro-2-fiuorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) in DMF (5 mL) was added cesium carbonate (100 mg, 0.31 mmol, 0.5 equiv.). The resulting mixture was stirred at room temperature for 30 min. Then N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)acetamide (213 mg, 0.92 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at room temperature overnight, diluted with water, and extracted with EA (3 ^χ 20 mL). The organic layers were combined, washed with brine, dried over Na ₂ S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM, 0→8%) to yield 2-(2-acetamido-3- fluoropyridin-4-yl)-2-oxoethyl (3R,8aS)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C24H21CIF2N4O5: 518.12, measured (ES, m/z): 519.10 [M+H]*.

Step 6: N-(4-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3 -fluoropyridin-2- yl)acetamide.

To a mixture of 2-(2-acetamido-3-fluoropyridin-4-yl)-2-oxoethyl (3R,8aS)- 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexah ydroindolizine-3- carboxylate (216 mg, 0.42 mmol, 1.0 equiv.) and ammonium acetate (321 mg, 4.16 mmol, 10.0 equiv.) in toluene (4 mL) was added acetic add (1 ml_). The resulting mixture was stirred at 100 °C for 1 h. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column (MeOH/DCM, 0→10%) to yield N-(4-(2-((3S,8aR)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5-yl)-3- fluoropyridin-2-yl)acetamide as a yellow oil. LC/MS: mass calculated for C24H2iCIF ₂ Ne02: 498.14, measured (ES, m/z): 499.10 [M+H] ⁺ .

Step 7: N-(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)acetamide.

A mixture of N-(4-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridi n-2- yl)acetamide (150 mg, 0.30 mmol, 1.0 equiv.), trimethoxymethane (2 mL), azidotrimethylsilane (2 mL) and acetic acid (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to yield N-(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H20CIF2N9O2: 551.14, measured (ES, m/z): 552.10 [M+H] ⁺ .

Step 8: (3S,8aR)-3-(5-(2-Amino-3-fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 Hi- one.

To a solution of N-(4-(2-((3R,8aS)-7-(3S-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)acetamide (140 mg, 0.25 mmol, 1.0 equiv.) in THF (2 mL) was added HCI (1 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reversal phase chromatography on C18 (MeCN/hkO (0.05%CF3COOH)) to yield (3R,8aS)-3-(5-(2-amino-3-fluoropyridin-4-yl)-1H-imidazol-2-y l)-7-(3-chloro- 2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid. The racemic product (60 mg) was separated by chiral-HPLC to yield (3R,8aS)-3-(5-(2-amino-3-fluoropyridin-4-yl)-1H-imidazol-2-y l)-7-(3-chloro- 2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-oneas a white solid.

LC/MS: mass calculated for C23H18CIF2N9O: 509.13, measured (ES, m/z): 510.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.05 - 12.27 (m, 1H), 9.84 (s, 1 H), 7.97 (t, J = 8.2 Hz, 1 H), 7.67 - 7.76 (m, 2 H), 7.45 (d, J = 3.8 Hz, 1 H), 6.99 - 7.17 (m, 1 H), 6.12 (s, 2 H), 5.69 (d, J = 2.5 Hz, 1 H), 5.03 (d, J = 8.4 Hz, 1 H), 3.60 - 3.80 (m 1 H), 2.62 - 2.84 (m, 1 H), 2.50 - 2.60 (m, 1 H), 2.08 - 2.26 (m, 2 H), 1.93 - 2.02 (m, 2 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ - 112.86, -142.19.

Example 127 (3S*,8aS*)-3-(5-(2-((S*)-1-(1,3,4-oxadiazol-2-yl)ethoxy)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C27H21CIF2N10O3: 606.15, measured (ES, m/z): 607.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.83 (s, 1 H), 9.24 (s, 1 H), 7.89 - 8.01 (m, 2 H), 7.63 - 7.76 (m, 2 H), 7.48 - 7.61 (m, 1 H), 6.49 (q, J = 6.7 Hz, 1H), 5.67 (d, J = 2.6 Hz, 1 H), 5.08 (d, J = 8.8 Hz, 1 H), 3.64 - 3.80 (m,

1 H), 2.71 - 2.87 (m, 1 H), 2.55 - 2.64 (m, 1 H), 2.04 - 2.34 (m, 2 H), 1.85 - 2.03 (m, 2 H), 1.76 (d, J = 6.7 Hz, 3 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -142.45, - 112.77.

Example 128 (3S*,8aR*)-3-(5-(2-{(S*)-1 -(1 ,3,4-oxadiazol-2-yl)ethoxy)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

NyO

U

N-N S* N

'NT O j

Ό

F

Cl

LC/MS: mass calculated for C27H21CIF2N10O3: 606.15, measured (ES, m/z): 607.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.81 (s, 1 H), 9.23 (s, 1 H), 7.85 - 8.00 (m, 2 H), 7.63 - 7.76 (m, 1 H), 7.52 - 7.64 (m, 2H), 6.48 (q, J =

6.6 Hz, 1H), 5.67 (d, J = 2.5 Hz, 1 H), 5.02 (d, J = 8.4 Hz, 1 H), 3.63 - 3.81 (m,

1 H), 2.62 - 2.79 (m, 2 H), 2.03 - 2.29 (m, 2 H), 1.87 - 2.02 (m, 2 H), 1.75 (d, J =

6.7 Hz, 3 H). ¹⁶ F NMR (282 MHz, DMSO-de) δ -143.01, -112.86.

Example 129 (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl- 4-d)-7-(3-chloro-2-f1uoro-6-(1 H-tetrazol-1 -yl)phenyl-5-d)-2, 3, 8, 8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H16D2CIF2N9O: 511.14, measured (ES, m/z): 512.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.58 - 11.97 (m, 1 H), 9.81 (s, 1 H), 8.03 (dd, J = 10.5, 8.2 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 6.39 (dd, J = 8.2, 2.3 Hz, 1 H), 6.22 (s, 2 H), 5.60 - 5.72 (m, 1 H), 4.97 (d, J = 8.4 Hz, 1 H), 3.62 - 3.72 (m, 1 H), 2.61 - 2.74 (m, 1 H), 2.49 - 2.53 (m, 1 H), 2.03 - 2.16 (m, 2 H), 1.92 - 1.98 (m, 2 H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -70.83, - 112.88.

Example 130 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (3-fluoro-2-(oxetan-3-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 3-Fluoro-2-(oxetan-3-yl)pyridine.

A mixture of 2-bromo-3-fluoropyridine (2.0 g, 11.37 mmol, 1.0 equiv.), 3- bromooxetane (1.9 g, 13.64 mmol, 1.2 equiv.), sodium iodide (0.43 g, 2.84 mmol, 0.25 equiv.), zinc powder (1.5 g, 22.73 mmol, 2.0 equiv.), pyridine-2, 6- bis(carboximidamide) (0.093 g, 0.57 mmol, 0.05 equiv.), NiCl2(dry) (0.11 g, 0.57 mmol, 0.05 equiv.) and TFA (0.13 g, 1.14 mmol, 0.1 equiv.) in DMAc (30 mL) was stirred at 60 °C under N2 atmosphere for 15 h. The resulting mixture was filtered out. The filtrate was diluted with water, extracted with EA (3 X 30 mL). The organic layers were combined and washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel column (EA/PE, 0→30%) to yield 3-fluoro-2-(oxetan-3-yl)pyridine as a light yellow oil. LC/MS: mass calculated for CeHeFNO: 153.06, measured (ES, m/z): 154.10 [M+H] ⁺ . Step 2: 3-Fluoro-4-iodo-2-(oxetan-3-yl)pyridine.

To a solution of 3-fluoro-2-(oxetan-3-yl)pyridine (370 mg, 2.42 mmol, 1.0 equiv.) in THF (10 mL) was dropwise added LDA (1.6 mL, 3.14 mmol, 1.3 equiv.) under -65 °C. The mixture was stirred at that temperature for 30 min. To the resulting mixture was then added I2 (920 mg, 3.62 mmol, 1.5 equiv.) in THF (3 mL). The resulting mixture was stirred for additional 1 h, diluted with water, and extracted with EA (3 ^χ 20 mL). The organic layers were combined, washed with brine and dried over N32S04 and concentrated. The residue was purified by flash silica gel column EA/PE (0→80%) to yield 3-fluoro-4-iodo-2-(oxetan-3- yl)pyridine as an off-white solid. LC/MS: mass calculated for CsHyFINO: 278.96, measured (ES, m/z): 279.95 [M+H]*.

Step 3: 4-(1-Ethoxyvinyl)-3-fluoro-2-(oxetan-3-yl)pyridine.

A mixture of 3-fluoro-4-iodo-2-(oxetan-3-yl)pyridine (278 mg, 1.00 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (540 mg, 1.49 mmol, 1.5 equiv.) and

Pd(PPh3)4 (115 mg, 0.10 mmol, 0.1 equiv.) in 1,4-dioxane (5 mL) was refluxed at 90 °C under N2 overnight. The resulting mixture was concentrated. The residue was purified by flash column chromatography on neutral AI2O3 column (EA/PE, 0→15%) to yield 4-(1-ethoxyvinyl)-3-fluoro-2-(oxetan-3-yl)pyridine as a colorless oil. LC/MS: mass calculated for C12H14FNO2: 223.10, measured (ES, m/z): 224.05 [M+H] ⁺ .

Step 4: 2-Bromo-1-(3-fluoro-2-(oxetan-3-yl)pyridin-4-yl)ethan-1-one.

A mixture of 4-(1-ethoxyvinyl)-3-fluoro-2-(oxetan-3-yl)pyridine (600 mg, 2.69 mmol, 1.0 equiv.) and MBS (239 mg, 1.34 mmol, 0.5 equiv.) in THF/H2O (V/V= 6 mL) was stirred at room temperature for 30 min. The resulting mixture was diluted with water (10 mL), extracted with EA (3 ^χ 10 mL). The organic layers were combined, dried over N32S04 and concentrated to yield a light yellow liquid of 2-bromo-1-(3-fluoro-2-(oxetan-3-yl)pyridin-4-yl)ethan-1-one. LC/MS: mass calculated for C12H14FNO2: 272.98, measured (ES, m/z): 273.90, 275.90 [M+H, Μ+Η+2Γ·

Step 5: 2-(3-Fluoro-2-(oxetan-3-yl)pyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate. To a mixture of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) in DMF (5 mL) was added cesium carbonate (120 mg, 0.37 mmol, 0.6 equiv.). The resulting mixture was stirred at room temperature for 30 min. To the resulting mixture was then added 2-bromo-1-(3-fluoro-2-(oxetan-3- yl)pyridin-4-yl)ethan-1-one (253 mg, 0.92 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature overnight, diluted with water and extracted with EA (3 ^χ 20 mL). The organic layers were combined, washed with brine, dried over N32S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel

(MeOH/DCM, 0→8%) to yield 2-(3-fluoro-2-(oxetan-3-yl)pyridin-4-yl)-2-oxoethyl (3R,8aS)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C25H22CIF2N3O5: 517.12, measured (ES, m/z): 518.05 [M+H]÷. Step 6: (3S,8aR)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro- 2-(oxetan- 3-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindo lizin-5(1H)-one.

To a mixture of 2-(3-fluoro-2-(oxetan-3-yl)pyridin-4-yl)-2-oxoethyl (3R,8aS)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a- hexahydroindolizine-3-carboxylate (195 mg, 0.38 mmol, 1.0 equiv.) and ammonium acetate (290 mg, 3.77 mmol, 10.0 equiv.) in toluene (5 mL) was added acetic acid (1 mL). The resulting reaction mixture was heated at 100 °C with stirring for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (MeOH/DCM, 0→10%) to yield (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)- 3-(5-(3-fluoro-2-(oxetan-3-yl)pyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C25H22CIF2N5O2: 497.14, measured (ES, m/z): 498.10 [M+H] ⁺ .

Step 7: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro- 2-(oxetan-3-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin-5(1H)- one.

A mixture of (3R,8aS)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro- 2-(oxetan-3-yl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin-5(1H)- one (140 mg, 0.28 mmol, 1.0 equiv.), trimethoxymethane (2 mL), azidotrimethylsilane (2 mL) and acetic acid (3 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was purified by reversal phase chromatography on C18 (MeCN/h½0 (0.05%CF ₃ COOH)) to yield (3R,8aS)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(oxetan-3-yl)pyridin- 4-yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. The racemic product (78 mg) was further separated by chiral-HPLC to yield (3R,8aS)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2 -(oxetan-3-yl)pyridin- 4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C2eH2iCIF2Ne02: 550.14, measured (ES, m/z): 551.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.05 - 12.78 (m, 1 H), 9.84 (s, 1 H), 8.43 (d, J = 5.0 Hz, 1 H), 7.82 - 8.03 (m, 2 H), 7.72 (dd, J = 8.7, 1.5 Hz, 1 H), 7.51 - 7.59 (m, 1 H), 5.70 (d, J = 2.5 Hz, 1 H), 5.04 (d, J = 8.5 Hz, 1 H), 4.85 - 4.97 (m, 4 H), 4.58 - 4.77 (m, 1 H), 3.65 - 3.85 (m, 1 H), 2.62 - 2.83

(m, 1 H), 2.50 - 2.60 (m, 1 H), 2.03 - 2.31 (m, 2 H), 1.85 - 2.02 (m, 2 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.86, -130.28.

Example 131 (3R*,8aR*)-3-(5-(6-amino-2-fluoropyridin-3-yl-4,5-d2)-1H- imidazol-2-yl-4-d)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl) phenyl)-2,3,8 _> 8a- tetrahydroindolizin-5(1 H)-one-8a-d

LC/MS: mass calculated for C23H14D4CIF2N9O: 513.15, measured (ES, m/z): 514.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.81 (s, 1 H), 7.90 - 7.99 (m, 1 H), 7.68 (dd, J = 8.7, 1.4 Hz, 1 H), 5.66 (dd, J = 8.0, 2.6 Hz, 1 H), 4.97 (t, J = 7.4 Hz, 1 H), 2.30 - 2.38 (m, 3 H), 2.20 - 2.23 (m, 1 H),1.95 - 2.08 (m, 1 H), 1.65 - 1.67 (m, 1 H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -70.81, -113.06. Example 132 (3S*,8aR>3-(5-(6-amino-2-fluoropyridin-3-yl-4,5-d2)-1H- imidazol-2-yl-4-d)-7-(3-chloro-2-fluoro-6-{1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a- tetrahydroindolizin-5(1 H)-one-8a-d

LC/MS: mass calculated for C23H14D4CIF2N9O: 513.15, measured (ES, m/z): 514.15 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 9.81 (s, 1 H), 7.88 - 7.97

(m, 1 H), 7.67 (dd, J = 8.7, 1.5 Hz, 1 H), 5.66 (d, J = 2.7 Hz, 1 H), 5.01 (d, J = 8.8 Hz, 1 H), 2.60 - 2.73 (m, 1 H), 2.43 - 2.46 (m, 1 H), 2.14 - 2.22 (m, 1 H), 2.02 - 2.07 (m, 1 H), 1.91 - 1.96 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ - 70.64, -112.75. Example 133 (3R*,8aR)-7-(3-chloro-2-fluoro-6-{1 H-tetrazol-1 -yl)phenyl)-3- (5-(2-fluoro-6-(methylamino)pyridin-3-yl-4,5-d2)-1H-imidazol -2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H18D2CIF2N9O: 525.16, measured (ES, m/z): 526.10 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 9.82 (s, 1 H), 7.90 - 8.10

(m, 1 H), 7.70 (dd, J = 8.7, 1.5 Hz, 1 H), 7.18 (s, 1 H), 6.98 (s, 1 H), 5.67 (d, J = 2.7 Hz, 1 H), 5.03 (d, J = 8.9 Hz, 1 H), 3.68 - 3.81 (m, 1 H), 2.72 - 2.88 (m, 4 H), 2.50 - 2.54 (m, 1 H), 2.08 - 2.29 (m, 2 H), 1.91- 2.07 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -70.44, -112.86. Example 134 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-

(3-fluoro-2-(methylamino)pyridin-4-yl)-1H-imidazol-2-yl)- 2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 2-(3-Fluoro-2-(n-methylacetamido)pyridin-4-yl)-2-oxoethyl (3S,8aR)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate.

To a mixture of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic add (200 mg, 0.62 mmol, 1.0 equiv.) in DMF (5 mL) was added cesium carbonate (120 mg, 0.37 mmol, 0.6 equiv.), followed by addition of N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N- methylacetamide (226 mg, 0.92 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature overnight, diluted with water, and extracted with EA (3 * 20 mL). The organic layers were combined, washed with brine, dried over N32S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM, 0→8%) to yield 2-(3- fluoro-2-(n-methylacetamido)pyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate as a yellow solid. LC/MS: mass calculated for C25H23CIF2N4O5: 532.13, measured (ES, m/z): 533.10 [M+H]*.

Step 2: 2-(3-Fluoro-2-(n-methylacetamido)pyridin-4-yl)-2-oxoethyl (3S,8aR)-7- (6-amino-3-chloro2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydr oindolizine-3- carboxylate.

To a mixture of 2-(3-fluoro-2-(n-methylacetamido)pyridin-4-yl)-2-oxoethyl (3S, 8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2, 3, 5,8,8a- hexahydroindolizine-3-cartx)xylate (275 mg, 0.52 mmol, 1.0 equiv.) and ammonium acetate (398 mg, 5.16 mmol, 10.0 equiv.) in 1 ,4-dioxane (5 mL) was added acetic add (1 mL). The resulting mixture was stirred at 100 °C for 1 h. The excess solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM, 0→10%) to yield N-(4-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 -yl)-n- methylacetamide as a yellow solid. LC/MS: mass calculated for C25H23CIF ₂ Ne02: 512.15, measured (ES, m/z): 513.15 [M+H] ⁺ . Step 3: N-(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridi n-2- yl)-n-methylacetamide.

A mixture of N-(4-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridi n-2- yl)-N-methylacetamide (150 mg, 0.29 mmol, 1.0 equiv.), trimethoxymethane (2 mL) and azidotrimethylsilane (2 mL) in acetic acid (2 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to yield N-(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)p henyl)-5-oxo- 1,2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridi n-2-yl)-n- methylacetamide as a yellow oil. LC/MS: mass calculated for C26H22CIF2N8O2: 565.16, measured (ES, m/z): 566.15 [M+H] ⁺ .

Step 4: (3S,8aR)-7-(3-Chloro-2-fiuoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(3-fluoro-

2-(methylamino)pyridin-4-yl)-1H-imidazol-2-yl)-2,3 _l 8,8a-tetrahydroindolizin-

5(1H)-one.

To a solution of N-(4-(2-((3R,8aS)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1l-l- imidazol-5-yl)-3- fluoropyridin-2-yl)-n-methylacetamide (190 mg, 0.34 mmol, 1.0 equiv.) in THF (2 ml_) was added HCI (1 mL, 2 M). The resulting mixture was stirred at 50 °C for 2 h, then concentrated under reduced pressure. The residue was purified by reversal phase chromatography on C18 (MeCN/hbO (0.05%CF3COOH)) to yield (3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3-fluoro-2- (methylamino)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrah ydroindolizin-5(1H)- as a yellow solid. The racemic product (78 mg) was further separated by chiral- HPLC to yield (3R, 8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5- (3-fluoro-2-(methylamino)pyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured (ES, m/z): 524.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.15 (s, 1 H), 9.84 (s, 1 H), 7.92 - 8.03 (m, 1 H), 7.68 - 7.84 (m, 2 H), 7.45 (d, J = 3.7 Hz, 1 H), 7.08 (s,

1 H), 6.57 (s, 1 H), 5.69 (d, J = 2.5 Hz, 1 H), 5.04 (d, J = 8.4 Hz, 1 H), 3.60 - 3.80 (m, 1 H), 2.82 - 2.94 (m, 3 H), 2.65 - 2.80 (m, 1 H), 2.56 - 2.60 (m, 1 H), 1.88 - 2.26 (m, 4 H). ¹⁶ F NMR (282 MHz, DMSO-de) δ -112.85, -143.81.

Example 135 (3S,8a*S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(2-(ethyl(2-hydroxyethyl)amino)-3-fluoropyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C27H2eCIF2N902: 581.19, measured (ES, m/z): 582.20 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) 69.57 (s, 1 H), 7.90 (d, J = 5.7 Hz, 1 H), 7.75 - 7.85 (m, 2 H), 7.50 - 7.57 (m, 1 H), 7.24 - 7.31 (m, 1 H), 5.73 (d, J = 2.6 Hz, 1 H), 5.15 - 5.22 (m, 1 H), 4.26 - 4.38 (m, 1 H), 3.76 - 3.86 (m, 2 H), 3.62 - 3.74 (m, 4 H), 2.61 - 2.73 (m, 3 H), 2.36 - 2.47 (m, 1 H), 2.07 - 2.23 (m, 1 H), 1.80 - 1.94 (m, 1 H), 1.28 (t, J = 7.0 Hz, 3 H). ¹⁶ F NMR (376 MHz, Methanol-d*) 6 -76.98, -113.88, -134.07.

Example 136 (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazoM-yl)phenyl)-3- (5-(2-(ethyl(2-hydroxyethyl)amino)-3-fluoropyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C27H26CIF2N8O2: 581.19, measured (ES, m/z): 582.20 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) δ 9.57 (s, 1 H), 7.75 - 7.90 (m, 2 H), 7.48 - 7.57 (m, 2 H), 7.24 - 7.33 (m, 1 H), 5.73 (d, J = 2.8 Hz, 1 H), 5.14 - 5.21 (m, 1 H), 3.84 - 3.97 (m, 1 H), 3.74 - 3.80 (m, 2 H), 3.56 - 3.67 (m, 4 H), 2.84 - 2.95 (m, 1 H), 2.56 - 2.65 (m, 1 H), 2.16 - 2.40 (m, 3 H), 1.98 - 2.12 (m, 1 H), 1.23 (t, J = 7.0 Hz, 3 H). ¹⁹ F NMR (376 MHz, Methanol-cU) 6 - 76.92, -113.16, -135.42. Example 137 (3R ^w ,8aR)-3-(5-(1 H-indol-3-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindoli zin-5(1H)-one

LC/MS: mass calculated for C2eH2oCIFNeO: 514.14, measured (ES, m/z): 515.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 11.33 - 12.05 (m, 1 H), 10.56 - 11.22 (m, 1 H), 9.78 (s, 1 H), 7.88 - 8.08 (m, 2 H), 7.64 - 7.76 (m, 1 H), 7.41 -

7.52 (m, 1 H), 7.22 - 7.40 (m, 1 H), 6.93 - 7.18 (m, 3 H), 5.40 - 5.60 (m, 1 H), 4.94 - 4.96 (m, 1 H), 3.59 - 3.71 (m, 1 H), 2.61 - 2.91 (m, 2 H), 1.78 - 2.10 (m, 4 H). ¹⁸ F NMR (376 MHz, DMSO-de) 6 -112.81.

Example 1383-(4-(2-((3S,8aR ^w )-7-(3-chloro-2-fluoro-6-(1H-tetrazoM- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)oxetane-3-carbonitrile

Step 1: 3-(3-Fluoro-4-iodopyridin-2-yl)oxetane-3-cartx>nitrile.

To a solution of 2,3-difluoro-4-iodopyridine (1.0 g, 4.15 mmol, 1.0 equiv.) in toluene (15 mL) was added lithium bis(trimethylsilyl)amide solution 1.0 M in THF (6.2 mL, 6.23 mmol, 1.5 equiv.) dropwise under N2 at -10 °C. After stirring for 40 min at -10 °C, oxetane-3-carbonitrile (0.41 g, 4.98 mmol, 1.2 equiv.) was added dropwise. The reaction mixture was warmed to room temperature slowly and stirred for 2 h, then quenched with saturated NhUCI, extracted with EA, dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography with EA/PE (0→40%) to yield 3-(3-fluoro-4- iodopyridin-2-yl)oxetane-3-carbonitrile as a white solid. LC/MS: mass calculated for CeHeFItoO: 303.95, measured (ES, m/z): 305.00 [M+H] ⁺ .

Step 2: 3-(4-(1-Ethoxyvinyl)-3-fluoropyridin-2-yl)oxetane-3-carbonit rile.

To a solution of 3-(3-fluoro-4-iodopyridin-2-yl)oxetane-3-carbonitrile (1.8 g, 5.31 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) was added tributyl(1- ethoxyvinyl)tin (3.8 g, 10.62 mmol, 2.0 equiv.), bis(triphenylphosphine) palladium(ll) chloride (0.28 g, 0.40 mmol, 0.075 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C overnight, then cooled to room temperature and quenched with water. The reaction mixture was extracted with EA. The organic layers were combined, washed with brine, dried and concentrated under vacuum. The residue was purified by silica gel chromatography on silica gel (0→20% ethyl acetate/petroleum ether) to yield (S)-2-((1,4-dioxan-2-yl)methoxy)-4-(1-ethoxyvinyl)-3-fluorop yridine as a yellow solid. LC/MS: mass calculated for C13H13FN2O2: 248.10, measured (ES, m/z): 249.25 [Μ+ΗΓ. Step 3: 3-(4-(2-Bromoacetyl)-3-fluoropyridin-2-yl)oxetane-3-carbonit rile.

To a solution of 3-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)oxetane-3- carbonitrile (0.40 g, 1.61 mmol, 1.0 equiv.) in tetrahydrofuran (6 mL) and water (2 mL) was added N-bromosuccinimide (0.26 g, 1.45 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 0.5 h, quenched with water and extracted with EA. The organic layers were combined, washed with brine, dried and concentrated under vacuum. The residue was purified by silica gel chromatography on silica gel (0→20% ethyl acetate/petroleum ether) to yield 3-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)oxetane-3-carbonit rile as a yellow oil. LC/MS: mass calculated for CnHeBrFtoCfe: 297.98, measured (ES, m/z): 298.95, 300.95 [M+H, M+H+2] ⁺ .

Step 4: 2-(2-(3-Cyanooxetan-3-yl)-3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3, 5,8, 8a-hexahydroindolizine-3-carboxylic acid (0.20 g, 0.53 mmol, 1.0 equiv.) in DMF (5 mL) was added potassium carbonate (0.11 g, 0.79 mmol, 1.5 equiv.), followed by 3-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)oxetane-3- carbonitrile (0.24 g, 0.79 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was purified by reverse column chromatography on C18 with (CHsCN/water (0.05%TFA): 5—70%) to yield 2-(2-(3-cyanooxetan-3-yl)-3- fluoropyridin-4-yl)-2-oxoethyl (3R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate as a brown solid. LC/MS: mass calculated for C27H20CIF2N7O5: 595.12, measured (ES, m/z): 596.05 [M+H] ⁺ .

Step 5: 3-(4-(2-((3S,8aR*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2- yl)oxetane-3-carbonitrile.

To a solution of 2-(2-(3-cyanooxetan-3-yl)-3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (0.12 g, 0.20 mmol, 1.0 equiv.) in toluene (5 mL) and acetic acid (0.25 mL) was added ammonium acetate (0.31 g, 4.03 mmol, 20.0 equiv.). The reaction mixture was stirred at 100 °C for 1 h, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 1-(4-(2-((3S,8aR)- 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5, 8,8a-hexahydroindolizin-3- yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2-yl)cyclopropane-1-carboni trile as a brown solid. The racemic mixture was purified by prep-chiral-HPLC with MeOH (0.1%DEA) to yield 3-(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)oxetane-3-carbonitrile as a white solid.

LC/MS: mass calculated for C27H2oCIF2Ng02: 575.14, measured (ES, m/z): 576.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.40 (s, 1 H), 9.85 (s, 1 H), 8.38 - 8.53 (m, 1 H), 7.81 - 8.20 (m, 2 H), 7.60 - 7.78 (m, 2 H), 5.71 (d, J = 2.5 Hz, 1 H), 5.11 - 5.32 (m, 4 H), 5.05 (d, J = 8.5 Hz, 1 H), 3.69 - 3.89 (m, 1 H), 2.62 - 2.84 (m, 1 H), 2.57 - 2.61 (m, 1 H), 2.09 - 2.29 (m, 2 H), 1.96 - 2.09 (m, 2 H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -112.85, -127.22.

Example 139 1-(4-(2-((3S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)cyclopropane-1-carbonitrile

LC/MS: mass calculated for C27H20CIF2N9O: 559.14, measured (ES, m/z): 560.15 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d*) 69.60 (s, 1H), 8.37 - 8.43 (m, 1H), 7.79 - 7.94 (m, 3H), 7.54 - 7.63 (m, 1H), 5.78 (d, J = 2.8 Hz, 1H),

5.20 - 5.35 (m, 1 H), 3.90 - 4.10 (m, 1 H), 2.91 - 3.08 (m, 1 H), 2.65 - 2.83 (m, 1H), 2.41 - 2.58 (m, 1H), 2.15 - 2.39 (m, 2H), 1.93 - 2.17 (m, 1H), 1.73 - 1.91 (m, 4H)/ ¹⁹ F NMR (282 MHz, Methanol-d*) 6 -77.25, -113.59, -126.83.

Example 140 (3*R,8aS)-3-(5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-imidazol-2 - yl)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazoM -yl)phenyl)-

2,3,8,8a-tetrahydroindolizin-5(1H)-one

,0 HN' a,

,(R‘)

N s

,’N

:F ₃

LC/MS: mass calculated for C27H19CIF4N8O: 582.13, measured (ES, m/z): 583.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.32 (d, J = 1.1 Hz, 1H), 8.30 - 8.40 (m, 2H), 7.91 - 8.01 (m, 3H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.23 - 7.29 (m, 1H), 5.72 (d, J = 2.8 Hz, 1H), 5.20 - 5.26 (m, 1H), 3.70 - 3.84 (m, 1H), 2.94 - 3.09 (m, 1H), 2.53 - 2.67 (m, 1H), 2.31 - 2.47 (m, 1H), 2.09 - 2.22 (m, 2H), 1.89 - 2.02 (m, 1H)/ ¹⁸ F NMR (376 MHz, DMSO-de) δ -59.52, -74.06, - 112.65.

Example 141 (3*S,8a*R)-7-(3-chloro-2-fluoro-6-{1 H-tetrazol-1-yl)phenyl)-3- (5-{3-fluoro-2-((*R)-1-(oxazol-2-yl)ethoxy)pyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C28H22CIF2N9O3: 605.15, measured (ES, m/z): 606.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.82 (s, 1H), 8.08 (s,

1H), 7.83 - 8.02 (m, 2H), 7.64 - 7.74 (m, 1H), 7.50 - 7.61 (m, 2H), 7.20 (s, 1H), 6.33 (q, J = 6.6 Hz, 1H), 5.67 (d, J = 2.5 Hz, 1H), 5.02 (d, J = 8.4 Hz, 1H), 3.65 - 3.79 (m, 1 H), 2.60 - 2.79 (m, 1 H), 2.03 - 2.29 (m, 3H), 1.86 - 2.03 (m, 2H), 1.69 (d, J = 6.6 Hz, 3H)/ ¹⁹ F NMR (282 MHz, DMSO-de) 6 -142.97, -112.90. Example 142 (3*S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3- (5-(3-fluoro-2-((*S)-1-(oxazol-2-yl)ethoxy)pyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C28H22CIF2N9O3: 605.15, measured (ES, m/z): 606.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.82 (s, 1H), 8.08 (s,

1H), 7.79 - 8.02 (m, 2H), 7.69 (dd, J = 8.6, 1.5 Hz, 1H), 7.50 - 7.61 (m, 2H),

7.20 (s, 1H), 6.34 (q, J = 6.6 Hz, 1H), 5.68 (d, J = 2.5 Hz, 1H), 5.02 (d, J = 8.4 Hz, 1 H), 3.66 - 3.79 (m, 1 H), 2.61 - 2.78 (m, 1 H), 2.03 - 2.34 (m, 3H), 1.86 -

2.20 (m, 2H), 1.69 (d, J = 6.7 Hz, 3H)/ ¹⁹ F NMR (282 MHz, DMSO-de) 6 -142.99, -112.90.

Example 143 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-(( ^w S)-3,3,3-trifluoro-2-hydroxypropyl)pyridin-4-yl)-1H-im idazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: 2-(2-(2-((Tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl )-3- fluoropyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate.

To a solution of (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (0.20 g, 0.53 mmol, 1.0 equiv.) in N.N-dimethylfonnamide (5 mL) was added potassium carbonate (0.11 g, 0.79 mmol, 1.5 equiv.), followed by addition of 2-bromo-1-(2-(2-((tert- butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-3-fluoropyrid in-4-yl)ethan-1-one (0.44 g). The reaction mixture was stirred at room temperature for 1 h, then purified by reverse phase chromatography on C18 with CHsCN/water (5→100%) to yield 2-(2-(2-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl )-3- fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate as a yellow solid. LC/MS: mass calculated for CazHsACIFsNeOsSi: 740.20, measured (ES, m/z): 741.05 [M+H] ⁺ .

Step 2: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-

2-(3,3,3-trifluoro-2-hydroxypropyl)pyridin-4-yl)-1H-imida zol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a mixture of 2-(2-(2-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl )-

3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate (180 mg, 0.24 mmol 1.0 equiv.) and ammonium acetate (374 mg, 4.86 mmol, 20.0 equiv.) in toluene (10 mL) was added acetic acid (0.3 mL). The reaction mixture was stirred at 100 °C for 1 h, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0→10%) to yield (3S)-3-(5-(2-(2-((tert-butyldimethylsilyl)oxy)-3,3,3- trifluoropropyl)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-( 3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C26H20CIF5N8O2: 720.22, measured (ES, m/z): 721.40 [M+H] ⁺ .

Step 3: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro- 2-((*S)-3,3,3-trifluoro-2-hydiOxypiOpyl)pyridin-4-yl)-1H-imi dazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of (3S,8aR)-3-(5-(2-(2-((tert-butyldimethylsilyl)oxy)-3,3,3- trifluoropropyl)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-( 3-chloro-2-fluoro-6- (1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H) -one (110 mg, 0.15 mmol, 1.0 equiv.) in THF (5 ml_) was added triethylamine trihydrofluoride (123 mg, 0.76 mmol, 5.0 equiv.). The reaction mixture was stirred at 70 °C for 1.5 h, then concentrated under reduced pressure and the residue was purified by reverse phase chromatography with ChbCN/water (5→35%) to yield a racemic product, which was further purified by chiral HPLC with Hex(0.1 %DEA): EtOH=50:50 to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-((*S)-3,3,3-trifluoiO -2- hydroxypropyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetra hydroindolizin- 5(1H)-one as a white solid.

LC/MS: mass calculated for CMHZOCIFSNSOZ: 606.13, measured (ES, m/z): 607.10 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) 69.57 (s, 1H), 8.32 (d, J

= 5.1 Hz, 1H), 7.92 - 8.01 (m, 1H), 7.77 - 7.86 (m, 1H), 7.64 - 7.51 (m, 2H),

5.74 (d, J = 2.6 Hz, 1H), 5.17 (d, J = 8.8 Hz, 1H), 4.43 - 4.55 (m, 1H), 3.85 - 3.99 (m, 1H), 3.19 - 3.26 (m, 1H), 3.05 - 3.15 (m, 1H), 2.80 - 2.97 (m, 1H), 2.56 - 2.68 (m, 1 H), 2.15 - 2.37 (m, 3H), 1.97 - 2.14 (m, 1H)/ ¹⁹ F NMR (376 MHz, Methanol-d*) 6 -81.18, -113.52, -129.57.

Example 144 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-((*R)-3,3,3-trifluoro-2-hydroxypropyl)pyridin-4- yl)-1H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2eH2oCIF5Ne02: 606.13, measured (ES, m/z): 607.05 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) 69.57 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.91 - 8.01 (m, 1H), 7.79 - 8.88 (m, 1H), 7.61 (d, J = 4.1 Hz, 1H), 7.55 (dd, J = 8.7, 1.6 Hz, 1H), 5.74 (d, J = 2.7 Hz, 1H), 5.17 (d, J = 8.7 Hz, 1H),

4.42 - 4.57 (m, 1H), 3.82 - 4.07 (m, 1 H), 3.20 - 3.28 (m, 1H), 3.07 - 3.17 (m, 1H), 2.80 - 2.95 (m, 1H), 2.56 - 2.68 (m, 1H), 2.16 - 2.39 (m, 3H), 2.00 - 2.14 (m, 1H). ¹⁸ F NMR (376 MHz, Methanol-cU) δ -81.18, -113.52, -129.56.

Example 145 (3S,8aR)-3-[5-{6-amino-5-deuterio-2-fluoro-3-pyridyl)-4- deuterio-1 H-imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]- 2,3,8 _| 8a-tetrahydro-1H-indolizin-5-one

LC/MS: mass calculated for C23H16CID2F2N9O: 511.14, measured (ES, m/z): 512.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.82 (s, 1H), 7.91 - 8.03 (m, 2H), 7.67 - 7.73 (m, 1 H), 5.68 (d, J = 2.7 Hz, 1 H), 5.00 (d, J = 8.7 Hz, 1 H),

3.62 - 3.75 (m, 1 H), 2.60 - 2.78 (m, 1 H), 2.50 - 2.52 (m, 1 H), 2.03 - 2.20 (m, 2H), 1.90 - 2.00 (m, 2H)/ ¹⁹ F NMR (376 MHz, DMSO-de) δ -70.74, -112.84. Example 146 (3S,8aR)-3-[5-(6-amino-2-fluoro-3-pyridyl)-1H-imidazol-2-yl] - 7-[3-chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-8a-deuterio-1 ,2,3,8- tetrahydroindolizin-5-one

Step 1: 1-(Tert-butyl) 2-methyl (2S)-5-hydroxypyrrolidine-1,2-dicarboxylate-5-d To a solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2- dicarboxylate (20 g, 82.22 mmol, 1.0 equiv) in methanol-d (120 mL) was added NaBD* (5.16 g, 123.33 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with D2O (10 mL). The resulting mixture was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-35% ethyl acetate/petroleum ether) to yield the 1-(tert-butyl) 2-methyl (2S)-5-hydroxypyrrolidine-1 ,2- dicarboxylate-5-d as a yellow oil.

Step 2: l-(Tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1,2-dicarboxylate-5-d To a solution of 1-(tert-butyl) 2-methyl (2S)-5-hydroxypyrrolidine-1,2- dicarboxylate-5-d (10 g, 40.61 mmol, 1.0 equiv) in MeOH (100 mL) was added p-toluenesulfonic acid monohydrate (1.9 g, 10.15 mmol, 0.25 equiv). The mixture was stirred at room temperature overnight The solvent was removed under vacuum and the residue was purified by silica gel column with EA/PE (0%-35%) to yield the 1-(tert-butyl)2-methyl-(2S)-5-methoxypyrrolidine-1,2- dicarboxylate -5-d as a yellow oil. Step 3: 1-(Tert-butyl) 2-methyl (2S)-5-((2,2-dimethyl-4-oxo-4H-1 ,3-dioxin-6- yl)methyl) pyrrolidine-1 ,2-dicarboxylate-5-d

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-methoxypyrrolidine-1 ,2- dicarboxylate-5-d (2.5 g, 10.151 mmol, 1.0 eq.), ((2,2-dimethyl-4-methylene- 4H-1,3-dioxin-6-yl)oxy)trimethylsilane (3.3 g, 15.397 mmol, 1.5 eq.) in MTBE (30 mL) at-78°C was added boron trifluoride etherate(1.7 g, 11.978 mmol, 1.2 eq.). The resulting mixture was maintained stirring at -78°C for 1 h then warmed to room temperature and maintained stirring for 1 h, then quenched with NaHCOa solution (100 mL) and the aqueous layer was extracted with MTBE (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EA/PE) to yield the l-(tert-butyl) 2-methyl (2S)-5-((2,2-dimethyl-4-oxo-4H-1 ,3-dioxin-6-yl)methyl)pyrrolidine-1 ,2- dicarboxylate -5-d as a yellow solid. LC/MS: mass calculated for CISHMDNO: 370.19, measured: 371.20 [M+HJ*.

Step 4: Methyl (2S)-5-((2,2-dimethyl-4-oxo4H-1,3-dioxin-6- yl)methyl)pyrrolidine-2- carboxylate-5-d

To a solution of 1-(tert-butyl) 2-methyl (2S)-5-((2,2-dimethyl-4-oxo-4H- 1 ,3-dioxin-6-yl)methyl)pyrrolidine-1 ,2-dicarboxylate-5-d (1.5 g, 4.05 mmol, 1.0 eq.) in DCM (22.5 mL) was added TFA (4.5 mL). The mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure to yield the methyl (2S)-5-((2,2-dimethyl-4-oxo-4H-1 ,3-dioxin-6- yl)methyl)pyrrolidine-2-carboxylate-5-d as a yellow oil. LC/MS: mass calculated for CisHieDNOs: 270.13, measured: 271.30 [M+H]*.

Step 5: Methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate-8a-d A solution of methyl (2S)-5-((2,2-dimethyl-4-oxo-4H-1,3-dioxin-6- yl)methyl)pyrrolidine- 2-carboxylate-5-d (1.0 g, 3.70 mmol, 1.0 eq.) in toluene (10 mL) was heated at 110°C with stirring for 1 h. The mixture was quenched with water (50 mL) and extracted with EA (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% methanol/DCM) to yield the methyl (3S)-5,7- dioxooctahydroindolizine-3-carboxylate-8a-d as a yellow oil. LC/MS: mass calculated for CioHi2DN04: 212.09, measured: 213.10 [M+H]÷.

Step 6: Methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,5,8,8a- hexahydro indolizine-3-carboxylate-8a-d

To a solution of methyl (3S)-5,7-dioxooctahydroindolizine-3-carboxylate- 8a-d (472 mg, 2.22 mmol, 1.0 eq.) in DCM (10 mL) was added N-phenyl- bis(trifluoromethanesulfonimide) (1193 mg, 3.34 mmol, 1.5 eq.) followed by triethylamine (450 mg, 4.447 mmol, 2.0 eq.). The reaction mixture was stirred at room temperature overnight, quenched with water (100 mL), and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-100% EA/PE) to yield the methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate-8a-d as a yellow oil. LC/MS: mass calculated for CnHnDFaNOeS: 344.04, measured 345.05 [M+H] ⁺ .

Step 7: Methyl (3S)-7-(6-amino-3-chloro2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydro indolizine-3-carboxylate-8a-d

To a mixture of methyl (3S)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate-8a-d (673 mg, 1.95 mmol, 1.0 eq.), Pd(dppf)Cl2 (149 mg, 0.196 mmol, 0.1 eq.) in 1,4-dioxane (10 mL) and HzO (1 mL) was added (6-amino-3-chloro-2-fluorophenyl)boronic acid (555 mg, 2.93 mmol, 1.5 eq.), K2CO3 (810 mg, 5.86 mmol, 3.0 eq.). The mixture was stirred at 90 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% methanol/DCM) to yield the methyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate-8a-d as a yellow solid. LC/MS: mass calculated for CieHisCIDFNaOa: 339.09, measured 340.10 [M+H] ⁺ .

Step 8: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic-8a-d acid

To a solution of methyl (3S)-7-(6-amino-3-chloro2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate-8a-d (602 mg, 1.77 mmol, 1.0 eq.) in THF (10 mL) and H2O (5 mL) was added lithium hydroxide (212 mg,

8.85 mmol, 5.0 eq.). The reaction mixture was stirred at room temperature for 2 h, adjusted pH 5 with HCI (1M), and then extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic- 8a-d acid as a yellow solid. LC/MS: mass calculated for C15H13CIDFN2O3: 325.07, measured 326.20 [M+H] ⁺ .

Step 9: 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate- 8a-d

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a -hexahydroindolizine-3-carboxylic-8a-d acid (465 mg, 1.428 mmol, 1.0 eq.) in DMF (5 mL) was added cesium carbonate (279 mg, 0.856 mmol, 0.6 eq.) followed by N-(5-(2-bromoacetyl) -6-fluoropyridin-2-yl)acetamide (472 mg, 1.716 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for

2 hours, quenched with water (50 mL), and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% methanol/DCM) to yield the 2-(6-acetamido-2-fluoropyridin-3-yl) -2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine -3-carboxylate-8a-d as a yellow solid. LC/MS: mass calculated for C24H20CIDF2N4O5: 519.12, measured: 520.30 [M+H]÷.

Step 10: N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl-8a-d)-1H-imidazol-5-yl)-6-fluoropyri din-2-yl)acetamide To a solution of 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate-8a-d (541 mg, 1.04 mmol, 1.0 eq.) in toluene (10 mL) and acetic acid (1 mL) was added ammonium acetate (803 mg, 10.42 mmol, 10.0 eq.). The mixture was stirred at 90°C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-10% MeOH/DCM) to yield the N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-

1,2,3, 5,8, 8a-hexahydroindolizin-3-yl-8a-d)-1H-imidazol-5-yl)-6-fluorop yridin-2- yl)acetamide as a yellow solid. LC/MS: mass calculated for C24H2oCIDF2Ne02: 499.14, measured: 500.30 [Μ+ΗΓ-

Step 11 : N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3, 5,8, 8a-hexahydroindolizin-3-yl-8a-d)-1H-imidazol-5-yl)-6-fluorop yridin-2- yl)acetamide

To a solution of N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a- hexahydroindolizin-3-yl-8a-d)-1 H-imidazol-5-yl)-6-fluoropyridin-2- yl)acetamide (341 mg, 0.682 mmol, 1.0 eq.) in acetic acid (10 mL) were added azidotrimethylsilane (787 mg, 6.831 mmol, 10.0 eq.) and trimethoxymethane (724 mg, 6.822 mmol, 10.0 eq.). The reaction mixture was stirred at 60°C for 4 h. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to yield the N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l) -5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl-8a-d)-1 H-imidazol-5-yl)-6-fluoropyridin-2- yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H19CIDF2N9O2: 552.15, measured: 553.35 [M+H]*.

Step 12: (3S)-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-tetrahydroindo lizin-5(1H)-one-8a-d To a solution of N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo -1 ,2,3,5,8,8a-hexahydroindolizin-3-yl-8a-d)-1 H-imidazol-5-yl)- 6-fluoropyridin-2-yl)acetamide (152 mg, 0.275 mmol, 1.0 eq.) in THF (1 mL) was added 4 N HCI solution (1 mL). The mixture was stirred at 50°C for 3 h. After cooling to room temperature, the reaction was diluted with water and extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by reverse phase chromatography on a C18 column (eluent: 5% to 50% (v/v) CHsCN and H2O with 0.05% NFUHCOs) and chiral-HPLC using a column: CHIRALPAK IA-3, 4.6*50mm,3pm ; Mobile Phase A: Hex ( 0.1%DEA ): EtOH=50:50, Mobile Phase B:; Flow rate:1 mL/min to yield (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-y l)-7-(3- chloro2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one-8a-d as a white solid.

LC/MS: mass calculated for C23H17CIDF2N9O: 510.14, measured (ES, m/z): 511.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 11.78 (s, 1H), 9.83 (s, 1H), 7.92 - 8.07 (m, 2H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.04 (d, J = 3.9 Hz, 1H), 6.41 (dd, J = 8.2, 2.2 Hz, 1H), 6.25 (s, 2H), 5.69 (d, J = 2.5 Hz, 1H), 5.00 (d, J =

8.3 Hz, 1H), 2.65 - 2.73 (m, 1H), 2.47 - 2.50 (m, 1H), 1.91 - 2.19 (m, 4H)/ ¹⁹ F NMR (282 MHz, DMSO-de) 6 -70.80, -112.87.

Example 147 (3S,8aR)-3-[5-(6-amino-5-deiiterio-2-fluoro-3-pyridyl)-1H- imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl] -2,3,8,8a- tetrahydro-1 H-indolizin-5-one fl R

Cl'

_L S o NH

¾ N·H ₂

Step 1: 2-(6-Acetamido-2-fluoropyridin-3-yl-5-d)-2-oxoethyl (3S)-7-(6-amino-3- chloro2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine -3-carboxylate.

To a solution of 2-(2-(2-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropiOpyl )- 3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate (180 mg, 0.24 mmol, 1.0 equiv.) and ammonium acetate (374 mg, 4.86 mmol, 20.0 equiv.) in toluene (10 mL) was added acetic add (0.3 mL). The reaction mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with

MeOH/DCM (0—10%) to yield (3S)-3-(5-(2-(2-((tert-butyldimethylsilyl)oxy)- 3,3,3-trifluoropropyl)-3-fluoropyridin-4-yl)-1H-imidazol-2-y l)-7-(3-chloro-2-fluoro- 6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C24H20DCIF2N4O5: 519.12, measured (ES, m/z): 520.05 [M+H] ⁺ .

Step 2: N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2 -yl-3-d)acetamide.

Under an inert atmosphere of nitrogen, a mixture of 2-(6-acetamido-2- fluoropyridin-3-yl-5-d)-2-oxoethyl(3S)-7-(6-amino-3-chloro-2 -fluorophenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (700 mg, 1.35 mmol, 1.0 equiv.) and NH4OAC (1.0 g, 13.46 mmol, 10.0 equiv.) in AcOH (8 mL) and toluene (80 mL) was stirred at 110 °C for 1 h. The solvent was removed under vacuum and the residue was applied onto a silica gel column (40 g,

MeOH/DCM: 1/20) to yield N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridi n-2-yl- 3-d)acetamide as a yellow solid.

Step 3: N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-6-fluoropyridin-2-yl-3- d)acetamide.

A mixture of N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2-yl-3- d)acetamide (520 mg, 1.040 mmol, 1.00 equiv), TMSN3 (1.2 g, 10.40 mmol, 10.0 equiv.) and trimethoxymethane (1.1 g, 10.40 mmol, 10.0 equiv.) in AcOH

(15 mL) was stirred at 65 °C for 3 h. The solvent was removed and the residue was purified by flash column chromatography on silica gel (40 g, MeOH/DCM: 1/20) to yield N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridi n-2-yl- 3-d)acetamide as a light yellow solid. LC/MS: mass calculated for C25H19DCIF2N9O2: 552.15, measured (ES, m/z): 553.05 [M+H]÷.

Step 4: (3S,8aR)-3-[5-(6-Amino-5-deuterio-2-fluoro-3-pyridyl)-1 H-imidazol-2-yl]-

7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-2,3,8,8a-te trahydro-1H-indolizin-5- one.

A mixture of N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-6- fluoropyridin-2-yl-3-d)acetamide (200 mg, 0.36 mmol, 1.0 equiv.) in THF (4 mL) and HCI (4 mL, 4 M) was stirred at 50 °C for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (40 g, MeOH/DCM: 1/15) to yield (3S)-3-(5-(6-amino-2-fluoropyridin-3-yl-5-d)-

1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-y l)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a white solid. The solid was further purified by prep-chiral-HPLC (Column: CHIRALPAK IA, 2*25cm, Sum; Mobile Phase A:Hex:DCM=3: 1(0.5% 2 M NH ₃ -MeOH)~HPLC, Mobile Phase B:EtOH~HPLC; Flow rate:18 mL/min; Gradient:20 B to 20 B in 21 min; 220/254 nm; RT1:14.048; RT2:16.708; Injection Volumn:1 ml; Number Of Runs:5) to yield (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl-5-d)-1H-imidazol -2-yl)-7-(3-chloro- 2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C23H17CIDF2N9O: 510.14, measured (ES, m/z): 511.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.76 (s, 1H), 9.83 (s, 1H), 7.90 - 8.10 (m, 2H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.04 (s, 1H), 6.23 (s,

2H), 5.69 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 8.5 Hz, 1H), 3.69 - 3.76 (m, 1H), 2.67 - 2.73 (m, 1H), 2.50 - 2.53 (m, 1H), 2.05 - 2.21 (m, 2H), 1.94 - 2.01 (m, 2H)/ ¹⁸ F NMR (376 MHz, DMSO-de) -70.92, -112.87.

Example 148 (3S,8aR)-3-[5-(6-amino-4-deuterio-2-fluoro-3-pyridyl)-4- deuterio-1 H-imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1 -yQphenyl]- 2,3,8,8a-tetrahydro-1H-indolizin-5-one

LC/MS: mass calculated for C23HieCID2F2NeO: 511.14, measured (ES, m/z): 512.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.79 (s, 1H), 9.84 (s, 1 H), 7.94 - 8.02 (m 1 H), 7.67 - 7.77 (m, 1 H), 6.41 (d, J = 2.2 Hz, 1 H), 6.26 (s,

2H), 5.69 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 8.3 Hz, 1H), 3.77 - 3.66 (m, 1H), 2.61 - 2.80 (m, 1 H), 2.54 - 2.58 (m, 1 H), 1.95 - 2.23 (m, 4H)/ ^ig F NMR (282 MHz, DMSO-de) δ -70.87, -112.88.

Example 149 (3S,8aR)-3-[5-(6-amino-4,5-dideuterio-2-fluoro-3-pyridyl)-4- deuterio-1 H-imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1 -yQphenyl]- 2,3,8,8a-tetrahydro-1H-indolizin-5-one Aj ^N

R a·

N _L S

O NH r ‘N NH ₂

Step 1: (3S,8aR)-3-(5-(6-Amino-2-fluoro-5-iodopyridin-3-yl-4-d)-4-io do-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

A mixture of (3R,8aS)-3-(5-(6-amino-2-fluoropyridin-3-yl-4-d)-1 H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (322 mg, 0.63 mmol, 1.0 equiv.) and NIS (255 mg, 1.13 mmol, 1.8 equiv.) in ChbCOOH/TFA (V/V=10:1, 5.5 ml_) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EA (3 ^χ 20 mL). Then the organic layers were combined, washed with brine, and dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0—10%) to yield (3R,8aS)-3-(5-(6-amino-2-fluoro-5- iodopyridin-3-yl-4-d)-4-iodo-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a brown solid. LC/MS: mass calculated for C23H15DCIF2I2N9O: 761.93, measured (ES, m/z): 762.85 [M+H] ⁺ .

Step 2: (3S,8aR)-3-[5-(6-Amino-4,5-dideuterio-2-fluoro-3-pyridyl)-4- deuterio- 1H-imidazol-2-yl]-7-[3-chloiO-2-fluoro-6-(tetrazol-1-yl)phen yl]-2,3,8,8a- tetrahydro-1 H-indolizin-5-one.

To a mixture of (3R,8aS)-3-(5-(6-amino-2-fluoro-5-iodopyridin-3-yl-4-d)- 4-iodo-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one (333 mg, 0.44 mmol, 1.0 equiv.) and zinc powder (828 mg, 12.66 mmol, 29.0 equiv.) was added CD3COOD (7 mL) followed by D2O (7 mL) under N2 atmosphere. The resulting mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by reversal phase chromatography on C18 (MeCN/hbO (0.05%CF3COOH)) to yield (3R,8aS)-3-(5-(6-amino-2-fluoropyridin-3-yl-4,5-d2)-1H-imida zol-2-yl-4-d)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 Hi- one as a white solid. The racemic product (230 mg) was separated by Chiral- HPLC to yield (3R,8aS)-3-(5-(6-amino-2-fluoropyridin-3-yl-4,5-d2)-1H-imida zol- 2-yl-4-d)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C23H15CID3F2N9O: 512.15, measured (ES, m/z): 513.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.79 (s, 1H), 9.84 (s, 1H), 7.93 - 8.01 (m, 1H), 7.68 - 7.76 (m, 1H), 6.27 (s, 2H), 5.69 (d, J = 2.5 Hz, 1H), 5.00 (d, J = 8.4 Hz, 1H), 3.77 - 3.66 (m, 1H), 2.62 -2.80 (m, 1H), 2.55 -

2.59 (m, 1H), 1.89 -2.23 (m, 4H)/ ^ig F NMR (282 MHz, DMSO-de) δ -70.87, - 112.87.

Example 150 (3S,8aR)-3-[5-(6-amino-4-deuterio-2-fluoro-3-pyridyl)-1H- imidazol-2-yl]-7-[3-chloro-2-fluoro-6~(tetrazol-1-yl)phenyl] -2,3,8 _l 8a- tetrahydro-1 H-indolizin-5-one

Step 1: 2-(6-Acetamido-2-fluoropyridin-3-yl-4-d)-2-oxoethyl (3S,8aR)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate.

To a solution of (3R)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (800 mg, 2.46 mmol, 1.0 equiv.) in DMF (10 mL) was added cesium carbonate (482 mg, 1.48 mmol, 0.6 equiv.), followed by N-(5-(2-bromoacetyl)-6-fluoropyridin-2-yl-4-d)acetamide (816 mg, 2.96 mmol, 1.2 equiv.). The resulting mixture was stirred at room temperature overnight, diluted with water, and extracted with EA (3 * 20 mL). The organic layers were combined, washed with brine, dried over Na2S04 and concentrated. The resulting residue was purified by flash column chromatography on silica gel (MeOH/DCM, 0→8%) to yield 2-(6-acetamido-2- fluoropyridin-3-yl-4-d)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C24H20DCIF2N4O5: 519.12, measured (ES, m/z): 520.15 [M+H]*. Step 2: N-(5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6 -fluoropyridin-2-yl-4- d)acetamide.

To a mixture of 2-(6-acetamido-2-fluoropyridin-3-yl-4-d)-2-oxoethyl (3S, 8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2, 3, 5,8,8a- hexahydroindolizine-3-carboxylate (1.4 g, 2.69 mmol, 1.0 equiv.) and ammonium acetate (2.1 g, 26.93 mmol, 10.0 equiv.) in 1 ,4-dioxane (15 mL) was added acetic add (5 mL). The resulting mixture was stirred at 100 °C for 1 h. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM, 0→10%) to yield N-(5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2 -yl-4-d)acetamide as a yellow solid. LC/MS: mass calculated for C24H20DCIF2N6O2: 499.14, measured (ES, m/z): 500.10 [M+H]÷.

Step 3: N-(5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-6-fluoropyridin-2-yl-

4-d)acetamide.

A mixture of N-(5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridi n-2-yl- 4-d)acetamide (1.1 g, 2.10 mmol, 1.0 equiv.), trimethoxymethane (5 mL), azidotrimethylsilane (5 mL) and acetic add (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to yield N-(5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-6- fluoropyridin-2-yl-4-d)acetamide as a yellow solid. LC/MS: mass calculated for C25H19DCIF2N9O2: 552.15, measured (ES, m/z): 553.10 [M+H] ⁺ .

Step 4: (3S,8aR)-3-[5-(6-Amino-4-deuterio-2-fluoro-3-pyridyl)-1 H-imidazol-2-yl]- 7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetra hydro-1H-indolizin-5- one.

To a solution of N-(5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yOphenyO-S-oxo-I^.S.S.e.Sa-hexahydroindolizin-S-yO-IH-imidaz ol-S-yO-e- fluoropyridin-2-yl-4-d)acetamide (520 mg, 0.94 mmol, 1.0 equiv.) in THF (2 ml) was added HCI (4 ml_). The resulting mixture was stirred at 50 °C for 2 h, then concentrated under reduced pressure and the resulting residue was purified by reversal phase chromatography on C18 column (MeCN/H20 (0.05% CFsCOOH)) to yield (3R,8aS)-3-(5-(6-amino-2-fluoropyridin-3-yl-4-d)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid. The racemic product (150 mg) was further separated by chiral-HPLC to yield (3R,8aS)-3-(5-(6-amino-2- fluoropyridin-3-yl-4-d)-1H-imidazol-2-yl)-7-(3-chloro-2-fluo ro-6-(1H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C23H17CIDF2N9O: 510.14, measured (ES, m/z): 511.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.78 (s, 1H), 9.84 (s,

1H), 7.94 - 8.02 (m, 1H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H), 7.04 (dd, J = 4.2, 1.9 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 6.25 (s, 2H), 5.70 (d, J = 2.5 Hz, 1H), 4.99 (d, J = 8.4 Hz, 1 H), 3.66 - 3.77(m, 1 H), 2.66 - 2.76 (m, 1 H), 2.47 - 2.54 (m, 1 H), 1.95 -2.23 (m, 4H)/ ¹⁸ F NMR (282 MHz, DMSO-de) δ -70.81, -112.83. Example 151 (3S,8aR)-3-[5-(6-amino-4,5-dideuterio-2-fluoiO-3-pyridyl)-1H - imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl] -2,3,8,8a- tetrahydro-1 H-indolizin-5-one

Step 1: 6-Fluoro-3,4,5-triiodopyridin-2-amine

N-lodosucdnimide (NIS, 9.5 g, 42.02 mmol, 2.0 equiv.) was added to a solution of 6-fluoro-4-iodopyridin-2-amine (5.0 g, 21.01 mmol, 1.0 equiv.) in AcOH (50 mL) and TFA (5 ml_). The resulting mixture was maintained stirring at room temperature overnight, quenched with water (30 mL), adjusted to pH 8 with ammonium hydroxide solution, and extracted with EA (200 mL). The organic layer was separated and dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE/EA from 0% to 60% to yield 6-fluoro- 3,4,5-triiodopyridin-2-amine as a yellow solid. LC/MS: mass calculated for C5H2FI3N2: 489.73, measured (ES, m/z): 490.75 [M+H]*

Step 2: 6-Fluoropyridin-3,4,5-d3-2-amine

6-Fluoro-3,4,5-triiodopyridin-2-amine (1.0 g, 2.04 mmol, 1.0 equiv.) and Zn (668 mg, 10.21 mmol, 5.0 equiv.) were added to a solution of CDsCOOD (8.0 mL) and D2O (8.0 mL). The resulting mixture was maintained stirring at room temperature overnight, diluted with EA (100 mL) and washed with NaHCOa solution (30 mL). The organic phase was dried by N32S04 and concentrated under reduced pressure. The residue was purified by silica gel column with PE/EA 0~50% to yield 6-luoropyridin-3,4,5-d3-2-amine as a yellow solid. LC/MS: mass calculated for C5H2D3FN2: 115.06, measured (ES, m/z): 116.10 [Μ+ΗΓ

Step 3: 6-Fluoro-5-iodopyridin-3,4-d2-2-amine

6-Fluoropyridin-3,4,5-d3-2-amine (460 mg, 4.00 mmol, 1.0 equiv.) was dissolved in DMF (5 mL) and then NIS (899 mg, 4.00 mmol, 1.0 equiv.) was added at 0 °C. The resulting mixture was maintained stirring at room temperature for 2 h, extracted with EA (100 mL). The organic layer was dried over N32S04 and concentrated under reduced pressure. The residue - 6-fluoro- 5-iodopyridin-3,4-d2-2-amine - was used in the next step without further purification. LC/MS: mass calculated for C5H2D2FIN2: 239.95, measured (ES, m/z): 240.95 [M+H]÷.

Step 4: N-(6-fluoro-5-iodopyridin-2-yl-3,4-d2)acetamide

6-Fluoro-5-iodopyridin-3,4-d2-2-amine (700 mg, 2.92 mmol, 1.0 equiv.) was added to AC2O (10 mL) and the mixture was stirred at room temperature overnight, diluted with water, extracted with EA (100 mL) and washed with NaHCOs (aq.) solution. The organic phase was dried by N32S04 and concentrated under reduced pressure. The residue - of N-(6-fluoro-5- iodopyridin-2-yl-3,4-d2)acetamide - was used in the next step without further purification. LC/MS: mass calculated for C7H4D2FIN2O: 281.96, measured (ES, m/z): 282.95 [M+H] ⁺

Step 5: N-(5-(1-ethoxyvinyl)-6-fluoropyridin-2-yl-3,4-d2)acetamide

To a mixture of N-(6-fluoro-5-iodopyridin-2-yl-3,4-d2)acetamide (1.4 g, 5.03 mmol, 1.0 equiv.) and tributyl(ethynyl)stannane (2.7 g, 7.54 mmol, 1.5 equiv.) and Pd(PPh3)4 (581 mg, 0.50 mmol, 0.1 equiv.) was added 1,4-dioxane (25.0 mL). The mixture was stirred at 100 °C for 17.0 h under an atmosphere of nitrogen. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to yield N-(5-(1-ethoxyvinyl)-6-fluoropyridin-2-yl-3,4-d2)acetamide as a yellow solid. LC/MS: mass calculated for C11H11D2FN2O2: 226.25, measured (ES, m/z): 227.10 [M+H] ⁺

Step 6: N-(5-(2-bromoacetyl)-6-fluoropyridin-2-yl-3,4-d2)acetamide

NBS (378 mg, 2.12 mmol, 0.8 equiv.) added to a solution of N-(5-(1- ethoxyvinyl)-6-fluoropyridin-2-yl-3,4-d2)acetamide (600 mg, 2.65 mmol, 1.0 equiv.) was dissolved in THF (4 mL) and water (1 mL)at 0 °C and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was then diluted with water and extracted with EA (100 mL). The organic layer was dried by N32S04 and concentrated under reduced pressure. The residue - N-(5-(2- bromoacetyl)-6-fluoropyridin-2-yl-3,4-d2)acetamide - was used for the next step without further purification. LC/MS: mass calculated for CgHeD2BrFN202:

275.99, measured (ES, m/z): 278.95 [M+H+2]*

Step 7: 2-(6-Acetamido-2-fluoropyridin-3-yl-4,5-d2)-2-oxoethyl (3S,8aR)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

A mixture of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (302 mg, 0.80 mmol,

1.0 equiv.) and K2CO3 (166 mg, 1.20 mmol, 1.5 equiv.) in CHsCN (5 mL) was stirred at room temperature for 0.5 h. To the resulting mixture was added a solution of N-(5-(2-bromoacetyl)-6-fluoropyridin-2-yl-3,4-d2)acetamide (332 mg, 1.20 mmol, 1.0 equiv.) in CHsCN (5 mL). The reaction mixture was stirred for 2 h at room temperature and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (0 - 10 % DCM/MeOH) to yield 2-(6-acetamido-2-fluoropyridin-3-yl-4,5-d2)-2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C25HI8D2CIF ₂ N70 ₅ :573.13, measured (ES, m/z): 574.20 [Μ+ΗΓ

Step 8: N-(5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxo-1,2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridi n-2-yl- 3,4-d2)acetamide

2-(6-Acetamido-2-fluoropyridin-3-yl-4,5-d2)-2-oxoethyl (3S,8aR)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (300 mg, 0.52 mmol, 1.0 equiv.), ammonium acetate (806 mg, 10.45 mmol, 20.0 equiv.) and acetic add (0.25 mL) were dissolved in toluene (10.0 mL) and the reaction mixture was stirred at 90 °C for 1.5 h. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel with DCM/MeOH from 0~10% to yield N-(5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)p henyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2-yl-3,4- d ₂ )acetamide as a yellow solid. LC/MS: mass calculated for C25H18D2CIF2N9O2: 553.15, measured (ES, m/z): 554.25 [M+H]* Step 9: (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl-4,5-d2)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3 _l 8,8a-tetrahydroindolizin- 5(1H)-one

N-(5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-y l)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2-yl-3,4- d2)acetamide (150 mg, 0.27 mmol, 1.0 equiv.) was dissolved in HCI (4 M, 2.5 mL) and THF (2.5 ml_) and the mixture was stirred at 50°C for 1 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase chromatography on C18 column with MeCN/hbO (0-60%) to yield 3-(5- (6-amino-2-fluoropyridin-3-yl-4,5-d2)-1H-imidazol-2-yl)-7-(3 -chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid, which was further purified by chiral-HPLC with (Hex:DCM=3:1)(0.1%DEA):EtOH=80:20 to yield (3S,8aR)-3-(5-(6-amino-2- fluoropyridin-3-yl-4,5-d2)-1H-imidazol-2-yl)-7-(3-chloro-2-f iuoiO-6-(1H-tetrazol- 1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as an off-white solid.

LC/MS: mass calculated for C23HieCID2F2NgO: 510.14, measured (ES, m/z): 512.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.69 (s, 1H), 7.72 - 7.91 (m, 1 H), 7.56 - 7.62 (m, 1 H), 7.33 (d, J = 2.6 Hz, 1 H), 5.63 (d, J = 2.7 Hz, 1 H),

5.08 (d, J = 9.4 Hz, 1 H), 3.65 - 3.76 (m, 1 H), 2.74 - 2.91 (m, 1 H), 2.50 - 2.52 (m, 1H), 2.20 - 2.32 (m, 1H), 2.06 -2.18 (m, 1H), 1.90 - 1.97 (m, 1H), 1.80 - 1.92 (m, 1H)/ ¹⁹ F NMR (376 MHz, DMSO-de) 6 -70.14, -73.83, -112.39.

Example 1526-[2-[(3S,8a*R)-7-[3-chloro-2-fluoro-6-[4- (trifluoromethyiytriazol-1-yl]phenyl]-5-oxo-2,3,8,8a-tetrahy dro-1H-indolizin-

3-yl]-1 H-imidazol-5-yl]-1 H-quinolin-2-one

LC/MS: mass calculated for C28H20CIF4N7O2: 609.13, measured (ES, m/z): 610.20 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 9.06 (s, 1H), 7.96 - 8.09 (m, 2H), 7.91 (dd, J = 8.6, 2.0 Hz, 1 H), 7.81 (dd, J = 8.7, 7.6 Hz, 1 H), 7.56

(dd, J = 8.7, 1.6 Hz, 1H), 7.36 - 7.41 (m, 2H), 6.64 (d, J = 9.5 Hz, 1H), 5.73 (d,

J = 2.7 Hz, 1H), 5.19 (d, J = 8.6 Hz, 1H), 3.84 - 4.00 (m, 1H), 2.95 - 3.11 (m, 1H), 2.59 - 2.70 (m, 1H), 2.00 - 2.45 (m, 4H)/ ¹⁸ F NMR (282 MHz, Methanol-d*)

6 -62.57, -113.49. Example 153 (3S,8aR)-3-[4-(6-amino-2-fluoro-3-pyridyl)-1 H-imidazol-2-yl]-

7-[3-chloro-5-deuterio-2-fluoro-6-(tetrazol-1-yl)phenyl]- 2 _l 3 _l 8,8a-tetrahydro-

1H-indolizin-5-one

LC/MS: mass calculated for C23H17CIDF2N9O: 510.14, measured (ES, m/z): 511.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.77 (s, 1H), 9.84 (s, 1H), 7.96 - 8.07 (m, 2H), 7.04 (s, 1H), 6.41 (dd, J = 8.3, 2.2 Hz, 1H), 6.25 (s, 2H), 5.69 (d, J = 2.5 Hz, 1H), 4.99 (d, J = 8.3 Hz, 1H), 3.65 - 3.79 (m, 1H), 2.65 - 2.77 (m, 1H), 2.51 - 2.56 (m, 1H), 2.07 - 2.22 (m, 2H), 1.93 - 1.99 (m, 2H)/ ¹⁸ F NMR (282 MHz, Methanol-cU) δ -70.82, -112.89.

Example 154 (3S,8aR)-3-[5-(6-amino-2-fluoro-3-pyridyl)-4-deuterio-1H- imidazol-2-yl]-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl] -2,3,8 _l 8a- tetrahydro-1 H-indolizin-5-one

LC/MS: mass calculated for C23H17CIDF2N9O: 510.14, measured (ES, m/z): 511.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.79 (brs., 1 H), 9.82 (s,

1 H), 7.90 - 8.13 (m, 2 H), 7.69 (dd, J = 8.7, 1.5 Hz, 1 H), 6.39 (dd, J = 8.3, 2.2 Hz, 1 H), 6.27 (brs., 2 H), 5.67 (d, J = 2.7 Hz, 1 H), 4.98 (d, J = 8.5 Hz, 1 H), 3.62 - 3.75 (m, 1 H), 2.60 - 2.75 (m, 1 H), 2.50 - 2.52 (m, 1 H), 2.20 - 2.24 (m,

2 H), 1.83 - 7.98 (m, 2 H)/ ¹⁰ F NMR (376 MHz, DMSO-de) δ -70.84, -112.87. Example 155 (3*S,8aR)-3-(5-(3-chloro-2-(1-hydroxycyclopropyl)pyridin-4- yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one Step 1: 2-(1-((Tert-butyldimethylsilyl)oxy)vinyl)-3-chloropyridine.

To a solution of 1 -(3-chloropyridin-2-yl)ethan-1 -one (2.0 g, 12.86 mmol, 1.0 equiv.) and triethylamine (13.9 g, 38.57 mmol, 3.0 equiv.) in DCM (20 mL) was added TBSOTf (4.4 g, 16.71 mmol, 1.3 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (1 x 50 mL) and washed with water and brine (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→100% ethyl acetate/petroleum ether) to yield the 2-(1-((tert- butyldimethylsilyl)oxy)vinyl)-3-chloropyridine as a yellow oil. LC/MS: mass calculated for CnHaoCINOSi: 269.10, measured (ES, m/z): 270.05 [M+H] ⁺ .

Step 2: 2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloropyri dine.

To a solution of diethylzinc (5.6 mL, 8.34 mmol, 1.5 equiv.) in DCM (20 mL) was added chloroiodomethane (2.5 g, 13.90 mmol, 2.5 equiv.) under nitrogen at 0 °C. After 0.5 h of stirring, 2-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3- chloropyridine (1.5 g, 5.56 mmol, 1.0 equiv.) in DCM (5 mL) was added at 0 °C. The resulting mixture was maintained under nitrogen and stirred at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→20% ethyl acetate/petroleum ether) to yield the 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloropyri dine as a yellow oil. LC/MS: mass calculated for CuhtaCINOSi: 283.12, measured (ES, m/z): 284.20 [M+H] ⁺ .

Step 3: 2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloro-4-i odopyridine.

To a solution of diisopropylamine (342 mg, 3.38 mmol, 1.2 equiv.) in tetrahydrofuran (10 mL) was added n-butyllithium (1.4 mL, 3.38 mmol, 1.2 equiv.). After 0.5 h of stirring, 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3- chloropyridine (800 mg, 2.82 mmol, 1.0 equiv.) was added the above mixture at -78 °C. The mixture was maintained stirring at -78 °C for 1 h, to which was added I2 (787 mg, 3.10 mmol, 1.1 equiv.) in tetrahydrofuran (2 mL). The resulting mixture was maintained under nitrogen and stirred at room temperature for 2 h, then quenched with saturated ammonium chloride solution (20 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→20% ethyl acetate/petroleum ether) to yield the 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloropyri dine as a yellow oil. LC/MS: mass calculated for Ci4H2iCIINOSi: 409.01 , measured (ES, m/z): 410.15 [M+H] ⁺ .

Step 4: 2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloro-4-( 1- ethoxyvinyl)pyridine.

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloro-4- iodopyridine (780 mg, 1.90 mmol, 1.0 equiv.) in 1 ,4-dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.4. g, 3.81 mmol, 2.0 equiv.), Pd(PPh3)4 (220 mg, 0.19 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 4 h. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0→30% ethyl acetate/petroleum ether) to yield the 2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)-3-chloro-4-(1-ethoxyviny l)pyridine as a yellow oil. LC/MS: mass calculated for CiehfceCINCkSi: 353.16, measured (ES, m/z): 354.30 [M+H] ⁺ . Step 5: 2-Bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3 - chloropyridin-4-yl)ethan-1-one.

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloro-4- (l-ethoxyvinyl)pyridine (600 mg, 1.70 mmol, 1.0 equiv.) in THF (8 mL) was added H2O (2 mL) was added NBS (241 mg, 1.36 mmol, 0.8 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the 2-bromo-1 -(2-( 1 -((tert- butyldimethylsilyl)oxy)cyclopropyl)-3-chloropyridin-4-yl)eth an-1-one as a yellow oil. LC/MS: mass calculated for CieH23BrCIN02Si: 403.04, measured (ES, m/z): 404.05, 406.05 [M+H, M+H+2]*.

Step 6: 2-(2-(1 -((Tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloropyridin- 4-yl)-2- oxoethyl(8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloro-4- iodopyridine (780 mg, 1.90 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) was added tributyl(1-ethoxyvinyl)stannane (1.4. g, 3.81 mmol, 2.0 equiv.) followed by Pd(PPh3)4 (220 mg, 0.19 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 4 h. After cooling to room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0→30% ethyl acetate/petroleum ether) to yield the 2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3-chloro-4-( 1- ethoxyvinyl)pyridine as a yellow oil. LC/MS: mass calculated for C32H35Cl2FNe0 ₅ Si: 700.18, measured (ES, m/z): 701.15 [M+H]*.

Step 7: (8aR)-3-(5-(2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)- 3- chloropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of 2-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3- chloropyridin-4-yl)-2-oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate (340 mg, 0.49 mmol, 1.0 equiv.) in toluene (10 mL) and acetic acid (1 mL) was added ammonium acetate (748 mg, 9.69 mmol, 20.0 equiv.). The mixture was stirred at 100 °C for 1 h and the solvent was removed under vacuum. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0→10%) to yield (8aR)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)- 3- chloropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C32H35Cl2FNe02Si: 680.20, measured (ES, m/z): 681.15 [M+H] ⁺ . Step 8: (3*S,8aR)-3-(5-(3-Chloro-2-(1-hydroxycyclopropyl)pyridin-4-y l)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of (8aR)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)-3-chloropyridin-4-yl)-1H -imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1H)- one (290 mg, 0.43 mmol, 1.0 equiv.) in THF (4 mL) was added triethylamine trihydrofluoride (1 mL). The mixture was stirred at 70 °C for 1 h and then concentrated. The residue was purified by reverse phase chromatography on C18 column with CH3CN/0.05% TFA water (5→50%) to yield a residue, which was further purified by chiral-HPLC with MtBE(0.1 %DEA): EtOH=70:30 to yield (3*S,8aR)-3-(5-(3-chloro-2-(1-hydroxycyclopropyl)pyridin-4-y l)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a-tetrahydroindolizin- 5(1H)-one as an off-white solid.

LC/MS: mass calculated for C2eH2iCl2FNs02: 566.11, measured (ES, m/z): 567.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.83 (s, 1H), 8.40 (d, J = 5.1 Hz, 1H), 7.90 - 8.01 (m, 3H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.06 (d, J = 8.7 Hz, 1H), 3.69 - 3.85 (m, 1H), 2.65 - 2.70 (m, 2H), 2.18 - 2.29 (m, 1H), 2.07 - 2.16 (m, 1H), 1.90 - 2.04 (m, 2H), 0.96 - 1.09 (m, 4H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -73.66, -112.86.

Example 156 (3*R,8aR)-3-(5-(2-(((S)-1,4-dioxan-2-yl)methoxy)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C28H25CIF2N8O4: 610.17, measured (ES, m/z): 611.15 [M+H] ⁺ . ¹ H-NMR: (400 MHz, Methanol-cU) 69.58 (s, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.79 - 7.89 (m, 2H), 7.57 (dd, J = 8.7, 1.6 Hz, 1H), 7.38 (t, J = 5.0 Hz, 1H), 5.75 (d, J = 2.8 Hz, 1H), 5.19 - 5.24 (m, 1H), 4.35 - 4.47 (m, 2H), 3.49 - 4.05 (m, 8H), 2.87 - 3.02 (m, 1H), 2.63 - 2.78 (m, 1H), 2.35 - 2.59 (m, 1H), 2.19 - 2.32 (m, 2H), 1.90 - 2.03 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-d*) δ -77.09, -113.93, -143.30

Example 157 (3*S,8aR)-3-(5-(2-(((S)-1,4-dioxan-2-yl)methoxy)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C28H25CIF2N8O4: 610.17, measured (ES, m/z): 611.15 [M+H] ⁺ . ¹ H-NMR: (400 MHz, Methanol-d*) δ 9.58 (s, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.79 - 7.89 (m, 2H), 7.57 (dd, J = 8.7, 1.6 Hz, 1H), 7.38 (t, J = 5.0 Hz, 1H), 5.75 (d, J = 2.8 Hz, 1H), 5.28 (dd, J = 9.9, 1.7 Hz, 1H), 4.35 - 4.47 (m, 2H), 3.49 - 4.05 (m, 8H), 2.87 - 3.02 (m, 1H), 2.63 - 2.78 (m, 1H), 2.35 - 2.59 (m, 1H), 2.19 - 2.32 (m, 2H), 1.90 - 2.03 (m, 1H). ¹⁸ F NMR (376 MHz, Methanol-d*) δ -77.19, -113.52, -143.29. Example 158 (3*S,8a*R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(3-fluoro-2-(3-hydroxy-3-methylbutyl)pyridin-4-yl)-1H-imi dazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1 : 2-(2-(3-((Tert-butyldimethylsilyl)oxy)-3-methylbutyl)-3-fluo ropyridin-4-yl)- 2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

To a mixture of 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (170 mg, 0.45 mmol, 1.0 equiv.) and potassium carbonate (81 mg, 0.59 mmol, 1.3 equiv.) in acetonitrile (5.0 mL) was added 2-bromo-1-(2-(3-((tert-butyldimethylsilyl)oxy)-3- methylbutyl)-3-fluoropyridin-4-yl)ethan-1-one (282 mg, 0.68 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 2 h, quenched with water and extracted with EA twice. The combined organic layers were washed with brine, dried over NsfcSO* and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→10% methanol/dichloromethane) to yield 2-(2-(3-((tert-butyldimethylsilyl)oxy)-3- methylbutyl)-3-fluoropyridin-4-yl)-2-oxoethyl 7-(3-chloro-2-fluoro-6-(1H-tetrazol- 1-yl)phenyl)-5-oxo-1 ,2,3,5, 8,8a-hexahydiOindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C34hUiCIF2Ne05Si: 714.26, measured (ES, m/z): 715.15 [M+H] ⁺ .

Step 2: (3S)-3-(5-(2-(3-((Tert-butyldimethylsilyl)oxy)-3-methylbutyl )-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoiO-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one.

To a mixture of 2-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbutyl)-3- fluoropyridin-4-yl)-2-oxoethyl 7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (210 mg, 0.29 mmol, 1.0 equiv.) in toluene (3 mL) and acetic acid (0.3 mL) was added ammonium acetate (226 mg, 2.94 mmol, 10.0 equiv.). The reaction mixture was stirred at 100 °C for 2.0 h, quenched with water and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 3-(5-(2-(3-((tert- butyldimethylsilyl)oxy)-3-methylbutyl)-3-fluoropyridin-4-yl) -1H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one as a yellow solid. LC/MS: mass calculated for C34H4iCIF2Ne02Si: 694.28, measured (ES, m/z): 695.40 [M+H] ⁺ .

Step 3: (3*S,8a*R)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3-(5-(3- fluoro-2-(3-hydroxy-3-methylbutyl)pyridin-4-yl)-1H-imidazol- 2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

A mixture of 3-(5-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbutyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (180 mg, 0.26 mmol, 1.0 equiv.) in THF (1.0 mL) and hydrochloric acid (1.0 mL, 4 M) was stirred at room temperature for 2 h. The reaction mixture was concentrated and the resulting residue was purified by reverse phase chromatography on C18 column (120 g, ACN/H2O (0.05%CF ₃ COOH): 0-→35%) and further purified by prep-chiral-HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro- 2-(3-hydroxy-3-methylbutyl)pyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C28H27CIF2N8O2: 580.19, measured (ES, m/z): 581.25 [M+H] ⁺ . ¹ H-NMR: (300 MHz, DMSO-de) δ 9.78 (s, 1 H), 8.34 (d, J = 5.3 Hz, 1 H), 7.81 - 7.97 (m, 2 H), 7.55 - 7.75 (m, 2 H), 5.67 (d, J = 2.5 Hz, 1 H), 5.06 (d, J = 8.8 Hz, 1 H), 3.86 - 3.90 (m, 1 H), 2.85 -2.89 (m, 2 H), 2.73 (t,

J = 15.0 Hz, 1 H), 2.55 - 2.62 (m, 1 H), 2.06 - 2.32 (m, 2 H), 1.83 - 2.02 (m, 2 H), 1.67 - 1.79 (m, 2 H), 1.15 (s, 6 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.92, -113.11, -128.94.

Example 159 (3*S,8a*S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3- (5-(3-fluoro-2-(3-hydroxy-3-methylbiityl)pyridin-4-yl)-1H-im idazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C28H27CIF2N8O2: 580.19, measured (ES, m/z): 581.25 [M+H] ⁺ . ¹ H-NMR: (300 MHz, DMSO-de) 69.76 (s, 1 H), 8.34 (d, J = 5.4 Hz, 1 H), 7.76 - 7.95 (m, 3 H), 7.57 - 7.70 (m, 1 H), 5.67 (d, J = 2.5 Hz, 1 H), 5.04 (t, J = 7.8 Hz, 1 H), 4.05 - 4.23 (m, 1 H), 2.84 - 2.96 (m, 2 H), 2.56 - 2.65 (m, 1 H), 2.32 - 2.48 (m, 2 H), 2.20 - 2.30 (m, 1 H), 1.86 - 2.06 (m, 1 H),

1.64 - 1.79 (m, 3 H), 1.15 (s, 6 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.86, - 113.06, -129.05.

Example 160 (3*S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 - (5-(2-(1,1-difluoro-2-hydroxyethyl)-3-fluoropyridin-4-yl)-1H -imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: Ethyl 2,2-difluoro-2-(3-fluoropyridin-2-yl)acetate.

To a solution of 2-bromo-3-fluoropyridine (5.0 g, 28.40 mmol, 1.0 equiv.) in DMSO (70 mL) were added ethyl 2-bromo-2,2-difluoroacetate (8.6 g, 42.60 mmol, 1.5 equiv.) and Cu (3.6 g, 56.80 mmol, 2.0 equiv.). The resulting mixture was stirred at 50 °C for 8 h, then diluted with EA and KH2PO4 solution, and stirred for 0.5 h at 25 °C. The resulting mixture was filtered and washed with EA (200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→20% ethyl acetate/petroleum ether) to yield ethyl 2,2-difluoro-2-(3-fluoropyridin-2-yl)acetate as a yellow oil. LC/MS: mass calculated for C9H8F3NO2: 219.05, measured (ES, m/z): 220.20 [M+H] ⁺ . Step 2: 2,2-Difluoro-2-(3-fluoropyridin-2-yl)ethan-1-ol.

To a solution of ethyl 2,2-difluoro-2-(3-fluoropyridin-2-yl)acetate (4.3 g, 19.60 mmol, 1.0 equiv.) in EtOH (80 mL) was added NaBhU (0.70 g, 19.60 mmol, 1.0 equiv.). The resulting mixture was stirred at 25 °C for 1 h. The solvent was removed under vacuum and the residue was partitioned between water and EA. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2,2-difluoro- 2-(3-fluoropyridin-2-yl)ethan-1-ol. LC/MS: mass calculated for CyHeFsNO: 177.04, measured (ES, m/z): 178.15 [M+H]*.

Step 3: 2-(2-((Tert-butyldimethylsilyl)oxy)-1 , 1-difluoroethyl)-3-fluoropyridine.

To a solution of 2,2-difluoro-2-(3-fluoropyridin-2-yl)ethan-1-ol (1.6 g, 9.00 mmol, 1.0 equiv.) in DCM (30 mL) were added TBSOTf (3.1 g, 11.70 mmol, 1.3 equiv.) and 2,6-lutidine (2.9 g, 27.10 mmol, 3.0 equiv.). The resulting mixture was stirred at 25 °C for 1 h. The mixture was partitioned between DCM (100 mL) and water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0→10% ethyl acetate/petroleum ether) to yield 2-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-3-flu oropyridine as a yellow oil. LC/MS: mass calculated for Ci3H2oF3NOSi: 291.13, measured (ES, m/z): 292.05 [M+H] ⁺ .

Step 4: 2-(2-((Tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-3-flu oro-4- iodopyridine.

To a solution of 2-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-3- fluoropyridine (2.3 g, 7.80 mmol, 1.0 equiv.) in THF (30 mL) was added LDA (0.90 g, 8.60 mmol, 1.1 equiv.). The resulting mixture was stirred at -70 °C for 0.5 h. To the mixture was then added I2 (2.0 g, 7.80 mmol, 1.0 equiv.). The resulting mixture was stirred at 25 °C for 1 h, quenched with NhUCI and extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0→10% ethyl acetate/petroleum ether) to yield 2-(2-((tert-butyldimethylsilyl)oxy)-1 , 1-difluoroethyl)-3-fluoro-4-iodopyridine. LC/MS: mass calculated for CiaHigFalNOSi: 417.02, measured (ES, m/z): 418.10 [M+H] ⁺ .

Step 5: 2-(2-((Tert-butyldimethylsilyl)oxy)-1 , 1-difluoroethyl)-4-(1-ethoxyvinyl)-3- fluoropyridine.

To a solution of 2-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-3- fluoro-4-iodopyridine (1.5 g, 3.60 mmol, 1.0 equiv.) in 1,4-dioxane (40 mL) were added trimethyl((tributylstannyl)ethynyl)silane (2.0 g, 5.40 mmol, 1.5 equiv.) and Pd(PPh3)4 (0.4 g, 0.36 mmol, 0.1 equiv.). The resulting mixture was stirred at 90 °C for 16 h. The mixture was extracted with EA (150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on AI2O3 column (0→10% ethyl acetate/petroleum ether) to yield 2-(2-((tert- butyldimethylsilyl)oxy)-1 , 1-difiuoroethy l)-4-(1 -ethoxy vinyl)-3-fluoropyridine as a yellow oil. LC/MS: mass calculated for Ci7H2eF3N02Si: 361.17, measured (ES, m/z): 362.30 [M+H] ⁺ . Step 6: 2-Bromo-1-(2-(2-((tert-butyldimethylsilyl)oxy)-1 ,1-difiuoroethyl)-3- fluoropy ridi n-4-yl)ethan- 1 -one.

To a solution of 2-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-4-(1- ethoxyvinyl)-3-fluoropyridine (1.3 g, 3.50 mmol, 1.0 equiv.) in THF (20 mL) and H2O (5 mL) was added NBS (0.50 g, 3.20 mmol, 0.9 equiv.). The resulting mixture was stirred at 25 °C for 1 h, diluted with water and extracted with EA (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 2-bromo-1-(2-(2-((tert- butyldimethylsilyl)oxy)-1 , 1 -difiuoroethyl)-3-fluoropyridin-4-yl)ethan- 1 -one. LC/MS: mass calculated for CisFfeiBrFsNCfcSi: 411.05, measured (ES, m/z): 412.20, 414.20 [M+H, M+H+2]*.

Step 7: 2-(2-(2-((Tert-butyldimethylsilyl)oxy)-1 , 1 -difluoroethyl)-3-fluoropyridin-4- yl)-2-oxoethyl (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5 _l 8,8a- hexahydroindolizine-3-carboxylate.

To a solution of (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (299 mg, 0.90 mmol, 1.0 equiv.) in ACN (3 mL) was added K2CO3 (191 mg, 1.40 mmol, 1.5 equiv.). The resulting mixture was stirred at 25 °C for 0.5 h. To the mixture was then added 2-bromo-1-(2-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroe thyl)-3-fluoropyridin- 4-yl)ethan-1-one (380 mg, 0.90 mmol, 1.0 equiv.). The resulting mixture was stirred at 25 °C for 16 h and extracted with EA (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5→70% ethyl acetate/petroleum ether) to yield 2-(2-(2-((tert-butyldimethylsilyl)oxy)-1,1- difluoroethyl)-3-fluoropyridin-4-yl)-2-oxoethyl (8aR)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a yellow oil. LC/MS: mass calculated for C30H34CIF4N3O5S1: 655.19, measured (ES, m/z): 656.15 [M+H]*.

Step 8: (8aR)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(2-(2-((tert- butyldimethylsilyl)oxy)-1 ,1-difluoroethyl)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of 2-(2-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-3- fluoropyridin-4-yl)-2-oxoethyl (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (200 mg, 0.30 mmol, 1.0 equiv.) in acetic acid (0.3 mL) and toluene (3 mL) was added ammonium acetate (470 mg, 6.00 mmol, 20.0 equiv.). The resulting mixture was heated at 100 °C with stirring for 1 h, then cooled to room temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5- (2-(2-((tert-butyldimethylsilyl)oxy)-1 , 1-difluoroethyl)-3-fluoropyridin-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C3oH34CIF4Ns02Si: 635.21, measured (ES, m/z): 636.40 [M+H] ⁺ .

Step 9: (8aR)-3-(5-(2-(2-((Tert-butyldimethylsilyl)oxy)-1 , 1-difluoroethyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(2- ((tert-butyldimethylsilyl)oxy)-1 , 1 -difiuoroethyl)-3-fluoropyridin-4-yl)- 1 H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (170 mg, 0.20 mmol, 1.0 equiv.) in AcOH (2 mL) was added TMSNs (1 mL ) followed by addition of trimethoxymethane (1 mL). The resulting mixture was stirred at 25 °C for 16 h, then concentrated under reduced pressure and the residue was purified by reverse phase chromatography on C18 column with ACN/water (0.05% TFA) (5→90%) to yield (8aR)-3-(5-(2-(2-((tert-butyldimethylsilyl)oxy)-1,1- difluoroethyl)-3-fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C3iH33CIF4Ne02Si: 688.21, measured (ES, m/z): 689.35 [M+H] ⁺ .

Step 10: (3*S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(2- (1 ,1-difluoro-2-hydroxyethyl)-3-fluoropyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of (8aR)-3-(5-(2-(2-((tert-butyldimethylsilyl)oxy)-1,1- difluoroethyl)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (90 mg, 0.10 mmol, 1.0 equiv. ) in THF (2 mL) was added triethylamine trihydrofluoride (0.5 mL).

The resulting mixture was stirred at 80 °C for 1 h, then concentrated and the residue was purified by reverse phase chromatography on C18 column with ACN/water (0.05% TFA) (5→50%) and chiral-HPLC with hexanes (0.1%DEA):EtOH=50:50 to yield (3S*,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol- 1 -yl)phenyl)-3-(5-(2-(1 , 1-difluoro-2-hydroxyethyl)-3-fluoropyridin-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizirv5(1 H)-one as a white solid.

LC/MS: mass calculated for C25H19CIF4N8O2: 574.13, measured (ES, m/z): 575.10 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) δ 12.38 (s, 1H), 9.84 (s, 1H), 8.45 - 8.46 (m, 1H), 8.10 - 8.13 (m, 1H), 7.95 - 7.99 (m, 1H), 7.66 - 7.73 (m, 2H), 5.69 - 5.70 (m, 1H), 5.59 - 5.60 (m, 1H), 5.03 - 5.06 (m, 1H), 4.03 - 4.12(m, 2H), 3.71- 3.86 (m, 1H), 2.68 - 2.82(m, 1H), 2.53 - 2.58 (m, 1H), 2.18 - 2.29 (m, 1H), 2.07 - 2.12 (m, 1H), 1.88 - 1.97 (m, 2H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -105.46, -112.85, -126.96.

Example 161 (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(3- fluoro-2-((2-methoxyethyl)amino)pyridin-4-yl)-1H-imidazol-2- yl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eH24CIF2Ng02: 567.17, measured (ES, m/z): 568.10 [M+H] ⁺ . ¹ H-NMR: (300 MHz, DMSO-de) 6 12.10 (s, 1H), 9.81 (s, 1H), 7.95 (dd, J = 8.7, 7.8 Hz, 1H), 7.77 (d, J = 5.3 Hz, 1H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.42 (s, 1H), 7.02 - 7.19 (m, 1H), 6.32 - 6.57 (m, 1H), 5.67 (d, J = 2.5 Hz, 1H), 4.90 - 5.10 (m, 1H), 3.64 - 3.76 (m, 1 H), 3.44 - 3.54 (m, 4H), 3.25

(s, 3H), 2.64 - 2.77 (m, 1H), 2.50 - 2.55 (m, 1H), 2.06 - 2.23 (m, 2H), 1.92 - 2.00 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.84, -143.76.

Example 162 (3*R,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yi)phenyl)-3- (5-(3-fluoro-2-(1 -hydroxy cyclopropyl)pyridin-4-yl)-1 H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1 : 2-(2-(3-((Tert-butyldimethylsilyl)oxy)-3-methylbutyl)-3-fluo ropyridin-4-yl)- 2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate.

To a solution of (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1, 2,3,5, 8, 8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.80 mmol,

1.0 equiv.) in CHaCN (10 mL) was added K2CO3 (220 mg, 1.59 mmol, 2.0 equiv.) followed by addition of 2-bromo-1-(2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)-3-fluoropyhdin-4-yl)etha n-1-one (925 mg, 2.38 mmol, 3.0 equiv.). The mixture was stirred at room temperature for 1 h, diluted with water and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield the 2-(2-(1-((tert- butyldimethylsilyl)oxy)cydopropyl)-3-fluoropyridin-4-yl)-2-o xoethyl (8aR)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C32H35CIF2NeOsSi: 684.21, measured (ES, m/z): 685.30 [M+H] ⁺ .

Step 2: (8aR)-3-(5-(2-(1-((Tert-butyldimethylsilyl)oxy)cyclopropyl)- 3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one.

To a solution of 2-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-3- fluoropyridin-4-yl)-2-oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate (780 mg, 0.14 mmol, 1.0 equiv.) in toluene (1 mL) and acetic acid (0.1 mL) was added ammonium acetate (1.8 g, 22.77 mmol, 20.0 equiv.). The mixture was stirred at 100 °C for 1 h. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel with MeOH/DCM

(0→20%) to yield (8aR)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)- 3- fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chlorO-2-fluoro-6 -(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C32H35CIF ₂ N ₈ 02Si: 664.23, measured (ES, m/z): 665.40 [M+H] ⁺ . Step 3: (3*R,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3- fluoro-2-(1-hydroxycyclopropyl)pyridin-4-yl)-1H-imidazol-2-y l)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one.

To a solution of (8aR)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)-3-fluoropyridin-4-yl)-1H -imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-5(1H)- one (380 mg, 0.57 mmol, 1.0 equiv.) in THF (4 mL) was added triethylamine trihydrofluoride (1 mL). The mixture stirred at 70 °C for 1 h. The residue was purified by reverse phase chromatography on C18 column with CH3CN/0.05% TFA water (5→50%) to yield a residue, which was further purified by chiral- HPLC with MtBE(0.1 %DEA): EtOH=50:50 to yield (3*R,8aR)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol- 1 -yl)phenyl)-3-(5-(3-fluoro-2-(1- hydroxycyclopropyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin- 5(1H)-one as a light yellow solid.

LC/MS: mass calculated for C2eH2iCIF2Ne02: 550.14, measured (ES, m/z): 551.10 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) δ 12.20 (s, 1H), 9.81 (s, 1 H), 8.23 (d, J = 5.0 Hz, 1 H), 7.88 - 7.98 (m, 1 H), 7.80 - 7.88 (m, 1 H), 7.66 -

7.73 (m, 1H), 7.52 - 7.59 (m, 1H), 6.05 (s, 1H), 5.68 (d, J = 2.6 Hz, 1H), 5.02 (d, J = 8.6 Hz, 1H), 3.64 - 3.82 (m, 1H), 2.61 - 2.82 (m, 1H), 2.29 - 2.46 (m, 1H), 2.15 - 2.26 (m, 1H), 2.03 - 2.12 (m, 1H), 1.89 - 2.00 (m, 2H), 1.07 - 1.17 (m, 2H), 0.92 - 1.06 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.87, -126.26.

Example 163 (2*S)-2-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)propanenitrile LC/MS: mass calculated for C2eH2oCIF2NeO: 547.14, measured (ES, m/z): 548.15 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) δ 12.36 (brs, 1H), 9.84 (s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 7.92 - 8.01 (m, 2H), 7.69 - 7.80 (m, 1H), 7.63 (d, J = 4.0 Hz, 1H), 5.70 (d, J = 2.6 Hz, 1H), 5.05 (d, J = 8.8 Hz, 1H), 4.71 (q, J = 7.1 Hz, 1 H), 3.66 - 3.85 (m, 1 H), 2.64 - 2.82 (m, 1 H), 2.56 (d, J = 4.2 Hz, 1 H), 2.04 - 2.31 (m, 2H), 1.86 - 2.05 (m, 2H), 1.61 (d, J = 7.1 Hz, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.85, -128.95.

Example 164 (2*R)-2-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazoM- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)propanenitrile

LC/MS: mass calculated for C2eH2oCIF2NgO: 547.14, measured (ES, m/z): 548.15 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) δ 12.39 (brs, 1H), 9.84 (s, 1H), 8.42 (d, J = 5.0 Hz, 1H), 7.92 - 8.04 (m, 2H), 7.69 - 7.82 (m, 1H), 7.64 (d, J = 4.0 Hz, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.05 (d, J = 8.8 Hz, 1H), 4.71 (q, J = 7.1 Hz, 1H), 3.67 - 3.86 (m, 1H), 2.72 (t, J = 15.1 Hz, 1H), 2.56 (d, J = 4.2 Hz, 1H), 2.05 - 2.31 (m, 2H), 1.90 - 2.04 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -112.87, -128.93.

Example 1652-(4-(2-((3 ^w S,8a ^w R)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)- 1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroin dolizin-3-yl)- 1H-imidazol-5-yl)-3-fluoropyridin-2-yl)acetamide

LC/MS: mass calculated for C27H20CIF5N8O2: 618.13, measured (ES, m/z): 619.15 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) 12.02 - 12.70 (m, 1H), 9.34 (s, 1H), 8.24 (d, J = 5.0 Hz, 1H), 7.98 - 8.05 (m, 1H), 7.82 - 7.88 (m, 1H), 7.71 - 7.76 (m, 1H), 7.42 - 7.58 (m, 2H), 7.00 (s, 1H), 5.70 (d, J = 2.6 Hz, 1H), 5.03 (d, J = 8.7 Hz, 1H), 3.68 - 3.77 (m, 3H), 2.30 - 2.50 (m, 2H), 2.09 - 2.19 (m, 2H), 1.91 - 2.00 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -127.59, -112.90,

-59.57.

Example 166 (3S,8aR)-7-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5- [3- fluoro-2-(2-hydroxy-2-methyl-propoxy)-4-pyridyl]-1H-imidazol -2-yl]- 2,3,8,8a-tetrahydro-1H-indolizin-5-one

Step 1: 2-(3-Fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)-2-oxo ethyl (3S)-

7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-he xahydroindolizine-3- carboxylate.

To a solution of 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) in DMF (5 ml_) were added 2-bromo-1-(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin- 4-yl)ethan-1-one (226 mg, 0.74 mmol, 1.0 equiv.) and CS2CO3 (120 mg, 0.37 mmol, 0.6 equiv.). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0→30% MeOH/DCM) to yield 2-(3-fluoro-2-(2-hydroxy-2- methylpropoxy)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a yellow solid. LC/MS: mass calculated for C2eH2eCIF2N30e: 549.15, measured (ES, m/z): 550.20 [M+H] ⁺ .

Step 2: (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(4-(3-fluoro-2-(2 -hydroxy-2- methylpropoxy)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetra hydroindolizin- 5(1H)-one.

To a solution of 2-(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (250 mg, 0.46 mmol, 1.0 equiv.) in toluene (5.0 mL) and CHaCOOH (0.5 mL) was added NhUOAc (350mg, 4.55 mmol,

10.0 equiv.). The reaction mixture was stirred for 2 h at 110 °C, quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over NaaSO* and concentrated. The residue was purified by flash column chromatography on silica gel (0→30% MeOH/DCM) to yield 2-(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)-2-oxo ethyl (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate as a yellow oil. LC/MS: mass calculated for C2eH2eCIF2N503: 529.17, measured (ES, m/z): 530.15 [M+H] ⁺ .

Step 3: (3S _l 8aR)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-3-[5-[3-fluoro-2- (2-hydroxy-2-methyl-propoxy)-4-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-

1H-indolizin-5-one.

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3-fluoro- 2-(2-hydroxy- 2-methylpropoxy)pyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (100 mg, 0.19 mmol, 1.0 equiv.) in AcOH (3 mL) were added TMSNs (217 mg, 1.89 mmol, 10.0 equiv.) and trimethoxymethane (200 mg, 1.89 mmol, 10.0 equiv.).The reaction mixture was stirred overnight at room temperature, quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 column to yield (3S,8aR)-7-(3-chloro-2-fluoro-6- (1H-tetrazol-1-yl)phenyl)-3-(4-(3-fluoro-2-(2-hydroxy-2-meth ylpropoxy)pyridin-4- yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C27H25CIF2N8O3: 582.17, measured (ES, m/z): 583.15 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) δ 12.22 (s, 1H), 9.81 (s, 1 H), 7.90 - 8.00 (m, 1 H), 7.88 (d, J = 5.3 Hz, 1 H), 7.69 (dd, J = 8.7, 1.5 Hz, 1 H),

7.48 - 7.57 (m, 2H), 5.67 (d, J = 2.7 Hz, 1H), 5.02 (d, J = 8.7 Hz, 1H), 4.63 (s, 1H), 4.11 (s, 2H), 3.67 - 3.74 (m, 1H), 2.70 - 2.80 (m, 1H), 2.49 - 2.52 (m, 1H), 2.14 - 2.23 (m, 1H), 2.05 - 2.13 (m, 1H), 1.89 - 1.98 (m, 2H), 1.20 (s, 6H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.86, -143.22.

Example 167 (3S,8aR)-3-(5-(6-amino-2-(trifluoromethyl)pyridin-3-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro~6~(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 5-(1-Ethoxyvinyl)-6-(trifluoromethyl)pyridin-2-amine.

To a mixture of 5-bromo-6-(trifluoromethyl)pyridin-2-amine (3.0 g, 12.45 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL) was added tributyl(1- ethoxyvinyl)stannane (5 mL, 14.94 mmol, 1.2 equiv.), followed by addition of Pd(PPh3)4 (1.4 g, 1.25 mmol, 0.1 equiv.) under N2. The solution was stirred for at 90°C overnight under nitrogen, then diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under vacuum. The residue was purified by flash column chromatography on AI2O3 column (0→40% EA/PE) to yield 5-(1-ethoxyvinyl)-6- (trifluoromethyl)pyridin-2-amine as a yellow oil. LC/MS: mass calculated for C10H11F3N2O: 232.08, measured (ES, m/z): 233.05 [M+H]÷.

Step 2: 1-(6-Amino-2-(trifluoromethyl)pyridin-3-yl)-2-bromoethan-1-o ne.

To a mixture of 5-(1-ethoxyvinyl)-6-(trifluoromethyl)pyridin-2-amine (1.5 g, 6.46 mmol, 1.0 equiv.) in THF (15 mL) and water (5 mL) was added N- bromosucdnimide (0.92 g, 5.17 mmol, 0.8 equiv.). The reaction mixture was stirred at room temperature for 30 min, diluted with H2O and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2S04 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→50% EA/PE) to yield 1-(6-amino-2-

(trifluoromethyl)pyridin-3-yl)-2-bromoethan-1-one as a yellow solid. LC/MS: mass calculated for CeHeBrFstoO: 281.96, measured (ES, m/z): 282.95, 284.95 [M+H, M+H+2] ⁺ . Step 3: 2-(6-Amino-2-(trifluoromethyl)pyridin-3-yl)-2-oxoethyl (3S,8aR)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate.

A mixture of 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.79 mmol, 1.0 equiv.) and potassium carbonate (143 mg, 1.03 mmol, 1.3 equiv.) in acetonitrile (5 ml_) was stirred at room temperature for 20 min. 1-(6-Amino-2- (trifluoromethyl)pyridin-3-yl)-2-bromoethan-1-one (292 mg, 1.03 mmol, 1.3 equiv.) was added and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over NaaSO* and concentrated under vacuum to yield 2-(6-amino-2-(trifluoromethyl)pyridin- 3-yl)-2-oxoethyl 7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a light yellow solid. LC/MS: mass calculated for C24H18CIF4N7O4: 579.10, measured (ES, m/z): 580.10 [M+H] ⁺ .

Step 4: (3S,8aR)-3-(5-(6-Amino-2-(trifluoromethyl)pyridin-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a-tetrahydroindolizin-

5(1H)-one.

To a mixture of 3-(5-(2-(3-((tert-butyldimethylsilyl)oxy)-3-methylbutyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (320 mg, 0.55 mmol, 1.0 equiv.) in toluene (5 mL) and acetic acid (0.5 mL) was added ammonium acetate (425 mg, 5.52 mmol, 10.0 equiv.). The reaction mixture was stirred at 100 °C for 2.0 h, diluted with water and extracted with EA twice. The combined organic layers were washed with brine, dried over Na2S04, concentrated under vacuum. The residue was purified by reverse phase chromatography on C18 column (330 g, ACN/H2O (0.05%CF3COOH): 0→40%) and the residue was further purified by prep-chiral-HPLC to yield (3S,8aR)-3-(5-(6-amino-2- (trifluoromethyl)pyridin-3-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C24H18CIF4N9O: 559.13, measured (ES, m/z): 560.10 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) 6 12.31 (brs., 1 H), 9.83 (s, 1 H), 7.90 - 8.10 (m, 1 H), 7.67 - 7.81 (m, 2 H), 7.10 - 7.23 (m, 1 H), 6.75 (d, J = 8.6 Hz, 1 H), 6.54 (s, 2 H), 5.68 (d, J = 2.7 Hz, 1 H), 5.03 (d, J = 8.7 Hz, 1 H), 3.63 - 3.80 (m, 1 H), 2.66 - 2.79 (m, 1 H), 2.53 - 2.56 (m, 1 H), 2.05 - 2.30 (m, 2 H), 1.89 - 2.04 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -61.88, -73.47,

-112.82

Example 168 (3S,8a*R)-7-(3-chloro-2-fluoiO-6-(1H-tetrazol-1-yl)phenyl)-3 - (5-(3-f1uoro-2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)- 1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: (R)-2-((1-(benzyloxy)propan-2-yl)oxy)-3-fluoro-4-iodopyridin e

To a solution of (R)-1-(benzyloxy)propan-2-ol in THF (50 mL) was added NaH (1.9, 16.60 mmol, 2.0 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h, then 2,3-difluoro-4-iodopyridine (2.0 g, 8.30 mmol, 1.0 equiv.) was added. The mixture was slowly warmed to room temperature, and stirred for 5 h, then quenched with water (100 mL) and extracted with EA (50 mLx 3). The combined organic extracts were washed with brine, dried over anhydrous NaaSO*. filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by flash column chromatography on silica gel to yield (R)-2-((1-(benzyloxy)propan-2-yl)oxy)-3-fluoro-4-iodopyridin e as colorless oil. LC/MS: mass calculated for C15H15FINO2: 387.01, measured: 387.90 [M+H] ⁺ .

Step 2: (R)-2-((3-fluoro-4-iodopyridin-2-yl)oxy)propan-1-ol

To a solution of (R)-2-((1-(benzyloxy)propan-2-yl)oxy)-3-fluoro-4- iodopyridine in DCM (50 mL) was added BBra in DCM (5.2 mL, 2.0 equiv.) at - 78 °C. The mixture was stirred at -78 °C for 2 h until the starting material was totally converted. The reaction was quenched with water (6 mL) and extracted with EA (6 mLx 3). The combined organic extracts were washed with brine, dried over anhydrous NazSO*, filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by silica gel chromatography to yield (R)-2-((3-fiuoro-4-iodopyridin-2-yl)oxy)propan-1-ol as colorless oil. LC/MS: mass calculated for CeHeFINCfc: 296.97, measured: 298.00 [Μ+ΗΓ.

Step 3: (R)-2-((4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)oxy)propan-1- ol

To a solution of methyl (R)-2-((3-fluoro-4-iodopyridin-2-yl)oxy)propan-1- ol (248 mg, 0.83 mmol, 1.2 equiv.) in 1,4-dioxane (10 mL) was added tributyl(1- ethoxyvinyl)stannane (363 mg, 1.00 mmol, 1.2 equiv.) at room temperature. followed by addition of Pd(PPh3)4 (193 mg, 0.16 mmol, 0.2 equiv.). The mixture was stirred at 100 °C for 2 h till the starting material fully consumed. The reaction was quenched with H2O (2 mL) and extracted with EA (50 mL). The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on AI2O3 column to yield (R)-2-((4-(1- ethoxyvinyl)-3-fluoropyridin-2-yl)oxy)propan-1-ol as a yellow oil. LC/MS: mass calculated for C12H16FNO3: 241.11, measured: 242.05 [M+H]*.

Step 4: (R)-2-bromo-1-(3-fluoro-2-((1-hydroxypropan-2-yl)oxy)pyridin -4- yl)ethan-1-one

To a solution of (R)-2-((4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)oxy)propan- 1-ol (628 mg, 2.61 mmol, 1.0 equiv.) in THF/H2O (3:1) (15 mL) was added NBS (N-bromosuccinimide) (556 mg, 3.12 mmol, 1.2 equiv.) at room temperature. The mixture was stirred at room temperature, for 4 h, diluted with water and then extracted with EA (100 mL). The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield (R)-2-bromo-1-(3-fluoro-2-((1-hydroxypropan-2-yl)oxy)pyridin -4-yl)ethan- 1-one as a residue. The residue was used directly in the next step without any purification. LC/MS: mass calculated for CioHuBrFNOs: 290.99, measured: 292.10 [Μ+ΗΓ, 294.10 [Μ+Η+2Γ. Step 5: 2-(3-fluoro-2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)-2 -oxoethyl (3S)-7-(3-chloro-2-fiuoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate To a solution of (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1, 2,3, 5,8, 8a-hexahydroindolizine-3-carboxylic acid in DMF (5 mL) was added CS2CO3 (92 mg, 0.28 mmol, 0.6 equiv.). The mixture was stirred at room temperature, for 1h. Then, (R)-2-bromo-1-(3-fluoro-2-((1-hydroxypropan-2- yl)oxy)pyridin-4-yl)ethan-1-one (275 mg, 0.94 mmol, 2.0 equiv.) was added.

The resulting mixture was stirred at room temperature, for 3 h, diluted with water (6 mL) and extracted with EA (6 mLx 3). The combined organic extracts were washed with brine, dried over anhydrous N32S04, filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by flash column chromatography on silica gel to yield 2-(3-fluoro-2- (((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate as a yellow solid. LC/MS: mass calculated for CiehtaCIFzNeOe: 588.13, measured: 589.15 [M+HJ*. Step 6: (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3- fluoro-2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)-1H-imi dazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 2-(3-fluoro-2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4- yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (217 mg, 0.37 mmol, 1.0 equiv.) in toluene (10 mL) and AcOH (1 mL) was added ammonium acetate (284 mg, 3.69 mmol, 10.0 equiv.) and the reaction mixture was heated to reflux with stirring for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (50 mLx 3). The combined organic extracts were washed with brine, dried over anhydrous NaaSO*. filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by flash column chromatography on silica gel and preparative HPLC using a XBridge Prep OBD C18 150 mm x 30 mm x 5 pm column (eluent: 36% to 66% (v/v) ChbCN and H2O with 0.05% NH4HCO3) to yield the (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(((R)-1-hydroxypropan -2-yl)oxy)pyridin-4- yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C2eH23CIF2Ne03: 568.15, measured (ES, m/z): 569.05 [M+H]*. ¹ H-NMR: 1H NMR (300 MHz, DMSO-de) δ 12.27 (brs,

1H), 9.83 (s, 1H), 7.90 - 8.10 (m, 2H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.45 - 7.60 (m, 2H), 5.67 (d, J = 2.5 Hz, 1H), 4.60 - 5.10 (m, 2H), 4.18 -4.35 (m, 1H), 4.07 - 4.18 (m, 1H), 3.91 - 4.07 (m, 1H), 3.82 - 3.63 (m, 1H), 2.54 - 2.85 (m, 2 H), 2.05 - 2.40 (m, 2H), 1.80 - 2.05 (m, 2H), 1.14 (d, J = 6.2 Hz, 3H). ¹⁸ F NMR

(282 MHz, DMSO-de) δ -112.84, -143.07.

Example 169 (3S,8a*S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(3-f1uoro-2-(((R)-1-hydroxypropan-2-yl)oxy)pyridin-4-yl)- 1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

N=N

/, ci-^%

/

N ,s

O v NH

F ί <55 N IH

LC/MS: mass calculated for C2eH23CIF2Ne03: 568.15, measured (ES, m/z): 569.05 [M+H]*. ¹ H-NMR: (300 MHz, DMSO-de) δ 12.31 (brs, 1H), 9.83 (s, 1H), 7.86 - 8.01 (m, 2H), 7.69 (d, J = 8.7 Hz, 1H), 7.43 - 7.56 (m, 2H), 5.67 (d, J = 2.5 Hz, 1H), 5.15 - 5.35 (m 1H), 5.03 (d, J = 8.5 Hz, 1H), 3.65 - 3.89 (m, 1H), 3.45 - 3.64 (m, 3H), 2.65 - 2.89 (m, 2H), 2.01 - 2.45 (m, 2H), 1.87 - 2.01 (m, 2H), 1.15 - 1.35 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.84, -142.52. Example 170 (3*S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3- (5-(2-((*S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for CasHiaCIFsNeCk: 592.12, measured (ES, m/z): 593.05 [M+H]*. ¹ H-NMR: (400 MHz, DMSO-de) δ 9.82 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.90 - 8.15 (m, 2H), 7.55 - 7.75 (m, 2H), 5.70 (d, J = 2.7 Hz, 1H), 5.42 - 5.50 (m, 1H), 5.05 - 5.10 (m, 1H), 3.76 - 3.85 (m, 1H), 2.71 - 2.80 (m,

1H), 2.58 - 2.60 (m, 1H), 2.07 - 2.26 (m, 2H), 1.91 - 2.00 (m, 2H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -75.11, -112.82, -128.57.

Example 171 (3*S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3- (5-(3-fluoro-2-((*R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin- 4-yl)-1H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: 2,2,2-trifluoro- 1 -(3-fluoropyridin-2-yl)ethan- 1 -one

To a solution of 2-bromo-3-fluoropyridine (5.0 g, 28.41 mmol, 1.0 equiv.) in toluene (40 mL) was dropwise added n-butyllithium (14.8 mL, 36.94 mmol, 1.3 equiv.) under -65 °C under N2. After 30 min, 2,2,2-trifluoro-N-methoxy-N- methylacetamide (6.69 g, 42.62 mmol, 1.5 equiv.) was added to the mixture under -65 °C. The resulting mixture was maintained with stirring for additional 1h, then quenched with NhUCI (aq.), diluted with EA (40 mL) and extracted with EA (2 x 40 mL). The organic layers were combined, washed with brine, dried over N32S04 and concentrated. The residue was purified by flash column chromatography on silica gel (0→50% EA/PE) to yield 2,2,2-trifluoro-1-(3- fluoropyridin-2-yl)ethan-1-one as a yellow oil. LC/MS: mass calculated for C7H3F4NO: 193.02, measured: 212.00 [Μ+Η+Η2ΟΓ. Step 2: 2,2,2-trifluoro- 1-(3-fluoropyridin-2-yl)ethan-1-ol

To a solution of 2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-one (3.9 g, 20.04 mmol, 1.0 equiv.) in DCE (40 mL) was added sodium triacetoxyborohydride (5.5 g, 26.05 mmol, 1.3 equiv.) in several portions. The resulting mixture was stirred at room temperature overnight and diluted with water (50 mL), extracted with EA (3 ^χ 30 mL). The organic layers were combined, washed with brine, dried over N32S04, and concentrated to yield 2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-ol as a light yellow oil. LC/MS: mass calculated for C7H5F4NO: 195.03, measured: 196.02 [M+H] ⁺ .

Step 3: 2-(1 -((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3-fluo ropyridine To a solution of 2,2,2-trifluoro-1-(3-fluoropyridin-2-yl)ethan-1-ol (3.5 g) in DCM (40 mL) were added 2,6-dimethylpyridine (6.9 mL, 59.50 mmol, 3.0 equiv.) and TBSOTf (13.7 mL, 59.50 mmol, 3.0 equiv.). The resulting mixture was stirred at 60 °C overnight, diluted with water (20 mL) and extracted with EA (3 * 20 mL). The organic layers were combined, washed with brine, dried over N32S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→50% EA/PE) to yield 2-(1-((tert- butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3-fluoropyridi ne as a light yellow oil. LC/MS: mass calculated for C13H19F4NOS1: 309.12, measured: 310.00 [M+HJ\ Step 4: 2-(1 -((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3-fluo ro-5- iodopyridine

To a solution of 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoropyridine (1.0 g, 3.23 mmol, 1.0 equiv.) in THF (15 mL) was added LDA (2.4 mL, 4.85 mmol, 1.5 equiv.) at -55 °C under N2. After 30 min. I2 (1.6 g, 6.46 mmol, 2.0 equiv.) in THF was added. The resulting mixture was maintained stirring at -55 °C for 1h, diluted with aqueous N32S03 (20 mL), and extracted with EA (3 * 20 mL). The organic layers were combined, washed with brine, dried over Na2S04. and concentrated to yield 2-(1-((tert-butyldimethylsilyl)oxy)- 2,2,2-trifluoroethyl)-3-fluoro-4-iodopyridine as a dark red oil. LC/MS: mass calculated for C13H18F4INOS1: 435.01, measured: 435.95 [M+H] ⁺ .

Step 5: 2-(1 -((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4-(1 -ethoxyvinyl)-

3-fluoropyridine

A mixture of 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3- fluoro-4-iodopyridine (1.7 g, 3.91 mmol, 1.0 equiv.), tributyl(1- ethoxyvinyl)stannane (2.1 g, 5.86 mmol, 1.5 equiv.) and Pd(PPh3)4 (451 mg, 0.39 mmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was heated at 90 °C under N2 for 1.5 h. Upon cooling to room temperature, the solvent was removed and the residue was purified by flash column chromatography on neutral AI2O3 column (0→15% EA/PE) to yield 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-

4-(1-ethoxyvinyl)-3-fluoropyridine as a light yellow oil. LC/MS: mass calculated for C17H25F4NO2S1: 379.16, measured: 380.15 [M+H] ⁺ .

Step 6: 2-bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluo roethyl)-3- fluoropyridin-4-yl)ethan- 1 -one

A mixture of 2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4- (1- ethoxyvinyl)-3-fluoropyridine (850 mg, 2.24 mmol, 1.0 equiv.) and 1- bromopyrrolidine-2,5-dione (399 mg, 2.24 mmol, 1.0 equiv.) in THF/H2O (8 ml_) was stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted with DCM (3 ^χ 10 mL). The organic layers were combined, washed with brine, dried over N32S04 and concentrated under reduced pressure. The residue was used in the next step reaction without further purification. LC/MS: mass calculated for CishkoBrFtNCfcSi: 429.04, measured: 429.95 [Μ+ΗΓ, 431.95 [M+H+2] ⁺ .

Step 7: 2-bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluo roethyl)-3- fluoropyridin-4-yl)ethan- 1 -one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (250 mg, 0.77 mmol, 1.0 equiv.) in CHaCN (3 mL) was added potassium carbonate (128 mg, 0.92 mmol, 1.2 equiv.), followed by addition of 2-bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)- 2,2,2-trifluoroethyl)-3-fluoropyridin-4-yl)ethan-1-one (397 mg, 0.92 mmol, 1.2 equiv.), and the resulting mixture was stirred at room temperature overnight.

The resulting mixture was then diluted with water and extracted with EA (3 ^χ 20 mL). The organic layers were combined, washed with brine, dried over NaaSO* and concentrated. The residue was purified by flash column chromatography on silica gel (0→8% MeOH/DCM) to yield 2-(2-(1-((tert-butyldimethylsilyl)oxy)- 2,2,2-trifluoroethyl)-3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a light yellow oil. LC/MS: mass calculated for CaoHa-K^NsOsSi: 673.18, measured: 674.20 [M+H] ⁺ .

Step 8: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3-fluoropyridi n-4-yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a mixture of 2-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl) - 3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (130 mg, 0.19 mmol, 1.0 equiv.) and ammonium acetate (149 mg, 1.93 mmol, 10.0 equiv.) in toluene (3 ml_) was added acetic acid (23 mg, 0.38 mmol, 2.0 equiv.). The resulting mixture was stirred at 100 °C for 2 h and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3-fluoropyridi n-4-yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a light yellow oil. LC/MS: mass calculated for CaoHssCIFSNsCteSi: 653.20, measured: 655.20 [M+H] ⁺ .

Step 9: (3S)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluo roethyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-3-fluoropyridi n-4-yl)-1 H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (100 mg, 0.15 mmol, 1.0 equiv.), trimethoxymethane (1 ml_), azidotrimethylsilane (1 ml_) and acetic acid (2 mL) was stirred at room temperature for 24 h. The solvent was removed under reduced pressure to yield (3S)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2- trifluoroethyl)-3-fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a light yellow oil, which was used in the next step without further purification. LC/MS: mass calculated for CaiHs^lFsNeCfcSi: 706.20, measured: 707.10 [M+H]*.

Step 10: (3*S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3-(5-(2- ((*R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl)-1H-imidaz ol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)-2,2,2- trifluoroethyl)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3 -chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (175 mg, 0.25 mmol, 1.0 equiv.) in THF (4 mL) was added EtaN-SHF (1 mL). The resulting mixture was stirred at 50 °C for 2 h. The resulting mixture was concentrated and purified by reverse phase chromatography on C18 column (80g, 0→50% MeCN/H20 (0.05%CF3COOH)) to yield a residue. The racemic product was further separated by chiral-HPLC to yield (3S*,8aR*)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-((R*)-2,2,2-trif1uoro -1-hydroxyethyl)pyridin- 4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25H18CIF5N8O2: 592.12, measured (ES, m/z): 593.05 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) δ 9.78 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.89 - 8.07 (m, 1H), 7.97 - 7.88 (m,1H), 7.58 - 7.70 (m, 2H), 5.68 (d, J = 2.6 Hz, 1H), 5.40 - 5.53 (m, 1H), 5.05 - 5.07 (m, 1H), 3.76 - 3.85 (m,

1H), 2.65 - 2.72 (m, 1H), 2.55 - 2.58 (m, 1H), 2.20 - 2.30 (m, 1H), 2.07 - 2.16 (m, 1H), 1.85 - 2.00 (m, 2H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -73.84, -75.17, - 112.73, -128.28.

Example 172 (3*S,8a*S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (4-chloro-5-(2-((*S)-2,2,2-trifluoro-1 -hydroxyethyl)pyridin-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C25H18CI2F4N8O2: 608.09, measured (ES, m/z): 609.05 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) δ 13.19 (s, 1H), 9.82 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.71 (s, 1H), 7.81 - 8.02 (m, 2H), 7.66 - 7.77 (m, 2H), 7.05 - 7.25 (m, 1H), 5.67 (d, J = 2.6 Hz, 1H), 5.17 (q, J = 7.2 Hz, 1H), 5.00 (d, J = 8.7 Hz, 1 H), 3.77 - 3.80 (m, 1 H), 2.56 - 2.67 (m, 2H), 2.05 - 2.31 (m,

2H), 1.92 - 2.02 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.55, -75.66, - 112.73.

Example 173 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(4- chloro-5-(2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl )-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C25H18CI2F4N8O2: 608.09, measured (ES, m/z): 609.05 [M+H] ⁺ . ¹ H-NMR: (400 MHz, DMSO-de) 6 13.19 (s, 1H), 9.85 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 7.95 - 8.08 (m, 2H), 7.69 - 7.85 (m, 1H), 7.67 - 7.69 (m, 1H), 7.05 - 7.25 (m, 1H), 5.68 (d, J = 2.2 Hz, 1H), 5.10 - 5.30 (m, 1H),

4.99 (d, J = 8.7 Hz, 1H), 3.77 - 3.80 (m, 1H), 2.51 - 2.67 (m, 2H), 2.19 - 2.27 (m, 1H), 2.10 - 2.18 (m, 1H), 1.98 - 2.09 (m, 1H), 1.92 - 1.96 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.89, -75.66, -112.87

Example 174 (3S ^w ,8aS ^w )-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(2-((S*)-2,2,2-trifluoro-1-hydroxyethyl)pyiidin-4-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2sHi9CIF4Ne02:574, measured (ES, m/z):575.05 [M+H] ⁺ . ¹ H NMR: (300 MHz, DMSO-de) δ 9.82 (s, 1H), 8.58 (d, J = 5.4 Hz, 1H), 7.91 - 8.09 (m, 3H), 7.65 - 7.84 (m, 2H), 5.68 (d, J = 2.6 Hz, 1H),

5.05 - 5.26(m, 2H), 3.68 - 3.72 (m, 1 H), 2.70 - 2.90 (m, 1 H), 2.56 - 2.73 (m, 1H), 1.85 - 2.33 (m, 4H). ¹⁹ F NMR: (282 MHz, DMSO-de) δ -73.78, -75.71, - 112.76.

Example 175 (3S*,8aR*)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(2-((R ^w )-2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl)-1H-imid azol-2-yl)-

2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of (3S)-3-(5-(2-(1-(tert-butyldimethylsilyloxy)-2,2,2- trifluoroethyl)pyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2 -fluoro-6-(1H-tetrazol- 1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (150 mg, 0.218 mmol, 1 equiv.) in THF (4 ml) was added EbN-SHF (1 ml). The resulting mixture was stirred at 50 °C for 2 h. The resulting mixture was concentrated and purified by reverse phase chromatography on C18 (MeCN/hbO (0.05%CF3COOH)) to yield 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(2-((R )-2,2,2-trifluoro-1- hydroxyethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrah ydroindolizin-5(1H)- one. The racemic product was further separated by chiral-HPLC to yield

(3S*,8aR*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-3-(5-(2-((S*)-2,2,2- trifluoro-1-hydroxyethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25HigCIF4Ne02:574, measured:575.05 [M+H] ⁺ and (3S*,8aS*)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3-(5-(2- ((R*)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl)-1H-imidaz ol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25Hi9CIF4Ne02:574, measured: 575.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.82 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.02 - 7.81 (m, 3H), 7.77 - 7.66 (m, 2H), 5.67 (d, J = 2.6 Hz, 1H), 5.19 - 4.97 (m, 2H), 3.71 (s, 1H), 2.87 -2.71 (m, 1H), 2.56 (d, J = 4.3 Hz, 1H), 2.31 - 2.05 (m, 2H), 2.02 - 1.92 (m, 2H)./ ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.55, -75.66, - 112.73.

Example 1762-(4-(2-{(3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-3- fluoropyridin-2-yl)acetonitrile

Step 1: 2-(bromomethyl)-3-fluoro-4-iodopyridine

Under an inert atmosphere of nitrogen, to a mixture of (3-fluoro-4- iodopyridin-2-yl)methanol (1.1 g, 4.35 mmol, 1.0 equiv.) and CBr* (2.3 g, 6.96 mmol, 1.6 equiv.) in DCM (50 mL) was added PPha (1.4 g, 5.22 mmol, 1.2 equiv.) in portions at 0 °C, and the resulting mixture stirred at 0 °C for 1 h. The reaction was then quenched with water (50 mL), extracted with DCM (3 x 50 mL), dried over Na2S04, concentrated. The residue was purified by flash column chromatography on silica gel (0→25% EA/PE) to yield 2- (bromomethyl)-3-fluoro-4-iodopyridine as a light yellow solid.

Step 2: 2-(3-fluoro-4-iodopyridin-2-yl)acetonitrile

Under an inert atmosphere of nitrogen, to a mixture of 2-(bromomethyl)- 3-fluoro-4-iodopyridine (1.2 g, 3.80 mmol, 1.0 equiv.) and TMSCN (490 mg,

4.94 mmol, 1.3 equiv.) in THF (35 mL) was added TBAF (4.9 mL, 4.94 mmol, 1.3 equiv., 1 M in THF) at 0 °C. The reaction mixture was stirred at 70 °C for 1 h and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→20% EA/PE) to yield 2-(3-fluoro-4-iodopyridin- 2-yl)acetonitrile as a light yellow solid.

Step 3: 2-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)acetonitrile

Under an inert atmosphere of nitrogen, a mixture of 2-(3-fluoro-4- iodopyridin-2-yl)acetonitrile (900 mg, 3.44 mmol, 1.0 equiv.), tributyl(1- ethoxyvinyl)stannane (2.5 g, 6.87 mmol, 2.0 equiv.) and Pd(PPh3)2Cb (241 mg, 0.34 mmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was stirred at 100 °C for 2 h, then cooled to room temperature, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→25% EA/PE) to yield 2-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)acetonitrile as a light yellow solid.

Step 4: 2-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)acetonitrile To a mixture of 2-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)acetonitrile (650 mg, 3.15 mmol, 1.0 equiv.) in THF (20 mL) and H2O (6 mL) was added MBS (561 mg, 3.15 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature, for 1 h, diluted with EA (100 mL), washed with brine (3 x 30 mL), dried over Na2S04, and concentrated to yield 2-(4-(2-bromoacetyl)-3- fluoropyridin-2-yl)acetonitrile as a yellow solid.

Step 5: 2-(2-(cyanomethyl)-3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate

A mixture of (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (320 mg, 0.85 mmol, 1.0 equiv.) and CS2CO3 (166 mg, 0.51 mmol, 0.6 equiv.) in DMF (10 mL) was stirred at 40°C for 30 min. Then, 2-(4-(2-bromoacetyl)-3-fluoropyridin-2- yl)acetonitrile (326 mg, 1.27 mmol, 1.5 equiv.) was added to the mixture. The reaction mixture was maintained with stirring at room temperature for 4 h, then diluted with EA (100 mL), washed with water (3 x 20 mL), brine (2 x 20 mL), dried over NazSO*. and concentrated. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 2-(2- (cyanomethyl)-3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine -3-carboxylate. LC/MS: mass calculated for C25H18CIF2N7O4: 553.11, measured: 554.05 [M+H] ⁺ .

Step 6: 2-(4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-3-fl uoropyridin-2- yl)acetonitrile

Under an inert atmosphere of nitrogen, a mixture of 2-(2-(cyanomethyl)- 3-fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate (330 mg, 0.59 mmol, 1.0 equiv.) and NFUOAc (459 mg, 5.96 mmol, 10.0 equiv.) in AcOH (2 mL) and toluene (20 mL) was stirred at 110 °C for 1 h, then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 2-(4-(2-((3S)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-4-yl)-3-fluoropyridin-2-yl)acetonitrile as a yellow solid, which was further purified by prep-chiral-HPLC to yield 2-(4-(2-((3S,8aR)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizin-3-yl)- 1 H-imidazol-4-yl)-3-fluoropyridin-2-yl)acetonitrile as an off-white solid.

LC/MS: mass calculated for C25Hi8CIF2NgO:533.13, measured (ES, m/z): 534.15 [M+H] ⁺ . ¹ H NMR: (300 MHz, DMSO-de) δ 12.35 (s, 1H), 9.85 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 7.92 - 8.06 (m, 2H), 7.73 (dd, J = 8.7, 1.5 Hz,

1H), 7.55 - 7.67 (m, 1H), 5.72 (d, J = 2.6 Hz, 1H), 5.06 (d, J = 8.5 Hz, 1H), 4.35 (d, J = 2.0 Hz, 2H), 3.65 - 3.87 (m, 1H), 2.65 -2.85 (m, 1H), 2.55 -2.65 (m,

1H), 2.06 - 2.34 (m, 2H), 1.85 - 2.07 (m, 2H). ¹⁸ F NMR (282 MHz, DMSO-d6) δ -112.84, -127.82.

Example 177 (3S)-7-(3-chloiO-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(4-( 3- fluoro-2-(methoxymethyl)pyridin-4-yl)-1H-imidazol~2-yl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridine

To a mixture of (3-fluoropyridin-2-yl)methanol (9.0 g, 70.80 mmol, 1.0 equiv.) and imidazole (9.6 g, 142 mmol, 2.0 equiv.) in DMF (90 mL) was added TBSCI (12.8 g, 84.96 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature, for 4 h. The resulting mixture was then diluted with EA (700 mL), washed with water (3 x 150 mL), brine (2 x 150 mL), dried over N32S04, and concentrated. The residue was purified by flash column chromatography on silica gel (0→25% EA/PE) to yield 2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridine as a light yellow oil. LC/MS: mass calculated for Ci2H2oFNOSi: 241.13, measured: 242.10 [M+H]*·

Step 2: 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4-iodopyri dine

Under an inert atmosphere of nitrogen, to a mixture of 2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridine (16.0 g, 66.28 mmol, 1.0 equiv.) in THF (350 ml_) was added LDA (39.8 mL, 79.54 mmol, 1.2 equiv., 2 M in THF) at -78 °C. The mixture was stirred at -78 °C for 30 min., and then a solution of I2 (20.2 g, 79.54 mmol, 1.2 equiv.) in THF (80 mL) was added to the mixture at - 78°C. The reaction mixture was stirred at -78 °C for another 1 h, then quenched with saturated ammonium chloride solution (300 mL), extracted with EA (3 x 300 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→20% EA/PE) to yield 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4-iodopyri dine as a light yellow oil. LC/MS: mass calculated for C12H19FINOS1: 367.03, measured: 367.90 [M+H] ⁺ .

Step 3: (3-fluoro-4-iodopyridin-2-yl)methanol

To a mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4- iodopyridine (4.0 g, 10.89 mmol, 1.0 equiv.) in THF (60 mL) was added TBAF (12.0 mL, 11.98 mmol, 1.1 equiv., 1 M in THF). The reaction mixture was stirred at room temperature, for 2h, diluted with water, extracted with EA (150 mL), washed with brine (3 x 60 mL), dried over N32S04, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→50% EA/PE) to yield (3-fluoro-4-iodopyridin-2-yl)methanol as a light yellow oil.

Step 4: 3-fluoro-4-iodo-2-(methoxymethyl)pyridine

To a mixture of (3-fluoro-4-iodopyridin-2-yl)methanol (1.0 g, 3.95 mmol, 1.0 equiv.) in THF (18 mL) was added NaH (205 mg, 5.14 mmol, 1.3 equiv., 60%) at 0 °C, the reaction mixture was stirred at 0 °C for 20 min. To the resulting mixture was then added Mel (729 mg, 5.14 mmol, 1.3 equiv.) and the reaction mixture was maintained stirring at room temperature, for 3 h. The reaction was quenched with ice water (40 mL), extracted with EA (3 x 60 mL), dried over Na2S04, concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→25% EA/PE) to yield 3-fluoro-4-iodo-2-(methoxymethyl)pyridine as a light yellow solid.

Step 5: 4-(1-ethoxyvinyl)-3-fluoro-2-(methoxymethyl)pyridine

A mixture of 3-fluoro-4-iodo-2-(methoxymethyl)pyridine (950 mg, 3.56 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (2.6 g, 7.11 mmol, 2.0 equiv.) and Pd(PPh3)2Cl2 (250 mg, 0.36 mmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was stirred at 100 °C under N2 for 2 h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0→25% EA/PE) to yield 4-(1-ethoxyvinyl)-3-fluoro-2- (methoxymethyl)pyridine as a light yellow solid.

Step 6: 2-bromo-1-(3-fluoro-2-(methoxymethyl)pyridin-4-yl)ethan-1-on e

To a mixture of 4-(1-ethoxyvinyl)-3-fluoro-2-(methoxymethyl)pyridine (700 mg, 3.31 mmol, 1.0 equiv.) in THF (15 mL) and H2O (5 mL) was added NBS (590 mg, 3.31 mmol, 1.00 equiv.). The mixture was stirred at room temperature, for 1h. The resulting mixture was diluted with water and extracted with EA (100 mL), washed with brine (3 x 30 mL), dried over N32S04, and concentrated under reduced pressure to yield 2-bromo-1-(3-fluoro-2- (methoxymethyl)pyridin-4-yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for CeHeBrFNCte: 260.98, measured: 261.95 [M+H]*, 263.95 [Μ+Η+2Γ.

Step 7: 2-(3-fluoro-2-(methoxymethyl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.92 mmol, 1.0 equiv.) and CS2CO3 (181 mg, 0.55 mmol, 0.6 equiv.) in DMF (8 mL) was stirred at 40°C for 30 min. To the resulting mixture was then added 2-bromo-1-(3- fluoro-2-(methoxymethyl)pyridin-4-yl)ethanone (315 mg, 1.20 mmol, 1.3 equiv.) and the reaction mixture was stirred at room temperature, for 4 h. The reaction mixture was diluted with EA (100 mL), washed with water (3 x 20 mL), brine (2 x 20 mL), dried over N32S04, concentrated. The residue was purified by flash column chromatography (0→5% MeOH/DCM) to yield 2-(3-fluoro-2- (methoxymethyl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C24H22CIF2N3O5: 505.12, measured: 506.05 [M+H]*.

Step 8: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3-fluoro-2- (methoxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin-

5(1H)-one

Under an inert atmosphere of nitrogen, a mixture of 2-(3-fluoro-2- (methoxymethyl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate (310 mg, 0.61 mmol, 1.0 equiv.) and NhUOAc (472 mg, 6.13 mmol, 10.0 equiv.) in AcOH (2 ml_) and toluene (20 mL) was stirred at 110 °C for 1 h. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-3-(4-(3-fluoro-2-(methoxymethyl)pyrid in-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C24H22CIF2N5O2: 485.14, measured: 486.10 [M+H] ⁺ .

Step 9: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(4-(3-fluoro-2- (methoxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3-fluoro-2- (methoxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one (120 mg, 0.25 mmol, 1.0 equiv.), TMSNa (284 mg, 2.47 mmol, 10.0 equiv.) and trimethoxymethane (262 mg, 2.47 mmol, 10.0 equiv.) in AcOH (8 mL) was stirred at 65 °C for 2 h, then concentrated under reduced pressure. The residue was applied onto a C18 reverse column (40 g, ACN/H2O (0.05%TFA): 0→45%) for purification to yield (3S)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-3-(4-(3-fluoro-2-(methoxymethyl)pyridi n-4-yl)-1H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid.

LC/MS: mass calculated for C25H2iCIF2Ne02:538.14, measured (ES, m/z): 539.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.86 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.89 - 8.05 (m, 2H), 7.84 (d, J = 3.6 Hz, 1H), 7.73 (dd, J = 8.7, 1.5 Hz, 1H), 5.73 (d, J = 2.6 Hz, 1H), 5.13 (d, J = 8.9 Hz, 1H), 4.64 (d, J = 2.3 Hz, 2H), 3.74 - 3.84 (m, 1 H), 3.36 (s, 3H), 2.70 - 2.92 (m, 1 H), 2.55 - 2.65 (m, 1 H), 2.21 - 2.40 (m, 1 H), 2.09 - 2.20 (m, 1 H), 1.85 - 2.08 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.60, -112.80, -128.08.

Example 178 (3R,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazoM-yl)phenyl)-3-(4 - chloro-5-(2-(1-hydroxycyclopropyl)pyridin-4-yl)-1H-imidazol- 2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2eh½i Cl2FNe02:566.11 , measured (ES, m/z): 567.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 13.07 (s, 1H), 9.84 (s,

1H), 8.46 (d, J = 5.3 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.92 - 8.02 (m, 1H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H), 7.37 - 7.52 (m, 1H), 6.22 (s, 1H), 5.63 - 5.71 (m, 1H), 5.00 (d, J = 8.4 Hz, 1 H), 3.63 - 3.80 (m, 1 H), 2.54 - 2.76 (m, 2H), 1.86 - 2.33 (m, 4H), 1.20 - 1.31 (m, 2H), 1.05 - 1.19 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO- de) δ -112.84.

Example 179 (3R,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(4- fluoro-5-(2-(1-hydroxycyclopropyl)pyridin-4-yl)-1H-imidazol- 2-yl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one ci

Ν.

ΗΝ'

N o Step 1 : 2-(2-(1 -((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-2-o xoethyl

(8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.79 mmol, 1.0 equiv.) in CHaCN (6 mL) was added K2CO3 (165 mg, 1.19 mmol, 1.5 equiv.), followed by 2-bromo- 1 -(2-(1 -((tert- butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)ethan-1-one (441 mg, 1.19 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 1 h and then extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield 2-(2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-2-oxoethyl (8aR)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate as a yellow solid. LC/MS: mass calculated for CsaHseCIFNeOsSI: 666.22, measured: 667.30 [Μ+ΗΓ.

Step 2: (8aR)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)p yridin-4-yl)- 1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 2-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4- yl)-2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (390 mg, 0.59 mmol, 1.0 equiv.) in toluene (10 mL) and acetic acid (1 mL) was added ammonium acetate (901 mg, 11.69 mmol, 20.0 equiv.). The mixture was stirred at 100°C for 1h. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield (8aR)-3-(5- (2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl )-1H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one as a yellow solid. LC/MS: mass calculated for C32H3eCIFNe02Si: 646.24, measured: 647.35 [M+HJ*.

Step 3: (8aR)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)p yridin-4-yl)-4- fluoro- 1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1 -yl)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of (8aR)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-1H-imidazol -2-yl)-7-(3-chloiO-2- fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (150 mg, 0.23 mmol, 1.0 equiv.) in CHsCN (5 mL) was added 1-chloromethyl-4- fluoro-1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (82 mg, 0.23 mmol, 1.0 equiv.). The mixture was stirred at 60 °C for 1 h, partitioned between water and EtOAc (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield the (8aR)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-4-fluoro-1H -imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 Hi- one as a yellow solid. LC/MS: mass calculated for C32H35CIF2N8O2S1: 664.23, measured: 656.40 [M+H]*.

Step 4: (3*R,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(4-fluoro-5- (2-(1-hydroxycyclopropyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 8aR)-3-(5-(2-(1-((tert- butyldimethylsilyl)oxy)cyclopropyl)pyridin-4-yl)-4-fluoro-1H -imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 Hi- one (80 mg, 0.12 mmol, 1.0 equiv.) in THF (4 ml_) was added triethylamine trihydrofluoride (1 ml_). The residue was purified by reverse phase chromatography on C18 (CHsCN/water (0.05%TFA) 5%→50%) to yield a residue, which was purified by chiral-HPLC with Hex (0.1%DEA):EtOH=50:50 to yield (3*R,8aRi-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(4-fluoro-5- (2-(1-hydroxycyclopropyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one as an off-white solid.

LC/MS: mass calculated for C2eH2iCIF2Ne02 :550.14, measured (ES, m/z): 551.0 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.96 (s, 1H), 9.84 (s,

1 H), 8.40 (d, J = 5.3 Hz, 1H), 7.88 - 8.04 (m, 2H), 7.72 (dd, J = 8.7, 1.5 Hz,

1H), 7.23 - 7.35 (m, 1H), 6.23 (s, 1H), 5.64 - 5.71 (m, 1H), 4.96 (d, J = 8.4 Hz, 1 H), 3.63 - 3.81 (m, 1 H), 2.54 - 2.62 (m, 2H), 2.21 - 2.31 (m, 1 H), 2.08 - 2.20

(m, 1H), 1.95 -2.07 (m, 1H), 1.87 - 1.94 (m, 1H), 1.19 - 1.30 (m, 2H), 0.99 - 1.18 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.93, -127.09.

Example 1804-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoro-N-(2-methoxyethyl)picolinamide

LC/MS: mass calculated for C27H24CIF2N9O3: 595.17, measured:(ES, m/z) 596.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.84 (s, 1H), 8.66 (d, J = 5.4 Hz, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.05 - 8.15 (m, 1H), 7.98 (dd, J = 8.7, 7.8 Hz, 1 H), 7.67-7.79 (m, 2H), 5.71 (d, J = 2.6 Hz, 1 H), 5.09 (d, J = 8.8 Hz, 1 H), 3.62 - 3.81 (m, 3H), 3.25 - 3.50 (m, 5H), 2.53 - 2.83 (m, 2H), 1.91 - 2.29 (m, 4H). ^ig F NMR (282 MHz, DMSO-de) δ -112.81, -125.50.

Example 181 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropicolinamide

I ci·

LC/MS: mass calculated for C -24H ^u 18C¾IF2Nr9O^2: 537.12, measured (ES, m/z): 538.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.84 (s, 1H), 8.46 (d, J = 4.9 Hz, 1H), 8.03 -8.12 (m, 2H), 7.98 (dd, J = 8.7, 7.8 Hz, 1H), 7.80 (d, J = 3.8 Hz, 1H), 7.68 - 7.72 (m, 2H), 5.72 (d, J = 2.6 Hz, 1H), 5.11 (d, J = 8.9 Hz, 1H), 3.03 - 3.18 (m, 1H), 2.73 -2.91 (m, 1H), 2.51 - 2.57 (m, 1H), 2.23 -2.29 (m, 1H), 2.07 -2.16 (m, 1H), 1.92 - 2.05 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.80, -125.36.

Example 1824-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropicolinic acid

Step 1 : 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)-3 -fluoropyridine Under an inert atmosphere of nitrogen, a mixture of 2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoro-4-iodopyridine (24.0 g, 65.35 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (47.2 g, 130.69 mmol, 2.0 equiv.) and Pd(PPh3)2Cl2 (4.6 g, 6.53 mmol, 0.1 equiv.) in 1,4-dioxane (300 ml_) was stirred at 100 °C for 2 h, cooled to room temperature, and concentrated. The residue was purified by flash column chromatography on silica gel (0→20% EA/PE) to yield 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)-3 -fluoropyridine as a light yellow oil.

Step 2: 2-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro pyridin-4- yl)ethan-1-one

To a mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1-ethoxyvinyl)- 3-fluoropyridine (5.6 g, 17.98 mmol, 1.0 equiv.) in THF (100 ml_) and H2O (30 mL) was added NBS (3.2 g, 17.98 mmol, 1.0 equiv.). The reaction mixture was stirred at room temperature for 1h. The reaction mixture was diluted with EA (500 mL), washed with brine (3 x 100 mL), dried over N32S04, and concentrated to yield 2-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)ethan-1-one as an off-white solid. Step 3: 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

A mixture of (3S)-7-(6-amino-3-chloro-2-fiuorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (2.4 g, 7.39 mmol, 1.0 equiv.) and CS2CO3 (1.4 g, 4.43 mmol, 0.6 equiv.) in DMF (60 mL) was stirred at 40 °C for 30 min. Then 2-bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)ethan-1-one (4.0 g, 11.08 mmol, 1.5 equiv.) was added to the mixture. The reaction mixture was stirred at room temperature, for 4 h. The resulting mixture was then diluted with EA (600 mL), washed with water (3 x 150 mL), brine (2 x 150 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate as a light yellow solid. LC/MS: mass calculated for C29H34CIF2N3O5S1: 605.19, measured: 606.15 [M+H] ⁺ .

Step 4: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Under an inert atmosphere of nitrogen, a mixture of 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate (3.0 g, 4.95 mmol, 1.0 equiv.) and NH<OAc (3.0 g, 39.59 mmol, 8.0 equiv.) in

AcOH (10 mL) and toluene (100 mL) was stirred at 110 °C for 1 h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→8% MeOH/DCM) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a light yellow solid.

Step 5: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-

2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a -tetrahydroindolizin-

5(1H)-one

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fiuoropyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (1.8 g, 3.07 mmol, 1.0 equiv.), TMSNs (3.5 g, 30.71 mmol, 10.0 equiv.) and trimethoxymethane (3.2 g, 30.70 mmol, 10. 0 equiv.) in AcOH (60 mL) was stirred at 55 °C overnight, then concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 column (ACN/H2O (0.05%NmHC03): 0-→40%) and purified to yield a residue, which was further purified by prep-SFC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3-fluoro-2- (hydiOxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one as a white solid. LC/MS: mass calculated for C24H19CIF2N8O2: 524.13, measured: 525.05 [M+H]*. Step 6: 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropicolinic acid To a mixture of (3S,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)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (1.2 g, 2.28 mmol, 1.0 equiv.) in DCM (60 mL) and H2O (30 mL) was added TEMPO (179 mg, 1.15 mmol, 0.5 equiv.) and Phl(OAc)2 (2.2 g, 6.83 mmol, 3.0 equiv.). The reaction mixture was stirred at room temperature for 2 h, concentrated under reduced pressure. The residue was loaded onto a C18 reverse column (330 g, ACN/H2O (0.05%NhLHC03): 0→25%) and purified to yield 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)-3-fluoropicolinic acid as a white solid.

LC/MS : mass calculated for C24H17CIF2N8O3: 538.11, measured (ES, m/z): 539.05 [M+H]÷. ¹ H NMR (400 MHz, DMSO-de) δ 12.30 (br, 1H), 9.85 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.93 - 8.01 (m, 1H), 7.84 - 7.92 (m, 1H), 7.71 (d, J = 8.7 Hz, 1 H), 7.55 (d, J = 4.0 Hz, 1 H), 5.69 (d, J = 2.7 Hz, 1 H), 5.05 (d, J = 8.8 Hz, 1H), 3.65 - 3.85 (m, 1H), 2.63 - 2.86 (m, 1H), 2.52 - 2.62 (m, 1H), 2.15 -2.19 (m, 1H), 2.05 -2.14 (m, 1H), 1.89 -2.05 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.81, -127.49.

Example 183 (3S,8aR)-7-(3-chloiO-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-((1 -hydroxycyclopropyl)methoxy)pyridin-4-yl)-1 H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: Methyl 1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropane-1-carboxylate To a solution of methyl 1-hydroxycydopropane-1-carboxylate (1.0 g,

8.61 mmol, 1.0 equiv.) in DCM (20 mL) was added 3,4-dihydro-2H-pyran (0.8 g, 9.47 mmol, 1.1 equiv.), PFTS (0.2 g, 0.86 mmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 3 h, then concentrated under vacuum to yield a clear oil, which was dissolved in diethyl ether (50 mL), washed with saturated aqueous brine solution (25 mL), dried over sodium sulfate and concentrated under reduced pressure to yield methyl 1-((tetrahydro- 2H-pyran-2-yl)oxy)cyclopropane-1-carboxylate as colorless oil.

Step 2: (1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanol

To a solution of methyl 1-((tetrahydro-2H-pyran-2-yl)oxy)cydopropane-1- carboxylate (1.1 g, 5.49 mmol, 1 equiv.) in diethyl ether (20 mL) was added 1 M lithium aluminum hydride in THF (5.8 mL, 5.77 mmol, 1.05 equiv.). The reaction was heated at reflux under nitrogen for 2 h. Upon cooling to 25 °C, the mixture was poured into ice water. The organic layer was separated, washed with water (2 * 20 mL), dried over NaaSO* and concentrated under reduced pressure to yield (1-((tetrahydro-2H-pyran-2-yl)oxy)cydopropyl)methanol as colorless oil. Step 3: 3-fluoro-4-iodo-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cydopropyl)methoxy)pyridine

A solution of (1-((tetrahydro-2H-pyran-2-yl)oxy)cydopropyl) methanol (650 mg, 3.77 mmol, 1.2 equiv.) in DMF (8 mL) was added to sodium hydride

(150 mg, 3.77 mmol, 1.2 equiv.) under N2. After the mixture was stirred for 30 min, 2,3-difluoro-4-iodopyridine (758 mg, 3.14 mmol, 1.0 equiv.) was added to the mixture. The resulting mixture was stirred at room temperature for 2 h, then quenched with water, extracted with EA. The combined organic layer was washed with brine, dried over NaaSO*. and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→80% EA/PE) to yield 3-fluoro-4-iodo-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridine as colorless oil. LC/MS: mass calculated for C14H17FI2NO3: 393.02, measured: 394.00 [M+H] ⁺ . Step 4: 4-(1-ethoxyvinyl)-3-fluoro-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridine

To a solution of 3-fluoro-4-iodo-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridine (0.9 g, 2.29 g, 1.0 equiv.) in 1,4-dioxane (15 mL) was added 1-ethoxyvinyl-tri-n-butyltin (0.9 g, 2.52 mmol, 1.1 equiv.) followed by Pd(PPh3)4 (0.26 g, 0.23 mmol, 0.1 equiv.) under Na. The reaction mixture was stirred overnight at 100 °C, then cooled to room temperature, quenched with water, extracted with EA, dried over NaaSO*. and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with (0→20% EA/PE) to yield 4-(1-ethoxyvinyl)-3-fluoro-2-((1- ((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methoxy)pyridine as colorless oil. LC/MS: mass calculated for C18H24FNO4: 337.17, measured: 338.10 [M+H] ⁺ . Step 5: 2-bromo-1-(3-fluoro-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridin-4-yl)ethan-1-one

To a solution of 4-(1-ethoxyvinyl)-3-fluoro-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridine (620 mg, 1.84 mmol, 1.0 equiv.) in THF (10 mL) and water (3 mL) was added NBS (392 mg, 2.21 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 2 h, then quenched with water, extracted with EA, washed with brine, dried over NaaSO*. and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with (0→50% EA/PE) to yield 2-bromo-1-(3-fluoro-2-((1-((tetrahydro- 2H-pyran-2-yl)oxy)cyclopropyl)methoxy)pyridin-4-yl)ethan-1-o ne as colorless oil. LC/MS: mass calculated for CieHigBrFNO*: 387.05, measured: 388.00 [Μ+ΗΓ, 390.00 [Μ+Η+2Γ Step 6: 2-(3-fluoro-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6- (1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoli zine-3-carboxylate To a solution of (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.53 mmol,

1.0 equiv.) in DMF (5 mL) was added potassium carbonate (88 mg, 0.64 mmol, 1.2 equiv.), followed by 2-bromo-1-(3-fluoro-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridin-4-yl)ethan-1-one (267 mg, 0.69 mmol, 1.3 equiv.). The reaction mixture was stirred at room temperature for 2 h, then purified by reverse column chromatography on C18 column (330 g, CHsCN/water (0.05%CH ₃ COOH): 5→70%) to yield 2-(3-fluoro-2-((1- ((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methoxy)pyridin-4 -yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as an off-white solid. LC/MS: mass calculated for C32H3iCIF2Ne07: 684.19, measured: 685.10 [M+H] ⁺ . Step 7: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1 -yl)phenyl)-3-(5-(3-fluoro-2-(( 1 - ((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methoxy)pyridin-4 -yl)-1H-imidazol- 2-yl)-2 _l 3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of 2-(3-fluoro-2-((1-((tetrahydro-2H-pyran-2- yl)oxy)cyclopropyl)methoxy)pyridin-4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

(210 mg, 0.31 mmol, 1.0 equiv.) in toluene (15 mL) was added ammonium acetate (473 mg, 6.13 mmol, 20.0 equiv.) followed by the addition of acetic acid (0.4 mL) under N2. The reaction mixture was stirred for 1 h at 100 °C, then cooled to room temperature, and concentrated under vacuum. The residue was purified by silica gel chromatography with (0→10% MeOH/DCM) to yield (3S)- 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-flu oro-2-((1-((tetrahydro- 2H-pyran-2-yl)oxy)cydopropyl)methoxy)pyridin-4-yl)-1H-imidaz ol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a light yellow solid. LC/MS: mass calculated for C32H31CIF2N8O4: 664.21, measured: 665.10 [M+H] ⁺ . Step 8: (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1-yl) phenyl)-3-(5-(3- fluoro-2-((1-hydroxycydopropyl)methoxy)pyridin-4-yl)-1H-imid azol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(3-fluoro-2-((1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropy l)methoxy)pyridin-4- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (150 mg, 0.23 mmol, 1.0 equiv.) in THF (5 mL) was added 2 M HCI (1 mL). The mixture was stirred at room temperature for 1 h, then purified by reverse column chromatography on C18 column (330 g, CHsCN/water (5 mM NH4HCO3):

5— *70%) to yield (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(3-fluoro-2-((1-hydroxycydopropyl)methoxy)pyridin-4-yl)-1 H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C27H23CIF2NeO3:580.15, measured: (ES, m/z): 581.10 [M+H] ⁺ .NMR: (400 MHz, DMSO-de): 6 12.27 (s, 1 H), 9.84 (s, 1 H), 7.97 (dd, J = 8.7, 7.8 Hz, 1 H), 7.89 (d, J = 5.3 Hz, 1 H), 7.71 (dd, J = 8.7, 1.5 Hz, 1 H), 7.49 - 7.58 (m, 2 H), 5.69 (d, J = 2.7 Hz, 1 H), 5.60 (s, 1 H), 5.03 (d, J = 8.7 Hz, 1 H), 4.36 (s, 2 H), 3.65 - 3.80 (m, 1 H), 2.65 - 2.79 (m, 1 H), 2.55 (d, J = 4.2 Hz, 1 H), 2.06 - 2.26 (m, 2 H), 1.90 - 2.05 (m, 2 H), 0.61 - 0.73

(m, 4 H). ¹⁸ F NMR: (376 MHz, DMSO-de): 6 -112.88, -142.68.

Example 184 (3S,8aR)-3-(5-bromo-4-(3-fluoro-2-(hydroxymethyl- d2)pyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS calculated for C24HieBrCIF ₂ Ne02604.1, measured 605.1 (MH ⁺ ) and 607.0 (MH+2) ⁺ . ¹ H NMR (400 MHz, METHANOL-d4) δ 9.60 (s, 1H), 8.54 (d, J=5.87 Hz, 1H), 8.13-8.20 (m, 1H), 7.81-7.90 (m, 1H), 7.53-7.63 (m, 1H), 5.74 (d, J=2.93 Hz, 1H), 5.16 (d, J=8.80 Hz, 1H), 3.87-4.03 (m, 1H), 2.86-3.00 (m, 1H), 2.60-2.71 (m, 1H), 2.07-2.43 (m, 4H).

Example 185 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-((R)-1-hydroxyethyl)pyridin-4-yl)-1H-imidazol-2- yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for: C25H2iCIF ₂ N ₈ 02:538.14, (ES, m/z): 539.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.25 (s, 1H), 9.84 (s, 1H), 8.35 (dd, J = 5.1, 0.9 Hz, 1H), 7.98 (dd, J = 8.7, 7.7 Hz, 1H), 7.82 - 7.92 (m, 1H), 7.72 (dd, J = 8.7, 1.6 Hz, 1H), 7.57 (d, J = 3.3 Hz, 1H), 5.70 (d, J = 2.6 Hz, 1H), 5.15 - 5.29 (m, 1Η), 5.01 -5.10 (m, 2H), 3.67 - 3.79 (m, 1H), 2.69-2.78 (m, 1H), 2.53 - 2.58 (m, 1 H), 2.06 - 2.27 (m, 2H), 1.92 - 2.01 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) 6-112.91, -130.78.

Example 186 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-((S)-1-hydroxyethyl)pyridin-4-yl)-1H-imidazol-2- yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 1-(3-fluoropyridin-2-yl)ethan-1-ol

Under an inert atmosphere of nitrogen, CHaMgBr (80 mL) was added to a solution of 3-fluoropicolinaldehyde (10.0 g, 79.98 mmol, 1.0 equiv.) in THF (150 mL) 0 °C. The reaction mixture was stirred overnight at room temperature, then quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over NazSO*. and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 1-(3-fluoropyridin- 2-yl)ethan-1-ol as a yellow solid.

Step 2: 2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyridine

To a solution of 1-(3-fluoropyridin-2-yl)ethan-1-ol (8.5 g, 60.22 mmol, 1.0 equiv.) in DMF (300 mL) were added TBSCI (13.6 g, 90.33 mmol, 1.0 equiv.) and 1H-imidazole (6.1 g, 90.33 mmol, 1.5 equiv.). The reaction mixture was stirred overnight at room temperature and then quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by flash column chromatography on silica gel (0→100% EA/PE) to yield 2-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyridine as a yellow solid.

Step 3: 2-(1 -((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoro-4-iodopyridin e LDA (4.7 mL, 2.0 M) was added to a solution of 2-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyridine (2.0 g, 7.83 mol, 1.0 equiv.) in THF (30 mL) at -78 °C under N2. After 30 min, b (2.4 g, 9.40 mmol, 1.2 equiv.) in THF (5 mL) was added to the above mixture and the resulting mixture was stirred for 1 h, then quenched by the addition of saturated ammonium chloride aqueous solution and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over N32S04, concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→100% EA/PE) to yield 2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoro-4- iodopyridine as a yellow solid.

Step 4: 2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(1-ethoxyvinyl)- 3-fluoropyridine Under an inert atmosphere of nitrogen, to a solution of 2-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoro-4-iodopyridine (1.6 g, 4.20 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) were added tributyl(1-ethoxyvinyl)stannane (2.0 g, 5.46 mmol, 1.3 equiv.) and Pd(PPh3)4 (485 mg, 0.42 mmol, 0.1 equiv.). The reaction mixture was stirred for 8 h at 100 °C, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% EA/PE) to yield 2-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoro-4-iodopyridine as a yellow oil.

Step 5: 2-bromo-1-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluor opyridin-4- yl)ethan-1-one

NBS (601 mg, 3.38 mmol, 1.0 equiv.) was added to a solution of 2-(1- ((tert-butyldimethylsilyl)oxy)ethyl)-4-(1-ethoxyvinyl)-3-flu oropyridine (1.0 g, 3.38 mmol, 1.0 equiv.) in THF (10 mL) with H2O (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, quenched with brine, and extracted with EA three times. The organic layer was washed with brine three times, concentrated under reduced pressure. The residue was purified on flash column chromatography on silica gel (0→100% EA/PE) to yield 2-bromo-1-(2- (1 -((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyridin-4-yl)e than-1 -one as a yellow solid.

Step 6: 2-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyridin -4-yl)-2- oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of (3S)-7-(3-chloro2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (500 mg, 1.32 mmol,

1.0 equiv.) in DMF (10 ml_) were added 2-bromo-1-(2-(1-((tert- butyldimethylsilyl)oxy)ethyl)-3-fluoropyridin-4-yl)ethan-1-o ne (598 mg, 1.59 mmol, 1 equiv.) and CS2CO3 (259 mg, 0.79 mmol, 0.6 equiv.). The reaction mixture was stirred overnight at room temperature, then quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified on flash column chromatography on silica gel (0→30% MeOH/DCM) to yield 2-(2-(1- ((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyridin-4-yl)-2 -oxoethyl (3S)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid.

Step 7: (3S)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluor opyridin-4-yl)- 1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)p henyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 2-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyridin - 4-yl)-2-oxoethyl (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (250 mg, 0.37 mmol, 1.0 equiv) in toluene (5.0 mL) with CH3COOH (0.5 mL) was added NH4OAC (286 mg, 3.71 mmol, 10.0 equiv). The reaction mixture was stirred for 2 h at 110 °C, then quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0→30% MeOH/DCM) to yield (3S)- 3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluoropyri din-4-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a-tetrahydroindolizin- 5(1 H)-one as a yellow oil.

Step 8: (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 -(5-(3- fluoro-2-((*S)-1-hydroxyethyl)pyridin-4-yl)-1H-imidazol-2-yl )-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

EbN*3HF (50 mg, 0.34 mmol, 2.0 equiv.) was added to a solution of (3S)-3-(5-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-3-fluor opyridin-4-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one (110 mg, 0.17 mmol, 1.0 equiv.) in THF (3.0 mL).The reaction mixture was stirred at 80 °C for 3 h, then quenched with brine, extracted with MeOH/DCM=1:10 (v/v) three times. The organic layer was washed with brine three times, concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield (3S,8a*R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)- 3-(5-(3-fluoro-2-((*S)-1-hydroxyethyl)pyridin-4-yl)-1H-imida zol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one of yellow solid.

LC/MS: mass calculated for C2sH2iCIF2Ne02:538.14, measured: (ES, m/z): 539.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.25 (s, 1H), 9.84 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.98 (dd, J = 8.7, 7.8 Hz, 1H), 7.90 - 7.85 (m,

1H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H), 7.57 (d, J = 3.6 Hz, 1H), 5.70 (d, J = 2.5 Hz, 1H), 5.20 (d, J = 5.9 Hz, 1H), 5.02 -5.11 (m, 2H), 3.68 - 3.79 (m, 1H), 2.65 - 2.77 (m, 1 H), 2.53 - 2.57 (m, 1 H), 2.09 - 2.29 (m, 2H), 1.94 - 2.01 (m, 2H), 1.44 (d, J = 6.5 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.86, -130.80. Example 187 (3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-((R)-3-hydroxypiperidin-1-yl)pyridin-4-yl)-1H-im idazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2eH2eCIF2Ng02:593.19, measured: (ES, m/z): 594.15 [M+H] ⁺ . ¹ H NMR: (400 MHz, Acetic Acid-cU) δ 9.33 (s, 1H), 7.88 (d, J = 5.9 Hz, 1H), 7.58 - 7.72 (m, 2H), 7.38 (dd, J = 8.7, 1.5 Hz, 1H), 7.31 - 7.28 (m, 1H), 5.82 (d, J = 2.0 Hz, 1H), 5.24 (t, J = 8.0 Hz, 1H), 4.12 -4.25 (m,

1 H), 3.85 - 3.93 (m, 1 H), 3.65 - 3.72 (m, 1 H), 3.45 - 3.59 (m, 1 H), 3.23 - 3.35 (m, 2H), 2.42 - 2.55 (m, 3H), 2.18 -2.35 (m, 2H), 1.83 - 1.85 (m, 2H), 1.72 - 1.76 (m, 1H), 1.47 - 1.61 (m, 2H). ¹⁸ F NMR: (376 MHz, Acetic Add-d ₄ ) δ -76.41, -112.74, -129.56

Example 188 (3R,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-2-((S)-3-hydroxypiperidin-1-yl)pyridin-4-yl)-1H-im idazol-2-yl)- 2,3,8 _| 8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2eH2eCIF2Ne02:593.19, measured: (ES, m/z): 594.20 [M+H] ⁺ . ¹ H NMR (400 MHz, Acetic Acid-d*) 69.33 (s, 1H), 7.88 (d, J = 6.2 Hz, 1H), 7.72 (d, J = 3.1 Hz, 1 H), 7.55 - 7.65 (m, 1H), 7.33 - 7.44 (m, 2H), 5.84 (d, J = 2.5 Hz, 1H), 5.26 (d, J = 8.9 Hz, 1H), 3.83 - 3.98 (m, 2H), 3.37 - 3.40 (m, 1 H), 3.50 - 3.61 (m, 1 H), 3.33 - 3.45 (m, 2H), 2.59 - 2.71 (m, 1 H), 2.40 - 2.56 (m, 2H), 2.13-2.33 (m, 2H), 1.95-2.05 (m, 1H), 1.82 - 1.84 (m, 2H), 1.51 - 1.66 (m, 2H). ¹⁹ F NMR (376 MHz, Acetic Acid-d4) δ -76.47, -112.59, -129.23.

Example 189 (3S)-3-(5-(3-chloro-2-(hydroxymethyl-d2)pyridin-4-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H17CI2D2FN8O2: 542.11, measured (ES, m/z): 543.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 12.69 (brs., 1 H), 9.84 (s, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.05 - 8.11 (m, 2 H), 7.95 - 8.00 (m, 1 H),

7.70 - 7.75 (m, 1 H), 5.70 - 5.75 (m, 1 H), 5.07 (d, J = 8.8 Hz, 1 H), 4.57 (q, J = 7.0 Hz, 1 H), 3.73 - 3.80 (m, 1 H), 2.64 - 2.74 (m, 1 H), 2.51- 2.58 (m, 1 H),

2.17 - 2.30 (m, 1 H), 2.09 - 2.16 (m, 1 H), 1.91 - 2.00 (m, 2 H)./ ¹⁸ F NMR (376 MHz, DMSO-d6) δ -74.03, -112.85.

Example 190 (3S,8aR)-7-(3-ChloiO-2-fluoro-6-(4-(trifluoiOmethyl)-1H-1,2, 3- triazol-1-yl)phenyl)-3-(4-(3-fluoro-2-(2-hydroxy-2-methylpro poxy)pyridin-4- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C27H25CIF2N8O3: 582.2, measured (ES, m/z): 583.2 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol-d ₄ ) 69.60-9.57 (s, 1H), 7.98- 7.93 (m, 1H), 7.97 - 7.87 (m, 1H), 7.88-7.80 (m, 1H), 7.60-7.55 (m,1H), 7.39- 7.30 (m, 1 H), 5.80-5.72 (m, 1 H),5.32-5.23(m, 1 H), 4.25 (s, 2H), 4.02-3.85 (m,

1H), 2.97 (t, J = 15.5 Hz, 1H), 2.78-1.90 (m, 5H), 1.34 (s, 6H). ¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -113.5, -142.7.

Example 191 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2, 3- triazol-1-yl)phenyl)-3-(4-(3-fluoro-2-(2-hydroxy-2-methylpro poxy)pyridin-4- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one ci,

Step 1: 1-((3-Fluoro-4-iodopyridin-2-yl)oxy)-2-methylpropan-2-ol.

A mixture of 2,3-difluoro-4-iodopyridine (1.200 g, 4.89 mmol), 2- methylpropane diol (0.494 g, 5.48mmol), and CS2CO3 (1.785g, 5.478 mmol) in DMF (25 ml) was heated at 110°C for one hour. The reaction was cooled to room temperature and partitioned with water and EA. The organic was separated, washed with brine, and dried over Na2S0 ₄ . The solid was filtered and washed with EA. The filtrated was concentrated to yield a yellow solid, which was purified by ISCO normal phase column chromatography with heptane and EA as eluent (20% to 90% EA) to yield 1-((3-fluoro-4-iodopyridin- 2-yl)oxy)-2-methylpropan-2-ol as an oil. LC/MS: mass calculated for C9H11FINO2: 310.98, measured (ES, m/z): 312.0 [M+H] ⁺ .

Step 2: 1-(3-Fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)ethan- 1-one.

A mixture of 1-((3-fluoro-4-iodopyridin-2-yl)oxy)-2-methylpropan-2-ol (0.45g, 1.45mmol), tributyl(1-ethoxyvinyl)stannane (0.78g, 2.17mmol), and

Pd(PPh3)4 (167.1mg, 0.145mmol) in 1,4-dioxane (10mL) was purged with N2 for 10 minutes and heated at reflux overnight. The reaction mixture was cooled to room temperature, quenched with 2N HCI (5mL) and stirred for 30 minutes, then partitioned between water and EA. The organic was separated, washed with brine, and dried over N32S04. The solid was filtered and concentrated to yield a yellow solid. The residue was purified by flash column chromatography on silica gel with heptane and EA as eluent (10% to 80% EA) to yield 1-(3- fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for C11H14FNO3: 227.1, measured (ES, m/z): 228.1 [M+H] ⁺ .

Step 3: 2-Bromo-1 -(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)ethan-1 - one.

To a solution of 1-(3-fluoro2-(2-hydroxy-2-methylpropoxy)pyridin-4- yl)ethan-1-one (314mg, 1.382mmol), in AcOH (2 mL), pyridine^HBra (441.936mg, 1 ,382mmol) and HBr/CHaCOOH (0.5mL, 2.764mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The residue was partitioned with water and EA. The organic layer was separated, washed with water, then brine and dried over N32S04. The solid was filtered and concentrated to yield a clear oil. The oil was triturated with heptane. The residue was concentrated to yield 2-bromo-1 -(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)ethan-1 - one (-90% purity) as a clear oi. ¹ H NMR (400 MHz, CDCb) δ 8.01-7.27 (d, J= 8.2Hz, 1 H), 7.25-7.29 (m, 1 H), 4.49 (d, J=1.96 Hz, 2 H), 4.30 (s, 2H), 1.37 (s,

6H) Step 4: 2-(3-Fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)-2-oxo ethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate. To a solution of (3S,8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylic acid in ACN (5m L), was added CS2CO3 (114.1mg, 0.35mmol) and the mixture stirred at room temperature for 10 minutes. 2-Bromo-1 -(3-fluoro-2-(2-hydroxy- 2-methylpropoxy)pyridin-4-yl)ethan-1-one was then added. The reaction was heated at 40°C for one hour. The reaction was cooled to room temperature.

The solid was filtered through CELITE and washed with EA. The solvent was removed under vacuum to yield 2-(3-fluoro-2-(2-hydroxy-2- methylpropoxy)pyridin-4-yl)-2-oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro-6-(4- (trifluoromethyl)-l H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-cartx)xylate as a red oil. The red oil was used in the next step without further purification. LC/MS: mass calculated for CHhbsCIFsNsOe: 669.1, measured (ES, m/z): 670.1 [M+H] ⁺ .

Step 5: (3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-3-(4-(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyrid in-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of 2-(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyridin-4-yl)-2- oxoethyl (3S,8aR)-7-(3-chloro-2-fluoro6-(4-(trif1uoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (91 mg, 0.136mmol) in toluene (6mL) and AcOH (0.23mL) was added NH4OAC (157mg,

2.043mmol). The reaction mixture was heated at 100°C for 2 hours. The solvent was removed under vacuum. The residue was partitioned between water and DCM. The organic layer was washed with brine, dried over N32S04, and concentrated under reduced pressure. The residue was purified via high throughput mass directed reverse phase column chromatography to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-3-(4-(3-fluoro-2-(2-hydroxy-2-methylpropoxy)pyrid in-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C29H25CIF5N7O3: 649.2, measured (ES, m/z): 650.3 [M+H]*. ¹ H NMR (400 MHz, methanol^) 69.01 (s, 1 H), 7.88 (d, J

= 5.4 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.62-7.47 (m, 3H), 5.72 (d, J = 2.8 Hz, 1H), 5.18 (d, J = 8.8 Hz, 1H), 4.21 (s, 2H), 3.85-4.00 (m, 1H), 2.95 (t, J = 15.5 Hz, 1 H), 2.63 (dd, J = 16.6, 4.2 Hz, 1H), 1.96-2.45 (m, 4H), 1.34 (s, 6H). ¹⁸ F NMR (376 MHz, methanol-d4) δ -62.3, -113.6, -144.1.

Example 192: 5-(2-((8aR)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-4-yl)-3-fluoro-N-(methylsulfonyl)thiophene-2-carbox amide

LC/MS: mass calculated for C2eHi9CIFsN704S2: 687.05, measured (ES, m/z): 688.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 9.34 (s, 1 H), 7.90 - 8.05 (m, 1 H), 7.77 - 7.65 (m, 2 H), 7.31 (s, 1 H), 5.69 (d, J = 2.5 Hz, 1 H), 4.99 (d, J = 8.8 Hz, 1 H), 3.92 - 4.05 (m, 1 H), 3.34 (s, 3 H), 2.85 - 2.66 (m, 1 H),

2.40 - 2.45 (m, 1 H), 2.32 - 2.05 (m, 2 H), 2.03 - 1.86 (m, 2 H)./ ¹⁸ F NMR (282 MHz, DM SO) 6-59.54, -74.05, -112.84.

Example 193: 5-(2-((3S)-7-(3-chloro-6-(4-chloro-1 H-1 ,2,3-triazol-1 -yl)-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-4- yl)thiophene-2-carboxylic acid

LC/MS: mass calculated for C24Hi7Cl2FNe03S: 558.04, measured (ES, m/z): 559.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1 H), 7.87 - 7.96 (m, 2 H), 7.69 - 7.73 (m, 1 H), 7.53 - 7.64 (m, 2 H), 5.65 - 5.75 (m, 1 H), 5.09 - 5.16 (m, 1 H), 3.69 - 3.79 (m, 1 H), 2.93 - 3.02 (m, 1 H), 2.24 - 2.37 (m, 2 H),

1.94 - 2.15 (m, 3 H). ¹⁶ F NMR (376 MHz, DMS0-d6) δ -74.58, -112.86. Example 194 (3*S,8a*R)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (4-(3-fluoro-2-(hydroxymethyl-d2)pyridin-4-yl)-1H-imidazol-2 -yl)-2,3,8,8a- tetrahydro rtindolizin-5(1 H)-one

Cl .

F N· to

·"¾ ½

Step 1 : 2-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoropyrid in-4-yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

A mixture of ((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (260 mg, 0.80 mmol, 1.0 equiv.) and CS2CO3 (156 mg, 0.48 mmol, 0.6 equiv.) in DMF (12 mL) was stirred at 40 °C for 30 min. 2-Bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl- d2)-3-fluoropyridin-4-yl)ethan-1-one (437 mg, 1.20 mmol, 1.5 equiv.) was then added to the mixture. The reaction mixture was stirred at room temperature, for 4 h. The resulting mixture was then diluted with EA (120 mL), washed with water (3 x 30 mL), brine (2 x 20 mL), dried over Na2S04, and concentrated. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 2-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3- fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C2eH ₃ 2CID2F ₂ N ₃ 05Si: 607.20, measured: 608.10 [M+H] ⁺ . Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3-fluoro-2-

(hydroxymethyl-d2)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8 a-tetrahydroindolizin-

5(1H)-one

A mixture of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl-d2)-3-fluoropyrid in- 4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (280 mg, 0.46 mmol, 1.0 equiv.) and

NhUOAc (355 mg, 4.60 mmol, 10.0 equiv.) in AcOH (3 mL) and toluene (30 mL) was stirred at 110 °C for 1 h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→9% MeOH/DCM) to yield (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(4-(3-fluoro-2-(hydroxymeth yl-d2)pyridin-4-yl)- 1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C23H18CID2F2N5O2: 473.14, measured: 474.05 [Μ+ΗΓ.

Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(4-(3-fluoro- 2-(hydroxymethyl-d2)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a -tetrahydroindolizin- 5(1H)-one

A mixture of ((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3-fluoro-2- (hydroxymethyl-d2)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-t etrahydroindolizin- 5(1H)-one (200 mg, 0.422 mmol, 1.00 equiv), TMSNa (486 mg, 4.22 mmol, 10.0 equiv.) and trimethoxymethane (448 mg, 4.22 mmol, 10.0 equiv.) in AcOH (10 mL) was stirred at 50 °C for 4 h, then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyridin-4-yl)- 1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a light yellow solid, which was further purified by chiral-HPLC with to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-3-(4-(3-fluoro-2-(hydroxymethyl-d2)pyr idin-4-yl)-1H- imidazol-^-yO-^.S.e.ea-tetrahydroindolizin-Stl H)-one as a white solid.

LC/MS: mass calculated for C24H17CID2F2N8O2: 526.14, measured (ES, m/z): 527.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) d 12.27 (s, 1H), 9.85 (s, 1H), 8.35 (d, J = 5.0 Hz, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.90 (t, J = 5.4 Hz, 1H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 5.71 (d, J = 2.8 Hz, 1H), 5.24 (s, 1H), 5.05 (d, J = 8.7 Hz, 1H), 3.65 - 3.84 (m, 1H), 2.73 (t, J = 15.4 Hz,

1H), 2.54 - 2.62 (m, 1H), 2.17 - 2.30 (m, 1H), 2.06 - 2.16 (m, 1H), 1.89 - 2.05 (m, 2H). ¹⁶ F NMR (376 MHz, DMSO-d6) d -112.85, -130.23 Example 195: 5-{2-{(3*S,8aR)-7-(3-chloro-2-fluoro-6-{4-(trifluoromethyl)- 1H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-4-yl)-3-fluorothiophene-2-carboxylic acid

LC/MS: mass calculated for C2sHieCIFsNe03S: 610.06, measured (ES, m/z): 611.00 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) 69.28 (s, 1 H), 7.88 - 7.98 (m, 1 H), 7.59 - 7.72 (m, 2 H), 7.25 (s, 1 H), 5.66 (d, J = 2.5 Hz, 1 H), 4.99 (d, J = 8.7 Hz, 1 H), 3.67 - 3.77 (m, 1 H), 2.65 - 2.85 (m, 1 H), 2.40 - 2.48 (m, 1 H),

2.04 - 2.30 (m, 2 H), 1.83 - 2.01 (m, 2 H). ¹⁹ F NMR (282 MHz, DMSO) 6 -59.58, -73.96, -112.82, -113.48.

Example 196: 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-3~ fluorobenzamide

LC/MS: mass calculated for C25H19CIF2N8O2: 536.13, measured (ES, m/z): 537.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 12.15(brs„ 1 H), 9.82 (s, 1 H), 7.90 - 8.10 (m, 3 H), 7.75 - 7.83 (m,3 H), 7.30 - 7.40 (m, 2 H), 5.68 -5.73 (m, 1 H), 5.01 (d, J = 8.7 Hz, 1 H), 3.70 - 3.80 (m, 1 H), 2.71- 2.85 (m, 1 H),

2.55 - 260 (m, 1 H), 2.10 -2.25 (m, 2 H), 1.90 - 2.04 (m, 2 H)./ ¹⁹ F NMR (376 MHz, DMSO-d6) 6 -114.60, -112.91.

Example 1974-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)~5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)~1H-im idazol-4~yl)-2- fluorobenzamide

Step 1: 4-(1 -ethoxyvinyl)-2-fluorobenzamide

A mixture of 4-bromo-3-fluorobenzamide (500 mg, 1.89 mmol, 1.0 equiv.) and tributyl(1-ethoxyvinyl)tin (818 mg, 2.26 mmol, 1.2 equiv.) and Pd(PPh3)4 (218 mg, 0.19 mmol, 0.1 equiv.) in 1,4-dioxane (20 mL) was purged with N2 and then stirred at 100 °C for 3 hours. The mixture was quenched with water (1000 mL) and extracted with EA (1000 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with (0→50% EA/PE) to yield 4-(1- ethoxyvinyl)-2-fluorobenzamide as a yellow solid.

Step 2: 4-(2-bromoacetyl)-2-fluorobenzamide

NBS (1.4 g, 7.89 mmol, 5.0 equiv.) was added to a mixture of 4-(1- ethoxyvinyl)-2-fluorobenzamide (330 mg, 1.58 mmol, 1.0 equiv.) in THF (6 mL) and H2O (2 mL) and the mixture was stirred at room temperature for 3 hours, quenched with water (1000 mL) and extracted with EA (1000 mLx 3). The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel (0→50% EA/PE) to yield 4-(2-bromoacetyl)-2-fluorobenzamide as a yellow solid.

Step 3: 2-(4-carbamoyl-3-fluorophenyl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) and CS2CO3 (120 mg, 0.37 mmol, 0.6 equiv.) in DMF (15 mL) was added 4-(2-bromoacetyl)-2-fluorobenzamide (192 mg, 0.74 mmol, 1.2 equiv.). After 3 hours, the mixture was quenched with water (1000 mL) and extracted with EA (1000 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous NaaSO*. The solid was filtered and the filtrate was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel (0→50% EA/PE) to yield 2-(4- carbamoyl-3-fluorophenyl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid.

Step 4: 4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-2-fluorobenzamide

To 2-(4-carbamoyl-3-fluorophenyl)-2-oxoethyl (3S)-7-(6-amino-3-chloro- 2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (260 mg, 0.52 mmol, 1.0 equiv.) in AcOH (1 mL) and toluene (10 mL) was added CH3COONH4 (459 mg, 5.95 mmol, 10.0 equiv.). The reaction mixture was stirred at 100 °C for 3 hours, then quenched with water (1000 mL) and extracted with EA (1000 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous N32S04, filtered and concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with (0→50% EA/PE) to yield 4-(2-((3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizin-3-yl)-1H- imidazol-4-yl)-2-fluorobenzamide as a yellow solid.

Step 5: 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-2-fl uorobenzamide A solution of 4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)-2-fluorobenzamid (200 mg, 0.413 mmol, 1.0 equiv.) in AcOH (6 mL) were added trimethoxymethane (438 mg, 4.13 mmol, 10.0 equiv.) and TMSNa (476 mg, 4.13 mmol, 10.0 equiv.). The reaction mixture was stirred at 60 °C for 1 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC with Mobile Phase A: Water (0.05% NaHCOa), Mobile Phase B: ACN to yield the racemic product, which was separated by chiral-HPLC to yield 4-(2-((3S,8aR)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizin-3-yl)- 1H-imidazol-4-yl)-2-fluorobenzamide as a white solid. LC/MS: mass calculated for C24H17D2CIF2N8O2: 526.14, measured (ES, m/z): 527.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 12.31 (brs., 1 H), 9.84 (s, 1 H), 8.35 (d, J = 5.1 Hz, 1 H), 7.95 - 8.05 (m, 1 H), 7.82 - 7.93 (m, 1 H), 7.70 - 7.80 (m, 1 H), 7.55 - 7.85 (m, 1 H), 5.70 (d, J = 2.7 Hz, 1 H), 5.10 - 5.45 (m, 1 H), 5.05 (d, J = 8.8 Hz, 1 H), 3.66 - 3.85 (m, 1 H), 2.63 - 2.84 (m, 1 H),

2.52 - 2.60 (m, 1 H), 2.05 - 2.30 (m, 2 H), 1.85 - 2.05 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -112.86, -130.05.

Example 198 4-(2-((3S,8aS)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-2- fluorobenzamide

LC/MS: mass calculated for C25H19CIF2N8O2: 536.13, measured (ES, m/z): 537.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1 H),7.90 - 8.10 (m, 1 H), 7.40 - 7.90 (m, 5 H), 5.68 (d, J = 2.6 Hz, 1 H),4.90 - 5.00 (m, 1 H), 4.02 - 4.12 (m, 1 H), 2.30 - 2.35 (m, 3 H), 2.21 - 2.30 (m, 1 H), 1.90 - 2.02 (m,

1 H), 1.65 - 1.72 (m, 1 H)./ ¹⁹ F NMR (376 MHz, DMSO-d6) δ -73.46, -113.05.

Example 199 (3S)-7-(3-chloro-2-fluoiO-6-(1 H-tetrazol-1 -yl)phenyl)-3-(4- chloro-5-(2-oxo-1,2-dihydropyridin-4-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H17CI2FN8O2: 526.08, measured (ES, m/z): 527.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1 H), 11.80 (s, 1 H), 9.84 (s, 1 H), 7.92 - 8.03 (m, 2 H), 7.70 - 7.75 (m, 1 H), 7.30 - 7.40 (m, 1 H), 7.00 - 7.05 (m, 1 H), 5.71 (d, J = 2.5 Hz, 1 H), 5.03 (d, J = 8.4 Hz, 1 H), 3.67 - 3.80 (m, 1 H), 2.54 - 2.73 (m, 2 H), 2.05 - 2.26 (m, 2 H), 1.89 - 2.20 (m, 2 H)./ ¹⁸ F NMR (282 MHz, DMSO-d6) δ -112.86.

Example 200 (3S,8aR)-7-(3-chloro-6-(4-chloro-1H-1,2,3-triazol-1-yl)-2- fluorophenyl)-3-(4-(3-fluoro-2-oxo-1 ,2-dihydropyridin-4-yl)-1 H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

N'H

NV- ^C

R

Cl

F U s

O

O

LC/MS: mass calculated for C24H17CI2F2N7O2: 543.08, measured (ES, m/z): 544.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMS0-d6) δ 12.18 (brs., 1 H), 8.85 (s, 1 H), 7.93 - 7.95 (m, 2 H), 7.60 - 7.70 (m, 1 H), 7.31 - 7.38 (m, 1 H), 6.70 -

6.80 (m, 1 H), 5.68 - 5.72 (m, 1 H), 5.22 (d, J = 9.4 Hz, 1 H), 3.72 - 3.88 (m, 1 H), 2.87 - 3.03 (m, 1 H), 2.47 - 2.49 (m, 1 H), 2.27 - 2.39 (m, 1 H), 1.93 - 2.15 (m, 3 H). ¹⁸ F NMR (376 MHz, DMS0-d6) δ -112.87.

Example 201 (3S,8aR)-3-(5-(3-aminobenzo[d]isoxazol-5-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H19CIFN9O2: 531.13, measured (ES, m/z): 532.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-CI6+D2O) δ 9.74 (s, 1 H), 8.07 (s, 1 H), 7.80 - 7.92 (m, 3 H), 7.58 - 7.70 (m, 2 H), 5.66 - 5.67 (m, 1 H), 5.16 (d,

J = 4.8 Hz, 1 H), 3.68 - 3.81 (m, 2 H), 2.89 - 2.97 (m, 1 H), 2.57 - 2.58 (m, 1 H), 2.35 - 2.39 (m, 1 H), 2.05 - 2.10 (m, 2 H), 1.89 - 1.92 (m, 1 H)./ ¹⁸ F NMR (376 MHz, DMS0-d6) δ -73.80, -112.68.

Example 2025-(5-Chloro-2-((3S,8aS)-7-(3-chloro-2-fluoro-6-(4- (trifluoronnethyl)-l H-1 ,2,3-triazoM -yl)phenyl)-5-oxo-1 ,2, 3, 5, 8,8a- hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiophene-2-cart)o xamide

LC/MS: mass calculated for C25H17CI2F4N7O2S: 625.05, measured (ES, m/z): 626.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.86 (s, 1 H), 9.32 (d, J

= 1.1 Hz, 1H), 7.89 - 8.05 (m, 2 H), 7.65 - 7.72 (m, 2 H), 7.31 - 7.41 (m, 2 H), 5.67 (d, J = 2.3 Hz, 1H), 4.87 - 4.95 (d, J = 8.7 Hz, 1 H), 3.63 - 3.74 (m, 1 H), 3.20 - 3.22 (m, 1 H), 2.55 - 2.65 (m, 1 H), 2.11 - 2.28 (m, 1 H), 2.02 - 2.10 (m,1 H), 1.93 - 2.01 (m, 1 H), 1.89 - 1.92 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 - 59.61, -112.95

Example 2035-(5-Chloro-2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(4- (trifluoromethy l)-1 H-1 ,2,3-triazoM -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiophene-2-cart&g t;oxamide

LC/MS: mass calculated for C25H17CI2F4N7O2S: 625.05, measured (ES, m/z): 626.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.75 - 12.98 (m, 1 H), 9.25 - 9.36 (m, 1 H), 7.85 - 8.02 (m, 2 H), 7.62 - 7.72 (m, 2 H), 7.31 - 7.45 (m, 2 H), 5.60 - 5.75 (m, 1 H), 4.80 - 4.99 (m, 1 H), 3.95 - 4.10 (m, 1 H), 3.20 - 3.25 (m, 1 H), 2.30 - 2.39 (m, 2 H), 2.08 - 2.28 (m, 1 H), 1.86 - 1.98 (m,1 H), 1.62 - 1.73 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -59.64, -73.57, -113.12 Example 2044-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl )-1H- 1 ,2,3-triazoM -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)picolinamide

LC/MS: mass calculated for C2eHi9CIF4Ne02: 586.13, measured (ES, m/z): 587.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.13 (s, 1 H), 9.33 (s, 1 H), 8.51 (d, J = 5.1 Hz, 1 H), 8.32 (s, 1 H), 8.07 (s, 1 H), 7.94 (t, J = 8.2 Hz, 1

H), 7.82 - 7.90 (m, 2 H), 7.70 (dd, J = 8.7, 1.5 Hz, 1 H), 7.59 (s, 1 H), 5.68 (d, J = 2.5 Hz, 1 H), 5.00 (d, J = 8.5 Hz, 1 H), 3.60 - 3.77 (m, 1 H), 2.66 - 2.82 (m, 1 H), 2.41 - 2.45 (m, 1 H), 1.87- 2.30 (m, 4 H). ¹⁸ F NMR (300 MHz, DMSO-de) δ - 59.52, -112.77.

Example 2055-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)thiazole-2-carboxamide

Step 1: 5-bromothiazole-2-carboxamide

A mixture of 5-bromothiazole-2-carboxylic acid (1.4 g, 6.73 mmol, 1.0 equiv.), ammonium chloride (1.8 g, 33.65 mmol, 5.0 equiv.), N,N- diisopropylethylamine (1.0 g, 8.07 mmol, 1.2 equiv.) and HATU (3.1 g, 8.08 mmol, 1.2 equiv.) in N,N-dimethylformamide (14 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water, extracted with EA (3 * 10 ml). The organic layers were combined, washed with brine, dried over Na2SO< and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→35% EA/PE) to yield 5-bromothiazole-2-carboxamide as a yellow solid.

Step 2: 5-(1-ethoxyvinyl)thiazole-2-carboxamide

A mixture of 5-bromothiazole-2-carboxamide (960 mg, 4.64 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (2.5 g, 6.95 mmol, 1.5 equiv.) and Pd(PPh3)4 (536 mg, 0.46 mmol, 0.1 equiv.) in 1,4-dioxane (10 mL) was heated at 90 °C under N2 for 3 h. The resulting mixture was diluted with water, extracted with EA (3 ^χ 10 ml). The organic layers were combined, washed with brine, dried over N32S04. The residue was purified by silica gel column (0→50% EA/PE) to yield 5-(1-ethoxyvinyl)thiazole-2-carboxamide as a brown solid.

Step 3: 5-acetylthiazole-2-carboxamide

2M HCI (4 mL). was added to a solution of 5-(1-ethoxyvinyl)thiazole-2- carboxamide (900 mg, 4.54 mmol, 1.0 equiv.) in THF (4 ml). The resulting mixture was stirred at room temperature for 1 h and evaporated under vacuum. The residue was purified by flash column chromatography on silica gel

(0→50% EA/PE) to yield 5-acetylthiazole-2-carboxamide as an orange solid. Step 4: 5-(2-bromoacetyl)thiazole-2-carboxamide

Hydrogen bromide (190 mg, 2.35 mmol, 1.0 equiv.). was added to a mixture of 5-acetylthiazole-2-carboxamide (400 mg, 2.35 mmol, 1.0 equiv.) and pyridinium tribromide (676 mg, 2.11 mmol, 0.9 equiv.) in acetic acid (5 ml). The resulting mixture was stirred at room temperature for 2 h. The solid was filtered out, washed with water and dried in vacuo to yield 5-(2-bromoacetyl)thiazole-2- carboxamide as an orange solid.

Step 5: 2-(2-carbamoylthiazol-5-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

A mixture of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) and potassium carbonate (941 mg, 0.68 mmol, 1.1 equiv.) in CH3CN (3 mL) was stirred at room temperature for 1 h. 2-Bromo-1-(2-fluoro-6- (hydroxymethyl)pyridin-3-yl)ethan-1-one (184 mg, 0.74 mmol, 1.2 equiv.) was then added to the mixture. After 2 h, the resulting mixture was concentrated and purified by flash column chromatography on silica gel (0→100% EA/PE) to yield 2-(2-carbamoylthiazol-5-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as an orange solid.

Step 6: 5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)thiazole-2-carboxamide

To a mixture of 2-(2-carbamoylthiazol-5-yl)-2-oxoethyl (3S,8aR)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate (198 mg, 0.40 mmol, 1.0 equiv.) and ammonium acetate (310 mg, 4.02 mmol, 10.0 equiv.) in toluene (3 ml) was added acetic acid (48 mg, 0.80 mmol, 2.0 equiv.). The resulting mixture was heated at reflux for 1 h, then concentrated and the residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield 5-(2-((3S,8aR)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-4- yl)thiazole-2-carboxamide as a light yellow solid. Step 7: 5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiaz ole-2-carboxamide A mixture of 5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiaz ole-2-carboxamide (200 mg, 0.42 mmol, 1.0 equiv.), trimethoxymethane (1 mL), azidotrimethylsilane (1 mL) and acetic acid (2 ml) was stirred 48 h at 30 °C . The excess solvent was removed under vacuum and the residue was purified by reversal chromatography on C18 (MeCN/hfeO (0.05%CF3COOH): 0→50%) to yield a white solid. The racemic product (30 mg) was further separated by chiral-HPLC to yield 5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4- yl)thiazole-2-carboxamide as a white solid.

LC/MS: mass calculated for C22H17CIFN9O2S: 525.09, measured (ES, m/z): 526.00 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.09 (s, 1 H), 9.80 (s, 1 H), 8.07 (s, 1 H), 8.04 (s, 1 H), 7.95 (dd, J = 8.7, 7.8 Hz, 1 H), 7.67 - 7.74 (m, 2 H), 7.58 (d, J = 2.1 Hz, 1 H), 5.64 (d, J = 2.6 Hz, 1 H), 4.96 (d, J = 8.6 Hz, 1 H),

3.62 - 3.74 (m, 1 H), 2.69 -2.85 (m, 1 H), 2.51 - 2.53 (m, 1 H), 2.03 - 2.24 (m, 2 H), 1.85 - 1.98 (m, 2 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.41 , -112.81, - 112.86, -112.94, -113.33

Example 2064-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)picolinamide

LC/MS: mass calculated for C24H18CIFN9O2: 519.13, measured (ES, m/z): 520.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.72 (s, 1 H), 8.60 (d, J = 5.2 Hz, 1 H), 8.33 (s, 1 H), 7.99 (s, 1 H), 7.80 - 7.91 (m, 2 H), 7.59 (d, J = 8.7 Hz, 1 H), 5.62 (s, 1 H), 5.07 (d, J = 9.0 Hz, 1 H), 3.63 - 3.74 (m, 1 H), 2.69 - 2.91(m, 1 H), 2.53 - 2.59 (m, 1 H), 2.20 - 2.38 (m, 1 H), 2.05 - 2.17 (m, 1 H),

1.77-2.05 (m, 2 H). ¹⁹ F NMR (300 MHz, DMSO-de) δ -73.79, -112.69.

Example 2075-(2-((3S,8aR)-7-(3-Chloro-6-(4-chloro-1 H-1,2,3-triazol-1-yl)-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5- yl)thiophene-2-carboxamide

LC/MS: mass calculated for C24H18CI2FN7O2S: 557.06, measured (ES, m/z): 557.90 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.94 (s, 1 H), 8.81 (s, 1 H), 7.90 (t, J = 8.4Hz, 1 H), 7.75 - 7.86 (m, 1 H), 7.58-7.65 (m, 2 H), 7.42 (s, 1 H), 7.16 - 7.25 (m, 2 H), 5.66 (d, J = 2.7 Hz, 1 H), 4.97 (d, J = 8.8 Hz, 1 H), 3.63-3.73 (m, 1 H), 2.66-2.79 (m, 1 H), 2.40-2.46 (m, 1 H), 2.13-2.21 (m, 1 H),

2.02-2.10 (m, 1 H), 1.90-1.98 (m, 2 H). ¹⁸ F NMR (376 MHz, DMSO-de) δ - 112.98. Example 2085-(2-((3S,8aR)-7-(3-Chloro-6-(4-chloro-1H-1,2,3-triazol-1 -yl)-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5- yl)thiazole-2-carboxamide Step 1: 2-(2-carbamoylthiazol-5-yl)-2-oxoethyl (3S)-7-(3-chloro-6-(4-chloro-1H- 1,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexah ydroindolizine-3- carboxylate

CS2CO3 (95 mg, 0.29 mmol, 0.6 equiv.) was added to a solution of (3S)- 7-(3-chloro-6-(4-chloro-1 H-1 ,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.48 mmol, 1.0 equiv.) in DMF (3 ml_). After stirring at room temperature, for 30 min, 5-(2- bromoacetyl)thiazole-2-carboxamide (182 mg, 0.73 mmol, 2.0 equiv.) was added and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine, dried over

Na2S04 and concentrated. The residue was purified by purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield 2-(2- carbamoylthiazol-5-yl)-2-oxoethyl (3S)-7-(3-chloro6-(4-chloro-1 H-1 ,2,3-triazol- 1-yl)-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C23H17CI2FN6O5S: 578.03, measured: 579.05 [M+H]÷.

Step 2: 5-(2-((3S,8aR)-7-(3-chloro-6-(4-chloro-1 H-1,2,3-triazol-1-yl)-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5- yl)thiazole-2-carboxamide

To a solution of 2-(2-carbamoylthiazol-5-yl)-2-oxoethyl (3S)-7-(3-chloro- 6-(4-chloro-1 H-1 , 2, 3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (120 mg, 0.21 mmol, 1.0 equiv.) in toluene (5 mL) were added CHaCOOH (0.5 mL) and NH4OAC (160 mg, 2.07 mmol, 10.0 equiv.). The reaction mixture was stirred for 2 h at 110 °C, cooled to room temperature, quenched with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 column to yield 5-(2-((3S,8aR)-7-(3-chloro-6-(4- chloro-1 H-1 ,2,3-triazol-1-yl)-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)thiazole-2-carboxa mide as a white solid.

LC/MS: mass calculated for C23H17CI2FN8O2S: 558.06, measured (ES, m/z): 559.00 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.13 (s, 1 H), 8.83 (s, 1 H), 8.10 (s, 1 H), 8.05 - 8.08 (m, 1 H), 7.93 (t, J = 8.3 Hz, 1 H), 7.73 (s, 1 H), 7.58 - 7.69 (m, 2 H), 5.68 (d, J = 2.5 Hz, 1 H), 5.00 (d, J = 8.6 Hz, 1 H), 3.65- 3.77 (m, 1 H), 2.69-2.81 (m, 1 H), 1.91-2.26 (m, 5 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -113.04

Example 2095-(2-{(3S,8aS)-7-(3-Chloro-2-fluoro-6-{4-{trifluoromethyl )-1H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-4-yl)thiazole-2-carboxamide

LC/MS: mass calculated for C24H17CIF4N8O2S: 592.08, measured (ES, m/z): 593.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.35 (d, J = 1.0 Hz, 1 H), 8.08- 8.19 (m, 2 H),7.75- 8.03 (m, 1 H), 7.76 (s, 1 H), 7.71 (dd, J = 8.7, 1.5 Hz,

1 H), 7.62 (s, 1 H), 5.70 (d, J = 2.7 Hz, 1 H), 4.97 (t, J = 7.5 Hz, 1 H), 4.02- 4.17 (m, 1 H), 2.53- 2.54 (m, 1 H), 2.31- 2.42 (m, 2 H),2.17- 2.28 (m, 1 H), 1.96-

2.13 (m, 1 H), 1.60- 1.78 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -59.59, - 113.15.

Example 2105-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl )-1H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-4-yl)thiazole-2-carboxamide α·

LC/MS: mass calculated for C24H17CIF4N8O2S: 592.08, measured (ES, m/z): 593.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.88 -12.40(m, 1 H),

9.32 (d, J = 1.1 Hz, 1 H), 8.06 - 8.10 (m, 2 H),7.95- 7.99 (m, 1 H), 7.74 (s, 1 H), 7.70 (dd, J = 8.7, 1.5 Hz, 1 H), 7.61 (s, 1 H), 5.66 (d, J = 2.7 Hz, 1 H), 4.98 (d, J = 9.0 Hz, 1 H), 3.69- 3.70 (m, 1 H), 2.78- 2.86 (m, 1 H), 2.53- 2.54 (m, 1 H), 2.18- 2.26 (m, 1 H), 2.03- 2.12 (m, 1 H), 1.91- 2.02 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -59.56, -112.89

Example 211 5-(5-Chloro-2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol- 1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)thiophene-2-carboxamide

LC/MS: mass calculated for C23H17CI2FN8O2S: 558.06, measured (ES, m/z): 558.95 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.96 (s, 1 H), 9.84 (s, 1 H), 7.95- 8.00 (m, 2 H),7.70- 7.72 (m, 2 H), 7.42 (s, 1H), 7.35 (d, J = 3.9 Hz, 1 H), 5.65 (d, J = 2.3 Hz, 1 H), 4.91 (d, J = 8.7 Hz, 1 H), 3.67- 3.74 (m, 1 H), 2.59- 2.63 (m, 1 H), 1.92- 2.33 (m, 5 H). ¹⁸ F NMR (376 MHz, DMSO-de) δ - 113.55.

Example 2125-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl )-1H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-5-yl)picolinamide

LC/MS: mass calculated for C26H19CIF4N8O2: 586.13, measured (ES, m/z): 587.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.13 (s, 1 H), 9.33 (d, J = 1.1 Hz, 1 H), 8.96 (d, J = 2.1 Hz, 1 H), 8.23 (dd, J = 8.1, 2.2 Hz, 1 H), 7.90 - 8.07 (m, 3 H), 7.74 (s, 1 H), 7.70 (dd, J = 8.7, 1.5 Hz, 1 H), 7.54 (s, 1 H), 5.69

(d, J = 2.5 Hz, 1 H), 5.01 (d, J = 8.4 Hz, 1 H), 3.64 - 3.77 (m, 1 H), 2.63 - 2.78 (m, 1 H), 2.42 - 2.46 (m, 1 H), 1.83 - 2.33 (m, 4 H). ¹⁹ F NMR (300 MHz, DMSO- de) δ - 59.59, - 112.90.

Example 2135-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl )-1H- 1,2,3-tiiazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-5-yl)picolinamide

LC/MS: mass calculated for C2eHi9CIF4Ne02: 586.13, measured (ES, m/z): 587.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.88 - 12.94 (m, 1 H), 9.33 (s, 1 H), 8.95 (s, 1 H), 8.21 (d, J = 8.2 Hz, 1H), 7.89 - 8.08 (m, 3 H), 7.80

(s, 1 H), 7.69 (d, J = 8.7 Hz, 1 H), 7.56 (s, 1 H), 5.69 (s, 1 H), 5.01 (t, J = 7.5 Hz, 1 H), 4.02 -4.19 (m, 1 H), 2.17-2.43 (m, 4 H), 1.91 -2.12 (m, 1 H), 1.61 - 1.78 (m, 1 H). ¹⁹ F NMR (300 MHz, DMSO-de) δ - 59.64, - 73.57, - 113.19.

Example 2144-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-3- fluorothiophene-2-carboxamide

LC/MS: mass calculated for C23H17CIF2N8O2S: 542.09, measured (ES, m/z): 543.00 [M+H] ⁺ . ¹ H-NMR (400 MHz, DMSO-de) δ 11.76 - 12.57 (m, 1 H), 9.84 (s, 1 H), 7.97 (t, J = 8.2 Hz, 1 H), 7.60 - 7.80 (m, 3 H), 7.36 (s, 1 H), 7.20 (s, 1 H), 5.69 (s, 1 H), 5.01 (d, J = 8.6 Hz, 1 H), 3.67 - 3.77 (m, 1 H), 2.65 -

2.75 (m, 1 H), 2.15 - 2.20 (m, 1 H), 2.06 - 2.14 (m, 1 H), 1.86 - 1.97 (m, 2 H), 1.03- 1.14 (m, 1 H). ¹⁹ F-NMR (376 MHz, DMSO-de) δ -112.71, -120.00.

Example 2155-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazoi-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-3- fluorothiophene-2-carboxamide

LC/MS: mass calculated for C23H17CIF2N8O2S: 542.09, measured (ES, m/z): 543.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.84 (s, 1 H), 7.99 (dd, J = 8.4, 8.0 Hz, 1 H), 7.66 - 7.74 (m, 2 H), 7.20 - 7.35 (m, 1 H), 5.71 (d, J = 2.8 Hz, 1 H), 4.97 (t, J = 7.7 Hz, 1H), 4.08 - 4.19 (m, 1 H), 2.70 - 2.80 (m, 1 H),

2.50 - 2.53 (m, 1 H), 2.31 - 2.40 (m, 1 H), 2.19 - 2.30 (m, 1 H), 1.89 - 2.02 (m, 1 H), 1.75- 1.83 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -113.03, -117.76.

Example 2165-(2-((3S _l 8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-3- fluorothiophene-2-carboxamide

Step 1: 2-(5-carbamoyl-4-fluorothiophen-2-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (222 mg, 0.68 mmol, 1.0 equiv.) in DMF (8 mL) was added CS2CO3 (133 mg, 0.41 mmol, 0.6 equiv.), followed by methyl 4-(2-bromoacetyl)-3-fluorothiophene-2-carboxylate (200 mg, 0.75 mmol, 1.1 equiv.). The resulting mixture was stirred at room temperature, for 2 h, diluted with water (10 mL), and extracted with ethyl acetate (20 mL ^χ 3). The organic layers were combined, washed with brine three times, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield the 2-(5-carbamoyl-4-fluorothiophen-2-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate. LC/MS: mass calculated for C22H18CIF2N3O5S: 509.06, measured: 510.20 [M+H] ⁺ .

Step 2: 5-(2-((3S)-7-(6-amino3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-3-fluorothiophene -2-carboxamide To a mixture of 2-(5-carbamoyl-4-fluorothiophen-2-yl)-2-oxoethyl (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate (230 mg, 0.45 mmol, 1.0 equiv.) in toluene (10 mL) and acetic acid (1 mL) was added ammonium acetate (352 mg, 4.51 mmol, 10.0 equiv.) in portions at room temperature. The resulting mixture was stirred at 100 °C for 2 h, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified by purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield 5-(2-((3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-4-yl)-3- fluorothiophene-2-carboxamide as a yellow solid. LC/MS: mass calculated for C22H18CIF2N5O2S: 489.08, measured: 490.20 [M+H] ⁺ .

Step 3: 5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-3 -fluorothiophene-2- carboxamide

To a solution of 5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-3-fl uorothiophene-2- carboxamide (210 mg, 0.43 mmol, 1.0 equiv.) in AcOH (10 mL) was added TMSN3 (492.933 mg, 4.28 mmol) followed by addition of trimethoxymethane (455 mg, 4.28 mmol, 10.0 equiv.). The resulting mixture was maintained at

60 °C for 2 h. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC with Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN to yield the racemic product, which was further separated by Chiral-HPLC to yield 5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)-3- fluorothiophene-2-carboxamide as a white solid.

LC/MS: mass calculated for C23H17CIF2N8O2S: 542.09, measured (ES, m/z): 543.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.83 (s, 1 H), 7.98 (dd, J = 8.4, 8.0 Hz, 1 H), 7.66 - 7.74 (m, 3 H), 7.20 - 7.30 (m, 2 H), 5.67 (d, J = 2.8 Hz, 1 H), 5.02 (d, J = 9.2 Hz, 1 H), 3.65 - 3.72 (m, 1 H), 2.81 (t, J = 15.3 Hz, 1 H), 2.50 - 2.53 (m, 1 H), 2.19 - 2.30 (m, 1 H), 2.09 - 2.15 (m, 1 H), 1.84 -2.03 (m, 2 H). ^ig F NMR (376 MHz, DMSO-de) δ -112.75, -117.79.

Example 217 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (3-fluoro-1H-pyrazol-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrah ydroindolizin-

5(1H)-one

Step 1: 2-(3-fluoro- 1 H-pyrazol-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate

Potassium carbonate (400 mg, 2.90 mmol, 3.0 equiv.) was added to a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid (314 mg, 0.97mmol, 1.0 equiv.) in DMF (5 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then 2-bromo-1-(3- fluoro-1 H-pyrazol-4-yl)ethanone (200 mg) was added and the resulting mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase chromatography on C18 column (MeCN/hbO (0.05%TFA): 0→60%) to yield 2- (3-fluoro-1H-pyrazol-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C20H17CIF2N4O4: 450.09, measured: 451.10 [M+H] ⁺ .

Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro-1H-p yrazol-4- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of 2-(3-fluoro-1H-pyrazol-4-yl)-2-oxoethyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate (180 mg, 0.40 mmol, 1.0 equiv.) in AcOH (0.5 mL) and toluene (5 mL) was added NhUOAc (307 mg, 3.99 mmol, 10.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at 110 °C for 3 h, then concentrated under vacuum. The residue was purified by purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield the (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro-1 H-pyrazol-4-yl)-1 H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C2oHi7CIF ₂ NeO: 430.11, measured: 431.10 [M+H]*.

Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro- 1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro- 1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (60 mg, 0.14 mmol, 1.0 equiv.) in HOAc (3 mL) were added trimethoxymethane (148mg, 1.39 mmol, 10.0 equiv.), and TMSN3 (160 mg, 1.39 mmol, 10.0 equiv.). The resulting mixture was stirred at 25 °C overnight and concentrated under reduced pressure. The residue was purified by purified by flash column chromatography on silica gel (0→10% MeOH/DCM) and then separated by Chiral Prep-SFC with Mobile Phase A: Hex:DCM=1:1(10mM NHa-MeOH), Mobile Phase B: EtOH to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-3-(5-(3-fluoro-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as an white solid.

LC/MS: mass calculated for C2iHieCIF2NeO: 483.11, measured (ES, m/z): 484.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.21-12.53 (m, 1 H),

11.68 (br, 1 H), 9.82 (s, 1 H), 7.96 (t, J = 8.0 Hz, 1 H), 7.81 (s, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 6.98 (s, 1 H), 5.67 (s, 1 H), 4.97 (d, J = 8.4 Hz, 1 H), 3.62 - 3.75 (m, 1 H), 2.71-2.81 (m, 1 H), 2.52-2.67 (m, 1 H), 2.01-2.22 (m, 2 H), 1.86-2.00 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -135.64, -112.76.

Example 2184-(5-ChloiO-2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)thiophene-2-carboxamide

LC/MS: mass calculated for C23H17CI2FN8O2S: 558.06, measured (ES, m/z): 559.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.63 (br, 1 H), 9.83 (s, 1 H), 8.06 - 8.14 (m, 2 H), 7.96 (t, J = 8.2 Hz, 1 H), 7.85 (s, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.44 (s, 1 H), 5.66 (s, 1 H), 4.92 (d, J = 8.6 Hz, 1 H), 3.62-3.76 (m, 1 H), 2.49-2.66 (m, 2 H), 2.15-2.23 (m, 1 H), 2.07-2.11 (m, 1 H), 1.96-2.05 (m, 1 H), 1.87-1.92 (m, 1 H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -112.81.

Example 2194-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiophene-2- carboxamide

.N-

V _N s

H J o N· ci H ₂ N

LC/MS: mass calculated for C23H18CIFN8O2S: 524.09, measured (ES, m/z): 525.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.67 - 11.93 (m, 1 H), 9.83 (s, 1 H), 8.02 (s, 1H), 8.00 - 7.89 (m, 2H), 7.74 -7.67(m, 2 H), 7.30 -7.42 (m, 1 H), 7.24 (s, 1 H), 5.70 - 5.63 (m, 1 H), 4.98 (d, J = 8.6 Hz, 1 H), 3.63-4.13 (m, 1 H), 2.67-2.82 (m, 1 H), 2.49-2.58 (m, 1 H), 2.13-2.22 (m, 1 H), 2.03-2.11 (m, 1 H), 1.85-2.02 (m, 2 H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -112.66, -112.90, -113.05 Example 2205-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl )-1 H- 1,2,3-tiiazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-4-yl)thiophene~2-carboxamide

LC/MS: mass calculated for C25H18CIF4N7O2S: 591.09, measured (ES, m/z): 592.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-ck) 6 11.92 - 12.26 (m, 1 H),

9.20 - 9.42 (m, 1 H), 7.90 - 8.01 (m, 1 H), 7.77 - 7.89 (m, 1 H), 7.66 - 7.76 (m, 1 H), 7.61 (d, J = 3.8 Hz, 1 H), 7.39 - 7.49 (m, 1 H), 7.10 - 7.38 (m, 2 H), 5.65 - 5.82 (m, 1 H), 4.89 - 5.10 (m, 1 H), 3.99 - 4.35 (m, 1 H), 2.30 - 2.40 (m, 2 H), 2.10 - 2.20 (m, 1 H), 1.92 - 2.09 (m, 2 H), 1.60 - 1.75 (m, 1 H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -59.60, -113.75

Example 221 5-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H- 1,2,3-tiiazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izin-3-yl)-1H- imidazol-4-yl)thiophene-2-carboxamide

LC/MS: mass calculated for C25H18CIF4N7O2S: 591.09, measured (ES, m/z): 592.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-ck) δ 11.93 (s, 1 H), 9.33 (s, 1 H), 7.96 (t, J = 8.2 Hz, 1 H), 7.81 (s, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.62 (d, J = 3.9 Hz, 1 H), 7.43 (s, 1 H), 7.21 (d, J = 3.9 Hz, 1 H), 5.68 (s, 1 H), 4.97 (d, J = 8.6 Hz, 1 H), 3.60 - 3.80 (m, 1 H), 2.77 (t, J = 15.2 Hz, 1 H), 2.40 - 2.45 (m, 1 H), 2.13 -2.28 (m, 1 H), 2.01 - 2.12 (m, 1 H), 1.85 - 2.00 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -59.56, -112.77.

Example 222 (3S,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)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one Step 1: 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl) -2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid (9.3 g, 28.64 mmol, 1.0 equiv) and CS2CO3 (5.6 g, 17.18 mmol, 0.6 equiv) in DMF (90 mL) was stirred at40°C for 30 min. 2-Bromo-1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)ethan -1-one (14.5 g, 40.09 mmol, 1.4 equiv) was then added to the mixture. The resulting mixture was stirred at room temperature for 4h, then diluted with EtOAc (900 mL), washed with water (3 x 150 mL), brine (2 x 150 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (330g, MeOH/DCM: 1/20) to yield 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a light yellow solid. LC/MS: mass calculated for C2eH34CIF2N305Si: 605.19, measured: 606.15 [M+H] ⁺ .

Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-1H-imid azol-2-yl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (15 g, 24.75 mmol, 1.0 equiv) in AcOH (30 mL) and toluene (300 mL) was added NH4OAC (19.08 g, 247.47 mmol, 10.0 equiv) and the mixture was stirred at 110°C under N2 for 1h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (330 g, MeOH/DCM: 1/15) to yield (3S)-7-(6- amino-3-chloro-2-fluorophenyl)- 3-(5-(2-((tert-butyldimethylsilyloxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a light yellow solid. LC/MS: mass calculated for C2eH34CIF2Ns02Si: 585.21, measured: 586.15 [M+H]*.

Step 3: (3S,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)-2,3,8,8a-te trahydroindolizin- 5(1H)-one

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-((tert- butyldimethyl- silyloxy)methyl)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1H)-one (8.0 g, 13.65 mmol, 1.00 equiv), TMSN3 (15.7 g, 136.48 mmol, 10.0 equiv) and trimethoxymethane (14.48 g, 136.48 mmol, 10.00 equiv) in AcOH (60 mL) was stirred at 55°C overnight, then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to yield (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-3-(5-(3-fluoro-2-(hydroxyl methyl)pyridin-4-yl)-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid, which was further purified by prep-SFC(Column: Exsil Chieal-NR, 250mm*30mm,8um; Mobile Phase Alcoa, Mobile Phase B:MeOH(0.1% 2M NHa-MeOH); Flow rate:100 mL/min; Gradient: 50% B; 220 nm; RT1:6.78; RT2:8.45; Injection Volumn:3 ml; Number Of Runs:37;) to yield (3S,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)- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C24H19CIF2N8O2: 524.13, measured (ES, m/z): 525.00 [M+H]*. 1H NMR (300 MHz, DMSO-de) δ 12.22 (s, 1 H), 9.81 (s, 1 H), 8.32 (d, J = 5.0 Hz, 1 H), 7.96 (dd, J = 8.7, 7.8 Hz, 1 H), 7.90 - 7.83 (m, 1 H), 7.69 (dd, J = 8.7, 1.5 Hz, 1 H), 7.54 (d, J = 4.0 Hz, 1 H), 5.68 (d, J = 2.5 Hz, 1 H), 5.30 - 5.17 (m, 1 H), 5.03 (d, J = 8.5 Hz, 1 H), 4.62 (s, 2 H), 3.80 - 3.65 (m, 1 H), 2.78 - 2.62 (m, 1 H), 2.57 - 2.52 (m, 1 H), 2.28 - 2.03 (m, 2 H), 2.04 - 1.87 (m, 2 H). ¹⁹ F NMR (300 MHz, DMSO-de) 6 -112.84, -130.18.

Example 223 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2, 3- triazol-1 -yl)phenyl)-3-(5-(2-chloro-6-(hydroxymethyl)pyridin-3-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C2eHi9Cl2F4N702: 607.09, measured (ES, m/z): 608.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.14 (br, 1 H), 9.34 (s, 1 H), 8.44 (br, 1 H), 7.96 (t, J = 8.1 Hz, 1 H), 7.68-7.72 (m, 2 H), 7.54 (d, J = 8.0 Hz, 1 H), 5.72 (s, 1 H), 5.03-5.06 (m, 1 H), 4.54 (s, 2 H), 3.69-3.76 (m, 1 H), 2.65-2.75 (m, 1 H), 2.48-2.57 (m, 1 H), 2.16-2.30 (m, 1 H), 2.05-2.12 (m, 1 H), 1.95-2.03 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -59.58, -112.95.

Example 224: (3S,8aR)-3-(5-(3-Chloro-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin-

5(1H)-one Step 1: 4-bromo-3-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

NBS (2.8 g, 16.07 mmol, 1.5 equiv.) was added to a solution of 3-chloro- 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(2.0 g, 10.72 mmol, 1.0 equiv.) in DMF(20 mL) and the resulting mixture was stirred at 25 °C under nitrogen for 2 h. The reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 4-bromo-3-chloro-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazole as a white oil. LC/MS: mass calculated for CeHioBrCINaO: 263.97, measured: 264.90 [M+H]*, 266.90 [M+H+2]*. Step 2: 1-(3-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)eth an-1-one Tributyl(1-ethoxyvinyl)stannane (204 mg, 0.56 mmol, 1.5 equiv.) and Pd(pph3)4 (44 mg, 0.04 mmol, 0.1 equiv.) were added to a solution of 4-bromo- 3-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 mg, 0.38 mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) and the resulting mixture was stirred at 100 °C for 3 h under nitrogen. After being cooled to room temperature, the reaction mixture was quenched with water (50 mL), extracted with EA (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0→20% PE/EA) to yield 1-(3-chloro-1-(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazol-4-yl)ethanone as an yellow oil. LC/MS: mass calculated for

C10H13CIN2O2: 228.07, measured: 229.05 [M+H] ⁺ .

Step 3: 2-bromo-1-(3-chloro-1H-pyrazol-4-yl)ethan-1-one

To a solution of 1-(3-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4- yl)ethanone (650 mg, 2.84 mmol, 1.0 equiv.) in DCM (5 mL) was added PyHBra (819 mg, 2.56 mmol, 0.9 equiv.) followed by AcOH/HBr (0.02 mL). The resulting mixture was stirred at 25 °C for 16 h under nitrogen. The mixture was concentrated under vacuum to yield 2-bromo-1-(3-chloro-1H-pyrazol-4- yl)ethanone as a brown solid. LC/MS: mass calculated for CshUBrCI^O: 221.92, measured: 223.05 [M+H]*, 225.05 [M+H+2]*. Step 4: 2-(3-chloro-1H-pyrazol-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate

Potassium carbonate (153 mg, 1.12 mmol, 2.0 equiv.) was added to a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic add (180 mg, 0.55 mmol, 1.0 equiv.) in DMF (5 mL) and the mixture was stirred at room temperature for 0.5 h. 2-Bromo-1-

(3-chloro-1H-pyrazol-4-yl)ethanone (124 mg) was then added to the mixture. The resulting mixture was maintained under nitrogen and stirred at 25 °C for 2 h and then concentrated. The resulting residue was purified by prep-HPLC to yield 2-(3-chloro-1H-pyrazol-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a brown solid. Step 5: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-chloro-1H-p yrazol-4- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

NH4OAC (495 mg, 6.42 mmol, 10.0 equiv.) was added to a solution of 2- (3-chloro- 1 H-pyrazol-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (300 mg, 0.64 mmol, 1.0 equiv.) in toluene (5 ml_) and AcOH (0.2 mL). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h. then cooled to room temperature, and concentrated. The residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield the (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(5-(3-chloro-1H-pyrazol-4-y l)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a brown solid. LC/MS: mass calculated for C2oHi7Cl2FNeO: 446.08, measured: 447.00 [M+H]*.

Step 6: (3S,8aR)-3-(5-(3-chloro-1 H-pyrazol-4-yl)-1H-imidazol-2-yl)-7-(3-chloro- 2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindo lizin-5(1H)-one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-chloro- 1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (190 mg, 0.42 mmol, 1.0 equiv.) in AcOH (5 mL) were added trimethoxymethane (451 mg, 4.25 mmol, 1.0 equiv.) and TMSNs (489 mg, 4.25 mmol, 10.0 equiv.), the resulting mixture was maintained under nitrogen and stirred at 25 °C for 16 h, concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield a racemic product, which was separated by chiral-HPLC to yield (3S,8aR)-3-(5-(3-chloro-1 H- pyrazol-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-t etrazol-1-yl)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C21H16CI2FN8O: 499.08, measured (ES, m/z): 500.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 13.02 - 12.97 (m, 1 H),

11.72 - 11.93 (m, 1 H), 9.82 (s, 1 H), 7.94 - 7.98 (m, 2 H), 7.70(d, J = 8.4 Hz, 1 H), 7.17 (s, 1 H), 5.67 (s, 1 H), 4.97 (d, J = 8.4 Hz, 1 H), 3.61 - 3.78 (m, 1 H), 2.69 - 2.79 (m, 1 H), 2.45 -2.49 (m,1 H), 2.02 - 2.27(m, 2 H), 1.89 - 2.01 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.79.

Example 225: 5-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)picolinamide

LC/MS: mass calculated for C24H19CIFN9O2: 519.13, measured (ES, m/z): 520.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.06 (s, 1 H), 9.81 (s, 1 H), 8.97 (dd, J = 2.1, 0.8 Hz, 1 H), 8.23 (dd, J = 8.2, 2.2 Hz, 1 H), 7.90 - 8.04 (m, 3 H), 7.74 (d, J = 2.1 Hz, 1 H), 7.69 (dd, J = 8.7, 1.5 Hz, 1 H), 7.48 - 7.54

(m, 1 H), 5.67 (d, J = 2.6 Hz, 1 H), 5.00 (d, J = 8.6 Hz, 1 H), 3.63 - 3.81 (m, 1 H), 2.66 - 2.81 (m, 1 H), 2.51 - 2.57 (m, 1 H), 2.15 - 2.27 (m, 1 H), 2.04 - 2.15 (m, 1 H), 1.87-2.03 (m, 2 H). ¹⁸ F NMR (300 MHz, DMSO-de) δ -112.82. Example 2265-(2-((3R,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)picolinamide

LC/MS: mass calculated for C24H19CIFN9O2: 519.13, measured (ES, m/z): 520.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.21 (s, 1 H), 9.80 (s, 1 H), 8.95 (d, J = 2.1 Hz, 1 H), 8.21 (dd, J = 8.2, 2.2 Hz, 1 H), 7.87 - 8.01 (m, 3

H), 7.73 (s, 1 H), 7.67 (dd, J = 8.7, 1.5 Hz, 1 H), 7.46 - 7.53 (m, 1 H), 5.67 (d, J = 2.5 Hz, 1 H), 4.99 (t, J = 7.3 Hz, 1 H), 4.04 - 4.14 (m, 1 H), 2.15 - 2.45 (m, 4 H), 1.89 - 2.11 (m, 1 H), 1.58 - 1.77 (m, 1 H). ¹⁹ F NMR (300 MHz, DMSO-de) 6 - 113.03.

Example 227: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3- (5-(3-methoxy-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: ethyl 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate To a solution of ethyl 3-methoxy-1H-pyrazole-4-carboxylate (100 mg, 0.59 mmol, 1.0 equiv.) in CHsCN (3 mL) was added K2CO3 (243 mg, 1.76 mmol, 3.0 equiv.) followed by addition of PMBCI (183 mg, 1.17 mmol, 2.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at 50 °C for 3 h, and concentrated. The residue was purified by silica gel chromatography (0→20% PE/EA) to yield the ethyl 3-methoxy-1-(4- methoxybenzyl)-1 H-pyrazole-4-carboxylate as a white solid. LC/MS: mass calculated for C15H18N2O4: 290.13, measured: 291.10 [M+H] ⁺ .

Step 2: 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid

LiOH (868 mg, 20.67 mmol, 4.0 equiv.) was added to a solution of ethyl 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (1.5 g, 5.17 mmol, 1.0 equiv.) in EtOH (3 mL), THF (3 mL) and H2O (3 mL). The resulting mixture was maintained under nitrogen and stirred at 25 °C for 4 h., adjusted to pH 3-4 with HCI solution (2 M). The resulting mixture was filtered and the solid was dried in vacuo to yield the 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4- carboxylic acid as a white solid. LC/MS: mass calculated for C13H14N2O4: 262.10, measured: 547.30 [2M+Na] ⁺ . Step 3: 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbonyl chloride To a solution of 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4- carboxylic acid (400 mg, 1.52 mmol, 1.0 equiv.) in DCM (5 mL) was added (COCI)2 (384 mg, 3.05 mmol, 2.0 equiv.) followed by addition of DMF (0.05 mL). The resulting mixture was stirred at 25 °C for 2 h, then concentrated under reduced pressure to yield 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4- carbonyl chloride as a yellow solid.

Step 4: 2-diazo-1-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)eth an-1- one

To a solution of 3-methoxy-1-(4-methoxybenzyl)-1H-pyrazole-4-carbonyl chloride (300 mg, 1.07 mmol, 1.0 equiv.) in ACN (5 mL) at 0 °C was added TMSCHN2 (2.3 mL, 3.0 equiv.). The resulting mixture was stirred at 25 °C overnight and then concentrated under vacuum. The resulting residue was used in the next step without further purification. Step 5: 2-bromo-1-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)eth an-1- one

To a solution of 2-diazo-1-(3-methoxy-1-(4-methoxybenzyl)-1 H-pyrazol- 4-yl)ethanone (400 mg) in ACN (5 mL) at 0 °C was added HBr/H20 (1.2 mL, 6.0 equiv.). The resulting mixture was stirred at 25 °C for 2 h, quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2-bromo-1-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)eth anone as a yellow oil. LC/MS: mass calculated for CuHisBrtvkOs: 338.02, measured: 339.00 [Μ+ΗΓ, 341.00 [M+H+2] ⁺ . Step 6: 2-(3-methoxy-1-(4-methoxybenzyl)-1 H-pyrazol-4-yl)-2-oxoethyl (3S)-7- (6-amino-3-chloro2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydr oindolizine-3- carboxylate

K2CO3 (366 mg, 2.65 mmol, 3.0 equiv.). was added to a solution of (3S)- 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexah ydroindolizine-3- carboxylic acid (287 mg, 0.88 mmol, 1.0 equiv.) in DMF (5 mL). The mixture was stirred at 25 °C for 1 h. To the resulting mixture was then added 2-bromo- 1-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)ethanone (300 mg). The resulting mixture was stirred 4 h, then purified by reverse phase chromatography on C18 column (MeCN/hfcO (0.05%TFA): 0→60%) to yield 2- (3-methoxy-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-oxoethyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C2gH28CIFN*Oe: 582.17, measured: 583.30 [Μ+ΗΓ.

Step 7: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-methoxy-1-( 4- methoxybenzyl)-1H-pyrazol-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-t etrahydroindolizin-

5(1H)-one

To a solution of (3S)-2-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazol-4- yl)-2-oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1, 2,3, 5,8,8a- hexahydroindolizine-3-carboxylate (310 mg, 0.53 mmol, 1.0 equiv.) in AcOH (0.5 mL) and toluene (5 mL) was added NH<OAc (409 mg, 5.32 mmol, 10.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h, then concentrated under vacuum and the residue was purified by reverse phase chromatography on C18 column (MeCN/HaO (0.05%TFA): 0→60%) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-methoxy-1- (4-methoxybenzyl)-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for CajHaiCIFNeCfe: 562.19, measured: 563.30 [M+H] ⁺ .

Step 8: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-methoxy-1- (4-methoxybenzyl)-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3- methoxy-1-(4-methoxybenzyl)-1 H-pyrazol-4-yl)-1H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (120 mg, 0.21 mmol, 1.0 equiv.) in AcOH (5 mL) was added TMSNs (246 mg, 2.13 mmol, 10.0 equiv.) followed by addition of trimethoxymethane (226 mg, 2.13 mmol, 10.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at 25 °C for 3 h, concentrated under vacuum and the residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield the (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol- 1-yl)phenyl)-3-(5-(3-methoxy-1-(4-methoxybenzyl)-1 H-pyrazol-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizirv5(1 H)-one as an yellow oil. LC/MS: mass calculated for C30H27CIFN8O3: 615.19, measured: 616.10 [M+H] ⁺ . Step 9: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3- methoxy-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one To a solution of (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3-methoxy-1-(4-methoxybenzyl)-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one (40 mg, 0.065 mmol, 1.0 equiv.) in TFA (1 mL) was added anisole (0.1 mL). The resulting mixture was maintained under nitrogen and stirred at 70 °C overnight, concentrated in a vacuum and the residue was purified by silica gel chromatography (0→10% MeOH/DCM). The resulting racemic product was further separated by chiral Prep-SFC with Mobile Phase A: Hex:DCM=1:1(10mM NHa-MeOH), Mobile Phase B: EtOH to yield (3S,8aR)-7-(3-chloro-2-fluoiO-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3-methoxy- 1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C22H19CIFN9O2: 495.13, measured (ES, m/z): 496.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 11.30-12.10 (m, 2 H), 9.82 (s 1 H), 7.96 (t, J = 8.4 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 2 H), 6.88 (s, 1 H), 5.67 (s, 1 H), 4.97 (d, J = 8.0 Hz, 1 H), 3.88 (s, 3 H), 3.63 - 3.73 (m, 1 H), 2.54-

2.77 (m, 2 H), 1.96-2.07 (m, 4 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.82. Example 228: 6-Chloro-5-(2-((3S,8aS)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)picolinamide

Ay

Cl' 5-

^Cl "

O

LC/MS: mass calculated for C24H18CI2FN9O2: 553.09, measured (ES, m/z): 554.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.83 (s, 1 H), 8.76 (br, 1 H), 8.51 (d, J = 8.0 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 8.01 (s, 1 H), 7.97 (d, J = 8.3 Hz, 1 H), 7.94 (d, J = 2.8 Hz, 1 H), 7.75 (s, 1 H), 7.70 (dd, J = 8.7, 1.5 Hz, 1 H), 5.70 (d, J = 2.7 Hz, 1 H), 5.09 (d, J = 9.0 Hz, 1 H), 3.69-3.92 (m, 1 H), 2.66-

2.79 (m, 1 H), 2.49-2.60 (m, 1 H), 2.21-2.32 (m, 1 H), 1.92-2.14 (m, 3 H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -112.84.

Example 229: 6-Chloro-5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)picolinamide

LC/MS: mass calculated for C24H18CI2FN8O2: 553.09, measured (ES, m/z): 554.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.82 (s, 1 H), 8.73 (br, 1

H), 8.53 (d, J = 7.8 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.88-8.00 (m, 3 H), 7.60- 7.75 (m, 2 H), 5.69 (d, J = 2.7 Hz, 1 H), 5.04 (t, J = 7.6 Hz, 1 H), 4.04-4.16 (m,

1 H), 2.36-2.57 (m, 3 H), 2.17-2.32 (m, 1 H), 1.93-2.09 (m, 1 H), 1.64-1.76 (m,

1 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -113.07 Example 230 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (4-(trifluoromethyl)-1 H-pyrrol-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

F ₃ C

L NH

NH

VN ^rV

V"

Step 1 : 2-oxo-2-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)me thyl)-1 H- pyrrol-3-yl)ethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (150 mg, 0.47 mmol, 1.0 equiv.) in DMF (10 mL) was added K2CO3 (193 mg, 1.40 mmol, 3.0 equiv.), followed by addition of 2-bromo-1-(4-(trifluoromethyl)-1-((2-

(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)ethanone (180 mg, 0.47 mmol, 1.0 equiv.). The resulting mixture was stirred overnight, quenched with H2O and extracted with EA. The organic layers were combined, dried over N32S04, filtered, and concentrated. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield 2-oxo-2-(4-(trifluoromethyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)ethyl (3S,8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5 _l 8,8a-hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C28H32CIF4N305SI: 629.17, measured: 630.10 [M+H]*. Step 2: (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(4-(triflu oromethyl)-

1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrTOI-3-yl)-1H-i midazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 2-oxo-2-(4-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)ethyl (3S,8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate (220 mg, 0.32 mmol, 1.0 equiv.) in toluene (10 mL) was added NhUOAc (254 mg, 3.17 mmol, 10.0 equiv.) followed by addition of AcOH (1 mL). The resulting mixture was stirred for 3 h at 110 °C. After being cooled to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→100% EA/PE) to yield (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(4-(triflu oromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrol-3-yl)-1H-imidazol-2 -yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C28H32CIF4N ₅ 02Si: 609.19, measured: 610.10 [M+H]*. Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(4-

(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrrol-3-yl)-1H-imidazol-

2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(4- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py rrol-3-yl)-1H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (100 mg, 0.16 mmol, 1.0 equiv.) in AcOH (5 mL) was added trimethoxymethane (174 mg, 1.64 mmol, 10.0 equiv.), followed by addition of TMSNs (189 mg, 1.64 mmol, 10.0 equiv.). The resulting mixture was stirred at 25 °C overnight, concentrated under vacuum and the residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(4-

(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H -pyrrol-3-yl)-1H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for CaHsiC^NeCteSi: 662.20, measured: 663.10 [M+H]*.

Step 4: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(4-

(trifluoromethyl)-1H-pyrrol-3-yl)-1H-imidazol-2-yl)-2,3,8 ,8a-tetrahydroindolizin-

5(1H)-one

To a solution of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-3-(5-(4-(trifluoromethyl)-1-((2-(trimethylsilyl)e thoxy)methyl)-1H-pyrrol- 3-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-o ne (75 mg, 0.11 mmol, 1.0 equiv.) in DCM (1 ml_) was added TFA (1 mL). The resulting mixture was stirred for 3 h at 25 °C, then concentrated under vacuum. The residue was neutralized with NHu/MeOH (2 mL) and the solvent was removed. The residue was purified by chiral-HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-3-(5-(4-(trifluoromethyl)-1H-pyrrol-3- yl)-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one.

LC/MS: mass calculated for C23H17CIF4N8O: 532.11, measured (ES, m/z): 533.20 [M+H] ⁺ . 1 H NMR (400 MHz, DMSO-de) 69.77 (s, 1 H), 7.89 -

7.93 (m, 1 H), 7.70 (dd, J = 8.7, 1.5 Hz, 1 H), 7.25 (s, 1 H), 7.14 (s, 1 H), 6.85 (s, 1 H), 5.63 (d, J = 2.8 Hz, 1 H), 4.96 (d, J = 8.8 Hz, 1 H), 3.66- 3.70 (m, 1 H), 2.68 - 2.78 (m, 1 H), 2.46 - 2.50 (m, 1 H), 2.04 - 2.17 (m, 2 H), 1.94 - 1.99 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -55.32, -112.83. Example 231 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(2- (trifluoiOmethyO-IH.S'H-^.^-biimidazoll-Z-yl^.d.e.ea-tetrahy droindolizin-

5(1H)-one

Step 1 : 2-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1 H-imidazol-4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of (3S,8aR)-7-(6-amino-3-chloro2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (453 mg, 1.39 mmol, 1.0 equiv.) in DMF (10 mL) was added K2CO3 (578 mg, 4.18 mmol, 3.0 equiv.), followed by 2-bromo-1-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1 H-imidazol-4- yl)ethanone (526 mg, 1.39 mmol, 1.0 equiv.) and the resulting mixture was stirred for 11.5 h, then quenched with H2O, and extracted with EA. The organic layers were combined, dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield \ 2-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1 H-imidazol- 4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C2eH25CIF4N40 ₅ : 620.14, measured: 621.05 [M+H] ⁺ .

Step 2: (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(1-(4-methoxy benzyl)- 2-(trifluoromethyl)-1H _l 3 ^, H-[4,4 ^, -biimidazol]-2 ^, -yl)-2,3,8,8a-tetrahydroindolizin- 5(1H)-one

To a solution of 2-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1 H-imidazol- 4-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.0 g, 1.61 mmol, 1.0 equiv.) in AcOH/toluene (1 mL/10 mL) was added ammonium acetate (1.2 g, 16.1 mmol, 10.0 equiv.). The resulting mixture was stirred at 100 °C for 2 h under nitrogen. After being cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC (0→83% MeCN/hteO) to yield the (3S,8aR)-7-(6-amino-3-chloro-2- fluorophenyl)-3-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H, 3'H-[4,4'- biimidazol]-2'-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C2flH25CIF4NeC>2: 600.17, measured: 601.36 [M+H] ⁺ .

Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (1-(4- methoxybenzyl)-2-(trifluoromethyl)-1H,3'H-[4,4'-biimidazol]- 2'-yl)-2,3,8 _l 8a- tetrahydroindolizin-5(1 H)-one

To a solution of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(1-(4- methoxybenzyl)-2-(trifluoromethyl)-1H,3 ^, H-[4,4'-biimidazol]-2'-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (300 mg, 0.50 mmol, 1.0 equiv.) in acetic acid (5 mL) were added trimethoxymethane (530 mg, 4.99 mmol, 10.0 equiv.) and azidotrimethylsilane (575 mg, 4.99 mmol, 10.0 equiv.). The resulting mixture was maintained stirring at 70 °C for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC (0→46% MeCN/H ₂ 0) to yield the (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol- 1-yl)phenyl)-3-(1-(4-methoxybenzyl)-2-(trifluoromethyl)-1H,3 ^, H-[4,4 ^, -biimidazol]- 2'-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow oil. LC/MS: mass calculated for C30H24CIF4N9O2: 653.17, measured: 654.30 [M+H]*.

Step 4: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (2-

(trifluoromethyO-IH.S'H-^.^-biimidazoll-Z-yO^.d.S.ea-tetr ahydroindolizin-

5(1H)-one

To a solution of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yOphenyO-S-CI-C^methoxybenzyl^-CtrifluoromethyO-IH.S'H-^.^-b iimidazol]^'- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (200 mg, 0.31 mmol, 1.0 equiv.) in TFA (5 ml_) was added anisole (198 mg, 1.83 mmol, 6.0 equiv.). The resulting mixture was stirred at 50 °C for 2 h. The solution was concentrated and purified by silica gel chromatography (0→5% MeOH/DCM) to yield the racemic product, which was further separated by chiral-HPLC to yield (3S,8aR)-7-(3-chloro-2- fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(2-(trifluoromethyl)-1H ,3 ^, H-[4,4 ^, -biimidazol]- 2'-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as an off-white solid.

LC/MS: mass calculated for C23H17CIF4N8O: 533.11, measured (ES, m/z): 534.00 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-de) δ 13.58 (br, 1 H), 11.88 (br, 1 H), 9.83 (s, 1 H), 7.95 - 7.99 (m, 1 H), 7.72 (dd, J = 8.7, 1.5 Hz, 1 H), 7.23 - 7.54 (m, 2 H), 5.68 (d, J = 2.6 Hz, 1 H), 5.00 (d, J = 8.8 Hz, 1 H), 3.67 - 3.73 (m, 1 H), 2.67 - 2.74 (m, 1 H), 2.52 - 2.53 (m, 1 H), 2.20 - 2.34 (m, 1 H), 2.08 - 2.18 (m, 1 H), 1.94 - 2.06 (m, 2 H). ¹⁶ F NMR (282 MHz, DMSO-de) δ -61.16, - 112.77

Example 2325-{2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-{1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-2- fluorobenzamide ci,

YJ ί

N-N

V"

LC/MS: mass calculated for C25H19CIF2N8O2: 536.13, measured (ES, m/z): 537.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.03 (br, 1 H), 9.83 (s, 1 H), 7.97-7.98 (m, 2 H), 7.80 - 7.87 (m, 1 H), 7.54-7.71 (m, 4 H), 7.20 -7.31 (m,

1 H), 5.70 (s, 1 H), 4.91-5.13 (m, 1 H), 4.10-4.12 (m, 1 H), 2.37-2.46 (m, 3 H), 2.21-2.31 (m, 1 H), 1.97-2.10 (m, 1 H), 1.68-1.73 (m, 1 H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -113.00, -117.91.

Example 233 5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-2- fluorobenzamide

LC/MS: mass calculated for C2SH19CIF2N8O2: 536.13, measured (ES, m/z): 537.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.78 - 12.54 (m, 1 H),

9.82 (s 1 H), 7.94-7.98 (m, 2 H), 7.82 - 7.89 (m, 1 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.61 (s, 1 H), 7.51 (s, 1 H), 7.23-7.26 (m, 1 H), 5.66 (s, 1 H), 4.98 (d, J = 8.8 Hz, 1 H), 3.63 - 3.76 (m, 1 H), 2.71-2.83 (m, 1 H), 2.53-2.61 (m, 1 H), 2.17- 2.20 (m, 1 H), 2.01-2.10 (m, 1 H), 1.97-1.99 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.70, -117.92.

Example 234: 4-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)thiophene-2-carboxamide

;i

F i.0

N-N Step 1: 2-(5-carbamoylthiophen-3-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro- 2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-car boxylate

To a solution of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (654 mg, 2.01 mmol, 1.0 equiv.) in DMF (8 mL) was added K2CO3 (557 mg, 4.03 mmol, 2.0 equiv.). The mixture was stirred at 25 °C for 0.5 h. To the resulting mixture was then added 4-(2-bromoacetyl)thiophene-2-carboxamide (500 mg, 2.01 mmol, 1.0 equiv.) and the resulting mixture was stirred for 3.5 h. The solid was filtered out. The filtrate was concentrated under vacuum and the residue was purified by HPLC (20%→100% MeCN/hfeO) to yield the 2-(5-carbamoylthiophen-3-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a- hexahydroindolizine-3-carboxylate as a yellowish oi. LC/MS: mass calculated for C22H19CIFN3O5S: 491.07, measured: 492.10 [M+H] ⁺ .

Step 2: 4-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)thiophene-2-carbox amide

To a solution of 2-(5-carbamoylthiophen-3-yl)-2-oxoethyl (3S,8aR)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate (500 mg, 1.02 mmol, 1.0 equiv.) in toluene (10 mL) were added AcOH (1 mL) and NH4OAC (783 mg, 10.16 mmol, 10.0 equiv.). The reaction mixture was stirred for 3 h at 100 °C. After being cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (20%→100% EA/PE) to yield the 4-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)thiophene-2- carboxamide as a yellow oil. LC/MS: mass calculated for C22H19CIFN5O2S: 471.09, measured: 472.10 [M+HJ\ Step 3: 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)thiophene-2- carboxamide

To a solution of 4-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1,2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)thiophene-2- carboxamide (100 mg, 0.21 mmol, 1.0 equiv.) in AcOH (10 mL) were added trimethoxymethane (225 mg, 2.12 mmol, 10.0 equiv.) and TMSNa (244 mg,

2.12 mmol, 10.0 equiv.). The resulting mixture was stirred at room temperature, for 16 h. The residue was purified by Prep-HPLC and then separated by prep- SFC with Mobile Phase A: Hex:DCM=3:1(10mM NHs-MeOH), Mobile Phase B: EtOH to yield 4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)thiophene-2- carboxamide as a white solid. LC/MS: mass calculated for C23H18CIFN8O2S: 524.09, measured (ES, m/z): 525.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMS0-de+H ₂ 0) δ 9.75 (s, 1 H), 7.97 (d, J = 1.2 Hz, 1 H), 7.89 (t, J = 6.3 Hz, 1 H), 7.84 (d, J = 1.4 Hz, 1 H), 7.63 (dd, J = 8.7, 1.4 Hz, 1 H), 7.42 (s, 1 H), 5.64 (d, J = 2.8 Hz, 1 H), 5.03 (d, J = 9.2 Hz, 1 H), 3.67 - 3.72 (m, 1 H), 2.78 - 2.86 (m, 1 H), 2.51 - 2.54 (m, 1 H), 2.21 - 2.27

(m, 1 H), 2.09 - 2.14 (m, 1 H), 1.95 - 1.99 (m, 2 H). ¹⁹ F NMR (376 MHz, DMSO- de) 6 -73.50, -112.71.

Example 235 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2-fluoro-6-(hydroxymethyl)pyridin-3-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H18CIF2N8O2: 524.13, measured (ES, m/z): 525.00 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.08 (br, 1 H), 9.82 (s, 1 H), 8.42 (t, J = 8.8 Hz, 1 H), 7.95 (t, J = 8.2 Hz, 1 H), 7.69 (dd, J = 8.7, 1.5 Hz, 1 H), 7.46 (dd, J = 7.7, 2.2 Hz, 1 H), 7.35 (d, J = 4.1 Hz, 1 H), 5.68 (d, J = 2.5

Hz, 1 H), 5.44 - 5.57 (m, 1 H), 5.01 (d, J = 8.4 Hz, 1 H), 4.48 (s, 2 H), 3.64 - 3.81 (m, 1 H), 2.59 - 2.76 (m, 1 H), 2.55 - 2.50 (m, 1 H), 2.24 - 2.02 (m, 2 H), 2.00 - 1.85 (m, 2 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -69.11, -73.4, -112.88. Example 236 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2-chloro-6-(hydroxymethyl)pyridin-3-yl)-1H-imidazol-2-yl)-2 ,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 2-(2-chloro-6-(methoxycarbonyl)pyridin-3-yl)-2-oxoethyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2, 3,5,8, 8a-hexahydroindolizine-3-carboxylic acid (250 mg, 0.77 mmol, 1.0 equiv.) in DMF (5 mL) was added CS2CO3 (150 mg, 0.46 mmol, 0.6 equiv.). After 0.5 h., methyl 5-(2-bromoacetyl)-6-chloropicolinate (338 mg, 1.16 mmol, 1.5 equiv.) was added to the mixture and the reaction mixture was stirred overnight, then quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over NaaSO* and concentrated. The residue was purified by silica gel chromatography (0%→30% MeOH/DCM) to yield 2-(2-chloro-6-(methoxycarbonyl)pyridin-3-yl)-

2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C22H ₂ oCl2FN30e: 535.07, measured: 536.10 [M+H] ⁺ .

Step 2: methyl 5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-6-chloropicolinate

To a solution of 2-(2-chloro-6-(methoxycarbonyl)pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (300 mg, 0.56 mmol, 1.0 equiv.) in toluene (5 mL) and AcOH (0.5 mL) was added NhUOAc (431 mg, 1.15 mmol, 2.0 equiv.). The reaction mixture was stirred for 2 h at 110 °C, then quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0%→30% MeOH/DCM) to yield methyl 5- (2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-6-chloropicolinate as a yellow oil.

LC/MS: mass calculated for C22H20CI2FN5O3: 515.09, measured: 516.10 [Μ+ΗΓ.

Step 3: methyl 6-chloro-5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)picolinate

To a solution of methyl 5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)- 6-chloropicolinate (200 mg, 0.39 mmol, 1.0 equiv.) in AcOH (3 mL) were added TMSNa (446 mg, 3.87 mmol, 10 equiv.) and trimethoxymethane (411 mg, 3.87 mmol, 10.0 equiv.). The reaction mixture was stirred overnight at room temperature, quenched with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0%→30% MeOH/DCM) to yield methyl 6-chloro5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)picolinate as a yellow solid. LC/MS: mass calculated for C25H19CI2FN8O3: 568.09, measured: 569.05 [M+H]*.

Step 4: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(2-chloro-

6-(hydroxymethyl)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8,8a -tetrahydroindolizin-

5(1H)-one

To a solution of methyl 6-chloro-5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H- tetrazol- 1 -yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)picolinate (200 mg, 0.39 mmol, 1.0 equiv.) in THF (5 ml_) was added sodium borohydride (122 mg, 3.88 mmol, 10.0 equiv.). The reaction mixture was stirred at room temperature, for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0%→30% MeOH/DCM) to yield the racemic product, which was further purified by SFC to yield the (3S,8aR)-7-(3-chloro-2-fluoro-6- (1H-tetrazol-1-yl)phenyl)-3-(5-(2-chloro-6-(hydroxymethyl)py ridin-3-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid.

LC/MS: mass calculated for C24H19CI2FN8O2: 540.10, measured (ES, m/z): 541.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 12.07 - 12.25 (m, 1 H), 9.85 (s, 1 H), 8.41 - 8.51 (m, 1 H), 7.92-8.04 (m, 1 H), 7.72 (dd, J = 8.7, 1.5 Hz, 1 H), 7.68 (s, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 5.71 (d, J = 2.5 Hz, 1 H), 5.04 (d, J = 8.4 Hz, 1 H), 4.55 (s, 2 H), 3.67-3.81 (m, 1 H), 2.61-2.77 (m, 1 H), 2.51-2.57 (m, 1 H), 2.05-2.27 (m, 2 H), 1.94-2.03 (m, 2 H). ¹⁸ F NMR (282 MHz, DMSO-de)

6 -112.907.

Example 2373-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-2- fluorobenzamide

LC/MS: mass calculated for C25H19CIF2N8O2: 536.13, measured (ES, m/z): 537.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMS0-de+D20) 6: 9.81 (s, 1 H), 8.04

- 8.12 (m, 1 H), 7.94 (t, J = 8.4 Hz, 1 H), 7.83 (s, 1 H), 7.65 (dd, J = 8.7, 1.5 Hz, 1 H), 7.61 (s, 1 H), 7.47 - 7.39 (m, 1 H), 7.37 (d, J = 4.6 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1 H), 5.66 (d, J = 2.5 Hz, 1 H), 5.05 (d, J = 8.4 Hz, 1 H), 3.72 - 3.81 (m,

1 H), 2.57 - 2.83 (m, 2 H), 2.05 - 2.28 (m, 2 H), 1.73 - 2.00 (m, 2 H). ¹⁹ F-NMR (376 MHz, DMSO-de) δ -112.86, -116.62.

Example 2385-(2-((3*S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)thiophene-2-carboxamide Step 1: 2-(5-carbamoylthiophen-2-yl)-2-oxoethyl (3S,8aR)-7-(6-amino-3-chloro- 2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-car boxylate

To a solution of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (262 mg, 0.81 mmol, 1.0 equiv.) in DMF (3 mL) was added K2CO3 (222 mg, 1.612 mmol, 2.0 equiv.). The mixture was stirred at 25 °C for 0.5 h. To which 5-(2-bromoacetyl)thiophene-2- carboxamide (200 mg, 0.81 mmol, 1.0 equiv.) was added. The resulting mixture was stirred 1.5 h, quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0→50% EA/PE) to yield the 2-(5-carbamoylthiophen-2-yl)-2- oxoethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 ,8a- hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C22H19CIFN3O5S: 491.07, measured: 492.10 [M+H] ⁺ .

Step 2: 5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)thiophene-2-carboxamide

To a solution of 2-(5-carbamoylthiophen-2-yl)-2-oxoethyl (3S,8aR)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate (170 mg, 0.35 mmol, 1.0 equiv.) in toluene/AcOH (10:1) (3 mL) was added ammonium acetate (266 mg, 3.5 mmol, 10.0 equiv.). The resulting mixture was stirred 2 hours at 100 °C. After being cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0%→50% EA/PE) to yield the 5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)thiophene-2- carboxamide as a yellow oil. LC/MS: mass calculated for C22H19CIFN5O2S: 471.09, measured: 472.10 [Μ+Η]÷.

Step 3: 5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)thiophene-2- carboxamide

To a solution of 5-(2-((3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)t hiophene-2- carboxamide (90 mg, 0.19 mmol, 1.0 equiv.) in acetic add (5 mL) were added trimethoxymethane (202 mg, 1.91 mmol, 10.0 equiv.) and TMSNs (220 mg 1.91 mmol, 10.0 equiv.). The resulting mixture was stirred at room temperature for 2h. The residue was purified by Prep-HPLC and then separated by Chiral Prep-

SFC with Mobile Phase A: Hex:DCM=3:1(10mM NHs-MeOH), Mobile Phase B: EtOH to yield 5-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phen yl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)thiophene-2- carboxamide as a white solid.

LC/MS: mass calculated for C23H18CIFN8O2S: 524.09, measured (ES, m/z): 525.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.96 (s, 1H), 9.82 (s, 1H), 7.97 (t, J = 8.4 Hz, 1H), 7.76 - 7.91 (m, 1H), 7.70 - 7.72 (m, 1H), 7.62 (d, J = 3.8 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.20 - 7.21 (m, 2H), 5.66 (d, J = 2.8 Hz, 1H), 4.96 (d, J = 8.8 Hz, 1H), 3.66 - 3.71 (m, 1H), 2.74 -2.81 (m, 1H), 2.17 -2.20 (m, 1H), 2.06 -2.12 (m, 1H), 1.95 - 1.96 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.73. Example 239 (3*R,8a*R)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-

(5-(3-(trifluoromethyl)-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one ci. F V NH

-J.N w V

F F

N-N **'' ^■ F

4 N.Λ

LC/MS: mass calculated for C22HieCIF4NeO: 533.11, measured (ES, m/z): 534.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 13.51 (br, 1H), 11.92 (br,

1H), 9.83 (s, 1H), 8.09 (s, 1H), 7.97 (t, J = 8.2 Hz, 1H), 7.70 - 7.72 (m, 1H),

6.99 (s, 1H), 5.66 (d, J = 2.4 Hz, 1H), 4.98 (t, J = 7.2 Hz, 1H), 3.98 -4.22 (m, 1H), 2.18 -2.38 (m, 4H), 1.93 -2.12 (m, 2H). ^ig F NMR (376 MHz, DMSO-de) δ -60.09, -113.10. Example 296: (3*S,8a*R)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 3- (5-(3-(trifluoromethyl)-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one a, NH

•S 1 N

NH

F

F

N-N &

N‘

Step 1 : 2-oxo-2-(3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)me thyl)-1 H- pyrazol-4-yl)ethyl (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (168 mg, 0.52 mmol, 1.0 equiv.) in DMF (5 ml_) was added K2CO3 (143 mg, 1.03 mmol, 2.0 equiv.). The mixture was stirred at 25 °C for 0.5 h. To the resulting mixture was added 2- bromo-1-(3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)me thyl)-1H-pyrazol-4- yl)ethanone(200 mg, 0.52 mmol, 1.0 equiv.) and the resulting mixture was stirred 1.5 h. The solid was filtered off and the filtrate was concentrated. The residue was purified by Prep-HPLC with Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN to yield 2-oxo-2-(3-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl (3S,8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C27H3iCIF4N405Si: 630.17, measured: 631.25 [M+H] ⁺ .

Step 2: (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-(triflu oromethyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-imi dazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 2-oxo-2-(3-(trifluoromethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)ethyl (3S,8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 _l 8a-hexahydroindolizine-3-carboxylate (220 mg, 0.35 mmol, 1.0 equiv.) in toluene(5 ml_) were added AcOH (0.5 mL) and NH4OAC (269 mg, 3.49 mmol, 10.0 equiv.). The resulting mixture was heated at 100 °C for 3 h under nitrogen. After being cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-(triflu oromethyl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a brown oil. LC/MS: mass calculated for C27H3iCIF4Ne0 ₂ Si: 611.19, measured: 611.35 [M+H]*.

Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py razol-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3- (trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py razol-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (150 mg, 0.24 mmol, 1.0 equiv.) in HOAc (5 mL) were added trimethoxymethane (260 mg, 2.45 mmol, 10.0 equiv.) and TMSNs (260 mg, 2.45 mmol, 10.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at 25 °C for 16 h. The residue was purified by prep-HPLC with Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-3-(5-(3-(trifluoromethyl)-1-((2-(trimethylsilyl)e thoxy)methyl)-1H- pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a brown oil. LC/MS: mass calculated for C28H3oCIF4Ne02Si: 663.19, measured: 665.25 [Μ+ΗΓ.

Step 4: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(3-

(trifluoromethyl)-1H-pyrazol-4-yl)-1H-imidazol-2-yl)-2,3, 8,8a-tetrahydroindolizin-

5(1H)-one

To a solution of (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-3-(5-(3-(trifluoromethyl)-1-((2-(trimethylsilyl)e thoxy)methyl)-1H- pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (130 mg, 0.196 mmol, 1.0 equiv.) in DCM (3 ml_) was added TFA (3 mL). The resulting mixture was stirred at 25 °C for 2 h and then concentrated under vacuum. The residue was purified by reverse chromatography to yield the racemic product, which was further separated by chiral-HPLC to yield (3S,8aR)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(3-(trifluoromethyl)-1 H-pyrazol-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C22HieCIF4NgO: 533.11, measured (ES, m/z): 534.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 13.51 (br, 1H), 11.92 (br, 1 H), 9.83 (s, 1 H), 8.09 (s, 1 H), 7.97 (t, J = 8.2 Hz, 1 H), 7.70 - 7.72 (m, 1 H),

6.99 (s, 1H), 5.66 (d, J = 2.4 Hz, 1H), 4.98 (t, J = 7.2 Hz, 1H), 3.98 -4.22 (m, 1H), 2.18 -2.38 (m, 4H), 1.93 -2.12 (m, 2H). ^ig F NMR (376 MHz, DMSO-de) δ -60.01, -112.84.

Example 241 N-[4-[2-[(3S,8aR)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-5-yl]-6- (trifluoromethyl)-3-pyridyl]cyclopropanecarboxamide

LC/MS: mass calculated for C28H22CIF4N9O2: 627.15, measured (ES, m/z): 628.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.52 (s, 1H), 9.80 (s, 1H), 9.63 (s, 1H), 8.18 (d, J = 1.4 Hz, 2H), 7.96 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.19 - 7.45 (m, 1H), 5.67 (d, J = 2.4 Hz, 1H), 5.09 (d, J = 8.8 Hz, 1H), 3.65 - 3.82 (m, 1H), 2.48-2.75 (m, 2H), 2.23 -2.41 (m, 1H), 2.00-2.18 (m, 2H), 1.82 - 1.99 (m, 1 H), 1.72 - 1.80 (m, 1 H), 0.83 - 0.94 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -65.37, -73.49, -112.81.

Example 242 N-[4-[2-[(3S,8aS)-7-[3-Chloro-2-fluoro-6-{tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-i midazol-5-yl]~6- (trifluoromethyl)-3-pyridyl]cyclopropanecarboxamide

LC/MS: mass calculated for C28H22CIF4N9O2: 627.15, measured (ES, m/z): 628.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.89 (br, 1H), 12.82 (s, 1H), 9.82 (s, 1H), 9.67 (s, 1H), 8.21 (d, J = 17.5 Hz, 2H), 7.97 (t, J = 8.2 Hz,

1H), 7.70 (d, J = 8.7 Hz, 1H), 7.22 - 7.41 (m, 1H), 5.71 (d, J = 2.6 Hz, 1H), 5.07 (t, J = 7.6 Hz, 1H), 4.01 -4.18 (m, 1H), 2.31 -2.46 (m, 2H), 2.20-2.28 (m, 1H), 1.93 - 2.08 (m, 2H), 1.61 - 1.78 (m, 2H), 0.79 -0.95 (m, 4H). ¹⁹ F NMR

(282 MHz, DMSO-de) δ -65.54, -73.45, -113.38.

Example 243 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-i midazol-5-yl]-6- (trifluoromethyl)-3-pyridyl]-2,2,2-trideuterio-acetamide

HN _V

N— N

S Jl,

LC/MS: mass calculated for C2eHi7CID3F4Ne02: 604.16, measured (ES, m/z): 605.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.71 (s, 1H), 12.31 (s, 1H), 9.82 (s, 1H), 9.66 (s, 1H), 8.19 (s, 2H), 7.97 (t, J = 8.3 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 5.70 (d, J = 2.1 Hz, 1H), 5.07(d, J = 8.9 Hz, 1H), 3.66 -3.81 (m, 1H), 2.54 -2.73 (m, 2H), 2.23 -2.36 (m, 1H), 2.13 -2.20 (m, 1H), 2.03 -2.12 (m, 1H), 1.87 - 1.99 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -65.20, -73.44, - 112.87.

Example 244 N-[4-[2-[(3S,8aS)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-5-yl]-6-

(trifluoromethyl)-3-pyridyl]acetamide

>°

LC/MS: mass calculated for C2eH2oCIF4Ng02: 601.14, measured (ES, m/z): 602.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.87 (s, 1H), 12.59 (s, 1H), 9.82 (s, 1H), 9.68 (s, 1H), 8.19 (d, J= 12.2 Hz, 2H), 7.96 (t, J = 8.3 Hz,

1H), 7.70 (d, J = 8.7 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 5.07 (t, J = 7.4Hz, 1H), 4.03 - 4.16 (m, 1H), 2.37 -2.46 (m, 2H), 1.96 - 2.31 (m, 6H), 1.69 - 1.84 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -65.56, -73.42, -113.17.

Example 245 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-i midazol-5-yl]-6-

(trifluoromethyl)-3-pyridyl]acetamide

LC/MS: mass calculated for C2eH2oCIF4Ng02: 601.14, measured (ES, m/z): 602.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.68 (s, 1H), 12.29 (s, 1H), 9.81 (s, 1H), 9.65 (s, 1H), 8.17 (d, J= 3.1 Hz, 2H), 7.96 (t, J = 8.3 Hz, 1H),

7.70 (d, J = 8.6 Hz, 1H), 5.70 (d, J = 2.1 Hz, 1H), 5.07 (d, J =8.8 Hz, 1H), 3.68 - 3.79 (m, 1 H), 2.53 - 2.72 (m, 2H), 2.05 - 2.32 (m, 6H), 1.86 - 2.02 (m, 1 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -65.57, -73.44, -112.86.

Example 246 N-[4-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]- 5- oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-4-yl]-3-pyridyl]-2,2- difluoro-propanamide

LC/MS: mass calculated for CaeHaiCIFaNgOa: 583.15, measured (ES, m/z): 584.25 [M+H] ⁺ . ¹ H NMR (300 MHz, CDaOD-d*) 69.90 (s, 1H), 9.57 (s, 1 H), 8.40 - 8.50 (m, 1 H), 8.25 - 8.33 (m, 1 H), 8.24 (s, 1 H), 7.84 (t, J = 7.8 Hz,

1H), 7.52 - 7.60 (m, 1H), 5.65 - 5.77 (m, 1H),5.11 - 5.24 (m, 1H), 3.85 -4.04 (m, 1 H), 2.65 - 2.73 (m, 2H), 2.27 - 2.57 (m, 3H), 1.80 - 2.20 (m, 4H). ¹⁹ F NMR (282 MHz, CDsOD-d*) δ -77.02, -99.20, -113.75.

Example 247 N-[5-[2-[(3S,8aS)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-4-yl]-1 - methyl-pyrazol-4-yl]cyclopropanecarboxamide

LC/MS: mass calculated for C2eH24CIFNio02: 562.18, measured (ES, m/z): 563.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.92 (br, 1H), 9.76 - 9.90 (m, 1H), 7.99 (t, J = 8.2 Hz, 1H), 7.69 - 7.81 (m, 3H), 5.65 - 5.80 (m, 1H), 5.15

(t, J = 7.5 Hz, 1 H), 4.06 - 4.21 (m, 1 H), 3.80 - 3.86 (m, 3H), 2.62 - 2.88 (m, 1H), 2.21 -2.45 (m, 3H), 1.73 -2.19 (m, 2H), 1.62-1.72 (m, 1H), 0.71 - 0.83 (m, 4H). ¹⁸ F NMR (282 MHz, CDaOD-cU) δ -77.02, -99.20, -113.75 (d, J = 97.01 Hz). ¹⁹ F NMR (376 MHz, DMSO-de) δ -77.02, -99.20, -113.75. Example 248 N-[2-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]- 5- oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-4-yl]-3- thienyl]cyclopropanecarboxamide

LC/MS: mass calculated for CMHHCIFNSC^S: 564.13, measured (ES, m/z): 565.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.68 (br, 1H), 9.84 (d, J = 2.8 Hz, 1H), 7.99 (t, J = 8.1 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.15 - 7.31 (m, 1H), 6.67 (d, J =4.5 Hz, 1H), 5.68 - 5.79 (m, 1H), 5.02 - 5.19 (m, 1H), 3.63 -

3.85 (m, 1 H), 2.85 - 3.04 (m, 1H), 1.86 -2.16 (m, 4H), 1.72 - 1.84 (m, 1H), 0.81 - 0.94 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.67, -112.74. Example 249 N-(4-(2-((3S,8a*R)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)pyridin-3-yl)cyclopropanecart>oxamide

Step 1: 2-(3-bromopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5, 8,8a-hexahydroindolizine-3-carboxylic acid (612 mg, 1.88 mmol, 1.0 equiv.) in DMF (10 mL) was added cesium carbonate (430 mg, 1.32 mmol, 0.7 equiv.). The mixture was stirred at 35 °C for 0.5 h. To the mixture was then added 2-bromo-1-(3-bromopyridin-4-yl)ethan-1-one (841 mg, 3.02 mmol, 1.6 equiv.) and the resulting mixture was stirred 1.5 h, then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0→100% PE/EA) to yield the 2-(3-bromopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate as a yellow oil. LC/MS: mass calculated for C22HieBrCIFN304: 521.02, measured 522.00 [Μ+ΗΓ, 522.00 [M+H+2]*.

Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3-bromopyridi n-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of 2-(3-bromopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 _l 8a-hexahydroindolizine-3-carboxylate (581 mg, 1.11 mmol, 1.0 equiv.) in toluene (10 mL) and acetic add (1 mL) was added ammonium acetate (857 mg, 11.12 mmol, 10.0 equiv.). The mixture was stirred at 110°C for 2 h. After being cooled to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield the (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(4-(3-bromopyridin-4-yl)-1H -imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C22Hi ₈ BrCIFN ₅ 0: 501.04, measured: 501.95 [M+H]*, 503.95 [M+H+2] ⁺ .

Step 3: (3S)-3-(4-(3-bromopyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3- bromopyridin-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

(406 mg, 0.81 mmol, 1.0 equiv.) in acetic add (10 mL) were added azidotrimethylsilane (929 mg, 8.07 mmol, 10.0 equiv.) and trimethoxymethane (856 mg, 8.07 mmol, 10.0 equiv.). The reaction mixture was stirred at 65°C for 2 h, diluted with water and extracted with EA. The combined extracts were washed with water, dried over N32S04, filtered and purified by silica gel chromatography (0→10% MeOH/DCM) to yield (3S)-3-(4-(3-bromopyridin-4-yl)- 1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)p henyl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C23HieCIFNeO: 554.04, measured: 555.00 [M+H] ⁺ , 557.00 [M+H+2] ⁺ . Step 4: (3S)-3-(4-(3-aminopyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-3-(4-(3-bromopyridin-4-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 Hi- one (313 mg, 0.56 mmol, 1.0 equiv.) in ethanol (4 ml_) and H2O (1 ml_) were added sodium azide (110 mg, 1.69 mmol, 3.0 equiv.), sodium ascorbate (89 mg, 0.45 mmol, 0.8 equiv.), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (48 mg, 0.34 mmol, 0.6 equiv.), and copper sulfate pentahydrate (56 mg, 0.22 mmol, 0.4 equiv.). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (3 x 50 ml_). The combined extracts were washed with water, dried over N32S04, concentrated and purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield (3S)-3-(4-(3-aminopyridin-4-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a-tetrahydroindolizin- 5(1H)-one as a yellow solid. LC/MS: mass calculated for C23H19CIFN9O:

491.14, measured: 492.10 [M+HJ*.

Step 5: N-(4-(2-((3S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl) phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)pyridin-3- yl)cyclopropanecarboxamide

To a solution of (3S)-3-(4-(3-aminopyridin-4-yl)-1H-imidazol-2-yl)-7-(3- chloro2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 Hi- one (206 mg, 0.42 mmol, 1.0 equiv.) in pyridine (4 mL) was added cyclopropanecarboxylic acid (180 mg, 2.09 mmol, 5.0 equiv.), followed by addition of EDCI (160 mg, 0.84 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 3 h and concentrated. The residue was redissolved in methanol (4 mL) and ammonium hydroxide (0.4 mL) and stirred at room temperature for 1 h. The resulting mixture was then diluted with water and extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and purified by prep-HPLC with (0→30% MeCN/taO) to yield N-(4-(2-((3S,8a*R)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl) phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)pyridin-3- yl)cyclopropanecarboxamide as a white solid.

LC/MS: mass calculated for C27H23CIFN9O2: 559.16, measured (ES, m/z): 560.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.52 (s, 1H), 12.10 (s, 1H), 9.82 (s, 1H), 9.45 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.85 - 8.06 (m, 2H), 7.62 - 7.78 (m, 2H), 5.67 (s, 1 H), 5.08 (d, J = 8.9 Hz, 1 H), 3.58 - 3.86 (m, 1 H), 2.56 - 2.80 (m, 2H), 2.01 - 2.36 (m, 3H), 1.80 - 2.00 (m, 1 H), 1.57 - 1.80 (m, 1H), 0.72 - 0.99 (m, 4H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -112.79.

Example 250 N-(4-(2-((3S,8aS*)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)pyridin-3-yl)cyclopropanecarboxamide

H VN ⁴

F

Cl

! O

N-¾

N ¹ _V N

LC/MS: mass calculated for C27H23CIFN9O2: 559.16, measured (ES, m/z): 560.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.71 (s, 1H), 12.40 (s, 1H), 9.82 (s, 1H), 9.50 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.88 - 8.04 (m, 2H),

7.62 - 7.78 (m, 2H), 5.71 (d, J = 2.7 Hz, 1H), 5.06 (t, J = 7.5 Hz, 1H), 4.00 - 4.22 (m, 1H), 2.33 - 2.47 (m, 2H), 2.12 -2.32 (m, 2H), 1.86 -2.10 (m, 1H), 1.55 - 1.84 (m, 2H), 0.76 - 0.96 (m, 4H). ¹⁸ F NMR (282 MHz, DMSO-de) δ - 113.38.

Example 251 Ethyl N-[3-[2-[(3S)-7-[3-chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-i midazol-4-yl]-4- pyridyl]carbamate

LC/MS: mass calculated for CzehfcaCIFNgOa: 563.16, measured (ES, m/z): 564.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 13.13 - 13.40 (m, 1H), 13.00 (br, 1H), 9.82 (s, 1H), 9.06 - 9.14 (m, 1H), 8.49 - 8.65 (m, 2H), 8.03 (s, 1 H), 7.90 - 8.01 (m, 1 H), 7.71 (d, J = 8.7 Hz, 1 H), 5.63 - 5.75 (m, 1 H), 5.00 - 5.14 (m, 1H), 4.15 -4.34 (m, 2H), 3.78 - 3.86 (m, 1H), 2.51 -2.64 (m, 1H), 2.18 - 2.34 (m, 4H), 1.92 - 2.02 (m, 1H), 1.16 - 1.34 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -73.88, -113.19.

Example 252 N-[3-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-5- oxo-2, 3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-4-yl]-4- pyridyl]cyclopropanecarboxamide

LC/MS: mass calculated for C27H23CIFN9O2: 559.16, measured (ES, m/z): 560.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 13.31 - 13.77 (m, 1H), 12.60 - 13.28 (m, 1H), 9.83 (s, 1H), 9.15 (s, 1H), 8.85 (d, J = 6.3 Hz, 1H), 8.56 (d, J = 6.0 Hz, 1H), 8.08 (s, 1H), 7.97 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 5.60 - 5.80 (m, 1H), 5.13 (d, J = 8.7 Hz, 1H), 3.70 - 3.80 (m, 1H), 2.58 -

2.80 (m, 2H), 2.01 -2.37 (m, 3H), 1.60 - 2.00 (m, 2H), 0.80 - 1.15 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.42, -113.11.

Example 253 (3S)-3-[4-(4-Amino-3-pyridyl)-1 H-imidazol-2-yl]-7-[3-chloro-2- fluoro-6-(tetrazol-1-yl)phenyl]-2,3,8,8a-tetrahydro-1H-indol izin-5-one

LC/MS: mass calculated for C23HigCIFNeO: 491.14, measured (ES, m/z): 492.10 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) δ 9.83 (s, 1H), 8.59 (s, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.97 (t, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 6.9 Hz, 1H), 5.67 (d, J = 2.4 Hz, 1H), 5.06 (d, J = 8.8 Hz, 1H), 3.71 - 3.77 (m, 1H), 2.55 -2.77 (m, 2H), 2.11 - 2.29 (m, 2H), 1.86 - 2.04 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.24, -112.78.

Example 254 Ethyl N-[3-[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-i midazol-4-yl]-2- pyridyljcarbamate

SUBSTITUTE R, HN. .

F

Cl.

HI

LC/MS: mass calculated for CaetesCIFNeOs: 563.16, measured (ES, m/z): 564.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.96 (br, 1H), 9.83 (s, 1H), 8.16 - 8.45 (m, 2H), 7.98 (t, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.33 (t, J = 6.0 Hz, 1H), 5.69 (s, 1H), 5.06 (d, J = 8.7 Hz, 1H), 4.11 - 4.21 (m, 2H), 3.75 - 3.80 (m, 1 H), 2.55 - 2.81 (m, 2H), 2.05 - 2.37 (m, 3H), 1.85-2.05 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H). ¹⁸ F NMR (376 MHz, DMSO-de) δ - 74.11, -113.03.

Example 255 (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)pheny l]-3-[4-(1 - methyl-1 ,2,4-triazol-3-yl)-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one

LC/MS: mass calculated for C21H18CIFN10O: 480.13, measured (ES, m/z): 481.05 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD-d ₄ ) δ 9.58 (s, 1H), 8.50 (s, 1H), 7.76 - 7.92 (m, 2H), 7.51 - 7.60 (m, 1H), 5.70 - 5.82 (m, 1H), 5.19-5.35

(m, 1H), 3.84 - 4.10 (m, 4H), 2.90 - 3.10 (m, 1 H), 2.60 - 2.80 (m, 2H), 2.41 - 2.59 (m, 1H), 2.18-2.37 (m, 1H), 1.85-2.15 (m, 1H). ¹⁸ F NMR (282 MHz, CDaOD-d*) δ -77.11, -113.77.

Example 256 N-[4-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)phenyl]-5- oxo-2, 3,8, 8a-tetrahydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]-3-pyridyl ]-

2,2,2-trideuterio-acetamide

LC/MS: mass calculated for C25H18CID3FN9O2: 536.17, measured (ES, m/z): 537.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.85 - 13.35 (m, 1H), 12.35 - 12.80 (m, 1H), 9.84 (s, 1H), 9.66 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.29 - 8.37 (m, 1H), 8.22 (d, J = 11.7 Hz, 1H), 7.98 (t, J = 8.1 Hz, 1H), 7.72 (d, J =

9.9 Hz, 1H), 5.72 (s, 1H), 5.10 (d, J = 9.0 Hz, 1H), 3.72 - 3.76 (m, 1H), 2.55 - 2.67 (m, 2H), 2.40 -2.49 (m, 1H), 2.16 -2.36 (m, 2H), 2.03 -2.15 (m, 1H), 1.87 - 2.02 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.98, -113.05.

Example 257 N-[2-[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-i midazol-4-yl]-4- methoxy-phenyQcyclopropanecarboxamide

LC/MS: mass calculated for CaHMCIFNeOa: 588.18, measured (ES, m/z): 589.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.27 (s, 1H), 11.99 (s, 1H), 9.83 (s, 1H), 8.23 (d, J = 9.0 Hz, 1H), 7.98 (t, J = 8.2 Hz, 1H), 7.72 (d, J =

8.7 Hz, 1H), 7.65 (s, 1H), 7.23 (d, J = 2.9 Hz, 1H), 6.76 (dd, J = 9.0, 2.9 Hz, 1H), 5.66 (d, J = 2.6 Hz, 1H), 5.07 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H), 3.65 -3.74 (m, 1H), 2.63 -2.78 (m, 1H), 2.54 - 2.62 (m, 1H), 2.21 -2.34 (m, 1H), 2.11 - 2.19 (m, 1H), 2.01 -2.10 (m, 1H), 1.85 - 2.00 (m, 1H), 1.52 - 1.65 (m, 1H), 0.64 - 0.92 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.48.

Example 258 (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5-[3- (methylamino)-l H-indazol-6~yl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one

LC/MS: mass calculated for C26H22CIFN10O: 544.17, measured (ES, m/z): 545.05 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 13.90 - 14.90 (m, 1H), 11.95 (br, 1H), 9.84 (s, 1H), 8.12 (s, 1H), 7.99 (t, J = 8.0 Hz, 1H), 7.83 (d, J = 11.2 Hz, 1H), 7.73 (d, J = 12.8 Hz, 1H), 7.60 - 7.70 (m, 1H), 7.20 - 7.42 (m,

1H), 5.65 - 5.90 (m, 1H), 5.10 - 5.30 (m, 1H), 3.70 - 3.82 (m, 1H), 3.00 (t, J = 15.3 Hz, 1H), 2.89 (s, 3H), 2.53 -2.70 (m, 1H), 2.25 -2.48 (m, 2H), 2.07 - 2.25 (m, 2H), 1.76 -2.07 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -74.29, - 112.86. Example 259 N-[4-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1 -yl)phenyi]-5- oxo-2, 3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-4-yl]-1 -methyl- pyrazol-3-yl]cyclopropanecarboxamide

LC/MS: mass calculated for C2eH24CIFNio02: 562.18, measured (ES, m/z): 563.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 10.10 - 10.30 (m, 1H), 9.83 (s, 1H), 7.92 - 8.10 (m, 2H), 7.73 (d, J = 8.7 Hz, 1H), 7.16 (s, 1H), 5.63 - 5.80 (m, 1H), 5.05 - 5.25 (m, 1H), 4.10 -4.40 (m, 1H), 3.86 (s, 3H), 2.85 - 3.10 (m, 1H), 2.54 - 2.65 (m, 1H), 2.21 -2.45 (m, 1H), 1.70 -2.20 (m, 4H), 0.65 - 0.90 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -74.08, -112.61.

Example 260 (3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[4-[2- (methylamino)-3-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one

LC/MS: mass calculated for C24H21CIFN9O: 505.15, measured (ES, m/z): 506.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.75 (br, 1H), 10.35 - 11.00 (m, 1H), 9.85 (s, 1H), 8.21 - 8.31 (m, 1H), 7.99 (t, J = 8.4 Hz, 1H), 7.85 - 7.97 (m, 2H), 7.73 (d, J = 8.6 Hz, 1 H), 6.94 (t, J = 6.8 Hz, 1 H), 5.70 - 5.75 (m, 1 H),

5.03 - 5.08 (m, 1H), 3.69 - 3.90 (m, 1H), 3.12 (s, 3H), 2.60 -2.67 (m, 1H),

2.38 - 2.50 (m, 1H), 2.22 - 2.33 (m, 1H), 2.13 - 2.20 (m, 1H), 1.70 - 2.00 (m, 2H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -74.23, -113.09.

Example 261 : 6-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-5-o xo- 2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-5-yl]-1 H-quinolin-2-one

Cl, S

IH

V

LC/MS: mass calculated for C27H20CIFN8O2: 542.14, measured (ES, m/z): 543.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-ck) δ 11.94 (br, 1H), 9.84 (s, 1H), 7.84 - 8.10 (m, 5H), 7.72 (d, J = 13.2 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 6.59 (d, J = 9.6 Hz, 1H), 5.67 - 5.80 (m, 1H), 5.02 - 5.24 (m, 1H), 3.70 - 3.83

(m, 1 H), 2.86 - 3.06 (m, 1 H), 2.52 - 2.65 (m, 1 H), 2.26 - 2.45 (m, 1 H), 1.78 - 2.24 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.82, -112.70.

Example 262: Ethyl N-[3-[2-[(3S,8aS)-7-[3-chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-i midazol-4-yl]-2- pyridyljcarbamate

LC/MS: mass calculated for CiehtaCIFNeOa: 563.16, measured (ES, m/z): 564.15 [M+H]÷. ¹ H NMR (300 MHz, DMSO-de) 69.83 (s, 1H), 8.26 - 8.40 (m, 2H), 7.98 (t, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.25 - 7.35 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 5.10 (t, J = 7.3 Hz, 1H), 4.07 -4.23 (m,

3H), 2.52 - 2.64 (m, 1 H), 2.30 - 2.48 (m, 3H), 1.98 - 2.04 (m, 1 H), 1.76 - 1.86 (m, 1H), 1.10 - 1.26 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -73.90, -113.13.

Example 263: Ethyl N-[4-[2-[(3S,8aS)-7-[3-chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-i midazol-4-yl]-3- pyridyljcarbamate

LC/MS: mass calculated for C2eH23CIFNg03: 563.16, measured (ES, m/z): 564.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 13.24 (br, 1H), 12.48 (br, 1H), 9.82 (s, 1H), 9.40 (s, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J = 5.7 Hz, 1H), 7.98 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 5.69 (s, 1H),

5.09 (t, J = 7.2 Hz, 1H), 4.13 -4.29 (m, 3H), 2.54 - 2.59 (m, 1H), 2.25 -2.45 (m, 3H), 1.94 - 2.06 (m, 1 H), 1.75 - 1.88 (m, 1 H), 1.21 - 1.32 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.01, -113.18.

Example 264: N-[2-[2-[(3S,8aS)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-4-yl]-5- methoxy-phenyl]cyclopropanecarboxamide

LC/MS: mass calculated for C2eH2eCIFNe03: 588.18, measured (ES, m/z): 589.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 13.50- 14.80 (m, 1H), 9.83 (s, 1H), 7.98 (t, J = 8.4 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 6.84 (br, 1H), 5.75 (d, J = 2.6 Hz, 1H), 5.14 (t, J = 8.1 Hz,

1H), 4.11 -4.25 (m, 1H), 3.77 (s, 3H), 2.52 - 2.60 (m, 1H), 2.39-2.48 (m, 1H), 2.23 - 2.32 (m, 1 H), 1.97 - 2.06 (m, 1 H), 1.71 - 1.86 (m, 2H), 0.75 - 0.81 (m, 4H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -74.15, -113.14.

Example 265: (3S,8aS)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5- [3- (methylamino)-1H-indazol-6-yl]-1H-imidazol-2-yl]-2,3,8,8a-te trahydro-1H- indolizin-5-one s

H

LC/MS: mass calculated for C2eH22CIFNioO: 544.17, measured (ES, m/z): 545.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 14.60 (br, 1H), 11.87 (br, 1H), 9.85 (s, 1H), 8.11 (s, 1H), 8.00 (t, J = 8.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H),

7.73 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.77 (d, J = 2.6 Hz, 1H), 5.15 (t, J = 8.8 Hz, 1H), 4.13-4.29 (m, 1H), 2.88 (s, 3H), 2.53-2.67 (2H), 2.40 - 2.48 (m, 1 H), 2.26 - 2.34 (m, 1 H), 1.98 - 2.09 (m, 1 H), 1.77 - 1.93 (m, 1H). ^ig F NMR (376 MHz, DMSO-de) δ -74.11, -113.06.

Example 266: N-(2-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-5- methoxyphenyl)cyclopropanecarboxamide

LC/MS: mass calculated for C29H2eCIFNe03: 588.18, measured (ES, m/z): 589.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.48 (s, 1H), 12.18 (s, 1H), 9.82 (s, 1H), 8.11 (s, 1H), 7.97 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 6.62 (d, J = 11.6 Hz, 1H), 5.65 (s, 1H),

5.05 (d, J = 9.0 Hz, 1H), 3.63 - 3.77 (m, 4H), 2.53 - 2.74 (m, 2H), 2.19 - 2.35 (m, 1H), 2.11 - 2.19 (m, 1H), 2.00 - 2.10 (m, 1H), 1.84 - 2.01 (m, 1H), 1.52 - 1.68 (m, 1H), 0.69 - 0.94 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.57.

Example 267: N-[3-[2-[(3S,8aS)-7-[3-Chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-i midazol-4-yl]-4- pyridyl]cyclopropanecarboxamide

LC/MS: mass calculated for C27H23CIFN9O2: 559.16, measured (ES, m/z): 560.15 [M+H] ⁺ . ¹ H NMR (300 MHz, CDaOD-d*) δ 9.59 (s, 1H), 8.98 - 9.09 (m, 2H), 8.41 (d, J = 6.9 Hz, 1H), 7.79 - 7.92 (m, 2H), 7.58 (d, J = 8.7 Hz, 1H),

5.73 (d, J = 2.3 Hz, 1H), 5.23 (t, J = 7.8 Hz, 1H), 4.19 - 4.33 (m, 1H), 2.51 -

2.73 (m, 3H), 2.35 - 2.50 (m, 1H), 2.15 - 2.34 (m, 1H), 1.75 - 1.97 (m, 2H), 1.04 - 1.25 (m, 4H). ¹⁹ F NMR (282 MHz, CDsOD-d*) δ -77.02, -114.16.

Example 268: Ethyl N-[3-[2-[(3S,8aS)-7-[3-chloro-2-fluoro-6-(tetrazol-1- yl)phenyl]-5-oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-4-yl]-4- pyridyl]carbamate

LC/MS: mass calculated for C2eH23CIFNe03: 563.16, measured (ES, m/z): 564.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 13.26 (br, 1H), 12.98 (br, 1H), 9.82 (s, 1H), 9.08 (s, 1H), 8.53 (br, 2H), 7.92 - 8.05 (m, 2H), 7.71 (d, J = 8.7 Hz, 1 H), 5.68 (d, J = 2.3 Hz, 1 H), 5.09 (t, J = 7.0 Hz, 1 H), 4.21 - 4.35 (m,

2H), 4.09 - 4.20 (m, 1 H), 2.30 - 2.45 (m, 4H), 1.95 - 2.08 (m, 1 H), 1.75 - 1.88 (m, 1H), 1.28 (t, J = 7.0 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.74, - 113.21.

Example 269: (3S,8aS)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]-3-[5- [2- (methylamino)-3-pyridyl]-1 H-imidazol-2-yl]-2,3,8,8a-tetrahydro-1 H- indolizin-5-one

LC/MS: mass calculated for C24H21CIFN8O: 505.15, measured (ES, m/z): 506.15 [Μ+ΗΓ. ¹ H NMR (400 MHz, DMSO-de) 6 12.93 (br, 1H), 9.85 (s, 1H), 8.22 (d, J = 7.3 Hz, 1 H), 7.98 (t, J = 8.2 Hz, 1 H), 7.85 - 7.92 (m, 2H), 7.72 (d, J

= 8.7 Hz, 1H), 6.92 (t, J = 6.8 Hz, 1H), 5.71 (d, J = 2.5 Hz, 1H), 5.06 (t, J = 7.5 Hz, 1H), 4.03 -4.12 (m, 1H), 3.14 (s, 3H), 2.52 - 2.58 (m, 1H), 2.34 - 2.48 (m, 2H), 2.18 -2.30 (m, 1H), 1.92 - 2.06 (m, 1H), 1.69 - 1.79 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -74.05, -113.18. Example 270: 6-[2-[(3S,8aS)-7-[3-Chloro-2-fluoro-6-(tetrazoM-yl)phenyl]-5 - oxo-2,3,8,8a-tetrahydro-1 H-indolizin-3-yl]-1 H-imidazol-5-yl]-1 H-quinolin-2- one S j?

Cl. S H

N IH f

LC/MS: mass calculated for C27H20CIFN8O2: 542.14, measured (ES, m/z): 543.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 11.75 (s, 1H), 9.85 (s, 1H), 7.91 - 8.04 (m, 3H), 7.86 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.48 (br, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 6.50 (d, J = 9.6 Hz, 1 H), 5.71 (d, J = 2.5 Hz, 1H), 5.01 (t, J = 7.3 Hz, 1H), 4.02 -4.15 (m, 1H), 2.67 -2.72 (m, 2H), 2.22 - 2.43 (m, 2H), 1.99 -2.13 (m, 1H), 1.67 - 1.84 (m, 1H). ¹⁸ F NMR (282 MHz, DMSO-de) 6 -113.08.

Example 271: N-(2-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-4- methoxyphenyl)cyclopropanecarboxamide

LC/MS: mass calculated for C28H26CIFN8O3: 588.18, measured: 589.05 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 69.83 (s, 1H), 7.98 (t, J = 8.4 Hz, 1H), 7.65 - 7.74 (m, 2H), 7.14 (s, 1H), 6.76 - 7.06 (m, 1H), 5.73 - 5.77 (m, 1H),

5.12 - 5.15 (m, 1 H), 4.13 - 4.18 (m, 1 H), 3.77 - 3.82 (m, 3H), 2.53 - 2.69 (m,

1 H), 2.37 - 2.47 (m, 2H), 2.22 - 2.35 (m, 1 H), 1.95 - 2.05 (m, 1 H), 1.73 - 1.86 (m, 1H), 1.59 - 1.72 (m, 1H), 0.68 - 0.84 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO- de) 6 -74.10, -113.17.

Example 272 (3S,8aS)-3-(4-(4-Aminopyridin-3-yl)-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-

5(1H)-one

LC/MS: mass calculated for C23H19CIFN9O: 491.14, measured: 492.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.80 (s, 1H), 8.49 - 8.54 (m, 1H), 8.05 - 8.09 (m, 1H), 7.89 - 8.00 (m, 1H), 7.78 (s, 1H), 7.65 - 7.71 (m, 1H), 6.99 (d, J = 6.9 Hz, 1H), 5.69 (d, J = 2.5 Hz, 1H), 5.06 (t, J = 7.6 Hz, 1H), 4.06 -4.12 (m, 1 H), 2.36 - 2.56 (m, 3H), 2.21 - 2.26 (m, 1 H), 1.95 - 2.02 (m, 1 H), 1.67 - 1.83 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.28, -113.09.

Example 2736-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)quinazolin-

2(1H)-one

LC/MS: mass calculated for C2eHigCIFNg02:543.94, measured: 544.05 [M+H] ⁺ . 1H NMR (300 MHz, Methanol-d4) δ 9.61 (d, J = 2.2 Hz, 1H), 7.80 - 7.92 (m, 1H), 7.78 (s, 1H), 7.64 - 7.74 (m, 2H), 7.57 - 7.62 (m, 1H), 7.04 - 7.11 (m, 1H), 5.68 - 5.80 (m, 2H), 5.12 - 5.33 (m, 1 H), 3.98 - 4.44 (m, 1H), 3.01 (t,

J = 15.6 Hz, 1H), 2.62 -2.81 (m, 1H), 2.46 -2.60 (m, 1H), 2.25 - 2.43 (m, 2H), 1.90 - 2.09 (m, 1H).

Example 274 (3S,8aS)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(4- (1 -methyl-1 H-1 ,2,4-triazol-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C21 Hi8CIFNioO:480.13, measured: 481.10

[M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.81 (s, 1H), 8.65 (s, 1H), 7.91 - 8.04 (m, 2H), 7.69 (d, J = 8.7 Hz, 1H), 5.72 (d, J = 2.4 Hz, 1H), 5.01 -5.11 (m, 1H), 4.16 -4.22 (m, 1H), 3.91 - 3.95 (m, 3H), 2.22 - 2.47 (m, 4H), 1.94 - 2.03 (m, 1H), 1.75 - 1.91 (m, 1H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -73.65, -113.09. Example 275 N-(3-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4-yl)-1- methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide

LC/MS: mass calculated for C2eH24CIFNio02: 562.18, measured: 563.10 [Μ+ΗΓ. ¹ H NMR (400 MHz, DMSO-de) δ 9.83 (s, 1H), 8.04 (s, 1H), 7.94 - 8.01 (m, 1H), 7.65 - 7.74 (m, 2H), 5.75 (s, 1H), 5.06 - 5.24 (m, 1H), 4.21 -4.29 (m,

1H), 3.90 (s, 3H), 2.54 - 2.70 (m, 2H), 2.38 -2.47 (m, 1H), 2.21 -2.36 (m, 1H), 1.90 - 2.06 (m, 1 H), 1.75 - 1.92 (m, 2H), 0.72 - 0.86 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -74.09, -113.09.

Example 276 N-(2-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl )-5- methoxyphenyl)cyclopropanecarboxamide

LC/MS: mass calculated for CtthtaCIFNeOa: 588.18, measured: 589.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.46-12.51 (m, 1H), 12.13-12.22 (m, 1H), 9.83 (s, 1H), 8.08 - 8.15 (m, 1H), 7.92 - 8.04 (m, 1H), 7.67 - 7.76 (m, 1H),

7.54 - 7.62 (m, 1H), 7.47 - 7.52 (m, 1H), 6.57 - 6.67 (m, 1H), 5.66 (s, 1H), 5.02 - 5.10 (m, 1H), 3.70 - 3.76 (m, 4H), 2.56 - 2.71 (m, 1H), 1.95 -2.25 (m, 5H), 1.55 - 1.64 (m, 1H), 0.70 - 0.90 (m, 4H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -112.74, -113.37.

Example 2776-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)- 1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one

Step 1: 2-oxo-2-(2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)ethyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate

To a solution of (3S)-7-(6-amino3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (192 mg, 0.59 mmol, 1.0 equiv.) in CH3CN (10 mL) was added K2CO3 (204 mg, 1.48 mmol, 2.5 equiv.), followed by 6-(2-chloroacetyl)benzo[d]oxazol-2(3H)-one (200 mg, 0.74 mmol, 1.3 equiv.) and the reaction mixture was stirred overnight at 40 °C, quenched with water (10 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over N32S04 and concentrated. The residue was purified by flash column chromatography on silica gel (0→25% EA/PE) to yield 2-oxo-2-(2-oxo-1 ,4-di hydro-2 H- benzo[d][1 ,3]oxazin-6-yl)ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a white solid. LC/MS: mass calculated for CasH^CIFNsOe: 513.11, measured 514.10 [M+H] ⁺ .

Step 2: 6-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin- 2-one

To a solution of 2-oxo-2-(2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6- yl)ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (502 mg, 0.98 mmol, 1.0 equiv.) in toluene (10 mL) and acetic add (1 mL) was added ammonium acetate (753 mg, 9.77 mmol, 10.0 equiv.). The mixture was stirred at 110°C for 2 h. After being cooled to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 ml_). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the 6-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 ,4-dihydro-2H-benzo[d][1 ,3]oxazin-

2-one as a yellow solid. LC/MS: mass calculated for C25H21CIFN5O3: 493.13, measured: 494.10 [M+H]*.

Step 3: 6-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-2-one

To a solution of 6-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 ,4-dihydro-2H- benzo[d][1 ,3]oxazin-2-one (212 mg, 0.43 mmol, 1.0 equiv.) in acetic add (5 ml_) were added azidotrimethylsilane (496 mg, 4.30 mmol, 10.0 equiv.) and trimethoxymethane (457 mg, 4.30 mmol, 10.0 equiv.). The reaction mixture was stirred at room temperature overnight, diluted with water and extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC with (MeCN/hbO 0→30%) to yield 6-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one as a white solid.

LC/MS: mass calculated for C2eH2oCIFN803: 546.13, measured: 547.10 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) δ 11.73 - 11.79 (m, 1H), 10.10 - 10.15 (m, 1 H), 9.84 (s, 1 H), 7.91 - 8.01 (m, 1 H), 7.67 - 7.75 (m, 1 H), 7.56 - 7.65 (m, 2H), 7.33 - 7.39 (m, 1 H), 6.82 - 6.90 (m, 1 H), 5.66 - 5.73 (m, 1 H), 5.30 - 5.36

(m, 2H), 4.94 - 5.03 (m, 1 H), 3.65 - 3.82 (m, 1 H), 3.50 - 3.53 (m, 1 H), 2.65 - 2.80 (m, 1H), 2.06 - 2.20 (m, 2H), 1.90 - 1.98 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.81, -112.91.

Example 278 (3S,8aS)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-1H-imidazol-2-yl)- 2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for CaetooCIFNeOa: 546.13, measured: 547.15 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) δ 11.89 - 11.94 (m, 1H), 10.10- 10.15 (m, 1 H), 9.84 (s, 1 H), 7.92 - 8.03 (m, 1 H), 7.65 - 7.74 (m, 1 H), 7.55 - 7.64 (m, 2H), 7.33 - 7.38 (m, 1 H), 6.80 - 6.88 (m, 1 H), 5.69 (d, J = 2.5 Hz, 1 H), 5.29 -

5.35 (m, 2H), 4.92 - 5.02 (m, 1H), 4.05 -4.15 (m, 1H), 3.48 - 3.54 (m, 1H), 2.20 - 2.45 (m, 3H), 1.99 - 2.05 (m, 1H), 1.63- 1.74 (m, 1 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -113.07, -218.48.

Example 279 N-(2-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 5-oxo-1,2,3,5,8 _| 8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)-4- methoxyphenyl)cyclopropanecarboxamide

LC/MS: mass calculated for CaHzeCIFNeOa: 588.18, measured: 589.15 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) 69.83 (s, 1H), 7.93 - 8.03 (m, 1H),

7.64 - 7.78 (m, 3H), 7.15 (d, J = 2.9 Hz, 1H), 6.96 - 7.04 (m, 1H), 5.68 - 5.80 (m, 1H), 5.20 (d, J = 9.5 Hz, 1H), 3.68-3.82 (m, 4H), 2.85 - 2.98 (m, 1H), 2.52 - 2.67 (m, 1 H), 2.27 - 2.47 (m, 1 H), 2.03 - 2.22 (m, 2H), 1.83- 1.99 (m, 1H),

1.64 - 1.77 (m, 1H), 0.71 - 0.79 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO- de) δ - 74.41, -112.58.

Example 2806-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-

3,4-dihydroquinolin-2(1 H)-one

LC/MS: mass calculated for C24H2oCIF2NeO: 253.14 measured: 545.1 [M+H] ^{+ 1} H NMR (300 MHz, DMSO-de) δ 11.71 - 12.26 (m, 1H), 10.05 - 10.11 (m, 1H), 9.85 (s, 1H), 7.98 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.50 - 7.55 (m, 1H), 7.43 - 7.50 (m, 1H), 7.32 (s, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.69

(d, J = 2.4 Hz, 1H), 4.93 - 5.03 (m, 1H), 4.01 -4.16 (m, 1H), 3.40 - 3.52 (m, 1H), 2.91 (t, J = 7.5 Hz, 2H), 2.19 -2.49 (m, 5H), 1.97 -2.10 (m, 1H), 1.62 - 1.82 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -113.06, -218.29.

Example 281 6-{2-{(3S,8aR)-7-{3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8 _| 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-

3,4-dihydroquinolin-2(1 H)-one

LC/MS: mass calculated for C24H20CIF2N9O: 253.14 measured: 545.1 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) δ 12.17 (br, 1H), 10.07 - 10.12 (m, 1H), 9.85 (s, 1H), 7.91 - 8.03 (m, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.45 - 7.59 (m, 2H),

7.38 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.68 (d, J = 2.6 Hz, 1H), 5.02 (d, J = 8.6 Hz, 1H), 3.65 - 3.77 (m, 1H), 2.87 -2.97 (m, 2H), 2.71 - 2.87 (m, 1H), 2.51 - 2.57 (m, 2H), 2.45 -2.48 (m, 1H), 1.93 -2.25 (m, 4H). ^ig F NMR (282 MHz, DMSO-de) 6 -112.78, -218.42. Example 282 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (2-fluoro-6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one

R* H

N

Cl. N' ^■ «X

•N i F

■V Step 1: 2-(2-fluoro-6-(methylamino)pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- I^.S.S.S.Sa-hexahydroindolizine-S-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) in DMF (10 mL) was added cesium carbonate (120 mg, 0.37 mmol, 0.6 equiv.). The mixture was stirred at room temperature for 0.5 h. To the resulting mixture was added 2-bromo-1-(2-fluoro-6-(methylamino)pyridin-3-yl)ethan-1- one (152 mg, 0.62 mmol, 1.0 equiv.) and the mixture was maintained stirring for 1.5 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0→30% MeOH/DCM) to yield 2-(2-fluoro-6-(methylamino)pyridin-3-yl)-2-oxoethyl (3S)- 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexah ydroindolizine-3- carboxylate as an yellow solid. LC/MS: mass calculated for C23H21CIF2N4O4: 490.12, measured: 491.25 [Μ+Η]÷.

Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-fluoro-6- (methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrah ydroindolizin-5(1H)- one

To a solution of the 2-(2-fluoro-6-(methylamino)pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (300 mg, 0.66 mmol) in toluene (10 mL) was added acetic acid (1 mL), followed by ammonium acetate (707 mg, 9.12 mmol). The resulting mixture was stirred at 100° C for 2 h, then cooled to room temperature, and then concentrated. The residue was purified by silica gel chromatography (0→30% MeOH/DCM) to yield (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-3-(5-(2-fluoro-6-(methylamino)pyridin-3-yl)-1H -imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C23H2iCIF ₂ NeO: 471.14, measured: 472.30 [M+H] ⁺ . Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(2-fluoro- 6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetr ahydroindolizin- 5(1H)-one To a solution of the (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2- fluoro-6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8, 8a- tetrahydroindolizin-5(1H)-one (200 mg, 0.42 mmol) in glacial acetic acid (5 ml_) were added trimethoxymethane (1 mL) and azidotrimethylsilane (1 ml_). The resulting mixture was stirred at 60 °C for 2 h and concentrated. The resulting residue was added to 2N HCI (aq.)/THF (v/v 1:1) (4 mL). The reaction mixture was stirred at 50 °C for 0.5 h and adjusted to pH 7.0 with NaHCOa (aq.), then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to yield the racemic product, which was further purified by prep-HPLC to yield the (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1-yl)phenyl)-3-(5-(2-fluoro-6-(methylamino)pyridin-3-yl)-1H- imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as an white solid. LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured: 524.15 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) 6 11.89-11.95 (m, 1H), 9.84 (s, 1H), 7.91 - 8.11 (m, 2H), 7.70 (d, J = 8.7 Hz, 1H), 6.90 - 7.09 (m, 1H), 6.81 (d, J = 5.1 Hz, 1H), 6.40 (d, J =

8.3 Hz, 1H), 5.69 (d, J = 2.5 Hz, 1H), 4.99 (t, J = 7.2 Hz, 1H), 4.04 -4.15 (m, 1H), 2.71 -2.80 (m, 3H), 2.19 -2.51 (m, 4H), 1.96 -2.11 (m, 1H), 1.60 - 1.78 (m, 1H). ¹⁸ F NMR (282 MHz, DMSO-de) 6 -70.36, -113.07, -218.48

Example 2835-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)indolin-2-one

COJSXUU,

LC/MS: mass calculated for C2eH2oCIFNa02: 530.14, measured: 531.05 [M+H]*. ¹ H NMR (400 MHz, Methanol-dt) 69.59 (s, 1H), 7.84 (t, J = 8.7 Hz, 1H), 7.53 - 7.61 (m, 3H), 7.38 - 7.42 (m, 1H), 6.96 (d, J = 8.1 Hz, 1H), 5.76 (d,

J = 2.8 Hz, 1H), 5.13 - 5.18 (m, 1H), 4.22 -4.35 (m, 1H), 3.60 (s, 2H), 2.52 - 2.74 (m, 3H), 2.39 - 2.46 (m, 1 H), 2.09 - 2.23 (m, 1 H), 1.79 - 1.94 (m, 1 H). ¹⁸ F NMR (376 MHz, Methanol-cU) 6 -113.89.

Example 348: 5-{2-{(3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)indolin-2-one

LC/MS: mass calculated for C2eH2oCIFNe02: 530.14, measured: 531.05 [M+H]* ¹ H NMR (400 MHz, Methanol-cU) 69.60 (s, 1H), 7.83 (t, J = 8.7 Hz, 1H), 7.51 - 7.62 (m, 3H), 7.21 (s, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.73 (d, J = 2.8 Hz,

1H), 5.15 (d, J = 9.0 Hz, 1H), 3.83 - 3.96 (m, 1H), 3.59 (s, 2H), 2.92 - 3.05 (m,

1 H), 2.59 - 2.65 (m, 1 H), 2.27 - 2.40 (m, 1 H), 2.16 - 2.27 (m, 2H), 2.00 - 2.15 (m, 1H). ¹⁸ F NMR (376 MHz, Methanol-cU) δ -113.31.

Example 285 (1 S,3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)- 7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 -methoxy-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

—I D

F e- ^• NH ₂

Cl N' f HN-

Ό F

LC/MS: mass calculated for C24H2oCIF2Ng02:539.14, measured:540.1 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) (ppm)6: 9.84 (s, 1H), 7.94 - 8.04 (m, 1H), 7.79 - 7.94 (m, 1H), 7.68 - 7.74 (m, 1H), 7.56 (s, 1H), 6.79 (br, 1H), 6.46

(d, J = 8.3 Hz, 1H), 5.67 - 5.78 (m, 1H), 5.23 (d, J = 10.0 Hz, 1H), 3.99 -4.41 (m, 1H), 3.20 - 3.31 (m, 4H), 2.95 - 3.17 (m, 1H), 2.55 - 2.74 (m, 1H), 2.37 - 2.46 (m, 1H), 2.04 -2.30 (m, 1H). ¹⁸ F NMR (282 MHz, DMSO-de) (ppm) 6: - 69.23, -73.74, -112.72, -113.17.

Example 2865-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)- 1,3-dihydro-2H-benzo[d]imidazol-2-one LC/MS: mass calculated For C25H19CIFN9O2: 531.13, measured: 532.10 [M+H]* ¹ H NMR (400 MHz, Methanol-dt) δ 9.59 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.52 - 7.59 (m, 1H), 7.34 - 7.43 (m, 2H), 7.21 (s, 1H), 7.05 (d, J = 8.6 Hz, 1H), 5.74 (d, J = 2.7 Hz, 1H), 5.04 -5.15 (m, 1H), 4.30 -4.41 (m, 1H), 2.45 -2.71 (m, 3H), 2.33 - 2.45 (m, 1H), 2.12 -2.25 (m, 1H), 1.75 - 1.89 (m, 1H). ¹⁹ F

NMR (376 MHz, Methanol-dt) δ -113.82.

Example 2872-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5- oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)- N- methylbenzamide

To a solution of 2-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)benzoic acid (50 mg, 0.096 mol) in DMF(2.0 mL) was added DIEA (40 mg), followed by addition of CH ₃ NH ₂ *HCI(130 mg, 1.932 mmol) and HATU (55 mg, 0.144 mmol). The mixture was stirred at room temperature for 3 h, diluted with water, and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, wash with brine three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography on C18 column (0~60 % CH3CN/H20 (0.05% TFA)) to yield the 2-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)-N- methylbenzamide as a white solid.

LC/MS: mass calculated for C2eH22CIFNe02:532.2, measured: 533.20 [M+H]÷. ¹ H NMR (300 MHz, Methanol-dt) 69.60 (s, 1H), 7.80 - 7.90 (m, 1H), 7.46 - 7.74 (m, 5H), 7.38 - 7.43 (m, 1 H), 5.77 (d, J = 2.8 Hz, 1 H), 5.26 (d, J =

9.2 Hz, 1H), 3.87 -4.38 (m, 1H), 2.93 - 3.09 (m, 1H), 2.87 (s, 3H), 2.63 - 2.79 (m, 1H), 2.04 - 2.53 (m, 1H), 2.21 -2.40 (m, 2H), 1.92 - 2.16 (m, 1H).

¹⁹ F NMR (282 MHz, Methanol-dt) δ -113.34, -113.91. Example 2882-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1 ,2,3,5, 8, 8a-hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)-N,N- dimethylbenzamide

LC/MS: mass calculated for C27H24CIFNe02:546.983, measured: 547.25 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-cU) δ 9.53 (s, 1H), 7.69 - 7.84 (m, 2H), 7.46 - 7.57 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 5.67 (s, 1H), 5.06 - 5.16 (m, 1H), 3.77 - 3.93 (m, 1H), 2.99 - 3.02 (m, 3H), 2.82 - 2.98 (m, 1 H), 2.55 - 2.67 (m, 4H), 2.19 - 2.35 (m, 3H), 1.98 - 2.16 (m, 1H). ¹⁸ F NMR (282 MHz, Methanol-d*) δ -113.37..

Example 289 (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(4-( 2- (dimethylamino)phenyl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydro indolizin-

5(1H)-one

LC/MS: mass calculated for C2eH24CIFNeO:518.17, measured: 519.1 [M+H]÷. ¹ H NMR (300 MHz, DMSO-de) 6 11.72 - 12.08 (m, 1H), 9.82 (s, 1H), 7.91 - 8.08 (m, 2H), 7.66 - 7.76 (m, 1H), 7.49 - 7.58 (m, 1H), 7.02 - 7.25 (m, 3H), 5.66 - 5.79 (m, 1H), 5.00 - 5.15 (m, 1H), 3.69 -4.17 (m, 1H), 2.59 -2.82 (m, 5H), 1.97 - 2.50 (m, 6H), 1.66 -.89 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.88, -113.05.

Example 2902-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5- oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)b enzamide NH ₂

Cl F is)

§ "S V VO

“o

O

LC/MS: mass calculated for C25H20CIFN8O2: 518.93, measured: 519.10 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-dt) δ 9.59 (s, 1H), 7.79 - 7.90 (m, 1H), 7.70 - 7.78 (m, 1H), 7.52 - 7.71 (m, 6H), 5.78 (d, J = 2.8 Hz, 1H), 5.31 (d, J = 9.2 Hz, 1 H), 3.91 - 4.05 (m, 1 H), 2.85 - 3.04 (m, H), 2.69 - 2.77 (m, 1 H), 2.47

- 2.63 (m, 1 H), 2.24 - 2.41 (m, 2H), 1.94 - 2.09 (m, 1 H). ¹⁹ F NMR (282 MHz, Methanol-d*) δ -76.86, -113.49.

Example 291 (3S,8aS)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2-fluoro-6-(methylamino)pyiidin-3-yl)-1H-imidazol-2-yl)-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for CMH^CIFNSOS: 523.14, measured: 524.25 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) δ 9.58 (s, 1H), 7.99 (s, 1H), 7.82 (dd, J = 8.7, 7.6 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 3.4 Hz, 1H), 6.42 (dd, J = 8.4, 1.9 Hz, 1H), 5.73 (d, J = 2.8 Hz, 1H), 5.12 - 5.18 (m, 1H), 3.83 - 3.94 (m, 1H), 2.94 (t, J = 14.9 Hz, 1H), 2.88 (s, 3H), 2.59 - 2.65 (m, 1H), 2.26 - 2.37 (m, 1H), 2.17 - 2.39 (m, 2H), 1.99-2.11 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol- d4) δ -72.98, -113.30.

Example 2925-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-

1,3-dihydro-2H-benzo[d]imidazol-2-one

LC/MS: mass calculated For C25H19CIFN9O2: 531.13, measured: 532.10 [M+H]*. ¹ H NMR (400 MHz, Methanol-dt) δ 9.60 (s, 1H), 7.79 - 7.88 (m, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.35 - 7.41 (m, 2H), 7.21 (s, 1H), 7.02 - 7.12 (m, 1H), 5.73 (d, J = 2.8 Hz, 1H), 5.16 (d, J = 8.9 Hz, 1H), 3.83 - 3.96 (m, 1H), 2.92 - 3.04 (m, 1H), 2.59- 2.63 (m, 1H), 2.28 - 2.42 (m, 1H), 2.16-2.28 (m, 2H), 1.98-2.16 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-d ₄ ) δ -113.82.

Example 293 N-(2-(2-((3S)-7-(3-ChloiO-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4- yl)phenyl)methanesulfonamide s ,N.

F α· Hi

Or

LC/MS: mass calculated for C25H22CIFN8O3S: 568.12, measured: 569.1 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) 6 12.50 (br, 1H), 9.83 (s, 1H), 7.98 (t, J = 8.2 Hz, 1H), 7.67 - 7.76 (m, 3H), 7.49 (d, J = 8.0 Hz, 1H), 7.13 - 7.37 (m,

2H), 5.66 (d, J = 2.6 Hz, 1H), 5.06 (d, J = 8.7 Hz, 1H), 3.61 - 3.74 (m, 1H), 2.75 - 2.94 (m, 4H), 2.53 - 2.57 (m, 1 H), 1.94 - 2.31 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.44, -112.61.

Example 294 (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-( 2- isopropoxyphenyl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindol izin-5(1H)- one

LC/MS: mass calculated for C27H25CIFN702:533.17, measured: 534.3 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) δ (ppm): 9.84 (s, 1H), 8.00 (t, J = 8.3 Hz, 1H), 7.65 - 7.79 (m, 3H), 7.36 - 7.48 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 5.75 (d, J = 2.5 Hz, 1H), 5.20 (d, J = 9.1 Hz, 1H), 4.72 - 4.86 (m, 1 H), 3.69 - 3.83 (m, 1 H), 2.89 - 3.07 (m, 1 H), 2.55 - 2.60 (m, 1 H), 2.36 - 2.46 (m, 1 H), 1.87 - 2.21 (m, 3H), 1.34 (d, J = 5.9 Hz, 6H). ¹⁸ F NMR (282 MHz, DMSO-de) δ (ppm): -73.86, -112.75.

Example 295 N-(2-(2-((3S,8aR*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydiOindolizin-3-yl)-1H-im idazol-4- yl)phenyl)propionamide

LC/MS: mass calculated for C27H24CIFN802:546.17, measured (ES, m/z): 547.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.26 (s, 1H), 12.15 (s, 1H), 9.83 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 7.92 - 8.03 (m, 1H), 7.63 - 7.76 (m, 2H), 7.59 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 5.69 (d, J =

2.4 Hz, 1H), 5.05 (d, J = 8.8 Hz, 1H), 3.66 - 3.81 (m, 1H), 2.52 -2.77 (m, 2H), 1.88 - 2.43 (m, 6H), 1.01 - 1.16 (m, 3H). ¹⁹ F NMR (282 MHz, Methanol-cU) δ 76.95, 113.38.

Example 296 N-(2-(2-((3S,8aS ^w )-7-(3-Chloro-2-fluoro-6-(1 H-tetrazoi-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)phenyl)propionamide

LC/MS: mass calculated for C27H24CIFN8O2: 546.17, measured (ES, m/z): 547.15 [M+H] ⁺ . ¹ H NMR (300 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.47 (br, 1 H), 7.62-7.74 (m, 1 H), 7.49 (d, J = 7.7 Hz, 1 H), 7.30 - 7.36 (m, 2H), 7.25 (d, J

= 7.7 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 5.75 (s, 1H), 5.29 (t, J = 7.8 Hz, 1H), 4.01 - 4.21 (m, 1 H), 2.75 - 2.93 (m, 1 H), 2.40 - 2.64 (m, 6H), 1.73 - 1.87 (m, 1H), 1.24 - 1.35 (m, 4H). ¹⁸ F NMR (282 MHz, Methanol-cU) δ -76.96, -113.92. Example 2976-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H- benzo[d][1 ,3]oxazin-2(4H)-one

LC/MS: mass calculated for CzehfcoCIFNeOa: 546.13, measured (ES, m/z): 547.05[M+H]+. ¹ H NMR (300 MHz, Methanol-d*) δ 9.60 (s,1H), 7.80 -

7.93 (m, 1H), 7.70 - 7.85 (m, 1H), 7.50 - 7.70 (m, 3H), 7.04 (d, J = 8.3 Hz, 1H), 5.73 - 5.81 (m, 1 H), 5.37 - 5.44 (m, 2H), 5.20 - 5.36 (m, 1 H), 3.95 - 4.01 (m,

1 H), 2.92 - 3.07 (m, 1 H), 2.67 - 2.82 (m, 2H), 2.45 - 2.62 (m, 1 H), 2.21 - 2.43 (m, 1H), 1.96 -2.13 (m,1H). ¹⁹ F NMR (282 MHz, Methanol-d*) δ -77.06, - 113.49, -113.87.

Example 298 N-(2-(2-((3S,8aR*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5~oxo~1, 2,3,5, 8,8a-hexahydroindolizin-3-yl)~1 -methyl-1 H- imidazol-4-yl)phenyl)cyclopropanecarboxamide

LC/MS: mass calculated for CMHMCIFNSC^: 572.19, measured (ES, m/z): 573.15 [M+H]+. ¹ H NMR (300 MHz, DMSO-de) δ 9.83 (s, 1H), 8.01 - 8.05 (m, 1H), 7.97 (t, J = 8.2 Hz, 1H), 7.67 - 7.77 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.30 - 7.40 (m, 1H), 7.13 - 7.22 (m, 1H), 5.65 (d, J = 2.3 Hz, 1H), 5.28 (d, J = 9.3 Hz, 1 H), 3.88 (s, 3H), 3.67 - 3.82 (m, 1 H), 2.70 - 2.88 (m, 1 H), 2.56 - 2.66 (m, 1 H), 2.28 - 2.42 (m, 1 H), 1.97 - 2.26 (m, 3H), 1.62 - 1.74 (m, 1 H), 0.71 -

0.82 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.72, -112.66.

Example 2996-(2-((3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-1- methyl-1H-benzo[d]imidazol-2(3H)-one

LC/MS: mass calculated for C2eH2iCIFNg02: 545.15, measured (ES, m/z): 546.30[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 10.88 (br, 1H), 9.83 (s, 1H), 7.96 (t, J = 8.2 Hz, 1H), 7.70 (dd, J = 8.7, 1.5 Hz, 1H), 7.33-7.42 (m, 3H), 6.92 - 7.04 (m, 1 H), 5.70 (d, J = 2.5 Hz, 1 H), 4.97 - 5.07 (m, 1 H), 4.06 - 4.20

(m, 1H), 3.31 (s, 3H), 2.16 -2.43 (m, 3H), 1.95 - 2.08 (m, 2H), 1.68 - 1.80 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -73.41, -113.07.

Example 3006-(2-((3S,8aR*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)~5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)~1H-im idazol-5~yl)-1- methyl-1H-benzo[d]imidazol-2(3H)-one

Step 1: 2-(2-fluoro-6-(methylamino)pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate Bromoacetic add (1.0 g, 7.42 mmol, 1.1 equiv.) was added in portions to a stirred mixture of 1 -methyl- 1 ,3-dihydro-2H-benzo[d]imidazol-2-one (1.0 g, 14.91 mmol, 1.0 equiv.) in polyphosphoric add (14 g) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 115 °C for 1.5h. Upon the completion of the reaction, the mixture was poured into ice/water and stirred for 1h. The precipitated solids were collected by filtration and washed with water (3 x 20 mL) and dried in vacuo to yield 6-(2- bromoacetyl)- 1 -methyl- 1 ,3-dihydro-2H-benzo[d]imidazol-2-one (include 5-(2- bromoacetyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one, about 40%) as a gray solid. LC/MS: mass calculated for CioHsBrN202: 267.98, measured: 269.10 [M+H]\ 271.10 [M+H+2] ⁺ . Step 2: 2-(3-methyl-2-oxo-2, 3-dihydro- 1 H-benzo[d]imidazol-5-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3, 5,8, 8a-hexahydroindolizine-3-carboxylic acid (150 mg, 0.46 mmol, 1.0 equiv.) in acetonitrile (8 mL) was added potassium cartx)nate (127.7 mg, 0.92 mmol, 2.0 equiv.), followed by 6-(2-bromoacetyl)-1-methyM ,3-dihydro-2H- benzo[d]imidazol-2-one (248 mg, 0.92 mmol, 2.0 equiv.) and the reaction mixture was stirred for 1.5 h. The resulting mixture was then diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3x 20 mL), dried over anhydrous N32S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→25% EA/PE) to yield 2-(3-methyl-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5-yl)-2-oxoethyl (3S)- 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexah ydroindolizine-3- carboxylate (include 2-(1-methyl-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5-yl)- 2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate, as a yellow solid. LC/MS: mass calculated for C25H22CIFN4O5: 512.13, measured: 513.25 [M+H] ⁺ .

Step 3: 6-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1-methyl-1 ,3-dihydro-2H- benzo[d]imidazol-2-one

To a stirred solution of 2-(3-methyl-2-oxo-2,3-dihydro-1 H- benzo[d]imidazol-5-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (149 mg, 0.29 mmol, 1.0 equiv.) in HOAc (1.5 mL) and toluene (15 mL) was added ammonium acetate (193 mg, 2.51 mmol, 5.0 equiv.) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield 6-(2-((3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ,2,3,5, 8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-1- methyl-1 ,3-dihydro-2H-benzo[d]imidazol-2-one (include 5-(2-((3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-on e) as a brown solid. LC/MS: mass calculated for C25H22CIFNe02: 492.15, measured: 493.10 [M+H]*.

Step 4: 6-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1-methyl-1 ,3-dihydro- 2H-benzo[d]imidazol-2-one

To a stirred mixture of 6-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1-methyl-1 ,3- dihydro-2H-benzo[d]imidazol-2-one (50 mg, 0.10 mmol, 1.0 equiv.) and 5-(2- ((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 -methyl-1 ,3-dihydro-2H- benzo[d]imidazol-2-one (50 mg, 0.101 mmol, 1.00 equiv) in acetic acid (5.00 mL) were added trimethylorthoformate (0.5 mL) and TMSNa (0.5 mL) at room temperature. The resulting mixture was stirred for 2 h at 60 °C, then concentrated under vacuum. The residue was purified by prep-HPLC with Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN to yield a residue, which was purified by chiral-HPLC with MTBE (0.1%DEA): EtOH=50:50 to yield 6-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1-methyl-1 ,3-dihydro- 2H-benzo[d]imidazol-2-one as a white solid.

LC/MS: mass calculated for C2eH2iCIFNg02: 545.15, measured (ES, m/z): 546.30 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 611.71 (br, 1H), 10.76 (s, 1H), 9.82 (s, 1H), 7.96 (t, J = 8.6, 7.8 Hz, 1H), 7.70 (dd, J = 8.7, 1.4 Hz, 1H), 7.39 (d, J = 14.1 Hz, 3H), 6.92 (d, J = 8.1 Hz, 1H), 5.66 (d, J = 2.6 Hz, 1H),

4.98 (d, J = 8.6 Hz, 1H), 3.64 - 3.72 (m, 1H), 3.30 (s, 3H), 2.72 -2.85 (m, 1H), 2.51 - 2.54 (m, 1 H), 2.03 - 2.23 (m, 2H), 1.88 - 2.00 (m, 2H). ¹⁹ F NMR (376

MHz, DMSO-de) 6 -73.40, -112.82.

Example 301 Methyl 2-(2-((3S,8aR ^w )-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)phenylcarbamate H VIM.

Cl. “N·

HI

V

LC/MS: mass calculated for CMH^CIFNeOa: 548.15, measured (ES, m/z): 549.15[M+H] ⁺ . 1H NMR (300 MHz, Methanol-d*) δ 9.57 (s, 1H), 7.79 - 7.87 (m, 1H), 7.69 - 7.77 (m, 1H), 7.41 - 7.60 (m, 4H), 7.29 (t, J = 7.5 Hz, 1H), 5.77 (d, J = 2.6 Hz, 1 H), 5.27 (d, J = 9.7 Hz, 1 H), 3.90 - 4.02 (m, 1 H), 3.70 (s,

3H), 2.86 - 3.03 (m, 1H), 2.64 - 2.76 (m, 1H), 2.45 - 2.55 (m, 1H), 2.18 -2.38 (m, 2H), 1.93 -2.06 (m, 1H). ¹⁹ F NMR (282 MHz, Methanol-d*) δ -77.23, - 113.53.

Example 302 Methyl 2-(2-((3S,8aS*)-7-(3-chloro-2-fluoiO-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)phenylcarbamate

LC/MS: mass calculated for CMHMCIFNSOS: 548.15, measured (ES, m/z): 549.15[M+H]+. 1H NMR (300 MHz, Methanol-d*) δ 9.57 (s, 1H), 7.79 - 7.87 (m, 1H), Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.41 - 7.60 (m, 4H), 7.29 (t, J =

7.5 Hz, 1H), 5.77 (d, J = 2.6 Hz, 1H), 5.18 - 5.30 (m, 1H), 4.25 -4.33 (m, 1H), 3.70 (s, 3H), 2.56 - 2.75 (m, 3H), 2.40 - 2.52 (m, 1 H), 2.05 - 2.20 (m, 1 H), 1.85 - 1.98 (m, 1H). ¹⁹ F NMR (282 MHz, Methanol-d4) δ -77.09, -113.95. Example 3035-(2-((3S,8aR*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-1- methyl-1 H-benzo[d]imidazol-2(3H)-one

LC/MS: mass calculated for C2eH2iCIFNe02: 545.15, measured (ES, m/z): 546.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.91 (br, 1H), 10.84 (s, 1H), 9.82 (s, 1H), 7.96 (t, J = 8.2 Hz, 1H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.31 - 7.39 (m, 3H), 7.05 (d, J = 8.1 Hz, 1H), 5.68 (d, J = 2.7 Hz, 1H), 4.97 (t, J = 7.4

Hz, 1H), 4.04 - 4.13 (m, 1H), 3.26 (s, 3H), 2.20 - 2.44 (m, 4H), 1.98 - 2.07 (m, 1H), 1.64 - 1.74 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -73.41, -113.04. Example 304 N-(2-(2-((3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 -methyl-1 H- imidazol-4-yl)phenyl)cyclopropanecarboxamide

LC/MS: mass calculated for C28H26CIFN8O2: 572.19, measured (ES, m/z): 573.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.82 (s, 1H), 8.17 - 8.34 (m, 1 H), 7.98 (t, J = 8.2 Hz, 1H), 7.63 - 7.75 (m, 2H), 7.55 (d, J = 7.7 Hz, 1H), 7.18 - 7.32 (m, 1H), 7.03 - 7.12 (m, 1H), 5.69 (s, 1H), 5.14 - 5.24 (m, 1H), 4.00 - 4.19 (m, 1H), 3.81 (s, 3H), 2.52 - 2.67 (m, 2H), 2.25 - 2.47 (m, 2H), 2.04 - 2.20 (m, 1H), 1.66 - 1.85 (m, 1 H), 1.51 - 1.63 (m, 1 H), 0.79 - 0.87 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -74.20, -113.42.

Example 305 N-(2-(2-((3S,8aR*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)phenyl)isobutyramide

LC/MS: mass calculated for C28H26CIFN8O2: 560.19, measured (ES, m/z): 561.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.46 (s, 1H), 12.40 (s, 1H), 9.81 (s, 1H), 8.41 - 8.49 (m, 1H), 7.96 (t, J = 8.2 Hz, 1H), 7.61 - 7.70 (m, 3 H), 7.10 - 7.17 (m, 1H), 6.96 - 7.03 (m, 1H), 5.68 (d, J = 2.8 Hz, 1H), 4.95 -

5.03 (m, 1H), 4.06 -4.14 (m, 1H), 2.49 -2.61 (m, 2H), 2.33 - 2.46 (m, 2H), 2.19 -2.28 (m, 1H), 1.97 - 2.06 (m, 1H), 1.69 - 1.82 (m, 1H), 1.14 (t, J = 6.5 Hz, 6H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.49, -113.14.

Example 306 N-(2-(2-((3S,8aS*)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)phenyl)acetamide

LC/MS: mass calculated for C2eH22CIFNe02:532.15, measured (ES, m/z):533.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.30 (s, 1H), 12.15 (s, 1H), 9.84 (s, 1 H), 8.35 - 8.42 (m, 1H), 7.98 (t, J = 8.2 Hz, 1H), 7.72 (dd, J =

8.7, 1.5 Hz, 1H), 7.58 - 7.70 (m, 2H), 7.19 (s, 1H), 7.05 (s, 1H), 5.67 - 5.75 (m, 1 H), 5.07 (d, J = 8.7 Hz, 1 H), 3.66 - 3.80 (m, 1 H), 2.51 - 2.68 (m, 2H), 1.85 - 2.34 (m, 7H). 19F NMR (282 MHz, DMSO-de) δ -74.16, -113.38.

Example 307 N-(2-(2-((3S,8aR)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)phenyl)cyclopropanecarboxamide

Step 1: 2-(2-nitrophenyl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of the (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5, 8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.0 equiv.) in CHsCN (10 mL) was added 2-bromo-1-(2-nitrophenyl)ethan-1-one (158 mg, 0.62 mmol, 1.0 equiv.), followed by K2CO3 (196 mg, 1.42 mmol, 2.3 equiv.). The resulting mixture was stirred at room temperature, for 2 h, then was quenched with water and extracted with EA. The combined organic layer was washed with brine, dried over N32S04. The solids were filtered out The resulting organic phase was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to yield 2-(2-nitrophenyl)- 2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(2-nitrophenyl )-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of the 2-(2-nitrophenyl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate (150 mg, 0.31 mmol, 1.0 equiv.) in toluene (10 mL) were added ammonium acetate (264 mg, 3.07 mmol, 10.0 equiv.) and HOAc (0.1 mL). The resulting mixture stirred at 110 °C for 2 h, then concentrated under vacuum. The residue was purified by silica gel chromatography (0→10% MeOH/DCM) to yield the (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(2-nitrophenyl )-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. Step 3: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(4-(2- nitrophenyl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin- 5(1H)-one

To a solution of the (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(2- nitrophenyl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (1.0 g, 2.14 mmol, 1.0 equiv.) in HOAc (30 mL) were added trimethoxymethane (2 mL) and azidotrimethylsilane (2 mL). The resulting mixture stirred at 60 °C for 2 h, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→10% MeOH/DCM) to yield (3S)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(4-(2-nitrophenyl)-1 H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid.

Step 4: (3S)-3-(4-(2-aminophenyl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

Pd/C (50 mg) was added to a solution of the (3S)-7-(3-chloro-2-fluoro-6- (1H-tetrazol-1-yl)phenyl)-3-(4-(2-nitrophenyl)-1H-imidazol-2 -yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (220 mg, 0.42 mmol, 1.0 equiv.) in methanol (8 mL) and chlorobenzene (4 mL). The mixture was evacuated, filled with hydrogen and this process repeated three times. The resulting mixture was stirred 15 min at 25 °C. LCMS showed the desired product was generated. Water was added and the mixture was extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield (3S)-3-(4-(2-aminophenyl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as an yellow solid. LC/MS: mass calculated for C24H20CIFN8O: 490.14, measured: 491.10 [Μ+ΗΓ. Step 5: N-(2-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4- yl)phenyl)cyclopropanecarboxamide

To a solution of the (3S)-3-(4-(2-aminophenyl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1H)- one (150 mg, 0.31 mmol, 1.0 equiv.) in pyridine (5 mL) was added cyclopropanecarboxylic add (131 mg, 1.53 mmol, 5.0 equiv.), followed by EDCI (95 mg, 0.61 mmol, 2.0 equiv.). The resulting mixture was stirred room temperature overnight, and concentrated. The residue was purified by HPLC and SFC to yield N-(2-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4- yl)phenyl)cydopropanecarboxamide as a white solid.

LC/MS: mass calculated for C28H24CIFN8O2: 558.17, measured (ES, m/z): 559.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 12.34 - 12.78 (m, 2H), 9.83 (s, 1H), 8.29 - 8.49 (m, 1H), 7.92 - 8.04 (m, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.60 -7.69 (m, 2H), 6.97 - 7.25 (m, 2H), 5.71 (d, J = 2.5 Hz, 1H), 5.07 (t, J =

7.4 Hz, 1H), 4.06 - 4.16 (m, 1H), 2.44 - 2.62 (m, 2H), 2.20 -2.43 (m, 2H), 1.95 -2.11 (m, 1H), 1.54 - 1.85 (m, 2H), 0.78 - 0.88 (m, 4H). ¹⁹ F NMR (282 MHz,

DMSO- de) δ -73.54, -74.98, -113.30.

Example 308 (3S,8aS*)-3-(4-(2-Aminophenyl)-1 H-imidazol-2-yl)-7-(3-chloro- 2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 H)-one

Hj

F s?

Cl, V f Ό rs ^j

N-N

LC/MS: mass calculated for C24H20CIFN8O: 490.14, measured (ES, m/z): 491.10 [Μ+ΗΓ. ¹ H NMR (400 MHz, DMSO-de) 6 12.05 (s, 1H), 9.84 (s, 1H),

7.91 - 7.99 (m, 1H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.28 - 7.42 (m, 2H), 6.82 -

6.91 (m, 1H), 6.62 (dd, J = 8.1, 1.3 Hz, 1H), 6.42 -6.58 (m, 1H), 6.17 (s, 2H), 5.67 (d, J = 2.7 Hz, 1H), 5.00 (t, J = 7.1 Hz, 1H), 3.99 -4.10 (m, 1H), 2.29 - 2.45 (m, 3H), 2.17 -2.28 (m, 1H), 1.93 -2.07 (m, 1H), 1.65 - 1.76 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.40, -113.08.

Example 3096-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)benzo[d]oxazol-

2(3H)-one

H s

F Hi

Cl

LC/MS: mass calculated for C25H18CIFN8O3: 532.12, measured (ES, m/z): 533.10 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d*) δ 9.60 (s, 1H), 7.82 -

7.92 (m, 1H), 7.74 - 7.80 (m, 1H), 7.50 - 7.66 (m, 3H), 7.18 - 7.27 (m, 1H), 5.75 - 5.80 (m, 1H), 5.21 - 5.34 (m, 1H), 3.90 - 4.43 (m, 1H), 2.92 - 3.09 (m, 1H), 2.27 - 2.80 (m, 4H), 1.92 -2.14 (m, 1H). ¹⁹ F NMR (282 MHz, Methanol- d4) 6 -76.91, -113.44, -113.92.

Example 310 (3S,8aR*)-3-(4-(2-Aminophenyl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-

5(1H)-one

LC/MS: mass calculated for C24H20CIFN8O: 490.14, measured (ES, m/z): 491.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 11.95 (s, 1H), 9.83 (s, 1H), 7.95 (t, J = 8.2 Hz, 1H), 7.66-7.73 (m, 1H), 7.33 - 7.40 (m, 1H), 7.29 - 7.34 (m, 1 H), 6.83 - 6.91 (m, 1 H), 6.60 - 6.67 (m, 1 H), 6.43 - 6.56 (m, 1 H), 6.22 (s, 2H), 5.65 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 8.6 Hz, 1H), 3.62 - 3.73 (m, 1H), 2.59 -

2.74 (m, 1 H), 2.49 - 2.58 (m, 1 H), 2.04 - 2.22 (m, 2H), 1.86 - 2.01 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -73.41, -113.02.

Example 311 6-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)- 3,4- dihydroquinolin-2(1 H)-one

LC/MS: mass calculated for C27H22CIFN8O2: 544.15, measured (ES, m/z): 545.15 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d*) 69.57 (s, 1H), 7.77 - 7.89 (m, 1H), 7.71 (s, 1H), 7.47 - 7.62 (m, 3H), 6.99 (d, J = 8.3 Hz, 1H), 5.71 - 5.79 (m, 1H), 5.18 - 5.30 (m, 1H), 3.89 - 4.02(m, 1H), 2.89 - 3.09 (m, 3H),

2.43 -2.78 (m, 4H), 2.18 -2.40 (m, 2H), 1.93 - 2.10 (m, 1H). ¹⁸ F NMR (282 MHz, Methanol-d<) 6 -76.98, -113.52, -113.92.

Example 3125-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H- benzo[d]imidazol-2(3H)-one

LC/MS: mass calculated for C25H18CIFN8O2: 531.13, measured (ES, m/z): 532.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.68 - 12.21 (m, 1H), 10.05 - 10.71 (m, 2H), 9.84 (s, 1H), 7.91 - 8.03 (m, 1H), 7.69 - 7.74 (m, 1H), 7.29 - 7.36 (m, 2H), 6.85 - 7.21 (m, 2H), 5.62 - 5.73 (m, 1 H), 4.93 - 5.03 (m,

1 H), 3.71 - 4.09 (m, 1 H), 2.67 - 2.82 (m, 1 H), 2.53 - 2.64 (m, 1 H), 1.89 - 2.39 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.70.

Example 313 (3S)-3-(5-(3-Amino-1H-indazol-6-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro~6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-

5(1H)-one

LC/MS: mass calculated for C25H20CIFN10O: 530.15, measured (ES, m/z): 531.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 12.04 (br, 1H), 9.82 (s, 1H), 8.11 (s, 1H), 7.91 - 8.05 (m, 1H), 7.81 - 7.90 (m, 1H), 7.59 - 7.81 (m, 2H), 7.23 - 7.46 (m, 1H), 5.61 - 5.85 (m, 1H), 5.10 - 5.26 (m, 1H), 3.67 -4.10 (m, 1H), 2.90 - 2.98 (m, 1H), 2.51 -2.68 (m, 1H), 2.23 -2.44 (m, 2H), 2.07 -2.19 (m, 1H), 1.77 - 2.05 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -74.31, -112.70. Example 3145-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)i ndolin-2-one

LC/MS: mass calculated for C2eH2oCIFNe02: 530.14, measured (ES, m/z): 531.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 10.63 (s, 1H), 9.82 (s, 1H), 7.93 - 8.02 (m, 2H), 7.68 - 7.73 (m, 1H), 7.52 - 7.65 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 5.70 - 5.75 (m, 1H), 5.06 - 5.18 (m, 1H), 3.68 -4.21 (m, 1H), 3.57 (s, 2H), 2.96 (t, J = 15.2 Hz, 1H), 2.50 -2.59 (m, 1H), 2.24 - 2.42 (m, 2H), 2.02 -2.17 (m, 1H), 1.79 - 1.98 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -73.60, - 112.72. Example 315 (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-( 6- (dimethylamino)-2-fluoropyiidin-3-yl)-1H-imidazol-2-yl)-2,3, 8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C2sH22CIF2NgO: 537.16, measured (ES, m/z): 538.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.83 (s, 1H), 7.93 - 8.06

(m, 2H), 7.62 - 7.77 (m, 2H), 6.71 (d, J = 8.7 Hz, 1H), 5.67 - 5.79 (m, 1H), 5.10 - 5.21 (m, 1H), 3.69 -4.25 (m, 1H), 3.02 - 3.10 (m, 7H), 2.54 - 2.62 (m, 1H), 2.30 -2.45 (m, 1H), 1.95 -2.20 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ - 67.65, -73.93, -112.68. Example 316 Methyl (6-(2-((3S,8aR)-7-(3-chloro-2-fluoiO-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)pyridin-3-yl)carbamate

R H H

N ci. 6

Step 1: 2-(5-((methoxycarbonyl)amino)pyridin-2-yl)-2-oxoethyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8 _l 8a-hexahydroindolizine-3-carboxylate To a solution of (3S)-7-(6-amino3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (89 mg, 0.27 mmol, 1.0 equiv.) in DMF (3 mL) was added CS2CO3 (107 mg, 0.33 mmol, 1.2 equiv.), followed by 6-(2-bromoacetyl)-1 -methyl- 1 ,3-dihydro-2H-benzo[d]imidazol-2-one (150 mg, 0.55 mmol, 2.0 equiv.). The resulting mixture was stirred 1.5 h, quenched with water (3 x 20 mL), dried over N32S04, and concentrated. The residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield 2-(5-((methoxycarbonyl)amino)pyridin-2-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C24H22CIFN40e: 516.12, measured: 517.20 [M+H] ⁺ . Step 2: methyl (6-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)py ridin-3-yl)carbamate To a mixture of 2-(5-((methoxycarbonyl)amino)pyridin-2-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (120 mg, 0.23 mmol, 1.0 equiv.) in toluene (5 mL) and acetic acid (0.2 mL) was added ammonium acetate (179 mg, 2.32 mmol, 10.0 equiv.). The reaction mixture was stirred at 100 °C for 2 h and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (0→20% MeOH/DCM) to yield methyl (6-(2-((3S)- 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexah ydroindolizin-3- yl)-1H-imidazol-5-yl)pyridin-3-yl)carbamate as a yellow oil. LC/MS: mass calculated for C24H22CIFNe0 ₃ : 496.14, measured: 497.25 [M+H] ⁺ .

Step 3: methyl (6-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phe nyl)- 5-OXO-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)pyridin-3- yl)carbamate

To a stirred solution of methyl (6-(2-((3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5- yl)pyridin-3-yl)carbamate (110 mg, 0.22 mmol, 1.0 equiv.) in trimethylorthoformate (0.5 mL) and AcOH (5.00 mL) was added TMSN3 (0.5 mL) at room temperature. The resulting mixture was stirred at 60 °C for 2 h, then concentrated under reduced pressure. The residue was purified by prep- HPLC to yield methyl (6-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)pyridin- 3-yl)carbamate as a yellow solid.

LC/MS: mass calculated for C25H21CIFN9O3: 549.14, measured (ES, m/z): 550.10 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d*) δ 9.58 (s, 1H), 8.59 (d, J

= 2.5 Hz, 1H), 7.92-8.01 (m, 1H), 7.75-7.89 (m, 2H), 7.44-7.61 (m 2H), 5.73- 5.75 (m, 1H), 5.13 (t, J = 8.0 Hz, 1H), 4.27-4.41 (m, 1H), 3.75-3.89 (m, 3H), 2.35-2.67 (m, 4H), 2.01-2.27 (m, 2H), 1.75-1.97 (m, 1H). ¹⁸ F NMR (282 MHz, Methanol-d*) 6 -113.47, -113.82.

Example 317 (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(4-( 2- methoxyphenyl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizi n-5(1H)-one

F 'Ν' ci· i to ^N'

LC/MS: mass calculated for C25H21CIFN7O2: 505.14, measured (ES, m/z): 506.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.84 (s, 1H), 7.97-8.04 (m, 1H), 7.84-7.89 (m, 1H), 7.68-7.78 (m, 2H), 7.41-7.52 (m, 1H), 7.08-7.27 (m, 2H), 5.72-5.78 (m, 1H), 5.16-5.27 (m, 1H), 4.08-4.33 (m, 1H), 3.94 (s, 3H), 3.65-3.86 (m, 2H), 2.30-2.40 (m, 1H), 1.88-2.20 (m, 3H). ¹⁸ F NMR (282 MHz, DMSO-de) 6 -73.81, -112.87.

Example 3183-(4-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)ph enyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5- yl)phenyl)oxazolidin-2-one

H

N

Cl. }TX

Γ ■b s

LC/MS: mass calculated for C27H22CIFN8O3: 560.15, measured (ES, m/z): 561.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.84 (s, 1H), 7.93 - 8.09 (m, 2H), 7.67 - 7.91 (m, 5H), 5.65 - 5.80 (m, 1H), 5.10 - 5.25 (m, 1H), 4.47 (t, J = 7.6 Hz, 2H), 4.12 (t, J = 8.4 Hz, 2H), 3.65 - 3.85 (m, 1H), 2.99 (t, J = 15.2 Hz, 1 H), 2.53 - 2.66 (m, 1 H), 2.25 - 2.47 (m, 1 H), 2.06 - 2.20 (m, 2H), 1.80 - 2.04 (m, 1H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -73.84, -112.70.

Example 319 Methyl (4-(2-((3S,8aS)-7-(3-Chloro-2-(difluoromethoxy)-6- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5- yl)phenyl)carbamate s- f S H

V N

LC/MS: mass calculated for C2eH22CIF3N404: 546.13, measured (ES, m/z): 547.10 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) δ 11.96 (br, 1H), 9.63 (s,

1 H), 7.70 - 7.84 (m, 1 H), 7.56 - 7.69 (m, 2H), 7.29 - 7.55 (m, 4H), 7.09 (t, J = 72.2 Hz, 1 H), 5.91 (s, 1 H), 5.07 (t, J = 7.2 Hz, 1 H), 4.20 - 4.40 (m, 1 H), 3.67 (s,

3H), 2.57 - 2.75 (m, 2H), 2.25 - 2.44 (m, 2H), 2.00 - 2.20 (m, 1 H), 1.70 - 1.85 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -79.88, -112.76.

Example 320 Methyl (4-(2-((3S,8aS)-7-(3-Chloro-6-(difluoromethoxy)-2- fluorophenyl)-5 -oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)phenyl)carbamate

LC/MS: mass calculated for ΟΜΗΗΟΡΒΜΟ*: 546.13, measured (ES, m/z): 547.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 11.94 (br, 1H), 9.60 (s, 1H), 7.55 - 7.80 (m, 3H), 7.04 - 7.54 (m, 5H), 5.93 (s, 1H), 5.07 (t, J = 7.1 Hz, 1 H), 4.18 - 4.40 (m, 1 H), 3.67 (s, 3H), 2.56 - 2.75 (m, 2H), 2.25 - 2.46 (m, 2H),

1.96 - 2.23 (m, 1H), 1.68 - 1.90 (m, 1 H). ¹⁸ F NMR (282 MHz, DMSO-de) δ - 82.53, -113.67.

Example 321 4-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)pyridine 1 -oxide

LC/MS: mass calculated for C23H20CIFN8O2: 492.12, measured (ES, m/z): 493.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.84 (s, 1H), 8.36-8.42 (m, 2H), 7.93-8.13 (m, 2H), 7.79-7.90 (m, 2H), 7.66-7.79 (m, 1H), 5.71 (d, J = 2.6 Hz, 1H), 5.10 (d, J = 9.3 Hz, 1H), 2.76-2.93 (m, 1H), 2.53-2.65 (m, 1H), 2.21-2.44 (m, 1H), 1.78-2.20 (m, 4H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -74.31, - 112.76.

Example 322 Methyl (6-(2-((3S,8aS)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)pyridin-3-yl)carhamate

H

F !>" ci N

3·

LC/MS: mass calculated for C25H21CIFN9O3: 549.14, measured (ES, m/z): 550.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 (ppm): 11.86-12.26 (m, 1H), 9.76-9.90 (m, 2H), 8.52-8.64 (m, 1H), 7.92 - 8.02 (m, 1H), 7.83 - 7.91 (m,

1H), 7.65 - 7.82 (m, 2H), 7.45 (d, J = 2.0 Hz, 1 H), 5.63-7.73 (m, 1H), 4.96 -5.10 (m, 1 H), 3.66-3.76 (m, 4H), 2.58 - 2.84 (m, 2H), 1.90 - 2.25 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.40, -112.83, -112.90.

Example 323 Methyl (4-(2-((3S,8aR)-7-(3-Chloro-2-(difluoiOmethoxy)-6- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5- yl)phenyl)carbamate

LC/MS: mass calculated for C2eH22CIF3N*04: 546.13, measured (ES, m/z): 547.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.79 (br, 1H), 9.59 (s, 1H), 7.60 - 7.78 (m, 3H), 7.45 - 7.57 (m, 1H), 7.28 - 7.45 (m, 3H), 7.17 - 7.24

(m, 1H), 5.97 (d, J = 2.6 Hz, 1H), 5.07 (d, J = 8.4 Hz, 1H), 3.90 - 3.99 (m, 1H), 3.64 - 3.69 (m, 3H), 2.92 (t, J = 15.2 Hz, 1H), 2.59 - 2.67 (m, 1H), 1.97 - 2.28 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -82.39, -113.33.

Example 324 Methyl (4-(2-((3S)-7-(3-Chloro-2-fluoro-6-(2,2,2- trifluoroethoxy)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizi n-3-yl)-1H- imidazol-5-yl)phenyl)carbamate

LC/MS: mass calculated for C27H23CIF4N4O4: 578.13, measured (ES, m/z): 579.00 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 14.53 (br, 1H), 9.92 (s, 1 H), 7.89 - 8.10 (m, 1 H), 7.53 - 7.79 (m, 5H), 7.15 (d, J = 9.2 Hz, 1 H), 5.80 - 6.20 (m, 1H), 5.15 - 5.35 (m, 1H), 4.75 - 5.10 (m, 2H), 3.84 -4.43 (m, 1H),

3.69 (s, 3H), 2.58 - 3.09 (m, 2H), 1.75 - 2.43 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -72.45, -73.73, -115.11.

Example 325 Methyl (5-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)pyridin-2-yl)carbamate

Step 1: methyl (5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl) -5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)pyridin-2- yl)carbamate

To a solution of the methyl (5-(2-((3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5- yl)pyridin-2-yl)carbamate (200 mg, 0.43 mmol, 1.0 equiv.) in acetic acid (5 ml_) were added trimethoxymethane (1 mL) and azidotrimethylsilane (1 ml_). The resulting mixture stirred 60 °C for 2 h, then concentrated. The residue was then purified by prep-HPLC to yield the methyl (5-(2-((3S)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)pyridin-2-yl)carbamate as a yellow solid.

LC/MS: mass calculated for C25H21CIFN9O3: 549.12, measured (ES, m/z): 550.05 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 10.48 (s, 1H), 9.86 (s, 1H), 8.71-8.77 (m, 1H), 8.19 - 8.23 (m, 1H), 8.08 - 8.11 (m, 1H), 7.91- 8.01 (m,

2H), 7.72 - 7.78 (m, 1 H), 5.73 -5.80 (m, 1 H), 5.31 - 5.40 (m, 1 H), 3.82 - 4.32 (m, 1H), 3.71 - 3.78 (m, 3H), 3.00 - 3.21 (m, 1H), 2.67 -3.22 (m, 1H), 2.28 - 2.31 (m, 1 H), 1.78 - 2.21 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -74.50, - 112.50, -112.90.

Example 326 Methyl (6-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)pyridin-3-yl)carhamate

LC/MS: mass calculated for C25H21CIFN9O3: 549.14, measured (ES, m/z): 550.25 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 14.37 (br, 1H), 10.16 (s, 1H), 9.84 (s, 1H), 8.77-8.81 (m, 1H), 8.20 (d, J = 4.1 Hz, 1H), 7.86-8.09 (m,

3H), 7.69-7.77 (m, 1H), 5.68-5.78 (m, 1H), 5.03-5.25 (m, 1H), 3.70-3.82 (m,

4H), 2.90-3.11 (m, 1H), 2.56-2.70 (m, 2H), 2.30-2.47 (m, 1H), 2.03-2.21 (m,

1H), 1.79-2.01 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -74.36, -112.92. Example 327 (1 R,3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)- 7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 -methoxy-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H20CIF2N9O2: 539.14, measured (ES, m/z): 540.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 13.6- 14.9 (m , 1H) 9.86 (s, 1H), 7.90 - 8.10 (m, 2H), 7.45 - 7.80 (m, 2H), 6.60 - 7.00 (m, 2H), 6.40 -

6.50 (m, 1H), 5.71- 5.74 (m, 1H), 5.15 - 5.45 (m, 1H), 4.00 -4.12 (m, 1H), 3.55 - 3.70 (m, 1H), 3.28- 3.35 (m, 3H), 3.00 - 3.10 (m, 1H) 2.60 - 2.70 (m, 1H), 2.10 -2.30 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -69.04, -74.13, -112.63, - 113.05. Example 328 3-(5-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2-methyl-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

NH? t ^' N

LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured (ES, m/z): 524.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSOde) δ 10.11 (s, 1H), 7.82-8.05 (m, 3H), 7.56-7.77 (m, 2H), 6.72-6.95 (m, 2H), 6.45-6.50 (m, 1 H), 5.71 (d, J =

2.6 Hz, 1H), 4.68-4.74 (m, 1H), 3.83-3.97 (m, 2H), 2.84-2.95 (m, 1H), 2.31-2.45 (m, 1H), 2.10-2.15 (m, 1H), 1.80-1.88 (m, 1H), 1.14-1.27 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.62, -73.776.

Example 329 N-(2-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4- yl)phenyl)isobutyramide

LC/MS: mass calculated for C28H26CIFN8O2: 560.19, measured (ES, m/z): 561.10 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d*) δ 9.60 (s, 1H), 7.86-8.80 (m, 1 H), 7.35-7.66 (m, 5H), 5.78-5.88 (m, 1H), 5.23-5.34( m, 1H), 3.87-4.02 (m,

1H), 2.90-3.09 (m, 1H), 2.45-2.80 (m, 3H), 2.21-2.42 (m, 2H), 1.98-2.01 (m, 2H), 1.02-1.46 (m, 6H). ¹⁶ F NMR (282 MHz, Methanol-d*) δ -76.96, -113.51, - 113.94.

Example 330 N-(2-(2-((3S)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4- yl)phenyl)cyclopentanecarboxamide

LC/MS: mass calculated for C30H28CIFN8O2: 586.20, measured (ES, m/z): 587.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.81-9.90 (m, 1H), 7.89- 8.12 (m, 2H), 7.61-7.73 (m, 2H), 7.45-7.54 (m, 1H), 7.13-7.41 (m, 2H), 5.61 - 5.81 (m, 1H), 5.02-5.29 (m, 1H), 3.71-4.29 (m, 1H), 2.71-2.98 (m, 2H), 1.90-

2.50 (m, 5H), 1.28-1.94 (m, 9H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -74.29, - 112.65, -113.07.

Example 331 (3S)-3-(4-(1H-1,2,4-Triazol-3-yl)-1H-imidazol-2-yl)-7-(3-chl oro- 2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindo lizin-5(1H)-one s

Cl, ,.NH

HI

Step 1 : 2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-3-yl)ethyl

(3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8, 8a- hexahydroindolizine-3-carboxylate

To a solution of the (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.62 mmol, 1.3 equiv.) in CHaCN (10 mL) were added 2-bromo-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-3-yl)ethan-1-one (150 mg, 0.47 mmol, 1.0 equiv.) and K2CO3 (150 mg, 1.09 mmol, 2.3 equiv.). The resulting mixture was stirred at room temperature, for 5h, then was quenched with water and extracted with EA. The combined organic layer was washed with brine, dried over ΝΒΣΒΟ*. The solids were filtered out. The resulting organic phase was concentrated under vacuum. The residue was applied onto a silica gel column to yield 2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-3- yl)ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. Step 2: 2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-3-yl)ethyl

(3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8, 8a- hexahydroindolizine-3-carboxylate

To a solution of the 2-oxo-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- 1 ,2,4-triazol-3-yl)ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-

1,2,3,5,8,8a-hexahydroindolizine-3-cartx)xylate (150 mg, 0.26 mmol) in toluene (10 mL) were added ammonium acetate (264 mg, 3.07 mmol) and HOAc (0.1 mL). The resulting mixture stirred at 110 °C for 2 h, then cooled to room temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel to yield the (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-3-(5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-3-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid.

Step 3: (3S)-3-(5-(1 H-1 ,2,4-triazol-3-yl)-1 H-imidazol-2-yl)-7-(6-amino-3-chloro- 2-fluorophenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of the (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,4-triazol-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (100 mg, 0.18 mmol) in DCM (5 mL) was added TFA (3 mL). The resulting mixture stirred at room temperature, for 2 h, then concentrated to yield the (3S)-3-(5-(1H-1,2,4-triazol-3-yl)-1H-imidazol-2-yl)-7- (6-amino-3-chloro-2-fluorophenyl)-2,3,8,8a-tetrahydroindoliz in-5(1 H)-one as a yellow oil.

Step 4: (3S)-3-(4-(1 H-1 ,2,4-triazol-3-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro- 6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a stirred solution of (3S)-3-(5-(1H-1,2,4-triazol-3-yl)-1H-imidazol-2-yl)- 7-(6-amino-3-chloro-2-fluorophenyl)-2,3,8,8a-tetrahydroindol izin-5(1 H)-one (40 mg, 0.10 mmol, 1.0 equiv.) in AcOH (2.5 mL) were added azidotrimethylsilane (0.25 mL) and azidotrimethylsilane (0.25 mL) at room temperature. The mixture was stirred for 4 h at 60 °C and concentrated under reduced pressure. The residue was purified by reverse flash chromatography on C18 with the following conditions: mobile phase, A: TFA (0.05%) in water and B: ACN, 10% to 50% gradient in 20 min to yield (3S)-3-(4-(1H-1,2,4-triazol-3-yl)-1H-imidazol-2-yl)-7- (3-chloro2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetra hydroindolizin- 5(1H)-one as a yellow solid.

LC/MS: mass calculated for C20H16CIFN10O: 466.12, measured (ES, m/z): 467.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 9.80 (s, 1 H), 8.69-8.73 (m, 1H), 7.95-8.04 (m, 2H), 7.68-7.69 (m, 1H), 5.63-5.73 (m, 1H), 5.12-5.19 (m, 1H), 2.99-3.02 (m, 1H), 2.52-2.55 (m, 1H), 2.16-2.35 (m, 2H), 1.75-2.16 (m,

4H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -112.58, -112.64, -113.06.

Example 332 (3S)-3-(4-(1H-1,2,3-Triazol-5-yl)-1H-imidazol-2-yl)-7-(3-chl oro- 2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C20H16CIFN10O: 466.12, measured (ES, m/z): 467.10 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 9.59 (s, 1H), 7.98- 8.01 (m, 1H), 7.83-7.98 (m, 1H), 7.56-7.83 (m, 1H), 7.39-7.54 (m, 1H), 5.71- 5.76 (m, 1H), 5.13-5.21 (m, 1H), 3.90-4.45 (m, 1H), 2.88-3.04 (m, 1H), 2.55- 2.74 (m, 2H), 1.98-2.51 (m, 3H). ¹⁹ F NMR (282 MHz, Methanol-cU) δ -113.33, - 113.83.

Example 333 (3S)-3-(1H,1 ^, H-[2,4 ^, -Biimidazol]-2'-yl)-7-(3-chloiO-2-fluoro-6- (1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C21H17CIFN9O: 465.12, measured (ES, m/z): 466.05 [M+H] ⁺ . ¹ H NMR (300 MHz, Methanol-d*) δ 9.58 (s, 1H), 7.81 (t, J = 8.7, 1H), 7.49-7.67 (m, 1H), 7.38-7.46 (m, 1H), 7.04-7.12 (m, 2H), 5.73 (d, J = 2.9 Hz, 1H), 5.14 (d, J = 8.3 Hz, 1H), 3.73-4.05 (m, 1H), 2.75-2.91 (m, 1H), 2.54- 2.66 (m, 1H), 2.16-2.35 (m, 3H), 2.00-2.06 (m, 1H). ¹⁸ F NMR (282 MHz, Methanol-d*) δ -77.02, -113.87.

Example 334 (3S)-7-(3-chloro-2-Fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(1 - methyl-1H,1'H-[2,4'-biimidazol]-2'-yl)-2,3,8,8a-tetrahydroin dolizin-5(1H)- one

Sf

LC/MS: mass calculated for C22H19CIFN9O: 479.14, measured (ES, m/z): 480.15 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) 69.83 (s, 1H), 7.95-8.02 (m, 2H), 7.6-7.769 (m, 3H), 5.51-5.78 (m, 1H), 5.09-5.21 (m, 1H), 4.08-4.10 (m,

3H), 2.55-2.75 (m, 1H), 2.52-2.60 (m, 3H), 2.13-2.27 (m, 1H), 1.89-2.04 (m,

2H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -74.21, -112.98.

Example 335 (3S,8aR)-3-(5-(6-Amino-2-chloropyridin-3-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1,1 -dimethyl-2, 3, 8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H22Cl2FNgO: 553.13, measured (ES, m/z): 554.10 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) δ 9.86 (s, 1H), 7.93- 8.05 (m, 1H), 7.68- 7.77 (m, 1H), 7.40- 7.50 (m, 1H), 6.4&- 6.55 (m, 2H), 5.70 (s, 1H), 4.89- 4.95 (m, 1H), 3.77- 3.90 (m, 1H), 2.06- 2.40 (m, 3H), 1.90- 2.03 (m,

1H), 1.04-1.08 (m, 3H), 0.91- 0.95 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ - 73.41, -112.93.

Example 336 (3S,8aR)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1,1 -dimethyl-2, 3, 8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-1 , 1-dimethyl-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3- carboxylate To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.85 mmol,

1.0 equiv.) in N.N-dimethylformamide (10 mL) was added cesium carbonate (166 mg, 0.51 mmol, 0.6 equiv.), followed by N-(5-(2-bromoacetyl)-6- fluoropyridin-2-yl)acetamide (281 mg, 1.02 mmol, 1.2 equiv.). The resulting mixture was stirred for 1 h at room temperature, quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0→100% EA/PE) to yield 2-(6-acetamido-2-fluoropyridin- 3-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1 , 1 -dimethyl-5-oxo-

1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for θ2βΗ ₂ 5θΙΡ ₂ Ν4θ5: 546.15, measured: 547.25 [M+H]*.

Step 2: N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimeth yl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2- yl)acetamide

To a solution of 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-1 , 1 -dimethyl-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (180 mg, 0.33 mmol, 1.0 equiv.) in toluene (10 mL) were added ammonium acetate (254 mg, 3.29 mmol, 10.0 equiv.) and acetic acid (0.5 mL). The reaction mixture was stirred for 2 h at 110 °C, then cooled to room temperature, and concentrated. The residue was purified by flash column chromatography on silica gel (0→100% EA/PE) to yield N-(5-(2- ((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1-dimethyl-5-oxo -1,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-6-fluoropyridin-2-yl)acetamide as a brown solid. LC/MS: mass calculated for C2eH25CIF2Ne02: 526.17, measured: 527.15 [M+H]*.

Step 3: N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1 -y I) phenyl)- 1 , 1 - dimethyl-5-oxo-1,2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6- fluoropyridin-2-yl)acetamide

To a solution of N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-1,1- dimethyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imid azol-5-yl)-6- fluoropyridin-2-yl)acetamide (150 mg, 0.29 mmol, 1.0 equiv.) in acetic acid (5 mL) were added azidotrimethylsilane (0.2 mL) and trimethoxymethane (0.2 mL). The reaction mixture was stirred at 60 °C for 16 h and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0→100% EA/PE) to yield N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-1 ,1-dimethyl-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-6-fluoropyridin-2-yl)acetamide as a brown solid. LC/MS: mass calculated for C27H24CIF2N9O2: 579.17, measured: 580.25 [M+H] ⁺ .

Step 4: (3S,8a*R)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,1-dimethyl-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-1 ,1-dimethyl-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-6-fluoropyridin-2-yl)acetamide (110 mg, 0.19 mmol, 1.0 equiv.) in tetrahydrofuran (4 mL) was added hydrochloric acid (2 N) (2 mL). The reaction mixture was stirred at 50 °C for 4 h, then concentrated. The residue was purified by reverse phase chromatography on C18 column (0→60% CH3CN/H2O) to yield (3S,8a‘R)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol- 2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 , 1 -dimethyl-2, 3, 8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25H22CIF2N8O: 537.16, measured (ES, m/z): 538.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 11.92 (br, 1H), 9.85 (s, 1H), 7.98- 8.05 (m, 2H), 7.69-7.75 (m, 1H), 7.02- 7.08 (m, 1H), 6.35- 6.41 (m, 1H), 6.23 (s, 1H), 5.67 (s, 1H), 4.85 (t, J = 8.5 Hz, 1H), 3.80 (t, J = 9.6 Hz, 1H), 2.25- 2.35 (m, 2H), 2.06 -2.18 (m, 1H), 1.96 (t, J = 11.2 Hz, 1H), 1.02-1.06 (m, 3H), 0.90-0.93 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -70.79, -73.40, -

112.96.

Example 337 (3S,8aS)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 ,1 -dimethyl-2, 3, 8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H22CIF2N9O: 537.16, measured (ES, m/z): 538.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 14.21 (br, 1H), 9.86 (s, 1H), 7.95-8.07 (m, 1H), 7.86 (t, J = 9.4 Hz, 1H), 7.71- 7.76 (m, 1H), 7.60 (s, 1H), 6.79- 6.84 (m, 2H), 6.41-6.50 (m, 1H), 5.85 (d, J = 2.6 Hz, 1H), 5.19 (d, J =

10.2 Hz, 1H), 3.67 (d, J = 6.5 Hz, 1H), 2.67 (s, 1H), 2.14-2.44 (m, 2H), 1.99 (d,

J = 13.2 Hz, 1H), 0.97-1.01 (m, 3H), 0.82- 0.86 (m, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -73.68, -112.23.

Example 338 (3S,8aS)-3-(5-(6-Amino-2-chloropyridin-3-yl)-1H-imidazol-2- yl)-7-(3-chloiO-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,1-dim ethyl-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H22CI2FN9O: 553.13, measured (ES, m/z): 554.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 14.25 (br, 1H), 9.85 (s, 1H), 7.98- 8.04 (m, 1H), 7.74 (t, J = 8.7Hz, 1H), 7.65-7.70 (m, 2H), 6.80-6.84

(m, 2H), 6.52 (d, J = 8.5 Hz, 1H), 5.85 (d, J = 2.6 Hz, 1H), 5.19 (d, J = 10.4 Hz, 1H), 3.41 (t, J = 14.3 Hz, 1H), 2.67 (d, J = 15.6 Hz, 1H), 2.36 (t, J = 11.9 Hz,

1H), 2.20- 2.26 (m, 1H), 1.99 (d, J = 13.4 Hz, 1H), 0.98-1.01 (m, 3H), 0.82- 0.87 (m, 3H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -73.75, -112.16. Example 339 (3S)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(4-( 1- methyl-1 H-1 ,2,3-triazol-5-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-

5(1H)-one

S

F N' ci HN

O

N't

N

LC/MS: mass calculated for C21H18CIFN10O: 480.13, measured (ES, m/z): 481.15 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 13.0 (br, 1H), 9.83 (s,

1H), 7.95-8.02 (m, 1H), 7.93-7.95 (m, 1H), 7.69 -7.76 (m, 2H), 5.70 (d, J = 2.7 Hz, 1H), 5.09 (d, J = 9.0 Hz, 1H), 4.16- 4.25 (m, 3H), 2.75-2.80 (m, 1H), 2.52- 2.60 (m, 2H), 2.13- 2.27(m, 2H), 1.89-2.04 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO- de) 6 -74.61, -112.93.

Example 340 Methyl (4-(2-((3S,8aS)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl) phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)phenyl)carbamate

LC/MS: mass calculated for C2eH22CIFNeOa: 548.15, measured (ES, m/z): 549.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.91 (br, 1H), 9.83 (s, 1H), 7.93-8.02 (m, 2H), 7.69-7.73 (m, 3H), 7.58-7.60 (m, 2H), 5.72 (d, J = 2.8 Hz, 1H), 5.19 (d, J = 9.8 Hz, 1H), 3.62-3.75 (m, 1H), 3.70- 3.74 (m, 3H), 3.05- 3.14 (m, 1H), 2.89- 3.11 (m, 1H), 2.41-2.57 (m, 1H), 2.05-2.34 (m, 2 H), 1.94- 2.01(m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.69 Example 341 Methyl (4-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5- oxo-1 ,2,3,5, 8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)phenyl)carbamate

R s V NH

Cl.

N*.

LC/MS: mass calculated for CaeHzzCIFNeOa: 548.15, measured (ES, m/z): 549.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.91 (br, 1H), 9.83 (s, 1H), 7.93-8.02 (m, 2H), 7.69-7.73 (m, 3H), 7.58-7.60 (m, 2H), 5.72 (d, J = 2.8 Hz, 1H), 5.19 (d, J = 9.8 Hz, 1H), 3.62-3.75 (m, 1H), 3.70 - 3.74 (m, 3H), 3.05- 3.14 (m, 1H), 2.89- 3.11 (m, 1H), 2.41-2.57 (m, 1H), 2.05-2.34 (m, 2 H), 1.94- 2.01(m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.69.

Example 3424-[2-[(3S)-7-[3-Chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]- 5-oxo- 2,3,8,8a-tetrahydro-1H-indolizin-3-yl]-1H-imidazol-4-yl]-2-f luoro-benzoic acid

LC/MS: mass calculated for C25H18CIF2N7O3: 537.15, measured (ES, m/z): 538.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 13.24 (br, 1H), 9.84 (s,

1H) , 7.90 - 8.05 (m, 3H), 7.68 - 7.73 (m, 3H), 5.71 - 5.76 (m, 1H), 5.09 - 5.12 (m, 1H), 3.69 -4.25 (m, 1H), 2.78 -2.91 (m, 1H), 2.56 -2.61 (m, 1H), 2.26 - 2.36 (m, 1H), 2.07 -2.16 (m, 1H), 1.90 -2.07 (m, 2H).

Example 344 (rS,3S,8a*R)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 -methyl- 2, 3,8, 8a-tetrahydroindolizin-5(1H)-one

LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured (ES, m/z): 524.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.73 (s, 1H), 9.84 (s, 1H), 7.94 - 8.05 (m, 2H), 7.70 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.40 (d, J = 8.4

Hz, 1H), 6.21 (s, 2H), 5.69 (s, 1H), 5.01 -4.94 (m, 1H), 3.06 - 3.29 (m, 1H), 2.56 - 2.64 (m, 1H), 2.20 - 2.46 (m, 2H), 1.98 - 2.13 (m, 1H), 1.74 - 1.93 (m, 1H), 0.98 (d, J = 2.7 Hz, 3H). ¹⁸ F NMR (376 MHz, DMSO-de) δ -70.85, -112.72. Example 345 (1*R,3S,8a*R)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 -methyl- 2, 3,8, 8a-tetrahydroindolizin-5(1H)-one

NH ₂ LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured (ES, m/z): 524.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 11.82 (br, 1H), 9.80 (s, 1H), 7.85 - 8.09 (m, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 3.8 Hz, 1H), 6.36 (d, J = 8.7 Hz, 1H), 6.26 (s, 2H), 5.82 (s, 1H), 5.03 (t, J = 8.5 Hz, 1H), 3.75 - 3.90 (m, 1H), 3.16 - 3.28 (m, 1H), 2.80 -2.87 (m, 1H), 1.71 - 1.81 (m, 1H),

1.34 - 1.50 (m, 1H), 1.24 (s, 1H), 0.99 (d, J = 6.4 Hz, 3H). ¹⁸ F NMR (376 MHz, DMSO-de) 6 -70.77, -113.60.

Example 346 (1*S,3S,8a*S)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 -methyl- 2, 3,8, 8a-tetrahydroindolizin-5(1H)-one

*s s ci.

N

LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured (ES, m/z): 524.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- de) 6 11.92 (br, 1H), 9.84 (s, 1H), 7.86 - 8.14 (m, 2H), 7.70 (d, J = 8.7 Hz, 1H), 7.03 (s, 1H), 6.38 (d, J = 8.2 Hz, 1H), 6.24 (s, 2H), 5.67 (d, J = 2.3 Hz, 1H), 4.89 (t, J = 8.3 Hz, 1H), 3.51 -

3.71 (m, 1H), 2.54 - 2.60 (m, 1H), 2.22 - 2.47 (m, 2H), 1.90 - 2.12 (m, 1H),

1.71 - 181 (m, 1H), 1.02 (d, J = 6.3 Hz, 3H). ^ig F NMR (376 MHz, DMSO -de) 6- 70.78, -112.95.

Example 347 (3S)-3-(5-(6-Amino-2-chloropyridin-3-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 -methyl-2, 3, 8,8a- tetrahydroindolizin-5(1 H)-one

F ^■ NH ₂ ci. ^S J

N ^ •N

Cl

^Ne N

LC/MS: mass calculated for C24H20CI2FN9O: 539.12, measured (ES, m/z): 540.10 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.77 (s, 1H), 9.85 (s, 1H), 7.92 - 8.10 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H), 6.99 - 7.07 (m, 1H), 6.36 -

6.48 (m, 1H), 6.25 (s, 2H), 5.72 (d, J = 2.5 Hz, 1H), 4.98 (d, J = 8.6 Hz, 1H), 3.20 - 3.31 (m, 1H), 2.27 - 2.35 (m, 2H), 2.01 - 2.12 (m, 1H), 1.81 - 1.94 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -112.76. Example 348 (3S)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 -methyl-2, 3, 8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H2oCIF2NgO: 523.14, measured (ES, m/z): 524.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.77 (s, 1H), 9.85 (s, 1H), 7.92 - 8.10 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H), 6.99 - 7.07 (m, 1H), 6.36 - 6.48 (m, 1H), 6.25 (s, 2H), 5.72 (d, J = 2.5 Hz, 1H), 4.98 (d, J = 8.6 Hz, 1H),

3.15-3.21 (m, 1H), 2.61 -2.71 (m, 1H), 2.25 -2.37 (m, 2H), 2.01 -2.09 (m, 1H), 1.81 - 1.94 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H). ¹⁹ F NMR (282 MHz, DMSO- de) 6 -70.78, -112.73.

Example 349 (3S)-3-(5-(6-Amino-2-chloropyridin-3-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-1 ,1 -dimethyl-2, 3, 8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H22CI2FN9O: 53.13, measured (ES, m/z): 576.10 [M+Na] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 11.63 (s, 1H), 9.87 (s, 1H), 7.92 - 8.07 (m, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.49 (d, J = 8.5 Hz, 1H), 6.29 (s, 2H), 5.81 (d, J = 2.5 Hz, 1H), 4.96 (t, J = 5.8 Hz, 1H), 2.32 - 2.38 (m, 1H), 2.11 - 2.19 (m, 2H), 1.25 (s, 1H), 0.99 (s, 3H), 0.88 (s,

3H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -73.40, -112.49.

Example 350 (3S)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,1-dimethyl- 2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C25H22CIF2N9O: 537.16, measured (ES, m/z): 538.15 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-ck) δ 11.61 (s, 1H), 9.87 (s, 1H), 7.94 - 8.10 (m, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.03 (s, 1H), 6.39 (d, J = 9.1 Hz, 1 H), 6.24 (s, 2H), 5.80 (s, 1 H), 4.96 (d, J = 8.7 Hz, 1 H), 2.71 - 2.76 (m,

1H), 2.07 -2.24 (m, 3H), 1.23 - 1.29 (m, 1H), 0.86 (s, 3H), 0.99 (s, 3H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -70.81, -73.26, -112.47.

Example 351 (3S,8aR)-7-(3-Chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (2-(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8 _| 8a- tetrahydroindolizin-5(1 H)-one

Step 1: 2-oxo-2-(2-(trifluoromethyl)pyridin-4-yl)ethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (120 mg, 0.37 mmol, 1.0 equiv.) and CS2CO3 (72 mg, 0.22 mmol, 0.6 equiv.) in DMF (2 ml_) was maintained with stirring at room temperature for 10 min. 2-Bromo-1-(2- (trifluoromethyl)pyridin-4-yl)ethan-1-one (118 mg, 0.44 mmol, 1.2 equiv) was then added. The reaction mixture was stirred at room temperature overnight The resulting mixture was poured into water (10 mL), filtered, and the solid was collected and dried to yield 2-oxo-2-(2-(trifluoromethyl)pyridin-4-yl)ethyl (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate as a yellow solid. LC/MS: mass calculated for C23H18CIF4N3O4: 511.09, measured: 534.11 [M+Na]*. Step 2: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-

(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a -tetrahydroindolizin- 5(1H)-one

A mixture of (2-oxo-2-(2-(trifluoromethyl)pyridin-4-yl)ethyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate (108 mg, 0.21 mmol, 1.0 equiv.) and NhUOAc (162 mg, 2.11 mmol, 10.0 equiv.) in AcOH (0.2 mL) and toluene (2 ml_) was heated at 110 °C for 2 h with stirring. After being cooled to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (0→8% MeOH/DCM) to yield (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(5-(2-(trifluoromethyl)pyri din-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C23H18CIF4N5O: 491.11, measured: 492.10 [M+H] ⁺ .

Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(2-

(trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3 _l 8,8a-tetrahydroindolizin-

5(1H)-one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2- (trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-te trahydroindolizin- 5(1H)-one (98 mg, 0.20 mmol, 1.0 equiv.) in AcOH (5 mL) were added TMSN3 (229 mg, 1.99 mmol, 10.0 equiv.) and trimethoxymethane (211 mg, 1.99 mmol, 10.0 equiv.). The mixture was heated at 60 °C for 8 h and then concentrated under reduced pressure. The residue was purified by prep-HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(2- (trifluoromethyl)pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-te trahydroindolizin- 5(1H)-one as a white solid.

LC/MS: mass calculated for C24H17CIF4N8O: 544.11, measured (ES, m/z): 545.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 69.84 (s, 1H), 8.80 (d, J =

5.2 Hz, 1H), 8.44 - 8.21 (m, 2H), 8.15 - 7.85 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H), 5.70 (d, J = 2.6 Hz, 1H), 5.15 (d, J = 9.2 Hz, 1H), 3.81 - 3.85 (m, 1H), 2.80 - 2.92 (m, 1H), 2.51 -2.62 (m, 1H), 2.22 - 2.27 (m, 1H), 2.11 -2.20 (m, 1H), 1.81 -2.10 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -66.62, -113.05. Example 352 (3S,8aS)-3-(5-(6-Amino-2-chloropyridin-3-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-f1uoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H18CI2FN9O: 525.10, measured (ES, m/z): 548.10 [M+Na]+. ¹ H NMR (300 MHz, DMSO-de) δ 11.99 (s, 1H), 9.84 (s, 1H), 7.92 - 8.09 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.43 - 6.59 (m, 1 H), 6.30 (s, 2H), 5.69 (d, J = 2.6 Hz, 1 H), 4.99 (t, J = 7.1 Hz, 1 H),

3.81 - 3.85 (m, 1 H), 3.30 - 3.35 (m, 1 H), 2.21 - 2.44 (m, 1 H), 1.97 - 2.08 (m, 1H), 1.64 - 1.72 (m, 1H), 1.36 - 1.41 (m, 1H), 1.22 - 1.26 (m, 1 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -113.09.

Example 353 (3S,8aS)-7-(3-Chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2-(trifluoromethyl)pyiidin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a - tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C24H17CIF4N8O: 544.11, measured (ES, m/z): 545.25 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 9.84 (s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.44 - 8.21 (m, 2H), 8.15 - 7.85 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H),

5.70 (d, J = 2.6 Hz, 1H), 5.15 (d, J = 9.2 Hz, 1H), 4.04 -4.14 (m, 1H), 2.80 - 2.92 (m, 1H), 2.51 -2.62 (m, 1H), 2.22 - 2.27 (m, 1H), 2.11 -2.20 (m, 1H), 1.81 -2.10 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -66.62, -113.05. Example 354 (3S,8aR)-3-(5-(6-Ammo-2-chloropyridm-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H18CI2FN9O: 525.10, measured (ES, m/z): 548.10 [M+Na] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.99 (s, 1H), 9.84 (s, 1H), 7.92 - 8.09 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.43 -6.59 (m, 1H), 6.30 (s, 2H), 5.69 (d, J = 2.6 Hz, 1H), 4.99 (t, J = 7.1 Hz, 1H), 4.04 - 4.14 (m, 1H), 3.30 - 3.35 (m, 1H), 2.21 - 2.44 (m, 1H), 1.97 - 2.08 (m, 1H), 1.64 - 1.72 (m, 1H), 1.36 - 1.41 (m, 1H), 1.22 - 1.26 (m, 1 H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -113.09.

Example 355 Methyl (4-(2-((3S)-7-(3-chloro-2-fluoiO-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5- yl)phenyl)carbamate s H

F V NH

Cl. ΚΊί j) r

V

LC/MS: mass calculated for C2eH22CIFNa03: 548.15, measured (ES, m/z): 549.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 69.91 (s, 1H), 9.83 (s, 1H), 7.93 - 8.02 (m, 2H), 7.69 - 7.73 (m, 3H), 7.58 - 7.60 (m, 2H), 5.72 (d, J = 2.8 Hz, 1H), 5.19 (d, J = 9.8 Hz, 1H), 3.62 - 3.75 (m, 1H), 3.72 (s, 3H), 3.05 - 3.14 (m, 1H), 2.89 - 3.11 (m, 1H), 2.41 -2.57 (m, 1H), 2.05 - 2.34 (m, 2 H), 1.94 -2.01 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-de) δ -112.69.

Example 356 (3R,8aR)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H18CIF2N9O: 509.13, measured (ES, m/z): 510.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 11.95 (s, 1H), 9.84 (s, 1H), 7.83 - 8.11 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 3.9 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 6.27 (s, 1H), 5.69 (d, J = 2.5 Hz, 1H), 4.99 (t, J = 7.1 Hz, 1H), 3.60 - 3.71 (m, 1H), 3.61 - 3.71 (m, 1H), 2.11 -2.20 (m, 3H), 1.87 - 1.92 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -70.73, -113.08.

Example 357 (3R,8aS)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazoM-yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

LC/MS: mass calculated for C23H18CIF2N9O: 509.13, measured (ES, m/z): 510.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) 6 11.80 (s, 1H), 9.84 (s,

1H), 7.97 - 8.10 (m, 2H), 7.72 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 3.9 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 6.27 (s, 2H), 5.69 (d, J = 2.5 Hz, 1H), 5.00 (d, J = 8.3 Hz,

1 H), 3.60 - 3.85 (m, 1 H), 2.54 - 2.87 (m, 2H), 2.02 - 2.23(m, 2H), 1.93 - 1.98 (m, 2H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -70.78, -112.87. Example 358 (3S,8aR)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

H

F NH ₂

Cl, 6 N ξ F

N I-¾

^N v

Step 1: 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (180 mg, 0.55 mmol, 1.0 equiv.) and cesium carbonate (108 mg, 0.33 mmol, 0.6 equiv.) in N,N- dimethylfonmamide (5 mL) was added N-(5-(2-bromoacetyl)-6-fluoropyridin-2- yl)acetamide (183 mg, 0.67 mmol, 1.2 equiv.). The reaction mixture was stirred for 1h at room temperature, then quenched with water and the solid was collected by filtration and dried under vacuum to yield 2-(6-acetamido-2- fluoropyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C24H21CIF2N4O5: 518.12, measured: 519.10 [M+H] ⁺ .

Step 2: N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2 -yl)acetamide

To a solution of 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate (180 mg, 0.35 mmol, 1.0 equiv.) in toluene (5 mL) were added ammonium acetate (267 mg, 3.47 mmol, 10.0 equiv.) and acetic acid (0.5 mL). The reaction mixture was heated at 110 °C for 2 h. The excess solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (0→100% EA/PE) to yield N-(5-(2-((3S)-7-(6-amino-3-chloro- 2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)- 1H-imidazol-5-yl)-6- fluoropyridin-2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C24H2iCIF ₂ Ne02: 498.14, measured: 499.15 [M+H] ⁺ .

Step 3: N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3, 5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridi n-2- yl)acetamide

To a solution of N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2- yl)acetamide (150 mg, 0.30 mmol, 1.0 equiv.) in glacial acetic acid (3 mL) were added azidotrimethylsilane (0.2 mL, 1.50 mmol, 5.0 equiv.) and trimethoxymethane (0.2 mL, 1.50 mmol, 5.0 equiv.). The reaction mixture was stirred at 50 °C overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (0→100% EA/PE) to yield N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridi n-2- yl)acetamide as a yellow solid. LC/MS: mass calculated for C25H20CIF2N9O2: 551.14, measured: 574.15 [M+Na]*.

Step 4: (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-y l)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one

To a solution of N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-6- fluoropyridin-2-yl)acetamide (110 mg, 0.20 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) was added 4 N hydrochloric acid (1 mL). The reaction mixture was stirred at 50°C for 4 h. The residue was purified by silica gel chromatography (0→100% EA/PE) to yield (3S)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol- 2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol- 1 -yl)pheny l)-2 , 3, 8, 8a- tetrahydroindolizin-5(1 H)-one as a white solid. The racemic mixture was separated by prep-chiral-HPLC separation. The collected fractions were combined and concentrated under vacuum to yield (3S,8aR)-3-(5-(6-amino-2- fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C23Hi8CIF2NgO: 509.13, measured (ES, m/z): 510.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.91 (s, 1H), 9.84 (s,

1H), 7.91 - 8.09 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.04 (s, 1H), 6.39 (d, J = 8.2 Hz, 1H), 6.24 (s, 2H), 5.69 (d, J = 2.4 Hz, 1H), 4.99 (t, J = 7.1 Hz, 1H), 3.60 - 3.71(m, 1H), 2.45 - 2.49 (m, 2H), 2.34 - 2.40 (m, 2H), 1.97 -2.15 (m, 1H),

1.61 - 1.75 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -70.76, -113.08. Example 359 (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)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

H

F N ^• NH ₂ ci.

N ξ F

LC/MS: mass calculated for C23H18CIF2N9O: 509.13, measured (ES, m/z): 510.05 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ 11.91 (s, 1H), 9.84 (s, 1H), 7.91 - 8.09 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.04 (s, 1H), 6.39 (d, J = 8.2 Hz, 1H), 6.24 (s, 2H), 5.69 (d, J = 2.4 Hz, 1H), 4.99 (t, J = 7.1 Hz, 1H), 4.04 - 4.14 (m, 1H), 2.45 - 2.49 (m, 2H), 2.34 - 2.40 (m, 2H), 1.97 -2.15 (m, 1H),

1.61 - 1.75 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -70.76, -113.08.

Example 360 (6S*,8aR*)-6-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2 - yl)-2-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)hexahydropyrrolo[1 ,2-a]pyrazine-

1,4-dione

Step 1: Diethyl pyrrolidine-2,5-dicarboxylate

Diethyl-1-benzylpyrrolidine-2,5-dicarboxylate (5.0 g, 16.37 mmol) and Pd/C (500 mg) were dissolved in MeOH (50 mL) and the mixture was stirred at room temperature under Hz for 2 h. The solid was filtered, and the solvent was removed under vacuum to yield diethyl pyrrolidine-2,5-dicarboxylate as a white solid. LC/MS: mass calculated for C10H17NO4: 215.12, measured: 228.25 [M+Na]*.

Step 2: Diethyl 1-(((benzyloxy)carbonyl)glycyl)pyrrolidine-2,5-dicarboxylate Diethyl pyrrolidine-2, 5-dicarboxylate (3.2 g, 14.86 mmol, 1.0 equiv.),

EDCI (4.3 g, 22.30 mmol, 1.5 equiv.) and ((benzyloxy)carbonyl)glycine (3.7 g, 17.84 mmol, 1.2 equiv.) were dissolved in pyridine (60.0 mL) and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (0→ 11 % MeOH/DCM) to yield diethyl- 1 -

(((benzyloxy)carbonyl)glycyl)pyrrolidine-2, 5-dicarboxylate as a yellow solid. LC/MS: mass calculated for CzoHzeNzO?: 406.17, measured: 407.30 [M+H]*. Step 3: Ethyl 1,4-dioxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylate

Diethyl-1-(((benzyloxy)carboyl)glycyl)pyrrolidine-2, 5-dicarboxylate (5.1 g, 12.54 mmol) and Pd/C (510 mg) were dissolved in EtOH (50.0 mL) under Hz and stirred at 50 °C for 3 h. The solid was filtered and the solvent removed under vacuum. The residue was purified silica gel column chromatography (0→11% MeOH/DCM) to yield ethyl 1,4-dioxooctahydropyrrolo[1,2-a]pyrazine- 6-carboxylate as a white solid. LC/MS: mass calculated for C10H14N2O4: 226.23, measured (ES, m/z): 227.25 [M+H]*.

Step 4: Ethyl 2-(5-chloro-2-nitrophenyl)-1,4-dioxooctahydropyrrolo[1,2- a]pyrazine-6-carboxylate tert-BuONa (630.8 mg, 6.56 mmol, 1.1 equiv.) was added to a solution of ethyl 1 ,4-dioxooctahydropyrrolo[1 ,2-a]pyrazine-6-carboxylate (1.4 g, 5.96 mmol, 1.0 equiv.) in DMA (12.0 mL) at 0 °C and the reaction mixture was stirred for 30 minutes. A solution of 4-chloro-2-fluoro-1 -nitrobenzene (1.2 g, 7.16 mmol, 1.2 equiv.) in DMA (8.0 mL) was then added, the reaction mixture was stirred at room temperature for 2 h, then diluted with ice water (5 mL) and extracted with EA (150 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (0→11% MeOH/DCM) to yield ethyl-2-(2-amino-5-chlorophenyl)-1 ,4- dioxooctahydropyrrolo[1 ,2-a]pyrazine-6-carboxylate as a yellow solid. LC/MS: mass calculated for CieHieCINsOe: 381.07, measured (ES, m/z): 382.20 [Μ+ΗΓ.

Step 5: 2-(5-Chloro-2-nitrophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2-a]pyrazine-6- carboxylic add

Ethyl-2-(2-amino-5-chlorophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2- a]pyrazine-6-carboxylate (319 mg, 0.84 mmol, 1.0 equiv.), LiBr (726 mg, 8.34 mmol, 10.0 equiv.) and EtaN (253 mg, 2.51 mmol, 3.0 equiv.) were added to CHaCN (10.0 mL) and water (0.1 mL). The resulting mixture was stirred at room temperature for 2 h. Then the solvent was removed under vacuum and the pH was adjusted to 6 with HCI (2 M), and the resulting mixture extracted with EA (50 mL). The organic layer was separated and dried with NaaSO*. concentrated under vacuum to yield 2-(5-chloro-2-nitrophenyl)-1,4- dioxooctahydropyrrolo[1,2-a]pyrazine-6-carboxylic add as a yellow solid.. LC/MS: mass calculated for C14H12CIN3O6: 353.04, measured (ES, m/z): 354.00 [M+H]*.

Step 6: 2-(6-Acetamido-2-fluoropyridin-3-yl)-2-oxoethyl 2-(5-chloro-2- nitrophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2-a]pyrazine-6-carboxylate

2-(5-Chloro-2-nitrophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2-a]pyrazine-6- carboxylic add (200 mg, 0.56 mmol, 1.0 equiv.) and K2CO3 (78 mg, 0.56 mmol, 1.0 equiv.) were dissolved in CHaCN (8 mL), and the mixture was stirred at room temperature for 0.5 h. A solution of N-(5-(2-bromoacetyl)-6-fluoropyridin- 2-yl)acetamide (171 mg, 0.62 mmol, 1.1 equiv.) in CH3CN (2.0 mL) was then added, the resulting mixture was stirred for another 2 h at room temperature and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (EA/PE, 0→67%) to yield 2-(6-acetamido- 2-fluoropyridin-3-yl)-2-oxoethyl 2-(5-chloro-2-nitrophenyl)-1 ,4- dioxooctahydropyrrolo[1 ,2-a]pyrazine-6-carboxylate as a yellow solid. LC/MS: mass calculated for C23H19CIFN5O8: 547.09, measured (ES, m/z): 570.20 [M+Na]÷.

Step 7: N-(5-(2-(2-(5-chloro-2-nitrophenyl)-1,4-dioxooctahydropyrrol o[1,2- a]pyrazin-6-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)aceta mide

2-(6-Acetamido-2-fluoropyridin-3-yl)-2-oxoethyl 2-(5-chloro-2- nitrophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2-a]pyrazine-6-carboxylate (170 mg, 0.31 mmol, 1.0 equiv.), ammonium acetate (478 mg, 6.2 mmol, 20.0 equiv.) and acetic acid (2.0 mL) were added to toluene (20.0 mL), and the reaction mixture was stirred at 90 °C for 1.5 h. The solvent was removed under vacuum and the residue was purified by silica gel column with (0→10% MeOH/DCM) to yield N- (5-(2-(2-(5-chloro-2-nitrophenyl)-1,4-dioxooctahydropyrrolo[ 1,2-a]pyrazin-6-yl)- 1H-imidazol-5-yl)-6-fluoropyridirv2-yl)acetamide as a yellow solid. LC/MS: mass calculated for C23H19CIFN7O5: 527.11, measured (ES, m/z): 528.10 [Μ+ΗΓ. Step 8: N-(5-(2-(2-(2-amino-5-chlorophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2- a]pyrazin-6-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)aceta mide

N-(5-(2-(2-(5-chloro-2-nitrophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2- a]pyrazin-6-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)aceta mide (140 mg, 0.27 mmol, 1.0 equiv.), Fe (148 mg, 2.65 mmol, 10.0 equiv.) and NhUCI (42 mg, 0.80 mmol, 3.0 equiv.) were added to MeOH (10.0 mL) and water (2.0 mL). The mixture was stirred at 60 °C for 30 min. The solid was filtered and the solvent was removed under vacuum to yield N-(5-(2-(2-(2-amino-5-chlorophenyl)-1,4- dioxooctahydropyrrolo[1 ,2-a]pyrazin-6-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2- yl)acetamide as a residue, which was used in the next step without further purification. LC/MS: mass calculated for C23H21CIFN7O3: 497.14, measured (ES, m/z): 498.30 [M+H]*.

Step 9: N-(5-(2-(2-(5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-1 ,4-dioxooctahydro pyrrolo[1 ,2-a]pyrazin-6-yl)-1H-imidazol-5-yl)-6-fluoropyriclin-2-yl)a cetamide N-(5-(2-(2-(2-amino-5-chlorophenyl)-1 ,4-dioxooctahydropyrrolo[1 ,2- a]pyrazin-6-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)aceta mide (117 mg, 0.24 mmol, 1.0 equiv.), TMSNs (135 mg, 1.18 mmol, 5.0 equiv.) and trimethoxymethane (124 mg, 1.18 mmol, 5.0 equiv.) were dissolved in AcOH (5.0 mL), and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was purified by reverse phase chromatography on C18 column with (CH3CN/H2O (0.05% TFA): 0→60%) to yield N-(5-(2-(2-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1,4- dioxooctahydropyrrolo[1 ,2-a]pyrazin-6-yl)-1 H-imidazol-5-yl)-6-fluoropyridin-2- yl)acetamide as a yellow solid. LC/MS: mass calculated for C24H20CIFN10O3: 550.14, measured (ES, m/z): 551.35 [M+H]*.

Step 10: (6S*,8aR*)-6-(5-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-2-(5- chloro-2-(1 H-tetrazol-1-yl)phenyl)hexahydropyrrolo[1 ,2-a]pyrazine-1 ,4-dione N-(5-(2-(2-(5-chloro-2-(1 H-tetrazol-1-yl)phenyl)-1 ,4- dioxooctahydropyrrolo[1 ,2-a]pyrazin-6-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2- yl)acetamide (60.0 mg, 0.109 mmol) was dissolved in HCI (2 M, 2.5 mL) and THF (2.5 mL), and the mixture was stirred at 50°C for 1 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase chromatography on C18 column with MeCN/hbO (0.05% TFA) (0-60%) to yield 6-(5-(6-amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-2-(5-chloro-2-(1 H- tetrazol-1-yl)phenyl)hexahydropyrrolo[1,2-a]pyrazine-1 ,4-dione as a yellow solid, which was further purified by chiral-HPLC (Column: CHIRALART Cellulose-SB, 2*25cm,5um; Mobile Phase A:MTBE(0.5% 2M NHs-MeOH)- HPLC, Mobile Phase B:EtOH-HPLC; Flow rate:20 mL/min; Gradients B to 50 B in 11 min; 220/254 nm; RT1:5.525; RT2: 10.237; Injection Volumn:3 ml; Number Of Runs:2) to yield (6S*,8aR*)-6-(5-(6-amino-2-fluoropyridin-3-yl)-1H- imidazol-2-yl)-2-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)hexahy dropyrrolo[1 ,2- a]pyrazine-1,4-dione as pink solid and (6R*,8aR*)-6-(5-(6-amino-2- fluoropyridin-3-yl)-1 H-imidazol-2-yl)-2-(5-chloro-2-(1 H-tetrazol-1- yl)phenyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione as an off-white solid.

LC/MS calculated for C22H18CIFN10O2508.1, measured 509.2 (MhT). ¹ H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.70 - 7.96 (m, 5H), 7.35 - 7.49 (m, 1H), 6.43 (dd, J = 8.3, 2.0 Hz, 1H), 5.13 (s, 1H), 4.79 - 4.92 (m, 1H), 4.30 - 4.70 (m, 1H), 2.12 - 2.21 (m, 2H), 1.90 - 2.08 (m, 1H), 1.40 - 1.60 (m, 1H)./19F NMR (376 MHz, DMSO-d6) δ -69.95, -73.69. Example 361 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-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- tetrahydroindolizin-5(1 H)-one ci. ,p vn M

N·

V ^N

Step! (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)boronic acid

To a mixture of 8-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (50 mg, 0.291 mmol, 1.0 equiv.) and 4,4,4 ^, ,4 ^, ,5,5,5 ^, ,5'-octamethyl-2,2 ^, -bi(1 ,3,2- dioxaborolane) (147.999 mg, 0.583 mmol, 2.0 equiv.) in 1,4-dioxane (1 mL) was added potassium acetate (85.798 mg, 0.874 mmol, 3.0 equiv.), X-Phos Pd G2 (11.464 mg, 0.031 mmol, 0.05 equiv.) and X-Phos (6.946 mg, 0.015 mmol, 0.05 equiv.). The reaction mixture was stirred at 100 °C for 3 h under N2. The resulting mixture containing (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)boronic acid was used in the next step without any further purification. LC/MS: mass calculated, for CyHeBNO*: 181.05, measured: 182.10 [M+H] ⁺ .

Step 2. (3S)-7-(6-amino3-chloro-2-fluorophenyl)-3-(5-(2,3-dihydro- [1 ,4]dioxino[2,3-b]pyridin-8-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-

5(1H)-one

To a mixture of (2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)boronic acid (500 mg) in 1,4-dioxane (10 mL) was added (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-3-(5-iodo-1H-imidazol-2-yl)-2,3,8,8a-tetrahydr oindolizin-5(1H)- one (100 mg, 0.212 mmol, 1.0 equiv.), potassium carbonate (87.716 mg, 0.635 mmol, 3.0 equiv.), 1,1'bBis (di-t-butylphosphino)ferrocene palladium dichloride (13.788 mg, 0.021 mmol, 0.1 equiv.) and water (1 mL). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 2 h, then cooled to room temperature. Water was added, the mixture was extracted with EA. The combined extracts were dried over anhydrous NaaSO*. then concentrated. The residue was purified by silica gel chromatography with MeOH/DCM (0%-8%) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2,3-dihydro- [l.^dioxinop.S-blpyridin-e-yO-IH-imidazol^-yl^.S.e.ea-tetrah ydroindolizin- 5(1H)-one as a brown solid. LC/MS: mass calculated, for C24H21CIFN5O3: 481.13, measured: 482.10 [M+H]*·

Step 3. (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(2,3- dihydro-[1 ,4]dioxino[2,3-b]pyridin-8-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2,3- dihydro-[1 ,4]dioxino[2,3-b]pyridin-8-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one (50 mg, 0.104 mmol, 1.0 equiv.) in acetic acid (5 mL) were added azidotrimethylsilane (2.5 mL) and trimethoxymethane (2.5 mL). The reaction mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum. The residue was purified by HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-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- tetrahydroindolizin- 5(1H)-one as a white solid.

LC/MS: mass calculated for C25H20CIFN8O3: 534.13, measured (ES, m/z): 535.10 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d*) δ 9.57 (s, 1H), 7.78 - 7.84 (m, 1H), 7.51 - 7.71 (m, 4H), 5.73 (s, 1H), 5.12 - 5.25 (m, 1H), 4.35 - 4.58

(m, 4H), 3.83 - 3.97 (m, 1H), 2.73 - 2.98 (m, 1H), 2.56 - 2.67 (m, 1H), 2.13 - 2.41 (m, 3H), 1.97 - 2.11 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-d*) δ -113.44.

Example 362 (3S,8aR ^w )-3-(5-(1 H-pyrrolo[2,3-b]pyridin^4-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

To a mixture of (3S)-3-(5-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-imidazol-2- yl)-7-(6-amino-3-chloro-2-fluorophenyl)-2,3,8,8a-tetrahydroi ndolizin-5(1H)-one (90 mg, 0.194 mmol, 1.0 equiv.) in acetic acid (5 mL) were added azidotrimethylsilane (2.5 mL) followed by trimethoxymethane (2.5 mL). The reaction mixture was stirred at 50 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0-15%) to yield racemic product, which was further purified by chiral HPLC with (Hex:DCM=3:1)(0.1%DEA):EtOH=70:30 to yield (3S,8a*R)-3-(5-(1 H- pyrrolo[2,3-b]pyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloiO-2- fluoro-6-(1H-tetrazol- 1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid and

(3S,8a*S)-3-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-imidazo l-2-yl)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS calculated for C25H19CIFN9O: 515.15, measured 516.15 (MH) ⁺ . ¹ H NMR (400 MHz, Methanol-d4) 69.56 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.74 -

7.84 (m, 1H), 7.61 (s, 1H), 7.53 (dd, J = 8.7, 1.6 Hz, 1H), 7.36 - 7.48 (m, 2H),

6.85 (d, J = 3.6 Hz, 1H), 5.72 (d, J = 2.8 Hz, 1H), 5.16 - 5.22 (m, 1H), 3.83 - 3.95 (m, 1H), 2.87 - 3.03 (m, 1H), 2.56 - 2.66 (m, 1H), 2.18 - 2.38 (m, 2H), 2.03 - 2.16 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-d4) 6 -113.29. Example 363 (3S)-3-(5-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7 - (3-chloro-2-fluoro-6-(1H-pyrazol-5-yl)phenyl)-2,3,8,8a-tetra hydroindolizin-

5(1H)-one

Step 1: Ethyl (3S)-7-(6-Bromo-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a mixture of ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1.0 g, 2.83 mmol, 1.0 equiv.) and CuBr2 (633 mg, 2.83 mmol, 1.0 equiv.) in ACN (15 mL) was added at 0 °C tert-butyl nitrite (438 mg, 4.24 mmol, 1.5 equiv.). The resulting mixture was maintained under nitrogen and stirred at room temperature for 1 h. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-55% ethyl acetate/petroleum ether) to yield the ethyl (3S)-7-(6-bromo-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for Ci7HieBrCIFN0 ₃ , measured: 416.15 [M+H] ⁺ , 418.15 [M+H+2]*. Step 2: (3S)-7-(6-Bromo-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid

To a solution of ethyl (3S)-7-(6-bromo-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate(490 mg, 1.17 mmol, 1.0 equiv.) in THF/H2O (3:1, 8 mL) was added UOH*H ₂ 0 (99 mg, 2.35 mmol, 2.0 equiv. ). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated and adjusted pH to 2.0-3.0 with 1N HCI. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield the (3S)-7-(6-bromo-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid as a yellow solid. LC/MS: mass calculated for CisH^BrCIFNOa: 386.97, measured: 388.10 [M+H]÷, 390.10 [Μ+Η+2Γ.

Step 3: 2-(6-Amino-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7-(6-bromo-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate To a solution of (3S)-7-(6-bromo-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (560 mg, 1.44 mmol, 1.0 equiv.) in DMF (8 mL) was added K2CO3 (199 mg, 1.44 mmol, 1.0 equiv), the mixture was stirred at room temperature for 20 min. 1-(6-Amino-2-fluoropyridin- 3-yl)-2-bromoethan-1-one (504 mg, 2.16 mmol, 1.5 equiv.) was then added. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 x 100 mL). The organic layers were wash with water and brine, combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl DCM/MeOH) to yield the 2-(6-amino- 2-fluoropyridin-3-yl)-2-oxoethyl (3S)-7-(6-bromo-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid. LC/MS: mass calculated for C22Hi7BrCIF2N ₃ 04: 539.01 , measured: 540.00 [M+H] ⁺ , 542.00 [M+H+2]*.

Step 4: (3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7 -(6-bromo3- chloro-2-fluorophenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-on e

To a solution of 2-(6-amino-2-fluoropyridin-3-yl)-2-oxoethyl (3S)-6-(6- bromo-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate (810 mg, 1.49 mmol, 1.0 equiv.) in toluene/AcOH (10:1, 22 mL) was added NH4OAC (1.2 g, 15.56 mmol, 10.0 equiv.). The resulting mixture was maintained under nitrogen and stirred at 110 °C for 1 h. The reaction was concentrated, and the residue was purified by silica gel chromatography (0- 100% ethyl acetate/petroleum ether) to yield the (3S)-3-(4-(6-amino-2- fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(6-bromo-3-chloro-2- fluorophenyl)- 2,3,8, 8a-tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for C22Hi7BrCIF ₂ N ₅ 0: 519.03, measured: 520.00 [M+H]÷, 521.95 [Μ+Η+2Γ. Step 5: (3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7 -(3-chloro-2- fluoro-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pheny l)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-3-(4-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(6-bromo-3-chloro-2-fluorophenyl)-2,3,8,8a-tetrahydroi ndolizin-5(1H)-one (100 mg, 0.19 mmol, 1.0 equiv..) in 1,4-dioxane/H20 (4:1, 5 mL) were added 1-

(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-d ioxaborolan-2-yl)-1H- pyrazole (267 mg, 0.96 mmol, 5.0 equiv.. ), Cs ₂ C>3 (125 mg, 0.38 mmol, 2.0 equiv.), and Pd(PPh3)4 (22 mg, 0.01 mmol, 0.1 equiv..). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-20% ethyl acetate/petroleum ether) to yield the (3S)-3-(5-(6-amino-2-fluoropyridin-3- yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 -(tetrahydro-2H-pyran-2-yl)-1 H- pyrazol-4-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C30H28CIF2N7O2: 591.20, measured: 592.15 [Μ+ΗΓ.

Step 6: (3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7 -(3-chloro-2- fluoro-6-(1H-pyrazol-5-yl)phenyl)-2,3,8,8a-tetrahydroindoliz in-5(1H)-one

To a solution of (3S)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-4-yl)phenyl)- 2,3,8, 8a-tetrahydroindolizin-5(1H)-one (100 mg, 0.16 mmol, 1.0 equiv.) in DCM (5 ml_) at 0 °C was added TFA (1 ml_) . The resulting mixture was stirred at room temperature for 3 h. The reaction was concentrated and purified by reverse phase chromatography on C18 column (0-70% ACN/Water- 0.05%NH4HC03) to yield the (3S)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1 H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-pyrazol-4-yl)pheny l)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25H20CIF2N7O: 507.14, measured: 508.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) δ 13.09 (s, 1H), 12.00 (br, 1H), 7.99 (t, J = 9.3 Hz, 1 H), 7.75 (s, 1 H), 7.64 (t, J = 7.9 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H),

7.13 (s, 1H), 6.56 (s, 1H), 6.38 (dd, J = 8.2, 2.1 Hz, 1H), 6.32-6.35 (m, 2H),

5.75 (s, 1H), 5.08 (d, J = 8.6 Hz, 1H), 3.96-4.00 (m, 1H), 2.67-2.80 (m, 1H), 2.36-2.46 (m, 1H), 2.11-2.23 (m, 1H), 1.92-2.11 (m, 3H).

¹⁹ F NMR (376 MHz, DMSO-de) δ -70.51, -73.44, -116.74. Example 364 (3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7- (3-chloro-2-fluoro-6-(1H-imidazol-5-yl)phenyl)-2,3,8,8a-tetr ahydroindolizin-

5(1H)-one

Step 1 : (3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2- fluoro-6-(1-trityl-1 H-imidazol-5-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one To a solution of (3S)-3-(4-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(6-bromo-3-chloro-2-fluorophenyl)-2,3,8,8a-tetrahydroi ndolizin-5(1H)-one (100 mg, 0.19 mmol, 1.0 equiv.) in 1,4-dioxane/H20 (4:1, 5 mL) were added (1- trityl-1H-imidazol-5-yl)boronic acid (340 mg, 0.96 mmol, 5.0 equiv.), Cs203 (125 mg, 0.38 mmol, 2.0 equiv.), and Pd(PPh3)4 (22 mg, 0.01 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h. After cooling to room temperature, the reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0- 15% DCM/MeOH) to yield the (3S)-3-(4-(6-amino-2-fluoropyridin-3-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1-trityl-1H-imidazol- 5-yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as an off-white solid. LC/MS: mass calculated for C44H34CIF2N7O: 749.25, measured: 750.25 [M+H] ⁺ . Step 2: (3S)-3-(4-(6-Amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7 -(3-chloro-2- fluoro-6-(1H-imidazol-5-yl)phenyl)-2,3,8,8a-tetrahydroindoli zin-5(1H)-one

To a solution of (3S)-3-(4-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1-trityl-1H-imidazol-5-yl)phenyl )-2,3,8,8a- tetrahydroindolizin-5(1H)-one (120 mg, 0.16 mmol, 1.0 equiv.) in DCM (5 mL) at 0 °C was added TFA (0.1 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction was concentrated and purified by reverse phase chromatography on C18 column (0-80% ACN/Water-0.05%NH4HC03) to yield the (3S)-3-(4-(6-amino-2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7-(3-chloro- 2-fluoro-6-(1 H-imidazol-5-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C25H20CIF2N7O: 507.14, measured: 508.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-de) 6 12.35 (br, 1H), 7.99 (t, J = 9.3 Hz, 1H), 7.79 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.63-7.55 (m, 1H), 7.48 (s, 1H), 7.15 (s, 1H), 6.38 (dd, J = 8.3, 2.1 Hz, 1H), 6.33-6.36 (m, 2H), 5.78 (d, J = 2.6 Hz, 1H), 5.09 (d, J = 8.8 Hz, 1H), 3.97-4.10 (m, 1H), 2.72-2.85 (m, 1H), 2.41-2.50 (m,

1H), 2.13-2.28 (m, 1H), 1.88-2.13 (m, 3H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 - 70.45, -73.43, -117.13. Example 365 (3S)-3-(5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-imidazol-2-yl)- 7-(3-chloiO-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol -1-yl)phenyl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one Step 1. Ethyl (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-cartx)xylate

To a solution of ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1 g, 2.835 mmol, 1.0 equiv.) in acetonitrile (15 mL) was added azidotrimethylsilane (0.490 g, 4.252 mmol, 1.5 equiv.), followed by the addition of tert-butyl nitrite (0.438 g, 4.252 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with EA/PE (0%-45%) to yield ethyl (3S)-7-(6-azido- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate as a light yellow solid. LC/MS: mass calculated, for Ci7HieCIFN403: 378.09, measured: 379.20 [M+H]*.

Step 2. ethyl (3S)-7-(3-chloro-2-fluoro6-(4-(trifluoromethyl)-1H-1,2,3-tri azol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate

To a solution of ethyl (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1 g, 2.640 mmol, 1.0 equiv) and 4,4,4-trifluorobut-2-ynoic acid (1.822 g, 13.200 mmol, 5.0 equiv) in acetonitrile (15 mL) was added cuprous oxide (0.151 g, 1.056 mmol, 0.4 equiv). The reaction mixture was stirred at 80 °C for 2 h under N2. The solid was filtered out, and the resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography on EA/PE (0%-70%) to yield ethyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazoM- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate as a light yellow solid. LC/MS: mass calculated, for C20H17CIF4N4O3: 472.09, measured: 473.10 [M+H]*.

Step 3. (3R)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-tr iazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbalde hyde

To a solution of ethyl (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-hexahydroindol izine-3-carboxylate (1.1 g, 2.326 mmol, 1.0 equiv) in dichloromethane (20 mL) was added diisobutylaluminium hydride (4.653 mL, 1 M in DCM, 4.653 mmol, 3.0 equiv) in batches at -78 °C under N2. The reaction mixture was stirred for 2 h, quenched with potassium sodium tartrate solution, and the mixture was extracted with EA. The combined extracts were dried over anhydrous Na2S04. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with MeOH/DCM (0%-55%) to yield (3R)-7-(3-chloro-2-fluoro- 6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carbaldehyde as a light yellow solid. LC/MS: mass calculated, for C18H13CIF4N4O2: 428.07, measured: 429.05 [M+H]*.

Step 4. (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-3-(1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin -5(1H)-one

To a solution of (3R)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine- 3-carbaldehyde

(0.64 g, 1.493 mmol, 1.0 equiv.) in methanol (10 mL) and ammonium hydroxide (10 mL) was added glyoxal (2.166 g, 14.926 mmol, 10.0 equiv., 40% in water) in portions. The mixture was stirred at room temperature for 48 h. The resulting mixture was concentrated, then EA was added, washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0- 6%) to yield (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-tr iazol-1- yl)phenyl)-3-(1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated, for C20H15CIF4N6O: 466.09, measured: 467.00 [M+H]*.

Step 5. (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-3-(5-iodo-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroin dolizin-5(1H)-one To a solution of (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1,2,3- triazol-1 -yl)phenyl)-3-(1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (250 mg, 0.536 mmol, 1.0 equiv.) in DCM (10 mL) was added N- iodosuccinimide (240.977 mg, 1.071 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 10 min. Water was added, the mixture was extracted with EA. The combined extracts were washed with water, dried over anhydrous Na2SO< and concentrated. EtOH (10 mL), H2O (10 mL) and sodium sulfite (1.35 g, 10.711 mmol, 20.0 equiv.) was added to residue. The mixture was stirred overnight at 95 °C, then cooled to room temperature. Water was added, the mixture was extracted with EA. The combined extracts were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0-4%) to yield (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H- 1 ,2,3-triazol-1-yl)phenyl)-3-(5-iodo-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as an off-white solid. LC/MS: mass calculated, for

C ₂ oHi4CIF4lNeO: 591.99, measured: 592.95 [M+H]*.

Step 6. (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-3-(5-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyr rolo[2,3-d]pyrimidin- 5-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a mixture of (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl)phenyl)-3-(5-iodo-1H-imidazol-2-yl)-2,3,8,8a-te trahydroindolizin- 5(1H)-one (100 mg, 0.169 mmol, 1.0 equiv.) and 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-p yrrolo[2,3- djpyrimidine (316.632 mg, 0.844 mmol, 5.0 equiv.) in 1,4-dioxane (10 mL) and water (1 mL) was added potassium carbonate (69.952 mg, 0.506 mmol, 3.0 equiv.) and 1,T-bis (di-t-butylphosphino)ferrocene palladium dichloride (10.996 mg, 0.017 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 2 h. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EA. The combined extracts were dried over anhydrous N32S04 and concentrated. The residue was purified by flash column chromatography on silica gel with MeOH/DCM (0-5%) to yield (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H- 1,2,3-triazol-1-yl)phenyl)-3-(5-(7-((2-(trimethylsilyl)ethox y)methyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1H-imidazol-2-yl)-2,3,8,8a-tet rahydroindolizin- 5(1H)-one as a brown solid. LC/MS: mass calculated, for C32H32CIF4Ng02Si: 713.21, measured: 714.15 [M+H]*. Step 7. (3S)-3-(5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-imidazol-2-yl )-7-(3- chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl )phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

A solution of (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H- 1,2,3- triazol-1-yl)phenyl)-3-(5-(7-((2-(trimethylsilyl)ethoxy)meth yl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (110 mg, 0.154 mmol, 1.0 equiv.) in dichloromethane (6 ml_) and trifluoroacetic acid (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. To the resulting residue in methanol (6 mL) was added ammonia solution (1 mL, 7.0 M in methanol) and the mixture stirred at room temperature for 10 min. The resulting mixture was extracted with EA two times. The combined extracts were dried over anhydrous N32S04, then concentrated. The residue was purified by reverse phase chromatography with CH3CNZwater (5%-45%) to yield (3S)-3-(5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H- imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a grey solid.

¹ H NMR (400 MHz, Methanol-d4) d 9.23 (s, 1H), 9.00 (d, J = 1.0 Hz,

1H), 8.76 (s, 1H), 7.74 - 7.83 (m, 2H), 7.54 (dd, J = 8.6, 1.6 Hz, 1H), 7.37 (s, 1H), 5.71 (d, J = 2.8 Hz, 1H), 5.18 (d, J = 9.0 Hz, 1H), 3.82 - 3.99 (m, 1H), 2.92 - 3.06 (m, 1H), 2.54 - 2.72 (m, 1H), 2.19 - 2.45 (m, 3H), 2.01 - 2.18 (m, 1H). ¹⁹ F NMR (376 MHz, Methanol-d4) d - 62.60, -113.48, -114.01 .

Example 366 (3S)-3-(5-(5-chloro-1H-pyrazol-4-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-

5(1H)-one

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(5-chloro- 1 H-pyrazol-4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (40 mg) in acetic acid (1 mL) was added azidotrimethylsilane (0.5 mL) and trimethoxymethane (0.5 mL). The reaction mixture was stirred overnight at 50 °C. The resulting mixture was then concentrated under vacuum. The residue was purified by HPLC with Mobile Phase A: Water (0.05%TFA), Mobile Phase B: MeOH to yield (3S)-3-(5-(5-chloro-1H-pyrazol-4-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one as a white solid.

¹ H NMR (400 MHz, Methanol-d4) d 9.58 (s, 1H), 8.08 (s, 1H), 7.79 - 7.89 (m, 1H), 7.52 - 7.67 (m, 2H), 5.75 (d, J = 2.8 Hz, 1H), 5.26 (d, J = 10.1 Hz, 1H), 3.87 - 4.02 (m, 1H), 2.88 - 3.03 (m, 1H), 2.65 - 2.76 (m, 1H), 2.42 - 2.59 (m,

1H), 2.28 - 2.38 (m, 1H), 2.18 - 2.26 (m, 1H), 1.89 - 2.05 (m, 1H). ¹⁸ F NMR (376 MHz, Methanol-d4) -113.58.

Example 367 N-(4-(2-((3S,8aR)-7-(3-chloiO-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)methanesulfonamide To a mixture of N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fl uoropyridin-2- yl)methanesulfonamide (77 mg, 0.14 mmol, 1.0 equiv) in AcOH (3 mL) were added trimethoxymethane (153 mg, 1.44 mmol, 10 equiv) and TMSNa (166 mg, 1.44 mmol, 10.0 eq.). The mixture was then stirred at room temperature overnight. The mixture was concentrated. The residue was applied onto a C18 column (mobile phase: CHaCN (0.1% TFA) & H2O (0.1% TFA)) & Chiral-HPLC ((R,R) WHELK-01, 4.6*50mm, 3.5um;; Mobile Phase A:MtBE ( 0.1%DEA): Mobile phase B: EtOH=70:30 , Flow rate:1 mUmin; to yield N-(4-(2-((3S,8aR)- 7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 - yl)methanesulfonamide as a white solid.

LC/MS: mass calculated for C24H2oCIF2Ne03S:587.11, measured: 588.10 [M+H] ⁺ . ¹ H NMR (400 MHz, DMS0-d6) d 12.30 (s, 1H), 10.55 (s, 1H), 9.84 (s,

1 H), 8.12 (s, 1 H), 7.93-8.01 (m, 1H), 7.71 (dd, J = 8.7, 1.5 Hz, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 5.70 (d, J = 2.7 Hz, 1H), 5.04 (d, J = 8.7 Hz, 1H), 3.69-3.77

(m, 1H), 3.39 (s, 3H), 2.67-2.75 (m, 1H), 2.49-2.56 (m, 1H), 2.16-2.23 (m, 1H), 2.06-2.12 (m, 1H), 1.93-1.99 (m, 2H). ¹⁹ F NMR (376 MHz, DMS0-d6) d-112.85, -135.33.

Example 368 (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(2- fluoro-6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8, 8a- tetrahydroindolizin-5(1 H)-one

Step 1 : (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(4-(3-nitropyridi n-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of 6-fluoiO-5-iodopyridin-2-amine (4 g, 16.80 mmol) in tetrahydrofuran (50 mL) was added NaH (806.6 mg, 20.168 mmol) at 0 °C, after 30 min was added CH3I (3.578 g, 25.21 mmol). The resulting mixture was stirred at 0°C for 2 h. The residue was purified by silica gel chromatography (0- 50% ethyl acetate/petroleum ether) to yield (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-3-(4-(3-nitropyridin-4-yl)-1H-imidazol-2-yl)-2 , 3,8,8a- tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for CeHeFINa: 251.96, measured: 253.03 [M+HJ\

Step 2: 1 -(2-fluoro-6-(methylamino)pyridin-3-yl)ethan- 1 -one

To a solution of the 6-fluoro-5-iodopyridin-2-amine (1.5 g, 5.95 mmol) in 1,4-dioxane (30 mL) was added tributyl(1-ethoxyvinyl)stannane (4.3 g, 11.903 mmol), tetrakis(triphenylphosphine) palladium(O) (687.7 mg, 0.6 mmol). The resulting mixture was stirred at 100 °C overnight. The residue was purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to yield 1-(2- fluoro-6-(methylamino)pyridin-3-yl)ethan-1-one as an yellow solid. LC/MS: mass calculated for CeHeFtoO: 168.07, measured: 169.1 [M+H] ⁺ .

Step 3: 1-(2-fluoro-6-(methylamino)pyridin-3-yl)ethan-1-one

To a solution of the 1-(2-fiuoro-6-(methylamino)pyridin-3-yl)ethan-1-one (800 mg, 4.757 mmol) in glacial acetic acid (20 mL) and HBr (2 mL) was added pyridinium tribromide (380.1 mg, 2.4 mmol). The resulting mixture was stirred at room temperature for 2 h. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield 1-(2-fluoro-6- (methylamino)pyridin-3-yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for CeHeBrFtoO: 245.98, measured: 247.1 [M+H] ⁺ . Step 4: 2-(2-fluoro-6-(methylamino)pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2 _l 3,5,8,8a-hexahydroindolizine-3-carboxylate To a solution of the methyl 1-(2-fluoro-6-(methylamino)pyridin-3-yl)ethan- 1-one (152.2 mg, 0.616 mmol) in N,N-dimethylformamide (10 mL) were added cesium carbonate (120.4 mg, 0.370 mmol), and (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ,2,3,5, 8, 8a-hexahydroindolizine-3- carboxylic acid (200 mg, 0.616 mmol). The resulting mixture was stirred at 30 °C for 2 h. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 30% methanol/dichloromethane)) to yield 2-(2-fluoro-6-(methylamino)pyridin-3- yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as an yellow solid. LC/MS: mass calculated for C23H21CIF2N4O4: 490.12, measured: 491.1 [M+H]*. Step 5: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2-fluoro-6- (methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrah ydroindolizin-5(1H)- one

To a solution of the (3S)-2-(6-(methoxycarbonylamino)pyridin-3-yl)-2- oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (300 mg, 0.661 mmol) in toluene (10 mL) was added glacial acetic acid (1 mL), ammonium acetate (706.6 mg, 9.2 mmol). The resulting mixture was stirred at 100 °C for 2h. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% methanol/dichloromethane)) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)- 3-(5-(2-fluoro-6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl )-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as an yellow solid. LC/MS: mass calculated for C23H2iCIF ₂ NeO: 471.14, measured: 472.3[M+H] ⁺ . Step 6: (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-( 2-fluoro-6- (methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrah ydroindolizin-5(1H)- one

To a solution of the (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2- fluoro-6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8, 8a- tetrahydroindolizin-5(1H)-one (200 mg, 0.425 mmol) in gladal acetic acid (5 ml_) were added trimethoxymethane (1 ml_), and azidotrimethylsilane (1 mL). The resulting mixture stirred at 60 °C for 2 h and concentrated. The resulting residue was added to 2N HCI (aq.)/THF (1:1) (4 mL). The mixture was stirred at 50 °C for 0.5 h. The pH value was 7.0 used NaHCOsiaq.), the resulting mixture concentrated. The residue was purified by silica gel column then purified by Prep-HPLC to yield the (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(2-fluoro-6-(methylamino)pyridin-3-yl)-1H-imidazol-2-yl)- 2,3,8,8a- tetrahydroindolizin-5(1H)-one as an white solid.

LC/MS: mass calculated for C24H20CIF2N9O: 523.14, measured: 524.15 [M+H]÷. ¹ H NMR (300 MHz, DMSO-de) 6 11.92 (s, 1H), 9.84 (s, 1H), 7.91 - 8.11

(m, 2H), 7.70 (dd, J = 8.7, 1.5 Hz, 1H), 6.90 - 7.09 (m, 1H), 6.81 (d, J = 5.1 Hz, 1H), 6.40 (dd, J = 8.3, 2.2 Hz, 1H), 5.69 (d, J = 2.5 Hz, 1H), 4.99 (t, J = 7.2 Hz, 1H), 4.04 - 4.15 (m, 1H), 2.76 (d, J = 4.8 Hz, 3H), 2.19 - 2.51 (m, 4H), 1.96 - 2.11 (m, 1H), 1.60 - 1.78 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) δ -70.36, - 113.07, -218.48

Example 369 N-(2-(2-((3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)phenyl)cyclopropanecarboxamide

To a solution of the (3S)-3-(4-(2-aminophenyl)- 1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1H)- one (150 mg, 0.306 mmol) in pyridine (5 mL) were added cyclopropanecarboxylic add (131.522 mg, 1.528 mmol), and EDCI (94.867 mg, 0.611 mmol). The resulting mixture was stirred room temperature overnight. The residue was purified by HPLC and SFC to yield N-(2-(2-((3S,8aS)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)phenyl)cyclopropanecarboxamide as a white solid.

LC/MS: mass calculated for C28H24CIFN8O2: 558.17, measured: 559.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMS0-d6) d 12.56 (m, 2H), 9.83 (s, 1H), 8.38 (d, 1H), 7.92-8.04 (m, 1H), 7.63-7.73 (m, 3H), 6.97-7.25 (m, 2H), 5.71 (d, J = 2.5 Hz, 1H), 5.07 (t, J = 7.4 Hz, 1H), 4.06-4.16 (m, 1H), 2.44-2.62 (m, 2H), 2.20- 2.43 (m, 2H), 1.95-2.11 (m, 1H), 1.54-1.85 (m, 2H), 0.78-0.88 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO) d -73.54, -74.98, -113.30.

Example 370 N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 5-OXO-1, 2,3,5, 8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)pyridin-3- yl)cyclopropanecarboxamide

Step 1: 3-bromo-N-methoxy-N-methylnicotinamide

To a solution of 3-bromoisonicotinic acid (20.3 g, 100.493 mmol, 1.0 eq.) in DCM (250 ml_) were added HOBt (14.937 g, 110.542 mmol, 1.1 eq.), N.O- dimethylhydroxylamine hydrochloride (14.704 g, 150.739 mmol, 1.5 eq.), EDCI (21.191 g, 110.542 mmol, 1.1 eq.), and TEA (40.675 g, 401.97 mmol, 4.0 eq.). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to yield the 3-bromo-N- methoxy-N-methylnicotinamide as a yellow oil. LC/MS: mass calculated for CeHeBrNaCb: 243.98, measured: 244.90, 246.90 [M+H, M+H+2]*.

Step 2: 1 -(3-bromopyridin-4-yl)ethan-1 -one

To a solution of 3-bromo-N-methoxy-N-methylisonicotinamide (16.6 g, 67.73 mmol, 1.0 eq.) in THF (200 mL) was added methylmagnesium bromide (135.5 mL, 135.5 mmol, 2.0 eq.) at 0 °C under an atmosphere of nitrogen. The reaction mixture was stirred at 0°C for 4 h. The reaction was quenched with NhUCI solution (50 mL) and extracted with EA twice (100 mL x2), dried over N32S04, and concentrated to dryness. The residue was purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to yield the 1-(3- bromopyridin-4-yl)ethan-1-one as a yellow oil. LC/MS: mass calculated for CyHeBrNO: 198.96, measured: 199.90, 201.90 [M+H, M+H+2]*.

Step 3: 2-bromo-1-(3-bromopyridin-4-yl)ethan-1-one

To a solution of 1-(3-bromopyridin-4-yl)ethan-1-one (2.5 g, 12.498 mmol, 1.0 eq.) in acetic acid (30 mL) were added saturated HBr solution in acetic add (33%, 3 mL), and bromine (1.798 g, 11.248 mmol, 0.9 eq.). The mixture was stirred at room temperature for 2 h. The reaction was concentrated to yield 2- bromo-1-(3-bromopyridin-4-yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for C7H ₅ Br ₂ NO: 276.87, measured 277.85, 279.85 [M+H, M+H+2] ⁺ . Step 4: 2-(3-bromopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate

To a solution of (3S)-7-(3-chloro2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (502.3 mg, 1.547 mmol, 1.0 eq.) in DMF (10 ml_) were added 2-bromo-1-(3-bromopyridin-4-yl)ethan-1- one (690.3 mg, 2.4 mmol, 1.6 eq.), and cesium carbonate (503.9 mg, 1.5 mmol, 0.7 eq.). The mixture was stirred at 35°C for 2 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% PE/EA) to yield the 2-(3-bromopyridin-4-yl)-2- oxoethyl (3S)-7-(6-amino-3-chloro-2-fiuorophenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for CjaHieBrCIFNaCU: 521.02, measured 521.95, 523.95 [M+H, Μ+Η+2Γ.

Step 5: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(4-(3-bromopyridi n-4-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a solution of 2-(3-bromopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate (612.4 mg, 1.171 mmol, 1.0 eq.) in toluene (10 mL) and acetic acid (1 mL) was added ammonium acetate (903 mg, 11.7 mmol, 10.0 eq.). The mixture was stirred at 110°C for 2 h. After cooling to room temperature, the reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% DCM/methanol) to yield the (3S)-7-(6-amino-3-chloro- 2-fluorophenyl)-3-(4-(3-bromopyridin-4-yl)-1H-imidazol-2-yl) -2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow oil. LC/MS: mass calculated for C22Hi ₈ BrCIFN ₅ 0: 501.04, measured: 502.10, 504.10 [M+H, M+H+2]*. Step 6: (3S)-3-(4-(3-bromopyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chlor o-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one acid To a solution of (3S)-7-(6-amino3-chloro-2-fluorophenyl)-3-(4-(3- bromopyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindo lizin-5(1H)-one (412.3 mg, 0.820 mmol, 1.0 eq.) in acetic acid (10 mL) were added azidotrimethylsilane (944.785 mg, 8.201 mmol, 10.0 eq.), and trimethoxymethane (870.2 mg, 8.201 mmol, 10.0 eq.). The reaction mixture was stirred at 65°C for 2 h. The reaction mixture was diluted with water and extracted with EA. The combined extracts were washed with water, dried over N32S04, filtered and purified by silica gel chromatography (0-10% DCM/methanol) to yield (3S)-3-(4-(3-bromopyridin-4-yl)-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1H)- one acid as a yellow oil. LC/MS: mass calculated for C23H19CIFN9O: 554.04, measured 555.00, 557.00 [M+H, M+H+2]*.

Step 7: (3S)-3-(4-(3-aminopyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-3-(4-(3-bromopyridin-4-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1 Hi- one (215.6 mg, 0.388 mmol, 1.0 eq.) in ethanol (4 mL) and H2O (1 mL), were added sodium azide (75.6 mg, 1.164 mmol, 3.0 eq.), sodium ascorbate (61.5 mg, 0.3 mmol, 0.8 eq.), (1R,2R)-N,N'-Dimethyl-1,2-cyclohexanediamine (33.1 mg, 0.233 mmol, 0.6 eq.), and copper sulfate pentahydrate (38.7 mg, 0.16 mmol, 0.4 eq.). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (3 x50 mL). The combined extracts were washed with water, dried over Na2S04, filtered and purified by silica gel chromatography (0-10% DCM/methanol) to yield (3S)-3-(4-(3-aminopyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chlor o-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C23H19CIFN90: 491.14, measured: 492.10 [M+H]*.

Step 8: N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)pyridin-3- yl)cyclopropanecarboxamide

To a solution of (3S)-3-(4-(3-aminopyridin-4-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1H)- one (75.8 mg, 0.154 mmol, 1.0 eq.) in pyridine (2 mL) were added cyclopropanecarboxylic acid (66.3 mg, 0.770 mmol, 5.0 eq.), and EDCI (59.1 mg, 0.308 mmol, 2.0 eq.). The reaction mixture was stirred at room temperature for 3 h. The reaction was diluted with water and extracted with EA. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and purified by pre-HPLC with MeCN/H ₂ 0 (0-30%) to yield N-(4-(2-((3S)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-4-yl)pyridin-3- yl)cyclopropanecarboxamide as a white solid.

LC/MS: mass calculated for C27H23CIFNe02: 559.16, measured: 560.15 [M+H]*. ¹ H NMR (300 MHz, DMSO-de) 6 12.51 (s, 1H), 12.10 (s, 1H), 9.83 (s, 1H), 9.46 (s, 1H), 8.17 - 8.25 (m, 1H), 7.88 - 8.04 (m, 2H), 7.67 -7.77 (m, 2H), 5.68 (s, 1H), 5.04 - 5.13 (m, 1H), 3.70 - 3.76 (m, 1H), 2.55 - 2.65 (m, 2H), 2.09- 2.29 (m, 3H), 1.72 - 2.02 (m, 1H), 1.66 - 1.72 (m, 1H), 0.79 - 0.91 (m, 4H). ¹⁸ F NMR (282 MHz, DMSO-d6) 6 -112.79, -113.11, -113.38.

Example 371 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5- (5-chloro-2-fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

N

Ϊ

Ί NH

^F Cl

■a Step 1: (3S)-7-(3-chloro2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(5 -chloro-2- fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroind olizin-5(1H)-one

To a solution of 2-(5-chloro-2-fluoropyridin-4-yl)-2-oxoethyl 2-(6-amino-3- chloro-2-fluorophenyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1, 2-a]pyrimidine-6- carboxylate (200 mg, 0.4 mmol, 1.0 eq) in toluene/HOAc (4:1) (5.0 mL) was added NhUOAc (370 mg, 4.8 mmol, 11.9 eq). The resulting mixture was stirred at 60 °C overnight. After cooling to room temperature, the reaction mixture was concentrated and purified with silica gel column to yield (3S)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(5-chloro-2-fluoropyridin-4-yl)-1 H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a light yellow solid. Step 2: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(5-chloro- 2-fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroi ndolizin-5(1H)-one (3S)-7-(6-Amino-3-chloro-2-fluorophenyl)-3-(5-(5-chloro-2-fl uoropyridin- 4-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (160 mg, 0.3 mmol, 1.0 eq.) was dissolved in HOAc (5.0 mL). Then trimethoxymethane (3.0 mL) and TMSN3 (3.0 mL) were added, and the mixture was stirred for 6 h at room temperature. The mixture was concentrated. The resulting residue was purified by Prep-HPLC & Chiral-HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-3-(5-(5-chloro-2-fluoropyridin-4-yl) -1 H-imidazol-2-yl)-

2,3,8, 8a-tetrahydroindolizin-5(1H)-one.

LC/MS: (ES, m/z): 529.05 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-de) 69.82 (s, 1H), 8.31 (s, 1H), 7.93 -8.01 (m, 2H), 7.67 - 7.75 (m, 2H), 5.67 (d, J = 2.8 Hz, 1H), 5.05 (d, J = 8.7 Hz, 1H), 3.67 - 3.80 (m, 1H), 2.69 - 2.82 (m, 2H), 2.07 - 2.26 (m, 2H), 1.89 - 2.05 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -72.71, -

74.16, -113.02.

Example 372 (3S,8aR)-3-(5-(2-aminopyridin-4-yl)-4-chloro-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

Step 1: N-(4-bromopyridin-2-yl)acetamide

To a solution of 4-bromopyridin-2-amine (3 g, 17.340 mmol, 1.0 equiv) in DCM (30 mL) were added AC2O (3.54 g, 34.680 mol, 2.0 equiv) and EtsN (3.51 g, 34.680 mmol, 2.0 equiv). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32SO4 and concentrated. The residue was purified by silica gel chromatography (0 - 50% EtOAc/petroleum ether) to yield N-(4-bromopyridin-2- yl)acetamide as a yellow solid.

Step 2: 2-(4-(1-ethoxyvinyl)pyridin-2-yl)propan-2-ol

Under an inert atmosphere of nitrogen, to a solution of N-(4- bromopyridin-2-yl)acetamide (500.0 mg, 2.325 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) were added tributyl(1-ethoxyvinyl)stannane (1.008 g, 2.790 mmol, 1.2 equiv) and Pd(PPh3)4 (268.7 mg, 0.233 mmol, 0.1 equiv). The reaction mixture was stirred for 8 h at 100 °C. The reaction was concentrated under vacuum to yield 2-(4-(1-ethoxyvinyl)pyridin-2-yl)propan-2-ol as a yellow oil. Step 3: N-(4-(2-bromoacetyl)pyridin-2-yl)acetamide

To a solution of methyl 6-chloro-5-(1-ethoxyvinyl)picolinate (400 mg, 1.939 mmol, 1.0 equiv) in THF (6 mL) with H2O (3 mL) at 0°C was added NBS (345.5 mg, 1.939 mmol, 1.0 equiv). The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched with brine, extracted with EA three times. The combined organic layers were concentrated under vacuum, then the residue was purified on flash chromatography by silica gel (EA/PE:0%- 3%) to yield N-(4-(2-bromoacetyl)pyridin-2-yl)acetamide as a yellow solid.

Step 4: 2-(2-acetamidopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (250 mg, 0.770 mmol, 1.0 equiv) in DMF (5 mL) were added N-(4-(2-bromoacetyl)pyridin-2-yl)acetamide (237.5 mg, 0.92 mmol, 1.2 equiv) and CS2CO3 (150.5 mg, 0.46 mmol, 0.6 equiv).The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0-30% MeOH/DCM) to yield 2-(2-acetamidopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate as a yellow oil.

Step 5: N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydiOindolizin-3-yl)-1H-imidazol-5-yl)pyridin-2-yl)aceta mide To a solution of 2-(2-acetamidopyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate (200 mg, 0.399 mmol, 1.0 equiv) in toluene (5.0 mL) with CHsCOOH (0.5 mL) was added NhUOAc (307.8 mg, 3.99 mmol, 10 equiv). The reaction mixture was stirred for 2 h at 110 °C. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over N32S04 and concentrated. The residue was purified by silica gel chromatography (0-30% MeOH/DCM) to yield N-(4-(2-((3S)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin -3-yl)-1H-imidazol- 5-yl)pyridin-2-yl)acetamide as a yellow oil.

Step 6: N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)pyrid in-2-yl)acetamide To a solution of N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)pyrid in-2-yl)acetamide (100 mg, 0.208 mmol, 1.0 equiv) in HOAc (3 mL) were added TMSNa (239.6 mg, 2.079 mmol, 10.0 equiv) and trimethoxymethane (220.6 mg, 2.08 mmol, 10.0 equiv). The reaction mixture was stirred overnight at room temperature, quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography (0-20% MeOH/DCM) to yield N-(4-(2- ((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)pyridin-2-yl)aceta mide as a yellow solid.

Step 7: N-(4-(4-chloro-2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazoM-yl)phenyl)- S-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)pyridin-2- yl)acetamide

To a mixture of N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)pyridin- 2-yl)acetamide (200 mg, 0.375 mmol, 1.0 equiv) in DMF (8 mL) was added NCS (50 mg, 0.374 mmol, 1.0 equiv) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography (0-20% MeOH/DCM) to yield N-(4-(4- chloro-2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-5-oxo- 1 _l 2 _l 3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)pyr idin-2-yl)acetamide as a yellow solid. MS (ESI): mass calculated for C25H20CI2FN9O2 567.11 m/z, measured 568.20[M+H]+.

Step 8: (3S)-3-(5-(2-aminopyridin-4-yl)-4-chloro-1 H-imidazol-2-yl)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one To a solution of N-(4-(4-chloro-2-((3S)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)pyridin-2-yl)acetamide (150 mg, 0.264 mmol, 1.0 equiv) in THF (2 ml_) was added 2N HCI (2 ml_). The reaction mixture was stirred for 2 h at 70 °C. The mixture was concentrated under vacuum and purified by C18 column (eluent: 5% to 50% (v/v) CHaCN and H ₂ 0 containing 0.05% NH4HCO3) to yield (3S)-3- (5-(2-aminopyridin-4-yl)-4-chloro-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid.MS (ESI): mass calculated for C23H18CI2FN90525.10 m/z, measured 526.20[M+H] ⁺ .

Step 9: (3S,8aR)-3-(5-(2-aminopyridin-4-yl)-4-chloro-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3, 8, 8a-tetrahydroindolizin-5(1 H)- one

(3S)-3-(5-(2-Aminopyridin-4-yl)-4-chloro-1H-imidazol-2-yl )-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1 H)-one (100 mg, 0.190 mmol) was purified by SFC to yield (3S,8aR)-3-(5-(2-aminopyridin-4- yl)-4-chloro1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-

2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid.

LC/MS: (ES, m/z): 526.20 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-de) δ

12.74 (s, 1H), 9.84 (s, 1H), 7.92 -8.03 (m, 2H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H),

6.74 - 6.84 (m, 2H), 6.03 (d, J = 4.5 Hz, 2H), 5.67 (d, J = 2.5 Hz, 1H), 4.96 (d, J = 8.4 Hz, 1 H), 3.64 - 3.76 (m, 1 H), 2.53 - 2.73 (m, 2H), 1.83 - 2.30 (m, 4H). ¹⁹ F

NMR (282 MHz, DMSO-de) 6 -112.832.

Example 3735-(2-(7-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol -1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)thiophene-2-carboxylic acid

Cl·

OH

N'X o

Step 1: 2-(5-(ethoxycarbonyl)thiophen-2-yl)-2-oxoethyl 7-(5-chloro-2-(4- (trifluoromethyl)-l H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

Into a 50-mL round-bottom flask, was placed 7-(5-chloro-2-(4- (trifluoromethyl)-l H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid (250 mg, 0.586mmol, 1.0 equiv.) and K2CO3 (121.2 mg, 0.879 mmol, 1.2 equiv.) in CHaCN (20 mL), and the mixture was stirred at room temperature for 0.5 hour. To the resulting mixture was then added ethyl 5-(2-bromoacetyl)thiophene-2-carboxylate (194.8 mg, 0.7 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 4 hours. The mixture was quenched by water, extracted with DCM. The organic layer was concentrated under vacuum, dried over N32S04, filtered, and evaporated to dryness. The residue was purified by silica gel with DCM/MeOH (20:1). The collected fractions were combined and concentrated under vacuum to yield 2- (5-(ethoxycarbonyl)thiophen-2-yl)-2-oxoethyl 7-(5-chloro-2-(4-(trifluoromethyl)- 1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3- carboxylate as a yellow solid. Mass spectrum (ESI, m/z): calculated for C ₂ 7H22CIF ₃ N40eS: 623.09 [M+H], measured: 623.00.

Step 2: ethyl 5-(2-(7-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-4- yl)thiophene-2-carboxylate

Into a 100-mL round-bottom flask, was placed 2-(5- (ethoxycarbonyl)thiophen-2-yl)-2-oxoethyl 7-(5-chloro-2-(4-(trifluoromethyl)-1H- 1,2,3-triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindol izine-3-carboxylate (170 mg, 0.273 mmol, 1.0 equiv.) and NH4OAC (210.2 mg, 2.7 mmol, 10.0 equiv.) in toluene (30 mL) and HOAc (3 mL) was added. The mixture was stirred at 100 °C for 5 hours. The mixture was quenched by water, extracted with DCM. The organic layer was concentrated under vacuum. The residue was purified by silica gel with DCM/MeOH (20:1). The collected fractions were combined and concentrated under vacuum to yield ethyl 5-(2-(7-(5-chloro-2-(4- (trifluoromethyl)-l H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiophene-2-carbox ylate as a yellow solid. Mass spectrum (ESI, m/z): calculated for CayhtaCIFaNeOaS: 603.11 [M+H], measured: 603.05. Step 3: 5-(2-(7-(5-chloro-2-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiophene-2- carboxylic acid hydrochloride

Into a 50-mL round-bottom flask, was placed ethyl 5-(2-(7-(5-chloro-2-(4- (trifluoromethyl)-l H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-4-yl)thiophene-2-carboxylate (160 mg,

0.26 mmol, 1.0 equiv.) in THF (15 mL) and H ₂ 0 (3 mL). NaOH (53.0mg 1.3mmol S.Oequiv.) was then added. The mixture was stirred at 50 °C for 2 days. The mixture was concentrated. The residue was purified by Prep-HPLC with the following conditions: Column, Sun Fire Prep C18, Sum, 19*100mm; mobile phase, Water of 0.05% HCI and CHsCN ( 60% CH3CN up to 95% in 10 min, up to 100% in 2 min, down to 60% in 1 min; Detector, 220 nm, 254 nm. to yield 5-(2-(7-(5-chloro-2-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-4-yl)thiop hene-2-carboxylic acid hydrochloride as a white solid.

¹ H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 7.79 (s, 1H), 7.73 - 7.83 (m, 4H), 7.60 (s, 1H), 5.63 (s, 1H), 5.16 (d, J = 9.6 Hz, 1H), 3.69 - 3.78 (m, 1H), 2.89 - 2.93 (m, 1H), 2.28 - 2.35 (m, 2H), 2.02 - 2.21 (m, 2H), 1.88 - 2.01 (m, 1H). ¹⁸ F-NMR (376 MHz, DMSO-d6) δ (ppm): -59.49. Mass spectrum (ESI, m/z): calculated for C25H18CIF3N6O3S: 575.1 [M+H], measured: 575.05. Example 3747-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(7- methyl-5H-cyclopenta[b]pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8 ,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 4-chloro-5,6-dihydro-7H-cydopenta[b]pyridin-7-one

To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (4.0 g, 23.58 mmol, 1.0 equiv.) in DCM (40 mL) was added Mn(½ (26.4 g, 303.67 mmol, 12.876 equiv.). The mixture was stirred at room temperature for 16 h. The mixture was added water and the aqueous layer was extracted with DCM twice. The organic phases were combined, washed with water, concentrated to yield 4-chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one as a yellow solid.

Step 2: 4-chloro-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

To a solution of 4-chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (300 mg, 1.79 mmol, 1.0 equiv.) in THF (10 mL) was added MeBrMg (6 mL, 1.0 M) dropwise at 0 °C and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water and the mixture was extracted with EtOAc twice. The organic phases were combined, washed with H2O, concentrated to yield 4-chloro-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol as a yellow solid.

Step 3: 4-(1 -ethoxyvinyl)-7-methyl-6,7-dihydro-5H-cydopenta[b]pyridin-7- ol

To a solution of 4-chloro-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7- ol (600 mg, 3.27 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) were added tributyl(1-ethoxyvinyl)stannane (2.0 mL), X-Phos(156 mg, 0.33 mmol, 1.8 equiv.) and X-Phos-Pd-G3 (277 mg ,0.33 mmol, 0.1 equiv.). The mixture was stirred at 80 °C for 1 h under N2. The reaction was quenched with H2O and the aqueous layer was extracted with EtOAc. The organic phases were combined, washed with H2O, concentrated, and purified by silica gel column chromatography (120g, EA/PE: 1/25) to yield 4-(1-ethoxyvinyl)-7-methyl-6,7- dihydro-5H-cydopenta[b]pyridin-7-ol as a yellow solid.

Step 4: 2-bromo-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cydopenta[b]pyr idin-4- yl)ethan-1-one

To a solution of 4-(1-ethoxyvinyl)-7-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-7-ol (700 mg, 3.19 mmol, 1.0 equiv.) in THF (10 mL) and H2O (4 mL) was added NBS (512 mg, 2.89 mmol, 0.9 equiv.). The mixture was stirred at room temperature 1h. The reaction was quenched with H2O and the aqueous layer was extracted with EtOAc twice. The organic phases were combined, washed with H2O and concentrated to yield 2-bromo-1-(7-hydroxy-7- methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)ethan-1-one as a yellow solid. Step 5: 2-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)-2- oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of 2-bromo-1-(7-hydroxy-7-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)ethan-1-one (858 mg, 3.176 mmol, 2.0 equiv.) in CHaCN (10 mL) were added 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (516 mg, 1.589 mmol, 1.0 equiv.) and K2CO3 ( 220 mg, 1.592 mmol). The mixture was stirred at room temperature 1 h. The reaction was quenched with H2O and the aqueous layer was extracted with EtOAc twice. The organic phases were combined, washed with H2O, concentrated, and purified by silica gel column chromatography (120g, PE/EA: 1/30) to yield 2-(7-hydroxy-7-methyl-6,7-dihydro5H- cyclopenta[b]pyridin-4-yl)-2-oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a yellow solid.

Step 6: (3S)-7-(6-amino3-chloro-2-fluorophenyl)-3-(5-(7-hydroxy-7-me thyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl)-1H-imidazol-2-yl)-2,3, 8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of 2-(7-hydroxy-7-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)-2-oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (800 mg, 1.557 mmol, 1.0 equiv.) in toluene (2 mL) were added NhUOAc (1.2 g, 15.57 mmol, 10.0 equiv.) and AcOH (0.3 mL). The mixture was stirred at 110°C for 2h. The reaction was quenched with H2O and the aqueous layer was extracted with EtOAc twice. The organic phases were combined, washed with H2O, concentrated, and purified by silica gel column chromatography (120g, MeOH/DCM: 1/25) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(7-hydiOxy-7-m ethyl-6, 7-dihydro- 5H-cyclopenta[b]pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tet rahydroindolizin- 5(1H)-one as a yellow solid.

Step 7: 4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 5-oxo-

1 ,2,3,5, 8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-7-methyl-6, 7-dihydro- 5H-cyclopenta[b]pyridin-7-yl acetate

To a solution of (4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)methyl acetate (530 mg, 1.07 mmol, 1.0 equiv.) in HOAc ( 5 ml_) was added trimethoxymethane (2.4 mL,20 equiv.) followed by addition of TMSlsb (2.8 mL, 20 equiv). The resulting mixture was stirred at 60 °C for 1 h, then concentrated under reduced pressure and the residue was purified by C18 reversal column chromatography (eluent: 5% to 70% (v/v) ChbCN and H2O with 0.05% NH4HCO3) to yield 4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-7- methyl-6, 7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate as a yellow solid.

Step 8: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(7-methyl-5H- cyclopenta[b]pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrah ydroindolizin-5(1H)- one

A solution of 4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-7-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (550 mg, 0.93 mmol, 1 equiv.) in THF (6 mL) and 4N HCI (2 mL) was stirred at 50 °C for 1 h. The mixture was concentrated and purified by C18 gel chromatography (eluent: 5% to 70% (v/v) CHsCN and H2O with 0.05% NH4HCO3) to yield (3S)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-3-(5-(7-methyl-5H-cydopenta[b]pyridin- 4-yl)-1H-imidazol- 2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a white solid.

LC/MS: mass calculated for C27H22CIFN8O: 528.16, measured: 529.15 [Μ+ΗΓ. ¹ H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 9.84 (s, 1H), 8.39 (d, J = 5.3 Hz, 1H), 7.97 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 5.3 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 5.68 (d, J = 2.7 Hz, 1H), 5.03 (d, J = 8.4 Hz, 1H), 3.69-3.78 (m, 1H), 3.47-3.55 (m, 2H), 2.67-2.79 (m, 1H), 2.53-2.59 (m, 1H), 2.01-2.22 (m, 6H), 1.94-1.98 (m, 1H). ¹⁹ FNMR (376MHz, DMSO-d6) δ -112.95.

Example 376 (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1 H-imidazol-2- yl)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)hexahydroindolizin-5(1H)-one

To a solution of (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1 H- imidazol-2-yl)-7-(5-chloro-2-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a- tetrahydroindolizin-5(1 H)-one (0.1 g, 0.203 mmol, 1.0 equiv.) in EA (10 mL) were added Pt02 (0.014 g, 0.061 mmol, 0.3 equiv.) and TFA (0.030 mL, 0.407 mmol, 2.0 equiv.) and the mixture was stirred overnight at room temperature under H2 (10 atm.). The solid was filtered out. The filtrate was concentrated under vacuum and the residue was purified by reverse phase chromatography on C18 (80 g, MeCN/H ₂ 0 (0.05%CF ₃ COOH): 0»>45%) and separated by Chiral-HPLC (Column: CHIRALPAK IA-3, 4.6*50mm,3.0um; Mobile Phase: Hex (0.1% DEA): EtOH=60:40; Flow rate:1 mUmin) to yield (3S,8aR)-3-(5-(6-amino- 2-fluoropyridin-3-yl)-1 H-imidazol-2-yl)-7-(5-chloro-2-(1 H-tetrazol-1- yl)phenyl)hexahydroindolizin-5(1 H)-one as a white solid.

LC-MS (ES, m/z): 494.10 [M+H] ⁺ . ¹ H NMR: (400 MHz, DMSO-d6) 6 11.53 (s, 1 H), 9.83 (s, 1 H), 7.95 - 8.04 (m, 1 H), 7.78 (s, 1 H), 7.48 - 7.60 (m, 2 H), 6.95 - 7.05 (m, 1 H), 6.29 - 6.37 (m, 1 H), 6.15 - 6.25 (m, 2 H), 4.92 (d, J = 8.7 Hz, 1 H), 3.42 - 3.56 (m, 1 H), 2.68 - 2.79 (m, 1 H), 2.25 - 2.42 (m, 2 H),

1.99 - 2.16 (m, 3 H), 1.89 - 1.98 (m, 1 H), 1.79 - 1.87 (m, 1 H), 1.66 - 1.78 (m, 1 H). ^ig F NMR: (376 MHz, DMSO-cB) 6 -70.75.

Example 378 (3S,7R,8aR)-7-(3-chloiO-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)- 3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2- yl)hexahydroindolizin-5(1 H)-one N,

¾ ^'

Ί NH

^F α

F

HO

Step 1: (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxooctahydroindolizine-3-carboxylic acid

To a solution of (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (0.5 g, 1.324 mmol, 1.0 equiv.) in EA (20 mL) were added RO2 (0.090 g, 0.397 mmol, 0.3 equiv.) and TFA (0.197 mL, 2.647 mmol, 2.0 equiv.) and the mixture was stirred overnight at room temperature under H2 (15 atm.). The solid was filtered out The filtrate was concentrated under vacuum and the residue was purified by reverse phase chromatography on C18 (80 g, MeCN/H ₂ 0 (0.05%CF ₃ COOH): 0»>45%) to yield (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxooctahydroindolizine-3-carboxylic acid as a yellow solid. LC-MS (ES, m/z): 380.15 [M+H]*.

Step 2: 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2- oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxooctahydroindolizine-3-carboxylate

To a mixture of (8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5- oxooctahydroindolizine-3-carboxylic acid (0.15 g, 0.395 mmol, 1.0 equiv.) and CS2CO3 (0.077 g, 0.237 mmol, 0.6 equiv.) in DMF (5 mL) was added 2-bromo- 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)ethan-1-one (0.3 g) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with H2O, extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over N32S04, concentrated and purified by silica gel chromatography (0-3% MeOH/DCM) to yield 2-(2-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluoropyridin-4-yl)-2-oxoet hyl (8aR)-7-(3-chloro- 2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxooctahydroindolizine-3-carboxyla te as a yellow solid. LC-MS: (ES, m/z): 661.20 [M+H]*.

Step 3: (8aR)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluor opyridin-4-yl)- 1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)hexahydroindolizin-5(1H)-one

To a solution of 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoropyridin- 4-yl)-2-oxoethyl (8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5- oxooctahydroindolizine-3-carboxylate (0.1 g, 0.151 mmol, 1.0 equiv.) in toluene (5 mL) were added NH<OAc (0.117 g, 1.512 mmol, 10 equiv.) and AcOH ( 0.1 mL,) and the mixture was stirred for 1 h at 100 °C. The solvent was evaporated under vacuum and purified by reverse phase chromatography on C18 (0-50% ACN/H2O) to yield (8aR)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)hexahydroindolizin-5(1 H)-one as a yellow solid. LC-MS: (ES, m/z): 641.40 [M+H]*. Step 4: (3R*,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(3- fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)hexah ydroindolizin- 5(1H)-one

To a solution of (8aR)-3-(5-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- fluoropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)hexahydroindolizin-5(1H)-one (50 mg, 0.078 mmol, 1.0 equiv.) in THF (1 ml_) was added EtsN-SHF (1 mL) at room temperature and the solution was stirred for 2 h at room temperature. The solution was concentrated under vacuum and purified by reverse phase chromatography on C18 (80 g, MeCN/H ₂ 0 (0.05%CF ₃ COOH): 0»>45%) to yield (8aR)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyri din-4-yl)-1 H- imidazol-2-yl)hexahydroindolizin-5(1H)-one. The racemic product was separated by Chiral-HPLC (Column: (R,R) WHELK-01, 4.6*50mm,3.5um; Mobile Phase :Hex ( 0.1% DEA): EtOH=50:50; Flow rate:1 mL/min) to yield (3R*,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3 -(5-(3-fluoro-2- (hydroxymethyl)pyridin-4-yl)-1 H-imidazol-2-yl)hexahydroindolizin-5(1 H)-one as a white solid.

LC-MS: (ES, m/z): 527.15 [M+H]*. ¹ H-NMR: (400 MHz, DMSO-d6) 6 12.21 (s, 1 H), 9.85 (s, 1 H), 8.28 - 8.40 (m, 1 H), 7.85 - 7.92 (m, 1 H), 7.76 - 7.84 (m, 1 H), 7.47 - 7.57 (m, 2 H), 5.24 - 5.28 (m, 1 H), 4.96 (d, J = 8.5 Hz, 1 H), 4.61 (s, 2 H), 3.44 - 3.54 (m, 1 H), 2.72 - 2.84 (m, 1 H), 2.40 - 2.45 (m, 2 H), 2.14 - 2.23 (m, 2 H), 2.04 - 2.12 (m, 1 H), 1.76 - 2.03 (m, 3 H). ¹⁸ F-NMR: (376 MHz, DMSO-d6) δ -111.74, -130.10.

Example 379 (3S,8aR)-3-(5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-imidazol- 2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one Step 1: 5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine To a solution of 5-bromo-7H-pynOlo[2,3-d]pyrimidine (0.5 g, 2.525 mmol, 1.0 equiv.) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.131 g, 3.282 mmol, 1.3 equiv.) at 0 °C. The reaction mixture was stirred 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (0.505 g, 3.030 mmol, 1.2 equiv.) was added and the reaction mixture was stirred at room temperature, for 2 h. Water was added, the mixture was extracted with EA. The combined extracts were washed with water, saturated brine, and dried over anhydrous Na2S04, then concentrated and the resulting residue purified by chromatography on EA/PE (0-20%) to yield 5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow oil. LC- MS:(ES, m/z): 327.95 [M+H]+, 329.95 [M+H+2] ⁺ .

Step 2: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine (0.53 g, 1.614 mmol, 1.0 equiv) and 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.820 g, 3.229 mmol, 2.0 equiv.) in 1,4-dioxane (10 mL) were added potassium acetate (0.475 g, 4.843 mmol, 3.0 equiv.) and 1,T-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.132 g, 0.161 mmol, 0.1 equiv.). The reaction mixture was stirred at 100 °C for 3 h under N2. Water was added, the mixture was extracted with EA. The combined extracts were washed with water, saturated brine and dried over anhydrous Na2S04, then concentrated to yield 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a black oil. LC- MS:(ES, m/z): 376.20 [M+H]*.

Step 3: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-1H-imidazol-2-yl)- 2,3,8, 8a-tetrahydroindolizin-5(1H)-one

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-iodo-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (100 mg, 0.212 mmol, 1.0 equiv.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (397.0 mg, 1.0 mmol, 5.0 equiv.) in 1,4-dioxane (10 mL) and water (1 mL) were added potassium carbonate (87.716 mg, 0.635 mmol, 3.0 equiv.) and 1,T-bis (di-t- butylphosphino)ferrocene palladium dichloride (13.8 mg, 0.021 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EA. The combined extracts were dried over anhydrous N32S04, then concentrated and the resulting residue purified by chromatography on MeOH/DCM (0-8%) to yield (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-3-(5-(7-((2-(trimethylsilyl)ethoxy)me thyl)-7H-pyrrolo|2,3- d]pyrimidin-5-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a brown solid. LC-MS:(ES, m/z): 594.25 [M+H] ⁺ .

Step 4: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl)-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one (90 mg, 0.151 mmol, 1.0 equiv.) in acetic acid (5 mL) were added azidotrimethylsilane (2.5 mL) and trimethoxymethane (2.5 mL). The reaction mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum to yield (3S)-7-(3-chloro-2-fluoro-6- (1H-tetrazol-1-yl)phenyl)-3-(5-(7-((2-(trimethylsilyl)ethoxy )methyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1H-imidazol-2-yl)-2,3,8,8a-tet rahydroindolizin- 5(1H)-one as a brown solid. LC-MS:(ES, m/z): 647.15 [M+H] ⁺ .

Step 5: (3S,8aR)-3-(5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1H)- one

A solution of (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-3-(5-(7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidi n-5-yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (100 mg) in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was dissolved into ammonia solution (5 mL, 2 M in methanol) and stirred at room temperature, for 5 min. The resulting mixture was extracted with EA two times. The combined extracts were dried over anhydrous NasSO*, then concentrated. The residue was purified by silica gel column chromatography on MeOH/DCM (0-15%) yield a racemic product, which was purified by Chiral-HPLC with (Hex:DCM=3:1)(0.1%DEA):EtOH=70:30 to yield (3S,8a*R)-3-(5-(7H- pyrrolo[2,3-d]pyrimidin-5-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H- tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as an off-white solid and (3S,8a*S)-3-(5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-imidazol -2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1H)- one as a white solid.

LC-MS:(ES, m/z): 517.10 [M+H] ⁺ . ¹ H-NMR: (400 MHz, Methanol-d4) 6 9.58 (s, 1H), 9.23 (s, 1H), 8.75 (s, 1H), 7.72 - 7.83 (m, 2H), 7.52 - 7.59 (m, 1H), 7.35 (s, 1H), 5.72 (d, J = 2.8 Hz, 1H), 5.09 - 5.19 (m, 1H), 3.82 - 3.94 (m, 1H), 2.86 - 3.05 (m, 1H), 2.56 - 2.64 (m, 1H), 2.28 - 2.40 (m, 1H), 2.19 - 2.27 (m, 2H), 2.03 - 2.16 (m, 1H). ¹⁹ F-NMR: (376 MHz, Methanol-d4) δ -113.29.

Example 380 (3S,8aR)-3-(5-(2-amino-3-chloropyridin-4-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: N-(3-chloro-4-iodopyridin-2-yl)acetamide

A solution of 3-chloro4-iodopyridin-2-amine (2 g, 7.9 mmol, 1.0 equiv.) in acetic anhydride (20 mL) was stirred at 80 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (60-80% ethyl acetate/petroleum ether) to yield N-(3-chloro-4- iodopyridin-2-yl)acetamide as a white solid. LC-MS:(ES, m/z): 297.1 [M+H]*. Step 2: N-(3-chloro-4-(1-ethoxyvinyl)pyridin-2-yl)acetamide

To a solution of N-(4-chloro-3-cyanopyridin-2-yl)acetamide (1 g, 3.4 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) were added tributyl(1- ethoxyvinyl)stannane (2.4 g, 6.7 mmol, 2.0 equiv.) and Pd(PPh3)4 (389.7 mg,

0.3 mmol, 0.1 equiv.). The resulting mixture was stirred at 100 °C for 5 hrs. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (70-90% ethyl acetate/petroleum ether) to yield N-(3-chloro-4- (1-ethoxyvinyl)pyridin-2-yl)acetamide as a yellow solid.

LC-MS:(ES, m/z): 241.3 [M+H]*.

Step 3: N-(4-(2-bromoacetyl)-3-chloropyridin-2-yl)acetamide

To a solution of N-(3-chloro-4-(1-ethoxyvinyl)pyridin-2-yl)acetamide (200 mg, 0.8 mmol, 1.0 equiv.) in THF (4 mL) and H2O (1 mL) was added NBS

(133.1 mg, 0.7 mmol, 0.9 equiv.). The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was extracted with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to yield N-(4-(2-bromoacetyl)-3-chloropyridin-2-yl)acetamide as a yellow oil. LC-MS:(ES, m/z): 291.0 [M+H]*.

Step 4: 2-(2-acetamido-3-chloropyridin-4-yl)-2-oxoethyl (8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate To a solution of (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (200 mg, 0.6 mmol, 1.0 equiv.) in ACN (4 ml_) was added K2CO3 (102.1 mg, 0.7 mmol, 1.2 equiv.). The resulting mixture was stirred at 25 °C for 0.5 h. N-(4-(2-bromoacetyl)-3- chloropyridin-2-yl)acetamide (179.5 mg, 0.6 mmol, 1.0 equiv.) was then added in portions. The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated. The residue was purified by silica gel chromatography (0-20% MeOH/DCM) to yield 2-(2-acetamido-3-chloropyridin-

4-yl)-2-oxoethyl (8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid. LC-MS:(ES, m/z): 535.3 [M+H] ⁺ . Step 5: N-(4-(2-((8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-chloropyridin-2 -yl)acetamide

To a solution of 2-(2-acetamido-3-chloropyridin-4-yl)-2-oxoethyl (8aR)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizine-3- carboxylate (200 mg, 0.4 mmol, 1.0 equiv.) in acetic acid (0.3 mL) and toluene (3 mL) was added ammonium acetate (575.9 mg, 7.5 mmol, 20.0 equiv.). The resulting mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (0-20% MeOH/DCM) to yield N-(4-(2-((8aR)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin -3-yl)-1H-imidazol- 5-yl)-3-chloropyridin-2-yl)acetamide as a yellow solid. LC-MS:(ES, m/z): 515.3 [M+H] ⁺ .

Step 6: N-(3-chloro-4-(2-((8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-

5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5 -yl)pyridin-2- yl)acetamide

To a solution of N-(4-(2-((8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-chloropyridi n-2- yl)acetamide (50 mg, 0.09 mmol, 1.0 equiv.) in HOAc (2 mL) were added TMSNa (1 mL) and trimethoxymethane (1 mL). The resulting mixture was stirred at 25 °C for 4 hrs. The resulting mixture was concentrated to yield N-(3- chloro-4-(2-((8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)py ridin-2-yl)acetamide as a yellow oil. LC-MS:(ES, m/z): 658.3 [M+H]*. Step 7: (3R*,8aR)-3-(5-(2-amino-3-chloropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one

To a solution of N-(3-chloro-4-(2-((8aR)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)pyridin-2-yl)acetamide (40 mg, 0.07 mmol, 1.0 equiv.) in THF (1 ml_) was added HCI (1 ml_, 2 mmol, 2 M). The resulting mixture was stirred at 70 °C for 1 h. The residue was purified by reverse phase chromatography with ACN/water (0.05% TFA) (40-60%) and chiral-HPLC to yield (3R*,8aR)-3-(5-(2-amino-3- chloropyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1- yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC-MS:(ES, m/z):526.15 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 6 12.48- 12.63 (m, 1H), 9.85 (s, 1H), 7.97- 7.99 (m, 1H), 7.91- 7.93 (m, 2H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H), 7.32 (d, J = 5.7 Hz, 1H), 6.77- 6.85 (m, 2H), 5.70 (d, J = 2.7 Hz, 1H), 5.04 (d, J = 8.8 Hz, 1H), 3.75- 3.79 (m, 1H), 2.72- 2.74 (m, 1H),

2.56- 2.58 (m, 1H), 2.11- 2.26 (m, 2H), 1.89- 1.98 (m, 2H). ¹⁶ F NMR (376 MHz, DMSO-d6) 6 -112.88.

Example 381 (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-( 5- methyl-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 3-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine

To a solution of 5-methyl-1H-pyrrolo[2,3-c]pyridine (1 g, 7.6 mmol, 1.0 equiv) in acetonitrile (15 mL) was added N-bromosuccinimide (1.347 g, 7.566 mmol, 1.0 equiv). The reaction mixture stirred for 2 h at room temperature, then concentrated under vacuum. The residue was purified by silica gel chromatography with MeOH/DCM (0-12%) to yield 3-bromo-5-methyl-1H- pyrrolo[2,3-c]pyridine as an off-white solid. LC/MS:(ES, m/z): 211.00 [M+H] ⁺ , 213.00 [Μ+Η+2Γ. Step 2: 5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine To a solution of 3-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine (1.4 g, 6.633 mmol, 1.0 equiv.) in N,N-Dimethylformamide (10 mL) was added sodium hydride (0.345 g, 8.623 mmol, 1.3 equiv., 60%) at 0 °C. The reaction mixture was stirred 0.5 h. To the mixture was then added a solution of 2-

(trimethylsilyl)ethoxymethyl chloride (1.327 g, 7.960 mmol, 1.2 equiv.) in N,N- dimethylformamide (10 mL) and the reaction mixture was stirred at room temperature, for 1 h. The reaction was quenched by water, the mixture was extracted with EA. The combined extracts were washed with water, saturated brine and dried over anhydrous Na2S04. After concentration, the residue was purified by silica gel chromatography on EA/PE (0-70%) to yield 5-bromo-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow oil. LC/MS:(ES, m/z): 341.00 [M+H]*, 343.00 [M+H+2]*.

Step 3: 5-methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[2,3-c]pyridine

Under an atmosphere of nitrogen, to a mixture of 3-bromo-5-methyl-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (1.7 g, 4.981 mmol, 1.0 equiv.) and 4,4,4 ^, ,4 ^, ,5,5,5 ^, ,5 ^, -octamethyl-2,2 ^, -bi(1,3,2-dioxaborolane) (2.530 g, 9.961 mmol, 2.0 equiv.) in 1,4-dioxane (30 mL) were added potassium acetate (1.466 g, 14.942 mmol, 3.0 equiv.) and 1,T- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (0.407 g, 0.498 mmol, 0.1 equiv.). The reaction mixture was stirred at 100 °C for 3 h under N2, then cooled to room temperature. Water was added, the mixture was extracted with EA. The combined extracts were dried over anhydrous Na2SO*. concentrated. The residue was purified by silica gel chromatography with MeOH/DCM (0%-6%) to yield 5-methyl-3-(4, 4,5,5- tetramethyl· 1 ,3,2-dioxaborolan-2-yl)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H- pyrrolo[2,3-c]pyridine as brown oil. LC/MS:(ES, m/z): 389.35 [M+HJ\

Step 4: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(5-methyl-1-(( 2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 H-imidazol-2-yl)-

2,3,8,8a-tetrahydroindolizin-5(1H)-one

Under at atmosphere of nitrogen, to a mixture of (3S)-7-(6-amino-3- chloro-2-fluorophenyl)-3-(5-iodo-1H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin- 5(1H)-one (100 mg, 0.212 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) and water (1 mL) were added 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine (410.8 mg, 1.058 mmol, 5.0 equiv.), potassium carbonate (87.7 mg, 0.635 mmol, 3.0 equiv.) and 1,T-bis (di-t-butylphosphino)ferrocene palladium dichloride (13.8 mg, 0.021 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 3 h, then cooled to room temperature. Water was added, the mixture was extracted with EA. The combined extracts were dried over anhydrous NaaSO*. concentrated. The residue was purified by silica gel chromatography with MeOH/DCM (0%-15%) to yield (3S)-7-(6-amino-3-chloro- 2-fluorophenyl)-3-(5-(5-methyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H- pyrrolo[2,3-c]pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetra hydroindolizin-5(1 Hi- one as a brown solid. LC/MS:(ES, m/z): 607.15 [M+H] ⁺ . Step 5: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(5-methyl-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridin- 3-yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(5-methyl- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridi n-3-yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (110 mg, 0.181 mmol, 1.0 equiv.) in acetic acid (5 mL) were added azidotrimethylsilane (2.5 mL) and trimethoxymethane (2.5 mL). The reaction mixture was stirred overnight at 50 °C. The resulting mixture was concentrated under vacuum to yield (3S)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(5-methyl-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[2,3-c]pyridin-3-yl)-1 H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a brown solid. LC/MS:(ES, m/z): 660.15 [Μ+ΗΓ.

Step 6: (3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(5-methyl-1H- pyrrolo[2,3-c]pyridin-3-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetra hydroindolizin-5(1H)- one

A solution of (3S)-7-(3-chloro-2-fiuoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-( 5- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c ]pyridin-3-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (150 mg) in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum.

The residue was purified by reverse phase chromatography with CHsCN/water (5%-38%) to yield the product which was purified by HPLC to yield (3S)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(5-methyl-1 H-pyrrolo[2,3- c]pyridin-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as an off-white solid.

LC/MS: (ES, m/z): 530.15 [M+H] ⁺ . ¹ H NMR: (300 MHz, Methanol-cU) δ 9.58 (s, 1 H), 8.57 (s, 1 H), 7.74 - 7.89 (m, 2 H), 7.64 (s, 1 H), 7.50 - 7.58 (m, 1

H), 7.23 (s, 1 H), 5.72 (d, J = 2.8 Hz, 1 H), 5.07 - 5.20 (m, 1 H), 3.79 - 3.98 (m,

1 H), 2.89 - 3.10 (m, 1 H), 2.52 - 2.66 (m, 4 H), 1.98 - 2.46 (m, 4 H). ¹⁹ F NMR: (286 MHz, Methanol-d4) δ -113.32.

Example 382 (3R,8aS)-3-(5-(2-amino-3-methoxypyridin-4-yl)-1H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a- tetrahydroindolizin-5(1 H)-one

Step 1: N-(4-chloro-3-methoxypyridin-2-yl)acetamide

4-Chloro-3-methoxypyridin-2-amine (400 mg, 2.52 mmol, 1.0 equiv.) in acetic anhydride (15 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The mixture was added EA (50 mL) and then washed by NaHCO3(50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield a N-(4- chloro-3-methoxypyridin-2-yl)acetamide. LC/MS: mass calculated for CeHeCIN ₂ 02: 200.622, measured: 201.20 [M+H] ⁺

Step 2: N-(4-(1-ethoxyvinyl)-3-methoxypyridin-2-yl)acetamide

N-(4-chloro-3-methoxypyridin-2-yl)acetamide (300 mg, 1.50 mmol, 1.0 equiv.), tributyl(1-ethoxyvinyl)stannane (810 mg, 2.24 mmol, 1.5 equiv.), and bis(triphenylphosphine)palladium(ll) chloride (105 mg, 0.15 mmol, 0.1 equiv.) were dissolved in 1,4-dioxane (15 mL). The flask was evacuated and flushed three times with nitrogen and the mixture was stirred 2 h at 100 °C under an atmosphere of nitrogen. After cooling to room temperature, the reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to yield the N-(4-(1- ethoxyvinyl)-3-methoxypyridin-2-yl)acetamide as a yellow oil. LC/MS: mass calculated for C12H16N2O3: 236.267, measured: 237.25 [M+H]* Step 3: N-(4-(2-bromoacetyl)-3-methoxypyridin-2-yl)acetamide To a solution of N-(4-(1-ethoxyvinyl)-3-methoxypyridin-2- yl)acetamide(250 mg, 1.06 mmol, 1.0 equiv.) in tetrahydrofuran (12 mL) was added N-bromosuccinimide (170 mg, 0.95 mmol, 0.9 equiv.). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield N-(4-(2-bromoacetyl)-3- methoxypyridin-2-yl)acetamide. LC/MS: mass calculated for CioHnBrN203: 287.11, measured: 289.15 [M+H] ⁺ . Step 4: 2-(2-acetamido-3-methoxypyridin-4-yl)-2-oxoethyl (3S,8aS)-7-(3-chloro- 2-fluoro-6-(1H-tetrazoH-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate

(3S,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl) -5-oxo- I^.S.S.e.ea-hexahydroindolizine-S-carboxylic acid (180 mg, 0.48 mmol, 1.0 equiv.) in acetonitrile (20 mL) was added potassium carbonate (132 mg, 0.95 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 0.5h, and then N-(4-(2-bromoacetyl)-3-methoxypyridin-2-yl)acetamide (164 mg, 0.57 mmol, 1.2 equiv.) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and then purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to yield 2-(2-acetamido-3-methoxypyridin-4-yl)-2-oxoethyl (3S,8aS)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow oil. LC/MS: mass calculated for C26H23CIFN7O6: 583.956, measured: 584.10 [M+H]*

Step 5: N-(4-(2-((3S,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)p henyl)-5- oxo-1, 2, 3,5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-methoxypyrid in-2- yl)acetamide

To a mixture of 2-(2-acetamido-3-methoxypyridin-4-yl)-2-oxoethyl (3S,8aS)-7-(3-chloro-2-fluoro-6-(1 H-tetrazoH-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (160 mg, 0.27 mmol, 1.0 equiv.) in toluene (5 ml_) and acetic acid (0.5 mL) was added ammonium acetate (211 mg, 2.74 mmol, 20.0 equiv.). The resulting mixture was stirred at 100 °C for 1 h. The mixture was concentrated under reduced pressure and then purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to yield N-(4-(2- ((3S,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5 -oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-methoxypyridin- 2-yl)acetamide as a yellow oil. LC/MS: mass calculated for CtthtaCIFNgOa: 563.971, measured: 564.30 [Μ+ΗΓ

Step 5: (3R*,8aS)-3-(5-(2-amino-3-methoxypyridin-4-yl)-1 H-imidazol-2-yl)-7-(3- chloro2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 Hi- one

To a mixture of N-(4-(2-((8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- methoxypyridin-2-yl)acetamide (100 mg, 0.18 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL) was added 2M hydrochloric acid (5 mL). The resulting mixture was stirred at 70 °C for 1h. The mixture was concentrated under reduced pressure and then purified by Prep-HPLC to yield 3-(5-(2-amino-3- methoxypyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid which was further separated by Chiral-HPLC to yield (3R*,8aS)-3-(5-(2-amino-3- methoxypyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C24H2iCIFNe02: 521.934, measured: 522.05 [M+H]÷ ¹ H NMR (400 MHz, DMSO-de) δ 11.95 - 12.03 (m, 1H), 9.84 (d, J = 3.3 Hz, 1H), 7.89 - 8.05 (m, 1H), 7.62 - 7.79 (m, 2H), 7.67 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 5.3 Hz, 1H), 5.66 - 5.75 (m, 3H), 4.99 - 5.11 (m,1H), 3.68 - 3.74 (m, 1H), 3.56 - 3.64 (m, 3H), 2.71 - 2.81 (m, 1 H), 2.55 -2.57 (m, 1 H), 2.05 - 2.23 (m, 2H), 1.93 - 2.04 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.87.

Example 3836-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-7- fluoroindolin-2-one

Step 1: 6-bromo-7-fluoroindolin-2-one

To a solution of 6-bromo-7-fluoroindoline-2,3-dione (2.80 g, 11.48 mmol) in ethanol (50 mL) was added hydrazine hydrate (85%, 0.5 mL) under nitrogen. After the mixture was refluxed for 30 min, a yellow participate was formed and collected by filtration. The yellow precipitate was then dissolved in anhydrous ethanol (50 mL), and t-BuOK (4.03 g, 35.90 mmol) was added. The mixture was refluxed under nitrogen for 2 h before pouring into water. The mixture was acidified with dilute HCI to pH = 2 and extracted with EA. The combined organic phase was washed with water, brine, dried with NazSO*, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; eluent: PE:EA = 5:1) to yield 6-bromo-7-f!uoroindolin-2-one as a light-yellow solid. MS (ESI): mass calculated for CsHsBrFNO 228.95 m/z, measured 230.00 [M+H] ^" \

Step 2: 7-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one Under an inert atmosphere of nitrogen, to a solution of 6-bromo-7- fluoroindolin-2-one (500 mg, 2.174 mmol, 1.0 equiv) in 1,4-dioxane (10 mL), were added 4,4,4 ^, ,4',5,5,5 ^, ,5 ^, -octamethyl-2,2 ^, -bi(1 ,3,2-dioxaborolane (828 mg, 3.261 mmol, 1.5 equiv), Pd(dppf)Cl2 (159 mg, 0.217 mmol, 0.1 equiv), and KOAc (427 mg, 4.351 mmol, 2 equiv). The reaction mixture was stirred for 2 h at 90 °C. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with EA/PE (0-100%) to yield 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indolin-2-one as a yellow solid. MS (ESI): mass calculated for CuHvBFNOs 277.13 m/z, measured 278.15[M+H] ⁺ .

Step 3: 6-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-7-fluoroindolin-2-one

Under an inert atmosphere of nitrogen, to a solution of (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-3-(5-iodo-1H-imidazol-2-yl)-2, 3,8,8a- tetrahydroindolizin-5(1H)-one (200 mg, 0.423 mmol, 1.0 equiv) in 1,4-dioxane (5 ml_) with H2O (0.5 mL), were added 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indolin-2-one (176 mg, 0.635 mmol, 1.5 equiv), Pd(dppf)Cl2 (40 mg, 0.055 mmol, 0.1 equiv), K2CO3 (117 mg, 0.847 mmol, 2 equiv). The reaction mixture was stirred for 2 h at 90 °C. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield 6-(2- ((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-7-fluoroindolin-2 -one as a yellow solid. MS (ESI): mass calculated for C25H20CIF2N5O2495.13 m/z, measured 496.05[M+H]+.

Step 4: 6-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)- 5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-7-fluoroindolin-2-one

To a solution of 6-(2-((3S)-7-(6-amino-3-chloro2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-7-fl uoroindolin-2-one (60 mg, 1.121 mmol, 1.0 equiv) in AcOH (3 mL) were added TMSNa (139 mg, 1.207 mmol, 10 equiv), and trimethoxymethane (128 mg, 1.206 mmol, 10 equiv). The reaction mixture was stirred for overnight at room temperature. The mixture was concentrated under vacuum and purified by C18 column (eluent: 5% to 50% (v/v) CHsCN and H2O with 0.05% NFUHCOs) to yield 6-(2-((3S)-7- (3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-7-fluoroindolin-2 -one as an off-white solid.

LC/MS: mass calculated for C2eHi9CIF2Na02: 548.13, measured: 549.10 [M+H]÷. LC-MS: (ES, m/z): 549.10 [M+H] ⁺ ; ¹ H-NMR: ¹ H NMR (300 MHz, DMSO- de) 6 11.95 (s, 1H), 10.87 (s, 1H), 9.84 (s, 1H), 7.92 - 8.03 (m, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.55 - 7.66 (m, 1H), 7.31 (s, 1H), 7.08 (d, J = 7.9 Hz, 1H), 5.67 - 5.69 (m, 1H), 5.02 (d, J = 8.3 Hz, 1H), 3.66 - 3.76 (m, 1H), 3.57 (s, 2H), 2.47 - 2.53 (m, 2H), 2.07 - 2.23 (m, 2H), 1.92 - 2.02 (m, 2H). ¹⁸ F NMR (282 MHz, DMSO-de) δ -112.87, -135.48.

Example 384 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (7-fluoro-1H-indol-6-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahyd roindolizin-

5(1H)-one Step 1: 7-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboiOlan-2-yl)-1 H-indole

Under an inert atmosphere of nitrogen, to a solution of 6-bromo-7-fluoro- 1 H-indole (300 mg, 1.402 mmol, 1.0 equiv) in 1,4-dioxane (5 mL), were added 4 _l 4,4 ^, ,4 ^, ,5,5,5 ^, _l 5'-octamethyl-2,2 ^, -bi(1,3,2-dioxaborolane (534 mg, 2.103 mmol, 1.5 equiv), Pd(dppf)Cl2 (103 mg, 0.141 mmol, 0.1 equiv), and KOAc (275 mg, 2.802 mmol, 2 equiv). The reaction mixture was stirred for 2 h at 90 °C. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with EA/PE (0-50%) to yield 7-fluoro-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- indole as a yellow solid. MS (ESI): mass calculated for C14H17BFNO2261.13 m/z, measured 262.10[Μ+ΗΓ .

Step 2: (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(7-fluoro- 1 H-indol-6- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

Under an inert atmosphere of nitrogen, to a solution of (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-3-(5-iodo-1H-imidazol-2-yl)-2,3,8,8 a- tetrahydroindolizin-5(1H)-one (100 mg, 0.212 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) with H2O (0.5 mL), were added 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1 H-indole (83 mg, 0.318 mmol, 1.5 equiv),Pd(dppf)Cl2 (15 mg, 0.020 mmol, 0.1 equiv), K2CO3 (58 mg, 0.420 mmol, 2 equiv). The reaction mixture was stirred for 2 h at 90 °C. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield (3S,8aR)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(5-(7-fluoro-1H-indol-6-yl) -1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. MS (ESI): mass calculated for C25H20CIF2N5O 479.13 m/z, measured 480.10[M+H] ⁺ .

Step 3: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(7-fluoro- 1 H-indol-6-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(7-fluoro- 1 H-indol-6-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin -5(1 H)-one (100 mg, 0.208 mmol, 1.0 equiv) in AcOH (5 ml_) were added TMSN3 (240 mg, 2.083 mmol, 10 equiv), and trimethoxymethane (221 mg, 2.083 mmol, 10 equiv). The reaction mixture was stirred for overnight at room temperature. The residue was purified by preparative HPLC using a (Column: XBridge Prep OBD C18 Column, 30x150mm Sum; Mobile Phase A:Water (10MMOL/L NH4HCO3), Mobile Phase B:ACN; Flow rate:60 mL/min; Gradient: 33 B to 63 B in 7 min; 254 nm) to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(7- fluoro-1 H-indol-6-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

MS (ESI): mass calculated for C2eHieCIF2N80532.13 m/z, measured 533.10 [M+H]+. LC-MS: (ES, m/z): 533.10 [M+H]*. H-NMR: ¹ H NMR (300 MHz, DMSO-de) δ 11.85 (s, 1H), 11.49 (s, 1H), 9.85 (s, 1H), 7.98 (t, J = 8.2 Hz, 1H), 7.63 - 7.77 (m, 2H), 7.30 - 7.46 (m, 3H), 6.48 (s, 1 H), 5.70 (d, J = 2.6 Hz, 1 H),

5.04 - 5.07 (m, 1H), 3.66 - 3.76 (m, 1H), 2.73 - 2.83 (m, 1H), 2.52 - 2.60 (m,

1H), 1.99 - 2.24 (m, 4H). F-NMR: ¹⁹ F NMR (282 MHz, DMSO-de) δ -112.84, - 135.54.

Example 385 (3S,8aR)-3-(5-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazoM -yl)phenyl)-

2,3,8,8a-tetrahydroindolizin-5(1H)-one

Step 1: ethyl (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo-1, 2,3, 5,8,8a- hexahydroindolizine-3-carboxylate

To a solution of ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1 g, 2.835 mmol, 1.0 equiv.) in acetonitrile (15 mL) was added azidotrimethylsilane (0.490 g, 4.252 mmol, 1.5 equiv.), followed by the addition of tert-butyl nitrite (0.438 g, 4.252 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography with EA/PE (0%-45%) to yield ethyl (3S)-7-(6-azido- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate as a light yellow solid. LC-MS:(ES, m/z): 379.20 [M+H] ⁺ .

Step 2: ethyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-tr iazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate

To a solution of ethyl (3S)-7-(6-azido-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (1 g, 2.640 mmol, 1.0 equiv) and 4,4,4-trifluorobut-2-ynoic acid (1.822 g, 13.200 mmol, 5.0 equiv) in acetonitrile (15 mL) was added cuprous oxide (0.151 g, 1.056 mmol, 0.4 equiv). The reaction mixture was stirred at 80 °C for 2 h under N2. The solid was filtered out, and the resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography on EA/PE (0%-70%) to yield ethyl (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carboxyl ate as a light yellow solid (1.2 g, 96.1% yield). LC-MS:(ES, m/z): 473.10 [M+H] ⁺ . Step 3: (3R)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazoM- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbalde hyde

To a solution of ethyl (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-hexahydroindol izine-3-carboxylate (1.1 g, 2.326 mmol, 1.0 equiv) in dichloromethane (20 mL) was added diisobutylaluminium hydride (4.6 mL, 1 M in DCM, 4.653 mmol, 3.0 equiv.) in batches at -78 °C under N2. The reaction mixture was stirred for 2 h. The reaction was quenched with potassium sodium tartrate solution, and the mixture was extracted with EA. The combined extracts were dried over anhydrous NaaSO*. The resulting mixture was concentrated under vacuum.

The residue was purified by silica gel chromatography with MeOH/DCM (0%- 55%) to yield (3R)-7-(3-chloro-2-fiuoro-6-(4-(trifluoromethyl)-1H-1,2,3-tr iazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carbaldehyde as a light yellow solid. LC-MS:(ES, m/z): 429.05 [M+H] ⁺ .

Step 4: (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-tr iazol-1- yl)phenyl)-3-(1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin -5(1H)-one

To a solution of (3R)-7-(3-chloro-2-fiuoro-6-(4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine- 3-carbaldehyde (0.64 g, 1.493 mmol, 1.0 equiv.) in methanol (10 mL) and ammonium hydroxide

(10 mL) was added glyoxal (2.166 g, 14.926 mmol, 10.0 equiv., 40% in water) in batches. The mixture was stirred at room temperature for 48 h. The resulting mixture was concentrated, then EA was added, washed with brine and dried over anhydrous Na2S04, concentrated, and the residue purified by chromatography on MeOH/DCM (0-6%) to yield (3S)-7-(3-chloro-2-fluoro-6-(4- (trifluoromethyl)-l H-1 ,2,3-triazol-1-yl)phenyl)-3-(1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a yellow solid. LC-MS:(ES, m/z): 467.00 [M+H] ⁺ .

Step 5: (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1- yl)phenyl)-3-(5-iodo-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one To a solution of (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl)phenyl)-3-(1H-imidazol-2-yl)-2,3,8,8a-tetrahydr oindolizin-5(1H)-one (250 mg, 0.536 mmol, 1.0 equiv.) in DCM (10 mL) was added N- iodosuccinimide (241 mg, 1.071 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 10 min. Water was added, the mixture was extracted with EA. The combined extracts were washed with water, dried over anhydrous Na2SO*. concentrated. EtOH (10 mL), H2O (10 mL) and sodium sulfite (1.35 g, 10.711 mmol, 20.0 equiv.) was added to residue. The mixture was stirred overnight at 95 °C, then cooled to room temperature. Water was added, the mixture was extracted with EA. The combined extracts were dried over anhydrous NaaSO*, then concentrated. The resulting residue was purified by chromatography on MeOH/DCM (0-4%) to yield (3S)-7-(3-chloro-2-fluoro-6- (4-(trifluoromethyl)-1 H-1 ,2,3-triazol-1-yl)phenyl)-3-(5-iodo-1 H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as an off-white solid. LC-MS:(ES, m/z): 592.95 [M+H] ⁺ .

Step 6: tert-butyl 3-(2-((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-hexahydroindolizin-3-yl)-1 H-imidazol-5- yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

To a mixture of (3S)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3- triazol-1-yl)phenyl)-3-(5-iodo-1H-imidazol-2-yl)-2,3,8,8a-te trahydroindolizin- 5(1H)-one (100 mg, 0.169 mmol, 1.0 equiv.) and tert-butyl 3-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pynrolo[3,2-c]pyridine-1-carboxylate (116.1 mg, 0.337 mmol, 2.0 equiv.) in 1,4-dioxane (10 mL) and water (1 mL) were added potassium carbonate (69.9 mg, 0.506 mmol, 3.0 equiv.) and 1,1'- bis (di-t-butylphosphino)ferrocene palladium dichloride (11 mg, 0.017 mmol, 0.1 equiv.). The resulting mixture was maintained under nitrogen and stirred at 100 °C for 2 h. After cooling to room temperature, the reaction was quenched with water and the mixture was extracted with EA. The combined extracts were dried over anhydrous N32S04, then concentrated. The resulting residue was purified by chromatography on MeOH/DCM (0-5%) to yield tert-butyl 3-(2-((3S)- 7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazoH -yl)phenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-1 H-pyrrolo[3,2- c]pyridine-1-carboxylate as a yellow solid. LC-MS:(ES, m/z): 683.10 [M+H] ⁺ . Step 7: (3S,8aR)-3-(5-(1 H-pyrrolo[3,2-c]pyridin-3-yl)-1 H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl )phenyl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

A solution of tert-butyl 3-(2-((3S)-7-(3-chloro-2-fluoro-6-(4- (trifluoromethyl)-l H-1 ,2,3-triazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-1H-pyrrolo[3,2-c] pyridine-1- carboxylate (96 mg, 0.141 mmol, 1.0 equiv.) in dichloromethane (6 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography with CHsCN/water (5% - 45%) to yield the racemic product, which was purified by Chiral-HPLC with Hex(0.1%DEA):EtOH=70:30 to yield (3S,8a*R)-3-(5-(1H-pyrrolo[3,2-c]pyridin-3-yl)-1H-imidazol-2 -yl)-7-(3-chloro2- fluoro-6-(4-(trifluoromethyl)-1 H-1 ,2,3-triazoM-yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one as a white solid and (3S,8a*S)-3-(5-(1H- pyrrolo[3,2-c]pyridin-3-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(4-

(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-2,3,8,8a- tetrahydroindolizin- 5(1H)-one as an off-white solid.

LC-MS:(ES, m/z): 583.05 [M+H]*. ¹ H NMR: (400 MHz, Methanol-d ₄ ) 6 8.95 - 9.12 (m, 2 H), 8.18 (d, J = 5.9 Hz, 1 H), 7.75 - 7.86 (m, 1 H), 7.68 (s, 1 H), 7.54 (dd, J = 8.7, 1.6 Hz, 1 H), 7.47 (dd, J = 5.9, 1.1 Hz, 1 H), 7.28 (s, 1 H),

5.71 (d, J = 2.8 Hz, 1 H), 5.13 - 5.26 (m, 1 H), 3.84 - 3.95 (m, 1 H), 2.93 - 3.06 (m, 1 H), 2.56 - 2.65 (m, 1 H), 2.18 - 2.40 (m, 3 H), 2.03 - 2.16 (m, 1 H). ¹⁹ F-NMR: (376 MHz, Methanol-d4) 6 -62.60, -113.43.

Example 386 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2,3-dihydrofuro[2,3-b]pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8 ,8a- tetrahydroindolizin-5(1 H)-one

Cl

Γ 1 ΗΝ—

,N.

N

* Λ_ζ

Ν — Ν ^Ν

A mixture of (3S,8aR)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(2,3- dihydrofuro[2,3-b]pyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8a-t etrahydroindolizin- 5(1H)-one (80 mg, 0.172 mmol, 1.0 equiv.), trimethoxymethane (2 ml), azidotrimethylsilane (2 ml) and acetic acid (3 ml) was stirred at room temperature overnight. The reaction was concentrated and purified by reversal phase chromatography (0.05 % TFA, CHaCN/water, 0 % ~ 55 %) to yield 7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(2,3-dihydr ofuro[2,3-b]pyridin-4- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one (36 mg) as a white solid, which was separated by Chiral HPLC (Column: CHIRALPAK IE-3, 4.6*50mm, 3um; Mobile Phase A: MTBE ( 0.3% Isopropylamine): EtOH=70: 30; Flow rate: 1 mL/min) to yield (3R,8aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-3-(5-(2,3-dihydrofuro[2,3-b]pyridin-4-yl)-1H-imid azol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated, for C25H2oCIFNa02:518.14, measured: 519.05[M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) d 12.57 - 12.23 (m, 1H), 9.84 (s, 1H), 7.97 (dd, J = 8.7, 7.8 Hz, 1H), 7.84 (d, J = 5.5 Hz, 1H), 7.72 (dd, J = 8.7, 1.5 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 5.5 Hz, 1H), 5.70 (d, J = 2.4

Hz, 1H), 5.02 (d, J = 8.2 Hz, 1H), 4.60 (t, J = 8.6 Hz, 2H), 3.81 - 3.68 (m, 1H), 3.43 (t, J = 8.7 Hz, 2H), 2.75 - 2.53 (m, 2H), 2.27 - 1.87 (m, 4H). ¹⁹ F NMR (282 MHz, DMSO-d6) d -113.04.

Example 387 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (thieno[3,2-b]pyridin-7-yl)-1H-imidazol-2-yl)-2,3,8i8a-tetra hydroindolizin-

5(1H)-one

Step 1: 7-bromothieno[3,2-b]pyridine

With an inert atmosphere of nitrogen, a mixture of thieno[3,2-b]pyridin-7- ol (1.5 g, 9.922 mmol, 1.00 equiv), POBra (14.2 g, 49.53 mmol, 5 equiv),the reaction mixture was stirred at 65°C for 6 h. NaOH (aq.) (50 mL), water (50 mL) and chloroform(50 mL) were added. The phases were separated and the aqueous phase was extracted with more chloroform (2 X 50 mL). The organic phase was dried (Na2S04) and filtered and concentrated. The residue was applied onto a silica gel column (80g, EtOAc/PE: 1/3) to yield 7- bromothieno[3,2-b]pyridine as a yellow solid.MS (ESI): mass calculated for C?H4BrNS 212.92 m/z, measured 213.95 [M+H]*.

Step 2: 7-(1-ethoxyvinyl)thieno[3,2-b]pyridine

Under an inert atmosphere of nitrogen, a mixture of 7-bromothieno[3,2- bjpyridine (800 mg, 3.737 mmol, 1.00 equiv), tributyl(1-ethoxyvinyl)stannane (1.8 g, 4.984 mmol, 1.3 equiv), Pd(PPh3)2Cl2 (262 mg, 0.373 mmol, 0.1 equiv) in 1 ,4-dioxane (15 mL) was stirred at 90°C for 2 h and then concentrated. The residue was applied onto a silica gel column (80g, EtOAc/PE: 1/10) to yield 7- (1-ethoxyvinyl)thieno[3,2-b]pyridine as a yellow oil.MS (ESI): mass calculated for C11H11NOS 205.06 m/z, measured 206.05 [M+H]+.

Step 3: 2-bromo-1-(thieno[3,2-b]pyridin-7-yl)ethan-1-one

To a mixture of 7-(1-ethoxyvinyl)thieno[3,2-b]pyridine (310 mg, 1.510 mmol, 1.0 equiv) in THF (6 mL) with H2O (3 mL) was added NBS (269 mg, 1.511 mmol, 1.0 equiv), and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine, dried over N32S04 and concentrated to yield 2-bromo-1-(thieno[3,2-b]pyridin-7- yl)ethan-1-one as a yellow solid.MS (ESI): mass calculated for CgHeBrNOS 254.94 m/z, measured 276.05 [M+H] ⁺ .

Step 4: 2-oxo-2-(thieno[3,2-b]pyridin-7-yl)ethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizine-3-carbo xylate To a mixture of (3R)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (250 mg, 0.770 mmol, 1.0 equiv) in DMF (10 mL) was added CS2CO3 (151 mg, 0.463 mmol, 0.6 equiv), and the resulting mixture was stirred at room temperature for 30 min. 2-Bromo- 1-(thieno[3,2-b]pyridin-7-yl)ethan-1-one (296 mg, 1.156 mmol, 1.5 equiv) was then added, and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine, dried over

N32SO4 and concentrated. The residue was purified by silica gel chromatography (0-20% MeOH/DCM) to yield 2-oxo-2-(thieno[3,2-b]pyridin-7- yl)ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a yellow solid.MS (ESI): mass calculated for C24H19CIFN3O4S 499.08 m/z, measured 500.00[M+H] ⁺ .

Step 5: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(thieno[3,2-b] pyridin-7- yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one To a solution of 2-oxo-2-(thieno[3,2-b]pyridin-7-yl)ethyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate (250 mg, 0.500 mmol, 1.0 equiv) in toluene (10.0 mL) with ChfoCOOH (1 mL) was added NhUOAc (385 mg, 5.0 mmol, 10 equiv). The reaction mixture was stirred for 2 h at 110 °C. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(5-(thieno[3,2-b]pyridin-7- yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. MS (ESI): mass calculated for C24H19CIFN5OS 479.10 m/z, measured 480.20[M+H] ⁺ .

Step 6: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (thieno[3,2-b]pyridin-7-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetra hydroindolizin-5(1H)- one

To a solution of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5- (thieno[3,2-b]pyridin-7-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 Hi- one (180 mg, 0.375 mmol, 1.0 equiv) in HOAc (5 mL) were added TMSNa (432 mg, 3.750 mmol, 10.0 equiv), and trimethoxymethane (398 mg, 3.750 mmol, 10.0 equiv).The reaction mixture was stirred overnight at room temperature. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-3-(5-(thieno[3,2-b]pyridin-7-yl)-1H-imidazol-2-yl )-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a yellow solid. The yellow solid was further purified by preparative HPLC to yield (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H- tetrazol-1-yl)phenyl)-3-(5-(thieno[3,2-b]pyridin-7-yl)-1H-im idazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one as a white solid.

MS (ESI): mass calculated for C25H18CIFN8OS 532.10 m/z, measured 533.05[M+H] ⁺ . LC-MS: (ES, m/z): 533.05 [M+H] ^{+ 1} H-NMR: ¹ H NMR (300 MHz, DMSO-de) δ 12.44 (s, 1H), 9.85 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 8.08 (d, J = 5.6 Hz, 1 H), 7.92 - 8.03 (m, 2H), 7.65 - 7.77 (m, 2H), 7.53 (d, J = 5.6 Hz, 1 H),

5.69 (d, J = 2.7 Hz, 1H), 5.07 (d, J = 6.5 Hz, 1H), 3.73 - 3.83 (m, 1H), 2.90 (t, J = 15.3 Hz, 1H), 2.57 - 2.64 (m, 1H), 2.18-2.26 (m, 3H), 1.99 - 2.03 (m, 1H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -112.808

Example 388 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (6-methoxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: 3-bromo-6-methoxy-1H-pyrrolo[3,2-c]pyridine

A mixture of 7-fluoro-1H-pyrrolo[3,2-c]pyridine (1.0 g,7.3 mmol, 1.0 equiv) in THF 15 mLwas flowed added NBS (1.3 g, 7.304 mmol, 1.0 equiv) was stirred at room temperature for 1 h. The mixture was concentrated under vacuum. The residue was dissolved by the addition of H2O. The resulting solution was extracted with of ethyl acetate (3x 15 mL). The organic layers were combined, washed with brine, dried and concentrated. The residue was purified by silica gel chromatography (0-50% PE/EA) to yield 3-bromo-6- methoxy-1H-pyrrolo[3,2-c]pyridine as a yellow solid. LC/MS: mass calculated for CeHyBrNzO: 225.97, measured: 226.95 [Μ+Η+2Γ.

Step 2: 3-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py rrolo[3,2- c]pyridine

3-Bromo-6-methoxy-1H-pynOlo[3,2-c]pyridine (600 mg, 2.642 mmol, 1.0 eq.) in DMF (5 mL). The mixture was stirred at 15 min for 0°C. NaH (159 mg, 3.975 mmol, 1.5 eq., 60%) was then added, and the reaction mixture was stirred at 30 min for 0°C. SEMCI (661 mg, 3.965 mmol, 1.5 eq.) was added then added and the mixture stirred at room temperature for 2 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3x10 mL) then washed with water (3x 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-30% PE/EA) to yield 3-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-c]pyridine as a white solid. LC/MS: mass calculated for CuH2iBrN202Si: 356.06, measured:357.05 [M+H]*.

Step 3: 2-chloro-1-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one

To a solution of 3-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrrolo[3,2-c]pyridine (200.0 mg, 0.056 mmol, 1.0 equiv.) in dry tetrahydrofuran (5 ml_) under nitrogen was added n-butyllithium (0.3 mL, 0.75 mmol, 2.5 M, 1.2 equiv.) at -78 °C and the solution was stirred for 1.0 h at this temperature under N2. A solution of 1-chloro-3-(methoxy(methyl)amino)propan- 2-one (80 mg, 0.58 mmol, 1.1 equiv. in dry THF (1 mL) was added dropwise - 78 °C and the solution was allowed stirred at -78 °C for 1 h. The solution was quenched with diluted with water, extracted with EA, the combined organic phase was washed with water and brine, dried over Na2S04, after filtration and concentration, the residue was purified with silica gel column (EA:PE = 0% to 50%) to yield 2-chloro-1-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one as a yellow solid. LC/MS: mass calculated for CieH23CIN203Si: 354.12, measured: 355.10 [M+H]*.

Step 4: 2-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrrolo[3,2- c]pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

(3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylic acid (130 mg, 0.400 mmol, 1.0 equiv) in CHsCN (3 mL) was added K2CO3 (102 mg, 0.738 mmol, 2.0 eq.), the solution was stirred for 20min at room temperature. To the resulting mixture was then added 2-chloro-1-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one (172 mg, 0.553 mmol, 1.5 eq.). The resulting solution was stirred for overnight at room temperature. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column (DCM/MeOH) to yield 2-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrrolo[3,2-c]pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a brown solid. LC/MS: mass calculated for CsiHseCIFlsUOeSi: 642.21, measured: 643.40 [M+H]*. Step 5: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(6-methoxy-1-( (2-

(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3 -yl)-1H-imidazol-2-yl)-

2,3,8,8a-tetrahydroindolizin-5(1H)-one

2-(6-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrr olo[3,2- c]pyridin-3-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (127 mg, 0.197 mmol, 1.0 equiv) was dissolved in HOAc (0.3 mL) and toluene (3 ml_). To the resulting solution was then added CH3COONH4 (304 mg, 3.949 mmol, 10 eq.). The mixture was stirred at 110°C for 1.5 h. The mixture was concentrated. The residue was applied onto a silica gel column (DCM/MeOH) to yield (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-3-(5-(6-methoxy-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl )-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1H)-one as a yellow solid. LC/MS: mass calculated for CaiHaeCIFNeOaSi: 622.23, measured: 623.45 [M+1]*. Step 6: (3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-( 6-methoxy-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin- 3-yl)-1H-imidazol-2- yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one

To a mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(6- methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2- c]pyridin-3-yl)-1H- imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (80 mg, 0.128 mmol, 1.0 equiv) in AcOH (3 mL) were added trimethoxymethane (136 mg, 1.282 mmol, 10 eq.) and TMSN3 (148 mg, 1.285 mmol, 10 eq.). The mixture was stirred at room temperature for overnight. The mixture was concentrated. The residue was applied onto a silica gel column (DCM/MeOH) to yield (3S)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1-yl)phenyl)-3-(5-(6-methoxy-1-((2-

(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3 -yl)-1H-imidazol-2-yl)- 2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a yellow solid. LC/MS: mass calculated for C32H35CIFN903Si: 675.23, measured: 676.15 [M+1]*.

Step 7: (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(6- methoxy-1 H-pyrrolo[3,2-c]pyridin-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a- tetrahydroindolizin-5(1 H)-one

To a solution of (3S)-7-(3-chloro2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5-(6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol o[3,2-c]pyridin-3-yl)- 1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one (58 mg, 0.086 mmol, 1.0 equiv.) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 30°C for 1 h. The mixture was concentrated. MeOH (1 mL) and NH<OH (0.1 mL) were then added. The mixture was stirred at 25°C for 1h. The mixture was concentrated. The residue was applied onto a C18 column to yield (3S,8aR)-7- (3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(6-metho xy-1H-pyrrolo[3,2- c]pyridin-3-yl)-1 H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one as a white solid.

LC/MS: mass calculated for C2eH2iCIFNe02: 545.15, measured: 546.15 [M+H]*. ¹ H NMR (400 MHz, DMSO-de) 6 11.68 (s, 1H), 11.04 (s, 1H), 9.83 (s, 1H), 8.85 (s, 1H), 7.96 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 6.63 (s, 1H), 5.67 (d, J = 2.8 Hz, 1H), 5.00 (d, J = 8.3 Hz, 1H), 3.87 (s, 3H), 3.65-3.75 (m, 1H), 2.79 (t, J = 15.3 Hz, 1H), 2.53-2.57 (m, 1H), 1.92-2.21 (m, 4H). ¹⁹ F NMR (376 MHz, DMSO-de) 6 -112.62. Example 389 (3S,8aR)-3-(5-(2-ammopyridin-4-yl)-1H-imidazol-2-yl)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8a-tetrahy droindolizin-

5(1H)-one Step 1: N-(4-bromopyridin-2-yl)acetamide

To 4-bromopyridin-2-amine (2 g, 11.560 mmol, 1.0 equiv) was added AC2O (20 mL) and the resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated to dryness under reduced pressure, and the residue was washed with dilute NaHCOs (aq) to pH = 7 and extracted with EA. The combined organic phase was washed with water, brine, dried with NazSO*. then purified by column chromatography on silica gel with EA/PE (0-100%) to yield N-(4-bromopyridin-2-yl)acetamide as a yellow solid. MS (ESI): mass calculated for CyHyBrNaO 213.97 m/z, measured 215.00[M+H]+. Step 2: N-(4-(1-ethoxyvinyl)pyridin-2-yl)acetamide

Under an inert atmosphere of nitrogen, a mixture of N-(4-bromopyridin- 2-yl)acetamide (1 g, 4.650 mmol, 1.00 equiv), tributyl(1 -ethoxy vinyl)stannane (2.2 g, 6.092 mmol, 1.3 equiv), and Pd(PPh3)2Cl2 (326 mg, 0.464 mmol, 0.1 equiv) in 1 ,4-dioxane (15 mL) was stirred at 90°C for 2 h. The resulting mixture was then concentrated and the residue was applied onto a silica gel column (80 g, EtOAc/PE: 1/10) to yield N-(4-(1-ethoxyvinyl)pyridin-2-yl)acetamide as a yellow oil. MS (ESI): mass calculated for C11H14N2O2206.11 m/z, measured 207.15 [M+H] ⁺ . Step 3: N-(4-(2-bromoacetyl)pyridin-2-yl)acetamide

To a mixture of N-(4-(1-ethoxyvinyl)pyridin-2-yl)acetamide (400 mg,

1.939 mmol, 1.0 equiv) in THF (6 mL) with water (3 mL) was added NBS (345 mg, 1.938 mmol, 1.0 equiv), and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine, dried over N32S04 and concentrated to yield N-(4-(2-bromoacetyl)pyridin-2- yl)acetamide as a yellow solid. MS (ESI): mass calculated for CgHgBrtaQz 255.98 m/z, measured 258.95 [M+H+2]*.

Step 4: 2-(6-acetamidopyridin-3-yl)-2-oxoethyl (3R)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a mixture of (3R)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.924 mmol, 1.0 equiv) in DMF (5 mL) was added CS2CO3 (181 mg, 0.556 mmol, 0.6 equiv) and stirred at room temperature for 30 min. N-(4-(2-bromoacetyl)pyridin-2- yl)acetamide (475 mg, 1.848 mmol, 2 equiv) was then added, and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography (0-20% MeOH/DCM) to yield 2-(6-acetamidopyridin-3-yl)-2-oxoethyl (3R)-7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate as a yellow solid.MS (ESI): mass calculated for C24H22CIFN4O5500.13 m/z, measured 501.15[M+H] ⁺ .

Step 5: N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)pyridin-2-yl)aceta mide

To a solution of 2-(2-acetamidopyridin-4-yl)-2-oxoethyl (3R)-7-(6-amino- 3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindoliz ine-3-carboxylate (350 mg, 0.7 mmol, 1.0 equiv) in toluene (10.0 mL) with CH3COOH (1 mL) was added NH4OAC (539 mg, 6.993 mmol, 10 equiv). The reaction mixture was stirred for 2 h at 110 °C. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield N-(4-(2-((3S)-7- (6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahyd roindolizin-3-yl)- 1H-imidazol-5-yl)pyridin-2-yl)acetamide as a yellow solid. MS (ESI): mass calculated for Cz^saCIFNeGz 480.15 m/z, measured 481.15[M+H]*.

Step 6: N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1-yl)phenyl)-5-oxo 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)pyridin-2-yl)acetamide

To a solution of N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)pyrid in-2-yl)acetamide (200 mg, 0.416 mmol, 1.0 equiv) in AcOH (5 mL) were added TMSN3 (479 mg, 4.158 mmol, 10.0 equiv), and trimethoxymethane (441 mg, 4.156 mmol, 10.0 equiv).The reaction mixture was stirred overnight at room temperature. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-

1-yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)- 1H-imidazol-5- yl)pyridin-2-yl)acetamide as a yellow solid. MS (ESI): mass calculated for

C25H21CIFN9O2 533.15 m/z, measured 534.10[M+H] ⁺ .

Step 7: (3S,8aR)-3-(5-(2-aminopyridin-4-yl)-1 H-imidazol-2-yl)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)-one To a solution of N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)pyridin-

2-yl)acetamide (130 mg, 0.243 mmol, 1.0 equiv) in THF (5 mL) was added 4N HCI (2 mL). The reaction mixture was stirred 2h at 70 °C. The mixture was concentrated under vacuum and purified by C18 column (eluent: 5% to 60% (v/v) CHaCN and H2O with 0.05% NH4HCO3) to yield (3S)-3-(5-(2-aminopyridin- 4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol- 1-yl)phenyl)-2,3,8,8a- tetrahydroindolizin-5(1H)-one. The residue was further purified by preparative HPLC (Column: CHIRALPAK IA-3, 4.6*50mm, 3um; Mobile Phase A: MtBE ( 0.1% DBA): EtOH=50: 50; Flow rate: 1 mL/min; Gradients B to 20 B in 14 min; 220/254 nm) to yield (3S,8aR)-3-(5-(2-aminopyridin-4-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2,3,8,8 a-tetrahydroindolizin- 5(1H)-one as a white solid.

MS (ESI): mass calculated for C23H19CIFN9O 491.14 m/z, measured 492.05[M+H]+. LC-MS: (ES, m/z): 492.05 [M+H] ^{+ 1} H NMR (300 MHz, DMSO- de) 6 11.91 (s, 1H), 9.84 (s, 1H), 7.87 - 8.03 (m, 1H), 7.83 (d, J = 5.3 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 6.78 -6.87 (m, 2H), 5.76 (s, 2H), 5.69 (d, J = 2.6 Hz, 1H), 4.99 (d, J = 8.5 Hz, 1H), 3.71 (s, 1H), 2.72 (t, J = 15.4 Hz, 1 H),2.42- 2.52(m, 1H) 2.15-2.20 (m, 1H), 2.03 -2.18 (m, 1H), 1.83-

1.97 (m, 2H). ¹⁹ F NMR (282 MHz, DMSO-de) 6 -112.91.

Example 390 (3S,8aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3- (5- (2-{ethylamino)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3, 8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: N-ethyl-N-(3-fluoro-4-iodopyridin-2-yl)acetamide

Under an inert atmosphere of nitrogen, to a mixture of N-(3-fluoro-4- iodopyridin-2-yl)acetamide (2 g, 7.142 mmol, 1.00 equiv) in THF (20 mL) was added NaH (314 mg, 7.851 mmol, 1.1 equiv, 60%) at 0°C for 30 min. followed by addition of iodoethane (5.6 g, 35.905 mmol, 5 equiv). The reaction mixture was stirred at 60 °C for 2 h. The reaction was quenched with ice water (100 mL) and extracted with ethyl acetate (200 mLx 3). The combined organic layer was washed with brine, dried over Na2SO< and concentrated. The residue was purified by silica gel chromatography (0-100% EA/PE) to yield N-ethyl-N-(3- fluoro-4-iodopyridin-2-yl)acetamide as a yellow solid.MS (ESI): mass calculated for C9H10FIN2O 307.98 m/z, measured 308.95[M+H] ⁺ .

Step 2: N-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)-N-ethylacetamide

Under an inert atmosphere of nitrogen, a mixture of N-ethyl-N-(3-fluoro- 4-iodopyridin-2-yl)acetamide (1 g, 3.246 mmol, 1.00 equiv), tributyl(1- ethoxyvinyl)stannane (1.5 g, 4.153 mmol, 1.3 equiv), Pd(PPh3)2Cl2 (228 mg, 0.325 mmol, 0.1 equiv) in 1,4-dioxane (15 mL) was stirred at 90°C for 2 h. Concentrated. The residue was applied onto a silica gel column (80g, EtOAc/PE: 1/10) to yield N-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)-N- ethylacetamide as a yellow oil.MS (ESI): mass calculated for C13H17FN2O2 252.13 m/z, measured 253.05 [M+H] ⁺ .

Step 3: N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N-ethylacetamide To a mixture of N-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)-N- ethylacetamide (400 mg, 1.586 mmol, 1.0 equiv) in THF (6 mL) with H2O (3 mL) was added NBS (282 mg, 1.584 mmol, 1.0 equiv) and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine, dried over Na2S04, and concentrated to yield N- (4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N-ethylacetamide as a yellow solid.MS (ESI): mass calculated for CnHi2BrFN202 302.01 m/z, measured 305.00 [M+H+2]*.

Step 4: 2-(2-(N-ethylacetamido)-3-fluoropyridin-4-yl)-2-oxoethyl (3R)-7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate

To a mixture of (3R)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid (300 mg, 0.924 mmol, 1.0 equiv) in DMF (5 mL) was added CS2CO3 (181 mg, 0.556 mmol, 0.6 equiv) and the resulting mixture was stirred at room temperature for 30 min. N-(4-(2- bromoacetyl)-3-fluoropyridin-2-yl)-N-ethylacetamide (560 mg, 1.847 mmol, 2 equiv) was then added, and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography (0-20% MeOH/DCM) to yield 2-(2-(N- ethylacetamido)-3-fluoropyridin-4-yl)-2-oxoethyl (3R)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1 ^.S.S.S.Sa-hexahydroindolizine-S-carboxylate as a yellow solid. MS (ESI): mass calculated for C2eH25CIF2N405 546.15 m/z, measured 547.10[M+H] ⁺ .

Step 5: N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 -yl)-N- ethylacetamide

To a solution of 2-(2-(N-ethylacetamido)-3-fluoropyridin-4-yl)-2-oxoethyl (3R)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizine-3-carboxylate (350 mg, 0.640 mmol, 1.0 equiv) in toluene (10 ml_) with CHaCOOH (1 ml_) was added NhUOAc (493 mg, 6.396 mmol, 10 equiv). The reaction mixture was stirred for 2 h at 110 °C. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1,2, 3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3-fluoropyridin-2 -yl)-N- ethylacetamide as a yellow solid. MS (ESI): mass calculated for C2eH2sCIF2Ne02526.17 m/z, measured 527.10[M+H] ⁺ .

Step 6: N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5-oxo-

1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-3 -fluoropyridin-2-yl)-N- ethylacetamide

To a solution of N-(4-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-3-fluoropyridin-2-yl)-N- ethylacetamide (180 mg, 0.342 mmol, 1.0 equiv) in AcOH (5 ml_) were added TMSNs (394 mg, 3.420 mmol, 10.0 equiv), and trimethoxymethane (362 mg, 3.411 mmol, 10.0 equiv).The reaction mixture was stirred overnight at room temperature. The reaction was concentrated to dryness under reduced pressure to yield a residue, which was purified by column chromatography on silica gel with MeOH/DCM (0-15%) to yield N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6- (1 H-tetrazol-1-yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H- imidazol-5-yl)-3-fluoropyridin-2-yl)-N-ethylacetamide as a yellow solid. MS (ESI): mass calculated for C27H24CIF2N9O2579.17 m/z, measured 580.15[M+H] ⁺ .

Step 7: (3S,8aR)-7-(3-chloro-2-fluoro6-(1H-tetrazol-1-yl)phenyl)-3-( 5-(2- (ethylamino)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-2,3,8,8 a-tetrahydroindolizin- 5(1H)-one

To a solution of N-(4-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-3- fluoropyridin-2-yl)-N-ethylacetamide (130 mg, 0.224 mmol, 1.0 equiv) in THF (5 mL) was added 4N HCI (2 ml_). The reaction mixture was stirred 2h at 70 °C. The mixture was concentrated under vacuum and purified by C18 column (eluent: 5% to 60% (v/v) CH3CN and H20 with 0.05% NhUHCOs) to yield (3S)- 7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)5-(2-(ethylamino)-3 -fluoropyridin-4-yl)- 1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-one, which was further purified by preparative HPLC (Column: CHIRALPAK ID-3, 4.6*50mm, 3pm; Mobile Phase phenyl)-3-(A: MtBE (0.1% DBA): EtOH=70: 30; Flow rate: 1 mL/min; Gradient:20 B to 20 B in 14 min; 220/254 nm) to yield (3S,8aR)-7-(3- chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(2-(ethylam ino)-3-fluoropyridin- 4-yl)-1H-imidazol-2-yl)-2,3,8,8a-tetrahydroindolizin-5(1H)-o ne as a white solid.

MS (ESI): mass calculated for C25H22CIF2N9O 537.16 m/z, measured 538.20[M+H]+. LC-MS: (ES, m/z): 538.20 [M+H] ^{+ 1} H NMR (300 MHz, DMSO- de) δ 12.09 (s, 1H), 9.81 (s, 1H), 7.89-8.01 (m, 1H), 7.76 (d, J = 5.3 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 3.9, 2.1 Hz, 1H), 7.05 (t, J = 5.1 Hz,

1H), 6.37-6.47 (m, 1H), 5.67 (d, J = 2.6 Hz, 1H), 5.00 (d, J = 8.4 Hz, 1H), 3.63- 3.74 (m, 1H), 3.36 (dd, J = 7.3, 5.8 Hz, 2H), 2.67-2.78 (m, 1H), 2.49-2.54 (m,

1H), 2.04-2.21 (m, 2H), 1.92-1.99 (m, 2H), 1.13 (t, J = 7.1 Hz, 3H). : ¹⁸ F NMR (282 MHz, DMSO-de) δ -112.85, -112.94, -143.17, -143.59.

Example 391 (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-m ethyl-2,3,8,8a- tetrahydroindolizin-5(1 H)-one N

N

* f ^F ci

HO

Step 1: (S)-2-(5-(ethoxycarbonyl)pyrrolidin-2-ylidene)malonate

A mixture of ethyl (S)-5-thioxopyrrolidine-2-carboxylate (3.2 g, 18.472 mmol, 1.0 equiv.), bis(methoxycarbonyl)methylidene-imino-azanium (3.797 g, 24.014 mmol, 1.3 equiv.) and Grubbs Catalyst 1st Generation (1.524 g, 1.847 mmol, 0.1 equiv.) in benzene (45 mL) was stirred at 90 °C under nitrogen atmosphere for 2 h. The mixture was concentrated and purified by silica gel chromatography (0-80% EtOAc/petroleum ether) to yield dimethyl (S)-2-(5- (ethoxycarbonyl)pyrrolidin-2-ylidene)malonate as a light red oil. LC/MS: mass calculated for CizHiyNOe: 271.11, measured: 272.15 [M+H] ⁺ .

Step 2: 1-(tert-butyl) 2-ethyl (S)-5-(1,3-dimethoxy-1,3-dioxopropan-2- ylidene)pyrrolidine-1 ,2-dicarboxylate

To a solution of dimethyl (S)-2-(5-(ethoxycarbonyl)pyrrolidin-2- ylidene)malonate (5.7 g, 21.013 mmol, 1.0 equiv.), triethylamine (7.3 mL, 52.5 mmol, 2.50 equiv.) and DMAP (0.257 g, 2.101 mmol, 0.10 equiv.) in dichloromethane (100 mL) was added B0C2O (6.879 g, 31.519 mmol, 1.50 equiv.) and the mixture was stirred overnight at room temperature. The solution was concentrated and the residue was purified by silica gel chromatography (0- 50% EtOAc/petroleum ether) to yield 1 -(tert-butyl) 2-ethyl (S)-5-(1,3-dimethoxy- 1 ,3-dioxopropan-2-ylidene)pyrrolidine-1 ,2-dicarboxylate as a light red oil.

LC/MS: mass calculated for C17H25NO8: 371.16, measured: 372.30 [M+H]*. Step 3: 1 -(tert-butyl) 2-ethyl (2S)-5-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-5- methylpyrrolidine-1 ,2-dicarboxylate

Under an atmosphere of nitrogen, to a suspension of cuprous iodide (9.231 g, 48.468 mmol, 2.0 equiv.) in anhydrous diethyl ether (150 mL) at -50°C was added methylmagnesium bromide (32.3 mL, 96.9 mmol, 4.0 equiv., 3 mL) over a period of 15 min. After the addition was completed, the reaction mixture was gradually warmed room temperature and stirred for 40 min. Then the temperature of the mixture was lowered to -50°C, a diethyl ether solution (30 mL) of 1-(tert-butyl) 2-ethyl (S)-5-(1,3-dimethoxy-1,3-dioxopropan-2- ylidene)pyrrolidine-1,2-dicarboxylate (9.3 g, 24.234 mmol, 1.0 equiv.) was added. The reaction mixture was allowed to slowly warm to room temperature and then stirred for 1 h. Aqueous saturated NH4CI solution was added to quench the reaction. The mixture was filtered, and the filtrate was extracted with ethyl acetate twice. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-40% ethyl acetate/petroleum ether) to yield l-(tert-butyl) 2-ethyl (2S)-5-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-5- methylpyrrolidine-1,2-dicarboxylate as a light yellow oil. LC/MS: mass calculated for C18H29NO8: 387.19, measured: 410.05 [M+Na] ⁺ .

Step 4: l-(tert-butyl) 2-ethyl (2S)-5-(2-methoxy-2-oxoethyl)-5-methylpyrrolidine- 1 ,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-ethyl (2S)-5-(1 ,3-dimethoxy-1 ,3- dioxopropan-2-yl)-5-methylpyrrolidine-1,2-dicarboxylate (1.5 g, 3.872 mmol, 1.0 equiv.) in DMSO (15 mL) was added LiCI (1.641 g, 38.717 mmol, 10.0 equiv.) and H20 (0.2 mL). The reaction mixture was heated at 130°C for 6 h. The solution was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-60% EtOAc/petroleum ether) to yield 1 -(tert-buty I) 2- ethyl (2S)-5-(2-methoxy-2-oxoethyl)-5-methylpyrrolidine-1 ,2-dicarboxylate as a light red oil. LC/MS: mass calculated for Cieh^NOe: 329.18, measured: 330.20 [M+H]*. LC/MS: (ES, m/z): 330.20 [M+H] ⁺ .

Step 5: ethyl (2S)-5-(2-methoxy-2-oxoethyl)-5-methylpyrrolidine-2-carboxyl ate To a solution of 1-(tert-butyl) 2-ethyl (2S)-5-(2-methoxy-2-oxoethyl)-5- methylpyrrolidine-1 ,2-dicarboxylate (1.4 g, 4.250 mmol, 1.0 equiv.) in DCM (15 mL) was added trifluoroacetic acid (5 mL) at room temperature and the solution was stirred for 1 h at room temperature. The solution was concentrated and dissolved into dichloromethane. The pH value of the solution was adjusted to 8 and the solution was concentrated. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane) to yield ethyl (2S)-5-(2- methoxy-2-oxoethyl)-5-methylpyrrolidine-2-carboxylate as a light red oil.

LC/MS: mass calculated for C11H19NO4: 229.13, measured: 230.00 [M+H]*. Step 6: ethyl (2S)-1-(3-ethoxy-3-oxopropanoyl)-5-(2-methoxy-2-oxoethyl)-5- methylpyrrolidine-2-carboxylate

A mixture of ethyl (2S)-5-(2-methoxy-2-oxoethyl)-5-methylpyrrolidine-2- carboxylate (980 mg, 4.274 mmol, 1.0 equiv.), 3-ethoxy-3-oxopropanoic acid (1.129 g, 8.549 mmol, 2.0 equiv.), T3P (8.160 g, 12.823 mmol, 3.0 equiv., 50 wt % in EA) and triethylamine (2.4 mL, 17.1 mmol, 4.0 equiv.) in ethyl acetate (15 mL) was stirred at room temperature for overnight. The solution was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-5% methanol/dichloromethane) to yield ethyl (2S)-1-(3-ethoxy-3-oxopropanoyl)-5- (2-methoxy-2-oxoethyl)-5-methylpyrrolidine-2-carboxylate as a light yellow oil. LC/MS: mass calculated for CieHasNO: 343.16, measured: 344.15 [M+H]*. Step 7: diethyl (3S)-8a-methyl-5,7-dioxooctahydroindolizine-3,8-dicarboxylat e To a solution of ethyl (2S)-1-(3-ethoxy-3-oxopropanoyl)-5-(2-methoxy-2- oxoethyl)-5-methylpyrrolidine-2-carboxylate (1.3 g, 3.786 mmol, 1.0 equiv.) in ethanol (20 mL) was added sodium ethanolate (5.6 mL, 15.1 mmol, 4.0 equiv., 21% in EtOH) and the mixture was stirred for 1 h at 90 °C. After allowing to cool to 20 °C, the mixture was concentrated by Rotary Evaporator. The residue was acidified with 1N HCI and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to yield diethyl (3S)-8a-methyl-5,7-dioxooctahydroindolizine- 3,8-dicarboxylate as a light yellow oil (1.2 g). LC/MS: mass calculated for C15H21NO6: 311.14, measured: 312.00 [M+H]*.

Step 8: ethyl (3S)-8a-methyl-5,7-dioxooctahydroindolizine-3-carboxylate

A mixture of diethyl (3S)-8a-methyl-5,7-dioxooctahydroindolizine-3,8- dicarboxylate (1.2 g, 3.854 mmol, 1.0 equiv.) in acetic acid (10 mL) and water (1 mL) was stirred at 100 °C for 1 h. The mixture was concentrated to yield ethyl (3S)-8a-methyl-5,7-dioxooctahydroindolizine-3-carboxylate as a light red oil (950 mg). LC/MS: mass calculated for C12H17NO4: 239.12, measured:

240.10 [M+H]*.

Step 9: ethyl (3S)-8a-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

To a solution of ethyl (3S)-8a-methyl-5,7-dioxooctahydroindolizine-3- carboxylate (900 mg, 3.761 mmol, 1.0 equiv.) and triethylamine (1.3 ml_, 9.4 mmol, 2.50 equiv.) in dichloromethane (15 mL) was added N-phenyl- bis(trifluoromethanesulfonimide) (2.016g, 5.642 mmol, 1.50 equiv.) and the mixture was stirred for 2 h at room temperature. The solution was diluted with water and extracted with dichloromethane twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-5% methanol/dichloromethane) to yield ethyl (3S)-8a-methyl-5-oxo-7- (((trifluoromethyl)sulfonyl)oxy)-1 _l 2,3,5,8,8a-hexahydroindolizine-3-carboxylate as a light yellow oil. LC/MS: mass calculated for CiaHieFaNOeS: 371.07, measured: 372.05 [M+H]*.

Step 10: ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-8a-methyl-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate

A mixture of ethyl (3S)-8a-methyl-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (280 mg, 0.754 mmol, 1.00 equiv.), 6-amino-3-chloro-2-fluorophenylboronic acid (285.6 mg, 1.508 mmol, 2.0 equiv.), potassium phosphate (480.1 mg, 2.262 mmol, 3.00 equiv.) and Pd(dppf)Cl2.CH2Cl2 (57 mg, 0.075 mmol, 0.10 equiv.) in 1,4-dioxane (5.0 mL) and water (1 mL) was stirred for 2 h at 90 °C. After cooling to room temperature, the solution was diluted with water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (0-5% methanol/dichloromethane) to yield ethyl (3S)-7-(6- amino-3-chloro-2-fluorophenyl)-8a-methyl-5-oxo-1,2,3,5,8,8a- hexahydroindolizine-3-carboxylate as a light yellow solid. LC/MS: mass calculated for C18H20CIFN2O3: 366.11, measured: 367.10 [M+H]*.

Step 11: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-8a-methyl-5-oxo- 1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid

To a solution of ethyl (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-8a- methyl-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (260 mg, 0.709 mmol, 1.0 equiv.) in methanol (5 mL) was added aqueous LiOH solution (2.0 mL, 3M) and the solution was stirred at room temperature for 1 h. The solution was concentrated to 2 mL and then diluted with water. The pH value of the solution was adjusted to 3 and extracted with ethyl acetate twice. The organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-8a-methyl-5- oxo-1 ,2,3,5,8,8a-hexahydroindolizine-3-carboxylic acid as a brown solid, which used in the next step without further purification. LC/MS: mass calculated for CieHieCIFN2C>3: 338.08, measured: 339.05 [M+H]*.

Step 12: 2-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino- 3-chloro-2-fluorophenyl)-8a-methyl-5-oxo-1,2,3,5,8,8a-hexahy droindolizine-3- carboxylate

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-8a-methyl-5-oxo- I^.S.S.e.ea-hexahydroindolizine-S-carboxylic acid (220 mg, 0.649 mmol, 1.00 equiv.) and potassium carbonate (89.7 mg, 0.649 mmol, 1.00 equiv.) in DMF (2.0 mL) was stirred for 15 min at room temperature. 2-Bromo-1-(3-(((tert- butyldimethylsilyl)oxy)methyl)-2-fluorophenyl)ethan-1-one (268 mg, 0.97 mmol, 1.50 equiv.) was added and the mixture was stirred at room temperature for 1 h. The reaction was diluted with water and extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase chromatography on C18 (80, MeCN/hbO: 0»>50%) to yield 2- (3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-2-oxoethyl (3S)-7-(6-amino-3-chloro-2- fluorophenyl)-8a-methyl-5-oxo-1,2,3,5,8,8a-hexahydroindolizi ne-3-carboxylate as a light yellow solid. LC/MS: mass calculated for C24H22CIF2N3O5: 505.12, measured: 506.15 [M+H]*. Step 13: (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoiO-2- (hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-8a-methyl-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one A mixture of 2-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-2-oxoethyl (3S)-7- (6-amino-3-chloiO-2-fluorophenyl)-8a-methyl-5-oxo-1,2 _l 3,5,8,8a- hexahydroindolizine-3-carboxylate (50 mg, 0.1 mmol, 1.0 equiv.), ammonium acetate (76.1 mg, 0.99 mmol, 10.0 equiv.) and gladal acetic acid (6 mg, 0.1 mmol, 1.0 equiv.) in toluene (2 ml_) was stirred at 110 °C for 2 h. The reaction was concentrated and the residue was purified by reverse phase chromatography on C18 (80 g, MeCN/hfeO (0.05%CF3COOH): 0»>50%) to yield (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro-2- (hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-8a-methyl-2,3 ,8,8a- tetrahydroindolizin-5(1 H)-one as a light yellow solid. LC/MS: mass calculated for C24H22CIF2N5O2: 485.14, measured: 486.25 [M+H] ⁺ .

Step 14: (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- tetrahydroindolizin-5(1 H)-one

A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-3-(5-(3-fluoro-2- (hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-8a-methyl-2,3 ,8,8a- tetrahydroindolizin-5(1H)-one (20 mg, 0.041 mmol, 1.0 equiv.), azidotrimethylsilane (0.2 mL) and trimethoxymethane (0.2 mL) in glacial acetic acid (0.2 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography on C18 (40 g, MeCN/hteO (0.05%CF3COOH): 0»>50%) to yield (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-m ethyl-2,3,8 _l 8a- tetrahydroindolizin-5(1H)-one as a light yellow solid.

LC/MS: mass calculated for C25H21CIF2N8O2: 538.14, measured: 539.15 [M+H]*. ¹ H NMR: (300 MHz, methanol-di): 69.53 - 9.59 (m, 1 H), 8.27 - 8.60 (m, 2 H), 7.92 - 7.98 (m, 1 H), 7.79 - 7.86 (m, 1 H), 7.46 - 7.60 (m, 1 H), 5.73 - 5.82 (m, 1 H), 5.13 - 5.23 (m, 1 H), 4.99 -5.07 (m, 2 H), 2.78 - 3.03 (m, 1 H), 2.65 - 2.76 (m, 1 H), 2.46 - 2.59 (m, 1 H), 2.17 - 2.36 (m, 1 H), 1.98 - 2.13 (m, 2 H), 1.23 - 1.45 (m, 3 H).

Example 392: (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1 H-imidazol-2- yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-2, 3,8,8a- tetrahydroindolizin-5(1 H)-one

Step 1: (3S)-2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl 7-(6-amino-3- chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin e-3-carboxylate A mixture of (3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- I^.S.S.e.ea-hexahydroindolizine-S-carboxylic acid (500 mg, 1.540 mmol, 1.00 equiv) and CS2CO3 (301 mg, 0.924 mmol, 0.60 equiv) in DMF (8 mL) was stirred at room temperature for 10 min. N-(5-(2-bromoacetyl)-6-fluoropyridin-2- yl)acetamide (508 mg, 1.848 mmol, 1.20 equiv) was then added. The reaction mixture was stirred at room temperature overnight, then poured into water (100 mL) and filtered. The solid was collected to yield (3S)-2-(6-acetamido-2- fluoropyridin-3-yl)-2-oxoethyl 7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizine-3-carboxylate as yellow solid. LC/MS: mass calculated for C24H21CIF2N4O5: 518.12, measured: 541.05 [M+Na] ⁺ . Step 2: N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-1 ,2,3,5,8,8a- hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2 -yl)acetamide

A mixture of (3S)-2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl 7-(6- amino-3-chloro-2-fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroi ndolizine-3- carboxylate (450 mg, 0.867 mmol, 1.00 equiv) and NhUOAc (668 mg, 8.672 mmol, 10.00 equiv) in AcOH (0.5 mL) and toluene (10 mL) was stirred at 110 °C for 2 h, then concentrated. The resulting residue was applied onto a silica gel column (40 g, MeOH/DCM: 1/12) to yield N-(5-(2-((3S)-7-(6-amino-3-chloro-2- fluorophenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H -imidazol-5-yl)-6- fluoropyridin-2-yl)acetamide as yellow solid. LC/MS: mass calculated for C24H2iCIF ₂ Ne02: 498.14, measured: 499.10 [M+H]*. Step 3: N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)pheny l)-5-oxo- 1,2,3, 5,8, 8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridi n-2- yl)acetamide

A mixture of N-(5-(2-((3S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo- 1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-imidazol-5-yl)-6-fl uoropyridin-2- yl)acetamide (400 mg, 0.802 mmol, 1.00 equiv), trimethylsilylazide (TMSNs) (924 mg, 8.017 mmol, 10.00 equiv) and trimethoxymethane (851 mg, 8.017 mmol, 10.00 equiv) in AcOH (10 mL) was stirred at 65 °C for 2 h, then concentrated. The resulting residue was applied onto a silica gel column(40g, MeOH/DCM: 1/12) to yield N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1 H-tetrazol-1 - yl)phenyl)-5-oxo-1 ,2,3,5,8,8a-hexahydroindolizin-3-yl)-1 H-imidazol-5-yl)-6- fluoropyridin-2-yl)acetamide as yellow solid. LC/MS: mass calculated for C25H20CIF2N9O2: 551.14, measured: 552.10 [M+H]*.

Step 4: (3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-y l)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3, 8, 8a-tetrahydroindolizin-5(1H)- one

A mixture of N-(5-(2-((3S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1- yl)phenyl)-5-oxo-1,2,3,5,8,8a-hexahydroindolizin-3-yl)-1H-im idazol-5-yl)-6- fluoropyridin-2-yl)acetamide (330 mg, 0.598 mmol, 1.00 equiv) in THF (5 mL) and HCI (5 mL, 4M) was stirred at 50 °C for 2 h, then concentrated. The resulting residue was applied onto a C18 reverse phase column (330g,

ACN/H2O (0.05%NH4HC0 ₃ ): 5%»>40%>»45%) to yield (3S)-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-tetrahydroindolizin-5(1 H)-one as light yellow solid. The collected light yellow solid was purified by prep-chiral-HPLC (CHIRALPAK IC-3, 0.46*5cm;3um, (Hex:DCM=1:1)(0.1%DEA):EtOH=50:50, 25 °C) to yield:

(3S,8aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol- 2-yl)-7-(3-chloro-2- fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2, 3,8, 8a-tetrahydroindolizin-5(1 H)-one as a white solid, LC/MS (ES, m/z): mass calculated for C23H18CIF2N9O: 509.13, measured: 510.05 [M+H] ⁺ ;

¹ H-NMR (400 MHz, DMSO-d6) δ 11.60 - 12.02 (m, 1H), 9.84 (s, 1H), 7.88 - 8.11 (m, 2H), 7.72 (dd, J = 8.6, 1.5 Hz, 1H), 7.04 (s, 1H), 6.33 - 6.49 (m, 1 H), 6.25 (s, 2H), 5.70 (d, J = 2.6 Hz, 1 H), 4.99 (d, J = 8.5 Hz, 1 H), 3.60 - 3.90

(m, 1H), 2.71 (t, J = 14.8 Hz, 1H), 1.85 - 2.27 (m, 5H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -70.81, -112.88. and (3S,8aS)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-y l)-7-(3- chloro-2-fluoro-6-(1 H-tetrazol-1 -yl)phenyl)-2,3,8,8a-tetrahydroindolizin-5(1 H)- one as a white solid, LC/MS: mass calculated for C23H18CIF2N9O: 509.13, measured: 510.05 [M+H] ⁺ .

Biological and Formulation Examples Biological Example 1: Factor Xla inhibition assay utilizing a fluorophore- quencher pair peptide substrate

A fluorescence intensity (FLINT) based assay was used to monitor inhibition of Factor Xla. The peptide substrate, 5Fam-KLTRAETV-K5Tamra (purchased from New England Peptide) was chosen based on the FXI sequence. Conversion of zymogen FXI to its activated form, FXIa, occurs by proteolytic cleavage by FXIa at two sites, Arg146 and Arg180. The custom peptide used in this assay was based on the Arg146 cleavage site of FXI. The peptide substrate was designed with a fluorophore-quencher pair, where the fluorescence is quenched until FXIa cleaves the 8-mer peptide after the Arg residue. The substrate KM was fit to a substrate inhibition model whereby kc* = 0.86 S ^"1 , KM = 12.4 μΜ, K = 61.6 μΜ with an enzymatic efficiency, and kcat/KM = 69523 M V ¹ .

The Factor Xla FLINT assay was used with the following 5Fam- KLTRAETV-KSTamra assay buffer: 50 mM Tris, pH 7.5, 100 mM NaCI, 5 mM CaCh, 0.1 mg/mL BSA, 0.03% CHAPS. Assay buffer was prepared by mixing all ingredients fresh. 5Fam-KLTRAETV-K5Tamra peptide substrate was first prepared at 10 mM in 100% DMSO, then diluted to 3 mM in 100% DMSO. Assay buffer was then added directly to the 3 mM stock of substrate to prepare the 30 μΜ 2X working concentration (15 μΜ final concentration). The 2X Factor Xla stock solution was prepared by diluting 6.562 μΜ stock in 1X assay buffer for a 200 pM working stock solution (100 pM final concentration).

Test compound(s) were run in an 11 -point, 3-fold serial dilution with a final top compound concentration of 100nM. Final DMSO in assay was 2%. FXIa was preincubated with compound for 30-minutes and then substrate was added to initiate the reaction. The assay was run with kinetic (KIN) reads at 5 min intervals over 30 minutes. The time course was linear using 100 pM FXIa greater than 30 minutes. More specifically, the assay was run as follows:

• 100 nL of 0.01 mM test compound was dispensed into black 384- well non-binding Greiner BioOne 784900 plate for 0.1 μΜ final concentration; e 5 μΙ_ of 1X assay buffer was dispensed to column 24 (low control) and 5 μΙ_ 2X Factor Xla solution was dispensed to columns 1-23 (column 23 high control);

• the plate was centrifuged with a “cover” plate at 500 rpm for 1 min

• the plate was pre-incubated for 30 minutes at room temperature with plate covered; e 5 μΐ_ of 2X 5Fam-KLTRAE≡TV-K5T amra peptide substrate was dispensed into the entire plate, columns 1-24;

• the plate was centrifuged with a “cover" plate at 500 rpm for 1 min; e the plate was read monitoring fluorescence intensity on the BMG PHERAStar at room temperature, using fluorescence module 485 nm/520 nm.

Percent inhibition (ICso) curves were generated per compound tested, and data was analyzed using a 4-parameter logistic fit using GeneData Screener. The relative fluorescence unit (RFU) values were normalized to percent inhibition using the following equation:

% inhibition = ((HC-LC)-(compound -LC) / (HC-LQ) * 100 where LC - low control = mean signal of no Factor Xla or 100% inhibition of Factor Xla; HC - high control = mean signal of Factor Xla + 5Fam- KLTRAETV-KSTamra peptide substrate with DMSO only. An 11-point dose response curve for the test compound(s) was generated using GEN DATA to determine ICso value based on the following equation:

Y = Bottom + (To^Bottom)/(1 +1 ^((loglCso-XrHillSIope)) where Y is the % inhibition in the presence of X inhibitor concentration, Top = high control = mean signal of Factor Xla + 5Fam-KLTRAETV-K5Tamra peptide substrate with DMSO only; Bottom = low control - mean signal of no Factor Xla or 100% inhibition of Factor Xla; HillSIope - Hill coefficient; and ICso = concentration of compound with 50% inhibition in relation to top / high control. Biological Example 2: Kallikrein inhibition assay utilizing a quenched AMC peptide substrate

A fluorescence intensity (FLINT) based assay was used to monitor inhibition of human plasma kallikrein. The peptide substrate, Z-Gly-Pro-Arg- AMC (Purchased from Bachem; Catalog # 1-1150) was chosen based on its relatively low KM for kallikrein which enables running the assay at lower substrate concentrations to control background fluorescence. The kinetic parameters for this substrate were determined by fitting titration data to the Michaelis-Menten equation yielding a KM = 40 μΜ, kcat = 0.76 s ¹ , and kcat/KM = 18932 M V.

The Kallikrein FLINT assay was used with the following Z-Gly-Pro-Arg- AMC assay buffer: 50mM Tris, pH 7.5, 100mM NaCI, 5mM CaCb, 0.1 mg/m L BSA, 0.03% CHAPS. Assay buffer was prepared by mixing all ingredients fresh. 2X Z-Gly-Pro-Arg-AMC peptide substrate was prepared by diluting 10 mM stock into 1X assay buffer for a 100 μΜ working concentration (50 pM final concentration). The 2X kallikrein stock solution was prepared by diluting 14.76 pM stock in 1X assay buffer for a 4 nM working stock solution (2 nM final concentration).

Test compound(s) were run in an 11 -point, 3-fold serial dilution with a final top compound concentration of 1 pM. Final DMSO in assay was 2%. Plasma kallikrein was pre-incubated for 30-minute with compound and then 50pM substrate was added to initiate the reaction. The assay was run with kinetic (KIN) reads at 5 min intervals over 30 minutes. The time course was linear using 2 nM kallikrein greater than 30 minutes. More specifically, the assay was run as follows:

100 nL of 0.1 mM test compound was dispensed into black 384- well non-binding Greiner BioOne 784900 plate for 1 μΜ final concentration;

5 pL of 1X assay buffer was dispensed to columns 24 (low control) and 5 pL 2X human kallikrein enzyme solution was dispensed to columns 1-23 (column 23 high control); the plate was centrifuged with a “cover” plate at 500 rpm for 1 min the plate was pre-incubated for 30 minutes at room temperature with plate covered;

5 pL of 2X Z-Gly-Pro-Arg-AMC peptide substrate was dispensed into the entire plate, columns 1-24; the plate was centrifuged with a “cover” plate at 500 rpm for 1 min; the plate was read monitoring fluorescence intensity on the BMG PHERAStar at room temperature, using fluorescence module 340 nm/440 nm.

Percent inhibition (ICso) curves were generated per compound tested, and data was analyzed using a 4-parameter logistic fit using GeneData Screener. The relative fluorescence unit (RFU) values were normalized to percent inhibition using the following equation:

% inhibition = ((HC-LC)-(compound -LC) \ (HC-LC)) * 100 where LC - low control = mean signal of human kallikrein enzyme or 100% inhibition of human kallikrein enzyme; HC - high control = mean signal of

Factor Xla + Z-Gly-Pro-Arg-AMC peptide substrate with DMSO only.

An 11-point dose response curve for the test compound(s) was generated using GENDATA to determine ICso value based on the following equation:

Y = Bottom + (Top-Bottom)/(1 + 10 ^A ((loglCso-X)*H illSIope)) where Y is the % inhibition in the presence of X inhibitor concentration, Top = high control = mean signal of human kallikrein enzyme + Z-Gly-Pro-Arg- AMC peptide substrate with DMSO only; Bottom = low control - mean signal of no human kallikrein enzyme or 100% inhibition of human kallikrein enzyme; HillSIope - Hill coefficient; and ICso = concentration of compound with 50% inhibition in relation to top / high control.

Representative compounds of the present invention were tested according to the procedure described in Biological Example 1 and Biological Example 2 above, with results as listed in Table 3, below.

Table 3: Biological Activity, Representative Compounds of Formula (I)

FXIa Kin Kallikrein Kin

Example Inh ICso (nM) Inh ICso (nM)

1 12.6 67.9

2 1.9 9.3

3 3.9 5.4

4 91.7 867.4

5 4.2 48.8

6 0.6 6.6

7 6.4 70.1

8 3.7 17.7

9 2.1 8.5

10 36.1 26.8

11 11.4 30.5

12 2.7 35.5

13 4.2 68.6

14 3.8 6.5

15 3.7 27.5

16 61.0 330.1

17 3.0 29.0

18 82.1 465.3

19 2.4 7.4

20 1.0 9.5

21 6.3 65.5

22 47.8 102.9

23 50.1 264.7

24 74.4 92.0

25 >100 479.7

26 >100 269.6

27 >100 118.1

28 1.3 9.4

29 57.9 307.0

30 2.1 4.4

31 0.7 1.8 32 1.5 2.9

33 3.9 33.2

34 0.6 32.8

35 60.1 244.6

36 5.1 33.7

37 1.3 55.8

38 2.1 2.6

39 95.6 136.5

40 0.8 6.4

41 44.7 54.2

42 1.0 4.6

43 2.1 4.0

44 1.8 11.4

45 4.4 41.3

46 5.4 35.5

47 5.7 42.6

48 22.5 72.4

49 31.3 11.4

50 19.8 31.6

51 3.8 4.4

52 3.2 9.5

53 1.7 2.8

54 0.8 67.9

56 35.2 59.2

57 20.2 105.8

58 0.7 49.2

59 3.1 12.0

61 0.5 44.4

63 6.9 6.2

64 11.5 156.3

65 45.4 419.9

66 55.0 25.9

67 10.7 85.7

68 30.0 58.0

69 0.3 3.8

70 0.3 2.6

71 13.8 19.4

72 6.5 2.3

73 0.6 2.7

74 2.6 4.9

75 4.3 38.3

76 0.7 1.9

77 1.3 5.0

78 40.9 136.5

79 7.5 12.2

80 1.3 11.2 81 0.7 1.8

83 17.4 57.5

84 0.3 3.0

85 11.1 8.9

86 4.6 3.2

87 0.9 1.6

88 1.5 1.9

89 5.8 7.4

90 0.5 5.5

92 3.7 6.0

93 10.3 3.1

94 12.3 121.5

95 3.5 23.9

96 5.4 2.6

97 1.6 4.6

98 0.6 9.0

99 2.3 3.2

100 1.9 5.1

101 0.6 1.9

102 10.3 9.6

103 1.6 53.1

104 16.6 35.4

105 62.9 125.1

106 11.0 27.0

107 0.7 6.5

108 2.9 5.7

109 4.8 35.8

110 11.0 6.9

111 2.9 3.8

112 9.6 20.6

113 3.2 27.3

114 9.4 55.9

115 1.5 1.9

116 8.3 64.4

117 2.9 24.8

118 0.4 1.7

119 0.6 11.7

120 4.5 67.7

121 0.7 16.9

122 4.0 53.1

123 0.4 8.6

124 0.4 11.6

125 0.5 9.6

126 0.5 4.6

127 10.9 12.9

128 6.1 12.8 129 0.4 5.4

130 3.5 12.7

131 0.9 11.7

132 0.4 6.8

133 0.7 7.5

134 0.4 1.1

135 22.5 15.5

136 4.8 6.3

137 4.6 7.7

138 32.0 138.0

139 29.1 22.0

140 2.9 6.2

141 10.8 13.0

142 6.2 10.7

143 2.4 33.0

144 3.1 43.5

145 0.6 7.7

146 0.5 7.3

147 0.5 7.8

148 0.6 8.6

149 0.5 7.6

150 0.6 8.6

151 0.6 8.9

152 0.7 1.0

153 0.5 8.1

154 0.4 5.7

155 4.9 52.4

156 13.8 19.1

157 2.0 6.8

158 1.0 7.8

159 5.4 22.2

160 8.4 27.8

161 0.5 1.9

162 4.2 30.6

163 7.4 28.8

164 4.3 16.6

165 8.0 122.9

166 0.8 6.6

167 31.0 371.5

168 0.8 4.9

169 42.3 40.1

170 17.9 31.8

171 4.1 31.7

172 3.6 6.1

173 1.7 7.0

174 18.1 25.9 175 9.5 30.3

176 4.0 28.5

177 3.1 21.6

178 0.4 1.1

179 0.5 1.4

180 8.6 33.2

181 8.3 17.8

182 0.4 14.1

183 0.6 3.8

184 7.3 210.0

185 6.5 33.9

186 4.6 35.1

187 3.7 4.1

188 17.2 7.8

189 1.8 16.7

190 1.2 9.4

191 3.8 34.3

192 5.4 29.5

193 0.4 14.3

194 2.2 16.8

195 0.5 22.1

196 0.6 3.4

197 4.1 6.0

198 30.5 14.3

199 1.3 15.6

200 4.4 24.4

201 9.1 6.9

202 0.6 1.5

203 0.9 2.5

204 29.1 24.5

205 3.3 12.5

206 10.6 9.5

207 2.5 7.7

208 4.6 7.8

209 46.5 37.9

210 9.3 20.7

211 0.2 0.8

212 20.5 90.9

213 39.4 197.1

214 1.4 1.7

215 >100 117.2

216 19.6 27.4

217 4.5 32.6

218 0.3 0.7

219 2.1 1.9

220 5.0 9.7 221 2.3 7.7

222 1.8 12.6

223 15.9 138.3

224 0.5 8.0

225 2.6 16.6

226 10.2 38.4

227 3.5 11.4

228 18.8 162.2

229 54.9 342.3

230 0.4 11.1

231 37.1 84.6

232 >100 17.8

233 24.2 6.7

234 1.0 0.6

235 4.7 21.1

236 5.3 21.6

237 5.6 1.5

238 0.2 0.7

239 1.5 15.9

240 0.6 12.9

241 3.3 14.9

242 10.8 18.7

243 52.0 653.0

244 >100 730.1

245 76.8 558.1

246 1.8 141.2

247 0.7 15.6

248 1.0 1.5

249 0.2 0.4

250 0.2 0.7

251 32.2 226.4

252 0.6 4.5

253 >100 >1 uM

254 16.7 150.4

255 >100 >1 uM

256 1.4 67.5

257 0.5 0.7

258 0.3 0.8

259 2.7 21.0

260 >100 462.2

261 0.3 0.7

262 45.8 149.7

263 2.3 33.7

264 1.1 2.1

265 0.4 1.0

266 0.9 1.1 267 1.0 9.0

268 68.1 285.5

269 >100 792.7

270 0.2 0.4

271 0.8 0.9

272 >100 >1 μΜ

273 0.5 2.0

274 >100 >1 μΜ

275 24.4 15.6

276 0.6 1.2

277 0.2 1.1

278 0.5 1.9

279 0.9 1.5

280 0.6 1.2

281 0.3 0.8

282 1.2 9.0

283 3.5 5.9

284 1.3 3.5

285 9.1 206.6

286 1.5 1.1

287 -30.4 379.8

288 >200 1.1 μΜ

289 >200 491.7

290 134.0 1.2 μΜ

291 0.5 7.4

292 0.3 0.7

293 79.7 1.2 μΜ

294 77.0 46.2

295 0.7 2.6

296 0.6 5.4

297 0.3 1.0

298 >100 1.05 μΜ

299 5.2 5.6

300 1.4 2.0

301 3.1 17.7

302 10.4 29.1

303 0.9 4.4

304 >100 322.9

305 0.7 1.7

306 0.5 11.8

307 0.3 0.7

308 92.7 >100

309 1.9 1.3

310 33.6 >100

311 0.3 0.7

312 0.3 0.6 313 0.2 0.6

314 1.0 3.2

315 31.1 34.8

316 5.0 25.5

317 5.3 12.9

318 54.1 71.5

319 2.2. μΜ 454.6

320 23.5 3.8

321 78.7 342.5

322 0.8 10.3

323 18.9 36.3

324 14.3 95.0

325 1.2 7.0

326 1.0 12.4

327 0.6 9.5

328 3.4 45.9

329 0.5 1.3

330 0.9 2.4

331 347.1 2.4 uM

332 85.8 542.3

333 282.4 1.1 uM

334 210.9 7.3 μΜ

335 5.7 22.7

336 9.3 47.9

337 1.5 12.7

338 1.0 8.4

339 134.3 2.05 μΜ

340 0.3 1.9

341 0.2 1.3

342 22.6 405.1

344 202.3 1.3 uM

345 2.6 14.5

346 1.3 8.2

347 0.6 5.5

348 0.5 6.4

349 0.6 5.6

350 1.3 18.5

351 2.7 7.8

352 0.3 4.9

353 12.9 17.5

354 0.2 2.6

355 0.2 1.4

356 7.4 μΜ >10 μΜ

357 64.1 2.3 μΜ

358 0.3 6.8

359 0.5 11 360 12.0 110.0

361 0.7 6.1

362 0.1 2.5

363 >100 >1 μΜ

364 87.0 610.0

365 2.7 7.3

366 1.4 19.0

367 0.4 7.5

368 0.7 7.4

369 0.2 0.5

370 0.2 0.9

371 36.3 56.5

372 0.3 1.2

373 0.7 39.6

374 0.8 1.5

376 7.3 208.7

378 14.5 114.6

379 0.6 2.2

380 0.8 4.2

381 17.1 13.6

382 1.4 27.7

383 3.1 12.6

384 1.7 6.6

385 3.6 26.8

386 1.3 9.5

387 1.3 3.8

388 0.5 1.9

389 1.4 12.4

390 0.4 1.3

391 33.3 35.4

Formulation Example 1

Solid, Oral Dosage Form - Prophetic Example As a specific embodiment of an oral composition, 100 mg of any of Compound ID No. 354, prepared as described in Example 354, above is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.