Substituted fused heteroaryl lactam compounds

Abstract

The present disclosure relates to fused heteroaryl lactam 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 heteroaryl lactam compounds of Formula (I) and salts thereof may be useful to treat or prevent, for example, obesity, weight gain, and / or T2DM.

Description

[0001] Substituted Fused Heteroaryl Lactam Compounds

[0002] Background of the Invention

[0003] The present invention relates to novel fused heteroaryl lactam compounds. The invention also relates to the preparation of the fused heteroaryl lactam 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.

[0004] 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.

[0005] 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.

[0006] 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, the calcitonin 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.

[0007] Summary of the Invention

[0008] 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.

[0009] According to an embodiment of the invention there is provided a compound of Formula (I)

[0010]

[0011] or a pharmaceutically acceptable salt thereof;

[0012] wherein

[0013] R1is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-C0-C6alkyl- wherein the C1-C6alkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-C0-C6alkyl- are substituted with 0 to 6 R6; n is 0 or 1;

[0014] R2and R3are each independently selected from the group consisting of hydrogen, cyano, C1-C6alkyl substituted with 0 to 6 RSand C3-C7cycloalkyl substituted with 0 to 6 RS;

[0015] R2’, R3’, R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, C1-C6alkyl substituted with 0 to 6 RS, C1-C6alkoxy substituted with 0 to 6 RSand C3-C7cycloalkyl substituted with 0 to 6 RS;

[0016] or R2and R3, R2’ and R3’ or R4and R5can be taken together with the carbon to which they are attached to form a C3-C7spirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;

[0017] or when n is 1 then R2and R2’ or R2’ and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring; or when n is 0 then R2and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;

[0018] - 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 R2’ are attached then R3and R3’ are absent and when - is a bond connecting the carbons to which R2’ and R4are attached then R3’ and R5are absent;

[0019] R6is selected from the group consisting of (C6-C10aryl)-(C0-C4alkyl)-L-C0-C4alkyl-, (C2-C8alkenyl)-(C0-C4alkyl)-L-C0-C4alkyl-, (C3-C7cycloalkyl)-(C0-C4alkyl)-L-C0-C4alkyl-, (5- to 10-membered heteroaryl)-(C0-C4alkyl)-L-C0-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(C0-C4alkyl)-L-C0-C4alkyl-; wherein the R6group is substituted with 0 to 6 R6;

[0020] L is selected from a bond, O, NH and N(Ci-C3alkyl);

[0021] X is N or CR7;

[0022] 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 R6, Ci-C6alkoxy substituted with 0 to 6 R6, C3-C7cycloalkyl-C0-C6alkyl- substituted with 0 to 6 RS, (4- to 7-membered heterocycloalkyl)-C0-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;

[0023] or R7and R6taken together with the carbons to which they are attached form a fused C4-C7cycloalkyl ring or a fused 4- to 7-membered heterocycloalkyl ring;

[0024] R7ais C1-C6alkyl substituted with 0 to 6 RS;

[0025] R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-C6alkyl substituted with 0 to 6 RS;

[0026] 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 R6;

[0027] 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;

[0028] 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;

[0029] R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 R6, C3-C7cycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 RS, (C6-C10aryl)-C0-C6alkyl substituted with 0 to 6 RS, (5- to 10-membered heteroaryl)-C0-C6alkyl substituted with 0 to 6 RS,

[0030] 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 R6;

[0031] RSat each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, -NRS1RS2, C1-C3alkyl substituted with 0 to 6 fluoro, C1-C3alkoxy substituted with 0 to 6 fluoro and C1-C3alkoxy-C1-C3alkyl substituted with 0 to 6 fluoro;

[0032] RS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, C1-C3alkyl substituted with 0 to 6 RS3, C1-C3alkoxy-C1-C3alkyl- substituted with 0 to 6 RS3, C3-C7cycloalkyl-C0-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-C0-C3alkyl- substituted with 0 to 6 RS3;

[0033] 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

[0034] RS3at each occurrence is independently selected from halo, hydroxy, cyano, C1-C3alkyl and C1-C3alkoxy.

[0035] Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) is identical to the embodiment of Formula (I) provided above. 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.

[0036] Detailed Description of the Invention

[0037] 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.

[0038] E1 A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

[0039] E2 is the compound of E1 of Formula (I’);

[0040]

[0041] or a pharmaceutically acceptable salt thereof.

[0042] E3 is the compound of E2 of Formula (Ia)

[0043]

[0044] or a pharmaceutically acceptable salt thereof.

[0045] E4 is the compound of E3 of Formula (la-1) or (la-2)

[0046]

[0047] or a pharmaceutically acceptable salt thereof.

[0048] E5 is the compound of E4 of Formula (la-1)

[0049]

[0050] or a pharmaceutically acceptable salt thereof.

[0051] E6 is the compound of E2 of Formula (lb)

[0052]

[0053] or a pharmaceutically acceptable salt thereof. E7 is the compound of E6 of Formula (lb-1) or (lb-2)

[0054]

[0055] or a pharmaceutically acceptable salt thereof.

[0056] E8 is the compound of E1 of Formula (I”);

[0057]

[0058] or a pharmaceutically acceptable salt thereof.

[0059] E9 is the compound of E8 of Formula (Ic), (Id) or (le)

[0060]

[0061]

[0062] or a pharmaceutically acceptable salt thereof.

[0063] 5 E10 is the compound of E9 of Formula (lc-1), (lc-2), (Id-1), (Id-2), (le-1) or (le-2)

[0064]

[0065]

[0066] or a pharmaceutically acceptable salt thereof.

[0067] E11 is the compound of any one of E1 to E10 wherein R1is selected from the group consisting of hydrogen, C1-C3alkyl substituted with 0 to 4 fluoro or hydroxy, C3-C5cycloalkyl-C1-C3alkyl and (4- to 6-membered heterocycloalkyl)-C1-C3alkyl; or a pharmaceutically acceptable salt thereof.

[0068] E12 is the compound of E11 wherein R1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclobutylmethyl and oxetanylmethyl; ora pharmaceutically acceptable salt thereof.

[0069] E13 is the compound of any one of E1 to E12 wherein R2, R2’, R3, R3’, R4and R5are independently selected from the group consisting of hydrogen and Ci-Csalkyl substituted with 0 to 4 fluoro or hydroxy;

[0070] or R2and R3or R2’ and R3’ or R4and R5, taken together with the carbon to which they are attached form a Ca-Csspirocycloalkyl or 4- to 6-membered spiroheterocycloalkyl;

[0071] or when n is 1 then R2and R2’ or R2’ and R4taken together with the carbons to which they are attached can form a Cs-Cscycloalkyl ring;

[0072] or when n is 0 then R2and R4taken together with the carbons to which they are attached can form a C3-C5cycloalkyl ring; or a pharmaceutically acceptable salt thereof.

[0073] E14 is the compound of E13 wherein R2, R2’, R3, R3’, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl;

[0074] or R2and R3or R2’ and R3’ or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl;

[0075] or when n is 1 then R2and R2’ or R2’ and R4taken together with the carbons to which they are attached can form a cyclopropyl ring;

[0076] or when n is 0 then R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring; or a pharmaceutically acceptable salt thereof. E15 is the compound of any one of E1 to E14 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 R6and L is a bond; or a pharmaceutically acceptable salt thereof.

[0077] E16 is the compound of E15 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.

[0078] E17 is the compound of E1 of a formula selected from the group consisting of

[0079]

[0080]

[0081] or a pharmaceutically acceptable salt thereof.

[0082] E18 is the compound of E17 wherein R7is selected from -C(O)OR7a, -C(O)NR7bR7cand 5- to 6-membered heteroaryl-C0alkyl substituted with 0 to 2 R6;

[0083] R7ais C1-C3alkyl and R7band R7care independently hydrogen or C1-C3alkyl;

[0084] or a pharmaceutically acceptable salt thereof.

[0085] E19 is the compound of E18 wherein R7ais ethyl, R7band R7care hydrogen and the 5- to 6-membered heteroaryl-Coalkyl is selected from oxadiazolyl, thiazolyl, pyrazolyl and pyridazinyl and R6is Ci-C3alkyl; or a pharmaceutically acceptable salt thereof.

[0086] E20 is the compound of E19 wherein R7is selected from the group consisting of

[0087]

[0088] or a pharmaceutically acceptable salt thereof.

[0089] E21 is the compound of E20 wherein

[0090] R1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclobutylmethyl and oxetanylmethyl;

[0091] R2, R2’, R3, R3’, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl;

[0092] or R2and R3or R2’ and R3’ or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl;

[0093] or R2and R2or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring;

[0094] or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring; or a pharmaceutically acceptable salt thereof.

[0095] E22 is the compound of any one of E1 to E21 wherein the group

[0096]

[0097] selected from the group consisting of

[0098]

[0099] or a pharmaceutically acceptable salt thereof.

[0100] E23 is the compound of any one of E1 to E22 wherein Y is -C(O)NR8R9; or a pharmaceutically acceptable salt thereof.

[0101] E24 is the compound of E23 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.

[0102] E25 is the compound of any one of E1 to E22 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; or a pharmaceutically acceptable salt thereof.

[0103] E26 is the compound of E1 selected from the group consisting of

[0104] ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0105] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0106] ethyl 2-[2-(4-fluorophenyl)ethyl]-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6, 7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate;

[0107] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4-(4-{[(pyridin-3-yl)methyl] carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0108] ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4-(4-{[(pyridin-3-yl)methyl] carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate; ethyl (7R)-4-(4-{[(3,4-difluorophenyl)methyl]carbamoyl}phenyl)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0109] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-6-(2-hydroxyethyl)-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0110] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-6,7-dimethyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0111] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(1S,2S)-2-hydroxy-2,3-dihydro-1 / - / -inden-1-yl]carbamoyl}thiophen-2-yl)-7-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate; ethyl 2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate;

[0112] 4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(pyridin-3-yl)methyl]benzamide;

[0113] ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-7-(hydroxymethyl)-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate; ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-(hydroxymethyl)-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate; ethyl 2-[2-(4-fluorophenyl)ethyl]-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6-dihydro- 1,6-naphthyridine-3-carboxylate;

[0114] ethyl 2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate;

[0115] 4-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide; 5-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0116] 5-[(8R)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0117] 5-[(8S)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0118] 5-[(8R)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-8-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0119] 5-[(8S)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-8-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide; 5-{2-[2-(4-fluorophenyl)ethyl]-7,7-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0120] 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0121] ethyl rac-(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} thiophen-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0122] ethyl (8R)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate;

[0123] ethyl (8S)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate;

[0124] 4-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-3-(pyridazin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(pyridin-3-yl)methyl]benzamide;

[0125] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(6-{[(pyridin-3-yl)methyl]carbamoyl} pyridin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0126] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(1S,2S)-2-hydroxy-2,3-dihydro-1 / - / -inden-1-yl]carbamoyl}-1,3-thiazol-2-yl)-7-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;

[0127] 4-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-3-(5-methyl-1,3-thiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(pyridin-3-yl)methyl]benzamide;

[0128] (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxamide;

[0129] (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}thiophen-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxamide;

[0130] ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} thiophen-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate; and

[0131] 2-[2-(4-fluorophenyl)ethyl]-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6, 7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxamide;

[0132] or a pharmaceutically acceptable salt thereof.

[0133] E27 is a pharmaceutical composition comprising a compound of any one of E1 to E26 and a pharmaceutically acceptable excipient.

[0134] E28 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 E1 to E26, 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).

[0135] E29 is the method of E28 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)].

[0136] E30 is a compound of any one of E1 to E26 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 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).

[0137] E31 is the use of E20 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)].

[0138] E32 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 E26.

[0139] Any of the compounds described in embodiment E26, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of embodiment E26, or pharmaceutically acceptable salts thereof.

[0140] E33 is a compound of E1 of the formula

[0141]

[0142] or a pharmaceutically acceptable salt thereof.

[0143] E34 is a compound of E33 of the formula

[0144]

[0145] or a pharmaceutically acceptable salt thereof.

[0146] E35 is a compound of E33 or E34 of the formula

[0147]

[0148] or a pharmaceutically acceptable salt thereof.

[0149] E36 is the compound of any one of E33 to E35 wherein R7is a 5- to 6-membered heteroaryl-Coalkyl substituted with 0 to 2 R6; or a pharmaceutically acceptable salt thereof. E37 is the compound of any one of E33 to E36 wherein R7is oxadiazolyl substituted with 0 to 2 R6; or a pharmaceutically acceptable salt thereof.

[0150] E38 is a compound of any one of E1 or E33 to E37 selected from the group consisting of 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;

[0151] 4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide; and 2-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / - / -inden-1-yl]-1,3-oxazole-4-carboxamide; or a pharmaceutically acceptable salt thereof.

[0152] E39 is a pharmaceutical composition comprising a compound of any one of E33 to E38 and a pharmaceutically acceptable excipient.

[0153] E40 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 E33 to E38, 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).

[0154] E41 is a compound of Formula (I)

[0155]

[0156] or a pharmaceutically acceptable salt thereof;

[0157] wherein

[0158] R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-C0-C6alkyl- wherein the Ci-Cealkyl, C3-Cycycloalkyl-Co-C6alkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 R6; n is 0 or 1;

[0159] R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 R6andC3-Cycycloalkyl substituted with 0 to 6 R6;

[0160] R2’, R3’, R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, C1-C6alkyl substituted with 0 to 6 RS, C1-C6alkoxy substituted with 0 to 6 RSand C3-C7cycloalkyl substituted with 0 to 6 RS;

[0161] or R2and R3, R2’ and R3’ or R4and R5can be taken together with the carbon to which they are attached to form a C3-C7spirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;

[0162] or when n is 1 then R2and R2’ or R2’ and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring; or when n is 0 then R2and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;

[0163] - 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 R2’ are attached then R3and R3’ are absent and when - is a bond connecting the carbons to which R2’ and R4are attached then R3’ and R5are absent; R6is selected from the group consisting of (Cs-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)-I_-Co-C4alkyl-; wherein the R6group is substituted with 0 to 6 R6;

[0164] L is selected from a bond, O, NH and N(Ci-Csalkyl);

[0165] X is N or CR7;

[0166] 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 R6, Ci-C6alkoxy substituted with 0 to 6 R6, C3-C7cycloalkyl-C0-C6alkyl- substituted with 0 to 6 RS, (4- to 7-membered heterocycloalkyl)-C0-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;

[0167] or R7and R5taken 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 C1-C6alkyl substituted with 0 to 6 RS; R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-C6alkyl substituted with 0 to 6 RS;

[0168] 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 R6;

[0169] Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-Cscycloalkyl and 4- to 10-membered heterocycloalkyl, wherein Ring A is substituted with 0 to 6 R6;

[0170] 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;

[0171] R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 R6, Cs-Cycycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 R6, 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 R6, (C6-C10aryl)-C0-C6alkyl- substituted with 0 to 6 RS, (5- to 10-membered heteroaryl)-C0-C6alkyl- 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 R6;

[0172] R6at each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, oxo, -NRS1RS2, -Ci-Cealkyl-NRS1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, C1-Csalkoxy substituted with 0 to 6 fluoro, Cs-Cecycloalkyl substituted with 0 to 6 RS3and C1-Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro; or two R6groups when attached to adjacent carbon or nitrogen atoms can be taken together to form a fused Cs-Cycycloalkyl ring or a fused four- to 7-membered heterocycloalkyl ring;

[0173] 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-C7cycloalkylCo-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-Co-C3alkyl- substituted with 0 to 6 RS3;

[0174] 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

[0175] RS3at each occurrence is independently selected from halo, hydroxy, cyano, C1-C3alkyl and C1-C3alkoxy.

[0176] E42 is a compound of Formula (lx)

[0177]

[0178] or a pharmaceutically acceptable salt thereof;

[0179] wherein

[0180] R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C3-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 R6; n is 0 or 1;

[0181] R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 R6andCs-Cycycloalkyl substituted with 0 to 6 R6;

[0182] R2’, R3’, R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, C1-C6alkyl substituted with 0 to 6 RS, C1-C6alkoxy substituted with 0 to 6 RSand C3-C7cycloalkyl substituted with 0 to 6 RS;

[0183] or R2and R3, R2’ and R3’ or R4and R5can be taken together with the carbon to which they are attached to form a C3-C7spirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;

[0184] or when n is 1 then R2and R2’ or R2’ and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring; or when n is 0 then R2and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;

[0185] - 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 R2’ are attached then R3and R3’ are absent and when - is a bond connecting the carbons to which R2’ and R4are attached then R3’ and R5are absent;

[0186] R6is selected from the group consisting of (Cs-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 R6;

[0187] L is selected from a bond, O, NH and N(Ci-C3alkyl);

[0188] X is N or CR7;

[0189] 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 R6, Ci-C6alkoxy substituted with 0 to 6 R6, Cs-Cycycloalkyl-Co-Csalkyl- substituted with 0 to 6 R6, (4- to 7-membered heterocycloalkyl)-C0-C6alkyl- substituted with 0 to 6 RS, Ce-Cioaryl-Co-Cealkyl-substituted with 0 to 6 R6and 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 R6;

[0190] or R7and R5taken together with the carbons to which they are attached form a fused C4-C7cycloakyl ring ora fused 4- to 7-membered heterocycloalkyl ring;

[0191] R7ais CrCealkyl substituted with 0 to 6 R6;

[0192] R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-C6alkyl substituted with 0 to 6 RS;

[0193] 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 R6;

[0194] Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-Cscycloalkyl and 4- to 10-membered heterocycloalkyl, wherein Ring A is substituted with 0 to 6 R6;

[0195] 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;

[0196] R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 R6, Cs-Cycycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 R6, 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 R6, (C6-C10aryl)-C0-C6alkyl- substituted with 0 to 6 RS, (5- to 10-membered heteroaryl)-C0-C6alkyl- 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 R6;

[0197] R6at each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, oxo, -NRS1RS2, -Ci-C6alkyl-NRS1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, C1- Csalkoxy substituted with 0 to 6 fluoro, Cs-Cecycloalkyl substituted with 0 to 6 RS3and C Csalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro;

[0198] or two R6groups when attached to adjacent carbon or nitrogen atoms can be taken together to form a fused C3-C7cycloalkyl ring or a fused four- to 7-membered heterocycloalkyl ring;

[0199] 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-C7cycloalkylCo-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-Co-C3alkyl- substituted with 0 to 6 RS3;

[0200] 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

[0201] RS3at each occurrence is independently selected from halo, hydroxy, cyano, C1-C3alkyl and C1-C3alkoxy.

[0202] E43 is the compound according to any one of E1 to E31, E33 to E37 and E41 to E42 or a pharmaceutically acceptable salt thereof wherein the group

[0203]

[0204] selected from the group consisting of

[0205]

[0206] E44 is the compound according to E43 or a pharmaceutically acceptable salt thereof wherein the group Y is selected from the group consisting of

[0207]

[0208]

[0209] E45 is the compound according to E43 or a pharmaceutically acceptable salt thereof wherein the group Y is selected from the group consisting of

[0210]

[0211] E46 is the compound of any one of E 41 to E45 or a pharmaceutically acceptable salt thereof wherein R7is selected from the group consisting of

[0212]

[0213] E47 is a compound selected from the group consisting of the compounds of Examples 1 to 151 or a pharmaceutically acceptable salt thereof.

[0214] E48 is a pharmaceutical composition comprising a compound of any one of E41 to E47 and a pharmaceutically acceptable excipient.

[0215] E49 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 E41 to E47, 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).

[0216] 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.

[0217] Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds described herein.

[0218] In some examples 7-membered lactams are similar in potency to 6-membered lactams. For instance, 7-membered lactam Example 43 (33.2 nM) is similar in potency to 6-membered lactam Example 16 (39.2 nM). However, geminal methyl substituted 7-membered lactam Example 35 (0.55 nM) is 99-fold more potent than 6-membered geminal analogue Example 22 (54.3 nM) and 32-fold more potent than 6-membered geminal methyl analogue Example 23 (17.9 nM). This stark difference in potency is unexpected and clearly the 6-membered analogues cannot replicate the placement of substituents on the 7-membered ring which provides exquisite potency.

[0219] Definitions

[0220] 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.

[0221] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0222] “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.

[0223] 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.

[0224] 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. 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).

[0225] “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.

[0226] The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no

[0227] non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more

[0228] 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 number and 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.

[0229] “Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I).

[0230] “Cyano” refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., -C=N.

[0231] "Hydroxy" refers to an -OH group.

[0232] “Oxo” refers to a double bonded oxygen (=0).

[0233] "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 (“C1-C8alkyl”), 1 to 6 carbon atoms (“C1-C6alkyl”), 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.

[0234] “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 man contain, but are not limited to, 1-6 carbon atoms (“C1-C6haloalkyl”), 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.”

[0235] “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).

[0236] “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 (“C1-C8alkoxy”), 1 to 6 carbon atoms (“C1-C6alkoxy”), 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.

[0237] “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, (“C1-C6haloalkoxy”), 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-.

[0238] “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-C6alkenyl" 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.

[0239] “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-C8cycloalkyl”), 3 to 6 carbon atoms (“C3-C6cycloalkyl”), 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.

[0240] “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-C8cycloalkoxy”), 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.

[0241] 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 ring members, or 1 to 2 ring heteroatoms, provided that such heterocycloalkyl rings do not contain two contiguous oxygen or sulfur atoms.

[0242] 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.

[0243] 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.

[0244] Illustrative examples of heterocycloalkyl rings include, but are not limited to a monovalent radical of:

[0245]

[0246]

[0247] 1,4-oxaazepane 1,4-thieazepane 1,4-diazepane 1,4-dithiepane (1,4-oxaazepanyl) (1,4-thieazapanyl) (1,-diazepanyl)or(1,4-dithiepanyl)

[0248] "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 ("C6-C14aryl"), 6 to 12 carbon atoms ("C6-C12aryl"), or 6 to 10 carbon atoms ("C6-C10aryl"). 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.

[0249] 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.

[0250] 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.

[0251] Illustrative examples of monocyclic heteroaryl groups include, but are not limited to a monovalent radical of:

[0252]

[0253] pyrrole furan thiophene pyrazole imidazole isoxazole (pyrrolyl) (furanyl) (thiophenyl) (pyrazolyl) (imidazolyl) (isoxazolyl)

[0254]

[0255] 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)

[0256]

[0257] 1-oxa-2,4-diazole 1-oxa-2,5-diazole 1-oxa-3,4-diazole 1 -thia-2,3-diazole 1 -th ia-2,4-diazole (1-oxa-2,4-diazolyl) (1 -oxa-2,5-diazolyl) (1 -oxa-3,4-diazolyl) (1 -thia-2,3-diazolyl) (1-th ia-2,4-diazolyl)

[0258]

[0259] 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) illustrative examples of fused ring heteroaryl groups include, but are not limited to:

[0260]

[0261]

[0262] “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(C1-C4alkyl) or -N(C1-C4alkyl)2).

[0263] “Aminoalkyl” refers to an alkyl group, as defined above, that is substituted by 1, 2, or 3 amino groups, as defined herein.

[0264] 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.

[0265] 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.

[0266] “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).

[0267] "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.

[0268] 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.

[0269] 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 of excipients, 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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:

[0274] (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;

[0275] (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

[0276] (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).

[0277] Salts

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0282] For a 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.

[0283] 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;

[0284] (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

[0285] (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.

[0286] 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.

[0287] Solvates

[0288] 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 molecular complex comprising the compound of the invention, ora 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.

[0289] 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).

[0290] 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.

[0291] 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.

[0292] Complexes

[0293] 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).

[0294] Solid form

[0295] 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’).

[0296] 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 -SO3-Na+) or non-ionic (such as -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). Stereoisomers

[0297] Compounds of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds may include cis 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 (orZ / E) isomers are possible. Cis / trans isomers may also exist for saturated rings.

[0298] 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).

[0299] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0300] 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 diastereoisomers converted 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).

[0301] 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). Tautomerism

[0302] 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.

[0303] 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.

[0304] Isotopes

[0305] 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.

[0306] 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 as123I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulfur, such as35S.

[0307] 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.

[0308] 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.

[0309] In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds of the invention are deuterated.

[0310] 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.

[0311] 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.

[0312] Prodrugs

[0313] 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 hydrolytic cleavage 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.).

[0314] 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).

[0315] 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.

[0316] Some specific examples of prodrugs in accordance with the invention include:

[0317] (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-Cs alkyl (e.g., ethyl) or (Ci-Cs alkyl)C(=O)OCH2-(e.g., ‘BuC(=O)OCH2-); (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(C1-C8alkyl) (e.g., methylcarbonyl) or the alcohol is esterified with an amino acid;

[0318] (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;

[0319] (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+;

[0320] (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;

[0321] (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.

[0322] 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.

[0323] Metabolites

[0324] 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,

[0325] (i) where the compound of the invention contains an alkyl group, a hydroxyalkyl derivative thereof (-CH — > -COH):

[0326] (ii) where the compound of the invention contains an alkoxy group, a hydroxy derivative thereof (-OR — ► -OH);

[0327] (iii) where the compound of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR’ — > -NHR or -NHR);

[0328] (iv) where the compound of the invention contains a secondary amino group, a primary derivative thereof (-NHR — > -NH2); (v) where the compound of the invention contains a phenyl moiety, a phenol derivative thereof (-Ph -PhOH);

[0329] (vi) where the compound of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH); and

[0330] (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.

[0331] Protein Degraders

[0332] 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 calcitonin receptor or amylin receptor]. The bifunctional compounds of the disclosure can be used as therapeutics to treat a condition disclosed herein.

[0333] In one embodiment, a bifunctional compound of the disclosure has the formula:

[0334] [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.

[0335] Degron: 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).

[0336] 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.

[0337] 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)-, -OC(O)O-, - 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(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, - 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)-, C3-12carbocyclene, 3- to 12-membered heterocyclene, 5- to 12-membered heteroarylene, or arylene, or any combination thereof, wherein RLis H or C1-6alkyl. In one embodiment, In some embodiments, the Linker is C1-10 alkylene-NH-, wherein the nitrogen is bound to the degron. In one embodiment, the Linker is C1-10alkylene or 1-8 PEG units that are interrupted by or terminate in -(CH2)n-C(O)-NH-, where n’ is 0, 1, 2, 3, 4, or 5.

[0338] Nonlimiting examples of a Linker include -(CH2CH2-O)n"-(CH2)n-C(O)-, (CH2)n-C(O)-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- (CH2)n-, -(CH2)n-phenylene-(CH2)n-heterocyclylene- (CH2)n-O-, -(CH2)n- heterocyclylene-(CH2)n’ wherein RLis H or C1-6alkyl; 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.

[0339] Pharmaceutical Compositions

[0340] 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.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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. 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.

[0346] 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 a micronized 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.

[0347] 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. 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.

[0348] 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.

[0349] 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).

[0350] 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.

[0351] 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.

[0352] 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).

[0353] 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, or microcapsules. 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.

[0354] 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.

[0355] 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 µm, particularly 0.1 and 0.5 µm, and have a pH in the range of 5.5 to 8.0.

[0356] 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).

[0357] 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.

[0358] 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 may be 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.

[0359] Administration and Dosing

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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.

[0364] 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, the compounds 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.

[0365] 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.

[0366] Therapeutic Methods and Uses 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).

[0367] Co-administration

[0368] 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.

[0369] 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”.

[0370] 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.

[0371] Co-administration

[0372] 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.

[0373] 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”.

[0374] 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.

[0375] 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).

[0376] 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-reductase Inhibitors, Ezetimibe, Probucol, Ursodeoxycholic acid, TGR5 agonists, FXR agonists, Vitamin E, Betaine, Pentoxifylline, CB1 antagonists, Carnitine, A / -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. 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.

[0377] 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).

[0378] Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1'H-spiro[indazole-5,4'-piperidin]-1'-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid, gemcabene, and firsocostat (GS-0976) and phamaceutally acceptable salts thereof.

[0379] 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.

[0380] Exemplary KHK inhibitors include [(1R,5S,6R)-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.

[0381] 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.

[0382] Some exemplary BCKDK inhibitors include those described in US Patent Nos.

[0383] 11542270 and 11059833, including the following:

[0384] 5-(5-chloro-4-fluoro 3-methylthiophen-2-yl)-1 H-tetrazole;

[0385] 5-(5-chloro-3-difluoromethylthiophen-2-yl)-1 H-tetrazole;

[0386] 5-(5-fluoro-3-methylthiophen-2-yl)-1H-tetrazole;

[0387] 5-(5-chloro-3-methylthiophen-2-yl)-1H-tetrazole;

[0388] 5-(3,5-dichlorothiophen-2-yl)-1 H-tetrazole;

[0389] 5-(4-bromo-3-methylthiophen-2-yl)-1 H-tetrazole;

[0390] 5-(4-bromo-3-ethylthiophen-2-yl)-1 H-tetrazole; 5-(4-chloro-3-ethylthiophen-2-yl)-1H-tetrazole;

[0391] 3-chloro-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0392] 3-bromo-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0393] 3-(difluoromethyl)-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0394] 5,6-difluorothieno[3,2-b]thiophene-2-carboxylic acid; and

[0395] 3,5-difluorothieno[3,2-b]thiophene-2-carboxylic acid;

[0396] or a pharmaceutically acceptable salt thereof.

[0397] Some additional exemplary BCKDK inhibitors include those described in US Patent Application 18 / 060,027, filed November 30, 2022, including the following:

[0398] 6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0399] 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0400] 6-chloro-3-(2,4,5-trifluoro-3-methylphenyl)-1-benzothiophene-2-carboxylic acid;

[0401] 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid;

[0402] 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;

[0403] 3-(3-chloro-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid;

[0404] 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;

[0405] 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.

[0406] 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 W02010103437, W02010103438, 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 W02010140092, WO2010128425, W02010128414, W02010106457, 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.

[0407] 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. The Pat, 2010, 20(12), 1627-51.

[0408] 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), Ifchannel 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. 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)].

[0409] 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; ACE inhibitors (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.

[0410] 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.

[0411] Examples of suitable calcium channel blockers (L-type orT-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.

[0412] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0413] 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™).

[0414] 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.

[0415] 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.

[0416] 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.

[0417] Examples of suitable mineralocorticoid receptor antagonists include sprionolactone and eplerenone.

[0418] Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

[0419] 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.

[0420] 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.

[0421] 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.

[0422] 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.

[0423] 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.

[0424] 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.

[0425] 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.

[0426] 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. Kits

[0427] 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 ora 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.

[0428] 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.

[0429] Synthetic Methods

[0430] 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 the description 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.

[0431] 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.

[0432] 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.

[0433] 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.

[0434] 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.

[0435] 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 A / -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.

[0436] General Experimental Details

[0437] 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:

[0438] Abbreviations

[0439] APCI is atmospheric pressure chemical ionization;

[0440] aq is aqueous;

[0441] br is broad;

[0442] tBu is tert-butyl;

[0443] °C is degrees Celsius;

[0444] cAMP is cyclic adenosine monophosphate;

[0445] CAN is ammonium cerium (IV) nitrate;

[0446] CO2is carbon dioxide; CDCl3or CHLOROFORM-d is deutero-chloroform;

[0447] 6 is chemical shift;

[0448] d is doublet;

[0449] dd is doublet of doublets;

[0450] ddd is doublet of doublet of doublets;

[0451] dt is doublet of triplets;

[0452] DMSO is dimethyl sulfoxide;

[0453] DMSO-d6is deuterodimethylsulfoxide;

[0454] EC50 is 50% effective concentration;

[0455] EDCI is N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride;

[0456] Eq is equivalent;

[0457] ESI is electrospray ionization;

[0458] EtOAc is ethyl acetate;

[0459] EtOH is ethanol;

[0460] Et3N is triethylamine;

[0461] FAC is final assay concentration;

[0462] g is gram;

[0463] GMEAN is geometric mean;

[0464] HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;

[0465] HCI is hydrogen chloride (hydrochloric acid);

[0466] HPLC is high pressure liquid chromatography;

[0467] HOPO is 2-hydroxypyridine N-oxide;

[0468] hr(s) is hour(s);

[0469] L is liter;

[0470] LCMS is liquid chromatography mass spectrometry;

[0471] m is multiplet;

[0472] M is molar;

[0473] MeCN is acetonitrile;

[0474] mg is milligram;

[0475] MgSO4is magnesium sulfate;

[0476] MHz is mega Hertz;

[0477] min(s) is minute(s);

[0478] mL is milliliter;

[0479] mmol is millimole;

[0480] mol is mole;

[0481] MS (m / z) is mass spectrum peak;

[0482] MsCI is mesyl chloride; NH3is ammonia;

[0483] nm is nanometer;

[0484] NMR is nuclear magnetic resonance;

[0485] pH is power of hydrogen;

[0486] pM is picomolar;

[0487] ppm is parts per million;

[0488] psi is pounds per square inch;

[0489] q is quartet;

[0490] rt is room temperature;

[0491] RT is retention time;

[0492] s is singlet;

[0493] SFC is supercritical fluid chromatography;

[0494] t is triplet;

[0495] TEA is triethylamine;

[0496] TFA is trifluoroacetic acid;

[0497] THF is tetrahydrofuran;

[0498] ZPE is zero percent effect;

[0499] pL is microliter;

[0500] pmol is micromole; and

[0501] pM is micromolar.

[0502] 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.

[0503] General Experimental Methods:

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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 afford certain 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.

[0508] 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.

[0509] 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.

[0510] 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). 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.

[0511] The compounds of the invention can be prepared as described herein and according to the methods as described in Schemes 1 to 9.

[0512] Compounds of Formula (I) may be synthesized as shown in Scheme 1. The compounds of Formula A, Formula B, Formula C, and Formula C’ may be synthesized through literature methods well known to those skilled in the art or purchased commercially. Formula A, Formula B, and Formula C can be combined with a suitable base, such as sodium ethoxide, in a polar solvent, such as ethanol, at 80 °C for 2 - 24 hours to provide compounds of Formula D. Compounds of Formula D can be converted to compounds of Formula (I) directly 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.

[0513] Alternatively, compounds of Formula A, Formula B, and Formula C’ can be combined with a suitable base such as sodium ethoxide, in a polar solvent, such as ethanol, at 80 °C for 2 - 24 hours to provide compounds of Formula D’. Compounds of Formula D’ can then be converted to compounds of Formula (I) through oxidation with a suitable oxidant, such as ammonium cerium (IV) nitrate (CAN), in a suitable solvent or mixture of solvents, such as a 1:1 mixture (v / v) of acetonitrile and water, at 20 °C for 2-72 hours. Amidation with an amine using a suitable coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), a base such as triethylamine, optional addition of additives such as 2-hydroxypyridine 1 -oxide (HOPO), in a suitable solvent such as dichloromethane or dimethyl formamide, at 20 °C for 2 - 24 hours can provide compounds of Formula (I).

[0514] Scheme 1

[0515]

[0516] Alternatively, compounds of Formula (I) may be synthesized as illustrated in Scheme 2. For example, compounds of Formula D wherein X is CR7and R7is C(O)OR7a, can be converted to compounds of Formula E through oxidation with a suitable oxidant, such as ammonium cerium (IV) nitrate (CAN), in a suitable solvent or mixture of solvents, such as a 1:1 mixture (v / v) of acetonitrile and water, at 20 °C for 2-72 hours, followed by hydrolysis using a variety of methods known to those skilled in the art.

[0517] Scheme 2

[0518]

[0519] One such hydrolysis method that can be employed to provide compounds of Formula E after oxidation of compounds of Formula D, is treatment with an acid such as trifluoroacetic or hydrochloric acid, in a polar solvent such as hexafluoroisopropanol or acetonitrile, at temperatures from 20-60 °C for 2-24 hours. Compounds of Formula E can then be converted to compounds of Formula G via combination with a suitable acyl hydrazide such as compounds of Formula F, which may be purchased or synthesized from commercially available starting materials using procedures well known to those skilled in the art. Treatment of compounds of Formula E with compounds of Formula F, along with a suitable coupling agent such as O-(7-azabenzotriazol-1-yl)-N,M,N;M'-tetramethyluronium hexafluorophosphate (HATU), in the presence of a base such as diisopropylethylamine, and in an aprotic solvent such as 1,2-dichloroethane, can provide compounds of Formula G. Treatment of compounds of Formula G with Methyl N-(triethylammoniosulfonyl)carbamate (Burgess reagent) at temperatures from 20-70 °C can provide compounds of Formula (I).

[0520] An alternative approach to provide compounds of Formula (I) is the treatment of compounds of Formula E using conditions well known to those skilled in the art in the manner of a Curtius rearrangement via combination with diphenylphosphoryl azide and a suitable base such as triethylamine in a polar solvent such as tert-butanol from 20-80 °C for 2-24 hours followed by treatment with an acid such as hydrochloric acid in methanol to provide compounds of Formula H. Treatment of compounds of Formula H with conditions well known to those skilled in the art in the manner of a Sandmeyer reaction can provide compounds of Formula J where “LG” is an appropriate leaving group including a halide substituent such as iodine or bromine. Treatment of compounds of Formula H with tert-butyl nitrite and copper iodide or bromide in a polar solvent such as acetonitrile for 2-24 hours can provide compounds of Formula J. Compounds of Formula J can be reacted with a substituted boronic acid or boronate ester in the presence of a palladium catalyst and ligand complex such as (2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl)[2-(2’-amino-1,1'-biphenyl)]palladium(II) methanesulfonate and a suitable base such as cesium carbonate in a polar solvent such as 1,4-dioxane and water mixture from 20-80 °C for 2-24 hours, in the manner of a Suzuki reaction, to provide compounds of Formula (I). One skilled in the art will further recognize that compounds of Formula J can be utilized in numerous other metal-mediated coupling reactions in addition to Suzuki reactions to arrive at compounds of Formula (I). Some examples of those coupling reactions include but are not limited to Heck couplings, Negishi couplings, Ullman-type couplings, and Buchwald-Hartwig couplings.

[0521] Compounds within the scope of Formula (I) (i.e. compounds wherein n is 0, - is absent, X is CR7and R7is -C(O)OR7a) may be synthesized as shown below in Scheme 3.

[0522] Compounds of Formula A’, Formula B’, and Formula C’ may be synthesized by literature methods known by those skilled in the art or purchased commercially. Formula A’, Formula B’, and Formula C’ can be combined with a suitable base, such as sodium ethoxide, in a polar solvent, such as ethanol, at 80 °C for 2 - 24 hours to provide Formula D’ as shown in Scheme 3. Formula D’ can be converted to Formula E’ with the use of a suitable oxidant, such as ammonium cerium (IV) nitrate (CAN), in a 1:1 mixture of acetonitrile and water at 20 °C for 2 -72 hours. Formula E’ can be converted to compounds within Formula (I) by a number of methods. One such method is amidation of the carboxylic acid group of E’ with an amine HNR8R9, using any suitable coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and a base, such as triethylamine, with the optional addition of additives, such as 2-hydroxypyridine 1 -oxide, in a suitable solvent, such as dichloromethane or dimethyl formamide, at 20 °C for 2 -24 hours to provide compounds where Y is an amide group -C(O)NR8R9. Another method is conversion of compound E’ to an ester compound within Formula (I) by reacting the carboxylic group of E’ with an alcohol R8OH under known esterification conditions such as under acid catalysis to provide compounds wherein Y is -C(O)OR8.

[0523] Scheme 3

[0524]

[0525] wherein Y is -C(O)NR8R9, -C(O)OR8

[0526] Alternatively, compounds within Formula (I) wherein n is 0 and - is absent may be synthesized according to Scheme 4. Compounds of Formula A’, Formula B’, and Formula C’ may be synthesized by literature methods known by those skilled in the art or purchased commercially. The compounds of Formula A’, Formula B’, and Formula C’ can be combined with a suitable base, such as sodium ethoxide, in a polar solvent, such as ethanol, at 80 °C for 2 - 24 hours to provide the compound of Formula D” as shown in Scheme 4. The compound of Formula D” can be converted to compounds within Formula (I) with the use of a suitable oxidant, such as ammonium cerium (IV) nitrate (CAN), in a 1:1 mixture of acetonitrile and water at 20 °C for 2 - 72 hours.

[0527] Scheme 4

[0528]

[0529] Compounds wit

[0530] 7hin Form

[0531] 7ula I

[0532] = -C(O)R7„ or H

[0533] wherein X = CR7, and R7 7

[0534] Compounds within Formula (I) wherein n is 0 and - is a bond may be synthesized according to Scheme 5. The compounds of Formula A’, Formula B”, and Formula C’ may be synthesized by literature methods known by those skilled in the art or purchased commercially. The compounds of Formula A’, Formula B”, and Formula C’ can be combined with a suitable base, such as sodium ethoxide, in a polar solvent, such as ethanol, at 80 °C for 2 - 24 hours to provide compound Formula D’” as shown in Scheme 3. The compound of Formula D’” can be converted to a compound within Formula (I) wherein n is 0 and - is a bond with the use of a suitable oxidant, such as ammonium cerium (IV) nitrate (CAN), in a 1:1 mixture of acetonitrile and water at 20 °C for 2 - 72 hours.

[0535] Scheme 5

[0536]

[0537] Compounds within Formula (I) wherein n is 1 and each - is absent may be synthesized according to Scheme 6. The compounds of Formula A’, Formula B’”, and Formula C’ may be synthesized by literature methods known by those skilled in the art or purchased commercially. The compounds of Formula A’, Formula B’”, and Formula C’ can be combined with a suitable base, such as sodium ethoxide, in a polar solvent, such as ethanol, at 80 °C for 2 - 24 hours to provide the compound of Formula D”” as shown in Scheme 6. The compound of Formula D”” can be converted to a compound within Formula (I) wherein n is 1 and each -is absent with the use of a suitable oxidant, such as ammonium cerium (IV) nitrate (CAN), in a 1:1 mixture of acetonitrile and water at 20 °C for 2 - 72 hours.

[0538] Scheme 6

[0539]

[0540] Alternatively, compounds within Formula (I) may be synthesized according to Scheme 7. A compound of Formula K, possessing two different esters can be prepared according to methods described in Schemes 1-6. Substituents R7aand R8can be appropriately selected to enable selective conversion of either ester to the corresponding acids of structures L and L’. The carboxylic acid in a compound of structure L can be transformed to afford a compound of structure M. The remaining ester in a compound of structure M can be transformed according to methods previously described in Schemes 1-6 to afford compounds within Formula (I).

[0541] Similarly, compounds of Formula L’ can be transformed according to analogous methods to afford compounds of Formula (I).

[0542] Scheme 7

[0543]

[0544] Alternatively, compounds within Formula (I) wherein Y is -OR8or -NR8R9may be synthesized according to Scheme 8. Compounds of Formula N, wherein LG is a leaving group such as a halogen (F, Cl, Br, I), may be synthesized according to methods described in Schemes 1-6. Compounds of structure N can be converted to compounds of structure O via methods described previously. Compounds of structure O can be converted to a compound of Formlua (I) via displacement of the leaving group in structure O. For example, a compound of structure O, wherein the leaving group is Cl, may be treated with an amine (R8R9NH), XantPhos Pd G4, and CS2CO3 in a solvent such as t-AmOH at elevated temperature to afford a compound of Formula (I) wherein Y is -NR8R9. Alternatively, a leaving group, such as Cl, in a compound of structure O can be converted to a hydroxyl group upon treatment fo a compound of structure O with AcNHOH and K2CO3 in DMSO. This hydroxyl group can then be alkylated under Mitsunobu conditions to afford a compound of Formula (I) wherein Y is Y is -OR8.

[0545] Scheme 8

[0546]

[0547] N Compound within Formula (I)

[0548] wherein Y is -OR8, -NR8R9Alternatively, compounds within Formula (I) may be synthesized according to Scheme 9. One skilled in the art, will recognize that compounds of structure S can be prepareded by methods analogous to those highlighted in schemes 1-6. A compound of structure T possessing a chloropyridine moiety can be further prepared and reacted with an alcohol of structure U to obtain a compound of structure V. For example a compound of structure T can be treated with an alcohol of structure U, 5,7-Di-tert-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate, and pyridine in a solvent such as MTBE. The resulting intermediate can then be treated with Ir[ppy]2(dtbbpy)PF6, NiBr2(dtbbpy), quinuclidine, and pyridine in a solvent such as DMAc in the presence of blue light to afford a compound of structure V. A compound of structure V can then be converted to a compound of Formula (I) via a short sequence of reactions. For example, the ester of a compound of structure V can be converted to the corresponding carboxylic acid upon treatment with Lil in pyridine. The t-butyl carbamate protecting group in the resulting intermediate can be removed upon treatment with HCI in dioxane. The required lactam in a compound of Formula (I) can be prepared from the resulting amino acid intermediate upon treatment with HATU and DIEA in a solvent such as DMF.

[0549]

[0550] Unless stated otherwise, the variables in Schemes 1-9 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 R1, R2, R2’, R3, R3’, R4, R5, R6, R7, R7a, R8, R9, X, Ring A and Y are as defined in the embodiments, schemes, examples, and claims herein.

[0551] The synthetic intermediates having formulas A, A’, B, B’, B”, B’”, C, C’, D, D’, D”, D’”, D””, E, G, H, J, L, L’, M, M’, N, O, P, Q, R, S, T, U, and V as defined in the above Schemes are useful for preparing compounds of the invention and are provided as further aspects of this invention.

[0552] 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 limiting the scope of the invention in any manner.

[0553] The following illustrate the synthesis of various compounds of the present invention. 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.

[0554] 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 4A molecular sieves, until the following QC standards for water were attained: a) <100 ppm for dichloromethane, toluene, N,N-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.

[0555] 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, CoCl2, 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 μm), 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 Examples or Methods, purifications may vary: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate Rfs or retention times.

[0556] 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, 5) referenced to the deuterated solvent residual peaks (chloroform, 7.26 ppm; CD2HOD, 3.31 ppm; acetonitrile-d3, 1.94 ppm; dimethyl sulfoxide-d6, 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; brs, broad singlet; app, apparent. Depending on the NMR settings used, isolated aromatic protons in the compounds characterized below can provide erroneously small integration values, presumably due to their long relaxation times; in these cases, peaks were assigned as 1H, despite their low integrations.

[0557] 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.

[0558] Unless otherwise noted, chemical reactions were performed at room temperature (about 23 degrees Celsius).

[0559] Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0560] 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.

[0561] 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.

[0562] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedures.

[0563] 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 of elution). 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.

[0564] The compounds and intermediates described below were named using the naming convention provided with ACD / ChemSketch 2020.2.1.1, File Version C25H41, Build 121153 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming convention provided with ACD / ChemSketch 2020.2.1.1 is well known by those skilled in the art and it is believed that the naming convention provided with ACD / ChemSketch 2020.2.1.1 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Preparations P1-P3 described below can be used to prepare either Reference compounds 1 and 2 and / or compounds of the invention. Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0565] Preparation of Intermediates and Reference Compounds Preparation P1

[0566] Preparation of (5S)-5-(propan-2-yl)pyrrolidine-2, 4-dione (P1)

[0567]

[0568] C2 P1

[0569] Step 1. Synthesis of tert-butyl [(2S)-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-methyl-1-oxobutan-2-yl]carbamate (C1)

[0570] A mixture of L-Valine, n-[(1,1-dimethylethoxy)carbonyl]- (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 pL, 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 C1. The mixture was filtered cold to remove solid urea byproduct and the filtrate was washed three times with potassium bisulfate (1, aqueous) and then once with saturated brine. The separated organics were cooled in an ice / water bath, treated with MgSCU, 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 C1 as a colorless gum. Yield: 964 mg, 2.81 mmol, 62%. LCMS m / z 342.2 [M-H]’.

[0571] Step 2. Synthesis of tert-butyl (2S)-3,5-dioxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (C2) 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 C2. 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 C2 as a white foam. Yield: 428 mg, 1.77 mmol, 63%. LCMS m / z 242.3 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) 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).

[0572] Step 3. Synthesis of (5S)-5-(propan-2-yl)pyrrolidine-2, 4-dione (P1)

[0573] 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 P1. The mixture was concentrated under reduced pressure and co-distilled with ethyl acetate and heptane to afford P1 as a waxy, white solid. Yield: 236 mg, 1.67 mmol, 96%. LCMS m / z 142.2 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) 5 = 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).

[0574] Preparation P2

[0575] Preparation of (5F?)-5-(propan-2-yl)pyrrolidine-2, 4-dione (P2)

[0576]

[0577] C4 P2

[0578] 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 (C3)

[0579] A mixture of A / -(tert-butoxycarbonyl)-D-valine (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 pL, 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 C3. 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 MgSO4, filtered, and concentrated under reduced pressure to afford C3 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]-.

[0580] Step 2. Synthesis of terf-butyl (2R)-3,5-dioxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (C4) 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 C4. 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 C4 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, = 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).

[0581] Step 3. Synthesis of (5F?)-5-(propan-2-yl)pyrrolidine-2, 4-dione (P2)

[0582] A solution of tert-butyl (2F?)-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 P2. The mixture was concentrated under reduced pressure to afford P2 as a waxy, yellow solid. Yield: 380 mg, 2.69 mmol, 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 19x100mm 5um; Mobile phase A: 0.05% TFA in water (v / v); Mobile phase B:

[0583] 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 lO. Omin; Flow: 25mL / min). LCMS m / z 142.1 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) 6 = 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).

[0584] Preparation P3

[0585] Preparation of ethyl (2Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (P3)

[0586]

[0587] P3

[0588] Step 1. Synthesis of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (C5)

[0589] 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 1N HCI (50 mL) followed by water (50 mL), and the separated organics were dried over MgSCu, 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 C5. The mixture was concentrated and purified via silica gel chromatography (Gradient: 0 to 30% ethyl acetate in heptane) to afford C5 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, = 7.1 Hz, 2H), 3.42 (s, 2H), 2.94 - 2.83 (m, 4H), 1.27 (t, = 7.2 Hz, 3H).

[0590] Step 2. Synthesis of ethyl (2Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (P3)

[0591] A solution of ethyl 5-(4-fluorophenyl)-3-oxopentanoate (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 molar in ethanol, 3 mL, 0.34 Eq, 6 mmol) and stirred at 900for a further 5 hours until NMR analysis indicated conversion to P3. Concentration under reduced pressure afforded P3 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) 6 = 7.19 - 7.12 (m, 2H), 7.04 - 6.95 (m, 2H), 4.58 (s, 1 H), 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).

[0592] Preparation P4

[0593] Preparation of tert-butyl (2Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (P4)

[0594]

[0595] Step 1. Synthesis of 5-[3-(4-fluorophenyl)propanoyl]-2,2-dimethyl-1,3-dioxane-4, 6-dione (C13).

[0596] 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 brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford C13 as a yellow oil. This material was progressed directly to the following step. LCMS m / z 237.1 [(M-propan-2-one)+H]+.

[0597] Step 2. Synthesis of tert-butyl 5-(4-fluorophenyl)-3-oxopentanoate (C14).

[0598] A solution of C13 (from the previous step, <238 mmol) in fert-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 C14 as a light-brown oil. Yield: 28.0 g, 105 mmol, 44% over2 steps. LCMS m / z 289.2 [M+Na+],1H NMR (400 MHz, DMSO-cfe) 87.27 - 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).

[0599] Step 3. Synthesis of tert-butyl (2Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (P4).

[0600] To a solution of C14 (27.0 g, 101 mmol) in terf-butanol (450 mL) was added ammonium acetate (39.1 g, 507 mmol). After the reaction mixture had been stirred at 80 °C for 2 days, it was concentrated in vacuo, whereupon the residue was treated with ethyl acetate (200 mL). The resulting mixture was filtered; after rinsing of the filter cake with ethyl acetate (30 mL), the combined filtrates were concentrated under reduced pressure to provide P4 as a yellow oil. Yield: assumed quantitative.1H NMR (400 MHz, DMSO-cfe), integrations are approximate: 8 7.69 (brs, 1H), 7.29- 7.21 (m, 2H), 7.14-7.04 (m, 2H), 6.89 (brs, 1H), 4.28 (s, 1H), 2.82 -2.73 (m, 2H), 2.32 - 2.24 (m, 2H), 1.38 (s, 9H).

[0601] Preparation P5

[0602] (1 S,2S)-1-Amino-5-fluoro-4-methoxy-2,3-dihydro-1 / - / -inden-2-ol, hydrochloride salt (P5)

[0603]

[0604] Step 1. Synthesis of 5-fluoro-4-hydroxy-2,3-dihydro-1 / 7-inden-1-one (C30).

[0605] To a solution of 3-(3-fluoro-2-methoxyphenyl)propanoic acid (5.76 g, 29.1 mmol) in 1,2-dichloroethane (60 mL) was added trifluoromethanesulfonic acid (25.7 ml_, 291 mmol) at 25 °C, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction mixture had been treated with water (300 mL), it was extracted with ethyl acetate (3 x 200 mL), and 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. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) afforded C30 as a yellow solid. Yield: 4.32 g, 26.0 mmol, 89%. LCMS m / z 167.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 10.14 (br s, 1H), 7.22 (dd, component of ABX system, J = 11.0, 8.2 Hz, 1H), 7.12 (dd, component of ABX system, J = 8.3, 4.4 Hz, 1H), 3.02 -2.95 (m, 2H), 2.66 -2.59 (m, 2H).

[0606] Step 2. Synthesis of 5-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-one (C31).

[0607] To a solution of C30 (4.32 g, 26.0 mmol) in N,N-dimethylformamide (60 ml_) were added cesium carbonate (10.2 g, 31.3 mmol) and iodomethane (2.43 ml_, 39.0 mmol). After the reaction mixture had been stirred at 70 °C for 3 hours, it was diluted with water (400 ml_), and the resulting mixture was extracted with ethyl acetate (3 x 300 ml_). The combined organic layers were washed sequentially with water (300 ml_) and saturated aqueous sodium chloride solution (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) afforded C31 as a yellow solid. Yield: 4.20 g, 23.3 mmol, 90%. LCMS m / z 181.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 87.37 (dd, component of ABX system, J - 8.3, 4.7 Hz, 1H), 7.32 (dd, component of ABX system, J = 11.4, 8.3 Hz, 1H), 3.98 (d, = 1.8 Hz, 3H), 3.14-3.07 (m, 2H), 2.68 -2.62 (m, 2H).

[0608] Step 3. Synthesis of 5-fluoro-4-methoxy-2,3-dihydro-1 / - / -inden-1-ol (C32).

[0609] Sodium borohydride (1.32 g, 34.9 mmol) was added to a 0 °C solution of C31 (4.20 g, 23.3 mmol) in methanol (59 mL), whereupon the reaction mixture was stirred at 25 °C for 4 hours. Acetic acid (2 mL) was added, and the resulting mixture was concentrated under reduced pressure; the residue was diluted with ethyl acetate (30 mL), and the organic layer was washed with water (40 mL) before being concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 50% ethyl acetate in petroleum ether) provided C32 as a yellow solid. Yield: 4.01 g, 22.0 mmol, 94%. LCMS m / z 165.1 [(M - H2O)+H]+.1H NMR (400 MHz, CDCh) 87.02 (br dd, component of ABX system, J = 8.2, 4.4 Hz, 1 H), 6.97 (br dd, component of ABX system, J = 11.6, 8.2 Hz, 1H), 5.21 -5.16 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 3.08 (ddd, J = 16.5, 8.6, 5.0 Hz, 1H), 2.86-2.76 (m, 1H), 2.49 (dddd, J = 13.4, 8.4, 6.8, 5.0 Hz, 1H), 1.97 (dddd, J = 13.4, 8.6, 6.1, 4.9 Hz, 1H).

[0610] Step 4. Synthesis of 6-fluoro-7-methoxy-1 / 7-indene (C33).

[0611] A solution of C32 (4.01 g, 22.0 mmol) in dichloromethane (220 mL) was treated with 4-methylbenzene-1 -sulfonic acid (402 mg, 2.33 mmol), whereupon the reaction mixture was stirred at 25 °C for 3 hours. Water (40 mL) was then added, and the resulting mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified via silica gel chromatography (Eluent: petroleum ether), affording C33 as a colorless oil. Yield: 2.71 g, 16.5 mmol, 75%.1H NMR (400 MHz, CDCh) 8 7.06 - 6.99 (m, 2H), 6.80 (dt, J = 5.5, 1.9 Hz, 1 H), 6.52 (dt, J = 5.5, 2.0 Hz, 1 H), 4.03 (d, J = 1.8 Hz, 3H), 3.44 (t, = 2.0 Hz, 2H).

[0612] Step 5. Synthesis of (1aR,6aS)-4-fluoro-5-methoxy-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (C34).

[0613] To a -70 °C solution of C33 (1.20 g, 7.31 mmol) and (R, R)-(-)-A / , A / '-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(lll) chloride [(R, F?)-Jacobsen’s catalyst; 464 mg, 0.730 mmol] in dichloromethane (109 ml_) was added 4-methylmorpholine A / -oxide (3.43 g, 29.3 mmol), followed by 3-chloroperoxybenzoic acid (2.52 g, 14.6 mmol). After the reaction mixture had been stirred at -70 °C for 2 hours, it was treated with water (260 mL) and aqueous sodium hydroxide solution (2.0 M; 50 mL), then extracted with dichloromethane (3 x 150 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (120 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide C34 as a black oil, which was used directly in the following step. LCMS m / z 181.1 [M+H]+.1H NMR (400 MHz, CDCh) 87.12 (brs, 1H), 6.93 (brs, 1H), 4.29 -4.07 (m, 2H), 3.93 (brs, 3H), 3.10 (br AB quartet, JAB = 17.9 Hz, VAB= 116 Hz, 2H).

[0614] Step 6. Synthesis of terf-butyl [(1S,2S)-5-fluoro-2-hydroxy-4-methoxy-2,3-dihydro-1 / 7-inden-1-yl]carbamate (C35).

[0615] A solution of ammonia in methanol (7 M; 30 mL) was added to C34 (from the previous step; <7.31 mmol), whereupon the reaction mixture was stirred at 95 °C for 16 hours. Di-tert-butyl dicarbonate (4.85 g, 22.2 mmol) was added, and stirring was continued at 25 °C for 2 hours. Addition of water (60 mL) was followed by extraction with dichloromethane (3 x 50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 20% ethyl acetate in petroleum ether) provided a product composed of C35 and a small amount of its enantiomer as an orange solid (800 mg, 2.69 mmol, 37% over 2 steps). Isolation of C35 (560 mg, 1.88 mmol) was carried out using reversed-phase HPLC (Column: Chiral Technologies Chiralpak IC, 30 x 250 mm, 10 m; Mobile phase: 10% 2-propanol in hexane; Flow rate: 25 mL / minute). The first-eluting material was the enantiomer of C35, obtained as a white solid. Yield: 10.0 mg, 33.6 pmol, 0.5% over 2 steps. LCMS m / z 242.1 [(M - 2-methylprop-1-ene)+H]+.

[0616] The second-eluting material, also a white solid, was C35. Yield: 477 mg, 1.60 mmol, 22% over2 steps. LCMS m / z 242.1 [(M - 2-methylprop-1-ene)+H]+.1H NMR (400 MHz, DMSO-cfe) 87.20 (d, J= 8.7 Hz, 1H), 7.05 (dd, J= 12.1, 8.1 Hz, 1H), 6.77 (dd, J= 8.3, 4.2 Hz, 1H), 5.31 (d, J= 5.7 Hz, 1H), 4.68 -4.60 (m, 1H), 4.24 -4.14 (m, 1H), 3.84 (d, = 1.4 Hz, 3H), 3.16 (dd, J= 15.9, 7.2 Hz, 1H), 2.61 (dd, J= 15.9, 7.1 Hz, 1H), 1.43 (s, 9H).

[0617] Step 7. Synthesis of (1S,2S)-1-amino-5-fluoro-4-methoxy-2,3-dihydro-1H-inden-2-ol, hydrochloride salt (P5).

[0618] A 0 °C mixture of C35 (470 mg, 1.58 mmol) in methanol (11.2 mL) was treated with a solution of hydrogen chloride in 1,4-dioxane (4 M; 1.66 mL, 6.64 mmol). After the reaction mixture had been stirred at 20 °C for 3 hours, it was concentrated in vacuo to provide P5 as a white solid. Yield: 237 mg, 1.01 mmol, 64%. LCMS m / z 198.1 [M+H]+.1H NMR (400 MHz, DMSO-ds) 88.77 (br s, 3H), 7.30 (br dd, component of ABX system, J = 8.3, 4.3 Hz, 1 H), 7.19 (dd, component of ABX system, = 12.0, 8.3 Hz, 1H), 5.78 (brs, 1H), 4.47-4.39 (m, 1H), 4.37 -4.30 (m, 1H), 3.87 (d, = 1.6 Hz, 3H), 3.34 (dd, = 16.3, 6.9 Hz, 1H, assumed; partially obscured by water peak), 2.78 (dd, J = 16.3, 5.8 Hz, 1 H).

[0619] Preparation P6

[0620] (1S,2S)-1-Amino-5,7-difluoro-2,3-dihydro-1H-inden-2-ol (P6)

[0621]

[0622] Step 1. Synthesis of 4,6-difluoro-1H-indene (C36).

[0623] A mixture of 5,7-difluoro-2,3-dihydro-1H-inden-1-ol (5.51 g, 32.4 mmol) in aqueous sulfuric acid (1.5 M; 130 mL, 195 mmol) was heated at 120 °C for 13 hours, then at 130 °C for an additional 13 hours. The reaction mixture was extracted with pentane, and the organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, and water, dried over sodium sulfate, filtered, and concentrated at 45 °C and 200 mbar. Silica gel chromatography (Eluent: pentane) afforded C36 (5.20 g) as a colorless oil, a portion of which was advanced to the following step.1H NMR (400 MHz, CDCI3) 87.01 (ddd, J= 8.1, 2.1, 1.0 Hz, 1H), 6.93 (dtd, J= 5.6, 2.0, 0.8 Hz, 1H), 6.74 (td, J= 9.5, 2.1 Hz, 1H), 6.50 (dt, J= 5.7, 2.0 Hz, 1H), 3.45-3.41 (m, 2H).

[0624] Step 2. Synthesis of (1a / ?,6aS)-2,4-difluoro-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (C37).

[0625] 3-Chloroperoxybenzoic acid (70%, 11.1 g, 45.0 mmol) was dissolved in dichloromethane (100 ml_); the resulting solution was dried over sodium sulfate.

[0626] ( / ?, R)-(-)-A / , / V'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(lll) chloride [(F?, / ?)-Jacobsen’s catalyst; 1.01 g, 1.59 mmol] and 4-methylmorpholine A / -oxide (10.6 g, 90.5 mmol) were added to a -78 °C solution of C36 (from the previous step; 3.15 g, <19.6 mmol) in dichloromethane (114 mL). A portion of the solution of 3-chloroperoxybenzoic acid prepared above (0.45 M; 78 mL, 35.1 mmol) was then added dropwise, and the reaction mixture was stirred for 1 hour and 40 minutes at -78 °C. After rapid dropwise addition of a solution of dimethyl sulfide (6.5 mL, 88 mmol) in pentane (50 mL), aqueous sodium hydroxide solution (2 M; 100 mL) and pentane (100 mL) were added, and the resulting mixture was warmed to room temperature. The organic layer was washed sequentially with aqueous sodium hydroxide solution (2 M; 100 mL), water (100 mL), and saturated aqueous sodium chloride solution (100 mL). The aqueous layer was filtered through a thick pad of diatomaceous earth, and the filter cake was washed with pentane (100 mL); this filtrate was combined with the earlier organic layer, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluent: dichloromethane) afforded C37 as a brown oil (3.35 g). This material was progressed directly to the following step.1H NMR (400 MHz, CDCh) 86.75 (doublet of multiplets, J = 8.2 Hz, 1 H), 6.68 - 6.61 (br td, J = 9.2, 2.1 Hz, 1 H), 4.44 (ddd, J = 2.9, 1.3, 0.6 Hz, 1H), 4.14 (brt, J= 2.9 Hz, 1H), 3.22 (d, J= 18.4 Hz, 1H), 2.99 (brdd, J= 18.3, 2.7 Hz, 1H).

[0627] Step 3. Synthesis of (1S,2S)-1-amino-5,7-difluoro-2,3-dihydro-1 / 7-inden-2-ol (P6).

[0628] A solution of C37 (from the previous step; 3.35 g, <19.6 mmol) in 1,4-dioxane (19.9 mL) was added dropwise to ammonium hydroxide solution (25%, 78 mL, 1.0 mol). The resulting suspension was stirred for 49 hours, whereupon the reaction mixture was concentrated in vacuo to semi-dryness. The residue was purified by reversed-phase HPLC (Column: Silicycle SiliaSep™ C18; Mobile phase A: water containing 10 mM ammonium bicarbonate; Mobile phase B: acetonitrile; Gradient: 0% to 100% B; Flow rate: 140 mL / minute). The purified material was triturated in methyl fert-butyl ether (20 mL) to provide P6 as a white powder. Yield: 1.92 g, 10.4 mmol, 51% over 3 steps. LCMS m / z 186.0 [M+H]+. ee: >99%.1H NMR (400 MHz, methanol-cL) 86.84 (br d, J = 8.5 Hz, 1 H), 6.75 (br td, J = 9.6, 2.2 Hz, 1 H), 4.29 (br d, J = 3.6 Hz, 1H), 4.23 (ddd, = 6.2, 4.4, 3.6 Hz, 1H), 3.36 (ddq, J = 16.6, 6.2, 1.0 Hz, 1H), 2.77 (brdd, = 16.6, 4.4 Hz, 1H). Preparation P7

[0629] (1S,2S)-1-Amino-5-fluoro-2,3-dihydro-1 / - / -inden-2-ol (P7)

[0630]

[0631] Step 1. Synthesis of (1a / ?,6aS)-4-fluoro-6,6a-dihydro-1a / 7-indeno[1,2-5]oxirene (C38).

[0632] 3-Chloroperoxybenzoic acid (70%, 2.22 g, 9.00 mmol) was dissolved in dichloromethane (20 mL); the resulting solution was dried over sodium sulfate.

[0633] ( / ?, / ?)-(-)-A / , / V-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(lll) chloride [( / ?, / ?)-Jacobsen’s catalyst; 154 mg, 0.242 mmol] and 4-methylmorpholine A / -oxide (1.67 g, 14.3 mmol) were added to a solution of 6-fluoro-1 / - / -indene (85%, 452 mg, 2.86 mmol) in dichloromethane (19.0 mL), whereupon the solution was cooled to -78 °C. Some of the solution of 3-chloroperoxybenzoic acid prepared above (0.45 M; 13 mL, 5.8 mmol) was added dropwise, in two roughly equal portions. After 4 hours at -78 °C, the reaction mixture was treated with a solution of dimethyl sulfide (1.00 mL, 13.6 mmol) in dichloromethane (5 mL). Aqueous sodium hydroxide solution (2 M; 20 mL) and pentane (30 mL) were then added, and the resulting mixture was warmed to room temperature. The organic layer was washed sequentially with aqueous sodium hydroxide solution (2 M; 20 mL), water (20 mL), and saturated aqueous sodium chloride solution (2 x 10 mL), dried over sodium sulfate, and concentrated at 650 mbar and 45 °C. Silica gel chromatography (Eluent: dichloromethane) provided C38 as a brown oil that subsequently solidified. Yield: 320 mg, 2.13 mmol, 74%.1H NMR (400 MHz, CDCl3) δ 7.44 (br dd, J = 8.2, 5.2 Hz, 1 H), 6.96 - 6.91 (m, 1 H), 6.91 - 6.84 (m, 1 H), 4.24 (ddd, J = 2.8, 1.3, 0.6 Hz, 1 H), 4.14 (br d, J = 2.9 Hz, 1 H), 3.20 (d, half of AB quartet, J= 18.2 Hz, 1H), 2.98 (brdd, component of ABX system, J = 18.2, 3.1 Hz, 1H).

[0634] Step 2. Synthesis of (1S,2S)-1-azido-5-fluoro-2,3-dihydro-1 / - / -inden-2-ol (C39).

[0635] A solution of C38 (320 mg, 2.13 mmol) in ethanol (6.0 mL) was treated with sodium azide (221 mg, 3.40 mmol), followed by ammonium chloride (177 mg, 3.31 mmol) and water (1.5 ml_). After the reaction mixture had been heated at reflux for 2.5 hours, it was cooled, diluted with water (10 ml_), and extracted with ethyl acetate (3 x 10 ml_). The combined organic layers were washed sequentially with water (10 ml_) and saturated aqueous sodium chloride solution (10 ml_), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: 20% ethyl acetate in heptane) afforded C39 as a black oil. Yield: 200 mg, 1.0 mmol, 45%.1H NMR (400 MHz, CDCl3) δ 7.32 (brdd, J= 8.3, 5.1, 1H), 7.02 -6.92 (m, 2H), 4.66 (br d, half of AB quartet, J = 4.7 Hz, 1 H), 4.52 (ddd, component of ABXY pattern, J = 6.7, 5.6, 4.7 Hz, 1H), 3.31 (brdd, J= 16.3, 6.7 Hz, 1H), 2.87 (dd, J= 16.3, 5.7 Hz, 1H).

[0636] Step 3. Synthesis of (1S,2S)-1-amino-5-fluoro-2,3-dihydro-1H-inden-2-ol (P7).

[0637] Ethanol (1 mL) was used to wet 10% palladium on carbon (60.1 mg, 56.5 pmol), whereupon the reaction vessel was flushed with nitrogen. A solution of C39 (586 mg, 3.03 mmol) in ethanol (14 mL) was added, a hydrogen balloon was installed, and the system was flushed with hydrogen three times before being sealed and stirred at room temperature for approximately 3 hours. The reaction mixture was then flushed with nitrogen and filtered through diatomaceous earth; the filter cake was washed with ethanol (2 x 10 mL), and the combined filtrates were concentrated in vacuo. The residue was suspended in methyl terf-butyl ether (10 mL), heated to reflux, and cooled to room temperature. Filtration afforded P7 as a gray solid. Yield: 272 mg, 1.63 mmol, 54%. LCMS m / z 168.0 [M+H]+.1H NMR (400 MHz, methanol-d4) 8 7.33 (brdd, J= 9.0, 5.3 Hz, 1 H), 6.96 - 6.89 (m, 2H), 4.11 (td, J = 7.0, 6.0 Hz, 1H), 4.01 (brd, J = 5.9 Hz, 1H), 3.21 (brdd, J= 15.9, 6.9 Hz, 1H), 2.74 (dd, J= 15.9, 7.1 Hz, 1H).

[0638] Reference Compound 1

[0639] 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 / - / -pyrrolo[3,4-b]pyridine-3-carboxylate (RC-1)

[0640]

[0641] Step 1. Synthesis of 4-[(7S)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4,5,6,7-tetrahydro-1 H-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (C9)

[0642] A mixture of ethyl (2Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (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-formylbenzoicacid (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 C9. The mixture was used directly in the next step. LCMS m / z 491.2 [M-H]’.

[0643] Step 2. 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 (C10)

[0644] 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 C10. 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 C10 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]+. Step 3. 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-5H-pyrrolo[3,4-b]pyridine-3-carboxylate (RC-1)

[0645] A mixture of 1-(2-Furyl)methanamine (35 mg, 33 pL, 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-5H-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 pL, 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: Sunfire C18 19x100mm 5um; 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 8.5min, 25.0% H2O / 75.0% Acetonitrile linear to 5.0% H2O / 95.0% Acetonitrile to 9.0min, HOLD at 5% H2O / 95% Acetonitrile to 10.0min; Flow: 25mL / 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) δ = 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, 1 H), 2.35 (tdd, J = 3.3, 6.8, 10.2 Hz, 1 H), 1.03 (d, J = 6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H), 0.65 (d, J = 6.7 Hz, 3H).

[0646] Reference Compound 2

[0647] 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-5H-pyrrolo[3,4-b]pyridine-3-carboxylate (RC-2)

[0648]

[0649] Step 1. Synthesis of 4-[(7R)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (C11)

[0650] 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-Formylbenzoicacid (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 C11. The mixture was used directly in the next step. LCMS m / z 491.3 [M-H]’.

[0651] Step 2. Synthesis of 4-[(7R)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (C12)

[0652] 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 C12. 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 C12 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]+. Step 3. 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-5H-pyrrolo[3,4-b]pyridine-3-carboxylate (RC-2)

[0653] A mixture of 1-(2-Furyl)methanamine (26.8 mg, 24.8 pL, 1.1 Eq, 276 pmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (52.9 mg, 1.1 Eq, 276 pmol), 4-[(7R)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl]benzoic acid (123 mg, 1.0 Eq, 251 pmol), and 2-hydroxypyridine 1-oxide (27.9 mg, 1 Eq, 251 pmol) was treated with dimethylformamide (2 mL) followed by triethylamine (76.1 mg, 105 pL, 3.0 Eq, 752 pmol), and the mixture stirred at room temperature for 17 hours until LCMS analysis indicated conversion to RC-2. 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 orange residue. Purification via reversed-phase HPLC (Column: Sunfire C18 19x100mm 5um; Gradient: 50.0% H2O / 50.0% Acetonitrile linear to 40.0% H2O / 60.0% Acetonitrile in 8.5min, 40.0% H20 / 60.0% Acetonitrile linear to 5.0% H2O / 95.0% Acetonitrile to 9.0min, HOLD at 5% H2O / 95% Acetonitrile to 10.0min; Flow: 25mL / 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) δ = 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, 1H), 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, 1H), 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).

[0654] EXAMPLES

[0655] Examples 1 and 2

[0656] Synthesis of ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3- yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate, ENT-1 (1) and ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl] carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate, ENT-2 (2)

[0657]

[0658] Step 1. Synthesis of 4-{3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-1,4,5,6,7,8-hexahydro-1,6-naphthyridin-4-yl}benzoic acid (C6).

[0659] A mixture of ethyl (Z)-3-amino-5-(4-fluorophenyl)pent-2-enoate (79 mg, 1 Eq, 0.33 mmol), 6-methylpiperidine-2, 4-dione (42 mg, 1 Eq, 0.33 mmol) and 4-formylbenzoic acid (50 mg, 1 Eq, 0.33 mmol) was dissolved in ethanol (1.7 mL). The resulting solution was treated with 21% sodium ethoxide (0.11 g, 0.12 mL, 1 Eq, 0.33 mmol) and stirred at 80 °C for 19 hours. LCMS analysis indicated conversion to C6. The resulting orange suspension was used directly in the next step. LCMS m / z 479.2 [M+H]+.

[0660] Step 2. Synthesis of 4-{3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-5, 6,7,8-tetrahydro-1,6-naphthyridin-4-yl}benzoic acid (07).

[0661] The previous reaction mixture was cooled to room temperature, treated with 2 mL of a 1:1 mixture of acetonitrile and methanol followed by cerium (IV) ammonium nitrate (180 mg, 1 eq, 0.33 mmol), and stirred at room temperature. After 5 hours, additional CAN (180 mg, 0.33 mmol) was added, and stirring was continued at room temperature for another 19 hours. LCMS analysis indicated conversion to C7. The resulting suspension was partitioned between water and ethyl acetate, filtered overcelite, and the layers were separated. The organic layer was washed once with saturated brine, dried over MgSO4, filtered, and concentrated to afford C7 as a yellow solid, which was used without further purification in the next step. Yield: 86 mg, 0.18 mmol, 54% over 2 steps. LCMS m / z 477.3 [M+H]+.

[0662] Step 3. Synthesis of ethyl 2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (C8). A mixture of 3-pyridinemethylamine (9.8 mg, 9.2 pL, 1 Eq, 90 pmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (19 mg, 1.1 Eq, 99 pmol), 2-hydroxypyridine 1-oxide (10 mg, 1 Eq, 90 pmol), and 4-{3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl}benzoic acid (43 mg, 1 Eq, 90 pmol) was treated with dimethylformamide (1 mL), followed by triethylamine (27 mg, 38 pL, 3.0 Eq, 0.27 mmol), and the mixture was stirred at room temperature. After 72 hours, an additional equivalent of EDCI, HOPO, TEA, and 3-pyridinemethylamine was added, and stirring was continued at room temperature for 2 hours, then at 60 °C for 2 hours. LCMS analysis indicated conversion to C8. The reaction mixture was diluted with ethyl acetate and washed once with saturated aqueous sodium bicarbonate and once with saturated brine. The organic portion was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification via reversed-phase HPLC (Column: Sunfire C18 19x100mm 5um; Mobile phase A: 0.05% TFA in water (v / v); Mobile phase B: 0.05% TFA in acetonitrile (v / v); Gradient: 90.0% H2O / 10.0% Acetonitrile linear to 50% H2O / 50% Acetonitrile in 8.5min, HOLD at 5% H20 / 95% Acetonitrile to 10.0 min; Flow: 25mL / min) afforded C8 as a white solid. Yield: 16.2 mg, 28.6 umol, 32%. LCMS m / z 567.3 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ = 9.15 (t, J = 5.8 Hz, 1H), 8.57 (s, 1H), 8.47 (d, J = 4.5 Hz, 1H), 8.02 (s, 1H), 7.90 - 7.79 (m, 2H), 7.74 (br d, J = 7.8 Hz, 1 H), 7.37 (dd, J = 4.7, 7.8 Hz, 1H), 7.24 (dd, J= 5.7, 8.3 Hz, 2H), 7.21 (br d, J= 8.2 Hz, 2H), 7.10 (t, J= 8.8 Hz, 2H), 4.52 (d, J = 6.0 Hz, 2H), 3.89 (q, J= 7.1 Hz, 2H), 3.85 - 3.78 (m, 1H), 3.20 - 3.15 (m, 1H), 3.05 - 2.96 (m, 4H), 2.91 (dd, J= 10.1, 16.3 Hz, 1H), 1.24 (d, J = 6.5 Hz, 3H), 0.82 (t, J= 7.1 Hz, 3H).

[0663] Step 4: Isolation of ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate, ENT-1 (1) and ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate, ENT-2 (2)

[0664] Separation of C8 (15.9 mg, 28.1 umol) into its component enantiomers was carried out via supercritical fluid chromatography (Column: Chiral Technologies ID 21x250mm; Mobile phase: 65.0% CO2 / 35.0% methanol isocratic over 10 min. Flow: 75ml / min; Back Pressure: 120 Bar). The first-eluting enantiomer was designated as ENT-1 (1) and the second-eluting enantiomer was designated as ENT-2 (2). Both were obtained as white solids.

[0665] ENT-1 (1) - Yield: 3.9 mg, 6.9 umol, 25%. Retention time: 2.15 minutes (Analytical conditions. Column: Chiral Technologies OD-H 4.6x100mm 5um; Mobile phase: 60.0% CO2 / 40.0% methanol isocratic over 5 min. Flow: 1.5ml / min; Back Pressure: 120 Bar).

[0666] ENT-2 (2) - Yield: 4.1 mg, 7 umol, 26%. Retention time: 3.25 minutes (Analytical conditions identical to those used for 1). Example 35

[0667] Synthesis of 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1- yl]thiophene-3-carboxamide (35)

[0668]

[0669]

[0670] Step 1. Synthesis of tert-butyl 2-[2-(4-fluorophenyl)ethyl]-4-[4-(methoxycarbonyl)thiophen-2-yl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepine-3-carboxylate (C15).

[0671] Ethanol (5.1 mL) was added to a mixture of P4 (270 mg, 1.02 mmol), 6,6-dimethylazepane-2, 4-dione (158 mg, 1.02 mmol), and methyl 5-formylthiophene-3-carboxylate (173 mg, 1.02 mmol). The reaction mixture was stirred at 85 °C overnight, whereupon it was cooled to room temperature and treated with a solution of ammonium cerium(IV) nitrate (1.12 g, 2.04 mmol) in a mixture of water and acetonitrile (1:1, 6 mL). After this reaction mixture had been stirred at room temperature for 4 hours, it was diluted with water (20 mL) and stirred for 5 minutes; the resulting mixture was extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: dichloromethane for 2 column volumes, followed by 0% to 10% methanol in chloroform) provided C15 as an off-white / light-orange solid. Yield: 362 mg, 0.655 mmol, 64%. LCMS m / z 553.4 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.59 (t, J = 6.5 Hz, 1H), 8.46 (d, J = 1.4 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H), 7.23 (dd, J = 8.5, 5.7 Hz, 2H), 7.09 (t, J = 8.9 Hz, 2H), 3.80 (s, 3H), 3.07 - 2.98 (m, 4H), 2.69 (d, J = 6.5 Hz, 2H), 2.65 (br s, 2H), 1.27 (s, 9H), 0.94 (v br s, 6H).

[0672] Step 2. Synthesis of 2-[2-(4-fluorophenyl)ethyl]-4-[4-(methoxycarbonyl)thiophen-2-yl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepine-3-carboxylic acid (C16).

[0673] A solution of hydrogen chloride in 1,4-dioxane (4.0 M; 0.34 mL, 1.4 mmol) was added to a solution of C15 (75 mg, 0.14 mmol) in acetonitrile (0.68 mL). After the reaction mixture had been stirred at 50 °C for 4 hours, LCMS analysis indicated conversion to C16: LCMS m / z 497.3 [M+H]+. Solvents were removed under a stream of nitrogen; the residue was dissolved in dichloromethane (1 mL) and concentrated in the same manner to afford C16 as a tan / brown solid. This material was progressed directly to the following step.1H NMR (400 MHz, DMSO-cfe) δ 8.62 (t, J = 6.4 Hz, 1H), 8.44 (d, J = 1.4 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 7.26 (dd, J = 8.6, 5.7 Hz, 2H), 7.09 (t, J = 8.9 Hz, 2H), 3.80 (s, 3H), 3.10-2.97 (m, 4H), 2.71 (d, J = 6.3 Hz, 2H), 2.65 (brs, 2H), 0.93 (v brs, 6H).

[0674] Step 3. Synthesis of methyl 5-{3-(2-acetylhydrazine-1-carbonyl)-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}thiophene-3-carboxylate (C17).

[0675] To a mixture of C16 (from the previous step; <0.14 mmol), acetohydrazide (13 mg, 0.18 mmol), and O-(7-azabenzotriazol-1-yl)- / V, / V, / V’, / V-tetramethyluronium hexafluorophosphate (HATU; 66 mg, 0.17 mmol) was added / V, / V-dimethylformamide (0.73 mL), followed by N, N-diisopropylethylamine (0.13 mL, 0.75 mmol). After the reaction mixture had been stirred at 40 °C for 7 hours, LCMS analysis indicated conversion to C17: LCMS m / z 553.3 [M+H]+. Water (5 mL) was added, and the resulting mixture was extracted with dichloromethane (2 x 3 mL); the combined organic layers were washed with saturated brine (3 mL) and concentrated under a stream of nitrogen, affording C17 as a brown oil. This material was used directly in the following step.

[0676] Step 4. Synthesis of methyl 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}thiophene-3-carboxylate (C18).

[0677] Acetonitrile (0.72 mL) and N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were added to a mixture of C17 (from the previous step; <0.14 mmol), 4-methylbenzene-1 -sulfonyl chloride (36 mg, 0.19 mmol), and 4-(dimethylamino)pyridine (2.7 mg, 22 pmol). The reaction was stirred overnight at 40 °C, whereupon LCMS analysis indicated conversion to C18: LCMS m / z 535.2 [M+H]+. After the reaction mixture had been diluted with dichloromethane (5 mL) and washed with water (5 mL), the aqueous layer was extracted with dichloromethane (2 mL). The combined organic layers were washed with saturated brine (3 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide C18 as a dark-brown oil. One-half of this material was progressed to the following step.

[0678] Step 5. Synthesis of 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}thiophene-3-carboxylic acid (C19).

[0679] To a vial charged with C18 (one-half of the material from the previous step; 37 mg, <70 pmol) was added potassium trimethylsilanolate (13 mg, 0.10 mmol), followed by tetrahydrofuran (0.69 mL). The reaction mixture was allowed to stir at 40 °C for 15 minutes, whereupon it was diluted with water (3 mL) and acidified by addition of hydrochloric acid (1 M; 0.20 mL). After the mixture had been extracted with dichloromethane (2 x 2 mL), the combined organic layers were dried over sodium sulfate, filtered, and condensed under a stream of nitrogen to afford C19 as a brown oil (27 mg). This material was progressed directly to the following step. LCMS m / z 521.4 [M+H]+. Step 6. Synthesis of 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide (35).

[0680] To a mixture of C19 (27 mg from the previous step; <52 pmol), (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (8.3 pL, 67 pmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (13 mg, 68 pmol), and 2-hydroxypyridine 1 -oxide (7.5 mg, 68 pmol) was added N,N-dimethylformamide (0.52 mL), followed by N,N-diisopropylethylamine (36 µL, 0.21 mmol). After the reaction mixture had been stirred at 60 °C for 25 minutes, it was purified via reversed-phase HPLC (Column: Waters XBridge C18, 19 x 100 mm, 5 pm; Mobile phase A: 0.03% ammonium hydroxide in water (v / v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v / v); Gradient: 35% to 55% B over 8.5 minutes, then 55% to 95% B over 0.5 minutes, then 95% B for 1.0 minute; Flow rate: 25 mL / min) to afford 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide (35). Yield: 4.8 mg, 7.4 pmol, 11% over 5 steps. LCMS m / z 652.3 [M+H]+.1H NMR (600 MHz, DMSO-d6), integrations are approximate: δ 8.66 (t, J = 6.5 Hz, 1H), 8.54 (d, J= 8.5 Hz, 1H), 8.19 (d, J = 1.5 Hz, 1 H), 7.25 (d, J = 1.5 Hz, 1 H), 7.19 - 7.12 (m, 3H), 7.06 (dd, J = 8.5, 5.7 Hz, 2H), 7.04 -6.98 (m, 3H), 5.34 (d, J = 5.8 Hz, 1H), 5.18 (dd, J= 7.7, 7.7 Hz, 1H), 4.36 - 4.28 (m, 1H), 3.11 (dd, J = 15.5, 7.3 Hz, 1H), 2.96-2.88 (m, 4H), 2.76-2.65 (m, 4H), 2.69 (dd, J = 15.3, 7.8 Hz, 1 H), 2.38 (s, 3H), 1.20 - 0.67 (m, 6H).

[0681] Example 36

[0682] Synthesis of 4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1- yl]benzamide (36)

[0683]

[0684] 2) (NH4)2Ce(NO3)6

[0685]

[0686] Step 1. Synthesis of terf-butyl 2-[2-(4-fluorophenyl)ethyl]-4-[4-(methoxycarbonyl)phenyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepine-3-carboxylate (C20).

[0687] Ethanol (18.8 ml_) was added to a mixture of P4 (1.00 g, 3.77 mmol), 6,6-dimethylazepane-2, 4-dione (585 mg, 3.77 mmol), and methyl 4-formylbenzoate (619 mg, 3.77 mmol), whereupon the reaction mixture was heated at 80 °C for 2 hours. After cooling to room temperature, it was treated with a solution of ammonium cerium(IV) nitrate (4.13 g, 7.53 mmol) in a mixture of water and acetonitrile (1:1, 18 ml_), and stirred at room temperature for an additional 2 hours. Water (40 mL) was added, and the resulting mixture was filtered; the filter cake was washed with water (2 x 20 mL) to afford C20 as a beige solid. Yield: 1.55 g, 2.84 mmol, 75%. LCMS m / z 547.5 [M+H]+. Step 2. Synthesis of 2-[2-(4-fluorophenyl)ethyl]-4-[4-(methoxycarbonyl)phenyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylic acid (C21).

[0688] To a solution of C20 (1.55 g, 2.84 mmol) in acetonitrile (14 ml_) was added a solution of hydrogen chloride in 1,4-dioxane (4.0 M; 7.09 mL, 28.4 mmol). The reaction mixture was stirred at 50 °C for two hours, then at 60 °C for 4.5 hours, whereupon it was concentrated in vacuo to provide C21 as a dark solid. This material was progressed directly to the following step. LCMS m / z 491.4 [M+H]+.

[0689] Step 3. Synthesis of methyl 4-{3-(2-acetylhydrazine-1-carbonyl)-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepin-4-yl}benzoate (C22).

[0690] To a mixture of C21 (from the previous step; <2.84 mmol), acetohydrazide (270 mg, 3.64 mmol), and O-(7-azabenzotriazol-1-yl)-A / , / V, A / ’, A / '-tetramethyluronium hexafluorophosphate (HATU; 1.40 g, 3.68 mmol) was added 1,2-dichloroethane (14.1 mL), followed by N,N-diisopropylethylamine (2.0 mL, 11 mmol). After the reaction mixture had been stirred at room temperature overnight, a scoop of acetohydrazide was added, and the reaction mixture was heated at 40 °C for 1.5 hours, then at 60 °C for 1.5 hours. The reaction mixture was again treated with a scoop of acetohydrazide, and heating was continued at 70 °C overnight. The reaction mixture was directly loaded onto a silica gel column and purified via chromatography (Gradient: dichloromethane for 2 CV, then 0% to 10% methanol in dichloromethane) to provide C22 as a dark oil. Yield: 1.15 g, 2.10 mmol, 74% over 2 steps. LCMS m / z 547.5 [M+H]+.

[0691] Step 4. Synthesis of methyl 4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}benzoate (C23).

[0692] A mixture of C22 (870 mg, 1.59 mmol) and methyl / V-(triethylammoniosulfonyl)carbamate, inner salt (Burgess reagent; 1.14 g, 4.78 mmol) was dissolved in 1,4-dioxane (15.9 mL). The reaction mixture was heated at 90 °C for 1 hour and 20 minutes, whereupon methyl / V-(triethylammoniosulfonyl)carbamate, inner salt (1.14 g, 4.78 mmol) was again added, and heating at 90 °C was continued overnight. Methyl N-(triethylammoniosulfonyl)carbamate, inner salt (1.14 g, 4.78 mmol) was added once more; after 2 hours and 25 minutes of further heating at 90 °C, the reaction mixture was concentrated in vacuo, diluted with water (30 mL) and allowed to stir for 5 minutes. Dichloromethane (30 mL) was added, and stirring was continued for 5 minutes, whereupon the aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, concentrated in vacuo, and combined with a similar reaction carried out using C22 (283 mg, 0.518 mmol). Silica gel chromatography (Gradient: dichloromethane for 2 column volumes, followed by 0% to 8% methanol in dichloromethane) provided material that was then swirled in acetonitrile (20 mL) for 1 minute and filtered; rinsing of the filter cake with acetonitrile (5 ml_) afforded C23 as a white solid. Concentration of the combined filtrates under reduced pressure afforded an oil, which was slurried in acetonitrile (2 ml_) for 3 minutes. Filtration and washing of this filter cake with acetonitrile (1 ml_) provided additional C23 as a white solid. Combined yield: 272 mg, 0.515 mmol, 24%. LCMS m / z 529.5 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.57 (t, J= 6.5 Hz, 1H), 7.84 (d, J= 8.2 Hz, 2H), 7.17 (brs, 2H), 7.10 (dd, J= 8.6, 5.7 Hz, 2H), 7.04 (t, J= 8.9 Hz, 2H), 3.84 (s, 3H), 3.04 - 2.98 (m, 2H), 2.98 - 2.93 (m, 2H), 2.79 (d, J = 6.4 Hz, 2H), 2.73 (s, 2H), 2.28 (s, 3H), 0.98 (v brs, 6H).

[0693] Step 5. Synthesis of 4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}benzoic acid (C24).

[0694] A mixture of C23 (318 mg, 0.602 mmol) and potassium trimethylsilanolate (116 mg, 0.904 mmol) was dissolved in tetrahydrofuran (6.0 mL). After the reaction mixture had been stirred at 40 °C for 10 minutes, the reaction temperature was lowered to 35 °C and stirring was continued overnight. A spatula tip of potassium trimethylsilanolate was added, and heating was continued for 1 hour, whereupon the reaction mixture was diluted with water (5 mL) and subsequently treated with hydrochloric acid (1 M; 1 mL). The mixture was allowed to stir for a few minutes before being filtered; the filter cake was washed with water (10 mL) to provide C24 as a white solid. The filtrate was extracted with dichloromethane (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide additional C24 as a white solid. Combined yield: 270 mg, 0.525 mmol, 87%. LCMS m / z 515.5 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 13.02 (s, 1H), 8.57 (t, J = 6.4 Hz, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.13 (brs, 2H), 7.10 (dd, J= 8.6, 5.7 Hz, 2H), 7.04 (t, J= 8.9 Hz, 2H), 3.03-2.98 (m, 2H), 2.98 - 2.93 (m, 2H), 2.79 (d, J = 6.4 Hz, 2H), 2.73 (br s, 2H), 2.28 (s, 3H), 0.98 (v br s, 6H).

[0695] Step 6. Synthesis of 4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide (36).

[0696] To a mixture of C24 (30 mg, 58 pmol), (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (9.6 mg, 64 pmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (12 mg, 63 pmol), and 2-hydroxypyridine 1-oxide (7.1 mg, 64 pmol) was added N,N-dimethylformamide (0.58 mL), followed by N,N-diisopropylethylamine (51 µL, 0.29 mmol). The reaction mixture was stirred at 60 °C for 10 minutes, then at room temperature overnight. Small scoops of (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 2-hydroxypyridine 1-oxide were added, and heating was continued at 60 °C for 25 minutes, whereupon the reaction mixture was directly purified using 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: 5% to 95% B over 8.54 minutes, followed by 95% B for 1.46 minutes; Flow rate: 25 mL / minute) to provide 4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / - / -inden-1-yl]benzamide (36). Yield: 26.3 mg, 40.7 pmol, 70%. LCMS m / z 646.5 [M+ H]+.1H NMR (600 MHz, DMSO-d6), characteristic peaks: δ 8.77 (d, J= 8.5 Hz, 1H), 8.54 (t, J = 6.5 Hz, 1H), 7.81 (d, J= 7.9 Hz, 2H), 7.22 - 7.19 (m, 2H), 7.18-7.14 (m, 1H), 7.13 -7.08 (m, 4H), 7.05 (t, J = 8.9 Hz, 2H), 5.28 (t, J = 7.7 Hz, 1 H), 4.42 (q, J = 7.5 Hz, 1 H), 3.16 (dd, J = 15.4, 7.3 Hz, 1 H), 3.02 - 2.93 (m, 4H), 2.80 (d, J = 6.2 Hz, 2H), 2.78 - 2.71 (m, 3H), 2.31 (s, 3H), 0.99 (v br s, 6H).

[0697] Example 37

[0698] Synthesis of 2-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo- 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / 7-inden-1- yl]-1,3-oxazole-4-carboxamide (37)

[0699]

[0700]

[0701] Step 1. Synthesis of terf-butyl 4-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepine-3-carboxylate (C25).

[0702] Ethanol (1.6 mL) was added to a mixture of P3 (75 mg, 0.32 mmol), 6,6-dimethylazepane-2, 4-dione (49 mg, 0.32 mmol), and ethyl 2-formyl-1,3-oxazole-4-carboxylate (53 mg, 0.31 mmol). After the reaction mixture had been stirred at 40 °C overnight, it was cooled to room temperature and treated with a solution of ammonium cerium(IV) nitrate (0.35 g, 0.64 mmol) in a mixture of water and acetonitrile (1:1, 2 mL). This reaction mixture was stirred at room temperature for 1.5 hours, whereupon LCMS analysis indicated conversion to C25: LCMS m / z 552.5 [M+H]+. Water (10 mL) was added, and the resulting mixture was extracted with dichloromethane (2 x 5 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford C25 as an orange solid. Yield: 128 mg, 0.232 mmol, 75%.

[0703] Step 2. Synthesis of 4-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepine-3-carboxylic acid (C26). To a solution of C25 (121 mg, 0.219 mmol) in acetonitrile (1.1 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4.0 M; 0.548 mL, 2.19 mmol). After the reaction mixture had been stirred at 60 °C for 1 hour and 10 minutes, LCMS analysis indicated conversion to C26: LCMS m / z 496.3 [M+H]+. Solvents were removed under a stream of nitrogen to afford C26 as a dark solid, which was progressed directly to the following step.

[0704] Step 3. Synthesis of ethyl 2-{3-(2-acetylhydrazine-1-carbonyl)-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepin-4-yl}-1,3-oxazole-4-carboxylate (C27).

[0705] A mixture of C26 (from the previous step; <0.219 mmol), acetohydrazide (19.6 mg, 0.264 mmol), and O-(7-azabenzotriazol-1-yl)- / V, / , A / ’, A / -tetramethyluronium hexafluorophosphate (HATU; 100 mg, 0.263 mmol) was treated with N,N-dimethylformamide (1.1 mL), followed by A / , A / -diisopropylethylamine (0.192 mL, 1.10 mmol). After the reaction mixture had been stirred at 40 °C for 1 hour and 45 minutes, it was allowed to sit at room temperature overnight. Volatiles were removed under a stream of nitrogen at 40 °C, and the residue was diluted with ethyl acetate (3 mL) and washed with water (2 x 5 mL). The combined aqueous layers were extracted with ethyl acetate (3 mL), and the combined organic layers were then washed with saturated brine (5 mL), dried over sodium sulfate, filtered, and concentrated, affording C27 as a brown oil / solid (102 mg). This material was taken directly to the following step. LCMS m / z 552.3 [M+H]+.

[0706] Step 4. Synthesis of ethyl 2-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}-1,3-oxazole-4-carboxylate (C28).

[0707] A mixture of C27 (102 mg, from the previous step; <0.185 mmol), 4-methylbenzene-1-sulfonyl chloride (45.8 mg, 0.240 mmol), and 4-(dimethylamino)pyridine (3.39 mg, 27.7 pmol) was dissolved in acetonitrile (1.85 mL) and treated with N,N-diisopropylethylamine (96.6 µL, 0.555 mmol). After the reaction mixture had been stirred for 5 hours at 40 °C, it was allowed to stir at room temperature overnight, whereupon it was diluted with water (5 mL) and extracted with dichloromethane (2 x 3 mL). The combined organic layers were washed with saturated brine (3 mL), dried over sodium sulfate, filtered, and concentrated under a stream of nitrogen to provide C28 as a brown solid (83 mg). This material was used in the following reaction. LCMS m / z 534.3 [M+H]+.

[0708] Step 5. Synthesis of 2-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepin-4-yl}-1,3-oxazole-4-carboxylic acid (C29).

[0709] A solution of lithium hydroxide (19 mg, 0.79 mmol) in water (0.21 mL) was added to a solution of C28 (83 mg, from the previous step; <0.16 mmol) in tetrahydrofuran (0.83 mL), whereupon the reaction mixture was allowed to stir at room temperature for 1 hour and 20 minutes. Water (3 ml_) was then added, and the resulting mixture was acidified by addition of hydrochloric acid (1.0 M; 0.60 ml_). After extraction with dichloromethane (3 x 3 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated under a stream of nitrogen to provide C29 as a brown solid (38 mg). This material was taken directly into the following step. LCMS m / z 506.4 [M+H]+.

[0710] Step 6. Synthesis of 2-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepin-4-yl}-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1 / - / -inden-1 -yl]-1,3-oxazole-4-carboxamide (37).

[0711] A mixture of C29 (38 mg, from the previous step; <75 pmol), (1S,2S)-1-amino-2,3-dihydro-1 / - / -inden-2-ol (11 pL, 89 pmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (17 mg, 89 pmol), and 2-hydroxypyridine 1 -oxide (10 mg, 90 pmol) was dissolved in N,N-dimethylformamide (0.50 mL) and treated with N,N-diisopropylethylamine (65 µL, 0.37 mmol). After the reaction mixture had been stirred at 60 °C for 1 hour and 10 minutes, it was directly subjected to purification via reversed-phase HPLC (Column: Waters XBridge C18, 19 x 100 mm, 5 pm; Mobile phase A: 0.03% ammonium hydroxide in water (v / v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v / v); Gradient: 35% to 55% B over 8.5 minutes, then 55% to 95% B over 0.5 minutes, then 95% B for 1.0 minute; Flow rate: 25 mL / min), affording 2-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}- / V-[(1S,2S)-2-hydroxy-2,3-dihydro-1 / - / -inden-1-yl]-1,3-oxazole-4-carboxamide (37). Yield: 5.4 mg, 8.5 pmol, 4% over 5 steps. LCMS m / z 637.3 [M+H]+.1H NMR (600 MHz, DMSO-d6), integrations are approximate: δ 8.83 (t, J= 6.3 Hz, 1H), 8.75 (s, 1H), 8.24 (d, J= 8.9 Hz, 1H), 7.24-7.17 (m, 3H), 7.11 (dd, J= 8.6, 5.7 Hz, 2H), 7.06-7.00 (m, 3H), 5.34 (d, J = 5.9 Hz, 1 H), 5.20 (dd, J = 7.8, 7.8 Hz, 1 H), 4.44 - 4.38 (m, 1 H), 3.20 -3.11 (m, 5H), 2.80-2.75 (m, 4H), 2.71 (dd, J= 15.5, 7.6 Hz, 1H), 2.38 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H).

[0712] Example 38

[0713] A / -[(1S,2S)-5-Fluoro-2-hydroxy-4-methoxy-2,3-dihydro-1 / - / -inden-1-yl]-5-{2-[2-(4- fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H- pyrido[3,2-c]azepin-4-yl}thiophene-3-carboxamide (38)

[0714]

[0715] To a solution of C19 (20 mg, 38 pmol), P5 (14 mg, 60 µmol), 1H-benzotriazol-1-ol (10.4 mg, 77.0 pmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (14.7 mg, 76.7 pmol) in N,N-dimethylacetamide (1 mL) was added N,N-diisopropylethylamine (20 mg, 0.15 mmol). After the reaction mixture had been stirred at 25 °C for 6 hours, it was added to water (4 mL) and extracted with ethyl acetate (3x 2 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (4 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to provide A / -[(1S,2S)-5-fluoro-2-hydroxy-4-methoxy-2,3-dihydro-1H-inden-1-yl]-5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}thiophene-3-carboxamide (38) as a white solid. Yield: 16.6 mg, 23.7 pmol, 62%. LCMS m / z 700.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 6.5 Hz, 1 H), 8.56 (d, J = 8.4 Hz, 1 H), 8.22 (d, J = 1.5 Hz, 1 H), 7.27 (d, J = 1.5 Hz, 1H), 7.14 - 7.01 (m, 5H), 6.78 (dd, J= 8.3, 4.2 Hz, 1H), 5.44 (d, J= 5.7 Hz, 1H), 5.15 (t, J = 7.5 Hz, 1 H), 4.42 - 4.30 (m, 1 H), 3.86 (d, J = 1.4 Hz, 3H), 3.24 (dd, J = 16.0, 7.2 Hz, 1 H), 2.96 (br s, 4H), 2.81 - 2.64 (m, 5H), 2.41 (s, 3H), 0.97 (br s, 6H).

[0716] Example 39

[0717] N-[(1S,2S)-5,7-Difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-{2-[2-(4-fluorophenyl)ethyl]-8,8- dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4- yl}thiophene-2-carboxamide (39)

[0718]

[0719]

[0720] Step 1. Synthesis of tert-buty I 2-[2-(4-fluorophenyl)ethyl]-4-[5-(methoxycarbonyl)thiophen-2-yl]- 8.8-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1 / 7-pyrido[3,2-c]azepine-3-carboxylate (C40).

[0721] A solution of P4 (16.2 g, 61.1 mmol), 6, 6-dimethylazepane-2, 4-dione (9.48 g, 61.1 mmol), and methyl 5-formylthiophene-2-carboxylate (10.4 g, 61.1 mmol) in ethanol (300 mL) was stirred at 85 °C for 16 hours. The reaction mixture, containing C40, was used directly in the following step. LCMS m / z 555.3 [M+H]+.

[0722] Step 2. Synthesis of tert-butyl 2-[2-(4-fluorophenyl)ethyl]-4-[5-(methoxycarbonyl)thiophen-2-yl]- 8.8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepine-3-carboxylate (C41).

[0723] To a 0 °C mixture of C40 (reaction mixture from the previous step; <61.1 mmol) in ethanol was added a solution of ammonium cerium(IV) nitrate (64.8 g, 118 mmol) in a mixture of acetonitrile (180 mL) and water (180 mL). The reaction mixture was stirred at 20 °C for 2 hours, diluted with water (500 mL), and extracted with dichloromethane (2 x 300 mL). 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 40% ethyl acetate in dichloromethane) provided material that was combined with the product of a similar reaction carried out using C40 derived from P4 (5.40 g, 20.4 mmol) and triturated from a mixture of ethyl acetate (20 mL) and petroleum ether (100 mL), affording C41 as an off-white solid. Combined yield: 26.3 g, 47.6 mmol, 58% over 2 steps. LCMS m / z 553.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.60 (t, J = 6.4 Hz, 1H), 7.76 (d, J = 3.8 Hz, 1 H), 7.23 (dd, J= 8.6, 5.7 Hz, 2H), 7.14 - 7.05 (m, 3H), 3.84 (s, 3H), 3.11 -2.97 (m, 4H), 2.70 (d, J = 6.4 Hz, 2H), 2.66 (brs, 2H), 1.27 (s, 9H), 0.94 (brs, 6H).

[0724] Step 3. Synthesis of 2-[2-(4-fluorophenyl)ethyl]-4-[5-(methoxycarbonyl)thiophen-2-yl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepine-3-carboxylic acid (C42).

[0725] A solution of hydrogen chloride in 1,4-dioxane (4 M; 13.6 mL, 54.4 mmol) was added to a 0 °C solution of C41 (6.00 g, 10.9 mmol) in acetonitrile (150 mL), whereupon the reaction mixture was stirred for 20 hours at 60 °C. Removal of solvents under reduced pressure provided a residue, which was partitioned between water (50 ml_) and dichloromethane (50 ml_). The aqueous layer was extracted with dichloromethane (2 x 50 ml_), and the combined organic layers were washed with saturated aqueous sodium chloride solution (50 ml_), dried over sodium sulfate, filtered, and concentrated in vacuo to afford C42 as an off-white solid. Yield: 4.90 g, 9.87 mmol, 91%. LCMS m / z 497.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.70 (br s, 1H), 8.62 (t, J = 6.4 Hz, 1 H), 7.76 (d, J = 3.9 Hz, 1 H), 7.26 (dd, J = 8.5, 5.7 Hz, 2H), 7.14 - 7.05 (m, 3H), 3.84 (s, 3H), 3.12 - 2.97 (m, 4H), 2.72 (d, J = 6.4 Hz, 2H), 2.65 (br s, 2H), 0.94 (brs, 6H).

[0726] Step 4. Synthesis of methyl 5-{3-(2-acetylhydrazine-1-carbonyl)-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}thiophene-2-carboxylate (C43).

[0727] To a mixture of C42 (4.40 g, 8.86 mmol), acetohydrazide (991 mg, 13.4 mmol), and 1-[bis(dimethylamino)methylene]-1 / 7-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 4.38 g, 11.5 mmol) in N,N-dimethylformamide (44 mL) was added N,N-diisopropylethylamine (4.01 g, 31.0 mmol). After the reaction mixture had been stirred at 40 °C for 16 hours, it was combined with a similar reaction carried out using C42 (500 mg, 1.01 mmol), diluted with water (100 mL), and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed sequentially with water (50 mL) and saturated aqueous sodium chloride solution (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo, providing C43 (5.50 g) as a gray solid, most of which was used for the next step. LCMS m / z 553.3 [M+H]+.

[0728] Step 5. Synthesis of methyl 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl}thiophene-2-carboxylate (C44).

[0729] / , / V-Diisopropylethylamine (6.08 g, 47.0 mmol) was added to a mixture of C43 (from the previous step; 5.20 g, <9.41 mmol), 4-methylbenzene-1 -sulfonyl chloride (2.33 g, 12.2 mmol), and 4-(dimethylamino)pyridine (172 mg, 1.41 mmol) in acetonitrile (52.0 mL), whereupon the reaction mixture was stirred at 40 °C for 3 hours. Water (100 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 x 200 mL); the combined organic layers were sequentially washed with aqueous potassium carbonate solution (5%, 3 x 50 mL), hydrochloric acid (0.5 M; 2 x 50 mL), and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 70% ethyl acetate in dichloromethane) was followed by trituration from ethyl acetate / petroleum ether (10 mL / 40 mL) to afford C44 as a light-yellow solid. Yield: 3.70 g, 6.92 mmol, 74% over 2 steps. LCMS m / z 535.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 6.4 Hz, 1H), 7.64 (d, J= 3.9 Hz, 1H), 7.11 (dd, component of ABX system, J= 8.6, 5.7 Hz, 2H), 7.04 (dd, component of ABX system, J = 8.9, 8.8 Hz, 2H), 6.90 (d, J= 3.9 Hz, 1H), 3.80 (s, 3H), 3.05 - 2.91 (m, 4H), 2.77 (d, J = 6.5 Hz, 2H), 2.74 (br s, 2H), 2.39 (s, 3H), 0.98 (br s, 6H).

[0730] Step 6. Synthesis of 5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}thiophene-2-carboxylic acid (C45).

[0731] To a solution of C44 (3.58 g, 6.70 mmol) in a mixture of tetrahydrofuran (45 mL) and water (45 mL) was added lithium hydroxide (481 mg, 20.1 mmol), and the reaction mixture was stirred at 20 °C for 12 hours. It was then combined with a similar reaction carried out using C44 (150 mg, 0.281 mmol), acidified to pH 3 by addition of 1 M hydrochloric acid, and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo, providing C45 as an off-white solid. Combined yield: 3.50 g, 6.72 mmol, 96%. LCMS m / z 521.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.69 (t, J = 6.4 Hz, 1H), 7.53 (d, J= 3.8 Hz, 1H), 7.11 (dd, component of ABX system, J= 8.7, 5.8 Hz, 2H), 7.05 (dd, component of ABX system, J = 9.0, 8.8 Hz, 2H), 6.86 (d, J = 3.8 Hz, 1 H), 3.03 - 2.91 (m, 4H), 2.77 (d, J = 6.5 Hz, 2H), 2.73 (br s, 2H), 2.39 (s, 3H), 0.97 (br s, 6H).

[0732] Step 7. Synthesis of / V-[(1S,2S)-5,7-difluoro-2-hydroxy-2,3-dihydro-1 / 7-inden-1-yl]-5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepin-4-yl}thiophene-2-carboxamide (39).

[0733] A / , / V-Diisopropylethylamine (25 pL, 0.14 mmol), 1-[bis(dimethylamino)methylene]-1 / 7- 1.2.3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 24 mg, 63 pmol), and P6 (12 mg, 65 pmol) were added to a solution of C45 (25 mg, 48 pmol) in N, N-dimethylformamide (0.22 mL). After the reaction mixture had been stirred at room temperature for 2 hours, it was treated with saturated aqueous sodium bicarbonate solution and diluted with water; the aqueous layer was then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and azeotroped with heptane to provide an off-white solid. This material was 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: 30% to 70% B over 8.5 minutes, then 70% to 95% B over 0.5 minutes, then 95% B for 1.0 minute; Flow rate: 25 mL / min) to afford / V-[(1S,2S)-5,7-difluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl- 1.3.4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}thiophene-2-carboxamide (39). Yield: 28 mg, 41 pmol, 85%. LCMS m / z 688.3 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.78 (d, J = 8.5 Hz, 1H), 8.68 (t, J= 6.5 Hz, 1H), 7.57 (d, J= 3.9 Hz, 1H), 7.11 (dd, component of ABX system, J = 8.6, 5.7 Hz, 2H), 7.05 (dd, component of ABX system, J = 9.0, 8.8 Hz, 2H), 7.03 - 6.98 (m, 2H), 6.81 (d, J = 3.9 Hz, 1 H), 5.48 (d, J = 5.0 Hz, 1 H), 5.26 (dd, J = 8.6, 4.3 Hz, 1 H), 4.37 - 4.31 (m, 1 H), 3.27 (dd, J = 16.4, 6.4 Hz, 1 H), 2.98 - 2.93 (m, 4H), 2.77 (d, J = 6.4 Hz, 2H), 2.76 - 2.69 (m, 3H), 2.41 (s, 3H), 1.21 - 0.74 (m, 6H).

[0734] Example 40

[0735] 5-(3-{5-[(Dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden- 1-yl]thiophene-3-carboxamide (40)

[0736]

[0737] Step 1. Synthesis of methyl 5-(3-{2-[(dimethylamino)acetyl]hydrazine-1-carbonyl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)thiophene-3-carboxylate (C46). To a solution of C16 (870 mg, 1.75 mmol) in / V, / V-dimethylformamide (9 ml_) were added 2-(dimethylamino)acetohydrazide, dihydrochloride salt (533 mg, 2.80 mmol), 1-[bis(dimethylamino)methylene]-1 / - / -1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 866 mg, 2.28 mmol), and A / , / V-diisopropylethylamine (1.52 ml_, 8.73 mmol), whereupon the reaction mixture was stirred at 40 °C for 16 hours. It was then added to water (100 mL) and extracted with ethyl acetate (2 x 100 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo, providing C46 as an off-white solid. This material was progressed directly to the next step. LCMS m / z 596.3 [M+H]+.

[0738] Step 2. Synthesis of methyl 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)thiophene- 3-carboxylate (C47).

[0739] A / , / V-Diisopropylethylamine (1.50 mL, 8.61 mmol) was added to a mixture of C46 (from the previous step; <1.75 mmol), 4-methylbenzene-1 -sulfonyl chloride (425 mg, 2.23 mmol), and 4-(dimethylamino)pyridine (34.0 mg, 0.278 mmol) in acetonitrile (9.5 mL). After the reaction mixture had been stirred at 40 °C for 2 hours, it was diluted with water (100 mL) and the resulting mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo, whereupon silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) afforded C47 as a light-yellow solid. Yield: 843 mg, 1.46 mmol, 83% over 2 steps. LCMS m / z 578.3 [M+H]+.1H NMR (400 MHz, DMSO-d6), integrations are approximate: δ 8.69 (t, J = 6 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1 H), 7.14 (d, J = 1.5 Hz, 1 H), 7.13 - 7.01 (m, 4H), 3.75 (s, 3H), 3.67 (s, 2H), 3.01 - 2.91 (m, 4H), 2.78 (d, J = 6.5 Hz, 2H), 2.73 (br s, 2H), 1.98 (s, 6H), 0.98 (brs, 6H).

[0740] Step 3. Synthesis of 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)thiophene-3-carboxylic acid (C48).

[0741] To a solution of C47 (843 mg, 1.46 mmol) in tetrahydrofuran (8.5 mL) was added a solution of lithium hydroxide (105 mg, 4.38 mmol) in water (8.5 mL). After the reaction mixture had been stirred at 20 °C for 1 hour, it was adjusted to pH 3 by addition of 1 M hydrochloric acid. The resulting mixture was concentrated under reduced pressure and subsequently freeze-dried, providing C48 as a yellow solid (1.05 g). A portion of this material was progressed to the following step. LCMS m / z 564.2 [M+H]+.

[0742] Step 4. Synthesis of 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)-A / -[(1 S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide (40). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (357 mg, 1.86 mmol), 1H-benzotriazol-1-ol (252 mg, 1.86 mmol), and (1S,2S)-1-amino-2,3-dihydro-1 / - / -inden-2-ol (278 mg, 1.86 mmol) were added to a solution of C48 (from the previous step; 525 mg, <0.730 mmol) in A / , / \ / -dimethylformamide (9 mb), whereupon the reaction mixture was stirred for 1 hour at 20 °C. Water (50 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 x 50 mL); the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) was followed by reversed-phase HPLC (Column: C18; Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 0% to 60% B; Flow rate: 40 mL / minute), to afford 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepin-4-yl)- / V-[(1S,2S)-2-hydroxy-2,3-dihydro-1 H-inden-1-yl]thiophene-3-carboxamide (40) as a white solid. Yield: 227 mg, 0.327 mmol, 45% over 2 steps. LCMS m / z 695.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 6.5 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.23 (d, J= 1.4 Hz, 1H), 7.29 (d, J= 1.5 Hz, 1H), 7.23 -7.14 (m, 3H), 7.10 (dd, component of ABX system, J = 8.7, 5.8 Hz, 2H), 7.07 - 7.01 (m, 3H), 5.33 (brd, J= 5.7 Hz, 1H), 5.20 (t, J = 7.6 Hz, 1H), 4.41 -4.30 (m, 1H), 3.69 (s, 2H), 3.15 (dd, J = 15.5, 7.3 Hz, 1 H), 3.02 - 2.90 (m, 4H), 2.83 - 2.67 (m, 5H), 2.01 (s, 6H), 0.97 (br s, 6H).

[0743] Example 41

[0744] 5-(3-{5-[(Dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)-A / -[(1 S,2S)-2-hydroxy-2,3-dihydro-1H-inden- 1 -yl]thiophene-2-carboxam ide (41 )

[0745]

[0746]

[0747] Step 1. Synthesis of methyl 5-(3-{2-[(dimethylamino)acetyl]hydrazine-1-carbonyl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)thiophene-2-carboxylate (C49).

[0748] A / , / V-Diisopropylethylamine (1.21 g, 9.36 mmol) was added to a solution of C42 (776 mg, 1.56 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU; 891 mg, 2.34 mmol) in / V, / V-dimethylformamide (10 ml_), whereupon the reaction mixture was stirred at 25 °C for 30 minutes. 2-(Dimethylamino)acetohydrazide, dihydrochloride salt (366 mg, 3.12 mmol) was then added, and the reaction mixture was heated at 40 °C for 16 hours before being diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with a mixture of dichloromethane and methanol (10:1, 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. Purification via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) provided C49 as a yellow solid, which was progressed directly to the following step. LCMS m / z 596.2 [M+ H]+. Step 2. Synthesis of methyl 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)thiophene-2-carboxylate (C50).

[0749] To a 0 °C solution of C49 (from the previous step; <1.56 mmol), N, N-diisopropylethylamine (1.39 g, 10.7 mmol), and 4-(dimethylamino)pyridine (61.4 mg, 0.503 mmol) in acetonitrile (22 mL) was added 4-methylbenzene-1 -sulfonyl chloride (533 mg, 2.80 mmol). The reaction mixture was heated at 40 °C for 16 hours, whereupon it was concentrated to dryness under reduced pressure, diluted with saturated aqueous sodium carbonate solution (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, concentrated in vacuo, and purified via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane), affording C50 as a yellow solid. Yield: 747 mg, 1.29 mmol, 83% over 2 steps. LCMS m / z 578.2 [M+H]+.

[0750] Step 3. Synthesis of 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)thiophene-2-carboxylic acid (C51).

[0751] An aqueous solution of lithium hydroxide (2 M; 6 mL) was added to a 0 °C solution of C50 (747 mg, 1.29 mmol) in tetrahydrofuran (10 mL). After the reaction mixture had been stirred at 25 °C for 4 hours, it was concentrated in vacuo to remove most of the solvent, then acidified to pH 3 to 4 by addition of 2 M hydrochloric acid. Collection of the resulting precipitate via filtration provided C51 as a yellow solid. Yield: 400 mg, 0.710 mmol, 55%. LCMS m / z 564.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 8 13.20 (v brs, 1H), 8.71 (t, J= 6.4 Hz, 1H), 7.54 (d, J = 3.8 Hz, 1H), 7.12 (dd, component of ABX system, J = 8.6, 5.8 Hz, 2H), 7.05 (dd, component of ABX system, J = 8.9, 8.9 Hz, 2H), 6.92 (d, J = 3.8 Hz, 1 H), 3.88 (br s, 2H), 3.05 - 2.89 (m, 4H), 2.78 (d, J = 6.5 Hz, 2H), 2.74 (br s, 2H), 2.14 (br s, 6H), 0.97 (br s, 6H).

[0752] Step 4. Synthesis of 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl)-A / -[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-2-carboxamide (41).

[0753] To a solution of C51 (400 mg, 0.710 mmol), 1H-benzotriazol-1-ol (192 mg, 1.42 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (272 mg, 1.42 mmol) in N, N-dimethylformamide (6 mL) was added (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (159 mg, 1.06 mmol). The reaction mixture was stirred at 25 °C for 1.5 hours, whereupon it was purified using reversed-phase HPLC (Column: Welch Ultisil AQ-C18, 21.2 x 250 mm, 10 pm; Mobile phase A: water containing 0.1% ammonia; Mobile phase B: acetonitrile; Gradient: 40% to 95% B; Flow rate: 25 mL / minute), affording 5-(3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-6,7,8,9-tetrahydro-5 / - / -pyrido[3,2-c]azepin-4-yl)- / \ / - [(1 S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-2-carboxamide (41) as a white solid. Yield: 288 mg, 0.414 mmol, 58%. LCMS m / z 695.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 8.6 Hz, 1H), 8.70 (t, J = 6.5 Hz, 1H), 7.66 (d, J = 3.9 Hz, 1H), 7.24 -7.15 (m, 3H), 7.10 (dd, component of ABX system, J = 8.7, 5.8 Hz, 2H), 7.08 -7.01 (m, 3H), 6.86 (d, J= 3.8 Hz, 1H), 5.37 (d, J= 5.8 Hz, 1H), 5.20 (t, J = 7.7 Hz, 1H), 4.41 -4.31 (m, 1H), 3.70 (s, 2H), 3.15 (dd, J= 15.5, 7.3 Hz, 1H), 3.01 -2.91 (m, 4H), 2.83-2.69 (m, 5H), 2.03 (s, 6H), 0.98 (s, 6H).

[0754] Example 42

[0755] A / -[(1S,2S)-5-Fluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-{2-[2-(4-fluorophenyl)ethyl]-8,8- dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4- yl}thiophene-3-carboxamide (42)

[0756]

[0757] To a mixture of C19 (10 mg, 19 pmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI; 4.1 mg, 21 pmol), and 2-hydroxypyridine 1-oxide (2.3 mg, 21 pmol) were added acetonitrile (0.19 mL) and 4-methylmorpholine (5.8 mg, 57 pmol), followed by P7 (3.2 mg, 19 pmol). The reaction mixture was stirred at room temperature for 3 days, whereupon the solvent was evaporated under a stream of nitrogen. 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; Flow rate: 25 mL / min) provided A / -[(1S,2S)-5-fluoro-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}thiophene-3-carboxamide (42). Yield: 9.7 mg, 14 pmol, 74%. LCMS m / z 670.4 [M+H]+.1H NMR (600 MHz, DMSO-d6) δ 8.70 (t, J = 6.5 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1 H), 7.28 (d, J = 1.5 Hz, 1H), 7.13 - 7.08 (m, 3H), 7.08 -7.02 (m, 3H), 7.01 - 6.96 (m, 1H), 5.45-5.38 (m, 1H), 5.15 (t, J= 7.5 Hz, 1H), 4.42 -4.32 (m, 1H), 3.17 (dd, J= 15.9, 7.2 Hz, 1H), 3.01 -2.92 (m, 4H), 2.81 - 2.68 (m, 5H), 2.41 (s, 3H), 1.24 - 0.71 (br m, 6H). The compounds in Table 1 are or may be prepared using general methods according / analogous to the methods described in Schemes 1 to 6 and Examples 1, 2, and 35 -42, including modification as appropriate. Additional methods of preparation are outlined in Synthesis Methods A - N below.

[0758] Synthesis Method A (amidation of C19 intermediate)

[0759]

[0760] Synthesis Method B

[0761]

[0762] 2. (NH4)2Ce(NO3)6

[0763] 3. HCl

[0764]

[0765]

[0766] Synthesis Method D

[0767]

[0768]

[0769] 2. R8OH, Ph3P, DIAD, THF

[0770]

[0771] Synthesis Method E

[0772]

[0773] 3. HCl

[0774] 4,

[0775]

[0776] . c,23, DMSO 2. R8OH, Ph3P, DIAD, THF

[0777]

[0778] Prepared analogously to C16

[0779]

[0780] Prepared analogously to C15

[0781]

[0782]

[0783] Prepared analogously to C16

[0784]

[0785] or

[0786] other metal-mediated couplings

[0787]

[0788]

[0789] Synthesis Method K

[0790]

[0791]

[0792]

[0793]

[0794] 2. (NH4)2Ce(NO3)6

[0795] 3. HCl

[0796]

[0797] Table 1. Method of synthesis, structure, and physicochemical data for Examples 3 – 34 and 43 – 151.

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870] 1. The penultimate carboxylic acid intermediate in method I was converted to a tert-butyl ester, whereupon the resulting intermediate was alkylated on the lactam nitrogen by reaction with (2-bromoethoxy)(tert-butyl)di(methyl)silane. The silyl protecting group and the tert-butyl group were removed upon treatment with acid, and the resulting carboxylic acid was converted to the required amide.

[0871] 2. A mixture of Examples 31 and 107 was separated into its component enantiomers using supercritical fluid chromatography [Column: Regis Technologies, Pirkle Covalent (R, R) Whelk-01, 21.1 x250 mm, 5 pm; Mobile phase: 65:35 carbon dioxide / (methanol containing 0.2% ammonium hydroxide); Flow rate: 75 mL / minute; Back pressure: 120 bar]. The first-eluting enantiomer was designated as Example 107, and the second-eluting enantiomer was designated as Example 31. 3. Although a mixture of stereoisomers of Example 43 at the methyl group was subjected to 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: 20% to 60% B; Flow rate: 25 mL / min), predominantly one isomer was isolated, which was designated as Example 43.

[0872] 4. A mixture of Examples 45 and 46 was separated into its component enantiomers using supercritical fluid chromatography [Column: Chiral Technologies Chiralpak IH, 21 x250 mm, 5 pm; Mobile phase: 85:15 carbon dioxide / (methanol containing 0.2% ammonium hydroxide); Flow rate: 75 mL / minute; Back pressure: 120 bar]. The first-eluting enantiomer was designated as Example 45, and the second-eluting enantiomer was designated as Example 46.

[0873] 5. Reaction of ethyl 3-bromo-5-fluoropyridine-4-carboxylate with ethyl (2E)-3-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate in the presence of [1, T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) and potassium fluoride, followed by hydrogenation of the olefin over platinum(IV) oxide, provided ethyl 3-(3-ethoxy-3-oxopropyl)-5-fluoropyridine-4-carboxylate. After cyclization of this material via treatment with sodium methoxide in methanol, the product was treated with hydrochloric acid at elevated temperature to afford 4-fluoro-6,7-dihydro-5 / - / -cyclopenta[c]pyridin-5-one. Subsequent reduction with RuCI[(S, S)-TsDPEN(mesitylene)], formic acid, and triethylamine provided (5S)-4-fluoro-6,7-dihydro-5H-cyclopenta[c]pyridin-5-ol, which was converted to (5F?)-5-azido-4-fluoro-6,7-dihydro-5H-cyclopenta[c]pyridine by reaction with diphenyl phosphorazidate and 1,8-diazabicyclo[5.4.0]undec-7-ene. Hydrogenation over palladium on carbon provided the requisite (5F?)-4-fluoro-6,7-dihydro-5 / - / -cyclopenta[c]pyridin-5-amine.

[0874] 6. A mixture of Examples 98 and 99 was separated into its component enantiomers using supercritical fluid chromatography {Column: Chiral Technologies Chiralcel OD, 30x250 mm, 10 pm; Mobile phase: 4:1 carbon dioxide / [methanol containing 0.2% (7 M ammonia in methanol)]; Flow rate: 80 g / minute}. The first-eluting enantiomer was designated as Example 98, and the second-eluting enantiomer was designated as Example 99. The two Examples were then individually purified via reversed-phase HPLC (Column: Welch Xtimate C18, 21.2 x250 mm, 10 pm; Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 35% to 60% B; Flow rate: 25 mL / minute).

[0875] 7. A mixture of Examples 110 and 111 was separated into its component enantiomers using supercritical fluid chromatography {Column: Chiral Technologies Chiralcel OD, 30x250 mm, 10 pm; Mobile phase: 7:3 carbon dioxide / [methanol containing 0.2% (7 M ammonia in methanol)]; Flow rate: 120 g / minute}. The first-eluting enantiomer was designated as Example 110, and the second-eluting enantiomer was designated as Example 111.

[0876] 8. A mixture of Examples 113 and 114 was separated into its component enantiomers using supercritical fluid chromatography {Column: Chiral Technologies Chiralpak IB-N, 30 x 250 mm, 10 pm; Mobile phase: 7:3 carbon dioxide / [methanol containing 0.2% (7 M ammonia in methanol)]; Flow rate: 80 g / minute}. The first-eluting enantiomer was designated as Example 113, and the second-eluting enantiomer was designated as Example 114.

[0877] 9. Reaction of 6-fluoro-2H-1 -benzopyran with A / -bromosuccinimide in a mixture of water and tetrahydrofuran provided frans-3-bromo-6-fluoro-3,4-dihydro-2 / - / -1-benzopyran-4-ol, which was condensed with (2R)-2-phenylpropanoic acid in the presence of 1,3-dicyclohexylcarbodiimide and 4-(dimethylamino)pyridine. The resulting mixture of (3R,4R)-3-bromo-6-fluoro-3,4-dihydro-2 / - / -1-benzopyran-4-yl (2R)-2-phenylpropanoate and (3S,4S)-3-bromo-6-fluoro-3,4-dihydro-2H-1-benzopyran-4-yl (2 / ?)-2-phenylpropanoate was separated using silica gel chromatography (Gradient: 0% to 4% methyl tert-butyl ether in petroleum ether). The first-eluting diastereomer was reacted with sodium methoxide in methyl tert-butyl ether to afford the corresponding epoxide, which was reacted at elevated temperature with ammonia in 1,4-dioxane to provide the requisite homochiral frans-4-amino-6-fluoro-3,4-dihydro-2 / 7-1-benzopyran-3-ol. This material had an optical rotation of +29 (c 0.2, MeOH).

[0878] 10. A mixture of Examples 128 and 129 was separated into its component enantiomers using supercritical fluid chromatography [Column: Regis Technologies, Pirkle Covalent (R, R) Whelk-01, 21.1 x250 mm, 5 pm; Mobile phase: 3:1 carbon dioxide / (methanol containing 0.2% ammonium hydroxide); Flow rate: 75 mL / minute; Back pressure: 120 bar]. The first-eluting enantiomer was designated as Example 128, and the second-eluting enantiomer was designated as Example 129.

[0879] 11. A mixture of Examples 138 and 139 was separated into its component enantiomers using supercritical fluid chromatography {Column: Chiral Technologies Chiralpak IB, 30 x 250 mm, 10 pm; Mobile phase: 7:3 carbon dioxide / [methanol containing 0.2% (7 M ammonia in methanol)]; Flow rate: 80 g / minute}. The first-eluting enantiomer was designated as Example 138, and the second-eluting enantiomer was designated as Example 139.

[0880] 12. Starting material 3-[(4-methoxyphenyl)methyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde was prepared by reaction of 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde with 1-(chloromethyl)-4-methoxybenzene and potassium carbonate. As this installed the required substitution on the 1,3-benzoxazol-2(3H)-one, no further chemistry was needed at this position.

[0881] 13. After the iridium chemistry outlined in Synthesis Method L, the resulting material was deprotected with trifluoroacetic acid, followed by treatment with lithium iodide, providing 2-(3-amino-2,2-dimethylpropyl)-6-[2-(4-fluorophenyl)ethyl]-4-{3-[(4-methoxyphenyl)methyl]-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl}-5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine-3-carboxylic acid. Cyclization of this material using 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) and 1-methyl-1 / 7-imidazole afforded Example 151. The metabolite profile of the compounds of the invention can be evaluated in liver microsomes and hepatocytes (mouse, rat, rabbit, dog, monkey, and human), recombinant human cytochrome P450 enzymes, recombinant human UGT enzymes, and plasma from animals (mouse, rat, and dog).

[0882] General methods / reviews of obtaining metabolite profile and identifying metabolites of a compound are described in: Dalvie, et al., “Assessment of Three Human in Vitro Systems in the Generation of Major Human Excretory and Circulating Metabolites,” Chemical Research in Toxicology, 2009, 22, 2, 357-368, tx8004357 (acs.org); King, R., “Biotransformations in Drug Metabolism,” Ch.3, Drug Metabolism Handbook Introduction, https: / / doi.org / 10.1002 / 9781119851042.ch3; Wu, Y., etal, “Metabolite Identification in the Preclinical and Clinical Phase of Drug Development,” Current Drug Metabolish, 2021, 22, 11, 838-857, 10.2174 / 1389200222666211006104502; Godzien, J., etal, “Chapter Fifteen -Metabolite Annotation and Identification”.

[0883] Numerous publicly available and commercially available software tools are available to aid in the predictions of metabolic pathways and metabolites of compounds. Examples of such tools include, BioTransformer 3.0 (biotransformer.ca / new) which predicts the metabolic biotransformations of small molecules using a database of known metabolic reactions; MetaSite (moldiscovery.com / software / metasite / ) which predicts metabolic transformations related to cytochrome P450 and flavin-containing monooxygenase mediated reactions in phase I metabolism; and Lhasa Meteor Nexus (lhasalimited.org / products / meteor-nexus.htm) offers prediction of metabolic pathways and metabolite structures using a range of machine learning models, which covers phase I and phase II biotransformations of small molecules.

[0884] Calcitonin Receptor Assay 1

[0885] Calcitonin mediated agonist activity was determined by monitoring intracellular cyclic adenosine monophosphate (cAMP) levels in a cell-based functional assay utilizing an HTRF (Homogeneous Time-Resolved Fluorescence) cAMP detection kit (cAMP Dynamic Range Assay Kit; Revvity cat # 62AM4PEC) that measures cAMP levels in the cell. The method is a competitive immunoassay between native cAMP produced by the cells and cAMP labelled with the acceptor dye, d2. The two entities compete for binding to a monoclonal anti-cAMP antibody labeled with cryptate. The specific signal is inversely proportional to the concentration of cAMP in the cells.

[0886] Test compounds were solubilized to a concentration of 30 mM in 100% dimethyl sulfoxide (DMSO). An 11 -point dilution series using 1 in 3.162-fold serial dilutions was created in 100% DMSO with a top concentration of 6 mM. The serially diluted compound was spotted with an Echo Acoustic liquid handler (Beckman Coulter) into a 384-well assay plate (Corning Cat # 3570) at 50 nL / well with duplicate points at each concentration, at a 200x final assay concentration (FAC). The final compound concentration range in the assay was 30 pM to 300 pM, with a final DMSO concentration of 0.5%.

[0887] Frozen assay ready vials of CHO-TREx mCALCR-K01 hCALCR WT Cl B3 +Dox at 5E6 cel Is / vial were thawed, counted, and resuspended in assay buffer consisting of Hank’s Balanced Salt Solution (HBSS, Lonza Cat # 10-527) containing 20 mM (4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid (HEPES, Lonza Cat # 17-737E), 0.1% bovine serum albumin (BSA, Sigma Cat # A7979), and 250 pM 3-isobutyl-1-methylxanthine (IBMX, Sigma Cat # I5879) at a density of 2K cells / well. Cells were added to assay plate (10 pL / well for 2,000 cells / well final) containing the 20 nL of 200x FAC test compound and incubated at 37°C (95% 02: 5% CO2) for 30 minutes, with micro-clime lids (Labcyte, Cat No. LLS-0310). Following the 30-minute cell and compound incubation, intracellular cAMP levels were quantified as per Revvity’s protocol (5 pL of d2 and then 5 pL cryptate, incubated for 1 hour at room temperature). Emission spectra of samples were measured on a Pherastar plate reader (BMG Labtech Inc) using a HTRF protocol (excitation 320 nm; emission 665 nm and 620 nm). Data were analyzed using the ratio of fluorescence intensity at 620 and 665 nm for each well, extrapolated from the cAMP standard curve to express data as nanomolar (nM) cAMP for each well. Data expressed as nM cAMP were then normalized to control wells using ActivityBase (IDBS data management software). Zero percent effect (ZPE) was defined as nM cAMP generated from vehicle control (0.5% DMSO), while 100% effect, or one hundred percent effect (HPE), was defined as nM cAMP generated from stimulation with 10 uM 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 / - / -pyrrolo[3,4-b]pyridine-3-carboxylate (Compound RC-1). The concentration and % effect values for each compound were plotted by ActivityBase using a four-parameter logistic dose response equation, and the concentration required for 50% effect (EC50) was determined.

[0888] Calcitonin Receptor Assay 2

[0889] Calcitonin mediated agonist activity was determined by monitoring intracellular cyclic adenosine monophosphate (cAMP) levels in a cell-based functional assay utilizing an HTRF (Homogeneous Time-Resolved Fluorescence) cAMP detection kit (cAMP Dynamic Range Assay Kit; Revvity cat # 62AM4PEC) that measures cAMP levels in the cell. The method is a competitive immunoassay between native cAMP produced by the cells and cAMP labelled with the acceptor dye, d2. The two entities compete for binding to a monoclonal anti-cAMP antibody labeled with cryptate. The specific signal is inversely proportional to the concentration of cAMP in the cells.

[0890] Test compounds were solubilized to a concentration of 30 mM in 100% dimethyl sulfoxide (DMSO). An 11 -point dilution series using 1 in 3.162-fold serial dilutions was created in 100% DMSO with a top concentration of 6 mM. The serially diluted compound was spotted with an Echo Acoustic liquid handler (Beckman Coulter) into a 384-well assay plate (Corning Cat # 3570) at 50 nL / well with duplicate points at each concentration, at a 200x final assay concentration (FAC). The final compound concentration range in the assay was 30 pM to 300 pM, with a final DMSO concentration of 0.5%.

[0891] Assay ready vials of doxycycline induced CHO-Trex mCALCR KO1 hCALCR WT B3 frozen at 1E7 cells / vial were thawed, counted, and resuspended in assay buffer consisting of Hank’s Balanced Salt Solution (HBSS, Lonza Cat # 10-527) containing 20 mM (4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid (HEPES, Lonza Cat # 17-737E), 0.1% bovine serum albumin (BSA, Sigma Cat# A7979), and 250 pM 3-isobutyl-1 -methylxanthine (IBMX, Sigma Cat # I5879) at a density of 2K cells / well. Cells were added to assay plate (10 pL / well for 2,000 cells / well final) containing 10 pL / well assay buffer and 50 nL of 200x FAC test compound and incubated at 37°C (95% 02: 5% CO2) for 30 minutes, with micro-clime lids (Labcyte, Cat No. LLS-0310). Following the 30-minute cell and compound incubation, intracellular cAMP levels were quantified as per Revvity’s protocol of 1:20 regent in provided buffer. 5 pL of d2 and then 5 pL cryptate are added to the plate and incubated for 1 hour at room temperature).

[0892] Emission spectra of samples were measured on a Pherastar plate reader (BMG Labtech Inc) using a HTRF protocol (excitation 320 nm; emission 665 nm and 620 nm). Data were analyzed using the ratio of fluorescence intensity at 620 and 665 nm for each well,

[0893] Dual Amylin Calcitonin Agonist Biology Table

[0894] 1. Calcitonin Receptor Assay 2 EC50 data is reported unless otherwise noted

[0895] 2. Reported EC50 Data is from Calcitonin Receptor Assay 1

[0896] 3. Not Determined

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920] It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

1. CLAIMS2.We claim:

1. A compound of Formula (I)5. 7.or a pharmaceutically acceptable salt thereof;8.wherein9.R1is selected from the group consisting of hydrogen, Ci -Cealkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- wherein the Ci-Cealkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 R6; n is 0 or 1;10.R2and R3are each independently selected from the group consisting of hydrogen, cyano, Cr C6alkyl substituted with 0 to 6 R6and C3-C7cycloalkyl substituted with 0 to 6 R6;11.R2’, R3’, R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, Ci-Cealkyl substituted with 0 to 6 R6, CrCealkoxy substituted with 0 to 6 R6and C3-Cycycloalkyl substituted with 0 to 6 R6;12.or R2and R3, R2’ and R3’ or R4and R5can be taken together with the carbon to which they are attached to form a C3-C7spirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;13.or when n is 1 then R2and R2’ or R2’ and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring; or when n is 0 then R2and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;14.- 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 R2’ are attached then R3and R3’ are absent and when - is a bond connecting the carbons to which R2’ and R4are attached then R3’ and R5are absent;15.R6is selected from the group consisting of (C6-C10aryl)-(C0-C4alkyl)-L-C0-C4alkyl-, (C2-C8alkenyl)-(C0-C4alkyl)-L-C0-C4alkyl-, (C3-C7cycloalkyl)-(C0-C4alkyl)-L-C0-C4alkyl-, (5- to 10-membered heteroaryl)-(C0-C4alkyl)-L-C0-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(C0-C4alkyl)-L-C0-C4alkyl-; wherein the R6group is substituted with 0 to 6 R6; L is selected from a bond, O, NH and N(Ci-C3alkyl);16.X is N or CR7;17.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 R6, Ci-C6alkoxy substituted with 0 to 6 R6, C3-C7cycloalkyl-Co-Csalkyl- substituted with 0 to 6 R6, (4- to 7-membered heterocycloalkylj-Co-Cealkyl- substituted with 0 to 6 R6, C6-C14aryl-Co-Cealkyl-substituted with 0 to 6 R6and 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 R6;18.or R7and RBtaken together with the carbons to which they are attached form a fused C4-C?cycloakyl ring ora fused 4- to 7-membered heterocycloalkyl ring;19.R7ais Ci-Csalkyl substituted with 0 to 6 R6;20.R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-C6alkyl substituted with 0 to 6 RS;21.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 R6;22.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 R6;23.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;24.R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 R6, Cs-Cycycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 R6, 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 R6, (C6-Cioaryl)-Co-Cealkyl- substituted with 0 to 6 R6, (5- to 10-membered heteroaryl)-Co-Csalkyl- substituted with 0 to 6 R6,25.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 R6;26.R6at each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, oxo, -NRS1RS2, -Ci-C6alkyl-NRS1RS2, C1-C3alkyl substituted with 0 to 6 fluoro, C1-C3alkoxy substituted with 0 to 6 fluoro, C3-C6cycloalkyl substituted with 0 to 6 RS3and C1-C3alkoxy-C1-C3alkyl- substituted with 0 to 6 fluoro;27.or two R6groups when attached to adjacent carbon or nitrogen atoms can be taken together to form a fused C3-C7cycloalkyl ring or a fused four- to 7-membered heterocycloalkyl ring;28.RS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, Ci-C3alkyl substituted with 0 to 6 RS3, Ci-C3alkoxy-Ci-C3alkyl- substituted with 0 to 6 RS3, C3-C7cycloalkylC0-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-C0-C3alkyl- substituted with 0 to 6 RS3;29.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; and30.RS3at each occurrence is independently selected from halo, hydroxy, cyano, C1-C3alkyl and C1-C3alkoxy.

2. A compound of Formula (Ix)33. 35.or a pharmaceutically acceptable salt thereof;36.wherein37.R1is selected from the group consisting of hydrogen, Ci-Cealkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-C0-C6alkyl- wherein the C1-C6alkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 R6; n is 0 or 1;38.R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 R6andC3-Cycycloalkyl substituted with 0 to 6 R6;39.R2’, R3’, R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, C1-C6alkyl substituted with 0 to 6 RS, C1-C6alkoxy substituted with 0 to 6 RSand C3-C7cycloalkyl substituted with 0 to 6 RS;40.or R2and R3, R2’ and R3’ or R4and R5can be taken together with the carbon to which they are attached to form a C3-C7spirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;41.or when n is 1 then R2and R2’ or R2’ and 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; or when n is 0 then R2and R4can be taken together with the carbons to which they are attached to form a Cs-Cycycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;42.- 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 R2’ are attached then R3and R3’ are absent and when - is a bond connecting the carbons to which R2’ and R4are attached then R3’ and R5are absent;43.R6is selected from the group consisting of (Cs-Cioaryl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C2-C8alkenyl)-(C0-C4alkyl)-L-C0-C4alkyl-, (C3-C7cycloalkyl)-(C0-C4alkyl)-L-C0-C4alkyl-, (5- to 10- membered heteroaryl)-(C0-C4alkyl)-L-C0-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(C0-C4alkyl)-L-C0-C4alkyl-; wherein the R6group is substituted with 0 to 6 R6;44.L is selected from a bond, O, NH and N(Ci-C3alkyl);45.X is N or CR7;46.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 R6, Ci-C6alkoxy substituted with 0 to 6 R6, C3-C7cycloalkyl-Co-Csalkyl- substituted with 0 to 6 R6, (4- to 7-membered heterocycloalkylj-Co-Cealkyl- substituted with 0 to 6 R6, Ce-Cioaryl-Co-Cealkyl-substituted with 0 to 6 R6and 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 R6;47.or R7and R5taken together with the carbons to which they are attached form a fused C4-Cycycloakyl ring ora fused 4- to 7-membered heterocycloalkyl ring;48.R7ais C1-C6alkyl substituted with 0 to 6 RS;49.R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-C6alkyl substituted with 0 to 6 RS;50.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 R6;51.Ring A is selected from the group consisting of C6-C10aryl, 5- to 10-membered heteroaryl, C3-Cscycloalkyl and 4- to 10-membered heterocycloalkyl, wherein Ring A is substituted with 0 to 6 R6;52.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;53.R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 R6, Cs-Cycycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 R6, 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 R6, (C6-C10aryl)-C0-C6alkyl- substituted with 0 to 6 RS, (5- to 10-membered heteroaryl)-C0-C6alkyl- 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 R6;54.R6at each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, oxo, -NRS1RS2, -Ci-C6alkyl-NRS1RS2, C1-C3alkyl substituted with 0 to 6 fluoro, C1-C3alkoxy substituted with 0 to 6 fluoro, C3-C6cycloalkyl substituted with 0 to 6 RS3and C1-C3alkoxy-C1-C3alkyl- substituted with 0 to 6 fluoro;55.or two R6groups when attached to adjacent carbon or nitrogen atoms can be taken together to form a fused Cs-Cycycloalkyl ring or a fused four- to 7-membered heterocycloalkyl ring; 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-C7cycloalkylC0-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-C0-C3alkyl- substituted with 0 to 6 RS3;56.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; and57.RS3at each occurrence is independently selected from halo, hydroxy, cyano, C1-C3alkyl and C1-C3alkoxy.

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof wherein the group61.

62. selected from the group consisting of64.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof wherein the group Y is selected from the group consisting of68.

71.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof wherein the group Y is selected from the group consisting of74.

6. The compound according to claim 1 ora pharmaceutically acceptable salt thereof wherein R7is selected from the group consisting of77.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof;80.wherein81.R1is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-C0-C6alkyl- wherein the C1-C6alkyl, C3-C7cycloalkyl-C0-C6alkyl- and (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- are substituted with 0 to 6 R6; n is 0 or 1;82.R2and R3are each independently selected from the group consisting of hydrogen, cyano, Ci-Cealkyl substituted with 0 to 6 R6andCs-Cycycloalkyl substituted with 0 to 6 R6;83.R2’, R3’, R4and R5are each independently selected from the group consisting of hydrogen, halo, hydroxy, cyano, C1-C6alkyl substituted with 0 to 6 RS, C1-C6alkoxy substituted with 0 to 6 RSand C3-C7cycloalkyl substituted with 0 to 6 RS;84.or R2and R3, R2’ and R3’ or R4and R5can be taken together with the carbon to which they are attached to form a C3-C7spirocycloalkyl or a 4- to 7-membered spiroheterocycloalkyl;85.or when n is 1 then R2and R2’ or R2’ and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring; or when n is 0 then R2and R4can be taken together with the carbons to which they are attached to form a C3-C7cycloalkyl ring or a 4- to 7-membered heterocycloalkyl ring;86.- 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 R2’ are attached then R3and R3’ are absent and when - is a bond connecting the carbons to which R2’ and R4are attached then R3’ and R5are absent;87.R6is selected from the group consisting of (C6-Cioaryl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C2-C8alkenyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (C3-Cycycloalkyl)-(Co-C4alkyl)-L-Co-C4alkyl-, (5- to 10-membered heteroaryl)-(Co-C4alkyl)-l_-Co-C4alkyl- and (4- to 10-membered heterocycloalkyl)-(Co-C4alkyl)-I_-Co-C4alkyl-; wherein the R6group is substituted with 0 to 6 R6;88.L is selected from a bond, O, NH and N(Ci-C3alkyl);89.X is N or CR7;90.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 R6, Ci-C6alkoxy substituted with 0 to 6 R6, Cs-Cycycloalkyl-Co-Csalkyl- substituted with 0 to 6 R6, (4- to 7-membered heterocycloalkyl)-Co-C6alkyl- substituted with 0 to 6 R6, Ce-Cioaryl-Co-Csalkyl-substituted with 0 to 6 R6and 5- to 10 membered heteroaryl-Co-Cealkyl- substituted with 0 to 6 R6;91.or R7and R6taken together with the carbons to which they are attached form a fused C4-Cycycloakyl ring ora fused 4- to 7-membered heterocycloalkyl ring;92.R7ais C1-C6alkyl substituted with 0 to 6 RS;93.R7b, R7cand R7dare each independently selected from the group consisting of hydrogen and C1-C6alkyl substituted with 0 to 6 RS;94.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 R6;95.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;96.R8, R8’ and R9are selected from the group consisting of hydrogen, Ci-Cealkyl substituted with 0 to 6 R6, Cs-Cycycloalkyl which is optionally fused with a phenyl or a 5- to 6-membered heteroaryl and is substituted with 0 to 6 R6, (Ce-Cioary -Co-Cealkyl- substituted with 0 to 6 R6, (5- to 10-membered heteroaryl)-Co-C6alkyl- substituted with 0 to 6 R6,97.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 R6;98.R6at each occurrence is independently selected from the group consisting of halo, hydroxy, cyano, -NRS1RS2, Ci-Csalkyl substituted with 0 to 6 fluoro, C Csalkoxy substituted with 0 to 6 fluoro and CrCsalkoxy-Ci-Csalkyl- substituted with 0 to 6 fluoro;99.RS1and RS2at each occurrence are independently selected from the group consisting of hydrogen, C1-C3alkyl substituted with 0 to 6 RS3, C1-C3alkoxy-C1-C3alkyl- substituted with 0 to 6 RS3, C3-C7cycloalkyl-C0-C3alkyl- substituted with 0 to 6 RS3and (4- to 7-membered heterocycloalkyl)-C0-C3alkyl- substituted with 0 to 6 RS3;100.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 R33; and101.RS3at each occurrence is independently selected from halo, hydroxy, cyano, C1-C3alkyl and C1-C3alkoxy.

8. The compound of claim 7 of Formula (I”);104. 106.or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 of Formula (Ic), (Id) or (le)108.

109. or a pharmaceutically acceptable salt thereof.110.5 10. The compound of claim 9 of Formula (lc-1), (lc-2), (Id-1), (Id-2), (le-1) or (le-2)112.

114. 116.or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 wherein R1is selected from the group consisting of hydrogen, C1-C3alkyl substituted with 0 to 4 fluoro or hydroxy, C3-C5cycloalkyl-C1-C3alkyl- and (4- to 6-membered heterocycloalkyl)-C1-C3alkyl-; ora pharmaceutically acceptable salt thereof.

12. The compound of claim 11 wherein R1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclopropylmethyl, cyclobutylmethyl and oxetanylmethyl; or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 wherein R2, R2’, R3, R3', R4and R5are independently selected from the group consisting of hydrogen and C1-C3alkyl substituted with 0 to 4 fluoro or hydroxy; or R2and R3or R2’ and R3’ or R4and R5, taken together with the carbon to which they are attached form a C3-C5spirocycloalkyl or 4- to 6-membered spiroheterocycloalkyl;120.or R2and R2’ or R2and R4taken together with the carbons to which they are attached can form a C3-C5cycloalkyl ring; or when n is 0 then R2and R4taken together with the carbons to which they are attached can form a C3-C5cycloalkyl ring;121.or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 wherein R2, R2’, R3, R3, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl;123.or R2and R3or R2’ and R3’ or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl;124.or when n is 1 then R2and R2’ or R2’ and R4taken together with the carbons to which they are attached can form a cyclopropyl ring;125.or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 wherein R6is (C6aryl)-(Ci-C4alkyl)-L-Coalkyl- or (5- to 10-membered heteroaryl)-(Ci-C4alkyl)-L-Coalkyl-; wherein the R6is substituted with 1 to 2 R6and L is a bond;127.or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 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;129.or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 of a formula selected from the group consisting of132.

134.

18. The compound of claim 17 wherein R7is selected from -C(O)OR7a, -C(O)NR7bR7cand 5- to 6-membered heteroaryl-Coalkyl- substituted with 0 to 2 R6;137.R7ais C1-C3alkyl and R7band R7care independently hydrogen or C1-C3alkyl;138.or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 wherein R7ais ethyl, R7band R7care hydrogen and the 5- to 6- membered heteroaryl-Coalkyl- is selected from oxadiazolyl, thiazolyl, pyrazolyl and pyridazinyl and R6is Ci-Csalkyl;140.or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19 wherein R7is selected from the group consisting of144.

145. or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20 wherein147.R1is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclobutylmethyl and oxetanylmethyl;148.R2, R2’, R3, R3’, R4and R5are independently selected from the group consisting of hydrogen, methyl, hydroxymethyl and isopropyl;149.or R2and R3or R2’ and R3’ or R4and R5, taken together with the carbon to which they are attached form a spirocyclopropyl or spirocyclobutyl; or R2and R2or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring;150.or R2and R4taken together with the carbons to which they are attached can form a cyclopropyl ring;151.or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 wherein the group156.

157. or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22 wherein Y is -C(O)NR8R9;159.or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23 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-yi;161.or a pharmaceutically acceptable salt thereof.

25. The compound of claim 22 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)2NR8R9and163.-N(R8’)C(O)NR8R9; or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 of the formula166. 168.or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1 selected from the group consisting of170.ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;171.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;172.ethyl 2-[2-(4-fluorophenyl)ethyl]-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6, 7,8,9-tetrahydro-5 / 7-pyrido[3,2-c]azepine-3-carboxylate;173.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4-(4-{[(pyridin-3-yl)methyl] carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;174.ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7-(propan-2-yl)-4-(4-{[(pyridin-3-yl)methyl] carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;175.ethyl (7R)-4-(4-{[(3,4-difluorophenyl)methyl]carbamoyl}phenyl)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;176.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-6-(2-hydroxyethyl)-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;177.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-6,7-dimethyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;178.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl}thiophen-2-yl)-7-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate; ethyl 2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate;179.4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(pyridin-3-yl)methyl]benzamide;180.ethyl (7S)-2-[2-(4-fluorophenyl)ethyl]-7-(hydroxymethyl)-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate; ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-(hydroxymethyl)-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate; ethyl 2-[2-(4-fluorophenyl)ethyl]-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate;181.ethyl 2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6-dihydro-1,6-naphthyridine-3-carboxylate;182.4-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide; 5-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;183.5-[(8R)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;184.5-[(8S)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;185.5-[(8R)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-8-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;186.5-[(8S)-2-[2-(4-fluorophenyl)ethyl]-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-8-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;187.5-{2-[2-(4-fluorophenyl)ethyl]-7,7-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;188.5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;189.ethyl rac-(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} thiophen-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate; ethyl (8R)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate;190.ethyl (8S)-2-[2-(4-fluorophenyl)ethyl]-8-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxylate;191.4-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-3-(pyridazin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(pyridin-3-yl)methyl]benzamide;192.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(6-{[(pyridin-3-yl)methyl]carbamoyl} pyridin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;193.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-4-(4-{[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl}-1,3-thiazol-2-yl)-7-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate;194.4-[(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-3-(5-methyl-1,3-thiazol-2-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl]-N-[(pyridin-3-yl)methyl]benzamide;195.(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxamide;196.(7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}thiophen-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxamide;197.ethyl (7R)-2-[2-(4-fluorophenyl)ethyl]-7-methyl-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl} thiophen-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate; and198.2-[2-(4-fluorophenyl)ethyl]-5-oxo-4-(4-{[(pyridin-3-yl)methyl]carbamoyl}phenyl)-6, 7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-3-carboxamide;199.5-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]thiophene-3-carboxamide;200.4-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide; and201.2-{2-[2-(4-fluorophenyl)ethyl]-8,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-4-yl}-N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1,3-oxazole-4-carboxamide;202.or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1 selected from the group consisting of any of Examples 1 to 151 or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

30. 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 26, 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).

31. The method of claim 30 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)].

32. A compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof 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, 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).

33. The use of claim 32 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)].

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