Allosteric agonists and positive allosteric modulators of glucagon-like peptide 1 receptor

Abstract

The present disclosure relates to the discovery of small molecule compounds that act as GLP-1R agonists and / or as positive allosteric modulators (PAMs) of GLP-1R. Such compounds are useful to treat, ameliorate, and / or prevent insulin resistance and / or diabetes in a mammal.

Description

[0001] TITLE Allosteric Agonists and Positive Allosteric Modulators of Glucagon-Like Peptide 1 Receptor CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.63 / 646,402, filed May 13, 2024, which is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant R15GM140406 awarded by National Institutes of Health. The government has certain rights in the invention. BACKGROUND Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Insulin is a hormone produced by beta cells of the pancreatic islets and is responsible for regulating optimum level of blood glucose. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. In type 1 diabetes, the body does not make insulin, and in type 2 diabetes the body does not make or use insulin well. The glucagon-like peptide 1 receptor (GLP-1R) is a member of secretin-like class B family of G-protein coupled receptors (GPCRs) and plays an essential role in mediating the potentiation of insulin secretion. Hence, positive modulation of GLP-1R remains an effective strategy for the therapeutic treatment of type 2 diabetes and obesity. Like other class B GPCRs, GLP-1R has an extracellular N-terminal domain and a seven transmembrane domain (7TM). In ligand binding, its N-terminal domain binds to C- terminal residues of the peptide hormone and its 7TM domain interacts with the N-terminal residues of the peptide for signaling. The large nature of the orthosteric binding site for GLP- 1 hindered the development of orally active small molecule agonists of GLP-1R for therapeutic purpose. Although high-throughput screenings have typically been used to identify small molecule GLP-1R agonists, further development of the lead compounds has not been successful. Up to now, no small molecule drugs acting as GLP-1R agonists are available in the market. Thus, there is an unmet need in the art to develop small molecule drugs that target GLP-1R for the treatment of diabetes. The present disclosure addresses this unmet need. BRIEF SUMMARY OF THE DISCLOSURE In one aspect, disclosed herein is a compound of Formula (I), or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof: (I), wherein: X is selected from the group consisting of O, S, C(R1g)(R1h), and NRz; each occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is independently selected from the group consisting of H, halogen, -OH, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, and optionally substituted C1-C6alkoxy; R2and R3are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)- C2-C6alkenyl, optionally substituted -C(=O)OC1-C6alkyl, and optionally substituted -C(=O)OC2-C6alkenyl; R4is selected from the group consisting of -OH, optionally substituted C1-C6alkoxy, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heterocyclyl; m is 0 or 1; and Rzis selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C3-C10cycloalkyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)-C2-C6alkenyl, optionally substituted -S(=O)2-C1-C6alkyl, optionally substituted -S(=O)2- C3-C10cycloalkyl, optionally substituted -S(=O)2-phenyl, optionally substituted -C(=O)O-C1-C6alkyl, optionally substituted -C(=O)OC2-C6alkenyl, optionally substituted phenyl, and optionally substituted naphthyl; provided that, when Rzis -S(=O)2-C1-C6alkyl, optionally substituted -C(=O)-C1-C6alkyl, or optionally substituted -C(=O)-C2-C6alkenyl, then R4is -OH, optionally substituted C1-C6alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted heterocyclyl. In certain embodiments, the compound is a Glucagon-like peptide 1 receptor (GLP- 1R) agonist. In certain embodiments, the compound is a positive allosteric modulator (PAM) of GLP-1R. In certain embodiments, the compound selectively enhances GLP-1R activity. In certain embodiments, the compound has no significant effect on the activity of other G- protein-coupled receptors (GPCRs). In another aspect, provided herein is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of Formula (I), or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof. In another aspect, provided herein is a method of treating, ameliorating, and / or preventing insulin resistance and / or diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof, or a pharmaceutical composition as described herein. BRIEF DESCRIPTION OF THE DRAWINGS The following detailed description of certain embodiments of the disclosure will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosure, specific embodiments are shown in the drawings. It should be understood, however, that the disclosure is not limited to the precise arrangements. FIG.1 illustrates compounds reported to be positive allosteric modulators (PAMs) of GLP-1R. FIG.2A illustrates potential allosteric effect of four active compounds on human GLP-1R. The effect on luminescence of various concentrations of compounds on HEK293.Luc2P cells expressing human GLP-1R in the presence of GLP-1 (10 nM). FIG.2B illustrates the effect of various concentrations of GLP-1 on HEK293.Luc2P cells expressing human GLP-1R in the presence or absence of an active compound (5 µM). GLP-1R activation was assessed as luminescence normalized to protein concentration and plotted as luminescence fold change with respect to vehicle control (0.5% DMSO). Data is average of three independent experiments with at least three technical replicates for each condition and error bars for each concentration were plotted as SEM (n=3). Statistical analysis was done using 2-way ANOVA (****p<0.0001; **p<0.001; *p<0.5). The comparison is done between the data points of the dose response curve generated due to GLP-1’s effect on GLP-1R in the presence and absence of an active compound. FIG.3 illustrates glucose stimulated insulin production induced by GLP-1 and four active compounds in INS-1832 / 13 cells. INS-1832 / 13 cells were treated with GLP-1 (10 nM) and an active compound (5µM) in the presence of 16.7 mM glucose after 2 hours of starvation with KRB buffer. Data shown is average of three independent experiments and error bars for each concentration were plotted as SEM (n=3). FIG.4A illustrates time course of glucose levels in overnight-fasted CD1 / 6 mice (n = 6) treated intraperitoneally with indicated concentrations of an active compound or Sitagliptin. Treatment of compounds 6, 7, 23, and 24 followed 45 min later by an intraperitoneal dose of dextrose (2.5 g / kg). Compound 7 significantly lowered blood glucose concentration. Results are expressed as mean ± S.E.M. Analysis of variance was used to assess statistical significance: *p < 0.05, versus vehicle. FIG.4B illustrates time course of blood glucose levels in overnight-fasted CD1 / 6 mice (n = 6) treated intraperitoneally with indicated concentrations of an active compound or Sitagliptin. Treatment of 7 alone or 7 + Sitagliptin followed 45 min later by an intraperitoneal dose of dextrose (2.5 g / kg). Sitagliptin was used as controls in the study. Compound 6 and Sitagliptin evoked synergistically a significant reduction in blood glucose concentration. Results are expressed as mean ± S.E.M. Analysis of variance was used to assess statistical significance: *p < 0.05, versus vehicle. FIG.4C illustrates time course of blood glucose levels in overnight-fasted CD1 / 6 mice (n = 6) treated intraperitoneally with indicated concentrations of an active compound or Sitagliptin. Treatment of various concentrations of 7 followed 45 min later by an intraperitoneal dose of dextrose (2.5 g / kg). Compound 7 at 5 mg / kg body weight significantly reduced blood glucose concentration. Results are expressed as mean ± S.E.M. Analysis of variance was used to assess statistical significance: *p < 0.05, versus vehicle. FIG.5 illustrates potential binding sites of the compound 7 on the GLP-1R structure. The GLP-1R structure is shown as cartoons (PDB ID: 6X1A). Positive allosteric modulator (PAM) 7 docking regions from models are shown as colored spheres. The docking region with the worst docking score was colored in brown and the best docking score in green. DETAILED DESCRIPTION The present disclosure is related in one aspect to discovery of certain glucagon-like peptide 1 receptor (GLP-1R) agonists as well as the positive allosteric modulators (PAMs) of GLP-1R. The GLP-1R is a well-established target for the treatment of type 2 diabetes and thus GLP-1R agonist-based therapies emerge as an effective approach to treat diabetes. However, development of nonpeptidic agonist drugs targeting GLP-1R has remained unsuccessful. In the present disclosure, structure-based lead optimization, chemical syntheses, and in vitro assay validation helped lead to the identification of efficacious GLP-1R agonists or PAMs. Targeting the allosteric sites on GLP-1R represents a promising strategy for the development of small molecule drugs that can offer several potential benefits and help overcome problems associated with GLP- 1 peptide drugs. However, due to the lack of 3D structure information for GLP-1R until recently, past small molecule drug discovery efforts were often initiated by high-throughput screening. A rational design approach was attempted by first constructing a 3D model of the TM domain of GLP-1R in its active conformation, then performing in silico structure-based screening. Through in vitro experiments, several compounds were shown to function as a potential ago-PAM. For a number of years, GLP-1R has remained an effective target for the treatment of type-2 diabetes. Recent clinical data has demonstrated GLP-1R can also be targeted for weight loss, against heart disease, and drug and alcohol addiction treatment, making it one of the most intensively studied GPCRs. Given the challenge in developing small-molecule drugs functioning as GLP-1R agonists, the development of GLP-1R PAMs represents a promising approach that could offer cheap drugs with less side effects and more therapeutic benefit than the currently available peptide ones. Here, the potency of the 2-AT scaffold was optimized through medicinal chemistry and the efficacy of the lead compound was demonstrated through in vivo experiments. More than 1002-AT scaffold derivatives were synthesized and tested using the luciferase assay. Although many synthesized intermediates enhanced luciferase activity in the screening tests, some also showed activity when treated on HEK.luc2P cells without GLP-1R transient over-expression. These compounds were excluded from our consecutive experiments. Ultimately, four of them (6, 7, 23 and 24) were further studied by the insulin secretion assay and the in vivo animal work using the CD1 mice. Among them, although all four compounds significantly increased insulin secretion, compounds 6, 23 and 24 showed much less activity on glucose reduction in animal studies than 7. Possibly these three compounds may activate other pathways which induce in vitro insulin secretion, rather than through GLP-1R mediated signaling pathways. Therefore, they are not good candidates for further study. Compound 7 meets criteria to be considered as a good GLP-1R PAM.. In addition, despite several modifications, compound 7 has a MW of 299 and remains as one of the smallest known GLP-1R PAMs. Perhaps most interestingly, compound 7 can modulate the activity of the endogenously generated GLP-1. At the dose of 10 mg / kg b.w., the glucose level in the mice was reduced by 50% after 60 min; Co-treatment with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, suggested that 7 synergistically lowered the blood glucose level by approximately 75% after 60 min. All these properties and data indicate 7 is a great lead compound for further development. It should be noted that, when testing on HEK.luc2P cells transiently transfected with other class B1 GPCRs which share high sequence identity with GLP-1R such as the vasoactive intestinal polypeptide receptor 1, the gastric inhibitory polypeptide receptor, and the glucagon receptor, 7 also increased luciferase activity. This likely means that the selectivity of 7 on GLP-1R may need to be improved in the next steps. On the other hand, dual and triple agonists targeting GLP-1R along with other class B GPCRs have beendemonstrated with increased therapeutic benefit recently. The fact that 7 also activates othersimilar class B GPCRs could contribute to its observed efficacy in our animal studies. Overall, it is of interest to further explore the potential of compound 7 as a dual or triple agonist. The efficacy of a lead compound was demonstrated in animal studies which reduced the glucose level by 50% after 60 min. Docking studies suggested that the compound likely functions as a molecular glue between the GLP-1R and its peptide. The lead compound is small and has favorable pharmacological properties. Hence, this 2-AT derivative represents a promising GLP-1R PAM with great potential for further drug development. Definitions The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “amine” as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium ions as used herein. The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a “formyl” group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group. The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term “alkyl” as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “alkynyl” as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others. The term “aralkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term “heteroarylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term “heterocyclylalkyl” as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term “hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. The term “organic group” as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(=O)N(R)2, CN, CF3, OCF3, R, C(=O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(=O)R, C(=O)C(=O)R, C(=O)CH2C(=O)R, C(S)R, C(=O)OR, OC(=O)R, C(=O)N(R)2, OC(=O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(=O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(=O)R, N(R)N(R)C(=O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(=O)OR, N(R)C(=O)R, N(R)C(S)R, N(R)C(=O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(=O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. The term “room temperature” as used herein refers to a temperature of about 15 °C to 28 °C. The term “solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. The term “substantially” as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of” can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(=O)N(R)2, CN, NO, NO2, O NO2, azido, CF3, O CF3, R, O (oxo), S (thiono), C(=O), S(=O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(=O)R, C(=O)C(=O)R, C(=O)CH2C(=O)R, C(S)R, C(=O)OR, OC(=O)R, C(=O)N(R)2, OC(=O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(=O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(=O)R, N(R)N(R)C(=O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(=O)OR, N(R)C(=O)R, N(R)C(S)R, N(R)C(=O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(=O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1-C100)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. Compounds and Compositions In one aspect, the disclosure provides a compound of Formula (I), or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof: (I), wherein: X is selected from the group consisting of O, S, C(R1g)(R1h), and NRz; each occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is independently selected from the group consisting of H, halogen, -OH, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, and optionally substituted C1-C6alkoxy; R2and R3are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)-C2-C6alkenyl, optionally substituted -C(=O)OC1-C6alkyl, and optionally substituted -C(=O)OC2- C6alkenyl; R4is selected from the group consisting of -OH, optionally substituted C1-C6alkoxy, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heterocyclyl; m is 0 or 1; and Rzis selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C3-C10cycloalkyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)-C2-C6alkenyl, optionally substituted -S(=O)2-C1-C6alkyl, optionally substituted -S(=O)2-C3-C10cycloalkyl, optionally substituted -S(=O)2-phenyl, optionally substituted -C(=O)O-C1-C6alkyl, optionally substituted -C(=O)OC2-C6alkenyl, optionally substituted phenyl, and optionally substituted naphthyl. In certain embodiments, when Rzis -S(=O)2-C1-C6alkyl, optionally substituted - C(=O)-C1-C6alkyl, or optionally substituted -C(=O)-C2-C6alkenyl, then R4is -OH, optionally substituted C1-C6alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted heterocyclyl. In certain embodiments, when Rzis -S(=O)2-C1-C6alkyl, optionally substituted - C(=O)-C1-C6alkyl, or optionally substituted -C(=O)-C2-C6alkenyl, R4is -OH, optionally substituted C1-C6alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, and optionally substituted heterocyclyl. In certain embodiments, the optionally substituted C1-C6alkyl (by itself or as part of a larger substituent) includes optionally substituted C1-C6haloalkyl, optionally substituted C1- C6hydroxyalkyl, and / or optionally substituted C1-C6aminoalkyl. In some embodiments, X is selected from the group consisting of O, S, CH2, and NRz. In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is NRz. In some embodiments, at least one occurrence of R1a, R1b, R1c, R1d, R1e, and R1fis hydrogen. In some embodiments, at least two occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare hydrogen. In some embodiments, at least three occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare hydrogen. In some embodiments, at least four occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare hydrogen. In some embodiments, at least five occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare hydrogen. In some embodiments, R1a, R1b, R1c, R1d, R1e, and R1fare hydrogen. In some embodiments, R1ais hydrogen. In some embodiments, R1bis hydrogen. In some embodiments, R1cis hydrogen. In some embodiments, R1dis hydrogen. In some embodiments, R1eis hydrogen. In some embodiments, R1fis hydrogen. In some embodiments, one, and / or at least one, occurrence of R1a, R1b, R1c, R1d, R1e, and R1fis independently C1-C6alkyl. In some embodiments, at least one occurrence of R1a, R1b, R1c, R1d, R1e, and R1fis independently C1-C6alkyl. In some embodiments, at least two occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare independently C1-C6alkyl. In some embodiments, at least three occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare independently C1-C6alkyl. In some embodiments, at least four occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare independently C1-C6alkyl. In some embodiments, at five occurrences of R1a, R1b, R1c, R1d, R1e, and R1fare independently C1-C6alkyl. In some embodiments, R1a, R1b, R1c, R1d, R1e, and R1fare independently C1-C6alkyl. In some embodiments, R1ais C1-C6alkyl. In some embodiments, R1bis C1-C6alkyl. In some embodiments, R1cis C1-C6alkyl. In some embodiments, R1dis C1-C6alkyl. In some embodiments, R1eis C1-C6alkyl. In some embodiments, R1fis C1-C6alkyl. In some embodiments, at least one occurrence of R1a, R1b, R1c, R1d, R1e, and R1fis independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and / or t-butyl. In some embodiments, R1aand R1bare hydrogen. In some embodiments, R1cand R1dare hydrogen. In some embodiments, R1eand R1fare hydrogen. In some embodiments, R1a, R1b, R1cand R1dare hydrogen. In some embodiments, R1a, R1b, R1eand R1fare hydrogen. In some embodiments, R1c, R1d, R1eand R1fare hydrogen. In certain embodiments, R1ais H. In certain embodiments, R1ais C1-C6alkyl. In certain embodiments, R1bis H. In certain embodiments, R1bis C1-C6alkyl. In certain embodiments, R1cis H. In certain embodiments, R1cis C1-C6alkyl. In certain embodiments, R1dis H. In certain embodiments, R1dis C1-C6alkyl. In certain embodiments, R1eis H. In certain embodiments, R1eis C1-C6alkyl. In certain embodiments, R1fis H. In certain embodiments, R1fis C1-C6alkyl. In certain embodiments, R1gis H. In certain embodiments, R1gis C1-C6alkyl. In certain embodiments, R1his H. In certain embodiments, R1his C1-C6alkyl. In certain embodiments, R1ais CH3. In certain embodiments, R1ais CF3. In certain embodiments, R1ais CH2CH3. In certain embodiments, R1ais (CH2)2CH3. In certain embodiments, R1ais CH(CH3)2. In certain embodiments, R1ais (CH2)3CH3. In certain embodiments, R1ais CH2C(CH3)2. In certain embodiments, R1ais CH(CH3)CH2CH3. In certain embodiments, R1ais C(CH3)3. In certain embodiments, R1bis CH3. In certain embodiments, R1bis CF3. In certain embodiments, R1bis CH2CH3. In certain embodiments, R1bis (CH2)2CH3. In certain embodiments, R1bis CH(CH3)2. In certain embodiments, R1bis (CH2)3CH3. In certain embodiments, R1bis CH2C(CH3)2. In certain embodiments, R1bis CH(CH3)CH2CH3. In certain embodiments, R1bis C(CH3)3. In certain embodiments, R1cis CH3. In certain embodiments, R1cis CF3. In certain embodiments, R1cis CH2CH3. In certain embodiments, R1cis (CH2)2CH3. In certain embodiments, R1cis CH(CH3)2. In certain embodiments, R1cis (CH2)3CH3. In certain embodiments, R1cis CH2C(CH3)2. In certain embodiments, R1cis CH(CH3)CH2CH3. In certain embodiments, R1cis C(CH3)3. In certain embodiments, R1dis CH3. In certain embodiments, R1dis CF3. In certain embodiments, R1dis CH2CH3. In certain embodiments, R1dis (CH2)2CH3. In certain embodiments, R1dis CH(CH3)2. In certain embodiments, R1dis (CH2)3CH3. In certain embodiments, R1dis CH2C(CH3)2. In certain embodiments, R1dis CH(CH3)CH2CH3. In certain embodiments, R1dis C(CH3)3. In certain embodiments, R1eis CH3. In certain embodiments, R1eis CF3. In certain embodiments, R1eis CH2CH3. In certain embodiments, R1eis (CH2)2CH3. In certain embodiments, R1eis CH(CH3)2. In certain embodiments, R1eis (CH2)3CH3. In certain embodiments, R1eis CH2C(CH3)2. In certain embodiments, R1eis CH(CH3)CH2CH3. In certain embodiments, R1eis C(CH3)3. In certain embodiments, R1fis CH3. In certain embodiments, R1fis CF3. In certain embodiments, R1fis CH2CH3. In certain embodiments, R1fis (CH2)2CH3. In certain embodiments, R1fis CH(CH3)2. In certain embodiments, R1fis (CH2)3CH3. In certain embodiments, R1fis CH2C(CH3)2. In certain embodiments, R1fis CH(CH3)CH2CH3. In certain embodiments, R1fis C(CH3)3. In certain embodiments, R1gis CH3. In certain embodiments, R1gis CF3. In certain embodiments, R1gis CH2CH3. In certain embodiments, R1gis (CH2)2CH3. In certain embodiments, R1gis CH(CH3)2. In certain embodiments, R1gis (CH2)3CH3. In certain embodiments, R1gis CH2C(CH3)2. In certain embodiments, R1gis CH(CH3)CH2CH3. In certain embodiments, R1gis C(CH3)3. In certain embodiments, Rzis H. In certain embodiments, Rzis CH3. In certain embodiments, Rzis CF3. In certain embodiments, Rzis CH2CH3. In certain embodiments, Rzis (CH2)2CH3. In certain embodiments, Rzis CH(CH3)2. In certain embodiments, Rzis (CH2)3CH3. In certain embodiments, Rzis CH2C(CH3)2. In certain embodiments, Rzis CH(CH3)CH2CH3. In certain embodiments, Rzis C(CH3)3. In certain embodiments, Rzis cyclopropyl. In certain embodiments, Rzis C(=O)CH3. In certain embodiments, Rzis C(=O)OCH3. In certain embodiments, Rzis C(=O)OCH2CH3. In certain embodiments, Rzis C(=O)OCH2Ph. In certain embodiments, Rzis S(=O)2CF3. In certain embodiments, Rzis S(=O)2(cyclopropyl). In certain embodiments, Rzis S(=O)2(4-methylphenyl). In certain embodiments, X is -O-. In certain embodiments, X is -S-. In certain embodiments, X is -CH2-. In certain embodiments, X is -CH(CH3)-. In certain embodiments, X is -CH(CF3)-. In certain embodiments, X is -C(CH3)2-. In certain embodiments, X is - CH[(CH2)3CH3]-. In certain embodiments, X is -CH[(CH2)CH(CH3)2]-. In certain embodiments, X is -CH[C(CH3)3]-. In certain embodiments, X is -NH-. In certain embodiments, X is -N(CH3)-. In certain embodiments, X is -N(CF3)-. In certain embodiments, X is -N(CH2CH3)-. In certain embodiments, X is -NH[(CH2)2CH3]-. In certain embodiments, X is -NH(CH(CH3)2)-. In certain embodiments, X is -N[(CH2)3CH3]-. In certain embodiments, X is -N(CH2C(CH3)2]-. In certain embodiments, X is - N(CH(CH3)CH2CH3)-. In certain embodiments, X is -N(C(CH3)3)-. In certain embodiments, X is -N(cyclopropyl)-. In certain embodiments, X is -N(C(=O)CH3)-. In certain embodiments, X is -N(C(=O)OCH3)-. In certain embodiments, X is -N(C(=O)OCH2CH3)-. In certain embodiments, X is -N(C(=O)OCH2Ph)-. In certain embodiments, X is - N(S(=O)2CF3)-. In certain embodiments, X is -N(S(=O)2(cyclopropyl))-. In certain embodiments, X is -N(S(=O)2(4-methylphenyl))-. In certain embodiments, R2is H. In certain embodiments, R2is C(=O)(C1-C6alkyl). In certain embodiments, R2is C(=O)CH3. In certain embodiments, R3is H. In certain embodiments, R3is C(=O)(C1-C6alkyl). In certain embodiments, R3is C(=O)CH3. In certain embodiments, R2and R3are both H. In certain embodiments, R2is C(=O)CH3and R3is H. In certain embodiments, R2is H and R3is C(=O)CH3. In certain embodiments, R4is OH. In certain embodiments, R4is O(C1-C6alkyl). In certain embodiments, R4is optionally substituted phenyl. In certain embodiments, R4is phenyl. In certain embodiments, R4is 4-methylphenyl. In certain embodiments, R4is 4- chlorophenyl. In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain O R4R3N O S R2embodiments, the compound isR1eR1f. In certain embodiments, the compound is . In certain embodiments, the compound is . In certain 5 embodiments, the compound is . In certain embodiments, the compound is O 1 R4RdR1cR3N S R2R1eR1f. In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is O R4R3N S R2R1eR1f. In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is . In certain embodiments, the compound is a compound of Formula (A-I): (A-I). In certain embodiments, the compound is a compound of Formula (A-II): (A-II). In certain embodiments, the compound is a compound of Formula (B): (B). In certain embodiments, the compound is a compound of Formula (C): (C). In some embodiments, the compound is selected from the group consisting of: (2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone, ethyl 2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate, 2-((tert-butoxycarbonyl)amino)-6-ethyl- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, 1-(2-amino-3- (4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1-one, 1-(2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1-one, 1-(2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)ethan-1-one, ethyl 6-acetyl-2-amino-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 2-amino-6- cyclopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, diethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate, 2-((tert-butoxycarbonyl)amino)-6-(ethoxycarbonyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 2- amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, ethyl 2-amino-3-(4-chlorobenzoyl)-4,7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, benzyl 2-amino- 3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, ethyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate, 6-benzyl 3-ethyl 2-amino-4,7- dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate, benzyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, (2-amino-6-(cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(phenyl)methanone, (6-allyl-2-amino-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3-yl)(phenyl)methanone, ethyl 2- amino-6-isobutyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, 6-allyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate, (6-allyl-2-amino-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3-yl)(phenyl)methanone, (2-amino-6- (cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone, ethyl 2-amino-6-(cyclopropylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, (2-amino-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3-yl)(phenyl)methanone, (2-amino- 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone, ethyl 2- amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 2-amino- 5,5,7,7-tetramethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 2-amino-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carboxylate, (2- amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4-chlorophenyl)methanone, (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(p- tolyl)methanone, ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3- carboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H- thieno[2,3-c]thiopyran-3-carboxylate, 2-((tert-butoxycarbonyl)amino)- 4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylic acid, ethyl 2-amino- 4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylate, (2-amino-4,7- dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4-chlorophenyl)methanone, (2- amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(p-tolyl)methanone, ethyl 2- amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylate, ethyl 2-((tert- butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylate, 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3- carboxylic acid, (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(4- chlorophenyl)methanone, ethyl 6-allyl-2-amino-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 6-allyl-2-((tert- butoxycarbonyl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, 6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 6-acetyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, 6-acetyl-2-((tert- butoxycarbonyl)amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, diethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate, diethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate, 2-((tert-butoxycarbonyl)amino)-6- (ethoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, (2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin- 3-yl)(p-tolyl)methanone, ethyl 2-amino-6-(methylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 2-((tert- butoxycarbonyl)amino)-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, methyl 2-amino-3-(4-chlorobenzoyl)-4,7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, 1-(2-amino-3-(4- methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2,2,2-trifluoroethan-1-one, 2,2,2-trifluoro-N-(3-(4-methylbenzoyl)-6-(2,2,2-trifluoroacetyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide, 1-(2-amino-3- (4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)-2,2,2-trifluoroethan-1-one, N-(3-(4-chlorobenzoyl)-6-(2,2,2-trifluoroacetyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-2-yl)-2,2,2-trifluoroacetamide, (2- amino-6-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone, (2-amino-6-(methylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3-yl)(4-chlorophenyl)methanone, (2- amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4-chlorophenyl)methanone, or (2-amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone, (2-amino-6-methyl-4,5,6,7- tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone, (2-amino- 6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone, (2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4- chlorophenyl)methanone, 2-amino-6-methyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylic acid, ethyl 2-amino-6- methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, ethyl 2- amino-5-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, ethyl 2-amino-6-butyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, ethyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, ethyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, ethyl 2-amino-6-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6,6-dimethyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate, ethyl 2-amino-5,5-dimethyl- 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, and ethyl 2-amino-4- methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate. In certain embodiments, the compound of Formula (I) is a glucagon-like peptide 1 receptor (GLP-1R) agonist. In certain embodiment, the compound is a positive allosteric modulator (PAM) of GLP-1R. In certain embodiments, the compound selectively enhances GLP-1R activity. In certain embodiments, the compound has no significant effect on the activity of other G-protein-coupled receptors (GPCRs). Table 1. Exemplary compounds of the disclosure Structure Name (2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(p-tolyl)methanone ethyl 2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate 2-((tert-butoxycarbonyl)amino)-6-ethyl-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid 1-(2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3- c]pyridin-6(5H)-yl)ethan-1-one 1-(2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)ethan-1-one 1-(2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridin-6(5H)-yl)ethan-1-one ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate ethyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate diethyl 2-((tert-butoxycarbonyl)amino)-4,7- dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate 2-((tert-butoxycarbonyl)amino)-6-(ethoxycarbonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid ethyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate ethyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate benzyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate ethyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate 6-benzyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate benzyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate (2-amino-6-(cyclopropylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3-yl)(phenyl)methanone (6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(phenyl)methanone ethyl 2-amino-6-isobutyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate ethyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate 6-allyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate (6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(phenyl)methanone (2-amino-6-(cyclopropylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone ethyl 2-amino-6-(cyclopropylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(phenyl)methanone (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone ethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate ethyl 2-amino-5,5,7,7-tetramethyl-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate ethyl 2-amino-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3- carboxylate (2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(4-chlorophenyl)methanone (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(p- tolyl)methanone ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3- carboxylate ethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H- thieno[2,3-c]thiopyran-3-carboxylate 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3- c]thiopyran-3-carboxylic acid ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3- carboxylate (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4- chlorophenyl)methanone (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(p- tolyl)methanone ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3- carboxylate ethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H- thieno[2,3-c]pyran-3-carboxylate 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3- c]pyran-3-carboxylic acid (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(4- chlorophenyl)methanone ethyl 6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate ethyl 6-allyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate 6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylic acid ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate ethyl 6-acetyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate 6-acetyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid diethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate diethyl 2-((tert-butoxycarbonyl)amino)-4,7- dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate 2-((tert-butoxycarbonyl)amino)-6-(ethoxycarbonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(p-tolyl)methanone ethyl 2-amino-6-(methylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate ethyl 2-((tert-butoxycarbonyl)amino)-6-(methylsulfonyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate methyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate 1-(2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3- c]pyridin-6(5H)-yl)-2,2,2-trifluoroethan-1-one 1-(2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridin-6(5H)-yl)-2,2,2-trifluoroethan-1-one (2-amino-6-((trifluoromethyl)sulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone (2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(4-chlorophenyl)methanone (2-amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(4-chlorophenyl)methanone (2-amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(p-tolyl)methanone (2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3- yl)(p-tolyl)methanone (2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen- 3-yl)(p-tolyl)methanone (2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3- yl)(4-chlorophenyl)methanone 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid ethyl 2-amino-6-methyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate ethyl 2-amino-5-methyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate ethyl 2-amino-6-butyl-4,5,6,7-tetrahydrobenzo[b]thiophene- 3-carboxylate ethyl 2-amino-6-isopropyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate ethyl 2-amino-6-(tert-butyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate ethyl 2-amino-6-(trifluoromethyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate ethyl 2-amino-6,6-dimethyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate ethyl 2-amino-5,5-dimethyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate ethyl 2-amino-4-methyl-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate In another aspect, the disclosure provides a composition comprising at least one pharmaceutically acceptable carrier and the compound of the disclosure, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof. In certain embodiment, the composition of the disclosure is formulated for administration by a route selected from the group consisting of oral, parenteral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical. In certain embodiments, the composition further comprising at least one additional agent useful for treating, ameliorating, or preventing diabetes and / or insulin resistance in a subject. In certain embodiments, the at least one additional agent is selected from the group consisting of α-glucosidase inhibitor, lipase inhibitor, sulfonyl urea, meglitinide, biguanide, thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor. The compounds of the disclosure can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound of the disclosure, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert- butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compounds of the disclosure may exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, sites on, for example, the aromatic ring portion of compounds of the disclosure are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t- butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para-methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC). Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Methods Provided herein are methods of treating, ameliorating, and / or preventing a disease and / or disorder. In some embodiments, provided herein is a method of treating, ameliorating, and / or preventing insulin resistance and / or diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof, or a pharmaceutical composition of one or more compounds of the disclosure. In some embodiments, the diabetes is type II diabetes. In some embodiments, the compound is administered as a pharmaceutical composition to the subject. In some embodiments, the subject is further administered at least one additional agent useful for treating, ameliorating, and / or preventing diabetes and / or insulin resistance. In some embodiments, the at least one additional agent is selected from the group consisting of α-glucosidase inhibitor, lipase inhibitor, sulfonyl urea, meglitinide, biguanide, thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor. In some embodiments, administering the compound to the subject allows for administering a lower dose of the at least one additional agent as compared to the dose of the additional agent alone that is required to achieve similar results in treating, ameliorating, or preventing insulin resistance and / or diabetes. In some embodiments, administering the compound to the subject enhances the activity, and / or reduces at least one side effect, of the at least one additional agent. In some embodiments, the compound and the at least one additional agent are co-administered to the subject. In some embodiments, the compound and the at least one additional agent are co- formulated. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. The disclosure includes a method of treating, ameliorating, and / or preventing insulin resistance in a subject in need thereof by administering to the subject a therapeutically effective amount of the compound of the disclosure. The disclosure further includes a method of treating, ameliorating, and / or preventing diabetes in a subject in need thereof by administering to the subject a therapeutically effective amount of the compound of the disclosure. In certain embodiments, the diabetes is type II diabetes. In certain embodiment, the compound is administered as a therapeutic composition. The compound and the compositions are as described elsewhere herein. In other embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats, ameliorates, or prevents insulin resistance and / or diabetes. In certain embodiment, the additional therapeutic agent is as described elsewhere herein. In certain embodiments, administering the compound of the disclosure to the subject allows for administering a lower dose of the additional therapeutic agent compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating, ameliorating, or preventing insulin resistance and / or diabetes. For example, in other embodiments, the compound of the disclosure enhances the activity of the additional therapeutic compound, thereby allowing for a lower dose of the additional therapeutic compound to provide the same effect. In certain embodiments, the compound of the disclosure and the additional therapeutic agent are co-administered to the subject. In other embodiments, the compound of the disclosure and the additional therapeutic agent are coformulated and co-administered to the subject. In certain embodiments, the subject is a mammal. In other embodiments, the mammal is a human. Combination Therapies The compounds useful within the methods of the disclosure can be used in combination with one or more additional agents useful for treating or preventing diabetes and / or insulin resistance. These additional agents can comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional agents are known to treat, prevent, or reduce the symptoms of diabetes and / or insulin resistance. Non-limiting examples of anti-diabetic medications contemplated within the disclosure include: α-glucosidase inhibitors: inhibit upper GI enzymes (α-glucosidases) responsible for digesting carbohydrates, slowing absorption of glucose; also cause slower rise in postprandial blood glucose concentrations. Non-limiting examples: acarbose (Precose, Glucobay); miglitol (Glyset); voglibose (Vogseal, Volix, Basen); lipase inhibitors: inhibit pancreatic and gastric lipases, blocking fat absorption. Non- limiting examples: Orlistat (Xenical, Alli); sulfonyl ureas: act as insulin secretagogues, triggering insulin release by interacting with the ATP-dependent potassium channel of the pancreatic β-cells. The net result is that more insulin is released at all blood glucose concentrations. They are the most commonly used drugs for treatment of patients with type 2 diabetes, but, since they trigger release of insulin itself, the combination of insulin & sulfonyl ureas is not common. Non-limiting examples: 1stgeneration of sulfonyl ureas – acetohexamide, chlorpropamide (Diabinese), tolbutamide (Orinase), tolazamide; 2ndgeneration of sulfonyl ureas – gliclazide (Diamicron R, Diamicron MR), glyburide or glibenclamide (Diabeta, Micronase, Glynase), glipizide (Glucotrol, Glucotrol XL), glimepiride (Amaryl), gliquidone (Glurenorm); meglitinides: short-acting glucose-lowering drugs, acting by regulating ATP-dependent potassium channels in pancreatic β-cells like sulfonyl ureas; structurally different from sulfonylureas and act via different receptors as well. Non-limiting examples: mitiglinide (Glufast); nateglinide (Starlix); repaglinide (Prandix); biguanides: reduce glucose release from the liver and increase glucose uptake by skeletal muscle. Metformin is the preferred initial treatment of type 2 diabetes, with good glycemic efficacy, absence of weight gain and hypoglycemia, general tolerability and low cost. The combination of metformin & insulin is generally associated with lower weight gain than insulin by itself or the combination of insulin & sulfonylureas. The triple combination of a sulfonyl urea, metformin and insulin glargine has been shown to have fewer adverse effects, fewer lipid profile problems and lower cost than the triple combination of a sulfonyl urea, metformin and rosiglitazone. Non-limiting examples: metformin (Glucophage); phenformin (DBI); buformin (Glybigid, Glybigidum); thiazolidinediones: increase insulin sensitivity by acting on adipose, muscle and liver tissue to increase glucose utilization and decrease glucose production. The mechanism of action is not fully understood, but they seem to bind and activate one or more peroxisome proliferator-activated receptors (PPARs), regulating gene expression. Non-limiting examples: rosiglitazone (Avandia); pioglitazone (Actos); troglitazone (Rezulin); tesaglitazar (Pargluva); pramlintide (Symlin): also known as islet amyloid polypeptide, is a synthetic analog of human amylin that slows gastric emptying and suppresses glucagon, reducing postprandial rises in blood glucose levels; approved by the FDA to lower blood sugar in type 1 diabetes patients; incretin mimetics: these insulin secretagogues act as glucagon-like peptide-1 (GLP-1) membrane-receptor agonists. They act in a glucose-dependent manner, stimulating insulin secretion only when blood glucose levels are higher than normal. They also promote β- cell regeneration in animal models. Incretin mimetics decrease gastric motility and cause nausea. Non-limiting examples: exenatide, exedin-4 or AC2993 (Byetta); liraglutide, NN2211, or NNC 90-1170; it consists of a lipid conjugate of GLP-1, with high protein binding and a half-life of ~10 h in man; DPP-IV inhibitors: affect glucose regulation, inhibiting degradation of GLP-1. They generally cause fewer problems with hypoglycemia or weight gain as compared to standard treatments. Non-limiting examples include Sitagliptin (Januvia), Sitagliptin & Metformin (Janumet), Vildagliptin (Galvus), and Vildagliptin & Metformin (Eucreas); SGLT2 inhibitors: they supress SGLT2 protein, causing excess glucose to be excreted from the body rather than reabsorbed. Non-limiting examples: Dapaglifozin. A synergistic effect can be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emaxequation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations can be administered to the subject either prior to or after the onset of insulin resistance and / or diabetes. Further, several divided dosages, as well as staggered dosages can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the therapeutic formulations can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions of the present disclosure to a patient, preferably a mammal, more preferably a human, can be carried out using known procedures, at dosages and for periods of time effective to treat, ameliorate, or prevent insulin resistance and / or diabetes. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat, ameliorate, or prevent insulin resistance and / or diabetes. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses can be administered daily or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the disclosure is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of heart failure in a patient. In certain embodiments, the compositions of the disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the disclosure comprise a therapeutically effective amount of a compound of the disclosure and a pharmaceutically acceptable carrier. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. In certain embodiments, the compositions of the disclosure are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the disclosure are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the disclosure varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physical taking all other factors about the patient into account. Compounds of the disclosure for administration can be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In certain embodiments, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of insulin resistance and / or diabetes. Formulations can be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions of the disclosure include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the disclosure can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use can be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets can be uncoated or they can be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. Parenteral Administration For parenteral administration, the compounds of the disclosure can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents can be used. Additional Administration Forms Additional dosage forms of this disclosure include dosage forms as described in U.S. Patents Nos.6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this disclosure also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this disclosure also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations of the present disclosure can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time can be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds can be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the disclosure can be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation. In certain embodiments of the disclosure, the compounds of the disclosure are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. Dosing The therapeutically effective amount or dose of a compound of the present disclosure depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of heart failure in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound of the present disclosure can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different. For example, a dose of 1 mg per day can be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day can be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose can be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the inhibitor of the disclosure is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the viral load, to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. The compounds for use in the method of the disclosure can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this disclosure has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this disclosure can be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art- recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure of the present disclosure as set forth herein. EXAMPLES The disclosure is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the disclosure should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Example 1: Preparation of GLP1R allosteric activators Experimental Details All reactants and reagents were purchased commercially and used without further purification unless otherwise indicated. Starting material reagents were purchased from Oakwood Products Inc., Sigma Aldrich, TCI America (Portland, OR), Acros, and Alfa Aesar. Reactions were carried out under a dry, inert atmosphere of argon unless otherwise indicated. “Concentrated” refers to the removal of a solvent with a rotary evaporator followed by further evacuation with a two-stage mechanical pump. “High vacuum” refers to use of a thermos- fisher vacuum oven connected to a a two-stage mechanical pump. Yields refer to chromatographically and spectroscopically pure (>95%) compounds. Thin-layer chromatography was performed using silica gel 200 μM precoated polyester backed plates with a fluorescent indicator (mobile phase eluent 5-30% EtOAc / Hexanes or 2%-8% MeOH / DCM). Developed TLC plates were visualized with UV light (254 nm), iodine, KMnO4, or p-anisaldehyde staining. Flash column chromatography was conducted using an automated Biotage SP LC usually using normal-phase silica gel (Biotage 12S / M, 25S / M, 40M cartridges). FTIR was run using a Thermofisher Nicolet iS5 with KBr windows.1H NMR spectra were recorded at 400 MHz,13C NMR spectra were recorded at 100 MHz. Chemical shifts are reported in δ values (ppm) relative to an internal reference (0.05% v / v) of tetramethyl silane or the residual solvent signal. Peak-splitting patterns in the1H NMR are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Structural elucidation also involved use of 2-D correlation spectroscopy (ie-1H / 1H NMR or1H / 13C NMR: COSY, NOESY, HMBC, and HMQC). GC-MS was run on a Thermofisher Trace 1300 (GC) with an ISQ QD (MS) and AI / AS 1310 (autosampler). On a few selected samples, MS(ESI+) was obtained from a Waters Acquity UPLC TQD MS with DAD (Waters Acquity UPLC HSS C181.8 uM, 2.1 x 50 mm Column): Solvent A: 0.1% AcOH in H2O; Solvent B: 0.1% AcOH in CH3CN, eluting with 1) 0 min - 0.5 min; 95%A, 2) 0.5 – 2.5 min; 95% A → 95% B gradient, and 3) 2.5 min – 3.0 min; 95% B. Scheme 1: Elaboration of New Series I and II.

[0002] Scheme 2: Synthetic Route to Series I. O R X O NH O CN2S8, DEAX SO EtOH, RT or RT to 40oC 1j-1u 2j-2u RT to 60oC   Table 2. Summary of experimental results of Series I compounds. Reaction of Piperidones prepared according to Scheme 2 (1.0 eq.; 1j-1u), S8 (1.15-1.2 eq), ethyl cyanoacetate (1.15-1.2 eq.) and DEA (1.0 eq.) to afford adducts (2j-2u). Piperidones (1j-1t) were purchased commercially or synthesized. Piperidone (1u) was synthesized according to the procedure shown in Scheme 3. All yields are unoptimized and all chiral adducts were prepared racemic. Scheme 3: Synthetic Route to Piperidone 1u

[0003] Scheme 4: Synthetic Route to Series II. Table 3. Summary of experimental results of Series II compounds. 3 / 4 / 5) and DEA (1.0 eq.) to afford adducts (6-25) according to Scheme 4. *Piperidones (1c,1i, 1j-1t) were purchased commercially or synthesized. **Piperidone (1u) was synthesized according to the procedure shown in Scheme 3. All yields are unoptimized and all chiral adducts were prepared as racemates. Scheme 5: Synthetic Route to Carboxylic Acids. Table 4. Summary of experimental results of N-BOC Carboxylic Acids. Scheme 6: Series I Derivatization A: Piperidine N-Substitution Modification. Scheme 7: Series I Derivatization B: General Modification of 6-Membered Ring.

[0004] Scheme 8: Preparation of Key Intermediates for Series II N-Piperidine Derivatization. Scheme 9: Series II Derivatization A: General Modification of N-Piperidine Ring.

[0005] O Z O Z Base, Alkylating Agent 0 Deg. Celsius to RT NHR" N2H S 6-67% yield N R' S Intermediates Alkylated Products 37A (Z = Me) 38 (Z = Me, R' = MeSO2, R'' = NH2) 37B (Z = Cl) 39 (Z = Cl, R' = MeSO2, R'' = NH2) 40 (Z = Cl, R' = MeO2C, R'' = NH2) 41(Z = Cl, R' = CF3SO2, R'' = NH2)42 (Z = Me, R' = p-Ts, R'' = NH2) 43 (Z = Cl, R' = p-Ts, R'' = NH2) * 44 (Z = Me, R' = H, R'' = NHCOCF3) * 45 (Z = Cl, R' = H, R'' = NHCOCF3) *Products44and45gave the primary amine substituted product.Rest products 38-43 gave expected N-6 substituted product).  Table 5. Summary of biological results of compounds in Schemes 6-9. Preparation of 2-AT compounds Preparation of Ethyl 2-amino-5-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (93% 2a) and Ethyl 2-amino-7-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (7% 2a’) (Procedure A). To a suspension of 0.96 g (1.20 eq; 0.030 mol) of sulfur in 5 mL of EtOH, was added 3.2 mL (1.20 eq.; 0.030 mol) of cyanoacetic ethyl ester, and 3.0 mL (1.0 eq.; 0.025 mol) of 3- methylcyclohexanone (1a). The mixture was stirred at room temperature (25°C) for 10 min; After which, 2.6 mL (1.0 eq; 0.025 mol) of diethylamine was added slowly dropwise over 10 min. The resulting red mixture was stirred overnight at room temperature. The mixture was poured into a rapidly stirring beaker of 125 g of ice and 10 ml of water, and the resulting slurry vacuum filtered and rinsed with 3 × 5 ml of ice cold water:ethanol (1:1) to afford 5.0 g of crude 2a. This solid was recrystallized from 40 ml of 1:1 EtOH / H2O to afford 4.03 g (67.3%) of a 93:7 (5-Me:7-Me) regioisomeric mixture of 2a and 2a’ [Ethyl 2-amino-5- methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (93%, 2a) and Ethyl 2-amino-7- methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (7%, 2a’)] as a light yellow solid . mp 66.5–67.5 °C; IR (neat) 3422.80, 3311.02, 3156.93, 3070.54, 2983.94, 2944.78, 2920.90, 2887.82, 2864.48, 2843.98, 1643.57, 1577.06, 1485.95, 1450.98, 1427.88, 1408.35, 1384.35, 1366.57, 1341.40, 1318.50, 1273.38, 1258.70, 1223.00, 1162.25, 1149.42, 1129.64, 1112.88, 1078.42, 1025.81, 984.25, 971.76, 946.18, 934.13, 898.89, 878.02, 816.51, 799.75, 780.49, 765.88, 745.40, 639.46, 627.32, 548.69, 514.80, 464.81, 405.39 cm-1;1H NMR (400 MHz, d6-DMSO, 5-Me isomer only) d 0.99 (d, 3H, –CH3,), 1.24 (t, 3H, –OCH2CH3,), 1.3 (m, 1H), 1.7 (2H, m), 2.1 (1H, m), 2.45 (2H, m), 2.8 (1H, dd), 4.15 (2H, -OCH2CH3, m), 7.2 (2H, NH2,s);1H NMR (400 MHz, CDCl3, 93:7 [5-Me:7-Me major / minor isomer CH3chemical shift / integration provided, all rest of peaks provided are of major 5-Me (2a) isomer only and integration normalized as though it were isomerically pure]) δ 1.05 (d, J = 6.6 Hz, 2.73H, 5- Me CH3major isomer 2a peak), 1.19 (d, J = 6.8 Hz, 0.27H, selected 7-Me (2a’), CH3minor isomer peak), 1.38 (t, J = 3.84 Hz, 3H), 1.42 (m, 1H), 1.77 (m, 2H), 2.18 (qt, Jq =9.8 Hz, Jt = 2.24 Hz, 1H), 2.56 (m, 2H), 2.92 (dd, J = 4.24 Hz, 1H), 4.26 (q, J = 4.6 Hz, 2H), 5.93 (s, 2H);13C NMR (100 MHz, CDCl3, only data for major 5-Me (2a) isomer provided) δ 14.66 (s), 21.91 (s), 24.49 (s), 29.07 (s), 31.53 (t), 35.51 (s), 59.56 (s), 105.85 (s), 117.49 (s), 124.68 (s), 132.66 (s), 162.09 (s); GCMS (5-Me isomer, 2a) m / z (M)+239.13; GCMS (7-Me isomer, 2a’) m / z (M)+239.15.   Preparation of Ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (2b). Following the experimental operational details of Procedure A, a total of 3.0 mL g (1.0 eq; 24.87 mmol) of 2-methylcyclohexanone (1b), 3.30 mL (1.2 eq.; 30.0 mmol) of ethyl cyanoacetate and 962 mg (1.2 eq.; 30.0 mmol) of elemental S in 5 mL of EtOH was reacted with 2.6 mL (1.01 eq; 25.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution; however, the mixture was stirred 2 h at RT prior to ice water bath precipitation workup. A total of 1.0 g (16.8%) of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate (2b) as a light beige solid was obtained upon filtration and drying in vacuo (50oC; 1 torr): MP 66.4-67.4oC; IR (neat) 3409.17, 3300.51, 3225.14, 3164.17, 2972.89, 2932.97, 2902.00, 2864.24, 1728.65, 1639.16, 1588.52, 1567.74, 1484.40, 1479.73, 1453.49, 1442.12, 1405.33, 1382.78, 1368.93, 1342.64, 1324.33, 1301.68, 1275.96, 1257.46, 1181.78, 1147.42, 1116.13, 1103.02, 1053.12, 1024.36, 980.08, 950.78, 895.14, 854.96, 819.87, 785.09, 762.34, 743.37, 681.70, 629.44, 605.54, 483.66, 445.51 cm-1;1H NMR (400 MHz, CDCl3) δ 1.16 (d, J = 6.7 Hz, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.62 (m, 1H), 1.83 (m, 3H), 2.49 (m, 2H), 3.25 (m, 1H), 4.26 (m, 2H), 5.99 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.52 (q), 18.56 (t), 21.72 (q), 24.77 (t), 29.77 (d), 30.04 (t), 59.59 (t), 105.33 (d), 117.49 (s), 137.78 (s), 162.46 (s), 166.07 (s); GCMS m / z (M)+239.13.   Preparation of Ethyl 2-amino-6-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (2c). Following the experimental operational details of Procedure A, a total of 5.58 g (1.0 eq; 49.70 mmol) of 4-methylcyclohexanone (1c), 6.40 mL (1.2 eq.; 60.0 mmol) of ethyl cyanoacetate and 1.92 g (1.2 eq.; 60.0 mmol) of elemental S in 10 mL of EtOH was reacted with 5.2 mL (1.0 eq; 50.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution; however, the mixture was stirred 2 h at RT then heated to 40oC for 15 h prior to ice water bath precipitation workup using 70 mL 1:1 ice-water. A total of 10.68 g (89.8%) of ethyl 2-amino-6-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (2c) as a yellow solid was obtained upon filtration and drying in vacuo (60oC; 1 torr): MP 107-108.2oC; IR (neat) 3423.49, 3311.15, 3233.40, 3155.39, 2986.82, 2977.39, 2961.81, 2943.29, 2918.36, 2887.84, 2865.17, 2832.87, 1642.45, 1577.89, 1486.33, 1452.75, 1427.62, 1406.38, 1383.32, 1371.14, 1338.68, 1307.59, 1296.20, 1268.82, 1245.10, 1225.75, 1167.05, 1143.51, 1131.23, 1111.13, 1094.30, 1031.03, 1023.79, 984.59, 960.29, 940.98, 927.36, 894.90, 875.13, 839.51, 813.28, 792.50, 777.67, 745.96, 638.56, 612.22, 552.27, 523.10, 471.55, 424.35 cm-1;1H NMR (400 MHz, CDCl3) δ 1.03 (d, J = 6.52 Hz, 3H), 1.34 (t, J = 7.12 Hz, 4H), 1.84 (m, 2H), 2.12 (m, 1H), 2.54 (m, 1H), 2.62 (m, 1H), 2.87 (dt, Jd = 2.96 Hz, Jt = 17.44 Hz, 1H), 4.25 (q, J = 7.12 Hz, 2H), 5.94 (s, 2H);13C NMR (100 MHz, CDCl3) δ 14.65 (q), 21.66 (q), 26.91 (t), 29.49 (d), 31.30 (t), 32.83 (t), 59.53 (t), 105.80 (s), 117.37 (s), 132.28 (s), 162.00 (s), 166.30 (s); GCMS m / z (M)+239.16. Preparation of Ethyl 2-amino-6-propyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (2d). Following the experimental operational details of Procedure A, a total of 6.66 g (1.00 eq.; 47.5 mmol) of 4-propyl-1-cyclohexanone (1d), 6.10 mL (1.20 eq.; 57.0 mmol) of ethyl cyanoacetate and 1.83 g (1.20 eq.; 57.0 mmol) of elemental S in 9.6 mL of EtOH was reacted with 5.10 mL (1.03 eq; 48.9 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was stirred for 120 min at RT, heated to 40oC overnight, and cooled to RT. The mixture was then poured slowly into a rapidly stirring mixture of 125 mL 50% ice-water. Extra EtOH was added as necessary to complete the transfer of the mixture. The resulting slurry was then filtered, the filter cake washed with 10% EtOH / water (2 x 50 mL), followed by 100 mL of ice cold water. A total of 11.6 g (91.7%) of ethyl 2-amino-6-propyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (2d) as a beige colored solid was obtained after drying in vacuo (55oC; 1 torr): MP 63.2-64.2 °C; IR (neat) 3401.29, 3297.45, 3233.25, 3173.79, 3081.68, 2981.10, 2950.16, 2919.95, 2894.85, 2867.87, 2852.79, 1647.82, 1598.05, 1577.86, 1488.63, 1476.55, 1453.15, 1441.68, 1427.84, 1410.50, 1383.91, 1365.99, 1340.15, 1309.80, 1272.56, 1256.69, 1230.66, 1162.26, 1145.17, 114.56, 1062.28, 1027.47, 977.65, 959.75, 901.77, 885.56, 840.88, 819.17, 807.11, 778.99, 747.94, 734.53, 667.79, 642.96, 613.41, 585.59, 563.59, 525.64, 499.17, 448.28, 420.37, 405.07 cm-1;1H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.12 Hz, 3H), 1.33 (m, 5H); 1.73 (m, 1H), 1.86 (m, 1H), 2.13 (m, 1H), 2.57 (m, 2H), 2.86 (m, 1H), 4.25 (q, J = 7.12 Hz, 2H), 5.94 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.46 (q), 14.65 (q), 20.27 (t), 26.95 (t), 29.45 (t), 31.03 (t), 34.40 (d), 38.50 (t), 59.54 (t), 105.78 (s), 117.52 (s), 132.56 (s), 162.01 (s), 166.31 (s); GCMS m / z (M)+267.23. Preparation of Ethyl 2-amino-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophene- 3-carboxylate (2e). Following the experimental operational details of Procedure A, a total of 3.00 g (1.00 eq.; 18.1 mmol) of 4-(trifluoromethyl)-1-cyclohexanone (1e), 2.20 mL (1.15 eq.; 20.8 mmol) of ethyl cyanoacetate and 666 mg (1.15 eq.; 20.8 mmol) of elemental S in 20 mL of EtOH was reacted with 2.15 mL (1.15 eq; 20.8 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was stirred for 30 min at RT, heated to 40oC overnight, and cooled to RT. The mixture was then diluted with 30 mL of ice cold EtOH, and poured into a rapidly stirring mixture of 100 mL 50% ice-water. The resulting slurry was then filtered, the filter cake washed with 30% EtOH / water (2 x 50 mL), followed by 100 mL of ice cold water. A total of 4.74 g (89.5%) of Ethyl 2-amino-6-(trifluoromethyl)-4,5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (2e) as a pale orange colored solid was obtained after drying in vacuo (70oC; 1 torr): MP 133.0-134.0 °C; IR (neat) 3427.55, 3317.14, 3239.23, 3159.23, 3074.96, 2988.33, 2941.83, 2901.68, 2859.14, 1644.41, 1587.56, 1578.56, 1578.22, 1488.25, 1448.16, 1437.86, 1410.29, 1392.57, 1386.77, 1369.71, 1345.45, 1326.23, 1305.31, 1291.71, 1267.86, 1244.60, 1222.64, 1156.81, 113.33, 1109.23, 1064.63, 1024.08, 1014.68, 985.11, 968.09, 900.95, 885.96, 843.07, 812.55, 780.39, 746.57, 681.74, 639.73, 612.13, 578.02, 565.79, 513.17, 433.43, 422.45, 413.16, 405.50 cm-1;1H NMR (400 MHz, CDCl3) δ 1.34 (t, J = 7.12 Hz, 3H), 1.63 (m, 1H), 2.14 (m, 1H), 2.44 (m, 1H), 2.61 (m, 2H), 2.72 (m, 1H), 3.04 (dd, Jd = 16.6 Hz, Jd = 4.8 Hz, 1H), 4.26 (q, Jq = 7.12 Hz, 2H), 6.00 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.63 (q), 22.08 (tq, JC-C-C-F = 2.5 Hz), 23.89 (tq, JC-C-C-F = 3.0 Hz), 26.01 (t), 39.61 (d, Jq(C-C-F)= 27.2 Hz), 59.76 (t), 105.38 (s), 114.21 (s), 127.82 (s, Jq(C-F) = 277.0 Hz), 132.29 (s), 162.43 (s), 166.04 (s); GCMS m / z (M)+293.20. Preparation of Ethyl 2-amino-6-(propan-2-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (2f) (Procedure B). To a solution of 5.0 g (1.20 eq; 35.7 mmol) of 4-isopropylcyclohexanone (1f), 4.60 mL (1.2 eq.; 42.8 mmol) of ethyl cyanoacetate and 1.40 g (1.2 eq.; 42.8 mmol) of elemental S in 7.2 mL of EtOH was added 3.8 mL (1.03 eq; 36.8 mmol) of diethylamine, and the mixture stirred 2 hr at RT to form a slurry. This mixture was chopped up to afford a homogenous slurry and was then heated to 40oC overnight. The reaction mixture was cooled to RT, diluted with 400 mL of CHCl3 and partitioned with 200 mL of water in a 1-L separatory funnel. The aqueous layer was back extracted with two portions of CHCl3(2 x 100-mL). The combined organic extracts were washed with 100 mL brine, dried (MgSO4), and concentrated in vacuo afford a orange-red mixture containing predominantly the desired adduct (2f). This material was absorbed onto 20 g of SiO2 (DCM) and concentrated to a powder. This material was applied evenly to the top of 150 g of wet packed silica gel in a 350 mL filtration funnel (eluting slowly with hexanes → 10% EtoAc / Hexanes) in 200 mL fractions to afford 8.18 g (86.0%) of ethyl 2-amino-6-(propan-2-yl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (2f) as a light orange oil which crystallized into a yellow solid over a 2 day period: MP 57.5- 58.5 °C; IR (neat) 3419.97, 3311.37, 3160.71, 2979.50, 2969.69, 2918.87, 2890.15, 2831.10, 1638.04, 1645.55, 1582.05, 1488.14, 1473.47, 1428.16, 1407.62, 1382.30, 1363.69, 1339.30, 1300.24, 1266.71, 1232.70, 1149.74, 1128.21, 1113.11, 1088.49, 1026.77, 978.70, 968.15, 950.19, 905.28, 886.12, 866.28, 838.50, 816.22, 805.01, 779.16, 766.54, 746.38, 697.41, 636.60, 605.87, 580.52, 564.17, 543.35, 524.33, 504.70, 471.20, 447.63, 435.85, 427.92, 423.84, 415.80, 410.88 cm-1;1H NMR (400 MHz, CDCl3) δ 0.91 (d, J = 6.68 Hz, 3H), 0.94 (d, J = 6.68 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.32 (M, 1H), 1.48 (m, 1H), 1.56 (m, 1H), 1.89 (m, 1H), 2.24 (m, 1H), 2.53 (m, 2H), 2.91 (dm, Jd= 17.52 Hz, 1H), 4.25 (q, J = 7.12 Hz, 2H), 5.95 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.64 (q), 19.79 (q), 20.03 (q), 26.72 (t), 27.51 (t), 28.05 (t), 32.27 (d), 41.32 (d), 59.52 (t), 105.67 (s), 117.87 (s), 132.59 (s), 162.05 (s), 166.29 (s); GCMS m / z (M)+267.23. Preparation of Ethyl 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (2g). Following the experimental operational details reported in Procedure B, a total of 5.5 g (1.20 eq; 35.7 mmol) of 4-tert-butylcyclohexanone (1g), 4.60 mL (1.2 eq.; 42.8 mmol) of ethyl cyanoacetate and 1.40 g (1.2 eq.; 42.8 mmol) of elemental S in 7.2 mL of EtOH was reacted slowly dropwise with 3.8 mL (1.03 eq; 36.8 mmol) of diethylamine, the mixture stirred 2 hr at RT and then was heated to 40oC overnight. This was subjected to the same exact workup and filter funnel chromatography purification procedure utilized for adduct 2g to afford 8.99 g (89.5 %) of ethyl 2-amino-6-tert-butyl-4,5,6,7-tetrahydro-1-benzothiophene- 3-carboxylate (2g) as a pale orange oil / foam: IR (neat) 3431.67, 3326.32, 2947.39, 2901.04, 2864.80, 1664.11, 1651.43, 1577.85, 1483.67, 1442.41, 1430.99, 1408.49, 1392.85, 1385.31, 1363.58, 1338.99, 1308.58, 1264.02, 1246.02, 1227.28, 1170.55, 1145.92, 113.15, 1097.09, 1027.47, 975.30, 931.72, 898.38, 881.41, 843.03, 827.48, 780.99, 753.86, 736.35, 631.34, 592.84, 507.00, 486.13, 447.88, 427.50, 413.02, 401.12 cm-1;1H NMR (400 MHz, CDCl3) δ 0.91 (s, 9H), 1.25 (m, 1H), 1.32 (t, J = 7.12 Hz, 3H), 1.45 (m, 1H), 1.95 (m, 1H), 2.28 (m, 1H), 2.47 (m, 2H), 2.97 (m, 1H), 4.24 (q, J = 7.12 Hz, 2H), 5.95 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.63 (q), 24.56 (t), 26.18 (t), 27.45 (qtBu), 28.21 (t), 32.59 (s), 45.33 (d), 59.51 (t), 105.57 (s), 118.30 (s), 132.59 (s), 162.11 (s), 166.29 (s); GCMS m / z (M)+281.24.   Preparation of Ethyl 2-amino-5,5-dimethyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (2h). Following the experimental operational details of Procedure A, a total of 1.0 g (1.0 eq; 7.92 mmol) of 3,3-dimethylcyclohexanone (1h), 1.10 mL (1.2 eq.; 10.3 mmol) of ethyl cyanoacetate and 0.32 g (1.26 eq.; 10.0 mmol) of elemental S in 2 mL of EtOH was reacted with with 0.84 mL (1.02 eq; 8.1 mmol) of diethylamine added slowly dropwise over 10 min at RT to form a solution. The reaction mixture was stirred 2 h at RT then heated to 40oC for 20 h prior to ice water bath precipitation workup. A total of 1.83 g (91.5%) of ethyl 2-amino- 5.5-dimethyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (2h) as a light yellow solid was obtained upon filtration and drying in vacuo (50oC; 1 torr): MP 66.9-67.5oC; IR (neat) 3394.28, 3293.35, 3234.03, 3170.55, 2979.19, 2960.63, 2895.75, 2838.24, 1645.99, 1597.78, 1579.68, 1488.37, 1465.35, 1450.61, 1427.62, 1406.56, 1381.82, 1366.94, 1342.22, 1327.49, 1270.00, 1213.68, 1171.06, 1144.59, 1091.22, 1025.95, 983.15, 958.34, 928.60, 909.36, 887.99, 781.37, 734.91, 643.42 cm-1;1H NMR (400 MHz, CDCl3) δ 0.97 (s, 6H), 1.34 (t, J = 7.12 Hz, 3H), 1.52 (t, J = 6.4 Hz, 2H), 2.50 (m, 4H), 4.26 (q, J = 7.12 Hz, 2H), 5.93 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.66 (q), 22.20 (t), 28.39 (q), 29.36 (s), 36.08 (t), 40.92 (t), 59.57 (t), 106.10 (s), 116.46 (s), 132.15 (s), 162.23 (s), 166.20 (s); GCMS m / z (M)+253.16. Preparation of Ethyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydro-1-benzothiophene-3- carboxylate (2i). Following the experimental operational details of Procedure A, a total of 1.2 g (1.0 eq; 9.50 mmol) of 4,4-dimethylcyclohexanone, 1.10 mL (1.09 eq.; 10.3 mmol) of ethyl cyanoacetate and 0.32 g (1.05 eq.; 10.0 mmol) of elemental S in 2 mL of EtOH was reacted with 0.98 mL (1.0 eq; 9.50 mmol) of diethylamine added slowly dropwise over 10 min at RT. The reaction mixture was stirred 2 h at RT then heated to 40oC for 20 h prior to the ice water bath precipitation workup. A total of 2.25 g (93.5%) of ethyl 2-amino-6,6-dimethyl-4,5,6,7- tetrahydro-1-benzothiophene-3-carboxylate (2i) as a light yellow solid was obtained upon filtration and drying in vacuo (60oC; 1 torr): MP 120.6-121.8oC; IR (neat) 3406.74, 3298.79, 3234.38, 3164.23, 2988.84, 2970.46, 2950.16, 2921.31, 2898.33, 2863.53, 2844.89, 1647.66, 1594.70, 1584.64, 1489.13, 1463.87, 1440.74, 1426.83, 1405.00, 1379.86, 1368.56, 1360.37, 1342.90, 1322.00, 1299.74, 1277.56, 1260.46, 1214.86, 1170.49, 1132.04, 1090.53, 1035.11, 1024.77, 1006.48, 973.11, 924.92, 907.82, 880.65, 839.14, 803.48, 776.82, 740.67, 730.65, 638.05, 618.42, 569.99, 520.06 cm-1;1H NMR (400 MHz, CDCl3) δ 0.98 (s, 6H), 1.34 (t, J = 7.12 Hz, 3H), 1.48 (t, J = 6.44 Hz, 2H), 2.27 (br s, 2H), 2.70 (t, J = 6.40 Hz, 2H), 4.26 (q, J = 7.12 Hz, 2H), 5.93 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.68 (q), 24.81 (t), 28.03 (q), 30.44 (s), 35.91 (t), 38.26 (t), 59.57 (t), 105.79 (s), 117.18 (s), 131.18 (s), 162.00 (s), 166.35 (s); GCMS m / z (M)+253.16. Preparation of Ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylate (2j) (Procedure A). A total of 5.0 g (1.00 eq; 50.0 mmol) of 4-pyranone (oxan-4-one, 1j), 6.40 mL (1.20 eq.; 60.0 mmol) of ethyl cyanoacetate and 1.92 g (1.20 eq.; 60.0 mmol) of elemental S in 10 mL of EtOH was reacted with 5.20 mL (1.00 eq; 50.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution; however, the mixture completely solidified while stirring 30 min at RT. A total of 5 mL of EtOH was then added to the mixture to form a stirrable slurry. The reaction mixture was heated to 40oC for 30 min, cooled to RT overnight, and was then poured into a rapidly stirring mixture of 75 mL 50% ice-water. This slurry was filtered, the filter cake washed with 20 mL of ice cold 50% EtOH / water, followed by 50 mL of ice cold 10% EtOH / water. A total of 9.70 g (85.4%) of ethyl 2-amino-4,7-dihydro-5H- thieno[2,3-c]pyran-3-carboxylate (2j) as a beige solid was obtained after drying in vacuo (60oC; 1 torr): MP 170.0-170.4 °C; IR (neat) 3433.62, 3324.71, 3248.69, 3172.57, 3073.03, 2980.38, 2952.67, 2934.89, 2902.49, 2859.00, 2845.55, 2753.65, 1650.97, 1580.48, 1488.22, 1459.30, 1437.95, 1417.64, 1383.07, 1368.78, 1352.32, 1339.78, 1303.16, 1278.55, 1258.08, 1225.99, 1164.28, 1123.99, 1088.95, 1021.67, 997.67, 971.90, 961.07, 890.68, 869.66, 844.22, 800.10, 777.02, 746.31, 746.31, 641.35, 613.66, 577.88, 520.67, 481.81, 469.81, 432.66, 408.96 cm-1;1H NMR (400 MHz, CDCl3) δ 1.33 (t, J =7.12 Hz, 3H), 2.82 (m, 2H), 3.91 (t, J =5.6 Hz, 2H), 4.26 (q, J = 7.12 Hz, 2H), 4.55 (t, J = 1.8 Hz, 2H), 6.08 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 14.58 (q), 27.85 (t), 59.70 (t), 64.73 (t), 65.26 (t), 105.45 (s), 114.85 (s), 130.36 (s), 162.48 (s), 166.01 (s); GCMS m / z (M)+227.09. Preparation of Ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylate (2k). Following the experimental operational details of Procedure A, a total of 5.0 g (1.00 eq; 43.0 mmol) of 4-thiopyranone (oxan-4-thione or thian-4-one, 1k), 5.5 mL (1.20 eq.; 51.6 mmol) of ethyl cyanoacetate and 1.66 g (1.20 eq.; 51.6 mmol) of elemental S in 9 mL of EtOH was reacted with 4.50 mL (1.00 eq; 43.0 mmol) of diethylamine added slowly dropwise over 10 min at RT to form a solution. The reaction mixture was heated to 40oC for 30 min, cooled to RT overnight, and was then poured into a rapidly stirring mixture of 100 mL 50% ice-water. This slurry was filtered, the filter cake washed with 50% EtOH / water (3 x 75-mL), followed by 100 mL of ice cold water. A total of 8.79 g (84.0%) of ethyl 2-amino- 4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylate (2k) as a beige solid was obtained after drying in vacuo (65oC; 1 torr): MP 87.4-87.9 °C; IR (neat) 3388.78, 3292.05, 3237.44, 3154.13, 3069.88, 3978.33, 3936.40, 2887.80, 2813.60.1647.16, 1587.46, 1569.28, 1484.48, 1443.28, 1418.62, 1404.56, 1383.88, 1361.34, 1335.89, 1294.01, 1268.75, 1241.52, 1199.05, 1184.22, 1158.36, 1132.43, 1110.28, 1029.34, 1000.66, 950.18, 889.86, 851.01, 830.22, 784.12, 748.57, 742.37, 690.86, 591.20, 567.04, 519.49, 499.54, 427.94, 409.42, 401.12 cm-1;1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, J = 6.96 Hz, 3H), 2.84 (m, 4H), 3.54 (s, 2H), 4.16 (q, J = 6.88 Hz, 2H), 7.29 (br s, 2H);13C NMR (100 MHz, DMSO-d6) δ 14.33 (q), 24.18 (t), 25.24 (t), 28.32 (t), 58.79 (t), 102.93 (s), 112.14 (s), 131.16 (s), 162.15 (s), 164.80 (s); GCMS m / z (M)+243.07. Cl   Preparation of Ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate (free base form of 2l) (Step 1). Following the experimental operational details of Procedure A, a total of 5.66 g (1.00 eq; 50.0 mmol) of 1-methyl-4-piperidinone (1l), 6.4 mL (1.20 eq.; 60.0 mmol) of ethyl cyanoacetate and 1.92 g (1.20 eq.; 60.0 mmol) of elemental S in 10 mL of EtOH was reacted with 5.20 mL (1.00 eq; 50.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was heated to 40oC for 30 min, cooled to RT overnight, and was then poured into a rapidly stirring mixture of 100 mL 50% ice-water. This slurry was filtered, the filter cake washed with 50% EtOH / water (3 x 50 mL), followed by 100 mL of ice cold water. A total of 11.51 g (95.8%) of ethyl 2-amino-6-methyl-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate (2l) as a yellow solid was obtained after drying in vacuo (70oC; 1 torr): mp 102.6 – 103.1oC. This material was taken directly into the next purification reaction step (Step 2). Preparation of Ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate hydrochloride (2l) (Step 2). To a solution of 11.51 g (1.0 eq; 47.89 mmol) of the free base form of 2l in 50 mL of 20% EtOH / DCM cooled to 0oC, was added 14.1 mL (1.2 eq.; 56.5 mmol) of 4M HCl in dioxanes to form a yellow slurry which after 10 min was diluted with 50 mL of ether. The slurry was filtered, the filter cake washed with 50 mL of ether, followed by 30 mL of 10% EtOH / ether. The solid was dried (70-80oC; 1 torr) to afford 13.16 g (99.2%; 95.1% overall yield) of ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (2l) as a yellow powder: MP above 250 °C; IR (neat) 3658.64, 3363.00, 3193.37, 3123.60, 3055.23, 2979.62, 2888.102672.65, 2573.40, 2540.78, 2435.16, 1655.22, 1578.60, 1487.73, 1471.77, 1432.16, 1418.02, 1376.07, 1361.88, 1346.49, 1320.75, 1287.96, 1267.27, 1246.09, 1178.68, 1161.35, 1130.46, 114.73, 1089.26, 1053.34, 1030.09, 991.19, 960.75, 949.64, 892.76, 851.60, 775.28, 748.76, 661.27, 562.09, 481.10, 461.42, 414.33 cm-1;1H NMR (400 MHz, DMSO-d6) δ 1.26 (t, J = 7.08 Hz, 3H), 2.82 (d, J = 3.8 Hz, 3H), 2.98 (m, 2H), 3.24 (m, 1H), 3.52 (m, 1H), 4.03 (m, 1H), 4.18 (q, J = 7.04 Hz, 3H), 7.50 (br s, 2H), 11.42 (br s, 1H);13C NMR (100 MHz, DMSO-d6) δ 14.32 (q), 23.71 (t), 41.44 (q), 49.81 (t), 49.86 (t), 59.00 (t), 101.51 (s), 106.79 (s), 128.87 (s), 164.22 (s), 164.50 (s); GCMS m / z (2k – HCl fragment M)+240.18. Preparation of Ethyl 2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate (2m). Following the experimental operational details of Procedure A, a total of 5.00 g (1.00 eq; 39.3 mmol) of 1-ethyl-4-piperidinone (1m), 5.0 mL (1.20 eq.; 47.2 mmol) of ethyl cyanoacetate and 1.51 g (1.20 eq.; 47.2 mmol) of elemental S in 9 mL of EtOH was reacted with 4.10 mL (1.00 eq; 39.3 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was heated to 40oC for 60 min, cooled to RT overnight, and was then poured into a rapidly stirring mixture of 100 mL 50% ice-water. This slurry was filtered, the filter cake washed with 50% EtOH / water (3 x 50 mL), followed by 100 mL of ice cold water. A total of 9.38 g (93.8%) of ethyl 2-amino-6-ethyl-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate (2m) as a yellow solid was obtained after drying in vacuo (65oC; 1 torr): MP 89.8-90.2°C; IR (neat) 3392.98, 3292.48, 3232.48, 3173.64, 3129.43, 3081.63, 2971.78, 2960.83, 2929.85, 2878.44, 2816.94, 2774.78, 2725.24, 166.90, 1645.49, 1600.90, 1584.36, 1492.46, 1467.55, 1453.10, 1428.49, 1410.71, 1371.981362.88, 1345.78, 1317.76, 12888.93, 1272.85, 1257.22, 1232.601196.71, 1169.55, 1154.83, 1133.75, 1108.61, 1092.80, 1074.80, 1056.72, 1023.70, 994.36, 964.18, 931055, 883.24, 850.68, 814.28, 805.67, 776.71, 735.53, 642.06, 584.16, 564.86, 564.86, 516.61, 502.24, 476.67,445.99, 422.27, 410.61, 404.76 cm-1;1H NMR (400 MHz, DMSO-d6) δ 1.04 (t, J = 7.12 Hz, 3H), 1.25 (t, J = 7.08 Hz, 3H), 2.47 (q, J = 7.13 Hz, 2H), 2.58 (t, J = 5.2 Hz, 2H), 2.66 (m, 2H), 3.27 (s, 2H), 3.36 (m, 1H), 4.15 (q, J = 7.08 Hz, 2H), 7.24 (br s, 2H);13C NMR (100 MHz, DMSO-d6) δ 12.36 (q), 14.32 (q), 21.18 (t), 49.86 (t), 50.48 (t), 50.99 (t), 58.65 (t), 102.14 (s), 113.37 (s), 130.00 (s), 163.15 (s), 164.92 (s); GCMS m / z (M)+254.18.   Preparation of Ethyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate (2n). Following the experimental operational details of Procedure A, a total of 5.00 g (1.00 eq; 36.0 mmol) of 1-cyclopropyl-4-piperidinone (1n), 4.6 mL (1.20 eq.; 43.0 mmol) of ethyl cyanoacetate and 1.39 g (1.20 eq.; 43.0 mmol) of elemental S in 8 mL of EtOH was reacted with 3.7 mL (1.00 eq; 36.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was heated to 40oC for 60 min, cooled to RT overnight, and was then poured into a rapidly stirring mixture of 100 mL 50% ice-water to produce a dark oil. Added EtOH in 5 x 50-mL intervals to afford a orange slurry. This slurry was filtered, the filter cake washed with 50% EtOH / water (3 x 50 mL), followed by 100 mL of ice cold water. A total of 5.60 g (58.3%) of ethyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate (2n) as an orange solid was obtained after drying in vacuo (65oC; 1 torr): MP 70.1-70.6 °C; IR (neat) 3527.71, 3414.28, 3370.95, 3265.01, 3226.14, 3121.96, 3070.87, 2998.60, 2938.54, 2901.43, 2826.40, 2782.33, 2762.23, 2738.03, 1658.84, 1641.98, 1611.40, 1598.89, 1578.12, 1486.93, 1465.96, 1451.96, 1431.28, 1413.92, 1386.48 , 1360.39, 1349.78, 1338.21, 1299.20, 1274.52, 1256.88, 1233.95, 1215.21, 1173.37, 1132.73, 1111.10, 1020.25, 1014.34, 975.80, 963.42, 934.62, 874.37, 826.73, 798.77, 779.14, 732.72, 698.69, 633.99, 605.50, 566.37, 548.69, 530.50, 497.39, 459.97, 418.95, 408.83 cm-1;1H NMR (400 MHz, DMSO-d6) δ 0.36 (m, 2H), 0.44 (m, 2H), 1.24 (t, J = 6.48 Hz, 3H), 1.81 (s, 1H), 2.64 (m, 2H), 2.77 (m, 2H), 3.44 (m, 2H), 4.14 (q, J = 6.76 Hz, 2H), 7.24 (br s, 2H);13C NMR (100 MHz, DMSO-d6) δ 5.95 (t), 14.32 (q), 26.94 (t), 37.17 (d), 49.95 (t), 50.82 (t), 58.67 (t), 102.18 (s), 113.22 (s), 129.88 (s), 163.21 (s), 164.94 (s); GCMS m / z (M)+266.16.   Preparation of Ethyl 2-amino-6-(propan-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 3-carboxylate (free base form of 2o) (Step 1). Following the experimental operational details of Procedure A, a total of 3.90 g (1.00 eq; 27.6 mmol) of 1-(propan-2-yl)-4-piperidinone (1o), 4.0 mL (1.20 eq.; 33.1 mmol) of ethyl cyanoacetate and 1.06 g (1.20 eq.; 33.1 mmol) of elemental S in 9 mL of EtOH was reacted with 1.5 mL (1.00 eq; 27.6 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was heated to 40oC overnight, cooled to RT, and was then concentrated in vacuo. This material was absorbed onto a 8 g biotage precolumn (eluted with DCM to 10% MeOH / DCM) to afford 5.56 g (75.0%) of a dark red oil. This material was taken directly into the next purification reaction step (Step 2). Preparation of Ethyl 2-amino-6-(propan-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 3-carboxylate hydrochloride (2o) (Step 2). To a solution of 11.51 g (1.0 eq; 20.72 mmol) of the free base form of 2o in 55 mL of 20% EtOH / DCM cooled to 0oC, was added 6.22 mL (1.2 eq.; 24.9 mmol) of 4M HCl in dioxanes to form a yellow slurry which after 10 min was diluted with 55 mL of ether. The slurry was filtered, and the filter cake washed with 50 mL of ether. The solid was dried (70- 80oC; 1 torr) to afford 2.87 g (45.4%; overall yield) of a first crop of 2-amino-6-(propan-2- yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate hydrochloride (2o) as a tan powder. An addition 1.67 g (26.4% overall yield from 1o) of 2o was obtained from the mother liquor that was less pure which was not combined with crop 1 or included in the yield calculations: Crop 1: MP 204.6-205.1 °C; IR (neat) 3448.67, 3398.23, 3208.65, 3126.60, 2976.99, 2555.07, 2164.56, 1992.31, 1686.16, 1656.68, 1591.77, 1508.50, 1491.42, 1454.53, 1435.76, 1425.16, 1368.35, 1344.23, 1305.83, 1285.63, 1268.00, 1236.83, 1168.79, 1129.32, 1061.92, 1036.83, 1020.26, 930.28, 774.27, 414.08, 408.25, 402.67 cm-1;1H NMR (400 MHz, DMSO- d6) δ 1.25 (t, J = 7.08 Hz, 3H), 1.31 (d, J = 6.60 Hz, 3H), 1.34 (d, J = 6.64 Hz, 3H), 3.00 (m, 2H), 3.15 (m, 1H), 3.54 (m, 2H), 4.10 (m, 2H), 4.17 (q, J = 7.06 Hz, 2H), 7.50 (br s, 2H), 11.20 (br s, 1H);13C NMR (100 MHz, DMSO-d6) δ 14.32 (q), 16.11 (q), 16.97 (q), 24.25 (t), 44.62 (t), 45.73 (t), 55.65 (t), 58.96 (d), 101.37 (s), 107.33 (s), 129.44 (s), 164.28 (s), 164.52 (s) ; GCMS (Method 3) rt 19.36 m / z (M)+268.16.   Preparation of Ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate (2p). Following the experimental operational details of Procedure A, a total of 5.00 g (1.00 eq; 35.0 mmol) of 1-acetyl-4-piperidinone (1p), 4.52 mL (1.20 eq.; 43.0 mmol) of ethyl cyanoacetate and 1.39 g (1.20 eq.; 42.5 mmol) of elemental S in 8 mL of EtOH was reacted with 3.6 mL (1.00 eq; 35.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was heated to 40oC for 60 min, cooled to RT overnight, and was then poured into a rapidly stirring mixture of 100 mL 50% ice-water to a mango colored slurry. This slurry was filtered, the filter cake washed with 50% EtOH / water (3 x 75 mL), followed by 100 mL of ice cold water. A total of 8.78 g (93.5%) of ethyl 2-amino-6-acetyl- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (2p) as an orange solid was obtained after drying in vacuo (65oC; 1 torr): MP 147.5-148.2 °C; IR (neat) 3425.36, 3376.63, 3284.88, 3239.88, 3150.07, 3086.08, 2972.76, 2992.76, 2922.41, 2891.84, 2866.50, 2841.22, 1664.40, 1620.90, 1603.98, 1579.17, 1496.41, 1470.80, 1446.18, 1415.35, 1385.77, 1369.50, 1340.58, 1303.09, 1264.39, 1234.11, 1200.63, 1148.57, 1129.86, 1102.49, 1028.73, 995.39, 975.36, 963.82, 886.86, 849.72, 800.51, 778.60, 751.59, 733.72, 611.33, 592.35, 559.45, 536.35, 526.98, 516.07, 498.96 cm-1;1H NMR (400 MHz, DMSO-d6, 2:1 mixture of rotomers) δ 1.25 (m, 3H), 2.03 (s, 1H, minor rotomer), 2.07 (s, 2H, major rotomer), 2.64 (m, 0.67H, minor rotomer), 2.75 (m, 1.37H, major rotomer), 3.62 (m, 2H), 4.16 (m, 2H), 4.36 (bs, 1.33H, major rotomer), 4.39 (bs, 0.67H, minor rotomer), 7.33 (br s, 2H);13C NMR (100 MHz, DMSO-d6, 2:1 mixture of rotomers) δ 14.34 (q), 21.08 (q, major rotomer), 21.65 (q, minor rotomer), 26.42 (t, minor rotomer), 27.34 (t, major rotomer), 38.22 (t, minor rotomer), 40.03 (t, major rotomer), 43.12 (t, major rotomer), 44.14 (t, minor rotomer), 58.79 (t), 101.99 (s, minor rotomer), 102.02 (s, major rotomer), 111.93 (s, minor rotomer), 112.34 (s, major rotomer), 130.18 (s, major rotomer), 130.71 (s, minor rotomer), 163.52 (s, major rotomer), 163.62 (s, minor rotomer), 164.75 (s), 168.34 (s, major rotomer), 168.50 (minor rotomer); GCMS m / z (M)+268.15.   Preparation of Diethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (2q). Following the experimental operational details of Procedure A, a total of 8.56 g (1.00 eq; 50.0 mmol) of ethyl 4-oxopiperidine-1-carboxylate (1q), 6.4 mL (1.20 eq.; 60.0 mmol) of ethyl cyanoacetate and 1.92 g (1.20 eq.; 60.0 mmol) of elemental S in 10 mL of EtOH was reacted with 5.20 mL (1.00 eq; 50.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was heated to 40oC for 30 min, cooled to RT overnight, and was then poured into a rapidly stirring mixture of 100 mL 50% ice-water. This slurry was filtered, the filter cake washed with 50% EtOH / water (2 x 50 mL), followed by 100 mL of ice cold water. A total of 13.53 g (90.7%) of diethyl 2-amino-4,7- dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (2q) as a mango colored solid was obtained after drying in vacuo (65oC; 1 torr): MP 142.4-143.2 °C; IR (neat) 3421.35, 3318.60, 3251.45, 3195.50, 3159.45, 3082.73, 3013.77, 2979.62, 2956.62, 2938.28, 2928.63, 2901.66, 2855.56, 2837.57, 1726.25, 1684.09, 1664.71, 1622.71, 1587.19, 1571.64, 1494.10, 1485.23, 1462.16, 1440.82, 1420.24, 1413.94, 1385.84, 1366.81, 1329.97, 1292.47, 1258.97, 1227.40, 1200.66, 1161.03, 1141.40, 1124.49, 1107.43, 1046.56, 1025.29, 101.09, 987.32, 950.16, 884.43, 850.66, 834.94, 809.81, 796.74, 779.17, 769.72, 743.84, 693.68, 659.67, 643.61, 610.25, 559.63, 554.05, 533.40, 513.96, 461.51, 429.18, 422.85, 404.74 cm-1;1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J = 7.00 Hz, 3H), 1.25 (t, J = 7.06 Hz, 3H), 2.68 (m, 2H), 3.56 (bt, J = 5.4 Hz, 2H), 4.07 (q, J = 6.92 Hz, 2H), 4.16 (q, J = 7.00 Hz, 2H), 4.30 (s, 2H), 7.33 (br s, 2H);13C NMR (100 MHz, DMSO-d6, 55:45 mixture of rotomers) δ 14.28 (q), 14.54 (q), 26.38 (t, minor rotomer), 26.71 (t, major rotomer), 40.61 (t, minor rotomer), 40.92 (t, major rotomer), 42.27 (t), 58.79 (t), 60.89 (t), 102.05 (s), 111.98 (bs), 130.25 (s), 154.66 (s) 163.56 (s), 164.75 (s); GCMS m / z (M)+298.15.   Preparation of Prop-2-en-1-yl 4-oxopiperidine-1-carboxylate (1r). To a solution of 20.0 g (1.00 eq.; 130.2 mmol) of 4-piperidone monohydrate hydrochloride and 27.0 g (1.50 eq; 195 mmol) of potassium carbonate in 300 mL of water cooled to 5oC, was added 21.0 mL (1.50 eq; 195 mmol) of allyl chloroformate slowly dropwise over 5-10 min. The mixture was stirred 1 h at 5oC, warmed to RT and was then stirred 1 h. The mixture was saturated with solid NaCl and was then partitioned with ether (5 x 100-mL). The combined organic extracts were washed once with 50 mL of cold aqueous 5% NH3, 50 mL of drine, dried (MgSO4) and concentrated in vacuo to afford 19.15 g (80.8%) of prop-2-en-1-yl 4-oxopiperidine-1-carboxylate (1r) as a colorless oil: IR (neat) 3083.55, 2961.65, 2878.60, 2164.75, 1692.18, 1647.92, 1537.43, 1474.71, 1433.63, 1414.20, 1373.87, 1350.32, 1310.90, 1271.94, 1224.71, 1117.88, 1058.64, 991.71, 931.52, 864.90, 786.35, 766.04, 686.08, 660.54, 607.90, 549.05, 493.86, 413.87, 404.75 cm-1;1H NMR (400 MHz, CDCl3) δ 2.44 (t, J = 6.1 Hz, 4H), 3.77 (t, J = 6.2 Hz, 4H), 4.61 (dm, J = 5.6 Hz, 2H), 5.22 (dm, J = 10.4 Hz, 1H), 5.30 (dm, J = 17.2 Hz, 1H), 5.93 (m, 1H);13C NMR (100 MHz, CDCl3) δ 41.20 (t), 43.23 (t), 66.62 (t), 118.03 (t), 132.83 (d), 155.09 (s), 207.34 (s); GCMS m / z (M)+183.13.   Preparation of 3-Ethyl-6-(prop-2-en-1-yl)-2-amino-4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate (2r). Following the experimental operational details of Procedure A, a total of 4.00 g (1.00 eq.; 21.8 mmol) of prop-2-en-1-yl 4-oxopiperidine-1-carboxylate (1r), 2.67 mL (1.15 eq.; 25.1 mmol) of ethyl cyanoacetate and 805 mg (1.15 eq.; 25.1 mmol) of elemental S in 11 mL of EtOH was reacted with 2.37 mL (1.00 eq; 22.9 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was stirred for 30 min at RT, heated to 40oC overnight, cooled to RT, and was then poured into a rapidly stirring mixture of 100 mL 50% ice-water. This slurry was filtered, the filter cake washed with 10% EtOH / water (2 x 50 mL), followed by 100 mL of ice cold water. A total of 6.27 g (92.6%) of 3-ethyl-6-(prop-2-en-1-yl)-2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (2r) as a pale orange colored solid was obtained after drying in vacuo (65oC; 1 torr): MP 90.5-91.0 °C; IR (neat) 3431.11, 3326.48, 3250.33, 3155.92, 3091.43, 3013.48, 2973.63, 2949.25, 2922.38, 2900.77, 2853.54, 1686.90, 1665.71, 1588.34, 1572.70, 1496.70, 1473.42, 1456.61, 1442.32, 1427.03, 1413.27, 1385.13, 1366.29, 1330.14, 1293.59, 1259.62, 1201.58, 1142.41, 1118.01, 1042.01, 1027.62, 980.03, 954.09, 928.57, 889.01, 850.07, 829.53, 796.73, 779.06, 756.90, 743.73, 655.10, 630.49, 604.11, 550.02, 534.09, 515.37, 493.98, 460.40, 440.33, 407.83 cm-1;1H NMR (400 MHz, CDCl3) δ 1.30 (t, J=7.1 Hz, 3H), 2.80 (m, 2H), 3.65 (t, J=5.8 Hz, 2H), 4.22 (q, J=7.1 Hz, 2H), 4.39 (m, 2H), 4.59 (dm, J=5.4 Hz, 2H), 5.19 (dm, J=10.4 Hz, 1H), 5.28 (dm, J=17.2 Hz, 1H), 5.92 (m, 1H), 6.08 (br s, 2H);13C NMR (100 MHz, CDCl3, 1:1 mixture of rotamers) δ 14.59 (q), 26.97 (t, rotamer 1), 27.36 (t, rotamer 2), 41.35 (t, rotamer 1), 41.59 (t, rotamer 2), 42.84 (t), 59.76 (t), 66.35 (t), 105.20 (s), 113.23 (s, rotamer 1), 113.75 (s, rotamer 2), 117.67 (t), 131.29 (s, rotamer 1), 131.75 (s, rotamer 2), 133.13 (d), 155.28 (s), 162.65 (s), 165.93 (s); GCMS m / z (M)+- allyl fragment 269.11.   Preparation of Benzyl 4-oxopiperidine-1-carboxylate (1s). To a solution of 10.0 g (1.0 eq.; 65.10 mmol) of 4-piperidone monohydrate hydrochloride and 11.35 g (1.25 eq; 81.38 mmol) of potassium carbonate in 125 mL of water cooled to 5oC, was added 12.0 mL (81.375 mmol) of benzyl chloroformate slowly dropwise over 5-10 min. The mixture was stirred 1 h at 5oC, warmed to RT and was then stirred 1 h. The mixture was saturated with solid NaCl and was then partitioned with ether (5 x 100-mL). The combined organic extracts were washed once with 50 mL of cold aqueous 5% NH3, 50 mL of drine, dried (MgSO4) and concentrated in vacuo to afford 12.73 g (83.8%) of crude benzyl 4-oxopiperidine-1-carboxylate (1s) as a colorless oil which was used without further purification in the next reaction. GCMS m / z (M)+233.16. Preparation of 6-benzyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate (2s) (Procedure B). A mixture of 4.57 g (1.00 eq.; 19.61 mmol) of benzyl 4-oxopiperidine-1-carboxylate (1s), 2.4 mL (1.15 eq.; 22.55 mmol) of ethyl cyanoacetate, and 722.7 mg (1.15 eq.; 22.55 mmol) of elemental sulfur in 25 mL of absolute EtOH under Ar atmosphere, was added 2.33 mL (1.15 eq; 22.55 mmol) of diethylamine slowly dropwise over 5 – 10 min. The reaction mixture was stirred 120 min, then heated to 40oC while stirring overnight. The reaction mixture was cooled to RT, diluted with 400 mL of CHCl3and partitioned with 200 mL of water in a 1-L separatory funnel. The aqueous layer was back extracted with two portions of CHCl3(2 x 100-mL). The combined organic extracts were washed with 100 mL brine, dried (MgSO4), and concentrated in vacuo to afford 6.06 g (86.5% crude yield) of a green colored solid. This material was absorbed onto 20 g of SiO2(DCM) and concentrated to a powder. This material was applied evenly to the top of 150 g of wet packed silica gel in a 350 mL filtration funnel (eluting slowly with hexanes → 20% EtoAc / Hexanes) in 200 mL fractions to afford 5.10 g (72.2%) of 6-benzyl 3-ethyl 2-amino-4,7-dihydro-thieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate (2t) as a peach colored solid that was uniform by TLC (20% EtOAc / Hexanes). A portion of this solid was recrystallized from the min amount of 1% EtOH in 50% Et2O / hexanes to afford an analytical sample: MP 128.3-128.7 °C; IR (neat) 3850.25, 3741.33, 3420.37, 3300.74, 3067.61, 3028.49, 2970.31, 2946.93, 2915.92, 2857.69, 1680.40, 1660.46, 1606.71, 1578.54, 1561.43, 1495.78, 1471.94, 1450.45, 1441.25, 1427.00, 1376.25, 1366.51, 1340.89, 1299.72, 1264.28, 1209.65, 1190.32, 1148.83, 1119.83, 1035.34, 1002.19, 983.55, 954.59, 892.88, 867.54, 851.14, 776.49, 763.85, 719.91, 690.28, 661.07, 645.15, 591.07, 566.29, 529.19, 516.64, 454.98, 413.79, 401.12 cm-1;1H NMR (400 MHz, CDCl3) δ 1.32 (t, J = 7.08 Hz, 3H), 2.83 (m, 2H), 3.69 (t, J = 5.44 Hz, 2H), 4.25 (q, J = 7.12 Hz, 2H), 4.43 (s, 2H), 5.16 (s, 2H), 6.08 (br s, 2H), 7.33 (m, 5H);13C NMR (100 MHz, CDCl3, 1:1 mix of rotamers, 1Ar s buried) δ 14.60 (q), 26.99 (t, rotamer 1), 27.39 (t, rotamer 2), 41.40 (t, rotamer 1), 41.66 (t, rotamer 2), 42.90 (t), 59.78 (t), 67.49 (t), 105.24 (s), 128.12 (d), 128.24 (d), 128.69 (d), 131.31 (s, rotamer 1), 131.78 (s, rotamer 2), 136.79 (s), 155.45 (s), 162.65 (s), 165.94 (s); MS (ESI) calculated for C18H20N2O4S 360.1, found 361.3 [M + H]+.   Preparation of 6-tert-butyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate (2t). Following the experimental operational details of Procedure A, a total of 9.96 g (1.0 eq; 50.0 mmol) of 1-tert-butoxycarbonyl-4-piperidone (1t), 6.40 mL (1.2 eq.; 60.0 mmol) of ethyl cyanoacetate and 1.92 g (1.20 eq.; 60.0 mmol) of elemental S in 10 mL of EtOH was reacted with 5.20 mL (1.00 eq; 50.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution; however, the mixture completely solidified while stirring 30 min at RT. A total of 5 mL of EtOH was then added to the mixture to form a stirrable slurry. The reaction mixture was heated to 40oC for 30 min, gradually cooled to RT over a 2 h period, and was then poured into a rapidly stirring mixture of 75 mL 50% ice-water. This slurry was filtered, the filter cake washed with 100 mL of ice cold 10% EtOH / water. A total of 15.84 g (97.1%) of 6-tert-butyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate (2u) as a beige solid was obtained after drying in vacuo (60oC; 1 torr): MP 138.5-139.3 °C; IR (neat) 3430.89, 3319.08, 2973.98, 2899.59, 2857.73, 1657.25, 1581.02, 1484.52, 1472.73, 1444.79, 1407.26, 1383.51, 1367.99, 1334.66, 1292.54, 1260.50, 1242.19, 1200.99, 1163.32, 1145.01, 1122.61, 1029.62, 989.72, 951.80, 888.61, 866.17, 796.42, 778.27, 762.71, 743.99, 648.86, 532.78, 513.25, 464.46, 431.45, 423.60, 407.65 cm-1;1H NMR (400 MHz, CDCl3) δ 1.34 (t, J =7.08 Hz, 3H), 1.48 (s, 9H), 2.80 (m, 2H), 3.62 (t, J =5.56 Hz, 2H), 4.26 (q, J =7.12 Hz, 2H), 4.35 (s, 2H), 6.12 (br s, 2H);13C NMR (100 MHz, CDCl3, 1:1 mix rotomers) δ 14.59 (q), 27.26 (t), 28.22 (q), 40.64 (t, rotamer 1), 41.88 (t, rotamer 2), 42.31 (t, rotamer 1), 42.90 (t, rotamer 2), 59.70 (t), 80.11 (s), 105.18 (s), 114.11 (s, rotomer 1), 114.13 (s, rotomer 2), 131.61 (s, rotamer 1), 131.65 (s, rotamer 2), 154.81 (s), 162.64 (s), 165.97 (s); GCMS m / z (M)+326.17.   Preparation of 8-(3-chloropropane-1-sulfonyl)-1,4-dioxa-8-azaspiro[4.5]decane from 4- piperidinone hydrochloride monohydrate (Steps 1 and 2): Preparation of 1,4-dioxa-8-azaspiro[4.5]decane hydrochloride (Step 1). A mixture of 6.0 g (39.06 mmol) of 4-piperidinone hydrochloride monohydrate, 4.85 g (78.1 mmol) of ethylene glycol, and 600 mg (3.2 mmol) of p-toluenesulfonic acid monohydrate in 150 mL toluene in a Dean-Stark trap was heated to reflux for 24 h (theoretical amount of water collected). The reaction was cooled to RT and concentrated in vacuo. The residue was azeotroped with 5 x 25-mL of ether, and concentrated in vacuo. The residue was put on the high vacuum to afford 7.83 g (100%) of 1,4-dioxa-8 azaspiro [4.5]decane hydrochloride (Step 1 product) as a white solid: GCMS m / z (M – HCl Fragment)+143.19. Preparation of 8-(3-chloropropane-1-sulfonyl)-1,4-dioxa-8-azaspiro[4.5]decane (Step 2). The product of Step 1 was diluted with 50 mL of DCM and 10.9 mL (2.0 eq.; 78.4 mmol) of Et3N and stirred for 30 min under Ar to afford a white slurry which was cooled to - 10oC using an ice salt bath. To this mixture was added 4.8 mL (1.0 eq.; 39.2 mmol) of 3- chloropropyl-1-sulfonyl chloride in 30 mL of DCM slowly dropwise over 30 min. The mixture was allowed to slowly warm to RT over 2 h, and was then stirred overnight. The slurry was recooled to 0oC, the reaction vessel opened to the atmosphere, 50 mL of 50% sat aq. NaHCO3 added slowly over a 5-10 min period, and the reaction mixture stirred for an addition 25 min while warming to 15oC. This mixture was then partitioned with 50 mL of water, 50 mL of citric acid, dried (MgSO4), and concentrated in vacuo. The residue was put under high vacuum (40oC; 1 torr) to afford 11.00 g (99.3%) of 8-(3-chloropropane-1- sulfonyl)-1,4-dioxa-8-azaspiro[4.5]decane (Step 2 product) as a waxy pale yellow solid which was taken directly into Step 3 without further purification: MP 67.0-68.0 °C; IR (neat) 2957.74, 2930.33, 2880.74, 2857.39, 1464.25, 1447.98, 1429.20, 1412.53, 1369.13, 1345.42, 1317.59, 1286.76, 1226.12, 1173.46, 1145.91, 1115.93, 1039.77, 968.34, 956.99, 943.86, 896.19, 798.05, 771.44, 744.08, 700.58, 690.48, 658.63, 648.09, 593.93, 586.07, 563.15, 551.59, 536.80, 525.42, 498.79, 469.24, 429.53, 418.34 cm-1;1H NMR (400 MHz, CDCl3) δ 1.78 (t, J = 5.78 Hz, 4H), 2.27 (m, 2H), 3.06 (t, J = 7.32 Hz, 2H), 3.39 (t, J = 5.64 Hz, 4H), 3.66 (t, J = 6.16 Hz, 2H), 3.95 (s, 4H);13C NMR (100 MHz, CDCl3) δ 26.51 (t), 35.08 (t), 43.16 (t), 44.30 (t), 46.81 (t), 64.65 (t), 106.31 (s); GCMS m / z (M)+282.93 (M + 2)+284.91.   Preparation of 1-(cyclopropanesulfonyl)piperidin-4-one (1u) from 8-(3-chloropropane- 1-sulfonyl)-1,4-dioxa-8-azaspiro[4.5]decane: 8-(3-chloropropane-1-sulfonyl)-1,4-dioxa-8- azaspiro[4.5]decane (Step 3). To a solution of 11.00 g (38.8 mmol) of 8-(3-chloropropane-1-sulfonyl)-1,4-dioxa-8- azaspiro[4.5]decane in 175 mL of anhydrous THF cooled to -78oC under Ar, was added 32.0 mL (2.1 eq.; 80.1 mmol) of 2.5M n-BuLi in cyclohexanes slowly dropwise over a 10 min period to afford a yellow solution. The mixture was warmed to 0oC over 1.5 h forming a brown suspension which went into solution. This mixture was quenched by the addition of 40 mL of sat. aq. NH4Cl, and partitioned with 250 mL of EtOAc. The agqoueous solution was back extracted once with 70 mL of EtOAc. The organic extracts were combined, washed with brine (100 mL), dried (MgSO4), and concentrated in vacuo to afford 9.8 g (~100%) of 8-(3- chloropropane-1-sulfonyl)-1,4-dioxa-8-azaspiro[4.5]decane as a pale yellow solid. This material was used directly into Step 4 reaction without any further purification: MP 136.5- 137.5 °C; IR (neat) 3094.24, 3042.77, 2965.13, 2936.63, 2903.02, 2867.66, 1468.92, 144.40, 1422.82, 1380.63, 1363.60, 1349.47, 1340.04, 1305.73, 1272.76, 1254.74, 1220.98, 1191.07, 1150.36, 1112.78, 1061.33, 1047.19, 1029.16, 1008.47, 965.27, 941.20, 889.86, 827.19, 806.67, 789.78, 772.86, 743.37, 683.90, 64.62, 643.99, 592.27, 540.95, 484.27, 456.52, 422.48, 406.78 cm-1;1H NMR (400 MHz, CDCl3) δ 0.97 (m, 2H), 1.14 (m, 2H), 1.79 (t, J = 5.8 Hz, 4H), 2.25 (m, 1H), 3.40 (t, J = 5.64 Hz, 4H), 3.96 (s, 4H);13C NMR (100 MHz, CDCl3) δ 4.57 (t), 26.18 (d), 34.94 (t), 44.70 (t), 64.64 (t), 106.39 (s); GCMS m / z (M)+247.17. Preparation of 1-(cyclopropanesulfonyl)piperidin-4-one (1u), Step 4: To a solution of 8-(cyclopropanesulfonyl)-1,4-dioxa-8-azaspiro[4.5]decane (38.76 mmol), product of Step 3, in 160 mL of anhydrous acetone cooled to 0oC, was added 40 mL (4.1 eq; 160 mmol) of 4M aq. HCl containing 15 mL (4.6 eq.; 180 mmol) of 12M HCl. The reaction mixture was then warmed to RT over 2 h and then heated to 60oC for 4 days (monitoring the reaction by GCMS, adding 150 mL of 4:1 acetone / 5M HCL at beginning of final 24 h interval). The mixture was cooled to 0oC, and the solution pH adjusted to 7.5 using 6M NaOH. The aqueous layer was saturated with solid NaCl, and extracted into Et2O (4 x 150-mL portions). The combined ether extracts were washed with dat. aq. NaHCO3(40 mL), dried (MgSO4) and concentrated in vacuo. This material was absorbed onto 30 g of SiO2 (DCM) and concentrated to a powder. This material was applied evenly to the top of 150 g of wet packed silica gel in a 350 mL filtration funnel (eluting slowly with hexanes → 60% EtoAc / Hexanes) in nineteen 250-mL fractions (each fraction was monitored for product by GC / MS) to afford 4.75 g (60.3% yield) of 1-(cyclopropanesulfonyl)piperidin-4-one (1u) as a waxy pale yellow solid: MP 53.5-54.5 °C; IR (neat) 3105.91, 3093.57, 3039.36, 3024.07, 2991.41, 2963.33, 2918.98, 2883.88, 2873.37, 1711.02, 1680.31, 1550.08, 1471.95, 1455.30, 1445.83, 1418.89, 1405.81, 1377.34, 1359.18, 1330.35, 1305.09, 1296.30, 1245.43, 1218.88, 1191.00, 1151.00, 1108.30, 1074.51, 1044.94, 1035.45, 991.64, 970.13, 924.10, 883.89, 828.12, 774.06, 738.15, 693.86, 672.11, 599.45, 558.55, 541.26, 505.60, 465.05, 444.08, 431.98, 412.80, 404.58 cm-1;1H NMR (400 MHz, CDCl3) δ 1.00 (m, 2H), 1.17 (m, 2H), 2.31 (m, 1H), 2.54 (t, J = 6.2 Hz, 4H), 3.61 (t, J = 6.2 Hz, 4H);13C NMR (100 MHz, CDCl3) δ 4.86 (t), 27.29 (d), 41.40 (t), 46.04 (t), 206.00 (s); GCMS m / z (M)+203.16. to 40  Preparation of Ethyl 2-amino-6-(cyclopropanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate (2u). Following the experimental operational details of Procedure A, a total of 2.70 g (1.00 eq.; 13.3 mmol) of 1-(cyclopropanesulfonyl)piperidin-4-one (1u), 1.63 mL (1.15 eq.; 15.3 mmol) of ethyl cyanoacetate and 490 mg (1.15 eq.; 15.3 mmol) of elemental S in 10 mL of EtOH was reacted with 1.44 mL (1.05 eq; 14.0 mmol) of diethylamine added dropwise over 10 min at RT to form a solution. The reaction mixture was stirred for 30 min at RT, heated to 40oC overnight, cooled to RT, 30 mL of EtOH added to afford a solution which was then poured into a rapidly stirring mixture of 125 mL 50% ice-water. This slurry was filtered, the filter cake washed with 50% EtOH / water (1 x 30 mL), 10% EtOH / water (1 x 30 mL), followed by 100 mL of ice cold water. A total of 3.50 g (83.9%) of ethyl 2-amino-6- (cyclopropanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate (2u) as a beige colored solid was obtained after drying in vacuo (70oC; 1 torr): MP 161.0-162.0 °C; IR (neat) 3441.80, 3328.75, 3242.55, 3170.53, 3109.51, 3078.94, 3035.59, 2980.60, 2942.27, 2927.55, 2915.15, 2832.48, 1655.79, 1590.62, 1493.97, 1480.42, 1458.98, 1450.62, 1429.83, 1416.53, 1380.13, 1369.97, 1354.78, 1343.80, 1338.84, 1309.61, 1285.48, 1260.84, 1233.33, 1207.24, 1192.88, 1175.06, 1147.10, 1130.12, 1094.46, 1067.72, 1035.22, 1023.34, 990.09, 960.98, 931.80, 890.48, 853.02, 828.03, 803.82, 782.60, 757.13, 738.47, 689.96, 653.91, 637.50, 609.16, 589.42, 541.75, 519.87, 467.94, 435.46, 412.25 cm-1;1H NMR (400 MHz, CDCl3) δ 0.94 (m, 2H), 1.17 (m, 2H), 1.32 (m, 3H), 2.25 (m, 1H), 2.91 (m, 2H), 3.57 (m, 2H), 4.29 (m, 4H), 6.09 (br s, 2H);13C NMR (100 MHz, CDCl3) δ 5.04 (t), 14.60 (q), 27.39 (t), 27.75 (d), 43.69 (t), 44.49 (t), 59.88 (t), 105.19 (s), 112.44 (s), 131.13 (s), 162.63 (s), 165.80 (s); GCMS m / z (M)+330.21. (85.6%)   Preparation of (2-amino-6-methyl-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)(4- methylphenyl)methanone (6) (Procedure C). To a mixture of 460 mg (1.25 eq.; 4.10 mmol) of 4-methyl-1-cyclohexanone, 522 mg (1.0 eq.; 3.28 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile (3), and 131 mg (1.25 eq.; 4.10 mmol) of elemental sulfur in 6 mL of absolute EtOH under Ar atmosphere, was added 355 μL (1.25 eq; 4.10 mmol) of morpholine slowly dropwise over 5 – 10 min. The reaction mixture was then heated to 60oC and left to stir overnight. The reaction mixture was cooled to RT, diluted with 50 mL of EtOAc and transferred to a 125 mL separatory funnel. This organic solution washed twice with water (2 x 25-mL portion), and the aqueous extract was then back washed once with EtOAc (1 x 50 mL). The combined organic extracts were washed once with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 638.9 mg of crude (6) as an orange-yellow mixture. This material was absorbed onto 3.5 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 25M column (eluting with hexanes → 40% EtOAc / Hexanes) and concentrated to afford 801.5 mg (85.6%) of (2-amino-6-methyl-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)(4-methylphenyl)methanone (6) as a pale yellow foam: IR (neat) 3353.60, 3252.68, 3135.20, 3043.70, 3024.83, 2957.53, 2918.00, 2898.27, 2878.68, 2847.30, 2829.21, 1607.52, 1572.77, 1562.91, 1556.57, 1510.33, 1424.34, 1358.33, 1360.72, 1308.07, 1299.38, 1275.07, 1244.44, 1226.43, 1210.67, 1176.27, 1152.38, 1134.22, 1126.33, 1108.61, 1032.47, 1020.60, 989.44, 977.15, 942.72, 925.10, 911.86, 871.12, 841.52, 826.29, 801.15, 792.74, 767.88, 740.51, 714.93, 658.06, 633.44, 615.68, 594.77, 550.46, 531.20, 485.05, 469.98, 439.81, 416.34 cm-1;1H NMR (400 MHz, CDCl3) δ 0.99 (d, J = 6.6 Hz, 3H), 1.06-1.16 (m, 1H), 1.55-1.61 (m, 1H), 1.76-1.86 (m, 2H), 1.93-2.03 (m, 1H), 2.08-2.17 (m, 1H), 2.39 (s, 3H), 2.59 (dd, J = 16.1, 5.3 Hz, 1H), 6.56 (br s, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 21.69 (q), 21.69 (q), 27.77 (t), 29.68 (d), 31.35 (t), 33.08 (t), 116.12 (s), 118.25 (s), 127.95 (d, 2C), 128.79 (d, 2C), 131.26 (s), 139.50 (s), 140.79 (s), 164.05 (s), 192.95 (s); MS (ESI) calculated for C17H19NOS 285.1, found 286.3 [M + H]+.    Preparation of (2-amino-6,6-dimethyl-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)(4- methylphenyl)-methanone (7). Following the operational experimental details reported in Procedure C, a mixture of 517 mg (1.25 eq.; 4.10 mmol) of 4,4-dimethyl-1-cyclohexanone, 522 mg (1.0 eq.; 3.28 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile (3), and 131 mg (1.25 eq.; 4.10 mmol) of elemental sulfur in 6 mL of absolute EtOH under Ar atmosphere, was reacted by slow addition with 355 μL (1.25 eq; 4.10 mmol) of morpholine slowly dropwise over 5 – 10 min. The reaction mixture was then heated to 60oC and left to stir overnight. The workup and chromatographic purification was identical to that reported for the previous compound 6 to afford 946.7 mg (96.4%) of (2-amino-6,6-dimethyl-4,5,6,7-tetrahydro-1-benzothiophen-3- yl)(4-methylphenyl)methanone (7) as a yellow solid: mp 145.5 – 146.5oC; IR (neat) 3307.88, 3219.13, 3177.80, 3121.03, 3047.54, 3023.16, 2979.79, 2954.04, 2934.09, 2896.75, 2856.62, 1597.23, 1573.76, 1552.62, 1469.26, 1425.26, 1469.26, 1454.60, 1425.26, 1379.66, 1360.72, 1322.14, 1307.00, 1295.31, 1279.51, 1264.04, 1211.40, 1176.18, 1119.86, 1107.52, 1035.26, 1028.83, 1021.07, 1012.83, 991.29, 964.32, 949.40, 936.53, 909.80, 899.46, 832.38, 810.36, 796.67, 770.23, 743.56, 734.22, 717.08, 680.88, 669.24, 621.16, 597.25, 580.78, 563.71, 553.01, 537.44, 491.29, 476.94, 446.55, 431.50 cm-1;1H NMR (400 MHz, CDCl3) δ 0.96 (s, 6H), 1.26 (t, J = 6.3 Hz, 2H), 1.89 (tm, J = 6.3 Hz, 2H), 2.28 (m, 2H), 2.40 (s, 3H), 6.55 (br s, 2H).7.20 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 21.70 (q), 25.24 (t), 28.02 (q), 28.02 (q), 30.29 (s), 35.88 (t), 38.47 (t), 116.04 (s), 118.09 (s), 127.89 (d, 2C), 128.83 (d, 2C), 130.00 (s), 139.51 (s), 140.78 (s), 163.97 (s), 192.98 (s); MS (ESI) calculated for C18H21NOS 299.1, found 300.3 [M + H]+.     Preparation of (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(4- methylphenyl)methanone (8) (Procedure C). A mixture of 432 mg (1.25 eq.; 4.31 mmol) of 4-pyranone (oxan-4-one, 1j), 550 mg (1.0 eq.; 3.45 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile (3), and 138 mg (1.25 eq.; 4.31 mmol) of elemental sulfur in 6 mL of absolute EtOH under Ar atmosphere, was reacted by slow addition with 373 μL (1.25 eq; 4.31 mmol) of morpholine slowly dropwise over 5 – 10 min. The reaction mixture was then heated to 60oC and left to stir overnight. The workup and chromatographic purification was identical to that reported for the previous compound 6 to afford 766.5 mg (81.2%) of (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(4- methylphenyl)methanone (8) as a pale yellow solid: MP 142.5-143.5 °C; IR (neat) 3454.14, 34.15.56, 3343.25, 3303.52, 2978.63, 2961.99, 2930.76, 2910.07, 2861.33, 2835.53, 2746.70, 2359.36, 2340.80, 1731.28, 1604.76, 1573.87, 1553.08, 1509.95, 1438.89, 1400.07, 1358.24, 1340.17, 1299.90, 1273.21, 1255.83, 1340.17, 1299.90, 1273.21, 1255.83, 1221.46, 1208.28, 1168.70, 1111.29, 1088.74, 1019.03, 1004.52, 983.85, 966.73, 912.18, 868.66, 858.53, 835.65, 813.84, 797.52, 763.88, 733.60, 714.26, 668.20, 638.87, 620.51, 605.69, 573.86, 525.64, 479.89, 473.52, 424.48 cm-1;1H NMR (400 MHz, CDCl3) δ 2.00 (m, 2H), 2.39 (s, 3H), 3.65 (t, J = 5.4 Hz, 2H), 4.57 (bt, J = 1.84 Hz, 2H), 6.75 (br s, 2H), 7.20 (d, J = 7.88 Hz, 2H), 7.40 (d, J = 8.00 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 21.71 (q), 28.50 (t), 64.96 (t), 64.99 (t), 115.44 (s), 115.54 (s), 127.89 (d, 2C), 128.93 (d, 2C), 129.65 (s), 139.10 (s), 141.15 (s), 164.72 (s), 192.59 (s); GCMS m / z (M)+273.12.   Preparation of (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4- methylphenyl)methanone (9). Following the operational experimental details reported in Procedure C, a mixture of 501 mg (1.25 eq.; 4.31 mmol) of 4-thiopyranone (oxan-4-thione or thian-4-one, 1k), 550 mg (1.0 eq.; 3.45 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile (3), and 138 mg (1.25 eq.; 4.31 mmol) of elemental sulfur in 6 mL of absolute EtOH under Ar atmosphere, was reacted by slow addition with 373 μL (1.25 eq; 4.31 mmol) of morpholine slowly dropwise over 5 – 10 min. The reaction mixture was then heated to 60oC and left to stir overnight. The workup and chromatographic purification was identical to that reported for the previous compound 6 to afford 979.9 mg (98.1%) of (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4- methylphenyl)methanone (9) as a pale yellow solid: MP 106.0-107.0 °C; IR (neat) 3365.62, 3373.96, 3269.40, 2979.04, 2905.96, 1571.40, 1553.48, 1507.16, 1413.90, 1396.16, 1351.61, 1297.43, 1266.04, 1251.39, 1204.83, 1177.56, 1120.54, 1109.33, 1027.28, 1018.34, 979.91, 899.78, 828.30, 786.24, 766.17, 740.43, 713.18, 683.37, 614.81, 576.41, 519.97, 476.19, 431.82 cm-1;1H NMR (400 MHz, CDCl3) δ 2.22 (t, J = 5.84 Hz, 2H), 2.39 (s, 3H), 2.57 (t, J = 5.70 Hz, 2H), 3.61 (s, 2H), 6.51 (bs, 2H), 7.20 (d, J = 7.88 Hz, 2H), 7.42 (d, J = 8.04 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 21.72 (q), 25.24 (t), 25.73 (t), 30.07 (t), 114.41 (s), 116.73 (s), 128.10 (d, 2C), 129.04 (d, 2C), 131.56 (s), 139.08 (s), 141.42 (s), 162.78 (s), 192.76 (s); GCMS (M)+289.16.   Preparation of (2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- methylphenyl)methanone (10). With a few modifications but following the operational experimental details reported in Procedure C, a mixture of 505.4 mg (1.15 eq.; 3.97 mmol) of 1-ethyl-4-piperidinone (1m), 550 mg (1.0 eq.; 3.45 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile (3), and 127.4 mg (1.15 eq.; 4.31 mmol) of elemental sulfur in 6 mL of absolute EtOH under Ar atmosphere, was reacted by slow addition with 373 μL (1.25 eq; 4.31 mmol) of morpholine slowly dropwise over 5 – 10 min. The reaction mixture was then heated to 60oC and left to stir overnight. The workup was identical to that reported for the previous compound 6. The resulting black oil was absorbed onto 3.5 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 25M column (eluting with DCM → 10% MeOH / DCM) and concentrated to afford 843.6 mg (81.4%) of (2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(4-methylphenyl)methanone (10) as a dark yellow solid: IR (neat) 3658.56, 2979.52, 2970.54, 2888.03, 1577.03, 1471.49, 1381.44, 1251.66, 1148.81, 1072.59, 1013.89, 954.27, 829.61, 765.75, 741.62, 707.87, 597.50, 474.60, 415.13 cm-1;1H NMR (400 MHz, CDCl3) δ 1.10 (t, J = 7.16 Hz, 3H), 2.00 (m, 2H), 2.36 (s, 3H), 2.44 (t, J = 5.66 Hz, 2H), 2.50 (q, J = 7.2 Hz, 2H), 3.41 (bm, 2H), 6.82 (br s, 2H), 7.16 (d, J = 7.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 12.52 (q), 21.68 (q), 28.45 (t), 50.25 (t), 51.61 (t), 51.94 (t), 115.39 (s), 115.68 (s), 127.89 (d, 2C), 128.82 (d, 2C), 130.14 (s), 140.82 (s), 139.25 (s), 164.80 (s), 192.71 (s); GCMS m / z (M)+300.27.   Preparation of 1-[2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)- yl]ethan-1-one (11). Following the experimental operational details reported in Procedure C, a total of 608 mg (1.25 eq; 4.31 mmol) of 1-acetylpiperidin-4-one (1p), 550 mg (1.0 eq.; 3.45 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile and 138 mg (1.25 eq.; 4.31 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 373 μL (1.25 eq; 4.31 mmol) of morpholine added over 10 min, and was then heated to 60oC overnight. Using an analogous aqueous workup reported in procedure A for compound 6, but scaled up respectfully, a crude yield of 1.936 g of crude 11 was afforded as an orange foam. This material was absorbed using DCM onto 4.0 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 25M column (eluting with DCM → 10% MeOH / DCM) and concentrated to afford 1.086 g (100%) of 1-[2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl]ethan-1-one (11) as an offwhite solid: MP 205.2-205.7 °C; IR (neat) 3351.74, 3219.76, 3118.90, 3015.85, 2917.34, 2862.56, 1724.22, 1625.36, 1586.40, 1446.58, 1428.50, 1408.24, 1357.66, 1305.07, 1288.08, 1271.97, 1250.68, 1234.85, 1207.36, 1196.47, 1169.47, 1135.21, 1108.75, 1033.46, 1002.66, 983.45, 961.70, 913.57, 913.57, 843.20, 830.73, 798.41, 766.50, 736.40, 713.26, 690.14, 636.32, 605.31, 559.10, 528.74, 502.52, 475.82, 457.98, 419.49 cm-1;1H NMR (400 MHz, CDCl3, 2:1 mix of rotomers) δ 1.93 (m, 0.33H, minor rotomer), 2.01 (m, 1.67H, major rotomer), 2.07 (s, 2H, major rotomer), 2.11 (s, 1H, minor rotomer), 2.36 (s, 1H, minor rotomer), 2.38 (s, 2H, major rotomer), 3.37 (t, J = 5.62 Hz, 1.33H, major rotomer), 3.51 (t, J = 5.62 Hz, 0.67H, minor rotomer), 4.39 (bm, 0.33H, minor rotomer), 4.50 (bm, 1.67H, major rotomer), 6.94 (s, 1.33H, major rotomer), 6.98 (s, 0.67H, minor rotomer), 7.17 (t, J = 8.1 Hz, 0.33H, minor rotomer), 7.19 (t, J = 8.1 Hz, 1.67H, major rotomer), 7.33 (d, J = 8.0 Hz, 0.33H, minor rotomer), 7.36 (d, J = 8.0 Hz, 1.67H, major rotomer);13C NMR (100 MHz, CDCl3, 2:1 mix of rotomers) δ 21.64 (q, minor rotomer), 21.68 (q, major rotomer), 21.68 (q, major rotomer), 22.05 (q, minor rotomer), 27.89 (t, minor rotomer), 28.58 (t, major rotomer), 39.08 (t, minor rotomer), 41.21 (t, major rotomer), 43.85 (t, major rotomer), 45.17 (t, minor rotomer), 112.82 (s, major rotomer), 114.63 (s, major rotomer), 114.92 (s, minor rotomer), 115.09 (s, minor rotomer), 127.54 (d, minor rotomer), 127.71 (d, major rotomer), 128.86 (d, major rotomer), 128.90 (d, minor rotomer), 129.74 (s, major diastereomer), 131.79 (s, minor diasteroemer), 138.91 (s, minor rotomer), 139.10 (s, major rotomer), 141.14 (s, major rotomer), 141.22 (s, minor rotomer), 165.00 (s, minor rotomer), 165.10 (s, major rotomer), 169.35 (minor rotomer), 169.42 (s, major rotomer), 192.22 (s, major rotomer), 192.60 (s, minor rotomer); GCMS m / z (M)+314.21.   Preparation of Ethyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (12). Following the operational experimental details reported in Procedure C, a mixture of 738 mg (1.25 eq.; 4.31 mmol) of ethyl 4-oxopiperidine-1-carboxylate (1q), 550 mg (1.0 eq.; 3.45 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile (3), and 138 mg (1.25 eq.; 4.31 mmol) of elemental sulfur in 6 mL of absolute EtOH under Ar atmosphere, was reacted by slow addition with 373 μL (1.25 eq; 4.31 mmol) of morpholine slowly dropwise over 5 – 10 min. The reaction mixture was then heated to 60oC and left to stir overnight. The workup and chromatographic purification was identical to that reported for the previous compound 6 to afford 1.154 g (89.0%) of ethyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate (12) as a yellow foam: IR (neat) 3658.22, 3438.95, 3355.50, 3261.47, 2979.55, 2888.03, 1673.13, 1573.24, 1510.00, 1471.35, 1460.83, 1382.31, 1295.71, 1229.51, 1164.89, 1111.08, 1089.21, 999.53, 955.62, 913.90, 877.90, 831.11, 765.69, 742.78, 710.36, 607.30, 522.89, 481.91, 416.16 cm-1;1H NMR (400 MHz, CDCl3, mix of rotomers) δ 1.26 (m, 3H), 1.97 (t, J = 5.6 Hz, 2H), 2.39 (s, 3H), 3.40 (t, J = 5.52 Hz, 2H), 4.16 (m, 2H), 4.40 (s, 2H), 6.73 (br s, 2H), 7.19 (d, J = 7.84 Hz, 2H), 7.37 (d, J = 7.68 Hz, 2H);13C NMR (100 MHz, CDCl3, mix of rotomers, major rotomer reported) δ 14.87 (q), 21.72 (q), 28.16 (t), 41.24 (t), 42.96 (t), 61.76 (t), 114.32 (s), 115.46 (s), 127.88 (d, 2C), 129.01 (d, 2C), 130.79 (s), 139.06 (s), 141.26 (s), 155.62 (s), 164.65 (s), 192.60 (s); GCMS m / z (M)+344.24.   Preparation of Benzyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (13). Following the experimental operational details reported in Procedure C, a total of 3.66 g (1.25 eq; 15.70 mmol) of benzyl 4-oxopiperidine-1-carboxylate (1s), 2.00 g (1.0 eq.; 12.56 mmol) of 3-(4-methylphenyl)-3-oxopropanenitrile (3) and 500 mg (1.25 eq.; 15.70 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 1.36 mL (1.25 eq; 15.70 mmol) of morpholine added over 10 min and was then heated to 60oC overnight. Using an analogous aqueous workup reported in procedure A for compound 6, but scaled up respectfully, a crude yield of 6.1945 g of crude 13 was afforded as an orange-red foam. This material was absorbed using DCM onto 8.0 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 40M column (eluting with hexanes → 25% EtOAc / Hexanes) and concentrated to afford 5.00 g (97.9%) of benzyl 2-amino-3-(4- methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (13) as an amorphous light orange solid after drying (60oC; 1 torr) overnight in a vacuum oven: MP 81.5-82.5 °C; IR (neat) 3365.61, 3283.44, 2979.54, 2970.23, 2912.35, 1683.46, 1576.31, 1560.81, 1506.18, 1496.65, 1422.39, 1359.08, 1337.47, 1297.72, 1265.50, 1176.84, 1108.02, 1087.34, 1042.33, 1027.09, 1002.51, 973.63, 908.57, 868.18, 838.29, 802.94, 763.62, 734.71, 695.81, 634.87, 599.64, 559.29, 522.46, 498.46, 475.85, 448.74, 416.45, 410.78, 405.30 cm-1;1H NMR (400 MHz, CDCl3, rotomers) δ 1.99 (m, 2H), 2.40 (s, 3H), 3.44 (t, J = 5.4 Hz, 2H), 4.44 (s, 2H), 6.70 (s, 2H), 7.20 (d, J = 7.6 Hz, 2H), 7.38 (m, 7H);13C NMR (100 MHz, CDCl3, ~1:1 mix rotomers, 2 Ar s buried) δ 21.73 (q), 28.06 (t, rotomer 1), 28.32 (t, rotomer 2), 41.27 (t, rotomer 1), 41.52 (t, rotomer 2), 43.18 (t), 67.54 (t), 115.46 (s), 127.88, (d), 128.20 (d), 128.31 (d), 128.71 (d), 129.03 (d), 136.70 (s), 139.00 (s), 141.30 (s), 155.39 (s), 164.64 (s), 192.69 (s); GCMS m / z (M)+406.30, (M - Bn)+315.20.   Preparation of (2-amino-6-methyl-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)(4- chlorophenyl)methanone (14). With a few modifications but following the operational experimental details reported in Procedure C, a total of 791 mg (1.15 eq; 7.05 mmol) of 4-methyl-1-cyclohexanone (1c), 1.10 g (1.0 eq.; 6.12 mmol) of 3-(4-chlorophenyl)-3-oxopropanenitrile (4) and 226 mg (1.15 eq.; 7.05 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 610 μL (1.15 eq; 7.05 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. The crude solution was cooled to RT, then transferred dropwise to an Erlenmeyer containing 100 mL of rapidly stirring 50% ice / water (1 mL of EtOH added as a wash) to form a slurry. This material was filtered and dried (70oC; 1 torr) overnight in a vacuum oven to afford 1.39 mg (74.3%) of (2-amino-6-methyl-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)(4- chlorophenyl)methanone (14) as a yellow solid: MP 152.0-152.4 °C; IR (neat) 3356.37, 3248.21, 2955.18, 2912.02, 1593.60, 1573.85, 1486.68, 1421.04, 1356.77, 1296.68, 1275.53, 1174.67, 1123.81, 1087.68, 1013.65, 979.55, 911.95, 836.51, 825.60, 802.63, 776.01, 767.39, 733.56, 690.06, 636.31, 579.70, 553.87, 472.60, 405.26 cm-1;1H NMR (400 MHz, CDCl3) δ 0.99 (d, J = 6.6 Hz, 3H), 1.10 (m, 1H), 1.85 (m, 3H), 1.58 (m, 1H), 2.13 (m, 1H), 2.57 (m, 1H), 6.74 (s, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 21.65 (q), 27.96 (t), 29.63 (d), 31.29 (t), 33.08 (t), 115.60 (s), 118.57 (s), 128.46 (d, 2C), 129.18 (d, 2C), 130.70 (s), 136.43 (s) 140.74 (s), 165.17 (s), 191.43 (s); GCMS m / z (M)+305.21, (M+2)+307.20.   Preparation of (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(4- chlorophenyl)methanone (15). With a few modifications but following the operational experimental details reported in Procedure C, a total of 720 mg (1.15 eq; 7.05 mmol) of 4-pyranone (1j), 1.10 g (1.0 eq.; 6.12 mmol) of 3-(4-chlorophenyl)-3-oxopropanenitrile (4) and 226 mg (1.15 eq.; 7.05 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 610 μL (1.15 eq; 7.05 mmol) of morpholine added slowly dropwise over 10 min, the mixture heated to 60oC for 6 h, and then stirred at RT overnight (reaction didn’t go to completion but worked up anyway). The crude solution was cooled to RT, then transferred dropwise to an Erlenmeyer containing 100 mL of rapidly stirring 50% ice / water (1 mL of EtOH added as a wash) to form a slurry. The solid was filtered and then heated in 170 mL of 10% EtOH / DCM and filtered again to remove excess ketone. The filtrate solution was concentrated then absorbed using DCM onto 8.0 g of a silica gel and then dry packed into a Biotage samplet precartridge. This mixture was chromatographed over a Biotage 40M column (eluting with hexanes → 50% EtOAc / Hexanes) and concentrated to afford 989 mg (54.9%) of (2-amino-4,7-dihydro-5H- thieno[2,3-c]pyran-3-yl)(4-chlorophenyl)methanone (15) as a yellow solid after drying (60oC; 1 torr) overnight in a vacuum oven: MP 134.0-134.3 °C; IR (neat) 3327.19, 3226.21, 3126.51, 3034.80, 2971.45, 2926.35, 2890.21, 2855.89, 2818.02, 1569.78, 1551.25, 1486.83, 1457.64, 1433.98, 1424.18, 1380.18, 1365.43, 1346.08, 1297.89, 1282.73, 1227.06, 1207.94, 1176.10, 1136.46, 1084.89, 1011.32, 984.90, 970.60, 958.92, 920.17, 890.75, 871.51, 842.70, 833.45, 816.38, 766.87, 732.37, 709.91, 689.79, 637.10, 623.03, 606.63, 591.16, 564.20, 546.85, 504.45, 468.59, 428.43, 417.12, 409.31, 401.12 cm-1;1H NMR (400 MHz, CDCl3) δ 1.95 (m, 2H), 3.65 (t, J = 5.4 Hz, 2H), 4.56 (t, J = 1.8 Hz, 2H), 6.91 (s, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H);13C NMR (100 MHz, CDCl3, 1 Ar-C s buried) δ 28.40 (t), 64.64 (t), 64.73 (t), 114.80 (s), 115.56 (s), 128.39 (d, 2C), 128.89 (d, 2C), 136.57 (s), 140.05 (s), 165.48 (s), 190.84 (s); GCMS m / z (M)+293.13, (M+2)+295.14. Preparation of (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4- chlorophenyl)methanone (16). With a few modifications but following the operational experimental details reported in Procedure C, a total of 745 mg (1.15 eq; 6.41 mmol) of 4-thiopyranone or oxan-4-thione or thian-4-one (1k), 1.00 g (1.0 eq.; 5.57 mmol) of 3-(4-chlorophenyl)-3-oxopropanenitrile (4) and 206 mg (1.15 eq.; 6.41 mmol) of elemental S in 6 mL of EtOH was reacted with 560 μL (1.15 eq; 6.41 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. The crude solution was cooled to RT and partitioned between 170 mL of EtOAC and water (2 x 20-mL), followed by brine (20 mL). The organic layer was dried (MgSO4) and concentrated to afford 2.32 g of crude 16 as a red oil. The crude organic solution was absorbed using DCM onto 8.0 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 40M column (eluting with hexanes → 50% EtOAc / Hexanes) and concentrated to afford 1.575 g (91.3%) of (16) as a yellow foam. This material was dissolved in 20 mL of EtOH which was added slowly dropwise to a rapidly stirring solution of 100 mL of 50% ice / water to afford a yellow slurry which was filtered. The precipitate was filtered, washed with ice water (20 mL) and dried overnight (60oC; 1 torr) to afford 1.458 g (84.4%) of (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4- chlorophenyl)methanone (16) as a yellow solid: MP 218.9-219.5 °C; IR (neat) 3399.65, 3374.74, 3274.69, 3141.34, 2980.72, 2906.68, 1574.53, 1552.06, 1485.81, 1449.89, 1430.69, 1417.22, 1392.30, 1354.03, 1300.54, 1266.19, 1256.19, 1256.78, 1206.97, 1174.66, 1147.29, 1124.90, 1088.93, 1013.93, 982.86, 841.31, 900.93, 857.35, 839.22, 822.75, 794.55, 775.74, 759.80, 747.61, 719.76, 698.67, 682.42, 646.89, 610.33, 573.14, 542.04, 523.75, 488.79, 473.89, 435.78, 416.73, 404.51 cm-1;1H NMR (400 MHz, CDCl3) δ 2.17 (m, 2H), 2.58 (t, J = 5.4 Hz, 2H), 3.61 (s, 2H), 6.64 (s, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 25.27 (t), 25.70 (t), 30.31 (t), 114.76 (s), 116.24 (s), 128.71 (d, 2C), 129.34 (d, 2C), 131.06 (s), 137.02 (s), 140.31 (s) 163.79 (s), 191.31 (s); GCMS m / z (M)+309.11, (M+2)+311.11.   Preparation of (2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone (17). Following the experimental operational details reported in Procedure C, a total of 815 mg (1.29 eq; 7.20 mmol) of 1-methylpiperidin-4-one (1l), 1.00 g (1.0 eq.; 5.57 mmol) of 3-(4-chlorophenyl)-3-oxopropanenitrile (4) and 206 mg (1.15 eq.; 6.41 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 560 μL (1.15 eq; 6.41 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. The crude solution was cooled to RT, then transferred dropwise to an Erlenmeyer containing 100 mL of rapidly stirring 50% ice / water (2 mL of EtOH added as a wash) to form a brown slurry. This material was filtered and dried (70oC; 1 torr) overnight in a vacuum oven to afford 855 mg (50.0%) of (2-amino-6-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-3-yl)(4-chlorophenyl)methanone (17) as a brown solid: MP 170.9-171.6 °C; IR (neat) 2978.85, 2969.98, 2945.17, 2929.71, 2917.44, 2846.59.2796.05, 1589.96, 1578.41, 1472.26, 1446.45, 1431.47, 1404.81, 1376.80, 1361.80, 1345.17, 1303.65, 1278.65, 1263.67, 1254.19, 1194.82, 1169.70, 1136.59, 1126.92, 1084.74, 1046.76, 1008.52, 971.31, 918.04, 840.48, 831.25, 805.61, 774.63, 765.65, 730.28, 691.61, 641.68, 626.65, 615.92, 580.85, 564.49, 533.87, 528.32, 507.09, 474.48, 429.11, 414.96, 403.78 cm-1;1H NMR (400 MHz, CDCl3) δ 1.97 (m, 2H), 2.40 (s, 3H), 2.41 (t, J = 5.5 Hz, 2H), 3.37 (m, 2H), 6.90 (s, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 28.67 (t), 45.73 (q), 52.41 (t), 53.80 (t), 115.04 (s), 115.97 (s), 128.53 (d, 2C), 129.11 (d, 2C), 129.25 (s), 136.62 (s), 140.39 (s), 165.54 (s), 191.21 (s); GCMS m / z (M)+306.19, (M+2)+308.20.   Preparation of 1-[2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)- yl]ethan-1-one (18). Following the experimental operational details reported in Procedure C, a total of 1.10 g (1.39 eq; 7.79 mmol) of 1-acetyl-4-piperidinone (1p), 1.00 g (1.0 eq.; 5.57 mmol) of 3- (4-chlorophenyl)-3-oxopropanenitrile (4) and 253 mg (1.39 eq.; 7.79 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 674 μL (1.39 eq; 7.79 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. Using an analogous aqueous workup and drying procedure reported in procedure A for 7, but scaled up respectfully, to afford a crude mixture of 18. This was dissolved in 150 mL of 67% EtOAc / DCM; afterwhich, 100 mL of 1:1 ether / hexanes was added to form a slurry. This mixture was filtered to afford 1.751 g of essentially pure 1-[2-amino-3-(4-chlorobenzoyl)- 4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl]ethan-1-one (18) as a yellow powder after drying (60oC; 1 torr) overnight in a vacuum oven: MP 230.5-231.5 °C; IR (neat) 3342.66, 3228.25, 3129.14, 2979.64, 2916.04, 1624.91, 1585.29, 1564.21, 1448.95, 1429.10, 1412.10, 1359.67, 1305.26, 1280.71, 1268.31, 1251.16, 1234.18, 1195.12, 1165.64, 1134.83, 1082.11, 1033.22, 1011.81, 1001.68, 982.01, 962.73, 913.42, 860.07, 842.22, 823.03, 775.71, 727.16, 693.58, 618.14, 598.03, 568.72, 555.45, 527.82, 504.17, 493.56, 473.87, 459.58, 401.12 cm-1;1H NMR (400 MHz, DMSO-d6, 2:1 mix of rotomers) δ 1.74 (t, J = 5.3 Hz, 0.34H, minor rotomer), 1.88 (t, J = 5.1 Hz, 1.67H, major rotomer), 1.99 (s, 1H, minor rotomer), 2.02 (s, 2H, major rotomer), 3.38 (t, J = 5.5 Hz, 2H), 4.35 (m, 1.67H, major rotomer), 4.41 (m, 0.34H, minor rotomer), 7.38 (d, J = 8.4 Hz, 0.34H, minor rotomer), 7.43 (d, J = 8.4 Hz, 1.67H, major rotomer), 7.49 (d, J = 8.4 Hz, 2H), 8.26 (br s, 1.34H, major rotomer), 8.28 (br s, 0.66H, minor rotomer);13C NMR (100 MHz, DMSO-d6, 2:1 mix of rotomers) δ 21.25 (q, major rotomer), 21.65 (q, minor rotomer), 27.36 (t, minor rotomer), 28.13 (t, major rotomer), 27.75 (t), 38.05 (t, minor rotomer), 40.39 (t, major rotomer), 42.90 (t, major rotomer), 44.29 (t, minor rotomer), 112.46 (s, minor rotomer), 112.51 (s, major rotomer), 113.16 (s, minor rotomer), 113.51 (s, major rotomer) (s), 128.22 (d, both rotomers), 128.76 (s, major rotomer), 129.00 (d, minor rotomer), 129.11 (d, major diastereomer), 129.25 (s, minor rotomer), 134.69 (s), 140.68 (s), 166.52 (s, major rotomer), 166.62 (s, minor rotomer), 168.47 (s), 188.97 (s); GCMS m / z (M)+335.14, (M+2)+337.15.   Preparation of Ethyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (19). Following the experimental operational details reported in Procedure C, a total of 1.34 g (1.40 eq; 7.79 mmol) of ethyl 4-oxopiperidine-1-carboxylate (1q), 1.00 g (1.0 eq.; 5.57 mmol) of 3-(4-chlorophenyl)-3-oxopropanenitrile (4) and 253 mg (1.40 eq.; 7.79 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 674 μL (1.25 eq; 7.79 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. Using an analogous aqueous workup and drying protocol reported in Procedure A for compound 6, but scaled up respectfully, a crude yield of 2.65 g of crude 19 was afforded as an orange-yellow foam. This material was absorbed using DCM onto 8.0 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 40M column (eluting with hexanes → 50% EtOAc / Hexanes) and concentrated to afford 1.77 g of 19 and 880 mg of mixed fractions. The pure fractions were dissolved in 12 mL of EtOH and added slowly dropwise to a rapidly stirring solution of 100 mL of 1:1 ice-water. The resulting slurry was filtered, the filter cake washed with 50 mL of ice water to afford 1.586 g (78.1%) of ethyl 2- amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (19) as a light yellow powder solid after drying (60oC; 1 torr) overnight in a vacuum oven: MP 138.7- 139.3 °C; IR (neat) 3378.55, 3275.71, 2979.95, 2911.51, 1681.47, 1620.72, 1588.12, 1577.53, 1565.28, 1486.59, 1454.09, 1431.34, 1421.85, 1405.75, 1384.38, 1358.05, 1337.67, 1295.24, 1260.59, 1234.08, 1210.61, 1171.46, 1119.38, 1086.82, 1049.09, 1015.32, 997.80, 971.90, 954.21, 908.06, 883.70, 833.93, 810.36, 772.06, 761.91, 725.07, 692.04, 641.99, 609.37, 564.85, 518.55, 494.27, 469.78, 454.72 cm-1;1H NMR (400 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 1.92 (m, 2H), 3.41 (m, 2H), 4.15 (q, J = 7.08 Hz, 2H), 4.40 (m, 2H), 6.96 (br s, 2H), 7.39 (m, 4H);13C NMR (100 MHz, CDCl3, mix of rotomers) δ 14.85 (q), 28.31 (t), 41.25 (t), 42.93 (t), 61.83 (t), 114.41 (s, minor rotomer), 114.85 (s, major rotomer), 128.65 (d, 2C), 129.13 (d, 2C), 129.88 (s), 130.38 (s), 136.85 (s), 140.23 (s), 155.57 (s), 165.74 (s), 191.03 (s); GCMS m / z (M)+364.18, (M+2)+366.18.   Preparation of Benzyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (20). Following the operational experimental details reported in Procedure C, a total of 4.1 g (1.25 eq; 17.44 mmol) of benzyl 4-oxopiperidine-1-carboxylate, 2.50 g (1.0 eq.; 13.95 mmol) of 3-(4-chlorophenyl)-3-oxopropanenitrile (4) and 560 mg (1.25 eq.; 17.44 mmol) of elemental S in 6 mL of EtOH was reacted slowly with 1.50 mL (1.25 eq; 17.44 mmol) of morpholine slowly dropwise over 10 min and was then heated to 60oC overnight. Using an analogous aqueous workup reported in Procedure A for compound 6, but scaled up respectfully, a crude yield of 7.645 g of crude 20 was afforded as a dark orange-red foam. This material was absorbed onto 8.0 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 40M column (eluting with hexanes → 50% EtOAc / Hexanes) and concentrated to afford 5.81 g (97.6%) of benzyl 2-amino-3-(4- chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (20) as a yellow-orange foam which slowly solidified to an amorphous light orange solid: MP 88.6 – 89.6 °C; IR (neat) 3367.21, 3272.75, 2979.60, 2970.26, 2906.98, 1695.37, 1685.17, 1679.10, 1576.77, 1560.32, 1496.51, 1420.24, 1359.08, 1337.63, 1297.73, 1265.35, 1226.26, 1172.12, 1107.96, 1086.53, 1042.43, 1026.79, 1013.44, 1002.25, 974.10, 908.14, 867.92, 841.29, 822.29, 796.45, 773.81, 762.57, 733.39, 695.09, 643.74, 621.70, 599.97, 575.47, 556.43, 522.10, 498.67, 474.95, 453.52, 447.45, 409.97 cm-1;1H NMR (400 MHz, CDCl3) δ 1.94 (bm, 2H), 3.45 (bt, J = 5.1 Hz, 2H), 4.44 (bm, 2H), 5.16 (s, 2H), 6.88 (bs, 2H), 7.26-7.45 (bm, 9H);13C NMR (100 MHz, CDCl3, 1:1 mix of rotomers) δ 28.19 (t, rotomer 1), 28.42 (t, rotomer 2), 41.20 (t, rotomer 1), 41.45 (t, rotomer 2), 43.09 (t), 67.59 (t), 114.26 (s), 114.91 (s), 128.30 (d), 128.36 (d, 2C), 128.72 (s), 129.15 (s), 129.40 (s), 136.92 (s), 140.15 (s), 155.35 (s), 165.64 (s), 191.06 (s); GCMS m / z (M-Bn fragment)+335.13, (M+2)+337.13. Preparation of [2-amino-6-(cyclopropanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl](4-chlorophenyl)methanone (21). With a few modifications but following the operational experimental details reported in Procedure C, a total of 637.9 mg (1.15 eq; 3.14 mmol) of 1- (cyclopropanesulfonyl)piperidin-4-one (1u), 490 mg (1.0 eq.; 2.73 mmol) of 3-(4- chlorophenyl)-3-oxopropanenitrile (4) and 101 mg (1.15 eq.; 3.14 mmol) of elemental S in 6 mL of EtOH was reacted with 271 μL (1.15 eq; 3.14 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. The crude solution was cooled to RT and partitioned between 75 mL of EtOAc and water (2 x 20-mL), followed by brine (20 mL). The organic layer was dried (MgSO4) and concentrated to afford 1.23 g of crude 21 as a red-brown foam. This was absorbed using DCM onto 8.0 g of a silica gel dry packed in a Biotage samplet precartridge, chromatographed over a Biotage 40M column (eluting with hexanes → 50% EtOAc / Hexanes) and concentrated to afford 493.8 g (46.0%) of [2-amino-6- (cyclopropanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl](4- chlorophenyl)methanone (21) as a yellow foam.: IR (neat) 3655.96, 3400.00, 3297.49, 2979.58, 2970.66, 2888.04, 1728.85, 1681.81, 1577.09, 1485.78, 1471.94, 1425.27, 1391.80, 1382.50, 1330.73, 1302.94, 1288.40, 1251.63, 1189.58, 1174.23, 1144.59, 1087.27, 1071.73, 1042.60, 1011.22, 953.74, 886.88, 828.76, 805.89, 778.57, 752.32, 734.29, 686.09, 669.56, 594.86, 572.07, 559.41, 538.63, 518.10, 503.46, 475.71, 439.76, 421.22, 409.55 cm-1;1H NMR (400 MHz, CDCl3) δ 0.96 (m, 2H), 1.15 (m, 2H), 2.04 (t, J = 5.56 Hz, 2H), 2.26 (m, 1H), 3.29 (t, J = 5.64 Hz, 2H), 4.28 (m, 2H), 6.94 (br s, 2H), 7.39 (m 4H);13C NMR (100 MHz, CDCl3) δ 4.87 (t, 2C), 27.04 (d), 28.47 (t), 43.45 (t), 44.60 (t), 113.39 (s), 114.66 (s), 128.71 (d, 2C), 129.02 (d, 2C), 129.63 (s), 136.95 (s), 140.04 (s), 165.69 (s), 191.04 (s); MS (ESI) calculated for C17H17N2O3S2Cl 396.0, found 397.2 [M + H]+, found 399.2 [M + 2 + H]+.    Preparation of 1-(2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1- one (22). Following the experimental operational details reported in Procedure C, a total of 1.00 g (1.25 eq; 7.08 mmol) of 1-acetyl-4-piperidinone (1p), 823 mg (1.0 eq.; 5.67 mmol) of 3-oxo-3-phenylpropanenitrile (5) and 227 mg (1.25 eq.; 7.08 mmol) of elemental S in 6 mL of EtOH was reacted with 613 μL (1.25 eq; 7.08 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. The crude solution was cooled to RT diluted with 200 mL of EtOAC, heated until dissolution occurred, and cooled to RT. The organic layer was washed with water (2 x 20 mL), dried (MgSO4) and concentrated. The crude residue was absorbed using 10% MeOH in DCM onto 8.0 g of a silica gel in a Biotage samplet precartridge, chromatographed over a Biotage 40M column (eluting with DCM → 10% MeOH / DCM) and concentrated to afford 1.145 g (67.3%) of 1-(2-amino-3-benzoyl-4,7- dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1-one (22) as a beige solid: MP 202.1-203.1 °C; IR (neat) 3352.63, 3251.59, 3199.00, 3165.22, 3046.92, 2972.90, 2912.29, 2849.99, 1629.95, 1582.71, 1567.59, 1448.11, 1440.20, 1420.69, 1411.04, 1357.69, 1337.62, 130.44, 1266.25, 1235.81, 1220.79, 1173.28, 1156.83, 1125.81, 1173.28, 1156.83, 1125.81, 1073.37, 1034.11, 1002.37, 982.53, 926.31, 906.70, 851.30, 818.22, 796.61, 750.32, 698.43, 657.29, 648.79, 620.24, 588.34, 569.61, 550.71, 540.46, 516.08, 504.68, 478.67, 463.06, 452.78, 438.91, 424.04, 417.43, 408.77, 404.85 cm-1;1H NMR (400 MHz, DMSO-d6, 2:1 rotomers) δ 1.71 (m, 0.67H, minor rotomer), 1.85 (m, 1.34H, major rotomer), 1.97 (s, 2H, major rotomer), 2.02 (s, 1H, minor rotomer), 3.36 (s, 2H), 4.36 (m, 1.34H, major rotomer), 4.42 (m, 0.67H, minor rotomer), 7.41 (m, 5H), 8.22 (br s, 1.34 H, major rotomer), 8.25 (br s, 0.67H, minor rotomer);13C NMR (100 MHz, DMSO-d6, 2:1 rotomers) δ 21.21 (q, major rotomer), 21.64 (q, minor rotomer), 27.23 (t, minor rotomer), 27.97 (t, major rotomer), 40.39 (t, major rotomer), 38.87 (t, minor rotomer), 42.90 (t, major rotomer), 44.29 (t, minor rotomer), 112.66 (s, minor rotomer), 112.70 (s, major rotomer), 112.94 (s), 113.31 (s), 126.91 (d, minor rotomer), 127.00 (d, major rotomer), 128.11 (d, minor rotomer), 128.12 (d, major rotomer), 129.01 (s), 129.53 (s), 130.01 (s, minor rotomer), 130.04 (s, major rotomer), 142.09 (s, major rotomer), 142.11 (s, minor rotomer), 166.16 (s, major rotomer), 166.29 (s, minor rotomer), 168.47 (s, both rotomers), 190.51 (s); GCMS m / z (M)+300.22.   Preparation of Ethyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate (23). Following the experimental operational details reported in Procedure C, a total of 1.00 g (1.25 eq; 5.84 mmol) of ethyl 4-oxopiperidine-1-carboxylate (1q), 678.3 mg (1.0 eq.; 4.67 mmol) of 3-oxo-3-phenylpropanenitrile (5) and 187.3 mg (1.25 eq.; 5.84 mmol) of elemental S in 8 mL of EtOH was reacted with 505.3 μL (1.25 eq; 5.84 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. The crude solution was cooled to RT, and diluted with 80 mL of EtOAc. The organic layer was then washed with water (2 x 20 mL), dried (MgSO4) and concentrated to afford a crude mass of 1.7606 g. The crude residue was absorbed onto 8.3 g of silica gel dry-packed into Biotage samplet precartridge (using DCM and drying), chromatographed over a Biotage 40M column (eluting with hexanes → 50% EtOAc / Hexanes) and concentrated to afford 1.312 g (85.0%) of crude ethyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (23) as a foam. This material was dissolved in 30 mL of EtOH, and was added dropwise to a rapidly stirring ehrlenmeyer containing 125 mL of 50% ice / water to afford a precipitate which was filtered. The filter cake washed with water (2 x 20 mL), dried in vacuo (60oC; 1 torr) to afford 1.18 g (76.5%) of ethyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (23) as a tan solid: MP 81.0-82.0 °C; IR (neat) 3366.97, 3257.29, 3151.20, 3057.71, 2977.68, 2921.26, 2870.49, 2838.41, 1696.89, 1680.97, 1584.35, 1567.08, 1513.96, 1445.53, 1421.84, 1375.47, 1356.14, 1336.55, 1297.43, 1264.37, 1229.54, 1200.12, 1170.60, 1112.80, 1074.84, 1044.48, 1035.35, 99.97, 972.27, 913.33, 876.90, 844.38, 800.21, 767.13, 747.26, 700.37, 658.64, 616.48, 574.91, 549.36, 539.33, 517.75, 495.72, 486.11, 474.51, 449.72, 432.27, 414.93, 405.92 cm-1;1H NMR (400 MHz, CDCl3) δ 1.25 (m, 3H), 1.90 (m, 2H), 3.38 (m, 2H), 4.14 (m, 2H), 4.39 (m, 2H), 6.95 (br m, 2H), 7.43 (mc, 5H);13C NMR (100 MHz, CDCl3, rotomer broadening) δ 14.83 (q), 28.02 (t), 41.24 (t), 42.93 (t), 61.77 (t), 114.8 (br s), 115.08 (s), 127.26 (d), 128.04 (d), 130.70 (d), 141.92 (s), 155.60 (s), 165.42 (s), 192.54 (s); MS (ESI) calculated for C17H18N2O3S 330.1, found 331.2 [M + H]+.  Preparation of Prop-2-en-1-yl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (24). Following the experimental operational details reported in Procedure C, a total of 1.00 g (1.25 eq; 5.46 mmol) of prop-2-en-l-yl 4-oxopiperidine-l -carboxylate (Ir), 633.9 mg (1.0 eq.; 4.37 mmol) of 3-oxo-3-phenylpropanenitrile (5) and 175 mg (1.25 eq.; 5.46 mmol) of elemental S in 8 mL of EtOH was reacted with 472.2 pL (1.25 eq; 5.46 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60 °C overnight. The crude solution was cooled to RT, and diluted with 80 mL of EtOAc. The organic layer was then washed with water (2 x 20 mL), brine (20 mL), dried (MgSO-i) and concentrated to afford a crude mass of 1.846 g. The crude residue was absorbed onto 8.3 g of a silica gel dry- packed onto a Biotage samplet precartridge (using DCM then drying), chromatographed over a Biotage 40M column (eluting with hexanes 50% EtOAc / Hexanes) and concentrated to afford 1.437 g (96.1%) of crude (24) as a foam. This material was dissolved in 30 mL of EtOH, and was added dropwise to a rapidly stirring ehrlenmeyer containing 125 mL of 50% ice / water to afford a precipitate which was filtered. The filter cake washed wi th water (2 x 20 mL), dried in vacuo (60 °C; 1 torr) to afford 1.293 g (86.5%) of prop-2-en-l-yl 2-amino-3- benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5L7)-carboxylate (24) as a tan solid: MP 133.0- 134.0 °C; IR (neat) 3659.82. 3361.03. 3236.83, 3119.53, 3081.62, 2979.57, 2970.63.

[0006] 2930.35, 2887.83, 2852.21, 1771.58, 1690.29, 1647.45, 1586.86, 1572.72, 1541.13, 1527.19, 1507.78, 1470.99, 1458.65, 1446.08, 1419.41, 1381.35, 1338.81, 1313.78, 1299.14, 1272.37, 1252.08, 1228.73, , 1023.60. 998.77, 987.42, 959.66, 941.46, 914.26, 886.35, 832.54, 799.23, 763.28. 749.83, 702.99, 669.98, 649.09, 524.88. 482.87, 468.22, 454.00, 433.67, 410.83 cm’1; 'H NMR (400 MHz, CDCh) 5 1.92 (t, J = 5.4 Hz, 2H), 3.41 (t, J = 5.64 Hz, 2H), 4.42 (s, 2H), 4.60 (d, J = 5.48 Hz, 2H), 5.21 (dm, J= 10.2 Hz, 1H), 5.28 (dm, J= 14.0 Hz, 1H), 5.92 (m, 1H), 6.90 (br m, 2H), 7.42 (me, 5H);13C NMR (100 MHz, CDCh, 1: 1 mix of rotomers) 5 27.97 (t, rotomer 1), 28.17 (t, rotomer 2), 41.22 (t, rotomer 1), 41.40 (t, rotomer 2). 43.00 (t), 66.42 (t). 1 13.95 (s, rotomer 1), 114.25 (s. rotomer 2). 115.13 (s). 1 17.83 (t). 127.56 (d). 128.39 (d), 130.75 (d), 133.04 (d), 141.91 (s), 155.20 (s), 165.29 (s), 192.59 (s); MS (ESI) calculated for C18H18N2O3S 342.1, found 343.3 [M + H]+.

[0007] Preparation of [2-amino-6-(cyclopropanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl](phenyl)-methanone (25). With a few modifications but following the operational experimental details reported in Procedure C, a total of 637.4 mg (1.15 eq; 3.14 mmol) of 1- (cyclopropanesulfonyl)piperidin-4-one (1u), 396 mg (1.0 eq.; 2.73 mmol) of 3-oxo-3- phenylpropanenitrile (5) and 101 mg (1.15 eq.; 3.14 mmol) of elemental S in 6 mL of EtOH was reacted with 271 μL (1.15 eq; 3.14 mmol) of morpholine added slowly dropwise over 10 min and was then heated to 60oC overnight. The crude solution was cooled to RT, and diluted with 80 mL of EtOAC. The organic layer was then washed with water (2 x 20 mL), brine (20 mL), dried (MgSO4) and concentrated to afford a crude mass of 1.884 g of a wet reddish brown solid. The crude residue was absorbed onto 3.3 g of a silica gel dry-packed onto a Biotage samplet precartridge (using DCM then drying), chromatographed over a Biotage 25M column (eluting with hexanes → 50% EtOAc / Hexanes) and concentrated to afford 582.7 g of crude (25) as a foam. This material was rechromatographed using the identical conditions described above to afford 497.7 mg (50.7%) of 25 as a yellow foam. IR (neat) 3411.48, 3293.57, 3152.13, 3021.67, 2920.00, 2852.79, 1698.73, 1567.33, 1490.94, 1446.55, 1424.66, 1378.83, 1361.90, 1333.54, 1305.62, 1287.57, 1189.76, 1173.57, 1145.47, 1122.85, 1096.27, 1073.86, 1040.53, 1013.50, 984.96, 951.70, 905.68, 887.67, 825.32, 800.51, 784.12, 725.66, 700.20, 661.62, 646.74, 616.72, 588.29, 538.55, 516.76, 505.70, 484.37, 465.78, 437.51, 420.42, 410.69, 404.91 cm-1;1H NMR (400 MHz, CDCl3) δ 0.96 (m, 2H), 1.16 (m, 2H), 2.04 (t, J = 5.68 Hz, 2H), 2.26 (m, 1H), 3.28 (t, J = 5.68 Hz, 2H), 4.30 (s, 2H), 6.84 (br s, 2H), 7.40 (mc, 5H);13C NMR (100 MHz, CDCl3) δ 4.91 (t), 27.15 (d), 28.25 (t), 43.54 (t), 44.67 (t), 113.20 (s), 115.07 (s), 127.48 (d), 128.48 (d), 130.15 (s), 130.88 (d), 141.80 (s), 165.15 (s), 192.65 (s); MS (ESI) calculated for C17H18N2O3S2362.1, found 363.2 [M + H]+. Preparation of Ethyl 2-[(tert-butoxycarbonyl)amino]-6-(prop-2-en-1-yl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate (33). MP 174.6-175.2; IR (neat) 3263.21, 3083.40, 2976.69, 2926.27, 2791.02, 2759.42, 2358.54, 1710.97, 1671.05, 1641.40, 1579.92, 1541.54, 1477.09, 1465.96, 1426.94, 1389.35, 1364.63, 1336.88, 1289.43, 1266.51, 1241.72, 1213.49, 1145.32, 1116.22, 1059.28, 1038.83, 1021.45, 1002.62, 992.51, 951.40, 918.45, 908.30, 873.27, 827.12, 778.70, 764.99, 734.52, 672.12, 654.47, 623.11, 586.10, 554.49, 538.08, 506.37, 450.72, 430.05, 418.51 cm-1;1H NMR (400 MHz, CDCl3) δ 1.33 (t, J = 7.12 Hz, 3H), 1.50 (s, 9H), 2.72 (t, J = 5.68 Hz, 2H), 2.85 (s, 2H), 3.16 (d, J = 6.52 Hz, 2H), 3.50 (s, 2H), 4.28 (q, J = 7.12 Hz, 2H), 5.17 (d, J = 10.16 Hz, 1H), 5.22 (dd, Jd =17.16 Hz, Jd = 1.4 Hz, 1H), 5.90 (m, 1H), 10.26 (s, 1H);13C NMR (100 MHz, CDCl3) δ 14.45 (q), 27.37 (t), 28.37 (q), 50.20 (t), 51.32 (t), 60.45 (t), 60.86 (t), 82.10 (s), 109.75 (s), 118.29 (t), 122.74 (s), 129.80 (s), 135.27 (d), 150.51 (s), 152.25 (s), 166.25 (s); GCMS m / z (M - BOC)+Fragment 366.27. Preparation of Ethyl 2-[(tert-butoxycarbonyl)amino]-6-(methanesulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate (34). MP 90.1-90.5 °C; IR (neat) 3266.79, 2928.96, 2823.27, 2357.94, 1708.66, 1671.13, 1575.34, 1541.51, 1477.04, 1438.78, 1391.75, 1363.44, 1340.18, 1307.91, 1280.32, 1243.70, 1149.77, 1062.52, 1026.50, 1001.19, 958.23, 900.26, 869.17, 774.00, 732.90, 685.36, 625.22, 583.89, 551.14, 516.32, 468.65, 442.19, 407.07 cm-1;1H NMR (400 MHz, CDCl3) δ 1.36 (t, J = 7.12 Hz, 3H), 1.51 (s, 9H), 2.82 (s, 3H), 2.96 (t, J = 5.8 Hz, 2H), 3.55 (t, J = 5.92 Hz, 2H), 4.31 (m, 4H), 10.29 (s, 1H);13C NMR (100 MHz, CDCl3) δ 14.44 (q), 26.62 (t), 28.33 (q), 37.10 (d), 43.37 (q), 44.16 (t), 60.82 (t), 82.60 (s), 109.62 (s), 119.98 (s), 129.57 (s), 151.31 (s), 152.23 (s), 165.85 (s); GCMS m / z (M - BOC fragment)+304.17. Preparation of Ethyl 2-amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate hydrochloride (35). Intermediate was synthesized according to Procedure A and Compound 35 was synthesized by generating a chloride salt with the free base amine group. MP above 250 °C; IR (neat) 3656.32, 3377.13, 3219.54, 3143.73, 2980.00, 2888.26, 2738.30, 1992.86, 1659.42, 1592.42, 1575.33, 1491.03, 1417.95, 1385.49, 1343.47, 1299.14, 1254.41, 1129.60, 1087.04, 1018.25, 955.45, 903.83, 783.00, 492.78, 435.79, 403.81 cm-1;1H NMR (400 MHz, DMSO) δ 1.26 (t, J = 7.04 Hz, 3H), 1.46 (s, 6H), 1.66 (s, 6H), 2.86 (s, 2H), 4.18 (q, J = 7.06 Hz, 2H), 7.50 (s, 2H), 9.60 (s, 2H);13C NMR (100 MHz, DMSO) δ 14.33 (q), 26.16 (q), 29.79 (q), 36.79 (s), 55.24 (s), 56.07 (t), 59.05 (t), 101.61 (s), 117.63 (s), 127.36 (s), 163.92 (s), 164.48 (s); GCMS m / z (M)+267.18 (free base form). Preparation of 5-tert-butyl 3-ethyl 2-amino-4,6-dihydro-5H-thieno[2,3-c]pyrrole-3,5- dicarboxylate (36). 36 was synthesized according to Procedure A. MP 187.8-188.8 °C; IR (neat) cm-13416.09, 3292.37, 3257.33, 3163.82, 2979.59, 2905.18, 2870.36, 1665.05, 1594.09, 1578.04, 1533.90, 1496.09, 1474.33, 1457.64, 1442.31, 1409.09, 1367.97, 1345.58, 1300.52, 1260.74, 1191.34, 1167.19, 1130.09, 1109.42, 1047.26, 1032.47, 987.45, 957.00, 922.16, 884.68, 866.63, 848.12, 814.68, 781.71, 766.48, 756.55, 736.30, 637.22, 610.63, 571.07, 524.05, 457.34, 425.82, 406.14;1H NMR (400 MHz, CDCl3) δ 1.27 (m, 3H), 1.46 (d, J = 3.96 Hz, 9H), 4.20 (m, 2H), 4.40 (t, J = 3.56 Hz, 3H), 4.50 (t, J = 3.32 Hz, 1H), 6.06 (s, 2H);13C NMR (100 MHz, CDCl3) δ 14.52 (q), 28.66 (q), 49.77 (t), 50.08 (t), 51.76 (t), 79.94 (s), 101.50 (s), 114.71 (s), 136.99 (s), 154.49 (s), 165.15 (s), 166.78 (s); GCMS m / z (M - BOC)+212.1. Preparation of [2-amino-6-(methanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl](4-methylphenyl)methanone (37). Both intermediates (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- methylphenyl)methanone (37A) and (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone (37B) were synthesized from compounds 13 and 20, respectively, by the above 2-step procedure. Preparation of (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone (37B). Steps 1 and 2 were followed using a modification of the known procedure of WO 99 / 21617. To a cooled and stirred suspension of (1.5 g; 3.51 mmol) of 2-amino-3-(4- chlorobenzoyl)-6-benzyloxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (compound 20) in acetic acid (2 mL) was added a solution of HBr (33%) in acetic acid (3.51 mL). After stirring at room temperature for 4h, n-hexane was added, the hexane slurry mixed and the hexanes removed from the resulting suspension and discarded. The remaining mixture was concentrated under vacuum to give a solid. This solid was dried to provide a melting point of HBr salt (mp >260oC). This solid was then then suspended in water (10 mL) and neutralized dropwise to pH 10 (using a pH meter) using a 5% aq NaOH solution, filtered and dried (1 torr; 50oC) to afford 772.9 mg (75.3%) of free base form of 2-amino-3-(4-chlorobenzoyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine 37B as a light tan solid. Data for 37B: mp (HBr salt form) >260oC; Rest of Data is free Base Form 37B: IR (neat) 3361.16, 3243.30, 3158.35, 3092.61, 2978.64, 2969.83, 2909.94, 2811.85, 2786.68, 1593.79, 1573.22, 1561.64 cm-1;1H- NMR (DMSO-d6, 400 MHz, , NH exchanged out with water peak) δ 1.90 (m, 2H), 2.89 (t, J = 5.4 Hz, 2H), 3.87 (br s, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 8.27 (br s, 2H);13C NMR (100 MHz, DMSO-d6) δ^25.75 (t), 41.19 (t), 42.09 (t), 111.89 (s), 112.51 (s), 128.25 (d, 2C), 128.35 (s), 128.98 (d, 2C), 134.75 (s), 140.65 (s); 166.39 (s), 189.04 (s). Preparation of (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4-methyl- phenyl)methanone (37A) from Compound 13. Following the same procedure used for the preparation of 37B from compound 20, a total of 1.5 g (3.69 mmol) of compound 13 was converted to 754 mg (75.1%) of 37A (tan solid): mp (HBr salt form) >260oC; Rest of Data is free Base Form 37A: IR (neat) 3364.28, 3240.18, 3118.53, 2979.40, 2970.74, 2916.20, 2888.93, 1575.92, 1492.14 cm-1;1H-NMR (DMSO-d6, 400 MHz, NH exchanged out with water peak) δ 1.89 (m, 2H), 2.36 (s, 3H), 2.81 (t, J = 5.5 Hz, 2H), 3.81 (br s, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 8.06 (br s, 2H);13C NMR (100 MHz, DMSO-d6) ^ 21.03 (q), 26.41 (t), 41.52 (t), 42.51 (t), 112.62 (s), 113.04 (s), 127.23 (d, 2C), 128.58 (d, 2C), 128.90 (s), 139.26 (s), 139.94 (s), 165.42 (s), 190.50 (s). Preparation of [2-amino-6-(methanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl](4-methylphenyl)methanone (38) from 37A. A total of 120 mg (0.44 mmol) of compound 37A in 4.5 mL of DCM at 0oC and 79.5 μL (0.57 mmol, 1.3 equiv.) of Et3N was reacted with 37.4 μL (0.48 mmol, 1.1 equiv.) of MsCl and then warmed to RT for 12 h. Standard workup with EtOAc and sat aq. NaHCO3, followed by concentration and chromatography (eluted with hexanes to 50% EtOAc / Hexanes) over a Biotage 25M column afforded 44.7 mg (29.1%) of 38 as a yellow foam. IR (neat) 3395, 3100-3200 (br), 2979.39, 2970.49, 2923.46, 2854.01, 1670.66, 1574.62, 1557.15 cm-1;1H-NMR (CDCl3, 400 MHz, NH2 exchanged out with water peak in ^ 6.5-7.5 region) ^ 2.09 (t, J = 5.4 Hz, 2H), 2.40 (s, 3H), 2.82 (s, 3H), 3.25 (t, J = 5.6 Hz, 2H), 4.25 (br s, 2H), 7.20 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H);13C NMR (100 MHz, CDCl3) ^ 21.73 (q), 28.02 (t), 36.50 (q), 43.25 (t), 44.45 (t), 112.86 (s), 115.34 (s), 127.79 (d, 2C), 129.16 (d, 2C), 130.28 (s), 138.86 (s), 141.53 (s), 164.60 (s), 192.66 (s) Preparation of [2-amino-6-(methanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl](4-chlorophenyl)methanone (39) from 37B. A total of 170 mg (0.58 mmol) of compound 37B in 4.5 mL of DCM at 0oC and 105.2 μL (0.76 mmol, 1.3 equiv.) of Et3N was reacted with 56.2 μL (0.73 mmol, 1.25 equiv.) of MsCl and then warmed to RT for 12 h. Standard workup with DCM and sat aq. NaHCO3, followed by concentration and chromatography (eluted with hexanes to 60% EtOAc / Hexanes) over a Biotage 25M column afforded 79.9 mg (37.1%) of 39 as a yellow solid: mp 188.5-189.5oC; IR (neat) 3404 (br), 3282 (br), 3083.3, 3063.08, 3004.86, 2985.90, 2959.67, 2909.37, 2858.13 cm-1;1H-NMR (CDCl3, 400 MHz) δ 2.06 (t, J = 5.6 Hz, 2H), 2.83 (s, 3H), 3.27 (t, J = 5.6 Hz, 2H), 4.25 (br s, 2H), 6.83 (br s, 2H), 7.40 (mc, 4H);13C NMR (100 MHz, CDCl3) δ 28.29 (t), 36.52 (q), 43.19 (t), 44.41 (t), 113.20 (s), 114.85 (s), 128.84 (d, 2C), 129.09 (d, 2C), 129.77 (s), 137.14 (s), 140.03 (s), 165.46 (s), 191.15 (s). to RTPreparation of Methyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate (40) from 37B. A total of 170 mg (0.58 mmol) of compound 37B in 4.5 mL of DCM at 0oC and 105.2 μL (0.76 mmol, 1.3 equiv.) of Et3N was reacted with 56.1 μL (0.73 mmol, 1.25 equiv.) of methyl chloroformate and then warmed to RT for 12 h. Standard workup with DCM and sat aq. NaHCO3, followed by concentration and chromatography (eluted with hexanes to 60% EtOAc / Hexanes) over a Biotage 25M column afforded 106.6 mg (52.3%) of 40 as a yellow solid: mp 106-107oC; IR (neat) 3373.83 (br), 3269.62 (br), 3155.72, 3029.70, 2949.76, 2914.02, 2845.22, 1681.71, 1632.98, 1575.62, 1562.55 cm-1;1H NMR (CDCl3, 400 MHz, NH2 exchanged out with water peak in ^ 6.5-7.5 region) δ 1.92 (mc, 2H), 3.41 (mc, 2H), 3.71 (s, 3H), 4.40 (br s, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H);13C NMR (100 MHz, CDCl3, broadening of some peaks due to rotomers) δ 28.37 (broad t), 41.20 (broad t), 43.02 (t), 53.02 (q), 114.92 (s), 114.39 (broad s), 128.13 (s), 128.69 (d, 2C), 129.14 (d, 2C), 136.90 (s), 140.20 (s), 155.98 (s), 165.68 (s), 191.09 (s). Preparation of [2-amino-6-(trifluoromethanesulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl](4-methylphenyl)methanone (41) from 37A. A total of 100 mg (0.37 mmol) of compound 37A in 4.5 mL of DCM at 0oC and 66.3 μL (0.476 mmol, 1.3 equiv.) of Et3N was reacted with 67.6 μL (0.403 mmol, 1.1 equiv.) of trifluoromethanesulfonic anhydride and then warmed to RT for 12 h. Standard workup with EtOAc and sat aq. NaHCO3, followed by concentration and chromatography (eluted with hexanes to 50% EtOAc / Hexanes) over a Biotage 25M column afforded 45.9 mg (31%) of 41 as a yellow foam: IR (neat) 3438.22 (br), 3359.89 (br), 3275.97, 2955.68, 2923.02, 2853.24, 1574.13, 1562.79, 1509.89 cm-1;1H-NMR (CDCl3, 400 MHz) δ 2.12 (mc, 2H), 2.41 (s, 3H), 3.46 (mc, 2H), 4.67 (br s, 2H), 6.69 (br s, 2H), 7.22 (d, J = 7.9 Hz, 2H); 7.38 (d, J = 8.0 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 21.74 (q), 28.22 (t), 44.28 (t), 45.01 (t), 111.71 (s), 115.27 (s), 120.17 (q, JC-F = 321.3 Hz, CF3), 127.81 (d, 2C), 129.23 (d, 2C), 130.22 (s), 138.73 (s), 141.73 (s), 164.56 (s), 192.61 (s). Preparation of [2-amino-6-(4-methylbenzene-1-sulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl](4-methylphenyl)methanone (42) from 37A. A total of 120 mg (0.44 mmol) of compound 37A, 79.5 μL (0.57 mmol, 1.3 equiv.) of Et3N and 71 μL (0.88 mol; 2.0 equiv.) of pyridine in 4.5 mL of DCM at 0oC, was reacted with 92.1 mg (0.483 mmol, 1.1 equiv.) of p-TsCl then warmed to RT over 1 h and stirred for 12 h. Standard workup with EtOAc and 10% aq. NH4Cl in water, followed by drying with brine, concentration and chromatography (eluted with hexanes to 50% EtOAc / Hexanes) over a Biotage 25M column afforded 64.9 mg (34.7%) of 42 as a yellow foam: IR (neat) 3653.78, 3419.14 (br), 3286.77 (br), 2979.63, 2970.57, 2888.25, 1576.10 (strong), 1425.34, 1397.16 cm-1;1H-NMR (CDCl3, 400 MHz) δ 2.01 (t, J = 5.3 Hz, 2H), 2.42 (s, 3H), 2.44 (s, 3H), 3.10 (t, J = 5.3 Hz, 2H), 4.10 (br s, 2H), 6.58-6.90 (br s, 2H), 7.19 (d, J = 7.8 Hz, 2H); 7.29 (d, J = 8.2 Hz, 2H); 7.32 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H);13C NMR (100 MHz, CDCl3) δ 21.69 (q), 21.72 (q), 27.95 (t), 43.54 (t), 44.76 (t), 112.78 (s), 115.11 (s), 127.72 (d, 2C), 127.78 (d, 2C), 129.01 (d, 2C), 129.89 (d, 2C), 130.01 (s), 133.79 (s), 138.82 (s), 141.35 (s), 143.97 (s), 164.68 (s), 192.54 (s). Preparation of 2-amino-6-(4-methylbenzene-1-sulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl](4-chlorophenyl)methanone (43). A total of 250 mg (0.85 mmol) of compound 37B, 154.7 μL (1.11 mmol, 1.3 equiv.) of Et3N, 2 mg (0.016 mmol, 0.02 equiv.) of 4-DMAP catalyst, and 75.9 μL (0.94 mol; 1.1 equiv.) of pyridine in 4.5 mL of DCM at 0oC, was reacted with 179.1 mg (0.94 mmol, 1.1 equiv.) of p-TsCl then warmed to RT over 1 h and stirred for 12 h. Standard workup with EtOAc and 10% aq. NH4Cl in water, followed by brine, concentration and chromatography (eluted with hexanes to 50% EtOAc / Hexanes) over a Biotage 25M column afforded 96.9 mg (25.4%) of 43 as a yellow foam: IR (neat) 3411.46 (br), 3282.27 (br), 2917.91, 2970.57, 2850.36, 1574.69 (strong) 1426.47 (strong) cm-1;1H-NMR (CDCl3, 400 MHz) ^ 1.95 (mc, 2H), 2.42 (s, 3H), 3.08 (t, J = 5.3 Hz, 2H), 4.08 (br s, 2H), 6.82 (br s, 2H), 7.30 (m, 6H), 7.64 (d, J = 8.2 Hz, 2H);13C NMR (100 MHz, CDCl3) ^ 21.72 (q), 28.11 (t), 43.47 (t), 44.73 (t), 113.18 (s), 114.66 (s), 127.77 (d, 2C), 128.70 (d, 2C), 129.09 (d, 2C), 129.50 (s), 129.94 (d, 2C), 133.79 (s), 137.02 (s), 139.96 (s), 144.07 (s), 165.50 (s), 191.06 (s). Preparation of N-[3-(4-methylbenzoyl)-6-(trifluoroacetyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-2-yl]-2,2,2-trifluoroacetamide (44) from 37A. A total of 250 mg (0.91 mmol) of compound 37A, 165.7 μL (1.19 mmol, 1.3 equiv.) of Et3N, and 2 mg (0.016 mmol, 0.018 equiv.) of 4-DMAP catalyst in 4.5 mL of DCM at 0oC, was reacted with 177.9 mg (1.28 mmol, 1.4 equiv.) of trifluoroacetic anhydride then warmed to RT over 1 h and stirred for 12 h. Standard workup with EtOAc and 10% aq. NH4Cl in water, followed by brine, concentration and chromatography (eluted with hexanes to 50% EtOAc / Hexanes) over a Biotage 25M column afforded 25 mg (7.4%) of 44 as a yellow solid: Selected data for 44: mp 185.5-186.5oC: IR (neat) 3650.24, 3500-3400 (br), 3220.79, 3066.76, 2979.58, 2970.14, 2917.81, 2889.39, 2848.94, 1720.69, 1693.52, 1654.37, 1615.95, 1560.07, 1532.84, 1509.89, 1481.05 cm-1;1H-NMR (CDCl3, 400 MHz, 70:30 mixture of rotomers) δ 2.26 (t, J = 5.5 Hz, 1.4H / 2.0H, major rotomer), 2.31 (t, J = 5.4 Hz, 1.4H / 2.0H, major rotomer), 2.46 (s, 3H, both rotomers), 3.63 (t, J = 5.6 Hz, 1.4H / 2.0H, major rotomer), 3.71 (t, J = 5.6 Hz, 0.6H / 2.0H, minor rotomer), 4.78 (br s, 0.6H / 2.0H, minor rotomer), 4.81 (br s, 1.4H / 2.0H, major rotomer), 7.29 (d, J = 7.8 Hz, 2H, Ar-H both rotomers), 7.48 (m, 2H, Ar-H both rotomers), 12.14 (s, 0.7 / 1.0H, NHCOCF3, major rotomer), 12.21 (s, 0.3H / 1H, NHCOCF3, minor rotomer). Preparation of N-[3-(4-chlorobenzoyl)-6-(trifluoroacetyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-2-yl]-2,2,2-trifluoroacetamide (45) from 37B. A total of 250 mg (0.85 mmol) of compound 37A, 154.7 μL (1.11 mmol, 1.3 equiv.) of Et3N, and 2 mg (0.016 mmol, 0.019 equiv.) of 4-DMAP catalyst in 9.0 mL of DCM at 0oC, was reacted with 130.6 mg (0.94 mmol, 1.1 equiv.) of trifluoroacetic anhydride then warmed to RT over 1 h and stirred for 12 h. Standard workup with EtOAc and 10% aq. NH4Cl in water, followed by brine, concentration and chromatography (eluted with hexanes to 50% EtOAc / Hexanes) over a Biotage 25M column afforded 51.1 mg (12.3%) of 45 as a yellow foam: Selected data for 45: IR (neat) 3222.68, 3088.02, 2922.81, 2850.95, 1720.40, 1694.74, 1621.17, 1587.05, 1557.34, 1531.21 cm-1;1H-NMR (CDCl3, 400 MHz, 70:30 mixture of rotomers) δ 2.26 (mc, 2H, both rotomer), 3.65 (t, J = 5.4 Hz, 1.4H / 2.0H, major rotomer), 3.72 (t, J = 5.4 Hz, 0.6H / 2.0H, minor rotomer), 4.78 (br s, 0.6H / 2.0H, minor rotomer), 4.81 (br s, 1.4H / 2.0H, major rotomer), 7.49 (m, 4H, Ar-H both rotomers), 12.21 (s, 02H / 2H, NHCOCF3, both rotomer). Example 2: In Vitro Testing of Potential GLP-1R PAMs by CRE Luciferase Reporter Assay The Glucagon-like peptide 1 receptor (GLP-1R) is a physiologically and therapeutically important Class B G-protein coupled receptor (GPCR). Upon activation through the binding of Glucagon-like peptide 1 (GLP-1), an important incretin hormone secreted in response to food intake, GLP-1R stimulates glucose-dependent insulin secretion and reduces glucagon secretion to help maintain the glucose level in blood plasma. Recently, GLP-1R agonistic drugs have also been shown to markedly reduce body weight in people with obesity, protect against serious heart disease, and curb drug and alcohol addiction through clinic trials, making it one of the most interesting and most intensively studied Class B GPCRs. As an alternative approach, developing small molecule drugs functioning as the positive allosteric modulators (PAMs) of GLP-1R has attracted increasing interest, given the allosteric nature of GLP-1R and potential benefits of small molecule allosteric modulators such as oral administration and reduced side-effects. Recently, employing a simple ELISA type assay system, two current drugs, benzethonium chloride and tamoxifen, were found to enhance the binding of GLP-1R to exendin-4-GST (FIG.1). Novel compounds reported as GLP-1R PAMs may target either the extra-helical binding site or a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6 of GLP-1R based on computational approaches. In another study, high-throughput screening of a chemical library followed by structural optimization led to the discovery of compound V-0219 that exhibits enhanced efficacy of GLP-1R stimulation, high potency in the potentiation of insulin secretion, and minor off-target activities. In an effort to identify small molecule GLP-1R PAMs with drug-like properties, the 2-Aminothiophenes (2-AT) scaffold was investigated as potential PAMs of GLP-1R. The 2- AT scaffold has a low molecular weight, which is one of the lowest molecular weights of scaffolds known as PAMs of GLP-1R, and satisfies all requirements of Lipinski’s rule of five as well as Veber’s updated rule on the number of rotatable bonds. To further improve its positive allosteric modulating potency, this study focused on the structural modification and structure-activity relationship studies of the 2-AT scaffold. As a result, more than 1002-AT derivatives with a variety of structural changes were synthesized and evaluated for their positive modulating activities. Top-ranked compounds were further evaluated through in vivo animal studies. Results herein further validate 2-AT based derivatives as PAMs in GLP-1R drug discovery and the reported PAMs have the potential for further drug development. Medicinal chemistry optimization The structural optimization of compound 2-AT compounds of the disclosure were carried out in two consecutive stages. In the first stage, the cyclohexanone ring was systematically modified to introduce heteroatoms O, N or S at the carbon 6 position (Scheme 1 and Scheme 2). The methyl group attached to that ring was also replaced with other functional groups and its position varied. Compounds q and r whose N6 atom was attached by either a NCO2Et or a NCO2allyl group showed more than 100% increase in allosteric activities measured by the luciferase assay (Table 2). In addition, compound f with a propyl group at the C6position also showed similar increase by in vitro studies. These data suggested that the C6position in the cyclohexanone ring is important for the allosteric activities of the compounds. In the second stage, the role of the ester on the other side of the molecular scaffold was explored (Scheme 2). Replacing the ester with a ketone attached with either a benzene (23 and 24) or a toluene ring (11, 6 and 7) resulted in 168% increase of the positive allosteric activities of the compound (Table 3). In vitro activity of the synthesized compounds The activation of GLP-1R by GLP-1 in combination with the synthesized compounds was studied by luciferase assay responding to cAMP production using HEK.Luc2P cells transiently expressing human GLP-1R. The screening steps were performed on 103 intermediate compounds and final products. Compounds with best activities from one experiment were used as controls to compare and select the more active ones in another experiment. In total, 41 compounds (Table 2, Table 3, Table 4, and Table 5) were confirmed to be the PAMs of GLP-1R. GLP-1R activity stimulated by GLP-1 in combination with these compounds was increased up to two-folds than using GLP-1 alone. Next these compounds were further characterized through the generation of their individual dose- response curve. The dose-dependent responses of each compound (5 µM) in combination with different concentrations of GLP-1 (10-13-10-6M), or a combination of GLP-1 (10 nM) with different concentrations of the compound (0.78 µM-100 µM) were generated. Four compounds (6, 7, 23 and 24) showed significant allosteric effect in a dose dependent manner (FIG.2). These four compounds were chosen for further studies. Stimulation of Insulin Secretion The insulin secretion activity of four compounds (6, 7, 23 and 24) was assessed by in vitro insulin secretion assay using INS-1832 / 13 cells with / without GLP-1. In comparison with GLP-1 (10 nM) alone, the combination of each compound with GLP-1 can stimulate insulin secretion by more than 2-folds in the presence of 16.7 mM of glucose (FIG.3). Without GLP-1 and compared with the vehicle control, each compound alone also stimulated the production of insulin. However, the secretion of insulin by compound 7 alone was insignificant. Hence, these data indicated that 7 can enhance glucose-dependent insulin production in GLP-1R expressed cells and may even improve GLP-1’s efficacy sufficiently enough to have potential clinical ramifications functioning as a PAM of GLP-1R. Glucose Tolerance Test Four compounds’ effect on postprandial reduction of blood glucose level was studied by intraperitoneal glucose tolerance test (iGTT) using the CD1 mice. The results showed that compound 7 (10 mg / kg b.w.) significantly reduced blood glucose compared with the vehicle control (FIG.4A). Less significant reduction of glucose was observed when tested with three other compounds (6, 23 and 24). In the dose-response test, different doses of 7 resulted in significant difference of blood glucose levels at every time point (FIG.4B). At the dose of 5 mg / kg b.w., compound 7 significantly reduced the glucose level after 60 min. With the increased dose level at 10 mg / kg b.w. and 30 mg / kg b.w., it took only 30 min to significantly lower the glucose level after treated with 7. By 60 min, the glucose level was reduced by 50%. More importantly, by co-treatment with Sitagliptin (10 mg / kg b.w), an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV (DDP-4), compound 7 (10mg / kg b.w.) synergistically lowered the blood glucose level by approximately 75% after 60 min (FIG. 4C). Taken together, these in vivo data confirmed that compound 7 was an effective PAM of GLP-1R. Docking studies All the available structures of GLP-1R in its active state were downloaded and compared by docking score. In total eight structures were retained for docking studies (PDB ID: 6B3J, 6ORV, 6X1A, 6X19, 7C2E, 7DUR, 7LCI, an 7RTB). All the potential ligand- binding pockets on them were detected (FIG.5). Docking of the compound 7 to these pockets on all eight GLP-1R structures resulted in the varied docking score from -1.54 kcal / mol to -10.0 kcal / mol. The binding site with the best score is in the extracellular side of the transmembrane domain of GLP-1R near the N-terminus of the GLP-1 peptide. This binding site may provide unexpected benefits to the signaling action of GLP-1 PAM molecules. Enumerated Embodiments: The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance. Embodiment 1 provides a compound of Formula (I), or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof: (I), wherein: X is selected from the group consisting of O, S, C(R1g)(R1h), and NRz; each occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is independently selected from the group consisting of H, halogen, -OH, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, and optionally substituted C1-C6alkoxy; R2and R3are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)-C2-C6alkenyl, optionally substituted -C(=O)OC1-C6alkyl, and optionally substituted -C(=O)OC2- C6alkenyl; R4is selected from the group consisting of -OH, optionally substituted C1-C6alkoxy, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heterocyclyl; m is 0 or 1; and Rzis selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C3-C10cycloalkyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)-C2-C6alkenyl, optionally substituted -S(=O)2-C1-C6alkyl, optionally substituted -S(=O)2-C3-C10cycloalkyl, optionally substituted -S(=O)2-phenyl, optionally substituted -C(=O)O-C1-C6alkyl, optionally substituted -C(=O)OC2-C6alkenyl, optionally substituted phenyl, and optionally substituted naphthyl; provided that, when Rzis -S(=O)2-C1-C6alkyl, optionally substituted -C(=O)-C1-C6alkyl, or optionally substituted -C(=O)-C2-C6alkenyl, then R4is -OH, optionally substituted C1-C6alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted heterocyclyl. Embodiment 2 provides the compound of Embodiment 1, wherein each occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is each independently selected from the group consisting of H and optionally substituted C1-C6alkyl. Embodiment 3 provides the compound of any one of Embodiments 1-2, wherein at least one occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is selected from the group consisting of -CH3, -CF3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, - CH2C(CH3)2, -CH(CH3)CH2CH3, and -C(CH3)3. Embodiment 4 provides the compound of any one of Embodiments 1-3, wherein Rzis selected from the group consisting of H, -CH3, -CF3, -CH2CH3, -(CH2)2CH3, CH(CH3)2, - (CH2)3CH3, -CH2C(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, cyclopropyl, -C(=O)CH3, - C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OCH2Ph, -S(=O)2CF3, -S(=O)2(cyclopropyl), and - S(=O)2(4-methylphenyl). Embodiment 5 provides the compound of any one of Embodiments 1-4, wherein X is selected from the group consisting of -O-, -S-, -CH2-, -CH(CH3)-, -CH(CF3)-, -C(CH3)2-, - CH[(CH2)3CH3]-, -CH[(CH2)CH(CH3)2]-, -CH[C(CH3)3]-, -NH-, -N(CH3)-, -N(CF3)-, - N(CH2CH3)-, -NH[(CH2)2CH3]-, -NH(CH(CH3)2)-, -N[(CH2)3CH3]-, -N(CH2C(CH3)2]-, - N(CH(CH3)CH2CH3)-, -N(C(CH3)3)-, -N(cyclopropyl)-, -N(C(=O)CH3)-, -N(C(=O)OCH3)-, - N(C(=O)OCH2CH3)-, -N(C(=O)OCH2Ph)-, -N(S(=O)2CF3)-, -N(S(=O)2(cyclopropyl))-, and - N(S(=O)2(4-methylphenyl))-. Embodiment 6 provides the compound of any one of Embodiments 1-5, wherein X is selected from the group consisting of -O-, -S-, -NH-, -N(CH3)-, -N(CF3)-, -N(CH2CH3)-, - NH[(CH2)2CH3]-, -NH(CH(CH3)2)-, -N[(CH2)3CH3]-, -N(CH2C(CH3)2]-, - N(CH(CH3)CH2CH3)-, -N(C(CH3)3)-, -N(cyclopropyl)-, -N(C(=O)CH3)-, -N(C(=O)OCH3)-, - N(C(=O)OCH2CH3)-, -N(C(=O)OCH2Ph)-, -N(S(=O)2CF3)-, -N(S(=O)2(cyclopropyl))-, and - N(S(=O)2(4-methylphenyl))-. Embodiment 7 provides the compound of any one of Embodiments 1-6, wherein at least one of R2and R3is selected from the group consisting of H and -C(=O)(C1-C6alkyl), optionally wherein the C1-C6alkyl in R2and / or R3is independently -CH3. Embodiment 8 provides the compound of any one of Embodiments 1-7, wherein one of the following applies: (a) R2and R3are both H; or (b) R2is C(=O)CH3and R3is H. Embodiment 9 provides the compound of any one of Embodiments 1-8, wherein R4is selected from the group consisting of -OH, -O(C1-C6alkyl), and optionally substituted phenyl. Embodiment 10 provides the compound of any one of Embodiments 1-9, wherein R4is selected from the group consisting of phenyl, 4-methylphenyl, and 4-chlorophenyl. Embodiment 11 provides the compound of any one of Embodiments 1-4 and 7-10, wherein the compound is selected from the group consisting of: , , , , , , , , , and ; optionally wherein X is selected from the group consisting of O, S, and NRz. Embodiment 12 provides the compound of any one of Embodiments 1-6, wherein the compound is selected from the group consisting of: , , , , , , and . Embodiment 13 provides the compound of any one of Embodiments 1-6, wherein the compound is selected from the group consisting of: , , , , , , and . Embodiment 14 provides the compound of any one of Embodiments 1-5, which is selected from the group consisting of: , , and . Embodiment 15 provides the compound of any one of Embodiments 1-5, wherein the compound is selected from the group consisting of:

[0008] . Embodiment 16 provides the compound of any one of Embodiments 1-5, wherein the compound is a compound of Formula (A-I), Formula (A-II), Formula (B), or Formula (C): (A-I), (A-II), (B), or (C). Embodiment 17 provides the compound of any one of Embodiments 1-5, wherein the compound is selected from the group consisting of: and . Embodiment 18 provides the compound of any one of Embodiments 1-6, wherein the compound is selected from the group consisting of:

[0009] , , , , , and . Embodiment 19 provides the compound of any one of Embodiments 1-5, wherein the compound is selected from the group consisting of: , , , , and . Embodiment 20 provides the compound of any one of Embodiments 1-19, which is selected from the group consisting of: (2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone, ethyl 2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, 2-((tert-butoxycarbonyl)amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylic acid, ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, diethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate, 2-((tert-butoxycarbonyl)amino)-6-(ethoxycarbonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, ethyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate, benzyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate, ethyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate, O O ONNH2SO 6-benzyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate, benzyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate, (2-amino-6-(cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(phenyl)methanone, (6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(phenyl)methanone, ethyl 2-amino-6-isobutyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, 6-allyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate, (6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(phenyl)methanone, (2-amino-6-(cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(4-chlorophenyl)methanone, ethyl 2-amino-6-(cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate, (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(phenyl)methanone, (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone, ethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 2-amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 2-amino-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carboxylate, (2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone, (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(p- tolyl)methanone, ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3- c]thiopyran-3-carboxylate, 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3-c]thiopyran- 3-carboxylic acid, ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylate, (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4- chlorophenyl)methanone, (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(p-tolyl)methanone, ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3- c]pyran-3-carboxylate, 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3- carboxylic acid, (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(4- chlorophenyl)methanone, ethyl 6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 6-allyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, 6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 6-acetyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, 6-acetyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylic acid, diethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate, diethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate, 2-((tert-butoxycarbonyl)amino)-6-(ethoxycarbonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 3-carboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-6-(methylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, methyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate, (2-amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone, (2-amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone, (2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p- tolyl)methanone, (2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3- yl)(p-tolyl)methanone, (2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4- chlorophenyl)methanone, and 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof. Embodiment 21 provides a compound selected from the group consisting of: 1-(2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)- yl)ethan-1-one, 1-(2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1- one, 1-(2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)ethan-1-one, (2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(p-tolyl)methanone, 1-(2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)-2,2,2-trifluoroethan-1-one, 2,2,2-trifluoro-N-(3-(4-methylbenzoyl)-6-(2,2,2-trifluoroacetyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide, 1-(2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)-2,2,2-trifluoroethan-1-one, N-(3-(4-chlorobenzoyl)-6-(2,2,2-trifluoroacetyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-2-yl)-2,2,2-trifluoroacetamide, (2-amino-6-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(p-tolyl)methanone, (2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(4-chlorophenyl)methanone, ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-5-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6-butyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate, ethyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-5,5-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, and ethyl 2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof. Embodiment 22 provides the compound of any one of Embodiments 1-21, wherein the compound of the disclosure is a Glucagon-like peptide 1 receptor (GLP-1R) agonist. Embodiment 23 provides the compound of any one of Embodiments 1-22, wherein the compound is a positive allosteric modulator (PAM) of GLP-1R. Embodiment 24 provides the compound of any one of Embodiments 1-23, wherein the compound selectively enhances GLP-1R activity. Embodiment 25 provides the compound of any one of Embodiments 1-24, wherein the compound of the disclosure has no significant effect on the activity of other G-protein- coupled receptors (GPCRs). Embodiment 26 provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of any one of Embodiments 1- 25, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof. Embodiment 27 provides the pharmaceutical composition of Embodiment 26, wherein the compound of the disclosure is formulated for administration by a route selected from the group consisting of oral, parenteral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra- arterial, intravenous, intrabronchial, inhalation, and topical. Embodiment 28 provides the pharmaceutical composition of Embodiments 26 or 27, wherein the compound of the disclosure further comprises at least one additional agent useful for treating, ameliorating, and / or preventing diabetes and / or insulin resistance in a subject. Embodiment 29 provides the pharmaceutical composition of Embodiment 28, wherein the compound of the disclosure comprises at least one additional agent selected from the group consisting of α-glucosidase inhibitor, lipase inhibitor, sulfonyl urea, meglitinide, biguanide, thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor. Embodiment 30 provides a method of treating, ameliorating, and / or preventing insulin resistance and / or diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Embodiments 1-25, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof or the pharmaceutical composition of any one of Embodiments 26-29. Embodiment 31 provides the method of Embodiment 30, wherein the diabetes is type II diabetes. Embodiment 32 provides the method of Embodiments 30 or 31, wherein the compound is administered as a pharmaceutical composition to the subject. Embodiment 33 provides the method of any one of Embodiments 30-32, wherein the subject is further administered at least one additional agent useful for treating, ameliorating, and / or preventing diabetes and / or insulin resistance. Embodiment 34 provides the method of Embodiment 33, wherein the at least one additional agent is selected from the group consisting of α-glucosidase inhibitor, lipase inhibitor, sulfonyl urea, meglitinide, biguanide, thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor. Embodiment 35 provides the method of Embodiments 33 or 34, wherein administering the compound to the subject allows for administering a lower dose of the at least one additional agent as compared to the dose of the additional agent alone that is required to achieve similar results in treating, ameliorating, or preventing insulin resistance and / or diabetes. Embodiment 36 provides the method of any one of Embodiments 33-35, wherein administering the compound to the subject enhances the activity, and / or reduces at least one side effect, of the at least one additional agent. Embodiment 37 provides the method of any one of Embodiments 33-36, wherein the compound and the at least one additional agent are co-administered to the subject. Embodiment 38 provides the method of any one of Embodiments 33-37, wherein the compound and the at least one additional agent are co-formulated. Embodiment 39 provides the method of any one of Embodiments 30-38, wherein the subject is a mammal. Embodiment 40 provides the method of any one of Embodiments 30-39 wherein the subject is a human. The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this disclosure has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this disclosure may be devised by others skilled in the art without departing from the true spirit and scope of the disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I), or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof: (I), wherein: X is selected from the group consisting of O, S, C(R1g)(R1h), and NRz; each occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is independently selected from the group consisting of H, halogen, -OH, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, and optionally substituted C1-C6alkoxy; R2and R3are each independently selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)-C2-C6alkenyl, optionally substituted -C(=O)OC1-C6alkyl, and optionally substituted -C(=O)OC2- C6alkenyl; R4is selected from the group consisting of -OH, optionally substituted C1-C6alkoxy, - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted phenyl, optionally substituted naphthyl, and optionally substituted heterocyclyl; m is 0 or 1; and Rzis selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C3-C10cycloalkyl, optionally substituted -C(=O)-C1-C6alkyl, optionally substituted -C(=O)-C2-C6alkenyl, optionally substituted -S(=O)2-C1-C6alkyl, optionally substituted -S(=O)2-C3-C10cycloalkyl, optionally substituted -S(=O)2-phenyl, optionally substituted -C(=O)O-C1-C6alkyl, optionally substituted -C(=O)OC2-C6alkenyl, optionally substituted phenyl, and optionally substituted naphthyl; provided that, when Rzis -S(=O)2-C1-C6alkyl, optionally substituted -C(=O)-C1-C6alkyl, or optionally substituted -C(=O)-C2-C6alkenyl, then R4is -OH, optionally substituted C1-C6alkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)(C1-C6alkyl), optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, or optionally substituted heterocyclyl.

2. The compound of claim 1, wherein each occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is each independently selected from the group consisting of H and optionally substituted C1-C6alkyl.

3. The compound of any one of claims 1-2, wherein at least one occurrence of R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, if present, is selected from the group consisting of -CH3, -CF3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, -CH2C(CH3)2, -CH(CH3)CH2CH3, and - C(CH3)3.

4. The compound of any one of claims 1-3, wherein Rzis selected from the group consisting of H, -CH3, -CF3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3, CH2C(CH3)2, - CH(CH3)CH2CH3, -C(CH3)3, cyclopropyl, -C(=O)CH3, -C(=O)OCH3, -C(=O)OCH2CH3, - C(=O)OCH2Ph, -S(=O)2CF3, -S(=O)2(cyclopropyl), and -S(=O)2(4-methylphenyl).

5. The compound of any one of claims 1-4, wherein X is selected from the group consisting of -O-, -S-, -CH2-, -CH(CH3)-, -CH(CF3)-, -C(CH3)2-, -CH[(CH2)3CH3]-, - CH[(CH2)CH(CH3)2]-, -CH[C(CH3)3]-, -NH-, -N(CH3)-, -N(CF3)-, -N(CH2CH3)-, - NH[(CH2)2CH3]-, -NH(CH(CH3)2)-, -N[(CH2)3CH3]-, -N(CH2C(CH3)2]-, - N(CH(CH3)CH2CH3)-, -N(C(CH3)3)-, -N(cyclopropyl)-, -N(C(=O)CH3)-, -N(C(=O)OCH3)-, - N(C(=O)OCH2CH3)-, -N(C(=O)OCH2Ph)-, -N(S(=O)2CF3)-, -N(S(=O)2(cyclopropyl))-, and - N(S(=O)2(4-methylphenyl))-.

6. The compound of any one of claims 1-5, wherein X is selected from the group consisting of -O-, -S-, -NH-, -N(CH3)-, -N(CF3)-, -N(CH2CH3)-, -NH[(CH2)2CH3]-, - NH(CH(CH3)2)-, -N[(CH2)3CH3]-, -N(CH2C(CH3)2]-, -N(CH(CH3)CH2CH3)-, -N(C(CH3)3)-, -N(cyclopropyl)-, -N(C(=O)CH3)-, -N(C(=O)OCH3)-, -N(C(=O)OCH2CH3)-, - N(C(=O)OCH2Ph)-, -N(S(=O)2CF3)-, -N(S(=O)2(cyclopropyl))-, and -N(S(=O)2(4- methylphenyl))-.

7. The compound of any one of claims 1-6, wherein at least one of R2and R3is selected from the group consisting of H and -C(=O)(C1-C6alkyl), optionally wherein the C1-C6alkyl in R2and / or R3is independently -CH3.

8. The compound of any one of claims 1-7, wherein one of the following applies: (a) R2and R3are both H; or (b) R2is C(=O)CH3and R3is H.

9. The compound of any one of claims 1-8, wherein R4is selected from the group consisting of -OH, -O(C1-C6alkyl), and optionally substituted phenyl.

10. The compound of any one of claims 1-9, wherein R4is selected from the group consisting of phenyl, 4-methylphenyl, and 4-chlorophenyl.

11. The compound of any one of claims 1-4 and 7-10, wherein the compound is selected from the group consisting of: , , , , , , , , , and ; optionally wherein X is selected from the group consisting of O, S, and NRz.

12. The compound of any one of claims 1-6, wherein the compound is selected from the group consisting of:, , , , , , and .

13. The compound of any one of claims 1-6, wherein the compound is selected from the group consisting of: , , , , , , and .

14. The compound of any one of claims 1-5, which is selected from the group consisting of: , , , , , , and .

15. The compound of any one of claims 1-5, wherein the compound is selected from the group consisting of:

16. The compound of any one of claims 1-5, wherein the compound is a compound of Formula (A-I), Formula (A-II), Formula (B), or Formula (C):

17. The compound of any one of claims 1-5, wherein the compound is selected from thegroup consisting of: and .

18. The compound of any one of claims 1-6, wherein the compound is selected from the group consisting of:

19. The compound of any one of claims 1-5, wherein the compound is selected from the group consisting of:, and .

20. The compound of any one of claims 1-19, which is selected from the group consisting of: (2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone, ethyl 2-amino-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, 2-((tert-butoxycarbonyl)amino)-6-ethyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylic acid, ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 2-amino-6-cyclopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, diethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate,2-((tert-butoxycarbonyl)amino)-6-(ethoxycarbonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, ethyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate, benzyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate, ethyl 2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate, 6-benzyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate, benzyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate, (2-amino-6-(cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(phenyl)methanone, (6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(phenyl)methanone, ethyl 2-amino-6-isobutyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, allyl 2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)- carboxylate, 6-allyl 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate, (6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(phenyl)methanone,(2-amino-6-(cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(4-chlorophenyl)methanone, ethyl 2-amino-6-(cyclopropylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylate, (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(phenyl)methanone, (2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone, ethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylate, ethyl 2-amino-5,5,7,7-tetramethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 2-amino-5,6-dihydro-4H-thieno[2,3-c]pyrrole-3-carboxylate, (2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone,(2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(p- tolyl)methanone, ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3- c]thiopyran-3-carboxylate, 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3-c]thiopyran- 3-carboxylic acid, ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylate, (2-amino-4,7-dihydro-5H-thieno[2,3-c]thiopyran-3-yl)(4- chlorophenyl)methanone, (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(p-tolyl)methanone, ethyl 2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylate,ethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3- c]pyran-3-carboxylate, 2-((tert-butoxycarbonyl)amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3- carboxylic acid, (2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)(4- chlorophenyl)methanone, ethyl 6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate, ethyl 6-allyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, 6-allyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxylate,ethyl 6-acetyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate, 6-acetyl-2-((tert-butoxycarbonyl)amino)-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxylic acid, diethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate, diethyl 2-((tert-butoxycarbonyl)amino)-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate, 2-((tert-butoxycarbonyl)amino)-6-(ethoxycarbonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid, ethyl 2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 3-carboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-6-(methylsulfonyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylate,methyl 2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine- 6(5H)-carboxylate, (2-amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(4- chlorophenyl)methanone, (2-amino-6-tosyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p- tolyl)methanone, (2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p- tolyl)methanone, (2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3- yl)(p-tolyl)methanone, (2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4- chlorophenyl)methanone, and 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid,or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof.

21. A compound selected from the group consisting of: 1-(2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)- yl)ethan-1-one, 1-(2-amino-3-benzoyl-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl)ethan-1- one, 1-(2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)ethan-1-one, (2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(p-tolyl)methanone, 1-(2-amino-3-(4-methylbenzoyl)-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)-2,2,2-trifluoroethan-1-one, 2,2,2-trifluoro-N-(3-(4-methylbenzoyl)-6-(2,2,2-trifluoroacetyl)- 4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide,1-(2-amino-3-(4-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin- 6(5H)-yl)-2,2,2-trifluoroethan-1-one, N-(3-(4-chlorobenzoyl)-6-(2,2,2-trifluoroacetyl)-4,5,6,7- tetrahydrothieno[2,3-c]pyridin-2-yl)-2,2,2-trifluoroacetamide, (2-amino-6-((trifluoromethyl)sulfonyl)-4,5,6,7-tetrahydrothieno[2,3- c]pyridin-3-yl)(p-tolyl)methanone, (2-amino-6-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3- yl)(4-chlorophenyl)methanone, ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-5-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6-butyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate,ethyl 2-amino-6-isopropyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, ethyl 2-amino-5,5-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, and ethyl 2-amino-4-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof.

22. The compound of any one of claims 1-21, wherein the compound is a Glucagon-like peptide 1 receptor (GLP-1R) agonist.

23. The compound of any one of claims 1-22, wherein the compound is a positive allosteric modulator (PAM) of GLP-1R.

24. The compound of any one of claims 1-23, wherein the compound selectivelyenhances GLP-1R activity.

25. The compound of any one of claims 1-24, wherein the compound has no significant effect on the activity of other G-protein-coupled receptors (GPCRs).

26. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of any one of claims 1-25, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof.

27. The pharmaceutical composition of claim 26, which is formulated for administration by a route selected from the group consisting of oral, parenteral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical.

28. The pharmaceutical composition of claim 26 or 27, further comprising at least one additional agent useful for treating, ameliorating, and / or preventing diabetes and / or insulin resistance in a subject.

29. The pharmaceutical composition of claim 28, wherein the at least one additional agent is selected from the group consisting of α-glucosidase inhibitor, lipase inhibitor, sulfonyl urea, meglitinide, biguanide, thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor.

30. A method of treating, ameliorating, and / or preventing insulin resistance and / or diabetes in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-25, or a salt, solvate, stereoisomer, geometric isomer, and / or tautomer thereof, or the pharmaceutical composition of any one of claims 26-29.

31. The method of claim 30, wherein the diabetes is type II diabetes.

32. The method of claim 30 or 31, wherein the compound is administered as a pharmaceutical composition to the subject.

33. The method of any one of claims 30-32, wherein the subject is further administered at least one additional agent useful for treating, ameliorating, and / or preventing diabetes and / or insulin resistance.

34. The method of claim 33, wherein the at least one additional agent is selected from the group consisting of α-glucosidase inhibitor, lipase inhibitor, sulfonyl urea, meglitinide, biguanide, thiazolidinedione, pramlintide, incretin mimetic, DPP-IV inhibitor, and SGLT2 inhibitor.

35. The method of claim 33 or 34, wherein administering the compound to the subject allows for administering a lower dose of the at least one additional agent as compared to the dose of the additional agent alone that is required to achieve similar results in treating, ameliorating, or preventing insulin resistance and / or diabetes.

36. The method of any one of claims 33-35, wherein administering the compound to the subject enhances the activity, and / or reduces at least one side effect, of the at least one additional agent.

37. The method of any one of claims 34-36, wherein the compound and the at least one additional agent are co-administered to the subject.

38. The method of any one of claims 33-37, wherein the compound and the at least one additional agent are co-formulated.

39. The method of any one of claims 30-38, wherein the subject is a mammal.

40. The method of any one of claims 30-39, wherein the subject is a human.

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