Fused heterocyclic amide / sulfonamide compounds as agonists of the calcitonin / amylin receptors for the treatment of obesity

Abstract

The present disclosure relates to fused heterocyclic amide / sulfonamide compounds of Formula (I) as described herein and to their use in medicine; to pharmaceutical compositions containing them; to processes for their preparation; and to intermediates used in such processes. The fused heterocyclic amide / sulfonamide compounds of Formula (I) and salts thereof may be useful to treat or prevent, for example, obesity, weight gain, and / or T2DM.

Description

[0001] PC073237A

[0002] Fused Heterocyclic Amide / Sulfonamide Compounds

[0003] Background of the Invention

[0004] The present invention relates to novel fused heterocyclic amide / sulfonamide compounds. The invention also relates to the preparation of the fused heterocyclic amide / sulfonamide compounds and intermediates used in the preparation, compositions containing the compounds, and uses of the compounds including as agonists of the calcitonin / amylin receptors for the treatment of obesity.

[0005] The global prevalence of obesity is fueling a world-wide health crisis due to increased obesity related co-morbidities such as cardiovascular disease, Type-2 diabetes, chronic kidney disease and cancer. Until recently, life-style modification was the only therapeutic available to treat subjects with obesity. Unfortunately, this therapy is inadequate as most subjects achieve modest weight loss with life-style modification and regain the lost weight a few years after achieving maximal weight loss. Thus, new therapies are needed to treat people with obesity and stave off the oncoming healthcare epidemic. Recent pharmacotherapies developed more effectively manage obesity and weight loss based on the incretin proteins GLP-1 (glucagon-like peptide 1) and GIP (gastric inhibitory polypeptide). In 2014 liraglutide became the first of many novel GLP1 analogues approved for the treatment of obesity demonstrating significant weight loss in obese individuals. More recently, Tirzepatide a dual GLP1 and GIP agonist, demonstrated superior weight loss than GLP1 monotherapies highlighting the impact of pharmacologic combinations for combating obesity. However, new therapies are still needed as gastro-intestinal side effects from existing therapies can be difficult to tolerate. Additionally, more weight loss is needed to fully mitigate the risk of obesity associated comorbidities.

[0006] One novel class of drugs currently being explored for drug development are based on the hormone amylin. Amylin, a 37 amino acid polypeptide, is co-secreted with insulin by pancreatic beta cells following a meal. In subjects with Type-2 diabetes, amylin precipitates and forms fibrils in pancreatic beta cells causing cell death. However, despite these properties of human amylin, more stable amylin analogues have been generated and shown to promote satiety and suppress food intake. In addition to suppressing appetite, amylin reduces gastric emptying and suppresses glucagon secretion. More recently, several amylin peptide analogues, exemplified by cagrilintide, have advanced in clinical studies for weight loss as potential pharmacotherapeutics for obesity.

[0007] Amylin and related analogues signal through the calcitonin and amylin receptors expressed in the subcortical region of the hindbrain and the ventral tegmental area in the mesolimbic nucleus. Amylin receptors are G-protein coupled receptors comprised of a core calcitonin receptor (CALCR) and a co-receptor, receptor-activity modifying proteins (RAMP) 1, 2 or 3, forming amylin receptor (AmyR) 1, 2 and 3. In the absence of RAMP association, thecalcitonin receptor is a functional receptor and drives anorectic signaling as administration of a long-acting amylin agonist to mice lacking RAMP1 / 3 causes weight loss and appetite suppression. However, other studies have shown that the AmyR mediates some of the effects of amylin and salmon calcitonin on appetite. Indeed, loss of AmyR3 in mice prevents the anorectic effects of amylin and salmon calcitonin suggesting that AmyR3 is crucial for optimal reductions in food intake. Hence, strategies for activation of both receptors, referred to as dual amylin-calcitonin receptor agonists (DACRA) because of their ability to activate both, have been employed. To date, most AmyR / CALCR agonists created are peptide DACRAs such as cagrilintide. More recently an AmyR3 selective agonist was described that also caused potent weight loss. However, the development of small molecule CALCR / AmyR agonists remains limited. Accordingly, there remains a need for improved calcitonin / amylin receptor agonists. The compounds, combinations and methods of the present invention are believed to have one or more advantages, such as oral bioavailability for the treatment of obesity and co-morbidities associated with obesity such as cardiovascular disease, Type-2 diabetes, chronic kidney disease and cancer.

[0008] Summary of the Invention

[0009] The present invention provides, in part, compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such compounds may agonize the activity of the calcitonin / amylin receptors and may be useful in the treatment of obesity and co-morbidities associated with obesity such as cardiovascular disease, Type-2 diabetes, chronic kidney disease and cancer, and for the suppression of appetite, suppression of glucagon secretion and reduction of gastric emptying. Also provided are pharmaceutical compositions, comprising the compounds or salts of the invention, alone or in combination with additional anti-obesity therapeutic agents. The present invention also provides, in part, methods for preparing such compounds, pharmaceutically acceptable salts and compositions of the invention, and methods of using the foregoing. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0010] According to an embodiment of the invention there is provided a compound of Formula (I)

[0011]

[0012] or a pharmaceutically acceptable salt thereof;

[0013] wherein

[0014] Z is NR5’ or O;

[0015] Z1is -C(O)- or -S(O)2-;

[0016] R1and R5’ are each independently selected from the group consisting of hydrogen, Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- wherein the Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 Rs;

[0017] R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0018] R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, Ci-Cealkyl substituted with 0 to 6 Rs, Ci-Cealkoxy substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0019] or R2and R3or R4and R5can be taken together with the carbon to which they are attached to form a Ce-Cyspirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;

[0020] or R2and R4can be taken together with the carbons to which they are attached to form a C3-Cycycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;

[0021] - is absent or is a bond, provided only one - is a bond at a time and when - is a bond connecting the carbons to which R2and R4are attached then R3and R5are absent and when Z is O the - attached to O is absent and when Z is NR5’ and the - is a bond then R5’ is absent;

[0022] R6is selected from the group consisting of (C6-Cioaryl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C2-C8alkenyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C3-C7cycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (5- to 10-membered heteroaryl)-(Co-C4alkyl)-L-Co-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-; wherein the R6group is substituted with 0 to 6 Rs;

[0023] L is selected from a bond, O, NH and N(Ci-C3alkyl);

[0024] X is N or CR7;R7is selected from the group consisting of hydrogen, -C(O)OR7a, -C(O)NR7bR7c, -OC(O)NR7bR7c, -N(R7d)C(O)NR7bR7c, Ci-C6alkyl substituted with 0 to 6 Rs, Ci-C6alkoxy substituted with 0 to 6 Rs, Cs-Cycycloalkyl-Co-Cealkyl- substituted with 0 to 6 Rs, (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- substituted with 0 to 6 Rs, Ce-C aryl-Co-Cealkyl-substituted with 0 to 6 Rsand 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 Rs;

[0025] or R7and R6taken together with the carbons to which they are attached form a fused C4-C7cycloakyl ring or a fused 4- to 7-membered heterocycloalkyl ring;

[0026] R7ais Ci-Cealkyl substituted with 0 to 6 Rs;

[0027] R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-Cealkyl substituted with 0 to 6 Rs;

[0028] or R7band R7ctaken together with the nitrogen to which they are attached can form a 4- to 7-membered heterocycloalkyl which is substituted with 0 to 6 Rs;

[0029] Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-C8cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the Ce-C aryl and 5- to 10-membered heteroaryl are optionally fused with a Cs-Cycycloalkyl or a 4 to 7-membered heterocycloalkyl and Ring A is substituted with 0 to 6 Rs;

[0030] Y is selected from the group consisting of -C(O)NR8R9, -N(R8)C(O)R9, -C(O)OR8, -OR8, -NR8R9, -N(R8)S(O)2R9, -S(O)2R8, -S(O)2NR8R9and -N(R8’)C(O)NR8R9;

[0031] R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 Rs, Cs-C cycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs, 4 to 7-membered heterocycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs, (C6-C aryl)-Co-Cealkyl- substituted with 0 to 6 Rs, (5- to 10-membered heteroaryl)-Co-Cealkyl- substituted with 0 to 6 Rs,

[0032] or R8and R9when attached to a nitrogen can be taken together with the nitrogen to which they are attached to form a 4- to 7-membered heterocycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs;

[0033] Rsat each occurrence is independently selected from the group consisting of halo, hydroxy, oxo, cyano, -NRS1RS2, -Ci-Cealkyl-NRS1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, C1-Csalkoxy substituted with 0 to 6 fluoro, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro, C1-Csalkoxy-Ci-Csalkoxy- substituted with 0 to 6 fluoro, Cs-Cscycloalkyl substituted with 0 to 6 RS3, 4- to 7-membered heterocycloalkyl substituted with 0 to 6 RS3, 5- to 10-membered heteroaryl substituted with 0 to 6 RS3and C6-C10 aryl substituted with 0 to 6 RS3;

[0034] or two Rstaken together with the atoms to which they are attached can form

[0035] RS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 6 RS3, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6RS3, C3-C7cycloalkyl-Co-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-Co-C3alkyl- substituted with 0 to 6 RS3;

[0036] or RS1and RS2taken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl which is substituted with 0 to 6 RS3; and RS3at each occurrence is independently selected from halo, hydroxy, cyano, Ci-Csalkyl and Ci-Csalkoxy;

[0037] or an isotope thereof or a pharmaceutically acceptable salt of the compound or isotope thereof.

[0038] Described below are embodiments of the invention, where for convenience Embodiment 1” (E1”) is identical to the embodiment of Formula (I) provided above.

[0039] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0040] Detailed Description of the Invention

[0041] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0042] E1' A compound of Formula (I)

[0043]

[0044] or a pharmaceutically acceptable salt thereof;

[0045] wherein

[0046] Z is NR5’ or O;

[0047] Z1is -C(O)- or -S(O)2-;

[0048] R1and R5’ are each independently selected from the group consisting of hydrogen, Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- wherein theCi-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 Rs;

[0049] R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0050] R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, Ci-Cealkyl substituted with 0 to 6 Rs, Ci-Cealkoxy substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0051] or R2and R3or R4and R5can be taken together with the carbon to which they are attached to form a Cs-Cyspirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;

[0052] or R2and R4can be taken together with the carbons to which they are attached to form a C3-Cycycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;

[0053] - is absent or is a bond, provided only one - is a bond at a time and when - is a bond connecting the carbons to which R2and R4are attached then R3and R5are absent and when Z is O the - attached to O is absent and when Z is NR5’ and the - is a bond then R5’ is absent;

[0054] R6is selected from the group consisting of (C6-Cioaryl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C2-C8alkenyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C3-C7cycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (5- to 10-membered heteroaryl)-(Co-C4alkyl)-L-Co-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-; wherein the R6group is substituted with 0 to 6 Rs;

[0055] L is selected from a bond, O, NH and N(Ci-C3alkyl);

[0056] X is N or CR7;

[0057] R7is selected from the group consisting of hydrogen, -C(O)OR7a, -C(O)NR7bR7c, -OC(O)NR7bR7c, -N(R7d)C(O)NR7bR7c, Ci-C6alkyl substituted with 0 to 6 Rs, Ci-C6alkoxy substituted with 0 to 6 Rs, Cs-Cycycloalkyl-Co-Cealkyl- substituted with 0 to 6 Rs, (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- substituted with 0 to 6 Rs, Ce-C aryl-Co-Cealkyl-substituted with 0 to 6 Rsand 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 Rs;

[0058] or R7and R6taken together with the carbons to which they are attached form a fused C4-C7cycloakyl ring or a fused 4- to 7-membered heterocycloalkyl ring;

[0059] R7ais Ci-Cealkyl substituted with 0 to 6 Rs;

[0060] R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and Ci-Cealkyl substituted with 0 to 6 Rs;

[0061] or R7band R7ctaken together with the nitrogen to which they are attached can form a 4- to 7-membered heterocycloalkyl which is substituted with 0 to 6 Rs;

[0062] Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-C8cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein Ring A is substituted with 0 to 6 Rs;Y is selected from the group consisting of -C(O)NR8R9, -N(R8)C(O)R9, -C(O)OR8, -OR8, -NR8R9, -N(R8)S(O)2R9, -S(O)2R8, -S(O)2NR8R9and -N(R8’)C(O)NR8R9;

[0063] R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 Rs, Cs-C cycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs, (C6-Cioaryl)-Co-Cealkyl- substituted with 0 to 6 Rs, (5- to 10-membered heteroaryl)-Co-Cealkyl- substituted with 0 to 6 Rs,

[0064] or R8and R9when attached to a nitrogen can be taken together with the nitrogen to which they are attached to form a 4- to 7-membered heterocycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs;

[0065] Rsat each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, -NRS1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, Ci-Csalkoxy substituted with 0 to 6 fluoro, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro, Cs-Cscycloalkyl substituted with 0 to 6 RS3, 4- to 7-membered heterocycloalkyl substituted with 0 to 6 RS3, 5- to 10-membered heteroaryl substituted with 0 to 6 RS3and Ce-C aryl substituted with 0 to 6 RS3;

[0066] RS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 6 RS3, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 RS3, C3-C7cycloalkyl-Co-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-Co-C3alkyl- substituted with 0 to 6 RS3;

[0067] or RS1and RS2taken together with the nitrogen to which they are attached form a 4- to 7 membered heterocycloalkyl which is substituted with 0 to 6 RS3; and RS3at each occurrence is independently selected from halo, hydroxy, cyano, Ci-Csalkyl and Ci-Csalkoxy.

[0068] E1 A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined above for E1’ wherein

[0069] Z is NR5’ or O;

[0070] Z1is -C(O)- or -S(O)2-;

[0071] R1and R5’ are each independently selected from the group consisting of hydrogen, Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- wherein the Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-Cealkyl- are substituted with 0 to 6 Rs;

[0072] R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0073] R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, Ci-Cealkyl substituted with 0 to 6 Rs, Ci-Cealkoxy substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0074] or R2and R3or R4and R5can be taken together with the carbon to which they are attached to form a Cs-Cyspirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;or R2and R4can be taken together with the carbons to which they are attached to form a C3-Cycycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;

[0075] - is absent or is a bond, provided only one - is a bond at a time and when - is a bond connecting the carbons to which R2and R4are attached then R3and R5are absent and when Z is O the - attached to O is absent and when Z is NR5’ and the - is a bond then R5’ is absent;

[0076] R6is selected from the group consisting of (C6-Cioaryl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C2-C8alkenyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C3-C7cycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (5- to 10-membered heteroaryl)-(Co-C4alkyl)-L-Co-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-; wherein the R6group is substituted with 0 to 6 Rs;

[0077] L is selected from a bond, O, NH and N(Ci-C3alkyl);

[0078] X is N or CR7;

[0079] R7is selected from the group consisting of hydrogen, -C(O)OR7a, -C(O)NR7bR7c, -OC(O)NR7bR7c, -N(R7d)C(O)NR7bR7c, Ci-C6alkyl substituted with 0 to 6 Rs, Ci-C6alkoxy substituted with 0 to 6 Rs, Cs-Cycycloalkyl-Co-Cealkyl- substituted with 0 to 6 Rs, (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- substituted with 0 to 6 Rs, Ce-C aryl-Co-Cealkyl-substituted with 0 to 6 Rsand 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 Rs;

[0080] or R7and R6taken together with the carbons to which they are attached form a fused C4-C7cycloakyl ring or a fused 4- to 7-membered heterocycloalkyl ring;

[0081] R7ais Ci-Cealkyl substituted with 0 to 6 Rs;

[0082] R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-Cealkyl substituted with 0 to 6 Rs;

[0083] or R7band R7ctaken together with the nitrogen to which they are attached can form a 4- to 7-membered heterocycloalkyl which is substituted with 0 to 6 Rs;

[0084] Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-C8cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein Ring A is substituted with 0 to 6 Rs;

[0085] Y is selected from the group consisting of -C(O)NR8R9, -N(R8)C(O)R9, -C(O)OR8, -OR8, -NR8R9, -N(R8)S(O)2R9, -S(O)2R8, -S(O)2NR8R9and -N(R8’)C(O)NR8R9;

[0086] R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 Rs, Cs-Cycycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs, (Ce-C aryO-Co-Cealkyl- substituted with 0 to 6 Rs, (5- to 10-membered heteroaryl)-Co-Cealkyl- substituted with 0 to 6 Rs,

[0087] or R8and R9when attached to a nitrogen can be taken together with the nitrogen to which they are attached to form a 4- to 7-membered heterocycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs;Rsat each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, -NRS1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, Ci-Csalkoxy substituted with 0 to 6 fluoro and Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro;

[0088] RS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 6 RS3, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 RS3, C3-C7cycloalkyl-Co-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-Co-C3alkyl- substituted with 0 to 6 RS3;

[0089] or RS1and RS2taken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl which is substituted with 0 to 6 RS3; and RS3at each occurrence is independently selected from halo, hydroxy, cyano, Ci-Csalkyl and Ci-Csalkoxy.

[0090] E2 is the compound of ET or E1 of Formula (I’)

[0091]

[0092] or a pharmaceutically acceptable salt thereof.

[0093] E3 is the compound of E2 of Formula (la) or Formula (lb)

[0094]

[0095] or a pharmaceutically acceptable salt thereof.

[0096] E4 is the compound of E3 of Formula (la)

[0097]

[0098] or a pharmaceutically acceptable salt thereof.

[0099] E5 is the compound of E3 of Formula (lb)

[0100]

[0101] or a pharmaceutically acceptable salt thereof.

[0102] E6 is the compound of E1 of Formula (I”)

[0103]

[0104] or a pharmaceutically acceptable salt thereof.

[0105] E7 is the compound of E6 of Formula (Ic) or Formula (Id)

[0106]

[0107] or a pharmaceutically acceptable salt thereof.

[0108] E8 is the compound of E7 of Formula (Ic)

[0109]

[0110] or a pharmaceutically acceptable salt thereof.

[0111] E9 is the compound of E7 of Formula (Id)

[0112]

[0113] or a pharmaceutically acceptable salt thereof.

[0114] E10 is the compound of any one of E1 to E5 wherein R5’ is selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 4 fluoro or hydroxy, Cs-Cscycloalkyl-Ci-Csalkyl-and (4- to 6-membered heterocycloalkyl)-Ci-C3alkyl-; or a pharmaceutically acceptable salt thereof.

[0115] E11 is the compound of E10 wherein R5’ is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclobutylmethyl and oxetanylmethyl; ora pharmaceutically acceptable salt thereof.

[0116] E12 is the compound of E1' or E1 wherein Z1is -S(O)2-; or a pharmaceutically acceptable salt thereof.

[0117] E13 is the compound of E12 wherein each - is absent; or a pharmaceutically acceptable salt thereof.

[0118] E14 is the compound of E13 wherein Z is O; or a pharmaceutically acceptable salt thereof.

[0119] E15 is the compound of E13 wherein Z is NR5’; or a pharmaceutically acceptable salt thereof.

[0120] E16 is the compound of any one of E1 to E15 wherein R1is selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 4 fluoro or hydroxy, Cs-Cscycloalkyl-Ci-Csalkyl-and (4- to 6-membered heterocycloalkyl)-Ci-C3alkyl-; or a pharmaceutically acceptable salt thereof.

[0121] E17 is the compound of claim E16 wherein R1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclobutylmethyl and oxetanylmethyl; ora pharmaceutically acceptable salt thereof.E18 is the compound of any one of E1 to E17 wherein R2, R3, R4and R5are independently selected from the group consisting of hydrogen and Ci-Csalkyl substituted with 0 to 4 fluoro or hydroxy; or R2and R3or R4and R5, taken together with the carbon to which they are attached form a Cs-Csspirocycloalkyl or 4- to 6-membered spiroheterocycloalkyl;

[0122] or R2and R4taken together with the carbons to which they are attached can form a C3-Cscycloalkyl ring; or R4and R5’ taken together with the carbon and nitrogen to which they are attached can form a 4- to 7-membered heterocycloalkyl ring; or a pharmaceutically acceptable salt thereof.

[0123] E19 is the compound of E18 wherein R2, R3, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl;

[0124] or R2and R3or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl; or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring; or a pharmaceutically acceptable salt thereof.

[0125] E20 is the compound of any one of E1' to E19 wherein R6is (C6aryl)-(C1-C4alkyl)-L-C0alkyl- or (5- to 10-membered heteroaryl)-(C1-C4alkyl)-L-C0alkyl-; wherein the R6is substituted with 1 to 2 RSand L is a bond; or a pharmaceutically acceptable salt thereof.

[0126] E21 is the compound of claim 20 wherein R6is selected from the group consisting of 2-(4-fluorophenyl)ethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3,4-dichlorophenyl)ethyl and 2-(2-cyanophenyl)ethyl; or a pharmaceutically acceptable salt thereof.

[0127] E22 is the compound of E1 of a formula selected from the group consisting of

[0128]

[0129]

[0130] or a pharmaceutically acceptable salt thereof.

[0131] E23 is the compound of E22 wherein R7is selected from -C(O)OR7a, -C(O)NR7bR7cand 5- to 6-membered heteroaryl-C0alkyl- substituted with 0 to 2 RS; R7ais C1-C3alkyl and R7band R7care independently hydrogen or C1-C3alkyl; or a pharmaceutically acceptable salt thereof.

[0132] E24 is the compound of E23 wherein R7ais ethyl, R7band R7care hydrogen and the 5- to 6-membered heteroaryl-C0alkyl- is selected from oxadiazolyl, thiazolyl, pyrazolyl and pyridazinyl and RSis C1-C3alkyl; or a pharmaceutically acceptable salt thereof.E25 is the compound of E24 wherein R7is selected from the group consisting of

[0133]

[0134] or a pharmaceutically acceptable salt thereof.

[0135] E26 is the compound of E25 wherein R1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclobutylmethyl and oxetanylmethyl; R5’ is hydrogen or methyl; R2, R3, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl; or R2and R3or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl; or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring; or a pharmaceutically acceptable salt thereof.

[0136] E27 is the compound of any one of E1 to E26 wherein the group

[0137]

[0138] or a pharmaceutically acceptable salt thereof.

[0139] E28 is the compound of any one of E1 to E27 wherein Y is -C(O)NR8R9;

[0140] or a pharmaceutically acceptable salt thereof.

[0141] E29 is the compound of E28 wherein R8is hydrogen and R9is selected from the group consisting of 3,4-difluorophenylmethyl, pyridin-3-ylmethyl and 2-hydroxy-2,3-dihydro-1H-inden-1-yl; or a pharmaceutically acceptable salt thereof.

[0142] E30 is the compound of any one of E1 to E27 wherein Y is selected from the group consisting of -N(R8)C(O)R9, -C(O)OR8, -OR8, -NR8R9, -N(R8)S(O)2R9, -S(O)2R8, -S(O)2NR8R9and -N(R8’)C(O)NR8R9; ora pharmaceutically acceptable salt thereof.

[0143] E31 is the compound of E1 selected from the group consisting of

[0144] ethyl 8-[2-(4-fluorophenyl)ethyl]-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2, 3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate;

[0145] ethyl 8-[2-(4-fluorophenyl)ethyl]-1-methyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate;

[0146] 5-{8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0147] 5-{8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}- / V-[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0148] 5-{8-[2-(4-fluorophenyl)ethyl]-1,2,2-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}- / V-[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0149] 5-{8'-[2-(4-fluorophenyl)ethyl]-7'-(5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-f][1,4]oxazepin]-6'-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0150] 5-{7-[2-(4-fluorophenyl)ethyl]-4,4-dimethyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-pyrido[2,3-b][1,4,5]oxathiazepin-9-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0151] 5-{7-[2-(4-fluorophenyl)ethyl]-4,4-dimethyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ6-pyrido[2,3-f][1,2,5]thiadiazepin-9-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;5-{7-[2-(4-fluorophenyl)ethyl]-4,4,5-trimethyl-8-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ6-pyrido[2,3-f][1,2,5]thiadiazepin-9-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0152] 3-{8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-6-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]bicyclo[1.1.1]pentane-1-carboxamide;

[0153] 3-{8-[2-(4-fluorophenyl)ethyl]-1,2,2-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]cyclobutane-1 -carboxamide;

[0154] 3-{8-[2-(4-fluorophenyl)ethyl]-1,2,2-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-6-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]bicyclo[1.1.1]pentane-1-carboxamide;

[0155] or a pharmaceutically acceptable salt thereof,

[0156] or a pharmaceutically acceptable salt thereof.

[0157] E32 is a pharmaceutical composition comprising a compound of any one of E1' to E31 and a pharmaceutically acceptable excipient.

[0158] E33 is a method for treating or preventing a condition, disease, or disorder in a patient comprising administering to the patient a compound of any one of claims 1 to 31, wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onsetT2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0159] E34 is the method of E33 wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance,hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, and sleep apnea [e.g. obstructive sleep apnea (OSA)].

[0160] E35 is a compound of any one of E1' to E31 for use in a method for treating or preventing a condition, disease, or disorder in a patient, wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connectivetissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0161] 36. The use of claim 35 wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, and sleep apnea [e.g. obstructive sleep apnea (OSA)].

[0162] E37 is a method for modulating an amylin receptor and / or calcitonin receptor comprising contacting the amylin receptor and / or calcitonin receptor with a compound of any one of E1’ to E31.

[0163] E38 is a compound of Formula (I)

[0164]

[0165] or a pharmaceutically acceptable salt thereof;

[0166] wherein

[0167] Z is NR5’ or O;

[0168] Z1is -C(O)- or -S(O)2-;

[0169] R1and R5’ are each independently selected from the group consisting of hydrogen, Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- wherein the Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 Rs;

[0170] R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0171] R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, Ci-Cealkyl substituted with 0 to 6 Rs, Ci-Cealkoxy substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;

[0172] or R2and R3or R4and R5can be taken together with the carbon to which they are attached to form a Ce-Cyspirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;

[0173] or R2and R4can be taken together with the carbons to which they are attached to form a C3-Cycycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;

[0174] - is absent or is a bond, provided only one - is a bond at a time and when - is a bond connecting the carbons to which R2and R4are attached then R3and R5are absent and when Z is O the - attached to O is absent and when Z is NR5’ and the - is a bond then R5’ is absent;

[0175] R6is selected from the group consisting of (C6-Cioaryl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C2-C8alkenyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C3-C7cycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (5- to 10-membered heteroaryl)-(Co-C4alkyl)-L-Co-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-; wherein the R6group is substituted with 0 to 6 Rs;

[0176] L is selected from a bond, O, NH and N(Ci-C3alkyl);

[0177] X is N or CR7;R7is selected from the group consisting of hydrogen, -C(O)OR7a, -C(O)NR7bR7c, -OC(O)NR7bR7c, -N(R7d)C(O)NR7bR7c, Ci-C6alkyl substituted with 0 to 6 Rs, Ci-C6alkoxy substituted with 0 to 6 Rs, Cs-Cycycloalkyl-Co-Cealkyl- substituted with 0 to 6 Rs, (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- substituted with 0 to 6 Rs, C6-C10aryl-C0-C6alkyl- substituted with 0 to 6 Rsand 5- to 10 membered heteroaryl-C0-C6alkyl- substituted with 0 to 6 Rs; wherein the C6-C10aryl moiety of the C6-C10aryl-C0-C6alkyl- or the 5- to 10 membered heteroaryl moiety of the 5- to 10 membered heteroaryl-C0-C6alkyl- is optionally fused with a 5 to 7 membered cycloalkyl or 5 to 7 membered heterocycloalkyl;

[0178] or R7and R6taken together with the carbons to which they are attached form a fused C4-C7cycloakyl ring or a fused 4- to 7-membered heterocycloalkyl ring;

[0179] R7ais Ci-Cealkyl substituted with 0 to 6 Rs;

[0180] R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-Cealkyl substituted with 0 to 6 Rs;

[0181] or R7band R7ctaken together with the nitrogen to which they are attached can form a 4- to 7-membered heterocycloalkyl which is substituted with 0 to 6 Rs;

[0182] Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-C8cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein Ring A is substituted with 0 to 6 Rs;

[0183] Y is selected from the group consisting of -C(O)NR8R9, -N(R8)C(O)R9, -C(O)OR8, -OR8, -NR8R9, -N(R8)S(O)2R9, -S(O)2R8, -S(O)2NR8R9and -N(R8’)C(O)NR8R9;

[0184] R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 Rs, Cs-Cycycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs, (Ce-Cwaryl)-Co-Cealkyl- substituted with 0 to 6 Rs, (5- to 10-membered heteroaryl)-Co-Cealkyl- substituted with 0 to 6 Rs,

[0185] or R8and R9when attached to a nitrogen can be taken together with the nitrogen to which they are attached to form a 4- to 7-membered heterocycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs;

[0186] Rsat each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, -NRS1RS2, -Ci-C3alkylNRs1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, Ci-Csalkoxy substituted with 0 to 6 fluoro and Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro;

[0187] RS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 6 RS3, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 RS3, C3-C7cycloalkyl-Co-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-Co-C3alkyl- substituted with 0 to 6 RS3;

[0188] or RS1and RS2taken together with the nitrogen to which they are attached form a 4- to 7 membered heterocycloalkyl which is substituted with 0 to 6 RS3; and RS3at each occurrence is independently selected from halo, hydroxy, cyano, Ci-Csalkyl and C1-Csalkoxy.E39 is the compound of E38 selected from the group consisting of

[0189] ethyl 8-[2-(4-fluorophenyl)ethyl]-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2, 3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate;

[0190] ethyl 8-[2-(4-fluorophenyl)ethyl]-1-methyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)- 2.3.4.5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate;

[0191] 5-{8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}- / V-[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0192] 5-{8'-[2-(4-fluorophenyl)ethyl]-7'-(5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4',5'-dihydro-3'H-spiro[cyclopropane-1,2'-pyrido[3,2-f][1,4]oxazepin]-6'-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0193] 4-{8-[2-(4-fluorophenyl)ethyl]-1,2,2-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}- / V-[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0194] ethyl 8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate;

[0195] / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-(7'-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8'-[2-(4-fluorophenyl)ethyl]-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2-f][1,4]oxazepin]-6'-yl)thiophene-3-carboxamide;

[0196] / V-[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl]thiophene-3-carboxamide;

[0197] / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-{8'-[2-(4-fluorophenyl)ethyl]-7'- (5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2-f][1,4]oxazepin]-6'-yl}thiophene-3-carboxamide;

[0198] 4-[(2R)-8-[2-(4-fluorophenyl)ethyl]-2-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f|[1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0199] 4-{8-[2-(4-fluorophenyl)ethyl]-1-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}- / V-[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0200] 4-[(3R)-8-[2-(4-fluorophenyl)ethyl]-3-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f|[1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0201] 4-[1-(cyclopropylmethyl)-8-[2-(4-fluorophenyl)ethyl]-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2.3.4.5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]d iazepin-6-y I]- / -[( 1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1-yl]benzamide;4-{8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0202] 4-[(2S)-8-[2-(4-fluorophenyl)ethyl]-2-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f|[1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0203] 4-{8-[2-(4-fluorophenyl)ethyl]-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f|[1,4]oxazepin-6-yl}- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0204] 4-[(2S)-8-[2-(4-fluorophenyl)ethyl]-2-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0205] 4-[(2R)-8-[2-(4-fluorophenyl)ethyl]-2-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0206] 4-{8'-[2-(4-fluorophenyl)ethyl]-7'-(5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1, 2'-py rido[3, 2-f\[ 1,4]oxazepin]-6'-yl}- / V-[(1 S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1-yl]benzamide;

[0207] 5-[(2R)-8-[2-(4-fluorophenyl)ethyl]-2-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f|[1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0208] 4-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0209] 4-[(2S,3S)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]benzamide;

[0210] 5-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0211] / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl]thiophene-3-carboxamide;

[0212] 5-[(2R)-8-[2-(4-fluorophenyl)ethyl]-2-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;A / -[(1 S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / - / -inden-1 -yl]-5-{8'-[2-(4-fluorophenyl)ethyl]-7'-(5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2-f][1,4]oxazepin]-6'-yl}thiophene-3-carboxamide;

[0213] 5-(7'-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8'-[2-(4-fluorophenyl)ethyl]-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2- / ][1,4]oxazepin]-6'-yl)- / \ / -[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0214] / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-{(2R,3R)-7-{5- [(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-5-oxo- 2.3.4.5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl}thiophene-3-carboxamide;

[0215] 5-[(6aR,9aR)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0216] 5-[(6aS,9aS)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0217] 5-[(6aR,9aR)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0218] 5-[(6aS,9aS)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0219] 5-[(2R,3R)-3-ethyl-8-[2-(4-fluorophenyl)ethyl]-2-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2.3.4.5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0220] 5-[(2S)-2-(difluoromethyl)-8-[2-(4-fluorophenyl)ethyl]-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0221] 5-[(2R)-2-(difluoromethyl)-8-[2-(4-fluorophenyl)ethyl]-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0222] 5-[(2S)-2-(difluoromethyl)-8-[2-(4-fluorophenyl)ethyl]-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0223] 5-[(2R)-2-(difluoromethyl)-8-[2-(4-fluorophenyl)ethyl]-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;5-[(6aS,9a / ?)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0224] 5-[(6a / ?,9aS)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0225] 5-[(6aS,9a / ?)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0226] 5-[(6a / ?,9aS)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,6a,7,8,9,9a-hexahydro-5 / 7-cyclopenta[b]pyrido[3,2- / ][1,4]oxazepin-4-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0227] / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl]-1,3-oxazole-4-carboxamide;

[0228] (2R,3R)-7-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8-[2-(4-fluorophenyl)ethyl]-6-(7-{[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-2,3-dimethyl-3,4-dihydropyrido[3,2-f|[1,4]oxazepin-5(2H)-one;

[0229] / V-[(1R)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]-1,3-oxazole-4-carboxamide;

[0230] (2R,3R)-6-(7-{[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-7-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-3,4-dihydropyrido[3,2- / ][1,4]oxazepin-5(2H)-one;

[0231] / V-[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]- 2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- ][1,4]oxazepin-6-yl]-1,3-oxazole-4-carboxamide;

[0232] / V-[(1S,2S)-2-(dimethylamino)-2,3-dihydro-1 / 7-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]- 2.3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- ][1,4]oxazepin-6-yl]-1,3-oxazole-4-carboxamide;

[0233] (2R,3R)-6-(7-{[(1S,2S)-2-(dimethylamino)-2,3-dihydro-1 / 7-inden-1-yl]amino}thieno[2,3-c]pyridin- 2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0234] (2R,3R)-7-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-6-(7-{[(1S,2S)-5-fluoro-2-hydroxy- 2.3-dihydro-1 / 7-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-3,4-dihydropyrido[3,2- / ][1,4]oxazepin-5(2H)-one; / V-[(1 S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl]-1,3-thiazole-5-carboxamide;

[0235] 2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-1,3-thiazole-5-carboxamide;

[0236] / V-[(1R)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]-1,3-thiazole-5-carboxamide;

[0237] / V-[(1S,2S)-2-(dimethylamino)-2,3-dihydro-1 / 7-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]- 2.3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- ][1,4]oxazepin-6-yl]-1,3-thiazole-5-carboxamide;

[0238] 5-{(2R,3R)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-8-[2-(6-methylpyridin-3-yl)ethyl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl}- / \ / -[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0239] 2-{(2R,3R)-7-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2,3-dimethyl-8-[2-(6-methylpyridin-3-yl)ethyl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2- |[1,4]oxazepin-6-yl}- / \ / -[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-1,3-oxazole-4-carboxamide;

[0240] (2R,3R)-7-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-6-(2-{[(1S,2S)-5-fluoro-2-hydroxy- 2.3-dihydro-1 / 7-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-3,4-dihydropyrido[3,2-f|[1,4]oxazepin-5(2H)-one;

[0241] (2R,3R)-6-(2-{[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]amino}pyridin-4-yl)-7- {5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-3,4-dihydropyrido[3,2-f|[1,4]oxazepin-5(2H)-one;

[0242] / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-{(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl}thiophene-3-carboxamide;

[0243] / V-[(1R)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl]-5-{(2R,3R)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-8-[2-(6-methylpyridin-3-yl)ethyl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl}thiophene-3-carboxamide;

[0244] / V-[(1R)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl]-2-{(2R,3R)-7-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2,3-dimethyl-8-[2-(6-methylpyridin-3-yl)ethyl]-5-oxo-2,3,4,5-tetrahydropyrido[3,2- ][1,4]oxazepin-6-yl}-1,3-oxazole-4-carboxamide;

[0245] / V-[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-2-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3,4-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- ][1,4]oxazepin-6-yl]-1,3-oxazole-4-carboxamide;A / -[(1 S,2S)-2-(dimethylamino)-2,3-dihydro-1 / - / -inden-1 -yl]-2-[(2F?,3F?)-8-[2-(4-fluorophenyl)ethyl]-2,3,4-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]-1,3-oxazole-4-carboxamide;

[0246] / V-[(5F?)-4-fluoro-6,7-dihydro-5 / 7-cyclopenta[c]pyridin-5-yl]-2-[(2F?,3F?)-8-[2-(4-fluorophenyl)ethyl]-2,3,4-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]-1,3-oxazole-4-carboxamide;

[0247] / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-[(2F?,3F?)-8-[2-(4-fluorophenyl)ethyl]-2,3,4-trimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]-1,3-thiazole-5-carboxamide;

[0248] 5-[(2F?,3F?)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-5-oxo-7-(5,6,7,8-tetrahydro[1,2,4] triazolo[4,3-a]pyridin-3-yl)-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide; and

[0249] 5-[(2F?,3F?)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-5-oxo-7-(1 / 7-pyrazol-1-yl)-2,3,4,5-tetrahydropyrido[3,2-f|[1,4]oxazepin-6-yl]- / \ / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]thiophene-3-carboxamide;

[0250] or a pharmaceutically acceptable salt thereof.

[0251] E40 is a pharmaceutical composition comprising a compound of any one of E38 and E39 and a pharmaceutically acceptable excipient.

[0252] E41 is a method for treating or preventing a condition, disease, or disorder in a patient comprising administering to the patient a compound of any one of E38 and E39, wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0253] E42 is the compound of E1’, E1 or E38 of Formula (Ic)

[0254]

[0255] or a pharmaceutically acceptable salt thereof.

[0256] E43 is the compound of E42 wherein R1, R2, R3, R4and R5are each independently hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

[0257] E44 is the compound of E43 wherein Ri, R3 and R5 are each hydrogen and R2 and R4 are each methyl; or a pharmaceutically acceptable salt thereof.

[0258] E45 is the compound of any one of E1’, E1 to E9, E38 and E42 to E44 wherein R6is selected from 2-(4-cyclopropylphenyl)ethyl, 2-(4-pyrazol-1-yl)ethyl, 2-(4-fluorophenyl)ethyl and 2-(imidazo[1,2-a]pyridine-7-yl)ethyl; or a pharmaceutically acceptable salt thereof.

[0259] E46 is the compound of any one of E1’, E1 to E9, E38 and E42 to E45 wherein Ring A is a thiophene, pyridine orthienopyridine ring; ora pharmaceutically acceptable salt thereof.E47 is the compound of any one of ET, E1 to E9, E38 and E42 to E46 wherein the group

[0260]

[0261] or a pharmaceutically acceptable salt thereof.

[0262] E48 is the compound of any one of ET, E1 to E9, E38 and E42 to E47 wherein the

[0263]

[0264] or a pharmaceutically acceptable salt thereof.

[0265] E49 is the compound of any one of ET, E1 to E9, E38 and E42 to E48 wherein R7is selected from the group consisting of

[0266] N - N HN - N HN - N

[0267]

[0268] or a pharmaceutically acceptable salt thereof.E50 is the compound of any one of ET, E1 to E9, E38 and E42 to E49 selected from the group consisting of

[0269] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0270] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0271] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0272] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0273] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-8-{2-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0274] (2R,3R)-8-[2-(4-cyclopropylphenyl)ethyl]-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0275] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(imidazo[1,2-a]pyridin-7-yl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0276] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-8-{2-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0277] (2R,3R)-8-[2-(4-cyclopropylphenyl)ethyl]-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0278] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(imidazo[1,2-a]pyridin-7-yl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0279] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-8-{2-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0280] (2R,3R)-8-[2-(4-cyclopropylphenyl)ethyl]-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;(2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2- (imidazo[1,2-a]pyridin-7-yl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0281] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-8-{2-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0282] (2R,3R)-8-[2-(4-cyclopropylphenyl)ethyl]-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0283] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0284] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0285] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(3-oxo-2,3-dihydro-1,2-oxazol-5-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0286] (2R,3R)-6-(7-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-c]pyridin-2-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0287] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0288] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0289] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(3-oxo-2,3-dihydro-1,2-oxazol-5-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0290] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one; and

[0291] (2R,3R)-6-(2-{[(1R)-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2- (imidazo[1,2-a]pyridin-7-yl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0292] or a pharmaceutically acceptable salt thereof.E51 is a pharmaceutical composition comprising a compound of any one of E42 and E50 and a pharmaceutically acceptable excipient.

[0293] E52 is a method for treating or preventing a condition, disease, or disorder in a patient comprising administering to the patient a compound of any one of E42 to E50, wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowelsyndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0294] E54 is a compound of E1” selected from the group of compounds of Example 1 to Example 257 or an isotope thereof or a pharmaceutically acceptable salt of the compound or isotope thereof. E55 is a compound of E1” or E54 selected from the group consisting of (2 / ?,3 / ?)-6-(4-{[(1 / ?)-5,6-difluoro-2,3-dihydro-1 / 7-inden-1-yl]amino}thieno[2,3-c(]pyrimidin-6-yl)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4-dihydropyrido[3,2-f] [ 1,4]oxazepin-5(2H)-one;

[0295] 2-fluoro-4-({7-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-5-oxo-7-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}methyl)benzonitrile;

[0296] (2R,3R)-6-(2-{[(1R)-5,6-Difluoro-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f|[1,4]oxazepin-5(2 / - / )-one;

[0297] (2R,3R)-6-(4-{[(1R)-5,6-Difluoro-2,3-dihydro-1 / - / -inden-1-yl]amino}thieno[2,3-cf]pyrimidin-6-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f] [ 1,4]oxazepin-5(2H)-one;

[0298] (2R,3R)-8-[2-(4,4-difluorocyclohexyl)ethyl]-6-(4-{[(1R)-5,6-difluoro-2,3-dihydro-1 / - / -inden-1-yl]amino}thieno[2,3-cf]pyrimidin-6-yl)-2,3-dimethyl-7-{5-[(2 / ?)-1-methylpyrrolidin-2-yl]-1,3,4-oxadiazol-2-yl}-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;

[0299] (2R,3R)-6-(4-{[(1R)-5,6-difluoro-2,3-dihydro-1 / - / -inden-1-yl]amino}-2-methylthieno[2,3-cf]pyrimidin-6-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2- / ][1,4]oxazepin-5(2H)-one; and

[0300] (2R,3R)-6-(4-{[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]amino}thieno[3,2-cf]pyrimidin-6-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f|[1,4]oxazepin-5(2H)-one;

[0301] or an isotope thereof or a pharmaceutically acceptable salt of the compound or isotope thereof. E56 is a pharmaceutical composition comprising a compound of any one of E1”, E54 and E55 and a pharmaceutically acceptable excipient.

[0302] E57 is a method of for treating or preventing a condition, disease, or disorder in a patient comprising administering to the patient a compound of any one of E1 ”, E54 and E55, wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia,hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0303] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or pharmaceutically acceptable salts thereof, for any of the embodiment(s) described herein.

[0304] Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein.Definitions

[0305] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0306] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0307] “Compounds of the invention” include compounds of Formula (I) and the novel intermediates used in the preparation thereof. One of ordinary skill in the art will appreciate that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the invention include solvates, hydrates, isomorphs, polymorphs, esters, salt forms, prodrugs, and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed.

[0308] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0309] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of the compound of Formula (I)) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e., it may vary between 4.5 mg and 5.5 mg.

[0310] If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

[0311] “Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

[0312] The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no

[0313] non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more

[0314] non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=0) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different. Throughout the disclosure, it will be understood that the numberand nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art.

[0315] “Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

[0316] “Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -C=N.

[0317] " Hydroxy" refers to an -OH group.

[0318] “Oxo” refers to a double bonded oxygen (=0).

[0319] " Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-C12 alkyl”), 1 to 8 carbon atoms (“Ci-Cs alkyl”), 1 to 6 carbon atoms (“Ci-Ce alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, if used “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number.

[0320] “Haloalkyl” refers to an alkyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkyl groups may contain, but are not limited to, 1-6 carbon atoms (“Ci-Ce haloalkyl”), 1-4 carbon atoms (“C1-C4 haloalkyl”), or 1-2 carbon atoms (“C1-C2 haloalkyl”). More specifically, fluorinated alkyl groups may be specifically referred to as “fluoroalkyl.”

[0321] “Fluoroalkyl” refers to an alkyl group, as defined herein, wherein from one to all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0322] “Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms (“Ci-Cs alkoxy”), 1 to 6 carbon atoms (“Ci-Ce alkoxy”), 1 to 4 carbon atoms (“C1-C4 alkoxy”), or 1 to 3 carbon atoms (“C1-C3 alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, and the like.

[0323] “Haloalkoxy” refers to an alkoxyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkoxy groups may contain, but are not limited to, 1-6 carbon atoms, (“Ci-Ce haloalkoxy”),1-4 carbon atoms (“C1-C4 haloalkoxy”), or 1-2 carbon atoms (“C1-C2 haloalkoxy”). More specifically, fluorinated alkoxyl groups may be specifically referred to as “fluoroalkoxy.” “Alkoxyalkyl” refers to an alkyl group, as defined herein, that is substituted by an alkoxy group, as defined herein. Examples include, but are not limited to, CH3OCH2- and CH3CH2OCH2-.

[0324] “Alkenyl” refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, as used herein, the term " C2-Ce alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1 -propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.

[0325] “Cycloalkyl” refers to a fully saturated hydrocarbon ring system that has the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. Cycloalkyl groups may contain, but are not limited to, 3 to 12 carbon atoms (“C3-C12 cycloalkyl”), 3 to 8 carbon atoms (“C3-C8 cycloalkyl”), 3 to 6 carbon atoms (“C3-C6 cycloalkyl”), 3 to 5 carbon atoms (“C3-C5 cycloalkyl”) or 3 to 4 carbon atoms (“C3-C4 cycloalkyl”). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantanyl, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. The cycloalkyl group may be formed on a carbon of another ring and therefore may be designated as a “spirocycloalkyl” group such as a spirocyclpropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl group.

[0326] “Cycloalkoxy” refers to a cycloalkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of a cycloalkoxy radical to a molecule is through the oxygen atom. A cycloalkoxy radical may be depicted as cycloalkyl-O-. Cycloalkoxy groups may contain, but are not limited to, 3 to 8 carbon atoms (“C3-C8 cycloalkoxy”), 3 to 6 carbon atoms (“C3-C6 cycloalkoxy”), and 3 to 4 carbon atoms (“C3-C4 cycloalkoxy”). Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy and the like.

[0327] Heterocycloalkyl” refers to a fully saturated ring system containing the specified number of ring atoms and containing at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(O)q, where q is 0, 1 or 2) and where the heterocycloalkyl ring is connected to the base molecule via a ring atom, which may be C or N. Heterocycloalkyl rings include rings which are spirocyclic, bridged, or fused to one or more other heterocycloalkyl or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocycloalkyl portion of the ring system. Heterocycloalkyl rings may contain 1 to 4 heteroatoms selected from N, O, and S(O)qas ringmembers, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms.

[0328] Heterocycloalkyl rings may be optionally substituted, unsubstituted or substituted, as further defined herein. Such substituents may be present on the heterocyclic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto.

[0329] Heterocycloalkyl rings may include, but are not limited to, 3-8 membered heterocyclyl groups, for example 4-7 or 4-6 membered heterocycloalkyl groups, in accordance with the definition herein.

[0330] Illustrative examples of heterocycloalkyl rings include, but are not limited to a monovalent radical of:

[0331] oxirane thiarane aziridine oxetane thiatane azetidinetetrahydrofuran (oxiranyl) (thiaranyl) (aziridinyl) (oxetanyl) (thiatanyl) (azetidinyl) (tetrahydrofuranyl)

[0332] H

[0333] N

[0334] tetrahydrothiophene pyrrolidine tetrahydropyran tetrahydrothiopyran piperidine (tetrahydrothiophenyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl) (piperidinyl)

[0335] 1,4-dioxane 1,4-oxathiarane morpholine 1,4-dithiane piperazine thiomorpholine (1,4-dioxanyl) (1,4-oxathiaranyl) (morpholinyl) (1,4-dithianyl) (piperazinyl) (thiomorpholinyl)

[0336]

[0337] oxepane thiepane azepane 1,4-dioxepane 1,4-oxathiepane (oxepanyl) (thiepanyl) (azepanyl) (1,4-dioxepanyl) (1,4-oxathiepanyl)

[0338]

[0339] 1,4-oxaazepane 1,4-thieazepane 1,4-diazepane 1,4-dithiepane (1,4-oxaazepanyl) (1,4-thieazapanyl) (1,-diazepanyl)or(1,4-dithiepanyl)" Aryl" or “aromatic” refers to monocyclic, bicyclic (e.g., biaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms, in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Aryl groups may contain, but are not limited to, 6 to 20 carbon atoms (" C6-C20 aryl"), 6 to 14 carbon atoms (" Ce-Cuaryl"), 6 to 12 carbon atoms (" Ce-C^aryl"), or 6 to 10 carbon atoms (" Ce-C aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, and indenyl. Aryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0340] Similarly, "heteroaryl" or “heteroaromatic” refer to monocyclic, bicyclic (e.g., heterobiaryl, fused) or polycyclic ring systems that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in a ring in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation.

[0341] Heteroaryl groups may contain, but are not limited to, 5 to 20 ring atoms (“5-20 membered heteroaryl”), 5 to 14 ring atoms (“5-14 membered heteroaryl”), 5 to 12 ring atoms (“5-12 membered heteroaryl”), 5 to 10 ring atoms (“5-10 membered heteroaryl”), 5 to 9 ring atoms (“5-9 membered heteroaryl”), or 5 to 6 ring atoms (“5-6 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring. Thus, either 5- or 6-membered heteroaryl rings, alone or in a fused structure, may be attached to the base molecule via a ring C or N atom. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, triazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl and carbazolyl. Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. Heteroaryl groups may be optionally substituted, unsubstituted or substituted, as further defined herein.

[0342] Illustrative examples of monocyclic heteroaryl groups include, but are not limited to a monovalent radical of:

[0343]

[0344] pyrrole furan thiophene pyrazole imidazole isoxazole ( yrrolyl) (furanyl) (thiophenyl) (pyrazolyl) (imidazolyl) (isoxazolyl)O

[0345]

[0346] oxazole isothiazole thiazolyl 1,2,3-triazole 1,3,4-triazole 1-oxa-2,3-diazole (oxazolyl) (isothiazolyl) (thiazolyl) (1,2,3-triazolyl) (1,3,4-triazolyl) (1-oxa-2,3-diazolyl)

[0347]

[0348] 1 -oxa-2,4-diazole 1-oxa-2,5"diazole 1_oxa_3,4_diazole 1-thia-2,3-diazole 1-thia-2,4-diazole (1-oxa-2,4-diazolyl) (1-oxa-2,5-diazolyl) (1-oxa-3,4-diazolyl) (1 -thia-2,3-diazolyl) (l-thia-2,4-diazolyl)

[0349]

[0350] 1 -thia-2,5-diazole 1-thia-3,4-diazole tetrazole pyridine pyridazine pyrimidine pyrazine (1 -thia-2,5-diazolyl) (1 -thia-3,4-diazolyl) (tetrazolyl) (pyridinyl) (pyridazinyl) (pyrimidinyl) (pyrazinyl)

[0351] illustrative examples of fused ring heteroaryl groups include, but are not limited to:

[0352] benzofuran benzothiophene indole benzimidazole indazole

[0353]

[0354] (benzofuranyl) (benzothiophenyl) (indolyl) (benzimidazolyl) (indazolyi)

[0355] N

[0356]

[0357] benzotriazole pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine pyrrolo[3,2-b]pyridine (benzotriazolyl) (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl) (pyrrolo[3,2-b]pyridinyl)

[0358]

[0359] imidazo[4,5-b]pyridine imidazo[4,5-c]pyridine pyrazolo[4,3-d]pyridine py razolo[4, 3-c] py rid in e (imidazo[4,5-b]pyridinyl) (imidazo[4,5-c]pyridinyl) (pyrazolo[4,3-d]pyidinyl) (pyrazolo[4,3-c]pyidinyl)

[0360] pyrazolo[3,4-c]pyridine pyrazolo[3,4-b]pyridine isoindole indazole purine

[0361]

[0362] (pyrazolo[3,4-c]pyidinyl) (pyrazolo[3,4-b]pyidinyl) (isoindolyl) (indazolyi) (purinyl)indolizine imidazo[1,2-a]pyridine imidazo[1,5-a]pyridine pyrazolo[1,5-a]pyridine pyrrolo[1,2-b]pyridazine (indolininyl) (imidazo[1,2-a]pyrid inyl) (imidazo[1,5-a]pyrid inyl) (pyrazolo[1,5-a]pyridinyl) (pyrrolo[1,2-b] pyridazinyl)

[0363] imidazo[1,2-c]pyrimidine quinoline isoquinoline cinnoline quinazoline quinoxaline (imidazo[1,2-c]pyrimidinyl) (quinolinyl) (isoquinolinyl) (cinnolinyl) (azaquinazoline) (quinoxalinyl)

[0364] phthalazine 1,6-naphthyridine 1,7-naphthyridine 1,8-naphthyridine 1,5-naphthyridine

[0365]

[0366] (phthalazinyl) (1,6-naphthyridinyl) (1,7-naphthyridinyl) (1,8-naphthyridinyl) (1,5-naphthyridinyl)

[0367] 2,6-naphthyridine 2,7-naphthyridine pyrido[3,2-d]pyrimidine pyrido[4,3-d]pyrimidine

[0368]

[0369] (2,6-naphthyridinyl) (2,7-naphthyridinyl) (pyrido[3,2-d]pyrimidinyl) (pyrido[4,3-d]pyrimidinyl)

[0370]

[0371] pyrido[3,4-d]pyrimidine pyrido[2,3-d]pyrimidine pyrido[2,3-b]pyrazine pyrido[3,4-b]pyrazine (pyrido[3,4-d]pyrimidinyl) (pyrido[2,3-d]pyrimidinyl) (pyrido[2,3-b]pyrazinyl) (pyrido[3,4-b]pyrazinyl)

[0372]

[0373] pyrimido[5,4-d]pyrimidine pyrazino[2,3-b]pyrazine pyrimido[4,5-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) (pyrazino[2,3-b]pyrazinyl) Q|- (pyrimido[4,5-d]pyrimidinyl)

[0374] “Amino” refers to a group -NH2, which is unsubstituted. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NRxRy, where each of Rx and Ry is defined as further described herein. For example, “alkylamino” refers to a group -NRxRy, wherein one of Rx and Ry is an alkyl moiety and the other is H, and “dialkylamino” refers to -NRxRy wherein both of Rx and Ry are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(CI-C4 alkyl) or -N(CI-C4 alkyl^).

[0375] “Aminoalkyl” refers to an alkyl group, as defined above, that is substituted by 1, 2, or 3 amino groups, as defined herein.The term “pharmaceutically acceptable” means the substance (e.g., the compounds described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.

[0376] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0377] “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0378] " Excipient" as used herein describes any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0379] As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia.

[0380] Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples ofexcipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0381] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0382] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e., prophylactic, and palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

[0383] As used herein, the term, “subject, “individual” or “patient,” used interchangeably, refers to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0384] As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following:

[0385] (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;

[0386] (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting (or slowing) further development of the pathology or symptomatology or both); and

[0387] (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology or both).

[0388] Salts

[0389] Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound of the invention that is suitable for administration to a subject or patient.In addition, the compounds of Formula I may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula I; 2) purifying compounds of Formula I; 3) separating enantiomers of compounds of Formula I; or 4) separating diastereomers of compounds of Formula I.

[0390] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acid and xinofoate salts.

[0391] Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0392] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0393] Fora review on suitable salts, see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.

[0394] Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures (i) by reacting a compound of the invention with the desired acid or base;

[0395] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[0396] (iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure.

[0397] These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.

[0398] Solvates

[0399] The compounds of the invention, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecularcomplex comprising the compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

[0400] In addition, the compounds of Formula (I) may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of Formula (I); 2) purifying compounds of Formula (I); 3) separating enantiomers of compounds of Formula (I); or 4) separating diastereomers of compounds of Formula (I).

[0401] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0402] When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0403] Complexes

[0404] Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drughost inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, for example, hydrogen bonded complex (cocrystal) may be formed with either a neutral molecule or with a salt. Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together - see Chem Commun, 17;1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64(8), 1269-1288, by Haleblian (August 1975).

[0405] Solid form

[0406] The compounds of the invention may exist in a continuum of solid states ranging from amorphous to crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

[0407] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO'Na+, -COO'K+, or -SOs'Na+) or non-ionic (such as -N’N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0408] Stereoisomers

[0409] Compounds of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds may include c / s and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings.

[0410] The pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine).

[0411] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0412] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomersconverted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein).

[0413] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

[0414] Tautomerism

[0415] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino / amino, keto / enol, or oxime / nitroso group, lactam / lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0416] It must be emphasized that while, for conciseness, the compounds of the invention have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention.

[0417] Isotopes

[0418] The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0419] Examples of isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as2H (D, deuterium) and3H (T, tritium), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l,nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0420] Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies. The radioactive isotopes, such as, tritium and14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with positron emitting isotopes, such as,11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Substitution with deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability.

[0421] In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.

[0422] In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the invention are deuterated.

[0423] For purposes of describing deuterated analogs of the compounds of the invention representative groups within the variables R6, an Rsgroup on R7, an Rsgroup on Ring A, and Y that may be deuterated are described below. Representative groups within the compounds of the instant invention that may be deuterated include groups within the variable R6such as a 2-(4-fluorophenyl)ethyl, 2-(4,4-difluorocyclohexyl)ethyl or 2-(6-trifluoromethylpyridin-3-yl)ethyl group in which one or more hydrogen atoms in these groups has been replaced by the isotope deuterium. Certain deuterated versions of an R6moiety 2-(4-fluorophenyl)ethyl include but are not limited to:

[0424]

[0425] Certain deuterated versions of an R6moiety 2-(4,4-difluorocyclohexyl)ethyl in the instant compounds include but are not limited to:

[0426]

[0427] Certain deuterated versions of an R6moiety 2-(6-trifluoromethyl pyridine-3-yl)ethyl in the instant compounds include but are not limited to:

[0428]

[0429] Certain deuterated versions of a group Y in the instant compounds include but are not limited to:

[0430]

[0431] Certain deutero analogs of an Rsmethyl group attached to a Ring A moiety include but are not limited to:

[0432]

[0433] Certain deutero analogs of an RsN-methylpyrrolidin-2-yl moiety that can be attached to a R7 group include but are not limited to:

[0434] CDH2CD2H CD3

[0435] Ki, Ki, Ki,

[0436]

[0437] O* CT* CT*

[0438] For further purposes of illustration deuterated versions of the compound of Example 107 which is described hereinbelow include but are not limited to the following deuterated analogs:

[0439]

[0440] Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0441] Representative groups within compounds of the instant invention include Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d₆-acetone, d₆-DMSO.

[0442] Prodrugs

[0443] A compound of the invention may be administered in the form of a prodrug. Thus, certain derivatives of a compound of the invention which may have little or no pharmacological activity themselves may, when administered into or onto the body, be converted into a compound of the invention having the desired activity, for example by hydrolytic cleavage, particularly hydrolyticcleavage promoted by an esterase or peptidase enzyme. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘The Expanding Role of Prodrugs in Contemporary Drug Design and Development, Nature Reviews Drug Discovery, 17, 559-587 (2018) (J. Rautio, etal.).

[0444] Prodrugs in accordance with the invention may, for example, be produced by replacing appropriate functionalities present in compounds of the invention with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in ‘Design of Prodrugs’ by H. Bundgaard (Elsevier, 1985).

[0445] Thus, a prodrug in accordance with the invention may be (a) an ester or amide derivative of a carboxylic acid when present in a compound of the invention; (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group when present in a compound of the invention; (c) an amide, imine, carbamate or amine derivative of an amino group when present in a compound of the invention; (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivatives of a thiol group when present in a compound of the invention; or (e) an oxime or imine derivative of a carbonyl group when present in a compound of the invention.

[0446] Some specific examples of prodrugs in accordance with the invention include:

[0447] (i) when a compound of the invention contains a carboxylic acid functionality (-COOH), an ester thereof, such as a compound wherein the hydrogen of the carboxylic acid functionality of the compound is replaced by Ci-C8alkyl (e.g., ethyl) or (Ci-C8alkyl)C(=O)OCH2-(e.g., ‘BUC(=O)OCH2-);

[0448] (ii) when a compound of the invention contains an alcohol functionality (-OH), an ester thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by -CO(Ci-C8alkyl) (e.g., methylcarbonyl) or the alcohol is esterified with an amino acid;

[0449] (iii) when a compound of the invention contains an alcohol functionality (-OH), an ether thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by (Ci-C8alkyl)C(=O)OCH2- or-CH2OP(=O)(OH)2;

[0450] (iv) when a compound of the invention contains an alcohol functionality (-OH), a phosphate thereof, such as a compound wherein the hydrogen of the alcohol functionality of the compound is replaced by -P(=O)(OH)2or-P(=O)(O'Na+)2or-P(=O)(O')2Ca2+;

[0451] (v) when a compound of the invention contains a primary or secondary amino functionality (-NH2or -NHR where R H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is / are replaced by (C₁-C₁₀)alkanoyl, -COCH2NH2or the amino group is derivatized with an amino acid;

[0452] (vi) when a compound of the invention contains a primary or secondary amino functionality (-NH2or -NHR where R H), an amine thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound is / are replaced by -CH2OP(=O)(OH)2.Certain compounds of the invention may themselves act as prodrugs of other compounds the invention It is also possible for two compounds of the invention to be joined together in the form of a prodrug. In certain circumstances, a prodrug of a compound of the invention may be created by internally linking two functional groups in a compound of the invention, for instance by forming a lactone.

[0453] Metabolites

[0454] Also included within the scope of the invention are active metabolites of compounds of the invention, that is, compounds formed in vivo upon administration of the drug, often by oxidation or dealkylation. Some examples of metabolites in accordance with the invention include, but are not limited to,

[0455] (i) where the compound of the invention contains an alkyl group, a hydroxyalkyl derivative thereof (-CH — > -COH):

[0456] (ii) where the compound of the invention contains an alkoxy group, a hydroxy derivative thereof (-OR — > -OH);

[0457] (iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR’ — > -NHR or-NHR);

[0458] (iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (-NHR — > -NH2);

[0459] (v) where the compound of the invention contains a phenyl moiety, a phenol derivative thereof (-Ph -PhOH);

[0460] (vi) where the compound of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH); and

[0461] (vii) where the compound contains a hydroxy or carboxylic acid group, the compound may be metabolized by conjugation, for example with glucuronic acid to form a glucuronide. Other routes of conjugative metabolism exist. These pathways are frequently known as Phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, may also be subject to conjugation.

[0462] Protein Degraders

[0463] Disclosed herein are bifunctional compounds comprising a targeting ligand (i.e., compound of the disclosure) linked to an E3 ligase ligand or a ligand known to interact with the ubiquitin proteasome system (UPS) through a linker. The bifunctional compounds of the disclosure have the general structure: [Degron]-[Linker]-[Targeting Ligand], wherein the linker is covalently bound to at least one degron and covalently bound to at least one targeting ligand, wherein the degron is a compound capable of binding to a ubiquitin ligase such as an E3 Ubiquitin Ligase (e.g., cereblon (CRBN), von Hippel-Lindau (VHL), etc.), and the targeting ligand or compound of the disclosure is capable of binding to a targeted protein [the calcitoninreceptor or amylin receptor]. The bifunctional compounds of the disclosure can be used as therapeutics to treat a condition disclosed herein.

[0464] In one embodiment, a bifunctional compound of the disclosure has the formula:

[0465] [Degron]-[Linker]-[Compound of Formula (I)] wherein the linker is attached to the compound of Formula (I) at any one of positions R1, R2, R2’, R3, R3’, R4, R5, R6, R7and Y as set forth in E1.

[0466] Deqron: The degron is a compound that is highly effective in recruiting a targeted protein to a ubiquitin ligase for proteosomal degradation. The degron recruits the targeted protein through the linker and the targeting ligand (i.e., compound of the disclosure). In some embodiments, the degron is a compound that can bind to a ubiquitin ligase. In one embodiment, the degron can bind to an E3 ubiquitin ligase, such as cereblon, wherein the degron is thalidomide, lenalidomide, pomalidomide, or iberdomide, or newer IMiDs CRBN ligands, or analogues thereof (e.g., WO2019 / 060693, WO2019 / 140387, WO2019 / 236483). In one embodiment, the degron can bind to an E3 ubiquitin ligase, such as von Hippel-Lindau ligand (e.g., W02020 / 092907; WO2013106643; Buckley et al. J. Am. Chem. Soc. 2012, 134, 4465-4468; Soares et al. J. Med. Chem. 2019, 61, 599-618). In a further embodiment, the degron can bind to an E3 ubiquitin ligase, such as an inhibitor of apoptosis protein ligases (IAP1, IAP2, XIAP) (e.g., Itoh et al, J. Am. Chem. Soc. 2010, 132, 5820-5826; Mares et al. Commun. Biol. 2020, 3, 140; Tinworth et al. ACS Chem. Biol. 2019, 14, 342-347). In a further embodiment, the degron binds a ubiquitin proteasome protein that induces degradation, such as the Hsp70 / 90 chaperone complex (e.g., W02020 / 207395), Usp14 (e.g., WO2019 / 238886), UchL5 (e.g., WO2019238816), and Rpn11 (e.g., WO2019 / 238817). In some embodiments, the degron is an amino acid moiety (e.g., Zhang et al., J. Biol. Chem. 2023, 299, 8, 104994).

[0467] Linker: The Linker (“L”) provides a covalent attachment between the Targeting Ligand and the Degron. The Linker has two terminating groups, wherein one terminating group attaches to the Degron and the other terminating group attaches to the Targeting Ligand. The structure of the Linker may not be critical, provided it does not substantially interfere with the activity of the Targeting Ligand or the Degron. The optimal Linker length and composition may vary by target and may be estimated based upon, for example, 1) X-ray structures of the original Targeting Ligand bound to its target; and / or 2) computational modeling of the protein target and the UPS protein. Linker length and composition can be also modified to modulate metabolic stability and pharmacokinetic (PK) and pharmacodynamics (PD) parameters. In some embodiments, the Linker is designed and optimized based on SAR (structure-activity relationship) and X-ray crystallography of the Targeting Ligand with regard to the location of attachment for the Linker. In some embodiments, a target ligand can bind multiple protein targets, and selectivity of the bifunctional compounds disclosed herein can be achieved by varying the linker length such that the ligand can target a different binding pocket, e.g., deeper or shallower binding pockets than others.In some embodiments, the Linker is a C2-20 alkylene or a polyethylene glycol (PEG) chain. In other embodiments, the Linker may be an alkylene chain, a PEG chain, or a bivalent alkylene chain, each of which may be interrupted by or terminate with at least one of -O-, -S-, -N(RL)-, -C=C-, -C(O)-, -C(O)O-, -OC(O)-, -00(0)0-, - C(NORL)-, -C(O)N(RL)-, -C(O)N(RL)C(O)-, -C(O)N(RL)C(O)N(RL)-, -N(RL)C(O)-, -N(RL)C(O)N(RL)-, -N(RL)C(O)O-, -OC(O)N(RL)-, -C(NRL)-,-N(RL)C(NRL)-, -C(NRL)N(RL)-, - N(RL)C(NRL)N(RL)-, -OB(CH3)O--S(0)2-, -0S(0)-, -S(0)0-, -S(0)-, -0S(0)2-, -S(0)20-, - N(RL)S(O)2-, -S(O)2N(RL)-, -N(RL)S(O)-, -S(O)N(RL)-, -N(RL)S(O)2N(RL)-, -N(RL)S(O)N(RL)-, C3-12 carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or arylene, or any combination thereof, wherein RLis H or Ci-e alkyl. In one embodiment, In some embodiments, the Linker is Ci-io alkylene-NH-, wherein the nitrogen is bound to the degron. In one embodiment, the Linker is Ci-io alkylene or 1-8 PEG units that are interrupted by or terminate in -(CH2)n-C(0)-NH-, where n’ is 0, 1, 2, 3, 4, or 5.

[0468] Nonlimiting examples of a Linker include -(CH2CH2-O)n"-(CH2)n-C(O)-, (CH2)n-C(0)-N(RL)-(CH2CH2-O)n -(CH2)n’-C(O)-, -(CH2CH2-O)n"-(CH2)n’-N(RL)-C(O)-, -(CH2CH2-O)n"-(CH2)n’-C(O)-N(RL)-, -(CH2)n’-phenylene-N(RL)-C(O)-(CH2)n’-, -N(RL)-(CH2)n-O-phenylene-(CH2)n"-N(RL)-(CH2)n-, -(CH2)n’-C(O)-N(RL)-phenylene-C(O)-, -N(RL)-(CH2)n-phenylene-(CH2)n"-heterocyclylene-, -(CH2)n-phenylene-N(RL)-C(O)-(CH2CH2-O)n"-(CH2)n’-,-(CH2)n-phenylene-(CH2)n"-heterocyclylene-(CH2)n" C(O)-N(RL)-(CH2)n’-, -(CH2)n’-phenylene-O-(CH2)n’-heterocyclylene- (ChDn-, -(CH2)n-phenylene-(CH2)n-heterocyclylene- (CH2)n-0-, -(ChDn-heterocyclylene-(CH2)n’ wherein RLis H or Ci-e alkyl; n’ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n” is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0469] Pharmaceutical Compositions

[0470] In another embodiment, the invention comprises pharmaceutical compositions. For pharmaceutical composition purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

[0471] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0472] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0473] In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents.

[0474] In another embodiment, the invention comprises a parenteral dosage form. " Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents.

[0475] In another embodiment, the invention comprises a topical dosage form. " Topical administration" includes, for example, dermal and transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999.

[0476] Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention is dissolved or suspended in a suitable excipient. A typical formulation suitable for ocular or aural administration may be in the form of drops of amicronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[0477] For intranasal administration, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0478] In another embodiment, the invention comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0479] Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., etal., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., etal. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 2011; and Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

[0480] Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate,citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[0481] For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Dosing regimens may depend on the route of administration, dose scheduling, and use of flat-dose, body surface area or weight-based dosing. For example, for weight-based dosing, intravenously doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0482] Liposome containing compounds of the invention may be prepared by methods known in the art (See, for example, Chang, H. I.; Yeh, M. K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0483] Compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0484] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, ormicrocapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0485] The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0486] Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

[0487] For example, the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsions comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0488] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0489] A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds of the invention maybe formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co-precipitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the invention and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the invention are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0490] Administration and Dosing

[0491] Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

[0492] The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the invention may be administered orally, rectally, vaginally, parenterally, topically, intranasally, or by inhalation.

[0493] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0494] In another embodiment, the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0495] In another embodiment, the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, thecompounds of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may also be administered directly to the eye or ear.

[0496] The dosage regimen for the compounds of the invention or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg / kg (i.e., mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein. In another embodiment, total daily dose of the compound of the invention is from about 0.1 to about 50 mg / kg, and in another embodiment, from about 0.5 to about 30 mg / kg. It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.

[0497] Therapeutic Methods and Uses

[0498] The compounds of the invention may agonize the activity of calcitonin / amylin receptors and may be useful in the treatment of obesity and obesity related co-morbidities and suppression of and amelioration of other disease(s) mediated by the amylin and / or calcitonin receptors. Particularly, the compounds of Formula (I) may be used for treating or preventing a condition, disease, or disorder wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipidemia, metabolic acidosis, ketosis,diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

[0499] Co-administration

[0500] The compounds of the invention may be used alone, or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the compound of the invention, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein.

[0501] The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

[0502] A compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means thata compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

[0503] Co-administration

[0504] The compounds of the invention may be used alone, or in combination with one or more other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the compound of the invention, or pharmaceutically acceptable salt thereof, is used in combination with one or more other therapeutic agent discussed herein.

[0505] The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time to affect treatment of the subject. The two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

[0506] A compound of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "non-fixed combination" means that a compound of the invention, or a pharmaceutically acceptable salt thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

[0507] The combination agents are administered to a patient (e.g. a mammal or human) in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat the desired disease / disorder / condition (e.g., obesity, obesity related co-morbidities orT2DM).

[0508] In some embodiments, a compound of this invention may be co-administered with one or more other agents such as Orlistat, TZDs and other insulin-sensitizing agents, FGF21 analogs, Metformin, Omega-3-acid ethyl esters (e.g., Lovaza), Fibrates, HMG CoA-reductaseInhibitors, Ezetimibe, Probucol, Ursodeoxycholic acid, TGR5 agonists, FXR agonists, Vitamin E, Betaine, Pentoxifylline, CB1 antagonists, Carnitine, / V-acetylcysteine, Reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 as well as those in WO2010023594), Phentermine, Topiramate, GLP-1 receptor agonists, GIP receptor agonists, GIP receptor inhibitors and / or antagonists, dual GLP-1 receptor / glucagon receptor agonists (e.g., OPK88003, MEDI0382, JNJ-64565111, NN9277, Bl 456906), dual GLP-1 receptor / GIP receptor agonists [e.g., Tirzepatide (LY3298176), NN9423, NN9541, HS-20094, SCO-094, VK2735, CT-388, GMA-106, CT-868, HRS9531], dual GLP-1 receptor / glucagon receptor agonists (e.g. DD-01, PB-718, mazdutide, pemvidutide, pegapamodutide, survodutide, LM-008, IBI-362, AZD9550), dual GLP-1 receptor / GLP-2 receptor agonists (e.g. dapiglutide), dual GLP-1 receptor / amylin receptor agonists (e.g. amycretin), cagrilinitide / semaglutide, GLP-1 receptor agonist / GIP receptor antagonist (maridebart cafraglutide), dual GLP-1 receptor / FGF21 receptor agonists (e.g. HEC-88473, Bl 3006337), triple agonists of the GLP-1 receptor / glucagon receptor / GIP receptor (e.g. retatrutide), triple agonists of the GLP-1 receptor / glucagon receptor / FGF21 receptor (e.g.

[0509] DR10624), NPY2 receptor agonists (e.g. Bl 1820237), activin receptor type-2B modulators (e.g. bimagrumab), amylin receptor agonists, GPR75 modulators, delta-5 desaturase inhibitors, orexin 2 receptor modulators, Angiotensin-receptor blockers, an acetyl-CoA carboxylase (ACC) inhibitor, a ketohexokinase (KHK) inhibitor, ASK1 inhibitors, branched-chain alpha-keto acid dehydrogenase kinase inhibitors (BCKDK inhibitors), inhibitors of CCR2 and / or CCR5, PNPLA3 inhibitors, DGAT1 inhibitors, DGAT2 inhibitors, an FGF21 analog, FGF19 analogs, PPAR agonists, FXR agonists, AMPK activators [e.g., ETC-1002 (bempedoic acid)], SCD1 inhibitors or MPO inhibitors.

[0510] Exemplary GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide, danuglipron, orforglipron, lotiglipron, PF-06954522, HM15211, LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, efpeglenatide, CT-996, ECC5004, XW004, XW014, MDR-001, ZT002, KN-056, GL0034, GSBR-1290, noiiglutide, RGT-075, TTP-273, HRS-7535, GMA-105, TG103, GZR-18, GX-G6, ecnoglutide, PB-119, QLG2065, beinaglutide, those described in WO2018109607, those described in WO2019239319 (PCT / IB2019 / 054867 filed June 11, 2019), and those described in WO2019239371 (PCT / IB2019 / 054961 filed June 13, 2019).

[0511] Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1' / 7-spiro[indazole-5,4'-piperidin]-1 '-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid, gemcabene, and firsocostat (GS-0976) and phamaceutally acceptable salts thereof.

[0512] Exemplary FXR agonists include tropifexor (2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid), cilofexor (GS-9674), obeticholic acid, LY2562175, Met409, TERN-101 and EDP-305 and pharmaceutically acceptable salts thereof.

[0513] Exemplary KHK inhibitors include [(1 / ?,5S,6 / ?)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid and pharmaceutically acceptable salts thereof.

[0514] Exemplary DGAT2 inhibitors include (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide [including its crystalline solid forms (Form 1 and Form 2)]. See U. S. Patent No. 10,071,992.

[0515] Some exemplary BCKDK inhibitors include those described in US Patent Nos.

[0516] 11542270 and 11059833, including the following:

[0517] 5-(5-chloro-4-fluoro 3-methylthiophen-2-yl)-1H-tetrazole;

[0518] 5-(5-chloro-3-difluoromethylthiophen-2-yl)-1H-tetrazole;

[0519] 5-(5-fluoro-3-methylthiophen-2-yl)-1H-tetrazole;

[0520] 5-(5-chloro-3-methylthiophen-2-yl)-1H-tetrazole;

[0521] 5-(3,5-dichlorothiophen-2-yl)-1H-tetrazole;

[0522] 5-(4-bromo-3-methylthiophen-2-yl)-1H-tetrazole;

[0523] 5-(4-bromo-3-ethylthiophen-2-yl)-1H-tetrazole;

[0524] 5-(4-chloro-3-ethylthiophen-2-yl)-1H-tetrazole;

[0525] 3-chloro-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0526] 3-bromo-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0527] 3-(difluoromethyl)-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0528] 5,6-difluorothieno[3,2-b]thiophene-2-carboxylic acid; and

[0529] 3,5-difluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0530] or a pharmaceutically acceptable salt thereof.

[0531] Some additional exemplary BCKDK inhibitors include those described in US Patent Application 18 / 060,027, filed November 30, 2022, including the following:

[0532] 6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0533] 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0534] 6-chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid;

[0535] 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0536] 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2;

[0537] 3-(3-chloro-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid;

[0538] 3-(4-chloro-2,6-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0539] 6-chloro-3-(3-ethyl-2,4,5-trifluorophenyl)-1-benzothiophene-2-carboxylic acid; or ammonium 3-(3-ethyl-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylate;or a pharmaceutically acceptable salt thereof.

[0540] In some embodiments, a compound of this invention may be co-administered with one or more anti-diabetic agents. Suitable anti-diabetic agents include insulin, metformin, GLP-1 receptor agonists (described herein above), an acetyl-CoA carboxylase (ACC) inhibitor (described herein above), SGLT2 inhibitors (described herein above), monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, AM PK activators [e.g., ETC-1002 (bempedoic acid)], sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinides, a-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688), an a-glucoside hydrolase inhibitor (e.g., acarbose), a-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPARy agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), PPAR a / y agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), protein tyrosine phosphatase- 1B (PTP-1B) inhibitors [e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S. et al., Drug Discovery Today, 12(9 / 10), 373-381 (2007)], SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., those in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secretagogues, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, glucokinase activators (GKa) such as those described in WO2010103437, WO2010103438, WO2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 orGKM-001, insulin, insulin mimetics, glycogen phosphorylase inhibitors (e.g., GSK1362885), VPAC2 receptor agonists, glucagon receptor modulators such as those described in Demong, D. E. et al., Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R. M. et al., Annual Reports in Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J. C., Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high-affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611.Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g., PKCa, PKCb, PKCg), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g., SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILIbeta, and modulators of RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P. A., Goodwin, B. Expert Opin. Ther. Pat., 2010, 20(12), 1627-51.

[0541] The compounds of the present invention may be co-administered with anti-heart failure agents such as ACE inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril), Angiotensin II receptor blockers (e.g., candesartan, losartan, valsartan), Angiotensin-receptor neprilysin inhibitors (sacubitril / valsartan), If channel blocker Ivabradine, Beta-Adrenergic blocking agents (e.g., bisoprolol, metoprolol succinate, carvedilol), Aldosterone antagonists (e.g., spironolactone, eplerenone), hydralazine and isosorbide dinitrate, diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, Indapamide, Metolazone, Triamterene), or digoxin.

[0542] The compounds of the present invention may also be co-administered with cholesterol or lipid lowering agents including the following exemplary agents: HMG CoA reductase inhibitors (e.g., pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates (e.g., gemfibrozil, pemafibrate, fenofibrate, clofibrate); bile acid sequestrants (such as questran, colestipol, colesevelam); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; cholesterol absorption inhibitors (e.g., ezetimibe); nicotinic acid agents (e.g., niacin, niacor, slo-niacin); omega-3 fatty acids (e.g., epanova, fish oil, eicosapentaenoic acid); cholesteryl ester transfer protein inhibitors (e.g., obicetrapib) and PCSK9 modulators [e.g., alirocumab, evolocumab, bococizumab, ALN-PCS (inclisiran)].

[0543] The compounds of the present invention may also be used in combination with antihypertensive agents and such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of suitable anti-hypertensive agents include: alpha-adrenergic blockers; beta-adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACEinhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U. S. Patent Nos.

[0544] 5,612,359 and 6,043,265); Dual ET / AII antagonist (e.g., compounds disclosed in WO 00 / 01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginal agent is ivabradine.

[0545] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.

[0546] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0547] In one embodiment, a compound of invention may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (such as LASIX™), torsemide (such as DEMADEX™), bemetanide (such as BUMEX™), and ethacrynic acid (such as EDECRIN™); (b) thiazide-type diuretics such as chlorothiazide (such as DIURIL™, ESIDRIX™ or HYDRODIURIL™), hydrochlorothiazide (such as MICROZIDE™ or ORETIC™), benzthiazide, hydroflumethiazide (such as SALURON™), bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (such as LOZOL™); (c) phthalimidine-type diuretics such as chlorthalidone (such as HYGROTON™), and metolazone (such as ZAROXOLYN™); (d) quinazoline-type diuretics such as quinethazone; and (e) potassium-sparing diuretics such as triamterene (such as DYRENIUM™), and amiloride (such as MIDAMOR™ or MODURETIC™).

[0548] In another embodiment, a compound of the invention may be coadministered with a loop diuretic. In still another embodiment, the loop diuretic is selected from furosemide and torsemide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with furosemide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with torsemide which may optionally be a controlled or modified release form of torsemide.

[0549] In another embodiment, a compound of the invention may be co-administered with a thiazide-type diuretic. In still another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with chlorothiazide. In still another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be co-administered with hydrochlorothiazide.

[0550] In another embodiment, one or more compounds of Formula (I) or their pharmaceutically acceptable salts may be co-administered with a phthalimidine-type diuretic. In still another embodiment, the phthalimidine-type diuretic is chlorthalidone.Examples of suitable mineralocorticoid receptor antagonists include sprionolactone and eplerenone.

[0551] Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

[0552] Those skilled in the art will recognize that the compounds of this invention may also be used in conjunction with other cardiovascular or cerebrovascular treatments including Percutaneous Coronary Intervention (PCI), stenting, drug-eluting stents, stem cell therapy and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

[0553] Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when a compound of this invention and a second therapeutic agent are combined in a single dosage unit they may be formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric-coated. By enteric-coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that effects a sustained release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric-coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and / or enteric-release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

[0554] These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

[0555] Another approach may involve the formulation of a combination product in which both active components are combined with a material that effects a sustained release throughout the gastrointestinal tract of both active ingredients.

[0556] In some embodiments of combination therapy treatment, both the compounds of this invention and the other drug therapies are administered to patients such as mammals (e.g., humans, male or female) by conventional methods.In one embodiment, the compounds of this invention are administered in combination with another anti-obesity agent such as semaglutide, liraglutide, cagrilintide, tirzepatide, setmelanotide, orforglipron, danuglipron, apitegromab, retatrutide, pemvidutide, survodutide, mazdutide, taldefgrobep, orlistat, phentermine, phentermine-topiramate, bupropion-naltrxone and HU6 including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

[0557] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is administered in combination with a pharmaceutical composition comprising any one of semaglutide, liraglutide, cagrilintide, tirzepatide, setmelanotide, orforglipron, danuglipron, apitegromab, retatrutide, pemvidutide, survodutide, mazdutide, taldefgrobep, orlistat, phentermine, phentermine-topiramate, bupropion-naltrxone and HU6 or a pharmaceutically acceptable salt thereof simultaneously or at different times.

[0558] These agents and compounds of the invention may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

[0559] Kits

[0560] Another aspect of the invention provides kits comprising the compound of the invention or pharmaceutical compositions comprising the compound of the invention. A kit may include, in addition to the compound of the invention or pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes the compound or a pharmaceutical composition thereof and one or more therapeutic agents, such as any of the additional agents described hereinabove.

[0561] In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the invention in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises one or more compounds of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage and a container for the dosage.

[0562] Synthetic Methods

[0563] Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of thedescription contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available; 2) reported in the literature or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature.

[0564] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0565] The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0566] In the preparation of compounds of the invention it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition.

[0567] For example, if a compound contains a amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected.

[0568] Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as / V-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.

[0569] General Experimental Details

[0570] In the non-limiting Examples and Preparations that illustrate the invention and that are set out in the description, and in the following Schemes, the following the abbreviations, definitions and analytical procedures may be referred to:

[0571] Abbreviations

[0572] APCI is atmospheric pressure chemical ionization;

[0573] aq is aqueous;

[0574] br is broad;

[0575] tBu is tert-butyl;

[0576] °C is degrees Celsius;

[0577] cAMP is cyclic adenosine monophosphate;

[0578] CAN is ammonium cerium (IV) nitrate;

[0579] CO2 is carbon dioxide;

[0580] CDC or CHLOROFORM-d is deutero-chloroform;

[0581] 5 is chemical shift;

[0582] d is doublet;

[0583] dd is doublet of doublets;

[0584] ddd is doublet of doublet of doublets;

[0585] dt is doublet of triplets;

[0586] DMSO is dimethyl sulfoxide;

[0587] DMSO-de is deuterodimethylsulfoxide;

[0588] EC50 is 50% effective concentration;

[0589] EDCI is N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride;

[0590] Eq is equivalent;

[0591] ESI is electrospray ionization;

[0592] EtOAc is ethyl acetate;

[0593] EtOH is ethanol;

[0594] Et3N is triethylamine;

[0595] FAC is final assay concentration;

[0596] g is gram;

[0597] GMEAN is geometric mean;HATLI is 1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide

[0598] hexafluorophosphate;

[0599] HCI is hydrogen chloride (hydrochloric acid);

[0600] HPLC is high pressure liquid chromatography;

[0601] HOPO is 2-hydroxypyridine N-oxide;

[0602] hr(s) is hour(s);

[0603] L is liter;

[0604] LCMS is liquid chromatography mass spectrometry; m is multiplet;

[0605] M is molar;

[0606] MeCN is acetonitrile;

[0607] mg is milligram;

[0608] MgSC is magnesium sulfate;

[0609] MHz is mega Hertz;

[0610] min(s) is minute(s);

[0611] mL is milliliter;

[0612] mmol is millimole;

[0613] mol is mole;

[0614] MS (m / z) is mass spectrum peak;

[0615] MsCI is mesyl chloride;

[0616] NH3 is ammonia;

[0617] nm is nanometer;

[0618] NMR is nuclear magnetic resonance;

[0619] pH is power of hydrogen;

[0620] pM is picomolar;

[0621] ppm is parts per million;

[0622] psi is pounds per square inch;

[0623] q is quartet;

[0624] rt is room temperature;

[0625] RT is retention time;

[0626] s is singlet;

[0627] SFC is supercritical fluid chromatography;

[0628] t is triplet;

[0629] TEA is triethylamine;

[0630] TFA is trifluoroacetic acid;

[0631] THF is tetrahydrofuran;

[0632] ZPE is zero percent effect;

[0633] pL is microliter;pmol is micromole; and

[0634] pM is micromolar.

[0635] The Schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present invention. In the following Schemes, the general methods for the preparation of the compounds are shown either in racemic or enantioenriched form. It will be apparent to one skilled in the art that all of the synthetic transformations may be conducted in a precisely similar manner whether the materials are enantioenriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature.

[0636] General Experimental Methods:

[0637] The compounds of the invention, or their pharmaceutically acceptable salts, may be prepared by a variety of methods that are analogously known in the art. The reaction schemes described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art, illustrate methods for preparing the compounds. It will be appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0638] The starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-XII (published by Wiley-lnterscience)). Preferred methods include, but are not limited to, those described below.

[0639] During any of the following synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups (-PG), such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups In Organic Chemistry, John Wiley & Sons, 2007, which are hereby incorporated by reference. Due to the multitude of protection and deprotection possibilities, and the multitude of sequential changes that could occur to accommodate them, only one of these possible manipulations will generally be described.

[0640] Compounds of the present invention, or the pharmaceutically acceptable salts of said compounds, or their tautomers and radioisotopes, can be prepared according to the reaction schemes discussed herein below. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of: hydrogen, such as2H and3H; carbon, such as11C,13C and14C; fluorine, such as18F; chlorine, such as36CI; nitrogen, such as13N and15N; oxygen, such as15O,17O and18O. Substitution with heavier isotopes such as deuterium (D), i.e.,2H, may affordcertain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0641] The scope of the invention includes all crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomerates) thereof. Also within the scope of the invention are intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof, and all solvates and complexes of salts thereof as defined hereinbefore for compounds of Formula I. The invention includes all polymorphs of the aforementioned species and crystal habits thereof.

[0642] Unless otherwise indicated, the substituents in the schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.

[0643] One skilled in the art will recognize that, in some cases, the compounds will be generated as a mixture of diastereomers and / or enantiomers; these may be separated at various stages of the synthetic scheme using conventional techniques or a combination of such techniques, such as, but not limited to, crystallization, normal-phase chromatography, reversed-phase chromatography and chiral chromatography, to afford the single enantiomers of the invention; for example, see “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).

[0644] It will be understood by one skilled in the art that the various symbols, superscripts and subscripts used in the schemes, methods and examples are used for convenience of representation and / or to reflect the order in which they are introduced in the schemes and are not intended to necessarily correspond to the symbols, superscripts or subscripts in the appended claims. The schemes are representative of methods useful in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.

[0645] The compounds of the invention can be prepared as described herein and according to the methods as described in Schemes 1 to 2.

[0646] Scheme 1CO, Et o o CO, Et CO, Et

[0647]

[0648] Compounds of Formula (I) may be synthesized as shown in Scheme 1. The compounds of Formula A and Formula B may be synthesized through literature methods well known to those skilled in the art or purchased commercially. Formula A and Formula B can be combined with a suitable base, such as potassium tert-butoxide, in a suitable solvent, such as toluene, at ambient temperature for 2 - 24 hours to provide compounds of Formula C. Compounds of Formula C can be converted to compounds of Formula D with a suitable ammonia source, such as ammonium acetate, in a suitable solvent, such as acetic acid, at 80 °C for 16-24 hours. Compounds of Formula D can be converted to compounds of Formula E with the use of a suitable oxidant, such as ammonium cerium (IV) nitrate (CAN), in a suitable solvent or mixture of solvents, such as 1: 1 mixture (v / v) of acetonitrile and water, at 20 °C for 2 - 72 hours. Compounds of Formula E can be combined with Compounds of Formula F and a suitable coupling reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and a suitable base, such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, such as acetonitrile, at 0 °C, and then stirred at 50 °C for 16-24 hours to provide compounds of Formula G. Alternatively, compounds of Formula E and compounds of Formula F can be combined with a suitable azodicarboxylate, such as diisopropyl azodicarboxylate, and triphenylphosphine, and stirred at 20-50 °C for 16h to provide compounds of Formula G. Compounds of Formula G can be converted to Compounds of Formula H by demethylation using a suitable salt, such as lithiumiodide, in a suitable base, such as pyridine, at 90 °C for 16-48 hours, followed by amine deprotection using a suitable deprotection method, such as hydrochloric acid, in a suitable solvent, such as dioxane, at ambient temperature for 2-12 hours, followed by ring closure using a suitable coupling reagent such as 1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU), and a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dimethylformamide at ambient temperature for 8-16 hours. Compounds of Formula H can be converted to compounds of Formula I with the use of a suitable acid, such as hydrochloric acid, in a suitable solvent, such as dioxane, at 60-90 °C for 4-24 hours. Compounds of Formula I can be converted to compounds of Formula J by combining with a suitable amine, such as pyrrolidine, and a suitable coupling reagent, such as HATLI, and a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dimethylformamide at 20-70 °C for 16 hours. Alternatively, the amine can be substituted with acetohydrazide, and the resulting intermediate can be treated with a suitable dehydrating agent, such as 4-toluenesulfonyl chloride I dimethylaminopyridine ([DMAPTs]+CI-), and a suitable base, such as diisopropylethylamine, at ambient temperature for 2-12 hours to provide compounds of Formula K. Compounds of Formula J or Formula K can be converted to compounds of Formula (I) by hydrolysis with a suitable base, such as lithium hydroxide, in a suitable solvent, such as tetrahydrofuran at 20-50 °C for 16 hours, followed by coupling to an amine, such as (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol, using a suitable coupling reagent, such as N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDCI), an optional additive, such as 2-hydroxypyridine N-oxide (HOPO), and a suitable base, such as 4-methylmorpholine, in a suitable solvent, such as dimethylformamide, at ambient temperature for 2-24 hours.

[0649] Scheme 2

[0650]

[0651] Compounds of Formula (I) may be synthesized as shown in Scheme 2. Compounds of Formula E’ can be prepared using similar sequence as described in Scheme 1 starting with the compounds of Formula A and Formula B’, where PG is including but not limited to benzyloxy, which may be synthesized through literature methods well known to those skilled in the art or purchased commercially. Compounds of Formula K can be synthesized from compounds of Formula E’ using a suitable chlorinating source, such as phosphoryl chloride. Compounds of Formula K can be treated with a suitable demethylating reagent, such as lithium iodide, in a suitable base, such as pyridine at 90 °C for 16-48 hours, followed by a Curtius rearrangement using suitable reagents, such as hydrazine in a suitable solvent, such as pyridine to afford compounds of Formula M. Compounds of Formula N can be prepared from compounds of Formula M via the intermediacy of the corresponding diazonium salts in the presence of copper salts, such as copper chloride, together with thionyl chloride as the sulfur dioxide source under aqueous acidic conditions. Compounds of Formula N can be mixed with compounds of Formula O and a suitable base, such as triethylamine in a suitable solvent, such as dichloromethane, at ambient temperatures to give compounds of Formula P. Compounds of formula P can be treated under standard SnAr conditions using a suitable base, such as potassium tert-butoxide or cesium carbonate in asuitable solvent, such as acetonitrile at 80 °C for 16-48 hours to give compounds of Formula Q. Compounds of Formula R can be prepared by removal of PG to the carboxylic acid under suitable deprotection conditions, such as hydrogenolysis of a benzyl ester using palladium on carbon under an atmospheric pressure of hydrogen at ambient temperature. Compounds of Formula S can be prepared by amidation with a suitable amine, such as pyrrolidine, and a suitable coupling reagent, such as HATLI, and a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dimethylformamide at 20-70 °C for 16 hours. Alternatively, the amine can be substituted with acetohydrazide, and the resulting intermediate can be treated with a suitable dehydrating agent, such as 4-toluenesulfonyl chloride / dimethylaminopyridine ([DMAPTs]+CI-), and a suitable base, such as diisopropylethylamine, at ambient temperature for 2-12 hours to afford compounds of Formula T. Compounds of Formula (II) can be synthesized from compounds of Formula S or T using standard hydrolysis conditions using a suitable base, such as lithium hydroxide, in a suitable solvent, such as tetrahydrofuran at 20-50 °C for 16 hours, followed by coupling to an amine, such as (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol, using a suitable coupling reagent, such as N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDCI), an optional additive, such as 2-hydroxypyridine N-oxide (HOPO), and a suitable base, such as 4-methylmorpholine, in a suitable solvent, such as dimethylformamide, at ambient temperature for 2-24 hours.

[0652] Unless stated otherwise, the variables in Schemes 1-2 and 3-10 have the same meanings as defined herein. In some cases, intermediate compounds used to prepare compounds of Formula (I) may contain protecting groups, which may be appended or removed by additional steps in the synthetic sequence using conditions known in the art (March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition or Protecting Groups, 10 Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variables are as defined in the embodiments, schemes, examples, and claims herein.

[0653] The compounds in Table 2 are or may be prepared using general methods according to or analogous to the methods described herein including modification as appropriate. Additional methods of preparation are outlined in Schemes 3-10 (Synthesis Methods A - H) as described below. In Schemes 3-10 it is to be understood that “Formula 1” is synonymous with “Formula (I)”.

[0654] Scheme 3 depicts compounds within Formula 1 may be synthesized according to synthesis method A. Compounds of Formula A1 and A3 can be synthesized according to methods described herein or via literature methods well known to those skilled in the art. Compounds of Formula A1 can be converted to compounds of Formula A2 through a stepwise process: 1) Treatment with a metal halide salt such as lithium iodide in the presence of a suitable solvent such as pyridine, and heating at an elevated temperature, such as 100 °C. 2) Amide couplingwith a compound of Formula A3 under standard conditions such as 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate with an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as / V, / V-dimethylformamide. 3) Protecting group removal under acidic conditions, using for example HCI in dioxane, in a polar solvent such as acetonitrile. 4) Ring formation via an SNAr reaction using for example, potassium fluoride, an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as dimethylsufoxide at an elevated temperature, such as 100 °C. 5) Ester hydrolysis via treatment with a suitable base such as lithium hydroxide, in an appropriate solvent mixture such as water in tetrahydrofuran. Compounds of formula A2 can be converted to compounds within Formula 1 through treatment an appropriate amine, under standard amidation conditions such as 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate with an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as / V, / V-dimethylformamide.

[0655] Scheme 3 - Synthesis Method A

[0656]

[0657] Alternatively, Compounds within Formula 1 may be synthesized according to Scheme 4 -synthesis method B. Compounds of Formula B1 and B3 can be synthesized according methods described herein or via literature methods well known to those skilled in the art. Compounds of Formula B1 can be converted to compounds of Formula B2 through a stepwise process: 1) Treatment with a nucleophile such as B3 in the presence of a suitable base such as lithium diisopropylamide in a suitable solvent such as tetrahydrofuran. 2) Treatment with a metal halide salt such as lithium iodide in the presence of a suitable solvent such as pyridine, and heating at an elevated temperature, such as 100 °C. 3) Protecting group removal under acidic conditions,using for example HCI in dioxane, in a polar solvent such as acetonitrile. 4) Lactam formation using conditions well known in the literature such as treatment with chloro(dimethylamino)- / V, / \ / -dimethylmethaniminium hexafluorophosphate and 1-methyl-1 / - / -imidazole, with an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as acetonitrile. 5) Ester hydrolysis via treatment with a suitable base such as lithium hydroxide, in an appropriate solvent mixture such as water in tetrahydrofuran. Compounds of Formula B2 can be converted to compounds within Formula 1 through treatment an appropriate amine, under standard amidation conditions such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate with an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as / V, / V-dimethylformamide.

[0658] Scheme 4 - Synthesis Method B

[0659]

[0660] Compounds within

[0661] Formula 1

[0662] Alternatively, Compounds within Formula 1 may be synthesized according to Scheme 5 -synthesis method C. Compounds of Formula CT and C3’ can be synthesized according to methods described herein or via literature methods well known to those skilled in the art.

[0663] Compounds of Formula CT can be converted to compounds of Formula C2’ through a stepwise process: 1) Conversion of the 2-chloro-pyridine Formula CT to the 2-pyridone via treatment with acetohydroxamide acid, a suitable base such as potassium carbonate, in a suitable solvent such as dimethyl sulfoxide 2) Reaction with a compound of Formula C3’ under well-known Mitsunobu reaction conditions using triphenylphosphine and diisopropyl azodicarboxylate in a suitable solvent such as tetrahydrofuran. 3) Treatment with a metal halide salt such as lithiumiodide in the presence of a suitable solvent such as pyridine, and heating at an elevated temperature, such as 100 °C. 4) Protecting group removal under acidic conditions, using for example HCI in dioxane, in a polar solvent such as acetonitrile. 5) Lactam formation using conditions well known in the literature such as treatment with chloro(dimethylamino)- / V, / \ / -dimethylmethaniminium hexafluorophosphate and 1-methyl-1 / - / -imidazole, with an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as acetonitrile. 6) Ester hydrolysis via treatment with a suitable base such as lithium hydroxide, in an appropriate solvent mixture such as water in tetrahydrofuran. Compounds of formula C2’ can be converted to compounds within Formula 1 through treatment an appropriate amine, under standard amidation conditions such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate with an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as / V, / V-dimethylformamide.

[0664] Scheme 5 - Synthesis Method C

[0665] Synthesis Method C

[0666] 1. Acetohydroxamic acid, K2CO3, DMSO

[0667] C1’ C2’

[0668]

[0669] Compound withn

[0670] Formula 1

[0671] Alternatively, Compounds within Formula 1 may be synthesized according to Scheme 6 -synthesis method D. Compounds of Formula D1 can be synthesized according to methods described herein. Compounds of Formula D1 can be converted to compounds of Formula D2 through cross coupling with an appropriate amine using Buchwald-Hartwig amination conditions well-known in the literature such as treatment with a palladium catalyst, such as BrettPhos Pd G4, a suitable base such as cesium carbonate, in a suitable solvent such as dioxane, at an elevated temperature such as 100 °C. Compounds of Formula D2 can be converted to compounds within Formula 1 through methods well known in the literature to convert esters toheterocycles. Alternatively, compounds of Formula D1 can be converted to compounds of formula D3 through methods well known in the literature to convert esters to heterocycles. Compounds of Formula D3 can be transformed into compounds within Formula 1 using for example, the Buchwald-Hartwig amination conditions outlined above.

[0672] Scheme 6 - Synthesis Method D

[0673]

[0674] Compound within Formula 1 Alternatively, Compounds within Formula 1 may be synthesized according to Scheme 7 -synthesis method E. Compounds of Formula E1 can be synthesized according to methods described herein or via literature methods well known to those skilled in the art. Compounds of Formula E1 can be converted to compounds within Formula 1 via a stepwise process: 1) Lactam alkylation using a suitable electrophile such as methyl iodide, a suitable base such as possasium hydroxide, in a suitable solvent such as dimethyl sulfoxide. 2). Ester hydrolysis via treatment with a suitable base such as lithium hydroxide, in an appropriate solvent mixture such as water in tetrahydrofuran. 3) Amide formation with an appropriate amine under standard amide formation conditions such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1 -ium 3-oxide hexafluorophosphate with an appropriate base such as N, N-diisopropylethylamine, in an appropriate solvent such as / V, / V-dimethylformamide.

[0675] Scheme 7 - Synthesis Method E1. Mel, KOH, DMSO 2. LiOH, THF / H2O 3. R8R9NH Standard amide formation conditions

[0676]

[0677] E1 Compound within Formula 1 Alternatively, Compounds within Formula 1 may be synthesized according to Scheme 8 -synthesis method F. Compounds of Formula F1 --synthesized according to methods described herein or via literature methods well known to those skilled in the art — can be transformed into compounds within Formula 1 through Suzuki cross coupling. For example, treatment with the appropriate boronic ester F2 in the presence of a palladium catalyst such as cataCXium A Pd G4, with an appropriate base such as cesium carbonate, in a suitable solvent mixture such as dioxane / water, at elevated temperature such as 100 °C. Alternatively, compounds of Formula F1 can be treated with an appropriate nucleophile under conditions well known to those skilled in the art, to provide compounds within Formula 1.

[0678] Additionally, compounds of Formula F1 can be converted to compounds of Formula F3 using standard boronic ester formation conditions well known to those skilled in the art.

[0679] Compounds of formula F3 can be converted to compounds within Formula 1, via treatment with the Suzuki coupling conditions above and using the appropriate compound of formula F4 wherein X can be a suitable coupling partner such as a halide.

[0680] Scheme 8 - Synthesis Method FCl O cataCXium A Pd G4

[0681] Cs2CO3, dioxane / H20,A

[0682] or KF, t-AmOH, A

[0683]

[0684] Compoudn within

[0685] Formula 1

[0686] SNAr reaction cataCXium A Pd G4 Cs2CO3’ B2Pin2, KOAc dioxane / H2o,APd(dppf)Cl2’ dioxane Y

[0687]

[0688] Alternatively, Compounds within Formula 1 may be synthesized according to Scheme 9 - synthesis method G. Treatment of compounds of Formula G1-- synthesized according to methods described herein or via literature methods well known to those skilled in the art — with the appropriate amine using standard amide formation conditions such as 1- [bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate with an appropriate base such as / V, / V-diisopropylethylamine, in an appropriate solvent such as / V, / V-dimethylformamide can provide compounds of Formula G2. Treatment of compounds of Formula G2 using metal mediated cross N-, O- or C-cross coupling conditions well known to those skilled in the art can provide compounds within Formula 1.

[0689] Scheme 9 - Synthesis Method G

[0690] R8R9NH Standard amide formation conditions

[0691]

[0692] metal-mediated N-, O-, and C-cross couplings R = cyclopropyl, -OMe, -NHMe,

[0693] -NMe2, and other related substituents

[0694]

[0695] Compound within Formula 1

[0696] Alternatively, Compounds within Formula 1 may be synthesized according to Scheme

[0697] 10 - synthesis method H. Treatment of compounds related to P32-- synthesized according to methods described herein or via literature methods well known to those skilled in the art — using the appropriate cross coupling partner (such as H1), under Suzuki cross coupling conditions such as Sphos Pd G3 as a suitable palladium catalyst, cesium carbonate as a suitable base, in a suitable solvent mixture such as dioxane and water, at elevated temperatures such as 100 °C can provide compounds within Formula 1.

[0698] Scheme 10 - Synthesis Method H

[0699]

[0700] or other related

[0701] P32 Compound within Formula 1

[0702] compounds similarly

[0703] prepared

[0704] The synthetic intermediates having formulas A through T, A1, A2, B1, B2, CT, C2’, D1, D2, D3, E1, F1, F2, F3, F4, G1, G2 and P32 as defined in the above Schemes 1 to 10 are

[0705] useful for preparing compounds of the invention and are provided as further aspects of this invention.

[0706] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as

[0707] limiting the scope of the invention in any manner.

[0708] The following illustrate the synthesis of various compounds of the present invention.

[0709] Additional compounds within the scope of this invention may be prepared using the methods illustrated in these Examples, either alone or in combination with techniques generally known in the art. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein.Reactions were performed in air or, when oxygen- or moisture-sensitive reagents or intermediates were employed, under an inert atmosphere (nitrogen or argon). When appropriate, reaction apparatuses were dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure-Seal™ products from Sigma-Aldrich or DriSolv™ products from EMD Chemicals, Gibbstown, NJ) were employed. In some cases, commercial solvents were passed through columns packed with 4 molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, / V, / V-dimethylformamide, and tetrahydrofuran; b) <180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, solvents were further treated with metallic sodium, calcium hydride, or molecular sieves, and distilled just prior to use. Other commercial solvents and reagents were used without further purification. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. Products were generally dried under vacuum before being carried on to further reactions or submitted for biological testing.

[0710] When indicated, reactions were heated by microwave irradiation using Biotage Initiator or Personal Chemistry Emrys Optimizer microwave instruments. Reaction progress was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm excitation wavelength) and visualized under UV light and / or with I2, KMnO4, C0CI2, phosphomolybdic acid, or ceric ammonium molybdate stains. LCMS data were acquired on an Agilent 1100 Series instrument with a Leap Technologies autosampler, Gemini C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid, formic acid, or ammonium hydroxide modifiers. The column eluent was analyzed using a Waters ZQ mass spectrometer scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were generally acquired on an Agilent 1100 Series instrument using Gemini or XBridge C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid or ammonium hydroxide modifiers. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 injector, HP-1 column (12 m x 0.2 mm x 0.33 pm), and helium carrier gas. Samples were analyzed on an HP 5973 mass selective detector, scanning from 50 to 550 Da using electron ionization. Purifications were generally performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges. Chiral purifications were generally performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar instruments; ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or-OJ columns; and CO2 mixtures with methanol, ethanol, propan-2-ol, or acetonitrile, alone or modified using trifluoroacetic acid or propan-2-amine. UV detection was used to trigger fraction collection. For syntheses referencing procedures in other Examplesor Methods, purifications may vary: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate RfS or retention times.

[0711] Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (El) or electron scatter (ES) ionization sources. Proton nuclear magnetic spectroscopy (1H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on 300, 400, 500, or 600 MHz Varian, Bruker, or Jeol spectrometers. Chemical shifts are expressed in parts per million (ppm, 8) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-^, 1.94 ppm; dimethyl sulfoxide-cfc, 2.50 ppm; DHO, 4.79 ppm). The peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer model 343 polarimeter using a 1 dm cell. Silica gel chromatography was performed primarily using medium-pressure Biotage or ISCO systems using columns pre-packaged by various commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated values.

[0712] Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius).

[0713] Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0714] The terms “concentrated,” “evaporated,” and “concentrated in vacuo" refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60 °C. The abbreviation “min” and “h” stand for “minutes” and “hours” respectively. The term “TLC” refers to thin-layer chromatography, “room temperature or ambient temperature” means a temperature between 18 and 25 °C, “GCMS” refers to gas chromatography-mass spectrometry, “LCMS” refers to liquid chromatography-mass spectrometry, “UPLC” refers to ultra-performance liquid chromatography and “HPLC” refers to high-performance liquid chromatography, “SFC” refers to supercritical fluid chromatography.

[0715] Hydrogenation may be performed in a Parr Shaker under pressurized hydrogen gas, or in a Thales-nano H-Cube flow hydrogenation apparatus at full hydrogen and a flow rate between 1 and 2 mL / minute at the specified temperature.

[0716] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedures.

[0717] In some examples, chiral separations were carried out to separate enantiomers or diastereomers of certain compounds of the invention (in some examples, the separated enantiomers are designated as ENT-1 and ENT-2, according to their order of elution; similarly, separated diastereomers are designated as DIAST-1 and DIAST-2, according to their order ofelution). In some examples, the optical rotation of an enantiomer was measured using a polarimeter. According to its observed rotation data (or its specific rotation data), an enantiomer with a clockwise rotation was designated as the (+)-enantiomer and an enantiomer with a counter-clockwise rotation was designated as the (-)-enantiomer. Racemic compounds are indicated either by the absence of drawn or described stereochemistry, or by the presence of (+ / -) adjacent to the structure; in this latter case, the indicated stereochemistry represents just one of the two enantiomers that make up the racemic mixture.

[0718] The synthesized compounds and intermediates described below were named using the naming convention provided with ACD / ChemSketch 2020.2.1.1, File Version C25H41, Build 121153 and 2024.1.1, File Version C45H41, Build 139919 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming conventions provided with ACD / ChemSketch 2020.2.1.1 and 2024.1.1 are well known by those skilled in the art and it is believed that the naming conventions provided with ACD / ChemSketch 2020.2.1.1 and 2024.1.1 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules.

[0719] Reference Compound 1

[0720] Synthesis of ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(furan-2-yl)methyl]carbamoyl}phenyl)-5- oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridine-3-carboxylate (RC-1)

[0721]

[0722] refluxing

[0723] CF3COOH o EtOAc

[0724] C18

[0725] NH2O

[0726] C15

[0727]

[0728] Step 1. Synthesis of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (C14)

[0729] A solution of 3-(4-fluorophenyl)propionic acid (25 g, 1 Eq, 0.15 mol), Meldrum’s acid (21 g, 1 Eq, 0.15 mol), and 4-(dimethylamino)pyridine (27 g, 1.5 Eq, 0.22 mol) in dichloromethane (300 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (28 g, 1 Eq, 0.15 mol) in one portion. The mixture was stirred at 20 °C for 3 hours until LCMS analysis indicated conversion to the Meldrum’s acid adduct. The mixture was washed with 1 N HCI (50 mL) followed by water (50 mL), and the separated organics were dried over MgSO₄, filtered, and concentrated under reduced pressure to an oil. The oil was dissolved in ethanol and stirred at reflux for 5 hours until LCMS analysis indicated conversion to C14. The mixture was concentrated and purified via silica gel chromatography (Gradient: 0 to 30% ethyl acetate in heptane) to afford C14 as a colorless oil. Yield: 26.8 g, 112 mmol, 76%. LCMS m / z 239.1 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.19 - 7.10 (m, 2H), 7.01 - 6.92 (m, 2H), 4.18 (q, J= 7.1 Hz, 2H), 3.42 (s, 2H), 2.94 - 2.83 (m, 4H), 1.27 (t, J= 7.2 Hz, 3H).

[0730] Step 2. Synthesis of ethyl (2Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (C15)A solution of C14 (4.15 g, 1 Eq, 17.4 mmol) in ethanol (35 mL) was treated with ammonia (2 molar in ethanol, 43.5 mL, 5 Eq, 87.1 mmol) and stirred at 90 °C. After 18 hours, the mixture was treated with additional ammonia (2 M in ethanol, 3 mL, 0.34 Eq, 6 mmol) and stirred at 90 °for a further 5 hours until NMR analysis indicated conversion to C15.

[0731] Concentration under reduced pressure afforded C15 as a pale-yellow oil, which was used without further purification. Yield: 3.83 g, 16.1 mmol, 93%.1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.19 - 7.12 (m, 2H), 7.04 - 6.95 (m, 2H), 4.58 (s, 1H), 4.13 (q, J= 7.1 Hz, 2H), 2.86 (t, J = 7.9 Hz, 2H), 2.45 - 2.38 (m, 2H), 1.28 (t, J= 7.1 Hz, 3H).

[0732] Step 3. Synthesis of tert-butyl [(2S)-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate (C16)

[0733] A mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (990 mg, 1 Eq, 4.56 mmol) and Meldrum's acid (657 mg, 1 Eq, 4.56 mmol) was dissolved in dichloromethane (24 mL), cooled in an ice / water bath, and treated sequentially with dicyclohexylcarbodiimide (940 mg, 815 µL, 1 Eq, 4.56 mmol) and 4-(dimethylamino)pyridine (585 mg, 1.05 Eq, 4.78 mmol). The reaction was stirred in the bath for 4 hours until LCMS analysis indicated conversion to C16. The mixture was filtered cold to remove solid urea byproduct and the filtrate was washed three times with potassium bisulfate (1M, aqueous) and then once with saturated brine. The separated organics were cooled in an ice / water bath, treated with MgSC, and stirred in the bath for 1 hour before filtration and concentration under reduced pressure to afford a yellow gum. Purification via silica gel chromatography (Gradient: 30 to 100% ethyl acetate in heptane) afforded C16 as a colorless gum. Yield: 964 mg, 2.81 mmol, 62%. LCMS m / z 342.2 [M-H]-.

[0734] Step 4. Synthesis of tert-butyl (2S)-3,5-dioxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (C17) A solution of tert-butyl [(2S)-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate (960 mg, 1 Eq, 2.80 mmol) in ethyl acetate (20 mL) was stirred at reflux for 1 hour until LCMS analysis indicated conversion to C17. The reaction mixture was cooled and concentrated under reduced pressure to afford a foam. Purification via silica gel chromatography (Gradient: 0 to 60% ethyl acetate in heptane) afforded C17 as a white foam. Yield: 428 mg, 1.77 mmol, 63%. LCMS m / z 242.3 [M+H]+.1H NMR (400 MHz, CDCl3) 6 = 4.30 (d, J= 3.5 Hz, 1H), 3.13 (s, 2H), 2.37 (dt, J= 3.9, 7.0 Hz, 1H), 1.56 (s, 9H), 1.13 (d, J= 7.0 Hz, 3H), 0.94 (d, J= 7.0 Hz, 3H).

[0735] Step 5. Synthesis of (5S)-5-(propan-2-yl)pyrrolidine-2, 4-dione (C18)

[0736] A solution of tert-butyl (2S)-3,5-dioxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (420 mg, 1 Eq, 1.74 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL) and stirred at 20 °C for 30 minutes until LCMS analysis indicated conversion to C18. The mixturewas concentrated under reduced pressure and co-distilled with ethyl acetate and heptane to afford C18 as a waxy, white solid. Yield: 236 mg, 1.67 mmol, 96%. LCMS m / z 142.2 [M+H]+.1H NMR (400 MHz, CDCl3) 6 = 6.89 (br s, 1H), 3.92 - 3.85 (m, 1H), 3.06 - 2.90 (m, 2H), 2.18 (dtd, J = 3.9, 7.0, 13.8 Hz, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H).

[0737] Step 6. Synthesis of 4-[(7S)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4,5,6,7-tetrahydro-1 / 7-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (C19)

[0738] A mixture of C15 (79 mg, 1 Eq, 0.33 mmol), (5S)-5-(propan-2-yl)pyrrolidine-2, 4-dione (47 mg, 1 Eq, 0.33 mmol) and 4-formylbenzoic acid (50 mg, 1 Eq, 0.33 mmol) in ethanol (1.7 mL) was treated with sodium ethoxide (24 mg, 1 Eq, 0.33 mmol) in ethanol (0.5 mL) and stirred at 80 °C for 15 hours until LCMS analysis indicated conversion to C19. The mixture was used directly in the next step. LCMS m / z 491.2 [M-H]'.

[0739] Step 7. Synthesis of 4-[(7S)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (C20)

[0740] The previous reaction mixture was cooled to room temperature, treated with 2 mL of a 1:1 mixture of acetonitrile and water followed by cerium (IV) ammonium nitrate (180 mg, 1 Eq, 0.33 mmol), and stirred at room temperature. After 4.5 hours additional CAN (100 mg, 0.18 mmol) was added, and stirring was continued at room temperature for another 72 hours. LCMS analysis indicated conversion to C20. The mixture was partitioned between water and ethyl acetate and the separated organics were dried over MgSO₄, filtered, and concentrated under reduced pressure to afford C20 as an orange residue that was used without further purification in the next step. Yield: 166 mg, 0.338 mmol, 100% over 2 steps. LCMS m / z 491.4 [M+H]+.

[0741] Step 8. Synthesis of ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(furan-2-yl)methyl]carbamoyl}phenyl)-5-oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridine-3-carboxylate (RC-1)

[0742] A mixture of 1-(2-furyl)methanamine (35 mg, 33 µL, 1.1 Eq, 0.36 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (70 mg, 1.1 Eq, 0.36 mmol), 4-[(7S)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (160 mg, 1 Eq, 0.33 mmol), and 2-hydroxypyridine 1-oxide (37 mg, 1 Eq, 0.33 mmol) was treated with dimethylformamide (1.5 mL), followed by triethylamine (100 mg, 140 µL, 3 Eq, 0.99 mmol), and the mixture was stirred at 20 °C for 4.5 hours until LCMS analysis indicated conversion to RC-1. The reaction mixture was diluted with ethyl acetate and washed once each with 1M HCI, saturated aqueous sodium bicarbonate, and saturated brine. The separated organics were dried over MgSO₄, filtered, and concentrated to afford an amber gum. Initial purification via silica gel chromatography (Gradient: 30 to 100%ethyl acetate in heptane) and subsequent purification via reversed-phase HPLC (Column:

[0743] Sunfire C18 19 x 100 mm 5 µm; Mobile phase A: 0.05% TFA in water (v / v); Mobile phase B: 0.05% TFA in acetonitrile (v / v); Gradient: 65.0% H2O / 35.0% Acetonitrile linear to 25.0% H2O / 75.0% Acetonitrile in 8.5 min, 25.0% H2O / 75.0% Acetonitrile linear to 5.0% H2O / 95.0% Acetonitrile to 9.0 min, HOLD at 5% H2O / 95% Acetonitrile to 10.0 min; Flow: 25 mL / min) afforded RC-1 as a white solid. Yield: 4.4 mg, 0.008 mmol, 2.3%. LCMS m / z 570.4 [M+H]+.1H NMR (600 MHz, DMSO-d₆) 5 = 9.09 (t, J= 5.7 Hz, 1H), 8.92 (s, 1H), 7.91 (d, J= 8.5 Hz, 2H), 7.59 (d, J= 1.1 Hz, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.22 (dd, J= 5.7, 8.4 Hz, 2H), 7.11 - 7.05 (m, 2H), 6.41 (dd, J = 2.0, 3.1 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H), 4.53 - 4.51 (m, 1H), 4.50 (d, J= 5.6 Hz, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.18 - 3.15 (m, 1H), 3.14 - 3.11 (m, 1H), 3.10 - 3.06 (m, 1H), 3.06 - 3.01 (m, 1H), 2.35 (tdd, J= 3.3, 6.8, 10.2 Hz, 1H), 1.03 (d, J= 6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H), 0.65 (d, J = 6.7 Hz, 3H).

[0744] Reference Compound 2

[0745] Synthesis of ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(furan-2-yl)methyl]carbamoyl}phenyl)- 5-oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridine-3-carboxylate (RC-2)

[0746]

[0747] C24CAN

[0748]

[0749] Step 1. Synthesis of tert-butyl [(2R)-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate (C21)

[0750] A mixture of (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (1.086 g, 1 Eq, 4.998 mmol) and Meldrum's acid (720.4 mg, 1 Eq, 4.998 mmol) was dissolved in dichloromethane (25 mL). The clear, colorless solution was cooled in an ice / water bath and treated sequentially with dicyclohexylcarbodiimide (1.031 g, 894.5 µL, 1 Eq, 4.998 mmol) and 4-(dimethylamino) pyridine (641.2 mg, 1.05 Eq, 5.248 mmol). The reaction was allowed to stir in the bath for 16 hours, with slow warming to room temperature. LCMS analysis indicated conversion to C21. The mixture was filtered to remove solid urea byproduct and the filtrate was washed three times with sodium bisulfate (1M, aqueous) and then once with saturated brine. The separated organics were dried over MgSC, filtered, and concentrated under reduced pressure to afford C21 as a yellow gum, which was used without further purification. Yield: 1.72 g, 4.998 mmol, 100%. LCMS m / z 342.1 [M-H]’.

[0751] Step 2. Synthesis of tert-butyl (2R)-3,5-dioxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (C22) A solution of tert-butyl [(2R)-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate (1.716 g, 1 Eq, 4.998 mmol) in ethyl acetate (30 mL) was stirred at reflux for 3 hours until LCMS analysis indicated conversion to C22. The reaction mixture was cooled and concentrated under reduced pressure to afford a foam. Purification via silica gel chromatography (Gradient: 20 to 80% ethyl acetate in heptane) afforded C22 as a pale-yellow gum. Yield: 663 mg, 2.75 mmol, 55%. LCMS m / z 242.3 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) 5 = 4.31 (d, J= 3.5 Hz, 1H), 3.13 (s, 2H), 2.38 (dt, J = 3.9, 7.0 Hz, 1H), 1.57 (s, 9H), 1.14 (d, J= 7.0 Hz, 3H), 0.95 (d, J= 7.0 Hz, 3H).

[0752] Step 3. Synthesis of (5R)-5-(propan-2-yl)pyrrolidine-2, 4-dione (C23)

[0753] A solution of tert-butyl (2R)-3,5-dioxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (650 mg, 1 Eq, 2.69 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL) and stirred at rt for 45 minutes until LCMS analysis indicated conversion to C23. The mixture was concentrated under reduced pressure to afford C23 as a waxy, yellow solid. Yield: 380 mg, 2.69mmol, 100%. A portion of the crude was purified initially via silica gel chromatography (Gradient: 0 to 10% methanol in dichloromethane) and then via reversed-phase HPLC (Column: Sunfire C18 19x100 mm 5 µm; Mobile phase A: 0.05% TFA in water (v / v); Mobile phase B: 0.05% TFA in acetonitrile (v / v); Gradient: 95.0% H2O / 5.0% Acetonitrile linear to 50.0% H20 / 50.0% Acetonitrile in 8.5 min, 50.0% H20 / 50.0% Acetonitrile linear to 5.0% H2O / 95.0% Acetonitrile to 9.0 min, HOLD at 5% H2O / 95% Acetonitrile to 10.0 min; Flow: 25 mL / min). LCMS m / z 142.1 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.14 (br s, 1H), 3.88 (d, J= 3.9 Hz, 1H), 3.01 -2.94 (m, 2H), 2.17 (dtd, J = 4.1, 6.9, 13.8 Hz, 1H), 1.06- 0.90 (m, 6H).

[0754] Step 4. Synthesis of 4-[(7R)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4,5,6,7-tetrahydro-1 / 7-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (C24)

[0755] A mixture of ethyl (2Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (62 mg, 1 Eq, 0.26 mmol), (5R)-5-(propan-2-yl)pyrrolidine-2, 4-dione (37 mg, 1 Eq, 0.26 mmol) and 4-formylbenzoic acid (39 mg, 1 Eq, 0.26 mmol) was dissolved in ethanol (1.7 mL), treated with sodium ethoxide (19 mg, 1 Eq, 0.26 mmol) in ethanol (0.5 mL), and stirred at 80 °C for 22 hours until LCMS analysis indicated conversion to C24. The mixture was used directly in the next step. LCMS m / z 491.3 [M-H]-.

[0756] Step 5. Synthesis of 4-[(7R)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (C25)

[0757] The previous reaction mixture was cooled to room temperature, treated with 2 mL of a 1:1 mixture of acetonitrile and water followed by cerium (IV) ammonium nitrate (140 mg, 1 Eq, 0.26 mmol), and stirred at room temperature for 5 hours until LCMS analysis indicated conversion to C25. The mixture was partitioned between water and ethyl acetate and the separated organics were dried over MgSO4, filtered, and concentrated under reduced pressure to afford C25 as a yellow gum that was used without further purification in the next step. Yield: 123 mg, 0.251 mmol, 96% over 2 steps. LCMS m / z 491.3 [M+H]+.

[0758] Step 6. Synthesis of ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(furan-2-yl)methyl]carbamoyl}phenyl)-5-oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridine-3-carboxylate (RC-2)

[0759] A mixture of 1-(2-furyl)methanamine (26.8 mg, 24.8 µL, 1.1 Eq, 276 µmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (52.9 mg, 1.1 Eq, 276 µmol), 4-[(7R)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-6,7-dihydro-5 / 7-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (123 mg, 1.0 Eq, 251 µmol), and 2-hydroxypyridine 1-oxide (27.9 mg, 1 Eq, 251 µmol) was treated with dimethylformamide (2 mL) followed by triethylamine (76.1 mg, 105 µL, 3.0 Eq, 752 µmol), and the mixture stirred at room temperature for 17 hours until LCMS analysis indicated conversion to RC-2. The reaction mixture wasdiluted with ethyl acetate and washed once each with 1M HCI, saturated aqueous sodium bicarbonate, and saturated brine. The separated organics were dried over MgSO₄, filtered, and concentrated to afford an orange residue. Purification via reversed-phase HPLC (Column: Sunfire C18 19x100 mm 5 pm; Gradient: 50.0% H20 / 50.0% Acetonitrile linear to 40.0% H20 / 60.0% Acetonitrile in 8.5 min, 40.0% H20 / 60.0% Acetonitrile linear to 5.0% H2O / 95.0% Acetonitrile to 9.0 min, HOLD at 5% H2O / 95% Acetonitrile to 10.0 min; Flow: 25 mL / min) afforded RC-2 as a white solid. Yield: 2.5 mg, 0.004 mmol, 2%. LCMS m / z 570.3 [M+H]+.1H NMR (600 MHz, DMSO-d₆) 6 = 9.09 (t, J= 5.7 Hz, 1H), 8.92 (s, 1H), 7.91 (d, J= 8.4 Hz, 2H), 7.60 - 7.58 (m, 1 H), 7.37 (d, J = 8.2 Hz, 2H), 7.22 (dd, J = 5.7, 8.4 Hz, 2H), 7.08 (t, J = 8.8 Hz, 2H), 6.41 (dd, J= 1.8, 3.1 Hz, 1H), 6.30 (d, J= 3.1 Hz, 1H), 4.52 (d, J= 3.3 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.98 (q, J= 7.1 Hz, 2H), 3.18 - 3.15 (m, 1H), 3.14 - 3.11 (m, 1H), 3.11 - 3.06 (m, 1 H), 3.05 - 3.01 (m, 1 H), 2.35 (dt, J = 3.3, 6.9 Hz, 1 H), 1.03 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H), 0.65 (d, J= 6.9 Hz, 3H).

[0760] Preparation P1

[0761] 3-Ethyl 5-methyl 2-[2-(4-fluorophenyl)ethyl]-6-hydroxy-4-(4-{[(pyridin-3- yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate (P1 )

[0762]

[0763] C3

[0764]

[0765] Step 1. Synthesis of 5-[3-(4-fluorophenyl)propanoyl]-2,2-dimethyl-1,3-dioxane-4, 6-dione (C1).

[0766] 1,3-Dicyclohexylcarbodiimide (49.1 g, 238 mmol) and 4-(dimethylamino)pyridine (29.1 g, 238 mmol) were added to a solution of 3-(4-fluorophenyl)propanoic acid (40.0 g, 238 mmol) and 2, 2-dimethyl-1,3-dioxane-4, 6-dione (34.3 g, 238 mmol) in dichloromethane (500 mL). After the reaction mixture had been stirred at 20 °C for 16 hours, it was filtered, and the filter cake was washed with dichloromethane (200 mL). The combined filtrates were diluted with water (200 mL) and hydrochloric acid (1 M; 100 mL, 100 mmol), and the resulting mixture was extracted with dichloromethane (4 x 200 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo, providing C1 as a yellow solid (73.3 g). This was progressed directly to the following step. By1H NMR analysis, this material exists in its enolicform. LCMS m / z 237.0 [(M-propan-2-one)+H]+.1H NMR (400 MHz, DMSO-d₆) δ 7.28 (dd, J = 8.5, 5.7 Hz, 2H), 7.11 (t, J= 8.9 Hz, 2H), 3.29 (dd, J= 9.1, 6.5 Hz, 2H), 2.92 (dd, J= 9.0, 6.6 Hz, 2H), 1.64 (s, 6H).

[0767] Step 2. Synthesis of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (C2).

[0768] A mixture of C1 (from the previous step; 73.3 g, <238 mmol) in ethanol (470 mL) was stirred at 80 °C for 14 hours, whereupon it was concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) afforded C2 as a yellow oil (60.4 g). Yield: corrected for residual ethyl acetate and dichloromethane, 53.1 g, 233 mmol, 98% over 2 steps. LCMS m / z 239.1 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 7.23 (dd, J= 8.5, 5.7 Hz, 2H), 7.08 (t, J= 8.9 Hz, 2H), 4.07 (q, J= 7.1 Hz, 2H), 3.59 (s, 2H), 2.89 -2.82 (m, 2H), 2.80-2.73 (m, 2H), 1.17 (t, J= 7.1 Hz, 3H).

[0769] Step 3. Synthesis of dimethyl {[4-(tert-butoxycarbonyl)phenyl]methylidene}propanedioate (C3).

[0770] To a solution of dimethyl propanedioate (3.00 g, 22.7 mmol) and tert-butyl 4-formylbenzoate (3.65 g, 17.7 mmol) in / V, / V-dimethylformamide (60.0 mL) was added piperidine (754 mg, 8.85 mmol). After the reaction mixture had been stirred at 80 °C for 5 hours, it was partitioned between ethyl acetate and water; the resulting mixture was acidified to pH 5 by addition of 1 M hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo silica gel chromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether) provided C3 as a white oil. Yield: 2.68 g, 8.37 mmol, 47%. LCMS m / z 321.1 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 7.96 (d, J= 8.5 Hz, 2H), 7.84 (s, 1H), 7.58 (d, J= 8.3 Hz, 2H), 3.80 (s, 6H), 1.55 (s, 9H).

[0771] Step 4. Synthesis of 3-ethyl 1,1 -dimethyl 2-[4-(tert-butoxycarbonyl)phenyl]-6-(4-fluorophenyl)-4-oxohexane-1,1,3-tricarboxylate (C4).

[0772] To a solution of C3 (500 mg, 1.56 mmol) and C2 (744 mg, 3.12 mmol) in toluene (13.0 mL) was added potassium tert-butoxide (17.5 mg, 0.156 mmol) portion-wise, whereupon the reaction mixture was stirred at 25 °C for 2 hours. It was then diluted with ethyl acetate and water, and acidified to pH 5 by addition of 1 M hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using chromatography on silica gel (Gradient: 0% to 15% ethyl acetate in petroleum ether) afforded C4 as a colorless oil. By1H NMR analysis, this material exists as a mixture of isomers. Yield: 750 mg, 1.34 mmol, 86%.1H NMR (400 MHz, DMSO-d₆) δ [7.76 (d, J = 8.4 Hz) and 7.73 (d, J = 8.4 Hz), total 2H], 7.43 - 7.35 (m, 2H), [7.24 -7.18 (m), 7.07 (t, J = 8.9 Hz), and 6.97 -6.87 (m), total 4H], [4.54 (d, J= 10.2 Hz) and 4.43 (d, J = 9.8 Hz), total 1H], [4.21 -3.95 (m) and 3.71 (q, J= 7.1 Hz), total 4H], [3.60 (s) and 3.60 (s), total 3H], [3.42 (s) and 3.41 (s), total 3H], [2.93 - 2.72 (m) and 2.58 - 2.42 (m), total 4H,assumed; partially obscured by solvent peak], [1.54 (s) and 1.52 (s), total 9H], [1.13 (t, J= 7.1 Hz) and 0.81 (t, J= 7.1 Hz), total 3H],

[0773] Step 5. Synthesis of 3-ethyl 5-methyl 4-[4-(tert-butoxycarbonyl)phenyl]-2-[2-(4-fluorophenyl)ethyl]-6-hydroxy-1,4-dihydropyridine-3,5-dicarboxylate (C5).

[0774] A solution of C4 (2.97 g, 5.32 mmol) and ammonium acetate (2.05 g, 26.6 mmol) in acetic acid (20 mL) was stirred at 80 °C for 16 hours, whereupon it was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to provide C5 as a colorless oil (3.49 g). This material was taken directly to the following step. LCMS m / z 526.2 [M+H]+.

[0775] Step 6. Synthesis of 4-[3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-6-hydroxy-5-(methoxycarbonyl)-1,4-dihydropyridin-4-yl]benzoic acid (C6).

[0776] Trifluoroacetic acid (5.08 mL, 66.4 mmol) was added drop-wise to a solution of C5 (from the previous step; 3.49 g, <5.32 mmol) in dichloromethane (15.0 mL), whereupon the reaction mixture was stirred at 20 °C for 16 hours. Concentration in vacuo afforded C6 as a white oil (3.00 g), which was progressed to the following step. LCMS m / z 470.1 [M+H]+.

[0777] Step 7. Synthesis of 3-ethyl 5-methyl 2-[2-(4-fluorophenyl)ethyl]-6-hydroxy-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (C7).

[0778] To a solution of C6 (from the previous step; 3.00 g, <5.32 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.96 g, 10.2 mmol), and 1 / 7-benzotriazol-1-ol (1.38 g, 10.2 mmol) in / V, / V-dimethylformamide (40.0 mL) was added 1-(pyridin-3-yl)methanamine (1.73 g, 16.0 mmol). After the reaction mixture had been stirred at 25 °C for 16 hours, it was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in dichloromethane) provided C7 (3.20 g) as a colorless solid. Most of this material was used in the following step. LCMS m / z 560.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆), integrations are approximate: δ 10.38 (s, 1 H), 9.09 - 8.98 (m, 1 H), 8.54 (s, 1 H), 8.45 (d, J = 4.6 Hz, 1 H), 7.84 -7.76 (m, 2H), 7.70 (brd, J= 7.9 Hz, 1H), 7.38- 7.28 (m, 3H), [7.26 (d, J= 8.1 Hz) and 7.22 (d, J = 8.1 Hz), total 2H], 7.14 (t, J = 8.7 Hz, 2H), 4.55 (s, 1 H), 4.48 (d, J = 5.8 Hz, 2H), 4.07 - 3.96 (m, 2H), [3.69 (s) and 3.66 (brs), total 3H], 3.16-2.76 (m, 4H), 1.12 - 1.03 (m, 3H).

[0779] Step 8. Synthesis of 3-ethyl 5-methyl 2-[2-(4-fluorophenyl)ethyl]-6-hydroxy-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate (P1).Ammonium cerium(IV) nitrate (7.05 g, 12.9 mmol) was added portion-wise over 15 minutes to a solution of C7 (from the previous step: 2.48 g, <4.12 mmol) in a mixture of acetonitrile (20.0 mL) and water (20.0 mL). After the reaction mixture had been stirred at 20 °C for 3 hours, it was diluted with water (30 mL) and basified to pH 8 by addition of aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (4 x 70 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in dichloromethane, followed by elution with 10% methanol in dichloromethane) was followed by suspension of the resulting material in a 2:1 mixture of petroleum ether and ethyl acetate. After filtration, the filtrate was concentrated in vacuo to afford P1 as a light-yellow solid. Yield: 1.49 g, 2.67 mmol, 65% over 4 steps. LCMS m / z 558.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H), 9.19 (brt, J = 5.5 Hz, 1 H), 8.56 (s, 1 H), 8.46 (d, J = 4.8 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 2H), 7.73 (br d, J = 7.9 Hz, 1H), 7.36 (brdd, J= 7.8, 4.6 Hz, 1H), 7.29-7.19 (m, 4H), 7.13 (t, J= 8.7 Hz, 2H), 4.50 (d, J = 5.7 Hz, 2H), 3.75 (q, J = 7.1 Hz, 2H), 3.46 (s, 3H), 2.89 (br s, 4H), 0.66 (t, J = 7.1 Hz, 3H).

[0780] Preparation P2

[0781] 5-Ethyl 3-methyl 2-chloro-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3- yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate (P2)

[0782] P1

[0783]

[0784] Step 1. Synthesis of 3-ethyl 5-methyl 2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6-[(trifluoromethanesulfonyl)oxy]pyridine-3,5-dicarboxylate (C26).Triethylamine (998 mg, 9.86 mmol) and a solution of trifluoromethanesulfonic anhydride (2.23 g, 7.90 mmol) in dichloromethane (4 mL) were added dropwise to a 0 °C solution of P1 (1.10 g, 1.97 mmol) in dichloromethane (17 mL). After the reaction mixture had been stirred for 1 hour at 20 °C, it was treated with aqueous sodium bicarbonate solution and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo the residue was purified using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in dichloromethane) to provide C26 as a red solid. Yield: 800 mg, 1.16 mmol, 59%. LCMS m / z 690.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 9.23 (brt, J = 5.9 Hz, 1 H), 8.57 (d, J = 2.3 Hz, 1 H), 8.47 (dd, J = 4.8, 1.7 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 2H), 7.74 (dt, J = 7.8, 2.0 Hz, 1 H), 7.39 - 7.35 (m, 1 H), 7.34 (d, J = 8.5 Hz, 2H), 7.19 (dd, J = 8.6, 5.7 Hz, 2H), 7.08 (t, J= 8.9 Hz, 2H), 4.51 (d, J= 5.8 Hz, 2H), 3.97 (q, J= 7.1 Hz, 2H), 3.61 (s, 3H), 3.18 -3.10 (m, 2H), 3.06-2.99 (m, 2H), 0.82 (t, J= 7.1 Hz, 3H).

[0785] Step 2. Synthesis of 5-ethyl 3-methyl 2-chloro-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate (P2).

[0786] To a 0 °C solution of C26 (800 mg, 1.16 mmol) in acetonitrile (17 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4.0 M; 1.51 mL, 6.04 mmol). The reaction mixture was stirred for 16 hours at 60 °C, whereupon it was concentrated under reduced pressure, treated with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in dichloromethane), affording P2 as a yellow solid. Yield: 452 mg, 0.785 mmol, 68%. LCMS m / z 576.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 9.22 (brt, J= 5.9 Hz, 1H), 8.57 (d, J= 2.2 Hz, 1H), 8.47 (brd, J = 4.8 Hz, 1H), 7.95 (d, J= 8.3 Hz, 2H), 7.74 (dt, J= 8.0, 2 Hz, 1H), 7.37 (dd, J= 7.9, 4.8 Hz, 1H), 7.32 (d, J= 8.3 Hz, 2H), 7.24 (dd, J= 8.5, 5.6 Hz, 2H), 7.10 (t, J= 8.8 Hz, 2H), 4.50 (d, J= 5.8 Hz, 2H), 3.96 (q, J = 7.1 Hz, 2H), 3.60 (s, 3H), 3.13 - 3.05 (m, 2H), 3.05 - 2.97 (m, 2H), 0.81 (t, J= 7.1 Hz, 3H).

[0787] Preparation P3

[0788] te / Y-Butyl 5-(4-fluorophenyl)-3-oxopentanoate (P3)o

[0789]

[0790] Step 1. Synthesis of 5-[3-(4-fluorophenyl)propanoyl]-2,2-dimethyl-1,3-dioxane-4, 6-dione (C27).

[0791] To a solution of 3-(4-fluorophenyl)propanoic acid (40.0 g, 238 mmol) and 2,2-dimethyl-1,3-dioxane-4, 6-dione (34.3 g, 238 mmol) in dichloromethane (500 mL) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (47.9 g, 250 mmol) and 4-(dimethylamino)pyridine (34.9 g, 286 mmol). After the reaction mixture had been stirred at 20 °C for 16 hours, it was filtered; dichloromethane (200 mL), water (200 mL), and hydrochloric acid (1 M; 200 mL) were added to the filtrate, and the aqueous layer was extracted with dichloromethane (2 x 200 mL). The combined organic layers were washed sequentially with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford C27 as a yellow oil. This material was progressed directly to the following step. LCMS m / z 237.1 [(M-propan-2-one)+H]+.

[0792] Step 2. Synthesis of tert-butyl 5-(4-fluorophenyl)-3-oxopentanoate (P3).

[0793] A solution of C27 (from the previous step, <238 mmol) in tert-butanol (450 mL) was stirred at 80 °C for 20 hours, whereupon it was concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided P3 as a lightbrown oil. Yield: 28.0 g, 105 mmol, 44% over 2 steps. LCMS m / z 289.2 [M+Na+],1H NMR (400 MHz, DMSO-d₆) δ 7.27 - 7.20 (m, 2H), 7.08 (t, J = 8.9 Hz, 2H), 3.47 (s, 2H), 2.87 - 2.80 (m, 2H), 2.80 - 2.73 (m, 2H), 1.38 (s, 9H).

[0794] Preparation P4

[0795] Methyl 2-chloro-4-[4-(ethoxycarbonyl)phenyl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4- oxadiazol-2-yl)pyridine-3-carboxylate (P4)C28

[0796]

[0797]

[0798] Step 1. Synthesis of dimethyl {[4-(ethoxycarbonyl)phenyl]methylidene}propanedioate (C28).

[0799] To a solution of ethyl 4-formylbenzoate (10.0 g, 56.1 mmol) and dimethyl propanedioate (12.8 mL, 112 mmol) in / V, / V-dimethylformamide (100 mL) were added piperidine (2.22 mL, 22.4 mmol) and acetic acid (1.29 mL, 22.5 mmol). After the reaction mixture had been stirred at 80 °C for 2 hours, it was diluted with water (1.0 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) provided C28 as a white solid. Yield: 13.0 g, 44.5 mmol, 79%. LCMS m / z 293.2 [M+H]+.1H NMR (400 MHz, CDCl₃) δ 8.05 (d, J= 8.5 Hz, 2H), 7.79 (s, 1H), 7.47 (d, J= 8.4 Hz, 2H), 4.38 (q, J= 7.1 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 1.39 (t, J= 7.1 Hz, 3H).

[0800] Step 2. Synthesis of 3-terf-butyl 1, 1-dimethyl 2-[4-(ethoxycarbonyl)phenyl]-6-(4-fluorophenyl)-4-oxohexane-1,1,3-tricarboxylate (C29).

[0801] To a solution of C28 (13.0 g, 44.5 mmol) and P3 (17.8 g, 66.8 mmol) in acetonitrile (130 mL) was added potassium carbonate (1.23 g, 8.90 mmol), whereupon the reaction mixture was stirred at 25 °C for 16 hours. It was then concentrated in vacuo, and the residue was purified using silica gel chromatography [Gradient: 0% to 50% (1:1 ethyl acetate I dichloromethane) in petroleum ether] to provide C29 as a solid. Yield: 21.0 g, 37.6 mmol, 84%. LCMS m / z 581.3 [M+Na+],1H NMR (400 MHz, CDCl₃), mixture of diastereomers, integrations are approximate: δ[7.94 (d, J = 8.4 Hz) and 7.89 (d, J = 8.4 Hz), total 2H], [7.36 (d, J = 8.5 Hz) and 7.35 (d, J = 8.4 Hz), total 2H], [7.14 (dd, J = 8.5, 5.5 Hz) and 6.95 - 6.90 (m), total 2H], [6.94 (t, J = 8.7 Hz) and 6.85 (t, J= 8.7 Hz), total 2H], 4.40-4.28 (m, 4H), [4.10 (d, J= 7.0 Hz) and 3.72 (d, J = 6.4 Hz), total 1H], [3.63 (s) and 3.62 (s), total 3H], [3.55 (s) and 3.53 (s), total 3H], [3.02 -2.72 (m) and 2.59 (t, J= 7.0 Hz), total 4H], [1.38 (t, J= 7.1 Hz) and 1.37 (t, J= 7.1 Hz), total 3H], [1.35 (s) and 1.02 (s), total 9H],

[0802] Step 3. Synthesis of 3-terf-butyl 5-methyl 4-[4-(ethoxycarbonyl)phenyl]-2-[2-(4-fluorophenyl)ethyl]-6-hydroxy-1,4-dihydropyridine-3,5-dicarboxylate (C30).

[0803] A solution of C29 (21.0 g, 37.6 mmol) in acetic acid (100 mL) was treated with ammonium acetate (29.0 g, 376 mmol), whereupon the reaction mixture was stirred at 80 °C for 16 hours. It was then diluted with water (800 mL) and extracted with ethyl acetate (3 x 200 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was combined with a similar reaction carried out using C29 (10.1 g, 18.1 mmol) and purified by silica gel chromatography [Gradient: 0% to 50% (1:1 ethyl acetate I dichloromethane) in petroleum ether] to afford C30 as a white solid.1H NMR analysis indicated that this compound exists in its oxo form in deuterochloroform. Combined yield: 25.0 g, 47.6 mmol, 85%. LCMS m / z 548.3 [M+Na+]1H NMR (400 MHz, CDCl₃), integrations are approximate: δ 7.95 (d, J= 8.4 Hz, 2H), 7.89 (brs, 1 H), 7.23 - 7.16 (m, 4H), 6.97 (t, J = 8.7 Hz, 2H), 4.62 (d, J = 3.2 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2H), 3.76 (s, 3H), 3.54 (d, J= 3.2 Hz, 1H), 3.17-2.84 (m, 4H), 1.38 (t, J= 7.1 Hz, 3H), 1.30 (s, 9H).

[0804] Step 4. Synthesis of 3-terf-butyl 5-methyl 4-[4-(ethoxycarbonyl)phenyl]-2-[2-(4-fluorophenyl)ethyl]-6-hydroxypyridine-3,5-dicarboxylate (C31).

[0805] Ammonium cerium(IV) nitrate (34.0 g, 62.0 mmol) was added to a 0 °C mixture of C30 (12.5 g, 23.8 mmol), acetonitrile (120 mL), and water (120 mL). After the reaction mixture had been stirred at 25 °C for 5 hours, the resulting solid was collected via filtration, and washed with acetonitrile (20 mL) and water (150 mL) to afford C31 as a white solid. Yield: 10.3 g, 19.7 mmol, 83%. LCMS m / z 524.2 [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 12.64 (brs, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.32 (d, J= 8.4 Hz, 2H), 7.25 (dd, J= 8.6, 5.7 Hz, 2H), 7.15 (t, J= 8.8 Hz, 2H), 4.34 (q, J= 7.1 Hz, 2H), 3.44 (s, 3H), 2.95-2.82 (m, 4H), 1.33 (t, J= 7.1 Hz, 3H), 1.05 (s, 9H).

[0806] Step 5. Synthesis of 3-terf-butyl 5-methyl 4-[4-(ethoxycarbonyl)phenyl]-2-[2-(4-fluorophenyl)ethyl]-6-[(trifluoromethanesulfonyl)oxy]pyridine-3,5-dicarboxylate (C32).

[0807] This experiment was carried out in two identical batches. To a 0 °C solution of C31 (6.50 g, 12.4 mmol) in dichloromethane (200 mL) was added triethylamine (17.3 mL, 124 mmol), followed by dropwise addition of a solution of trifluoromethanesulfonic anhydride (5.22 mL, 31.0mmol) in dichloromethane (30 mL). After the reaction mixture had been stirred for 2 hours at 30 °C, it was diluted with aqueous sodium bicarbonate solution (250 mL). The aqueous layer was extracted with dichloromethane (2 x 100 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The two batches were combined at this point; silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) afforded C32 as a white solid. Combined yield: 13.4 g, 20.4 mmol, 82%. LCMS m / z 656.3 [M+H]+.1H NMR (400 MHz, CDCl₃) δ 8.10 (d, J= 8.5 Hz, 2H), 7.36 (d, J= 8.4 Hz, 2H), 7.16 (dd, J= 8.5, 5.5 Hz, 2H), 6.97 (t, J= 8.7 Hz, 2H), 4.41 (q, J= 7.1 Hz, 2H), 3.66 (s, 3H), 3.17 - 3.04 (m, 4H), 1.42 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H).

[0808] Step 6. Synthesis of 6-chloro-4-[4-(ethoxycarbonyl)phenyl]-2-[2-(4-fluorophenyl)ethyl]-5-(methoxycarbonyl)pyridine-3-carboxylic acid (C33).

[0809] A solution of hydrochloric acid in 1,4-dioxane (4 M; 16.2 mL, 64.8 mmol) was added to a 0 °C solution of C32 (8.50 g, 13.0 mmol) in acetonitrile (180 mL), whereupon the reaction mixture was stirred for 20 hours at 55 °C. It was then concentrated in vacuo the residue was purified using silica gel chromatography [Gradient: 0% to 40% (ethyl acetate containing 1% acetic acid) in petroleum ether] to provide C33 as a white solid. Yield: 5.00 g, 10.3 mmol, 79%. LCMS m / z 486.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d₆) δ 13.85 (br s, 1H), 8.04 (d, J= 8.2 Hz, 2H), 7.42 (d, J= 8.3 Hz, 2H), 7.27 (dd, J= 8.5, 5.7 Hz, 2H), 7.12 (t, J= 8.8 Hz, 2H), 4.34 (q, J= 7.1 Hz, 2H), 3.58 (s, 3H), 3.15 - 3.06 (m, 2H), 3.06 -2.98 (m, 2H), 1.34 (t, J= 7.1 Hz, 3H).

[0810] Step 7. Synthesis of methyl 5-(2-acetylhydrazine-1-carbonyl)-2-chloro-4-[4-(ethoxycarbonyl)phenyl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylate (C34).

[0811] 1-[Bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 8.04 g, 21.1 mmol) was added to a solution of C33 (7.90 g, 16.3 mmol) in / V, / V-dimethylformamide (120 mL), and the reaction mixture was stirred at 25 °C for 15 minutes. Acetohydrazide (1.81 g, 24.4 mmol) and / V, / V-diisopropylethylamine (8.50 mL, 6.30 g, 48.8 mmol) were then added, and stirring was continued at 40 °C for 2 hours, whereupon LCMS analysis indicated the presence of C34: LCMS m / z 542.0 (chlorine isotope pattern observed) [M+H]+. The reaction mixture was diluted with ethyl acetate (100 mL) and washed sequentially with ammonium chloride solution (100 mL) and water (100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified using silica gel chromatography (Gradient: 0% to 4% methanol in dichloromethane) to provide C34 as a white solid. Yield: 6.90 g, 12.7 mmol, 78%.

[0812] Step 8. Synthesis of methyl 2-chloro-4-[4-(ethoxycarbonyl)phenyl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate (P4).To a 20 °C solution of C34 (6.90 g, 12.7 mmol), 4-methylbenzene-1 -sulfonyl chloride (3.16 g, 16.6 mmol), and 4-(dimethylamino)pyridine (233 mg, 1.91 mmol) in acetonitrile (100 mL) was added / V, / V-diisopropylethylamine (4.94 g, 38.2 mmol). After the reaction mixture had been stirred at 40 °C for 1 hour, it was diluted with ethyl acetate (80 mL) and washed sequentially with aqueous ammonium chloride solution (100 mL) and water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided P4 as a white solid. Yield: 5.00 g, 9.54 mmol, 75%. LCMS m / z 524.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, CDCl₃) δ 7.98 (d, J= 8.4 Hz, 2H), 7.20 (d, J= 8.4 Hz, 2H), 7.03 (dd, J= 8.5, 5.5 Hz, 2H), 6.90 (t, J= 8.7 Hz, 2H), 4.38 (q, J= 7.1 Hz, 2H), 3.63 (s, 3H), 3.19 -3.12 (m, 2H), 3.08-3.01 (m, 2H), 2.24 (s, 3H), 1.39 (t, J= 7.1 Hz, 3H).

[0813] Preparation P5

[0814] 6-Chloro-4-[4-(ethoxycarbonyl)thiophen-2-yl]-2-[2-(4-fluorophenyl)ethyl]-5-

[0815]

[0816]

[0817] Step 1. Synthesis of dimethyl {[4-(ethoxycarbonyl)thiophen-2-yl]methylidene}propanedioate (C35).

[0818] Piperidine (3.49 mL, 35.2 mmol) and acetic acid (2.03 mL, 35.5 mmol) were added to a solution of ethyl 5-formylthiophene-3-carboxylate (13.0 g, 70.6 mmol) and dimethyl propanedioate (10.5 mL, 91.7 mmol) in methanol (250 mL). After the reaction mixture had been stirred at 80 °C for 4 hours, it was diluted with water (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 15% ethyl acetate in petroleum ether) afforded C35 as a white solid. Yield: 19.8 g, 66.4 mmol, 94%. LCMS m / z 299.1 [M+H]+.

[0819] Step 2. Synthesis of 3-terf-butyl 1, 1-dimethyl 2-[4-(ethoxycarbonyl)thiophen-2-yl]-6-(4-fluorophenyl)-4-oxohexane-1,1,3-tricarboxylate (C36).

[0820] To a solution of C35 (10.3 g, 34.5 mmol) and P3 (13.8 g, 51.8 mmol) in acetonitrile (200 mL) was added potassium carbonate (1.91 g, 13.8 mmol), whereupon the reaction mixture was stirred for 3 days at 20 °C. After addition of water (300 mL), the resulting mixture was extracted with ethyl acetate (3 x 200 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided C36 as a yellow oil. Yield: 10.5 g, 18.6 mmol, 54%. LCMS m / z 587.3 [M+Na+],

[0821] Step 3. Synthesis of 3-terf-butyl 5-methyl 4-[4-(ethoxycarbonyl)thiophen-2-yl]-2-[2-(4-fluorophenyl)ethyl]-6-hydroxy-1,4-dihydropyridine-3,5-dicarboxylate (C37).

[0822] Ammonium acetate (3.82 g, 49.6 mmol) was added to a solution of C36 (2.80 g, 4.96 mmol) in acetic acid (14 mL), whereupon the reaction mixture was stirred at 80 °C for 16 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (2 x 40 mL); the combined organic layers were washed sequentially with aqueous potassium carbonate solution (5%, 3 x 30 mL), water (50 mL), and saturated aqueous sodium chloride solution (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography [Gradient: 0% to 40% (1:1 mixture of ethyl acetate and dichloromethane) inpetroleum ether] afforded C37 as a yellow oil. Yield: 1.80 g, 3.39 mmol, 68%. LCMS m / z 554.2 [M+Na+],

[0823] Step 4. Synthesis of 3-tert-butyl 5-methyl 4-[4-(ethoxycarbonyl)thiophen-2-yl]-2-[2-(4-fluorophenyl)ethyl]-6-hydroxypyridine-3,5-dicarboxylate (C38).

[0824] To a 0 °C mixture of C37 (1.80 g, 3.39 mmol), acetonitrile (18 mL), and water (18 mL) was added ammonium cerium(IV) nitrate (6.32 g, 11.5 mmol), whereupon the reaction mixture was stirred at 20 °C overnight. The resulting solid was collected via filtration and washed with a mixture of acetonitrile (15 mL), water (10 mL), and petroleum ether (50 mL), providing C38 as a white solid. Yield: 1.35 g, 2.55 mmol, 75%. LCMS m / z 530.2 [M+H]+.

[0825] Step 5. Synthesis of 5-tert-butyl 3-methyl 2-chloro-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3,5-dicarboxylate (C39).

[0826] To a 0 °C solution of C38 (1.35 g, 2.55 mmol) and / V, / V-dimethylformamide (0.197 mL, 2.54 mmol) in dichloromethane (15 mL) was added oxalyl chloride (971 mg, 7.65 mmol). After the reaction mixture had been stirred for 16 hours at 40 °C, it was diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed sequentially with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) afforded C39 as a yellow solid. Yield: 1.37 g, 2.50 mmol, 98%. LCMS m / z 548.1 (chlorine isotope pattern observed) [M+H]+.

[0827] A similar reaction of C38 with oxalyl chloride, followed by slurrying of the chromatographed product in acetonitrile, produced C39 as a white solid.1H NMR (400 MHz, CDCl₃) δ 8.20 (d, J= 1.4 Hz, 1H), 7.54 (d, J= 1.4 Hz, 1H), 7.19 (dd, J= 8.5, 5.6 Hz, 2H), 6.98 (t, J= 8.7 Hz, 2H), 4.34 (q, J= 7.1 Hz, 2H), 3.77 (s, 3H), 3.14-3.00 (m, 4H), 1.36 (t, J= 7.1 Hz, 3H), 1.32 (s, 9H).

[0828] Step 6. Synthesis of 6-chloro-4-[4-(ethoxycarbonyl)thiophen-2-yl]-2-[2-(4-fluorophenyl)ethyl]-5-(methoxycarbonyl)pyridine-3-carboxylic acid (P5).

[0829] A solution of hydrochloric acid in 1,4-dioxane (4 M; 3.35 mL, 13.4 mmol) was added to a solution of C39 (1.47 g, 2.68 mmol) in acetonitrile (5.4 mL). After the reaction mixture had been stirred overnight at 40 °C, it was concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) to provide P5 as a white solid. Yield: 1.06 g, 2.15 mmol, 80%. LCMS m / z 492.1 (chlorine isotope pattern observed) [M+H]+.

[0830] Preparation P6Methyl 2-chloro-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl- 1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate (P6)

[0831]

[0832] Step 1. Synthesis of methyl 5-(2-acetylhydrazine-1-carbonyl)-2-chloro-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylate (C40).

[0833] To a mixture of P5 (4.76 g, 9.68 mmol), acetohydrazide (1.08 g, 14.6 mmol), and 1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 4.78 g, 12.6 mmol) in / V, / V-dimethylformamide (48 mL) was added / V, / V-diisopropylethylamine (4.38 g, 33.9 mmol). After the reaction mixture had been stirred at 40 °C for 16 hours, it was diluted with water (250 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed sequentially with water (2 x 200 mL) and saturated aqueous sodium chloride solution (2 x 200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford C40 as a yellow oil (5.07 g). This material was used directly in the following step. LCMS m / z 548.2 (chlorine isotope pattern observed) [M+H]+.

[0834] Step 2. Synthesis of methyl 2-chloro-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate (P6).

[0835] To a mixture of C40 (from the previous step; 5.07 g, <9.68 mmol), 4-methylbenzene-1-sulfonyl chloride (2.29 g, 12.0 mmol), and 4-(dimethylamino)pyridine (170 mg, 1.39 mmol) in acetonitrile (50 mL) was added / V, / V-diisopropylethylamine (8.06 mL, 46.3 mmol). The reaction mixture was stirred at 40 °C for 3 hours, whereupon it was diluted with water (250 mL) andextracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed sequentially with water (2 x 100 mL) and saturated aqueous sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated in vacua, silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided P6 as a yellow solid. Yield: 2.86 g, 5.40 mmol, 56% over 2 steps. LCMS m / z 530.1 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 8.47 (d, J= 1.5 Hz, 1H), 7.29 (d, J= 1.4 Hz, 1H), 7.13 (dd, component of ABX system, J= 8.6, 5.7 Hz, 2H), 7.06 (dd, component of ABX system, J = 9.0, 8.8 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.74 (s, 3H), 3.09 - 3.02 (m, 2H), 3.01 - 2.94 (m, 2H), 2.39 (s, 3H), 1.28 (t, J= 7.1 Hz, 3H).

[0836] Preparation P7

[0837] Methyl 2-chloro-5-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-4-[4- (ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylate (P7)

[0838] HATU

[0839]

[0840] Step 1. Synthesis of methyl 2-chloro-5-{2-[(dimethylamino)acetyl]hydrazine-1-carbonyl}-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylate (C41).

[0841] / V, / V-Diisopropylethylamine (1.32 mL, 7.58 mmol) and 1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 1.16 g, 3.05 mmol) were added to a solution of P5 (1.34 g, 2.72 mmol) in / V, / V-dimethylformamide (6.33 mL), whereupon the reaction mixture was stirred at room temperature for 15 minutes. 2-(Dimethylamino)acetohydrazide (312 mg, 2.66 mmol) was added, and stirring was continuedovernight. The reaction mixture was then treated dropwise with a mixture of saturated aqueous sodium bicarbonate solution and water (1:1, 25 mL); collection of the resulting solid via filtration afforded C41 as a brown solid. Yield: 1.19 g, 2.01 mmol, 76%. LCMS m / z 591.4 (chlorine isotope pattern observed) [M+H]+.

[0842] Step 2. Synthesis of methyl 2-chloro-5-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylate (P7).

[0843] A solution of C41 (1.19 g, 2.01 mmol) in acetonitrile (67 mL) was purged with nitrogen for 5 minutes, whereupon 4-(dimethylamino)pyridine (86.1 mg, 0.705 mmol) and N, N-diisopropylethylamine (1.05 mL, 6.03 mmol) were added, followed by 4-methylbenzene-1-sulfonyl chloride (576 mg, 3.02 mmol). After the reaction mixture had been stirred at 40 °C for 1 hour, it was treated with ethyl acetate (50 mL), and the resulting mixture was washed with water (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via supercritical fluid chromatography {Column: Chiral Technologies Chiralpak IM, 30.0 x 250 mm, 5 pm; Mobile phase: 85:15 carbon dioxide I [methanol containing 0.2% (7 M ammonia in methanol)]; Back pressure: 100 bar; Flow rate: 80 mL / minute} afforded P7 as a glass. Yield: 1.01 g, 1.76 mmol, 88%. LCMS m / z 573.3 (chlorine isotope pattern observed) [M+H]+.1H NMR (400 MHz, methanol-d4) 88.31 (d, J= 1.4 Hz, 1H), 7.35 (d, J= 1.4 Hz, 1H), 7.07 (dd, J= 8.5, 5.5 Hz, 2H), 6.95 (t, J= 8.8 Hz, 2H), 4.30 (q, J= 7.1 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 2H), 3.13-3.07 (m, 2H), 3.07 -3.00 (m, 2H), 2.11 (s, 6H), 1.34 (t, J= 7.1 Hz, 3H).

[0844] Preparation P8

[0845] Ethyl 5-{8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5- tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}thiophene-3-carboxylate (P8)

[0846]

[0847]

[0848] P8 Step 1. Synthesis of 2-chloro-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylic acid (C42).

[0849] A mixture of P6 (1.08 g, 2.04 mmol) and lithium iodide (4.10 g, 30.6 mmol) in pyridine (20.4 mL) was stirred at 85 °C for 3 hours. Removal of pyridine via concentration afforded C42, a portion of which was used in the following step. LCMS m / z 516.1 (chlorine isotope pattern observed) [M+H]+.

[0850] Step 2. Synthesis of ethyl 5-[3-({2-[(tert-butoxycarbonyl)amino]-2-methylpropyl}carbamoyl)-2-chloro-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl]thiophene-3-carboxylate (C43).

[0851] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (51 mg, 0.27 mmol) and 1 / - / -benzotriazol- 1-ol hydrate (41 mg, 0.27 mmol) were added to a solution of C42 (69 mg, 0.13 mmol) and tert-butyl (1-amino-2-methylpropan-2-yl)carbamate (50 mg, 0.27 mmol) indichloromethane (5 mL), whereupon the reaction mixture was stirred at room temperature for 19 hours. It was then partitioned between ethyl acetate (20 mL), aqueous lithium chloride solution (10 mL), and water (10 mL); the aqueous layer was extracted with ethyl acetate (2 x 10 mL), and the combined organic layers were concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided C43 as a yellow oil. Yield: 26 mg, 38 pmol, 29%. LCMS m / z 686.6 [M+H]+.

[0852] Step 3. Synthesis of ethyl 5-{3-[(2-amino-2-methylpropyl)carbamoyl]-2-chloro-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl}thiophene-3-carboxylate (C44).

[0853] To a solution of C43 (26 mg, 38 pmol) in acetonitrile (3 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 47 pL, 0.19 mmol). After the reaction mixture had been stirred at room temperature for 1 hour, it was concentrated in vacuo, and the residue was partitioned between saturated aqueous sodium bicarbonate solution (20 mL) and dichloromethane (15 mL). The aqueous layer was extracted with dichloromethane (2 x 15 mL), and the combined organic layers were concentrated in vacuo, affording C44 as a yellow oil. Yield: 22 mg, 38 pmol, quantitative. LCMS m / z 586.4 [M+H]+.

[0854] Step 4. Synthesis of ethyl 5-{8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepin-6-yl}thiophene-3-carboxylate (P8).

[0855] A solution of C44 (22 mg, 38 pmol) in dimethyl sulfoxide (0.4 mL) was treated with potassium fluoride (6.5 mg, 0.11 mmol) and / V, / V-diisopropylethylamine (13 pL, 75 pmol), whereupon the reaction mixture was heated at 90 °C for 3 hours. It was then partitioned between water (3 mL) and ethyl acetate (1 mL), and the aqueous layer was extracted with ethyl acetate (3x 1 mL). The combined organic layers were concentrated in vacuo to afford P8 as a yellow oil. Yield: 21 mg, 38 pmol, quantitative. LCMS m / z 550.5 [M+H]+.

[0856] EXAMPLES

[0857] Example 1

[0858] Ethyl 8-[2-(4-fluorophenyl)ethyl]-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2, 3,4,5- tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate (1)

[0859]

[0860] Step 1. Synthesis of 5-ethyl 3-methyl 2-({2-[(terf-butoxycarbonyl)amino]ethyl}amino)-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate (C8).

[0861] 1,8-Diazabicyclo[5.4.0]undec-7-ene (573 mg, 3.76 mmol) and tert-butyl (2-aminoethyl)carbamate (845 mg, 5.27 mmol) were added to a 0 °C mixture of P1 (700 mg, 1.26 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent; 833 mg, 1.88 mmol) in acetonitrile (5 mL), whereupon the reaction mixture was stirred at 50 °C for 16 hours. Water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 x 50 mL); the combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.Silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) provided C8 as a yellow solid. Yield: 500 mg, 0.715 mmol, 57%. LCMS m / z 700.3 [M+H]+.

[0862] Step 2. Synthesis of 2-({2-[(tert-butoxycarbonyl)amino]ethyl}amino)-5-(ethoxycarbonyl)-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3-carboxylic acid (C9).

[0863] To a 0 °C mixture of C8 (490 mg, 0.700 mmol) in tetrahydrofuran (5 mL) was added aqueous lithium hydroxide solution (2 M; 3.5 mL, 7.0 mmol). After the reaction mixture had been stirred at 50 °C for 16 hours, it was adjusted to a pH of 4 to 5 by addition of 1 M hydrochloric acid, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide C9 as a yellow oil. Yield: 223 mg, 0.325 mmol, 46%. LCMS m / z 686.3 [M+H]+.

[0864] Step 3. Synthesis of 2-[(2-aminoethyl)amino]-5-(ethoxycarbonyl)-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3-carboxylic acid, hydrochloride salt (C10).

[0865] A solution of hydrogen chloride in 1,4-dioxane (4 M; 4 mL, 16 mmol) was added to a 0 °C solution of C9 (200 mg, 0.292 mmol) in dichloromethane (2 mL). After the reaction mixture had been stirred at 25 °C for 3.5 hours, it was concentrated in vacuo to afford C10 as a yellow solid (223 mg). LCMS m / z 586.2 [M+H]+.

[0866] Step 4. Synthesis of ethyl 8-[2-(4-fluorophenyl)ethyl]-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate (1).

[0867] / V, / V-Diisopropylethylamine (295 mg, 2.28 mmol) and 1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 217 mg, 0.571 mmol) were added to a 0 °C solution of C10 (from the previous step; 223 mg, <0.292 mmol) in a mixture of / V, / V-dimethylformamide (15 mL) and dichloromethane (30 mL). After the reaction mixture had been stirred at 25 °C overnight, it was combined with a similar reaction carried out using material from C9 (10 mg, 15 pmol). After a standard workup, purification via reversed-phase HPLC (Column: Welch C18, 21.2 x 250 mm, 10 pm; Mobile phase A: water containing 0.1% ammonium hydroxide; Mobile phase B: acetonitrile; Gradient: 35% to 65% B) afforded ethyl 8-[2-(4-fluorophenyl)ethyl]-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate (1) as a white solid. Combined yield: 9.1 mg, 16.0 pmol, 5% over 2 steps. LCMS m / z 568.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 9.11 (brt, J = 6.0 Hz, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.46 (dd, J = 4.7, 1.7 Hz, 1H), 8.13 (brt, J = 6.3 Hz, 1H), 7.81 (d, J= 8.4 Hz, 2H), 7.71 (dt, J= 7.9, 2.0 Hz, 1H), 7.36 (dd, J= 7.9, 4.9 Hz, 1H), 7.28 -7.19 (m, 4H), 7.11 (t, J= 8.9 Hz, 2H), 7.05- 7.00 (m, 1H), 4.50 (d, J= 5.9 Hz, 2H), 3.80 (q, J= 7.1 Hz, 2H), 3.54-3.40 (m, 4H), 2.98-2.82 (m, 4H), 0.74 (t, J= 7.1 Hz, 3H).Example 2

[0868] Ethyl 8-[2-(4-fluorophenyl)ethyl]-1-methyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl] carbamoyljphenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate, trifluoroacetate salt (2)

[0869]

[0870] Step 1. Synthesis of 5-ethyl 3-methyl 2-[{2-[(tert-butoxycarbonyl)amino]ethyl} (methyl)amino]-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl) pyridine-3,5-dicarboxylate (C11).

[0871] A mixture of P1 (43 mg, 77 pmol), tert-butyl [2-(methylamino)ethyl]carbamate (27 mg, 0.15 mmol), benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOPreagent; 51 mg, 0.12 mmol), and / V, / V-diisopropylethylamine (27 pL, 0.15 mmol) in N, N-dimethylformamide (1 mL) was stirred at room temperature for 18 hours, whereupon the reaction mixture was partitioned between aqueous lithium chloride solution (10%, 2 mL) and ethyl acetate (3 mL). The aqueous layer was extracted with ethyl acetate (2 x3 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution and concentrated in vacuo. Chromatography on silica gel (Gradient: 0% to 10% methanol in dichloromethane) provided C11. Yield: 55 mg, 77 pmol, quantitative. LCMS m / z 714.4 [M+H]+.

[0872] Step 2. Synthesis of 5-ethyl 3-methyl 2-[(2-aminoethyl)(methyl)amino]-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate, hydrochloride salt (C12).

[0873] A solution of hydrogen chloride in 1,4-dioxane (4 M; 0.18 mL, 0.72 mmol) was added to a solution of C11 (50 mg, 70 pmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.5 mL). After the reaction mixture had been stirred at room temperature for 4 hours, concentration in vacuo afforded C12 as a yellow solid. Yield: 43 mg, 66 pmol, 92%. LCMS m / z 614.5 [M+H]+.

[0874] Step 3. Synthesis of 2-[(2-aminoethyl)(methyl)amino]-5-(ethoxycarbonyl)-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3-carboxylic acid (C13).

[0875] Aqueous sodium hydroxide solution (1 M; 0.65 mL, 0.65 mmol) was added to a solution of C12 (40 mg, 62 pmol) in a mixture of methanol (0.5 mL) and tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 4 hours, whereupon concentration in vacuo provided C13 as a light-yellow solid (39 mg). This material was taken directly to the following step. LCMS m / z 600.4 [M+H]+.

[0876] Step 4. Synthesis of ethyl 8-[2-(4-fluorophenyl)ethyl]-1-methyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate, trifluoroacetate salt (2).

[0877] 1-[Bis(dimethylamino)methylene]-1H-benzo[d][1,2,3]triazol-1-ium 3-oxide hexafluorophosphate (HBTU; 49 mg, 0.13 mmol) and / V, / V-diisopropylethylamine (22 pL, 0.13 mmol) were added to a solution of C13 (from the previous step; 39 mg, <62 pmol) in N, N-dimethylformamide (1 mL), whereupon the reaction mixture was stirred at room temperature for 4 hours. It was then diluted with water (2 mL) and saturated aqueous lithium chloride solution (1 mL), and extracted with ethyl acetate (3 x5 mL). The combined organic layers were concentrated in vacuo purification via reversed-phase HPLC (Column: Waters Sunfire C18, 19 x 100 mm, 5 pm; Mobile phase A: water containing 0.05% trifluoroacetic acid; Mobile phase B: acetonitrile containing 0.05% trifluoroacetic acid; Gradient: 30% to 40% B over 8.5 minutes, followed by 40% to 95% B over 0.5 minutes, then 95% B for 1.0 minute; Flow rate: 25mL / minute) afforded ethyl 8-[2-(4-fluorophenyl)ethyl]-1-methyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate, trifluoroacetate salt (2). Yield: 15.4 mg, 22.1 pmol, 36% over 2 steps. LCMS m / z 582.3 [M+H]+.

[0878] 1H NMR (600 MHz, DMSO-d6) 8 9.19 (t, J= 5.9 Hz, 1H), 8.70 (s, 1H), 8.62 (d, J= 5.1 Hz, 1H), 8.29 (t, J = 6.4 Hz, 1H), 8.10 - 8.02 (m, 1H), 7.83 (d, J= 8.3 Hz, 2H), 7.69 - 7.61 (m, 1H), 7.28 - 7.21 (m, 4H), 7.10 (t, J= 8.9 Hz, 2H), 4.57 (d, J= 5.7 Hz, 2H), 3.85 (q, J= 7.1 Hz, 2H), 3.53 -3.46 (m, 2H), 3.42 - 3.37 (m, 2H), 3.06 - 2.96 (m, 4H), 2.94 (s, 3H), 0.77 (t, J = 7.1 Hz, 3H).

[0879] Example 15

[0880] Ethyl 8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-5-oxo-6-(4-{[(pyridin-3- yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate

[0881]

[0882]

[0883] Step 1. Synthesis of 5-ethyl 3-methyl 2-({1-[(tert-butoxycarbonyl)amino]-2-methylpropan-2-yl}amino)-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate (C45).

[0884] A mixture of P2 (134 mg, 0.233 mmol), tert-butyl (2-amino-2-methylpropyl)carbamate (87.6 mg, 0.465 mmol), / V, / V-diisopropylethylamine (80 pL, 0.459 mmol) and potassium fluoride (40.5 mg, 0.697 mmol) in dimethyl sulfoxide (2 mL) was heated at 110 °C for 18 hours, whereupon the reaction mixture was partitioned between water (2 mL) and ethyl acetate (1 mL), and the aqueous layer was extracted with ethyl acetate (3 x 1 mL). The combined organic layers were concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to provide C45. Yield: 73 mg, 0.10 mmol, 43%. LCMS m / z 728.8 [M+H]+.

[0885] Step 2. Synthesis of 5-ethyl 3-methyl 2-[(1-amino-2-methylpropan-2-yl)amino]-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3,5-dicarboxylate (C46).

[0886] A solution of hydrogen chloride in 1,4-dioxane (4 M; 0.24 mL, 0.96 mmol) was added to a solution of C45 (70 mg, 96 pmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours, whereupon it was concentrated under reduced pressure and partitioned between ethyl acetate (10 mL) and aqueous sodium bicarbonate solution (20 mL). The aqueous layer was extracted twice with ethyl acetate (2 x 10 mL) and the combined organic layers were concentrated in vacuo, affording C46 as a yellow oil. Yield: 56 mg, 89 pmol, 93%. LCMS m / z 628.5 [M+H]+.

[0887] Step 3. Synthesis of 2-[(1-amino-2-methylpropan-2-yl)amino]-5-(ethoxycarbonyl)-6-[2-(4-fluorophenyl)ethyl]-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)pyridine-3-carboxylic acid (C47).

[0888] Lithium hydroxide (11 mg, 0.46 mmol) was added to a solution of C46 (56 mg, 89 pmol) in a mixture of tetrahydrofuran (3 mL) and methanol (1 mL). After the reaction mixture had beenstirred at 50 °C for 5 hours, concentration in vacuo provided C47. Yield: 23.0 mg, 37.5 pmol, 42%. LCMS m / z 614.5 [M+H]+.

[0889] Step 4. Synthesis of ethyl 8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate (15).

[0890] 1-[Bis(dimethylamino)methylene]-1 / 7-benzo[d][1,2,3]triazol-1-ium 3-oxide hexafluorophosphate (HBTU; 69 mg, 0.18 mmol) and / V, / V-diisopropylethylamine (79 pL, 0.45 mmol) were added to a solution of C47 (56 mg, 91 pmol) in / V, / V-dimethylformamide (2 mL). After the reaction mixture had been stirred at room temperature for 18 hours, it was diluted with water (2 mL) and saturated aqueous lithium chloride solution (1 mL). The resulting mixture was extracted with ethyl acetate (3 x 5 mL); the combined organic layers were concentrated in vacuo and purified via reversed-phase HPLC (Column: Waters XBridge C18, 19 x 100 mm, 5 pm; Mobile phase A: water containing 0.03% ammonium hydroxide (v / v); Mobile phase B: acetonitrile containing 0.03% ammonium hydroxide (v / v); Gradient: 35% to 45% B over 8.5 minutes, then 45% to 95% B over 0.5 minutes, then 95% B for 1.0 minute; Flow rate: 25 mL / min) to afford ethyl 8-[2-(4-fluorophenyl)ethyl]-2,2-dimethyl-5-oxo-6-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-2,3,4,5-tetrahydro-1 / 7-pyrido[2,3-e][1,4]diazepine-7-carboxylate (15). Yield: 6.5 mg, 11 pmol, 20%. LCMS m / z 596.2 [M+H]+.1H NMR (600 MHz, DMSO-d6) 8 9.13 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.47 (dd, J = 4.9, 1.7 Hz, 1H), 8.35 (t, J = 6.6 Hz, 1H), 7.83 (d, J= 8.4 Hz, 2H), 7.75 (brd, J= 7.9 Hz, 1H), 7.38 (dd, J= 7.9, 4.8 Hz, 1H), 7.27 - 7.21 (m, 4H), 7.10 (t, J= 8.9 Hz, 2H), 6.51 (s, 1H), 4.51 (d, J= 5.8 Hz, 2H), 3.83 (q, J= 7.1 Hz, 2H), 3.22 (d, J = 6.5 Hz, 2H), 2.97 - 2.87 (m, 4H), 1.22 (s, 6H), 0.75 (t, J = 7.1 Hz, 3H).

[0891] Example 16

[0892] / V-[(1S,2S)-5,6-Difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-(7'-{5-[(dimethylamino)methyl]- 1,3,4-oxadiazol-2-yl}-8'-[2-(4-fluorophenyl)ethyl]-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane- 1,2'-pyrido[3,2- / ][1,4]oxazepin]-6'-yl)thiophene-3-carboxamide (16)

[0893]

[0894]

[0895] Step 1. Synthesis of methyl 2-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)oxy]-5-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylate (C48).A solution of lithium diisopropylamide in a mixture of tetrahydrofuran, heptane, and ethylbenzene (2.0 M; 0.724 mL, 1.45 mmol) was added to a solution of P7 (377 mg, 0.658 mmol) and tert-butyl [(1-hydroxycyclopropyl)methyl]carbamate (173 mg, 0.924 mmol) in 1-methylpyrrolidin-2-one (3.3 mL). After the reaction mixture had been stirred at room temperature for 3 hours and 20 minutes, water and ethyl acetate were added, and the resulting mixture was acidified to pH 5 by addition of hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified using silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane), providing C48 as a brown oil. Yield: 404 mg, 0.558 mmol, 85%. LCMS m / z 724.4 [M+H]+.

[0896] Step 2. Synthesis of 2-[(1-{[(terf-butoxycarbonyl)amino]methyl}cyclopropyl)oxy]-5-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylic acid (C49).

[0897] A mixture of C48 (310 mg, 0.428 mmol) and lithium iodide (860 mg, 6.43 mmol) in pyridine (4.3 mL) was stirred at 100 °C for approximately 75 minutes. The reaction mixture was concentrated in vacuo to provide C49. One-third of this material was progressed to the following step. LCMS m / z 710.4 [M+H]+.

[0898] Step 3. Synthesis of 2-{[1-(aminomethyl)cyclopropyl]oxy}-5-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]pyridine-3-carboxylic acid, hydrochloride salt (C50).

[0899] A mixture of C49 (from the previous step, one-third of the crude product; <0.143 mmol), dichloromethane (0.71 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M; 0.714 mL, 2.86 mmol) was stirred at room temperature. After 1 hour, the reaction mixture was again treated with a solution of hydrogen chloride in 1,4-dioxane (4 M; 0.357 mL, 1.43 mmol), and stirring was continued for an additional 70 minutes. Removal of solvents in vacuo provided C50, which was taken directly to the following step. LCMS m / z 610.4 [M+H]+.

[0900] Step 4. Synthesis of ethyl 5-(7'-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8'-[2-(4-fluorophenyl)ethyl]-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2- / ][1,4]oxazepin]-6'-yl)thiophene-3-carboxylate (C51).

[0901] A mixture of C50 (from the previous step; ≤143 mmol), / V, / V-diisopropylethylamine (0.746 mL, 4.28 mmol), 1-methyl-1H-imidazole (34.1 μL, 428 μmol), and chloro(dimethylamino)- / V, / \ / -dimethylmethaniminium hexafluorophosphate (TCFH; 60.1 mg, 0.214 mmol) in N, N-dimethylformamide (4.8 mL) was stirred at room temperature for approximately 20 minutes. Water and ethyl acetate were added, and the organic layer was washed with aqueous lithium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford C51 as a red solid / oil. Yield: 59.2 mg, 0.100 mmol, 70% over 3 steps. LCMS m / z 592.2 [M+H]+.Step 5. Synthesis of 5-(7'-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8'-[2-(4-fluorophenyl)ethyl]-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2- / ][1,4]oxazepin]-6'-yl)thiophene-3-carboxylic acid (C52).

[0902] A mixture of C51 (59.2 mg, 100 pmol) and lithium hydroxide monohydrate (43.1 mg, 1.03 mmol) in a mixture of tetrahydrofuran (0.36 mL) and water (0.14 mL) was stirred at 60 °C for 40 minutes. After the reaction mixture had been neutralized by addition of a solution of hydrogen chloride in 1,4-dioxane (4 M; 0.233 mL, 0.932 mmol), it was concentrated in vacuo. The residue was azeotroped with toluene to provide C52 as a solid. A quarter of this material was used in a separate synthesis; one-half of the remainder was progressed to the following step. LCMS m / z 564.2 [M+H]+.

[0903] Step 6. Synthesis of / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-(7'-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8'-[2-(4-fluorophenyl)ethyl]-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2- / ][1,4]oxazepin]-6'-yl)thiophene-3-carboxamide (16).

[0904] 1-[Bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 18.5 mg, 48.7 μmol), / V, / V-diisopropylethylamine (26.1 pL, 150 pmol), and (1S,2S)-1-amino-5,6-difluoro-2,3-dihydro-1 / 7-inden-2-ol (6.93 mg, 37.4 pmol) were added to a solution of C52 (from the previous step; <37.5 pmol) in / V, / V-dimethylformamide (0.19 mL). The reaction mixture was stirred at room temperature for approximately 10 minutes, whereupon the reaction mixture was concentrated in vacuo. Purification via reversed-phase HPLC (Column: Waters XBridge C18, 19 x 100 mm, 5 pm; Mobile phase A: water containing 0.03% ammonium hydroxide (v / v); Mobile phase B: acetonitrile containing 0.03% ammonium hydroxide (v / v); Gradient: 5% to 95% B over 8.54 minutes, then 95% B for 1.46 minute; Flow rate: 25 mL / min) afforded / V-[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-(7'-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-8'-[2-(4-fluorophenyl)ethyl]-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2- / ][1,4]oxazepin]-6'-yl)thiophene-3-carboxamide (16). Yield: 4.4 mg, 6.0 pmol, 16% over 2 steps. LCMS m / z 731.3 [M+H]+.1H NMR (600 MHz, DMSO-d6) 88.81 (t, J= 6.5 Hz, 1H), 8.51 (d, J= 8.4 Hz, 1H), 8.18 (d, J= 1.4 Hz, 1H), 7.29 (d, J = 1.5 Hz, 1H), 7.16 -7.10 (m, 2H), 7.06 (t, J= 8.8 Hz, 2H), 7.03-6.98 (m, 2H), 5.42 (brd, J = 4 Hz, 1 H), 5.26 (dd, J = 8.5, 3.9 Hz, 1 H), 4.32 - 4.25 (m, 1 H), 3.68 (br s, 2H), 3.53 (dd, component of ABX system, J= 16.0, 6.4 Hz, 1H), 3.48 (dd, component of ABX system, J = 16.0, 6.4 Hz, 1 H), 3.27 (dd, J = 16.5, 6.3 Hz, 1 H), 2.96 - 2.85 (m, 4H), 2.72 (dd, J = 16.6, 4.6 Hz, 1H), 2.00 (brs, 6H), 1.16 - 1.10 (m, 2H), 0.81 - 0.75 (m, 2H).

[0905] Example 17 / V-[(1 S,2S)-5-Fluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-[(2R,3R)-8-[2-(4- fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5- tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl]thiophene-3-carboxamide (17)

[0906]

[0907]

[0908] Step 1. Synthesis of methyl 2-({(2R,3R)-3-[(tert-butoxycarbonyl)amino]butan-2-yl}oxy)-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate (C53).

[0909] A solution of lithium diisopropylamide in a mixture of tetrahydrofuran, heptane, and ethylbenzene (2.0 M; 0.566 mL, 1.13 mmol) was added dropwise to a 0 °C solution of P6 (200 mg, 0.377 mmol) and tert-butyl [(2R,3R)-3-hydroxybutan-2-yl]carbamate (143 mg, 0.756 mmol) in tetrahydrofuran (1.3 mL). After the reaction mixture had been stirred at 0 °C for 10 minutes, it was warmed to room temperature and stirred for an additional 16 hours. Saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted three times with ethyl acetate; the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 25% ethyl acetate in heptane) afforded C53 as a sticky white solid. Yield: 116 mg, 0.170 mmol, 45%. LCMS m / z 683.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 88.41 (d, J= 1.4 Hz, 1H), 7.19 (d, J= 1.4 Hz, 1H), 7.14 (brdd, J= 8.5, 5.7 Hz, 2H), 7.05 (t, J= 8.8 Hz, 2H), 6.80 (d, J= 8.6 Hz, 1H), 5.30 -5.20 (m, 1 H), 4.24 (q, J = 7.1 Hz, 2H), 3.89 - 3.77 (m, 1 H), 3.68 (s, 3H), 3.08 - 2.89 (m, 4H), 2.38 (s, 3H), 1.39 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H).

[0910] Step 2. Synthesis of 2-({(2R,3R)-3-[(tert-butoxycarbonyl)amino]butan-2-yl}oxy)-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylic acid (C54).

[0911] To a solution of C53 (116 mg, 0.170 mmol) in pyridine (1.7 mL) was added lithium iodide (341 mg, 2.55 mmol), whereupon the reaction mixture was heated at 105 °C for 10 hours, then allowed to stir at room temperature overnight. The reaction mixture was subsequently diluted with water and dichloromethane, acidified to pH 5 by addition of 1 M hydrochloric acid, and extracted six times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide C54 as a dark-orange solid. LCMS m / z 669.1 [M+H]+.Step 3. Synthesis of 2-{[(2 / ?,3 / ?)-3-aminobutan-2-yl]oxy}-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylic acid, dihydrochloride salt (C55).

[0912] To a solution of C54 (from the previous step; <0.170 mmol) in dichloromethane (1.0 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4 M; 0.426 mL, 1.70 mmol). After the reaction mixture had been stirred at room temperature for 1 hour, it was concentrated in vacuo to afford C55 as a dark solid. LCMS m / z 569.2 [M+H]+.

[0913] Step 4. Synthesis of ethyl 5-[(2 / ?,3 / ?)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]thiophene-3-carboxylate (C56).

[0914] N,N-Diisopropylethylamine (88.8 μL, 0.510 mmol), 1-methyl-1H-imidazole (54.2 μL, 0.680 mmol), and chloro(dimethylamino)- / V, / V-dimethylmethaniminium hexafluorophosphate (TCFH; 71.5 mg, 0.255 mmol) were added to a solution of C55 (from the previous step; <0.170 mmol) in / V, / V-dimethylformamide (5.5 mL). After the reaction mixture had been stirred at room temperature for 1 hour, it was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo, whereupon the residue was azeotroped with heptane (3x 10 mL). Purification using silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded C56 as a white solid. Yield: 52 mg, 94 pmol, 55% over 3 steps. LCMS m / z 551.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 88.58 (br d, J = 6.1 Hz, 1H), 8.35 (d, J= 1.4 Hz, 1H), 7.21 (d, J= 1.4 Hz, 1H), 7.12 (dd, component of ABX system, J= 8.6, 5.7 Hz, 2H), 7.06 (dd, component of ABX system, J= 8.9, 8.9 Hz, 2H), 4.46 -4.34 (m, 1 H), 4.24 (q, J = 7.1 Hz, 2H), 3.62 - 3.51 (m, 1 H), 2.99 - 2.87 (m, 4H), 2.40 (s, 3H), 1.27 (t, J= 7.1 Hz, 3H), 1.27 (d, J= 6.3 Hz, 3H), 1.19 (d, = 6.6 Hz, 3H).

[0915] Step 5. Synthesis of 5-[(2 / ?,3 / ?)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]thiophene-3-carboxylic acid (C57).

[0916] A room temperature solution of C56 (52 mg, 94 mmol) in tetrahydrofuran (0.70 mL) was treated sequentially with water (0.30 mL) and lithium hydroxide (23 mg, 0.96 mmol), whereupon the reaction mixture was heated at 60 °C for 2 hours. After cooling to room temperature, it was diluted with dichloromethane, acidified by addition of 1 M hydrochloric acid, and extracted six times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide C57 as a white solid. Yield: 49 mg, 94 pmol, quantitative. LCMS m / z 523.2 [M+H]+.Step 6. Synthesis of / V-[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-[(2F?,3F?)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]thiophene-3-carboxamide (17).

[0917] To a solution of C57 (15 mg, 29 mmol) in / V, / V-dimethylformamide (0.29 mL) were added / V, / V-diisopropylethylamine (15 mL, 86 pmol), 1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 14 mg, 37 μmol), and (1S,2S)-1-amino-5-fluoro-2,3-dihydro-1 / 7-inden-2-ol (9.6 mg, 57 pmol). After the reaction mixture had been stirred at room temperature for 1 hour, it was treated with saturated aqueous sodium bicarbonate solution and diluted with water. The aqueous layer was extracted three times with dichloromethane, whereupon the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was azeotroped with heptane and purified using reversed-phase HPLC (Column: Waters XBridge C18, 19 x 100 mm, 5 pm; Mobile phase A: water containing 0.03% ammonium hydroxide (v / v); Mobile phase B: acetonitrile containing 0.03% ammonium hydroxide (v / v); Gradient: 5% to 95% B over 8.54 minutes, then 95% B for 1.46 minute; Flow rate: 25 mL / min) to afford / \ / -[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-[(2F?,3F?)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-2,3,4,5-tetrahydropyrido[3,2- / ][1,4]oxazepin-6-yl]thiophene-3-carboxamide (17) as a light brown gum. Yield: 14.7 mg, 21.9 pmol, 76%. LCMS m / z 672.3 [M+H]+.1H NMR (600 MHz, DMSO-d6) 88.61 -8.56 (m, 2H), 8.25 (d, J= 1.4 Hz, 1H), 7.33 (d, J= 1.4 Hz, 1H), 7.12 (dd, J = 8.6, 5.7 Hz, 2H), 7.12 - 7.08 (m, 1 H), 7.08 - 7.03 (m, 3H), 6.98 (br td, J = 8.9, 2.6 Hz, 1 H), 5.40 (d, J= 5.7 Hz, 1H), 5.15 (t, J= 7.5 Hz, 1H), 4.44 -4.32 (m, 2H), 3.56 - 3.47 (m, 1H), 3.18 (dd, J = 15.9, 7.1 Hz, 1H), 2.97 -2.86 (m, 4H), 2.73 (dd, J= 15.9, 7.3 Hz, 1H), 2.43 (s, 3H), 1.27 (d, J = 6.3 Hz, 3H), 1.21 (d, J= 6.6 Hz, 3H).

[0918] Example 18

[0919] / V-[(1S,2S)-5,6-Difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-{8'-[2-(4-fluorophenyl)ethyl]-7'- (5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2- f] [ 1,4]oxazepin]-6'-yl}thiophene-3-carboxamide (18)

[0920]

[0921] C58

[0922]

[0923] Step 1. Synthesis of methyl 2-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclopropyl)oxy]-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylate (C58).

[0924] A reaction vial was charged sequentially with P6 (250 mg, 0.472 mmol), tert-butyl [(1-hydroxycyclopropyl)methyl]carbamate (106 mg, 0.566 mmol), 1-methylpyrrolidin-2-one (2.4 mL), and a solution of lithium diisopropylamide in a mixture of tetrahydrofuran, heptane, and ethylbenzene (2 M; 0.519 mL, 1.04 mmol), whereupon the reaction mixture was stirred at room temperature for 2 hours and 40 minutes. Water and ethyl acetate were added, and the resulting mixture was acidified to pH 5 by addition of hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography(Gradient: 5% to 80% ethyl acetate in heptane) to provide C58 as a white solid. Yield: 94.9 mg, 0.139 mmol, 29%. LCMS m / z 681.4 [M+H]+.

[0925] Step 2. Synthesis of 2-[(1-{[(terf-butoxycarbonyl)amino]methyl}cyclopropyl)oxy]-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylic acid (C59).

[0926] A mixture of C58 (94.9 mg, 139 mmol), lithium iodide (280 mg, 2.09 mmol), and pyridine (1.4 mL) was stirred at 90 °C for 22 hours, whereupon LCMS analysis indicated the presence of C59: LCMS m / z 667.4 [M+H]+. Dichloromethane and water were added, and the mixture was acidified to pH 5 by addition of 1 M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford C59 as an oil, which was progressed directly to the following step.

[0927] Step 3. Synthesis of 2-{[1-(aminomethyl)cyclopropyl]oxy}-4-[4-(ethoxycarbonyl)thiophen-2-yl]-6-[2-(4-fluorophenyl)ethyl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylic acid (C60).

[0928] A solution of C59 (from the previous step; <0.139 mmol) in dichloromethane (0.70 mL) was treated with a solution of hydrogen chloride in 1,4-dioxane (4 M; 0.348 mL, 1.39 mmol). The reaction mixture was stirred at room temperature for approximately 1 hour, whereupon it was concentrated in vacuo to provide C60 as a solid. This material was used directly in the following step. LCMS m / z 567.4 [M+H]+.

[0929] Step 4. Synthesis of ethyl 5-{8'-[2-(4-fluorophenyl)ethyl]-7'-(5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4', 5'-dihydro-3'H-spiro[cyclopropane-1, 2'-pyrido[3, 2-f][1, 4]oxazepin]-6'-yl}thiophene-3-carboxylate (C61).

[0930] A solution of C60 (from the previous step; <0.139 mmol) in / V, / V-dimethylformamide (4.6 mL) was treated sequentially with / V, / V-diisopropylethylamine (0.121 mL, 0.695 mmol), 1-methyl-1 / - / -imidazole (33.3 pL, 0.418 mmol), and chloro(dimethylamino)- / V, / V-dimethylmethaniminium hexafluorophosphate (TCFH; 50.8 mg, 0.181 mmol), whereupon the reaction mixture was stirred at room temperature for 20 hours. It was then partitioned between water and ethyl acetate, and the organic layer was washed with aqueous lithium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo, providing C61 as an oil. This material was progressed directly to the following step. LCMS m / z 549.1 [M+H]+.

[0931] Step 5. Synthesis of 5-{8'-[2-(4-fluorophenyl)ethyl]-7'-(5-methyl-1,3,4-oxadiazol-2-yl)-5'-oxo-4',5'-dihydro-3' / 7-spiro[cyclopropane-1,2'-pyrido[3,2- / ][1,4]oxazepin]-6'-yl}thiophene-3-carboxylic acid (C62).

[0932] A mixture of C61 (from the previous step; <0.139 mmol) and lithium hydroxide monohydrate (58.4 mg, 1.39 mmol) in a mixture of tetrahydrofuran (0.5 mL) and water (0.2 mL)was stirred at 50 °C for 70 minutes. After the reaction mixture had been diluted with ethyl acetate, it was acidified to pH 5 by addition of 1 M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered, and concentrated...

Claims

CLAIMSWe claim:

1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof;whereinZ is NR5’ or O;Z1is -C(O)- or -S(O)2-;R1and R5’ are each independently selected from the group consisting of hydrogen, Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- wherein the Ci-Cealkyl, Cs-Cycycloalkyl-Co-Cealkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 Rs;R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, Ci-Cealkyl substituted with 0 to 6 Rs, Ci-Cealkoxy substituted with 0 to 6 Rsand Cs-Cycycloalkyl substituted with 0 to 6 Rs;or R2and R3or R4and R5can be taken together with the carbon to which they are attached to form a Ce-Cyspirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;or R2and R4can be taken together with the carbons to which they are attached to form a C3-Cycycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;- is absent or is a bond, provided only one - is a bond at a time and when - is a bond connecting the carbons to which R2and R4are attached then R3and R5are absent and when Z is O the - attached to O is absent and when Z is NR5’ and the - is a bond then R5’ is absent;R6is selected from the group consisting of (C6-Cioaryl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C2-C8alkenyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C3-C7cycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (5- to 10-membered heteroaryl)-(Co-C4alkyl)-L-Co-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-; wherein the R6group is substituted with 0 to 6 Rs;L is selected from a bond, O, NH and N(Ci-Csalkyl);X is N or CR7;R7is selected from the group consisting of hydrogen, -C(O)OR7a, -C(O)NR7bR7c, -OC(O)NR7bR7c, -N(R7d)C(O)NR7bR7c, Ci-C6alkyl substituted with 0 to 6 Rs, Ci-C6alkoxy substituted with 0 to 6 Rs, Cs-Cycycloalkyl-Co-Cealkyl- substituted with 0 to 6 Rs, (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- substituted with 0 to 6 Rs, Ce-C aryl-Co-Cealkyl-substituted with 0 to 6 Rsand 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 Rs;or R7and R6taken together with the carbons to which they are attached form a fused C4-C7cycloakyl ring or a fused 4- to 7-membered heterocycloalkyl ring;R7ais Ci-Cealkyl substituted with 0 to 6 Rs;R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-Cealkyl substituted with 0 to 6 Rs;or R7band R7ctaken together with the nitrogen to which they are attached can form a 4- to 7-membered heterocycloalkyl which is substituted with 0 to 6 Rs;Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-C8cycloalkyl and 4- to 10-membered heterocycloalkyl, wherein the Ce-C aryl and 5- to 10-membered heteroaryl are optionally fused with a Cs-Cycycloalkyl or a 4 to 7-membered heterocycloalkyl and Ring A is substituted with 0 to 6 Rs;Y is selected from the group consisting of -C(O)NR8R9, -N(R8)C(O)R9, -C(O)OR8, -OR8, -NR8R9, -N(R8)S(O)2R9, -S(O)2R8, -S(O)2NR8R9and -N(R8’)C(O)NR8R9;R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 Rs, Cs-C cycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs, 4 to 7-membered heterocycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs, (C6-C aryl)-Co-Cealkyl- substituted with 0 to 6 Rs, (5- to 10-membered heteroaryl)-Co-Cealkyl- substituted with 0 to 6 Rs,or R8and R9when attached to a nitrogen can be taken together with the nitrogen to which they are attached to form a 4- to 7-membered heterocycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 Rs;Rsat each occurrence is independently selected from the group consisting of halo, hydroxy, oxo, cyano, -NRS1RS2, -Ci-Cealkyl-NRS1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, C1-Csalkoxy substituted with 0 to 6 fluoro, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro, C1-Csalkoxy-Ci-Csalkoxy- substituted with 0 to 6 fluoro, Cs-Cscycloalkyl substituted with 0 to 6 RS3, 4- to 7-membered heterocycloalkyl substituted with 0 to 6 RS3, 5- to 10-membered heteroaryl substituted with 0 to 6 RS3and C6-C10 aryl substituted with 0 to 6 RS3;or two Rstaken together with the atoms to which they are attached can formRS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 6 RS3, Ci-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 RS3, C3-C7cycloalkyl-Co-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-Co-C3alkyl- substituted with 0 to 6 RS3;or RS1and RS2taken together with the nitrogen to which they are attached form a 4- to 7- membered heterocycloalkyl which is substituted with 0 to 6 RS3; and RS3at each occurrence is independently selected from halo, hydroxy, cyano, Ci-Csalkyl and Ci-Csalkoxy;or an isotope thereof or a pharmaceutically acceptable salt of the compound or isotope thereof.

2. The compound of claim 1 of Formula (la) or Formula (lb)(la) oror a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 of Formula (la)or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 of Formula (I”)5. The compound of claim 4 of Formula (Ic) or Formula (Id)or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 of Formula (Ic)or a pharmaceutically acceptable salt thereof.

7. The compound of claim 3 wherein R5’ is selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 4 fluoro or hydroxy, Cs-Cscycloalkyl-Ci-Csalkyl- and (4- to 6-membered heterocycloalkyl)-Ci-C3alkyl-; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7 wherein R5’ is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclobutylmethyl and oxetanylmethyl; ora pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein R1is selected from the group consisting of hydrogen, Ci-Csalkyl substituted with 0 to 4 fluoro or hydroxy, Cs-Cscycloalkyl-Ci-Csalkyl- and (4- to 6-membered heterocycloalkyl)-Ci-C3alkyl-; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 wherein R1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclobutylmethyl and oxetanylmethyl; ora pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein R2, R3, R4and R5are independently selected from the group consisting of hydrogen and Ci-Csalkyl substituted with 0 to 4 fluoro or hydroxy;or R2and R3or R4and R5, taken together with the carbon to which they are attached form a C3-Csspirocycloalkyl or 4- to 6-membered spiroheterocycloalkyl;or R2and R4taken together with the carbons to which they are attached can form a C3-Cscycloalkyl ring;or R4and R5’ taken together with the carbon and nitrogen to which they are attached can form a 4- to 7-membered heterocycloalkyl ring;or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 wherein R2, R3, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl;or R2and R3or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl;or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring;or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claim 1 wherein R6is (C6aryl)-(C1-C4alkyl)-L-C0alkyl- or (5- to 10-membered heteroaryl)-(C1-C4alkyl)-L-C0alkyl-; wherein the R6is substituted with 1 to 2 RSand L is a bond;or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 wherein R6is selected from the group consisting of 2-(4-fluorophenyl)ethyl, 2-(4-trifluoromethylphenyl)ethyl, 2-(3,4-dichlorophenyl)ethyl and 2-(2-cyanophenyl)ethyl;or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 of a formula selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 wherein R7is selected from -C(O)OR7a, -C(O)NR7bR7cand 5- to 6-membered heteroaryl-C0alkyl- substituted with 0 to 2 RS;R7ais C1-C3alkyl and R7band R7care independently hydrogen or C1-C3alkyl;or a pharmaceutically acceptable salt thereof.

17. The compound of claim 16 wherein R7ais ethyl, R7band R7care hydrogen and the 5- to 6-membered heteroaryl-C0alkyl- is selected from oxadiazolyl, thiazolyl, pyrazolyl and pyridazinyl and RSis C1-C3alkyl;or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 wherein R7is selected from the group consisting ofand or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 whereinR1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclobutylmethyl and oxetanylmethyl;R5’ is hydrogen or methyl;R2, R3, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl;or R2and R3or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl;or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring;or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 wherein the groupY% / VW'I is selected from the group consisting ofY Y Y Yor a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 wherein Y is -C(O)NR8R9;or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 wherein R8is hydrogen and R9is selected from the group consisting of 3,4-difluorophenylmethyl, pyridin-3-ylmethyl and 2-hydroxy-2,3-dihydro-1H-inden-1-yl;or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 wherein R1, R2, R3, R4and R5are each independently hydrogen or methyl; or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23 wherein Ri, R3 and R5 are each hydrogen and R2 and R4 are each methyl; or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 wherein Ring A is a thiophene, pyridine or thienopyridine ring; or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 wherein the groupYI is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

27. The compound of any one of claim 1 wherein the group Y isor a pharmaceutically acceptable salt thereof.

28. The compound of of claim 26 wherein R7is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

29. A compound of claim 1 selected from the group consisting of (2R,3R)-6-(4-{[(1R)-5,6-difluoro-2,3-dihydro-1H-inden-1-yl]amino}thieno[2,3-d]pyrimidin-6-yl)-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-8-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;2-fluoro-4-({7-[(2R,3R)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-5-oxo-7-(5-oxo-4,5-dihydro- 1,3,4-oxadiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-6-yl]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}methyl)benzonitrile;(2R,3R)-6-(2-{[(1R)-5,6-Difluoro-2,3-dihydro-1H-inden-1-yl]amino}pyridin-4-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one;(2R,3R)-6-(4-{[(1R)-5,6-Difluoro-2,3-dihydro-1 / - / -inden-1-yl]amino}thieno[2,3-c(]pyrimidin-6-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f] [ 1,4]oxazepin-5(2H)-one;(2R,3R)-8-[2-(4,4-difluorocyclohexyl)ethyl]-6-(4-{[(1R)-5,6-difluoro-2,3-dihydro-1 / 7-inden-1-yl]amino}thieno[2,3-cflpyrimidin-6-yl)-2,3-dimethyl-7-{5-[(2R)-1-methylpyrrolidin-2-yl]-1,3,4-oxadiazol-2-yl}-3,4-dihydropyrido[3,2- / ][1,4]oxazepin-5(2H)-one;(2R,3R)-6-(4-{[(1R)-5,6-difluoro-2,3-dihydro-1 / - / -inden-1-yl]amino}-2-methylthieno[2,3-d]pyrimidin-6-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2- / ][1,4]oxazepin-5(2H)-one; and(2R,3R)-6-(4-{[(1S,2S)-5,6-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]amino}thieno[3,2-d]pyrimidin-6-yl)-8-[2-(4-fluorophenyl)ethyl]-2,3-dimethyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-3,4-dihydropyrido[3,2-f|[1,4]oxazepin-5(2H)-one;or an isotope thereof or a pharmaceutically acceptable salt of the compound or isotope thereof.

30. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

31. A method of for treating or preventing a condition, disease, or disorder in a patient comprising administering to the patient a compound of claim 1, wherein the condition, disease, or disorder is selected from the group consisting of obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), eating disorders (including binge eating syndrome, bulimia nervosa, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), weight gain such as weight gain caused by use of other agents (e.g., caused by use of steroids and / or antipsychotics, or caused by treatment of depression, or caused by use of agents on cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, nonalcoholic fatty liver disease [NAFLD, including related diseases such as steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascularcompliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g. necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, metabolic acidosis, ketosis, diabetes [e.g. Type 1 diabetes mellitus (T1D), Type 2 diabetes mellitus (T2DM), including pre-diabetes], idiopathic T1D (Type 1b), latent autoimmune diabetes in adults (LADA), early-onset T2DM (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney disorder, tubular dysfunction, proinflammatory changes to the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea [e.g. obstructive sleep apnea (OSA)], arthritis, osteoporosis, osteoarthritis, Parkinson’s disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., addiction to alcohol, nicotine, and / or drug).

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