Substituted bicyclic heteroaryl carboxamide analogs as mGluR5 negative allosteric modulators

This application claims the benefit of U.S. Provisional Application No. 61/968,323, filed on Mar. 20, 2014, which is incorporated herein by reference in its entirety.

This invention was made with government support under Grant No. 2R01-MH062646-12 awarded by the National Institute of Mental Health (NIMH), under Grant No. 5R01-MH073676-04 awarded by the National Institute of Mental Health (NIMH), under Grant No. 5R01-NS031373-15 awarded by the National Institute of Neurological Disorders and Stroke (NINDS), and Grant no. 1R01-DA023947-01 awarded by the National Institute on Drug Abuse (NIDA). The United States government has certain rights in the invention.

Glutamate (L-glutamic acid) is the major excitatory transmitter in the mammalian central nervous system, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGluRs) belong to family C (also known as family 3) of the G-protein-coupled receptors (GPCRs). They are characterized by a seven transmembrane (7TM) α-helical domain connected via a cysteine rich-region to a large bi-lobed extracellular amino-terminal domain ( FIG. 1 ). While the orthosteric binding site is contained in the amino-terminal domain, currently known allosteric binding sites reside in the 7TM domain. The mGluR family comprises eight known mGluRs receptor types (designated as mGluR1 through mGluR8). Several of the receptor types are expressed as specific splice variants, e.g. mGluR5a and mGluR5b or mGluR8a, mGluR8b and mGluR8c. The family has been classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology. Group I receptors (mGluR1 and mGluR5) are coupled to Gαq, a process that results in stimulation of phospholipase C and an increase in intracellular calcium and inositol phosphate levels. Group II receptors (mGluR2 and mGluR3) and group III receptors (mGluR4, mGluR6, mGluR7, and mGluR8) are coupled to Gαi, which leads to decreases in cyclic adenosine monophosphate (cAMP) levels. While the Group I receptors are predominately located postsynaptically and typically enhance postsynaptic signaling, the group II and III receptors are located presynaptically and typically have inhibitory effects on neurotransmitter release. Without wishing to be bound by theory, increasing evidence indicates mGluRs play an important role in lasting changes in synaptic transmission, and studies of synaptic plasticity in the Fmr1 knockout mouse have identified a connection between the fragile X phenotype and mGluR signaling.

The identification of small molecule mGluR antagonists that bind at the orthosteric site has greatly increased the understanding of the roles played by these receptors and their corresponding relation to disease. Because the majority of these antagonists were designed as analogs of glutamate, they typically lack desired characteristics for drugs targeting mGluR such as oral bioavailability and/or distribution to the central nervous system (CNS). Moreover, because of the highly conserved nature of the glutamate binding site, most orthosteric antagonists lack selectivity among the various mGluRs.

A more recent strategy that has been able to successfully deal with the aforementioned issues has been the design of compounds that bind the mGluR at a site that is topographically distinct from the orthosteric binding site, or an allosteric binding site. Selective negative allosteric modulators (NAMs) are compounds that do not directly deactivate receptors by themselves, but decrease the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Negative allosteric modulation is thus an attractive mechanism for inhibiting appropriate physiological receptor activation. Among the most studied and characterized small molecules are the mGluR5 NAMs, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP). Both MPEP and MTEP have proven efficacious in numerous rodent models of disease, including those for drug addiction and pain as well as anxiety. The compounds were also able to inhibit transient lower esophageal sphincter relaxation (TLESD), the major cause of gastroesophageal reflux disease (GERD), in dogs and ferrets. In addition, MPEP was efficacious in mouse models of fragile X syndrome (FXS) and Parkinson's disease (PD) as well as a baboon model of binge-eating disorder.

Although the utility of MPEP and MTEP as tool compounds has been clearly demonstrated, both molecules have issues that complicate or prevent their further development as therapeutic molecules. MPEP has been shown to directly inhibit the N-methyl-D-aspartate (NMDA) receptor activity at higher concentrations and is a positive allosteric modulator of mGluR4. While these selectivity issues are mitigated with MTEP, it is a potent inhibitor of cytochrome P450 1A2 and is efficiently cleared following intravenous administration to rhesus monkeys.

Potential adverse effects of known mGluR5 NAMs, however, could reduce their ultimate therapeutic utility. Further, conventional mGluR5 receptor modulators which target the orthosteric binding site can lack satisfactory aqueous solubility, exhibit poor oral bioavailability, and/or exhibit adverse effects. Therefore, there remains a need for methods and compositions that overcome these deficiencies and that effectively provide selective negative allosteric modulators for the mGluR5 receptor.

In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds useful as negative allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5), methods of making same, pharmaceutical compositions comprising same, and methods of treating disorders associated with glutamate dysfunction using same.

Disclosed are compounds having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein the compound exhibits partial or total inhibition of mGluR5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.

Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

Also disclosed are methods for manufacturing a medicament comprising combining at least one disclosed compound with a pharmaceutically acceptable carrier or diluent.

Also disclosed are methods for the treatment of a disorder associated with metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are methods for decreasing metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are methods for inhibiting metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are methods for negative allosteric modulation of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are methods for partial antagonism of metabotropic glutamate receptor activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are methods for modulating mGluR5 activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are methods for modulating mGluR5 activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are methods for inhibiting mGluR5 activity in at least one cell, comprising the step of contacting the at least one cell with at least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.

Also disclosed are uses of a compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof, in the manufacture of a medicament for the treatment of a disorder associated with glutamate dysfunction in a mammal.

Also disclosed are kits comprising at least one compound having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof, and one or more of: (a) at least one agent known to increase mGluR5 activity; (b) at least one agent known to decrease mGluR5 activity; (c) at least one agent known to treat a neurological and/or psychiatric disorder; (d) at least one agent known to treat a disease of uncontrolled cellular proliferation; or (e) instructions for treating a disorder associated with glutamate dysfunction.

While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

FIG. 1 is a schematic representation of an mGluR.

FIG. 2 illustrates allosteric modulation of mGluR5.

Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples and Figures included herein.

Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.

A. Definitions

As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-Ingold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, E/Z specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as CHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

As used herein, the term “orthosteric site” refers to the primary binding site on a receptor that is recognized by the endogenous ligand or agonist for that receptor. For example, the orthosteric site in the mGluR5 receptor is the site that glutamate binds.

As used herein, the term “mGluR5 receptor negative allosteric modulator” refers to any exogenously administered compound or agent that directly or indirectly inhibits the activity of the mGluR5 receptor in the presence of the endogenous ligand (such as glutamate) in an animal, in particular a mammal, for example a human. The term is synonymous with the terms “mGluR5 receptor allosteric inhibitor,” “mGluR5 receptor noncompetitive inhibitor,” “mGluR5 receptor allosteric antagonist,” and “mGluR5 receptor noncompetitive antagonist.”

As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more neurological and/or psychiatric disorder associated with glutamate dysfunction prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for negative allosteric modulation of metabotropic glutamate receptor activity prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for partial antagonism of metabotropic glutamate receptor activity prior to the administering step.

As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

For example, “diagnosed with a disorder treatable by modulation of mGluR5” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can modulate mGluR5. As a further example, “diagnosed with a need for modulation of mGluR5” refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition characterized by mGluR5 activity. Such a diagnosis can be in reference to a disorder, such as a neurodegenerative disease, and the like, as discussed herein. For example, the term “diagnosed with a need for negative allosteric modulation of metabotropic glutamate receptor activity” refers to having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by negative allosteric modulation of metabotropic glutamate receptor activity. For example, “diagnosed with a need for partial antagonism of metabotropic glutamate receptor activity” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by partial antagonism of metabotropic glutamate receptor activity. For example, “diagnosed with a need for treatment of one or more neurological and/or psychiatric disorder associated with glutamate dysfunction” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have one or more neurological and/or psychiatric disorder associated with glutamate dysfunction.

As used herein, the phrase “identified to be in need of treatment for a disorder,” or the like, refers to selection of a subject based upon need for treatment of the disorder. For example, a subject can be identified as having a need for treatment of a disorder (e.g., a disorder related to mGluR5 activity) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder. It is contemplated that the identification can, in one aspect, be performed by a person different from the person making the diagnosis. It is also contemplated, in a further aspect, that the administration can be performed by one who subsequently performed the administration.

As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

The term “contacting” as used herein refers to bringing a disclosed compound and a cell, target metabotropic glutamate receptor, or other biological entity together in such a manner that the compound can affect the activity of the target (e.g., spliceosome, cell, etc.), either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.

As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications.

Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

As used herein, “EC 50 ,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC 50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC 50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response. In a yet further aspect, the response is in vitro. In a still further aspect, the response is in a human embryonic kidney cell transfected with human mGluR5. In a yet further aspect, the response is a human embryonic kidney cell transfected with rat mGluR5. In an even further aspect, the response is in a human embryonic kidney cell transfected with a mammalian mGluR5.

As used herein, “IC 50 ,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an IC 50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein. In a further aspect, IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance. In a yet further aspect, the inhibition is measured in vitro. In a still further aspect, the inhibition is measured in a human embryonic kidney cell transfected with human mGluR5. In a yet further aspect, the inhibition is measured in a human embryonic kidney cell transfected with rat mGluR5. In an even further aspect, the inhibition is measured in a human embryonic kidney cell transfected with a mammalian mGluR5.

The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more —OCH 2 CH 2 O— units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more —CO(CH 2 ) 8 CO— moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

In defining various terms, “A 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “alkylamino” specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like. When “alkyl” is used in one instance and a specific term such as “alkylalcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkylalcohol” and the like.

This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “polyalkylene group” as used herein is a group having two or more CH 2 groups linked to one another. The polyalkylene group can be represented by the formula —(CH 2 ) a —, where “a” is an integer of from 2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA 1 where A 1 is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA 1 -OA 2 or —OA 1 -(OA 2 ) a -OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A 1 A 2 )C═C(A 3 A 4 ) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C═C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” also includes “heteroaryl,” which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term “non-heteroaryl,” which is also included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by the formula —NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

The term “dialkylamino” as used herein is represented by the formula —N(-alkyl) 2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A 1 or —C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula -(A 1 O(O)C-A 2 -C(O)O) a — or -(A 1 O(O)C-A 2 -OC(O)) a —, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

The term “ether” as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula -(A 1 O-A 2 O) a —, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

The term “halide” as used herein refers to the halogens fluorine, chlorine, bromine, and iodine.

The term “heterocycle,” as used herein refers to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Heterocycle includes pyridinde, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.

The term “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “azide” as used herein is represented by the formula —N 3 .

The term “nitro” as used herein is represented by the formula —NO 2 .

The term “nitrile” as used herein is represented by the formula —CN.

The term “silyl” as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A 1 , —S(O) 2 A 1 , —OS(O) 2 A 1 , or —OS(O) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S═O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R 1 is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group is independently halogen; —(CH 2 ) 0-4 R ∘ ; —(CH 2 ) 0-4 OR ∘ ; —O(CH 2 ) 0-4 R ∘ , —O—(CH 2 ) 0-4 C(O)OR ∘ ; —(CH 2 ) 0-4 CH(OR ∘ ) 2 ; —(CH 2 ) 0-4 SR ∘ ; —(CH 2 ) 0-4 Ph, which may be substituted with R ∘ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R ∘ ; —CH═CHPh, which may be substituted with R ∘ ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R ∘ ; —NO 2 ; —CN; —N 3 ; —(CH 2 ) 0-4 N(R ∘ ) 2 ; —(CH 2 ) 0-4 N(R ∘ )C(O)R ∘ ; —N(R ∘ )C(S)R ∘ ; —(CH 2 ) 0-4 N(R ∘ )C(O)NR ∘ 2 ; —N(R ∘ )C(S)NR ∘ 2 ; —(CH 2 ) 0-4 N(R ∘ )C(O)OR ∘ ; —N(R ∘ )N(R ∘ )C(O)R ∘ ; —N(R ∘ )N(R ∘ )C(O)NR ∘ 2 ; —N(R ∘ )N(R ∘ )C(O)OR ∘ ; —(CH 2 ) 0-4 C(O)R ∘ ; —C(S)R ∘ ; —(CH 2 ) 0-4 C(O)OR ∘ ; —(CH 2 ) 0-4 C(O)SR ∘ ; —(CH 2 ) 0-4 C(O)OSiR ∘ 3 ; —(CH 2 ) 0-4 OC(O)R ∘ ; —OC(O)(CH 2 ) 0-4 SR—, SC(S)SR ∘ ; —(CH 2 ) 0-4 SC(O)R ∘ ; —(CH 2 ) 0-4 C(O)NR ∘ 2 ; —C(S)NR ∘ 2 ; —C(S)SR ∘ ; —SC(S)SR ∘ , —(CH 2 ) 0-4 OC(O)NR ∘ 2 ; —C(O)N(OR ∘ )R ∘ ; —C(O)C(O)R ∘ ; —C(O)CH 2 C(O)R ∘ ; —C(NOR ∘ )R ∘ ; —(CH 2 ) 0-4 SSR ∘ ; —(CH 2 ) 0-4 S(O) 2 R ∘ ; —(CH 2 ) 0-4 S(O) 2 OR ∘ ; —(CH 2 ) 0-4 OS(O) 2 R ∘ ; —S(O) 2 NR ∘ 2 ; —(CH 2 ) 0-4 S(O)R ∘ ; —N(R ∘ )S(O) 2 NR ∘ 2 ; —N(R ∘ )S(O) 2 R ∘ ; —N(OR ∘ )R ∘ ; —C(NH)NR ∘ 2 ; —P(O) 2 R ∘ ; —P(O)R ∘ 2 ; —OP(O)R ∘ 2 ; —OP(O)(OR ∘ ) 2 ; SiR ∘ 3 ; —(C 1-4 straight or branched alkylene)O—N(R ∘ ) 2 ; or —(C 1-4 straight or branched alkylene)C(O)O—N(R ∘ ) 2 , wherein each R ∘ may be substituted as defined below and is independently hydrogen, C 1-6 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, —CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ∘ , taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R ∘ (or the ring formed by taking two independent occurrences of R ∘ together with their intervening atoms), is independently halogen, —(CH 2 ) 0-2 R ● , -(haloR ● ), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 OR ● , —(CH 2 ) 0-2 CH(OR ● ) 2 ; —O(haloR ● ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R ● , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR ● , —(CH 2 ) 0-2 SR ● , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR ● , —(CH 2 ) 0-2 NR ● 2 , —NO 2 , —SiR ● 3 , —OSiR ● 3 , —C(O)SR ● , —(C 1-4 straight or branched alkylene)C(O)OR ● , or —SSR ● wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R ∘ include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR* 2 , ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O) 2 R*, ═NR*, ═NOR*, —O(C(R* 2 )) 2-3 O—, or —S(C(R* 2 )) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2 ) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, —R ● , -(haloR ● ), —OH, —OR ● , —O(haloR ● ), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ● 2 , or —NO 2 , wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R † , —NR † 2 , —C(O)R † , —C(O)OR † , —C(O)C(O)R † , —C(O)CH 2 C(O)R † , —S(O) 2 R † , —S(O) 2 NR † 2 , —C(S)NR † 2 , —C(NH)NR † 2 , or —N(R † )S(O) 2 R † ; wherein each R † is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R † , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of Rt is independently halogen, —R ● , -(haloR ● ), —OH, —OR ● , —O(haloR ● ), —CN, —C(O)OH, —C(O)OR ● , —NH 2 , —NHR ● , —NR ● 2 , or —NO 2 , wherein each R ● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, brosylate, and halides.

The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

“Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

In some aspects, a structure of a compound can be represented by a formula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) . By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R n (a) is halogen, then R n (b) is not necessarily halogen in that instance.

Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and 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); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

The following abbreviations are used herein. AcOH: acetic acid. DMF: N,N-dimethyl formamide. DMSO: dimethylsulfoxide. ES-MS: electrospray mass spectrometry. EtOAc: ethyl acetate. IPA: isopropyl alcohol. LC-MS or LCMS: liquid chromatography/mass spectrometry. [M+H]+: protonated mass of the free base of the compound. MeOH: methanol. NMR: nuclear magnetic resonance. TEA: triethylamine. THF: tetrahydrofuran. TLC: thin layer chromatography.

Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

B. mGLUR5 Negative Allosteric Modulators

In one aspect, the invention relates to compounds useful as negative allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Negative allosteric modulators are noncompetitive antagonists and can include a range of maximal antagonist activity from partial antagonists to inverse agonists. In one aspect, the present invention relates to compounds that allosterically modulate mGluR5 receptor activity, affecting the sensitivity of mGluR5 receptors to agonists without acting as orthosteric agonists themselves. The compounds can, in one aspect, exhibit subtype selectivity. The compounds of the invention can be useful in the treatment neurological and psychiatric disorders associated with glutamate dysfunction and other diseases in which metabotropic glutamate receptors are involved, as further described herein. Generally, the disclosed compounds exhibit negative allosteric modulation of mGluR5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound. In further aspect, the human embryonic kidney cells are transfected with human mGluR5. In yet a further aspect, human embryonic kidney cells are transfected with mGluR5 of a mammal.

It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using.

1. Structure

In one aspect, the invention relates to compounds, or pharmaceutically acceptable salts thereof, having a structure represented by a formula:

wherein A is selected from N and CR 5 ; wherein R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 ; wherein R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b ; wherein each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b ; wherein each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Q is selected from N and CR 6 ; wherein R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 ; wherein R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b ; wherein each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b ; wherein each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein V is selected from N and CR 7 , provided that Q and V are not simultaneously N; wherein R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 ; wherein R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b ; wherein each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b ; wherein each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —; wherein the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2; wherein r is 0 or 1; wherein R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 8 is not halogen; wherein R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; provided that, when Z is —CR 8 (O) r R 9 — and r is 1, R 9 is not halogen; wherein each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl; wherein R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 ; wherein each occurrence of R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each occurrence of each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b ; wherein each occurrence of each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each occurrence of R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b ; wherein each occurrence of each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 ; wherein R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; wherein each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b ; wherein each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b ; wherein each of R 65a and R 65b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 65a and R 65b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle; wherein each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro; or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein the compound exhibits partial or total inhibition of mGluR5 response to glutamate as a decrease in response to non-maximal concentrations of glutamate in human embryonic kidney cells transfected with rat mGluR5 in the presence of the compound, compared to the response to glutamate in the absence of the compound.

In a further aspect, the compound exhibits partial inhibition of mGluR5 response. In a still further aspect, the compound exhibits total inhibition of mGluR5 response. In an even further aspect, the mGluR5 is rat mGluR5. In a yet further aspect, the mGluR5 is human mGluR5.

In a further aspect, the compound exhibits noncompetitive antagonism. In a still further aspect, the compound exhibits negative allosteric modulation. In a yet further aspect, the compound exhibits noncompetitive inhibition. In an even further aspect, the compound exhibits allosteric antagonism.

In a further aspect, the compound exhibits negative allosteric modulation with an IC 50 of less than about 30×10 −6 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC 50 of less than about 10×10 −6 M. In a yet further aspect, the compound exhibits negative allosteric modulation with an IC 50 of less than about 1.0×10 −6 M. In a still further aspect, the compound exhibits negative allosteric modulation with an IC 50 of less than about 1.0×10 −7 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC 50 of less than about 1.0×10 −8 M. In a yet further aspect, the compound exhibits negative allosteric modulation with an IC 50 of less than about 1.0×10 −9 M. In a still further aspect, the compound exhibits negative allosteric modulation inhibition with an IC 50 of between about 1×10 −5 M to about 1×10 −9 M. In an even further aspect, the compound exhibits negative allosteric modulation with an IC 50 of between about from about 1×10 −6 M to about 1×10 −9 M. In a yet further aspect, the compound exhibits negative allosteric modulation with an IC 50 of between about from about 1×10 −7 M to about 1×10 −9 M. In a still further aspect, the compound exhibits negative allosteric modulation with an IC 50 of between about 1×10 −8 M to about 1×10 −9 M.

In a further aspect, the compound exhibits partial or total inhibition with an IC 50 of less than about 30×10 −6 M. In an even further aspect, the compound exhibits partial or total inhibition with an IC 50 of less than about 10×10 −6 M. In a yet further aspect, the compound exhibits partial or total inhibition with an IC 50 of less than about 1.0×10 −6 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC 50 of less than about 1.0×10 −7 M. In an even further aspect, the compound exhibits partial or total inhibition with an IC 50 of less than about 1.0×10 −8 M. In a yet further aspect, the compound exhibits partial or total inhibition with an IC 50 of less than about 1.0×10 −9 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC 50 of between about 1×10 −5 M to about 1×10 −9 M. In an even further aspect, the compound exhibits partial or total inhibition with an IC 50 of between about from about 1×10 −6 M to about 1×10 −9 M. In a yet further aspect, the compound exhibits partial or total inhibition with an IC 50 of between about from about 1×10 −7 M to about 1×10 −9 M. In a still further aspect, the compound exhibits partial or total inhibition with an IC 50 of between about 1×10 −8 M to about 1×10 −9 M.

In a further aspect, a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or product of a disclosed method of making and a pharmaceutically acceptable carrier.

In a further aspect, a compound has a structure represented by a formula:

In a further aspect, a compound has a structure represented by a formula:

In further aspect, a compound has a structure represented by a formula:

In a further aspect, a compound has a structure represented by a formula:

In a further aspect, a compound has a structure selected from:

In a further aspect, a compound has a structures selected from:

In a further aspect, a compound has a structure selected from:

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In a further aspect, a compound has a structure selected from:

In a further aspect, a compound has a structure represented by a formula:

In a further aspect, a compound has a structure represented by a formula:

In a further aspect, a compound has a structure represented by a formula:

In a further aspect, a compound has a structure represented by a formula:

In a further aspect, a compound has a structure selected from:

In a further aspect, a compound has a structure selected from:

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In a further aspect, a compound has a structure represented by a formula:

In another aspect, a compound has a structure represented by a formula:

In another aspect, a compound has a structure represented by a formula:

In another aspect, a compound has a structure represented by a formula:

In another aspect, a compound has a structure selected from:

In a further aspect, a compound has a structure selected from:

In another aspect, a compound has a structure selected from:

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In a further aspect, a compound has a structure selected from:

a. A Groups

In one aspect, A is N or CR 5 . In a further aspect, A is N. In a still further aspect, A is CR 5 .

b. Q Groups

In one aspect, Q is selected from N and CR 6 . In a further aspect, Q is N. In a still further aspect, Q is CR 6 .

c. V Groups

In one aspect, V is selected from N and CR 7 , provided that Q and V are not simultaneously N. In a further aspect, V is N and Q is CR 6 . In a still further aspect, V is CR 7 and Q is CR 6 . In a yet further aspect, V is CR 7 and wherein Q is N.

d. Y Groups

In one aspect, Y is selected from —CR 8 R 9 —, —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2. In a further aspect, q is 0 or 1. In a still further aspect, q is 0 or 2. In yet a further aspect, q is 1 or 2.

In a further aspect, the sum of m and n is 1 or 2 when Y is —CR 8 R 9 —. In a still further aspect, the sum of m and n is 1 and Y is —CR 8 R 9 —. In yet a further aspect, the sum of m and n is 2 and Y is —CR 8 R 9 —.

In a further aspect, the sum of m and n is 2 when Y is —O—, —S(O) q —, and —NR 8 —; wherein q is 0, 1, or 2. In a still further aspect, the sum of m and n is 2 and Y is selected from —O—, —S—, and —NR 8 —. In yet a further aspect, the sum of m and n is 2 and Y is selected from —O—, —(S═O)—, and —NR 8 —. In an even further aspect, the sum of m and n is 2 and Y is selected from —O—, —SO 2 —, and —NR 8 —.

In a further aspect, the sum of m and n is 2 and Y is selected from —O— and —S(O) q —; wherein q is 0, 1, or 2. In a still further aspect, the sum of m and n is 2 and Y is selected from —O— and —S—. In yet a further aspect, the sum of m and n is 2 and Y is selected from —O— and —(S═O)—. In an even further aspect, the sum of m and n is 2 and Y is selected from —O— and —SO 2 —.

In a further aspect, the sum of m and n is 2 and wherein Y is selected from —S(O) q — and —NR 8 —; wherein q is 0, 1, or 2. In a still further aspect, the sum of m and n is 2 and wherein Y is selected from —S— and —NR 8 —. In yet a further aspect, the sum of m and n is 2 and wherein Y is selected from —(S═O)— and —NR 8 —. In an even further aspect, the sum of m and n is 2 and wherein Y is selected from —SO 2 — and —NR 8 —.

In a further aspect, the sum of m and n is 2 and Y is selected from —O— and —NR 8 —.

e. Z Groups

In one aspect, Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein r is 0 or 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1. In an even further aspect, r is 0. In a still further aspect, r is 1.

In a further aspect, Z is selected from —CR 8 NR 10a R 10b —, —(C═O)—, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In a still further aspect, Z is selected from —CR 8 (O) r R 9 —, —(C═O)—, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein r is 0 or 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1. In an even further aspect, r is 0. In a still further aspect, r is 1.

In a yet further aspect, Z is selected from —CR 8 OR 9 —, —(C═O)—, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In an even further aspect, Z is selected from —CR 8 R 9 —, —(C═O)—, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In a further aspect, Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein r is 0 or 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1. In an even further aspect, r is 0. In a still further aspect, r is 1.

In a still further aspect, Z is selected from —CR 8 OR 9 —, —CR 8 NR 10a R 10b —, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In yet a further aspect, Z is selected from —CR 8 R 9 —, —CR 8 NR 10a R 10b —, and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In an even further aspect, Z is selected from —CR 8 (O) r R 9 — and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1; wherein r is 0 or 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1. In an even further aspect, r is 0. In a still further aspect, r is 1.

In a further aspect, Z is selected from —CR 8 OR 9 — and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In a still further aspect, Z is selected from —CR 8 R 9 — and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In yet a further aspect, Z is selected from —CR 8 NR 10a R 10b — and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In an even further aspect, Z is selected from —(C═O)— and a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In a still further aspect, Z is a structure represented by a formula:

wherein m is an integer selected from 0, 1, and 2; wherein n is an integer selected from 0 and 1. In a further aspect, m is 0 or 1. In a still further aspect, m is 0 or 2. In yet a further aspect, m is 1 or 2. In an even further aspect, n is 0. In a still further aspect, n is 1.

In a further aspect, Z is a structure represented by a formula:

In a further aspect, Z is selected from a structure represented by a formula:

In a still further aspect, Z is selected from a structure represented by a formula:

In yet a further aspect, Z is selected from a structure represented by a formula:

In an even further aspect, Z is selected from a structure represented by a formula:

In a further aspect, Z is selected from a structure represented by a formula:

In a still further aspect, Z is selected from a structure represented by a formula:

In yet a further aspect, Z is selected from a structure represented by a formula:

In an even further aspect, Z is selected from a structure represented by a formula:

In a further aspect, Z is selected from a structure represented by a formula:

In a still further aspect, Z is selected from a structure represented by a formula:

In yet a further aspect, Z is selected from a structure represented by a formula:

In an even further aspect, Z is selected from a structure represented by a formula:

In a further aspect, Z is a structure represented by a formula:

In a still further aspect, Z is a structure represented by a formula:

In yet a further aspect, Z is a structure represented by a formula:

In an even further aspect, Z is a structure represented by a formula:

In a further aspect, Z is a structure represented by a formula:

In a still further aspect, Z is a structure represented by a formula:

In yet a further aspect, wherein Z is a structure represented by a formula:

In an even further aspect, Z is a structure represented by a formula:

In a further aspect, Z is a structure represented by a formula:

In a still further aspect, Z is a structure represented by a formula:

In yet a further aspect, Z is a structure represented by a formula:

In an even further aspect, Z is a structure represented by a formula:

In a further aspect, Z is a structure represented by a formula:

In a still further aspect, Z is a structure represented by a formula:

In yet a further aspect, Z is a structure represented by a formula:

In an even further aspect, Z is a structure represented by a formula:

In a further aspect, Z is a structure represented by a formula:

In a still further aspect, Z is a structure represented by a formula:

In yet a further aspect, Z is a structure represented by a formula:

In an even further aspect, Z is a structure represented by a formula:

In a further aspect, Z is a structure represented by a formula:

In a still further aspect, Z is a structure represented by a formula:

In yet a further aspect, Z is a structure represented by a formula:

In an even further aspect, Z is a structure represented by a formula:

In a further aspect, Z is a structure represented by a formula:

In a further aspect, Z is selected from —CR 8 (O) r R 9 —, —CR 8 NR 10a R 10b —, and —(C═O)—. In a still further aspect, Z is selected from —CR 8 (O) r R 9 — and —CR 8 NR 10a R 10b —. In yet a further aspect, Z is selected from —CR 8 (O) r R 9 — and —(C═O)—. In an even further aspect, Z is —CR 8 (O) r R 9 —. In a still further aspect, Z is —CR 8 NR 10a R 10b —. In yet a further aspect, Z is —(C═O)—.

In a further aspect, Z is selected from —CR 8 OR 9 —, —CR 8 NR 10a R 10b —, and —(C═O)—. In a still further aspect, Z is selected from —CR 8 OR 9 — and —(C═O)—. In yet a further aspect, Z is —CR 8 OR 9 —.

In a further aspect, Z is selected from —CR 8 R 9 —, —CR 8 NR 10a R 10b —, and —(C═O)—. In a still further aspect, Z is selected from —CR 8 R 9 — and —(C═O)—. In yet a further aspect, Z is —CR 8 R 9 —.

f. R 1 Groups

In one aspect, R 1 is selected from aryl and heteroaryl, and wherein R 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 .

In a further aspect, R 1 is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 .

In a further aspect, R 1 is aryl substituted with 0, 1, or 2 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 .

In a further aspect, R 1 is aryl substituted with 0 or 1 group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is phenyl substituted with 0 or 1 group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 .

In a further aspect, R 1 is aryl monosubstituted with a group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is phenyl monosubstituted with a group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR, —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 .

In a further aspect, R 1 is unsubstituted aryl. In a still further aspect, R 1 is unsubstituted phenyl.

In a further aspect, R 1 is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a yet further aspect, R 1 is pyrimidinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In an even further aspect, R 1 is pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 1 is heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In yet a further aspect, R 1 is pyrimidinyl substituted with 0, 1, or 2 groups independently selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR, —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In an even further aspect, R 1 is pyridinyl substituted with 0, 1, or 2 groups independently selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 1 is heteroaryl substituted with 0 or 1 group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is pyridinyl substituted with 0 or 1 group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In yet a further aspect, R 1 is pyrimidinyl substituted with 0 or 1 group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In an even further aspect, R 1 is pyridinyl substituted with 0 or 1 group selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 1 is heteroaryl monosubstituted with a group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In a still further aspect, R 1 is pyridinyl monosubstituted with a group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In yet a further aspect, R 1 is pyrimidinyl monosubstituted with a group selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 50 , —NR 51a R 51b , —SO 2 R 52 , and —(C═O)R 53 . In an even further aspect, R 1 is pyridinyl monosubstituted a group selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 1 is pyridinyl monosubstituted a group selected from —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In yet a further aspect, R 1 is pyridinyl monosubstituted a group selected from —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 1 is pyridinyl monosubstituted a group selected from —F, —Cl, methyl, and —CF 3 . In a still further aspect, R 1 is pyridinyl monosubstituted a group selected from —F, —Cl, and methyl. In yet a further aspect, R 1 is pyridinyl monosubstituted with —F. In an even further aspect, R 1 is pyridinyl monosubstituted with —Cl. In a still further aspect, R 1 is pyridinyl monosubstituted with -methyl.

In a further aspect, R 1 is unsubstituted heteroaryl. In a still further aspect, R 1 is unsubstituted pyridinyl. In yet a further aspect, R 1 is unsubstituted pyrimidinyl. In an even further aspect, R 1 is pyridinyl monosubstituted a group selected from —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 1 is pyridinyl substituted with 2 groups independently selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 1 is pyridinyl substituted with 2 groups independently selected from —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In yet a further aspect, R 1 is pyridinyl substituted with 2 groups independently selected from —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 1 is pyridinyl substituted with 2 groups independently selected from —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 1 is pyridinyl substituted with 2 groups independently selected from —F, —Cl, methyl, and —CF 3 . In yet a further aspect, R 1 is pyridinyl substituted with 2 groups independently selected from —F, —Cl, and methyl. In an even further aspect, R 1 is pyridinyl disubstituted with —F. In a still further aspect, R 1 is pyridinyl disubstituted with —Cl. In yet a further aspect, R 1 is pyridinyl disubstituted with -methyl.

g. R 2 Groups

In one aspect, R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a further aspect, R 2 is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 2 is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 2 is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 2 is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 2 is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 2 is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 2 is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 2 is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 2 is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 2 is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 2 is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 2 is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 2 is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 2 is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 2 is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 2 is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 2 is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 2 is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 2 is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 2 is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 2 is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 2 is selected from hydrogen and —CF 3 .

In a further aspect, R 2 is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 2 is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 2 is selected from hydrogen and methyl. In an even further aspect, R 2 is hydrogen.

h. R 3 Groups

In one aspect, R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 . In a further aspect, R 3 is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 3 is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 3 is selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , —SO 2 R 62 , and —(C═O)R 63 . In a still further aspect, R 3 is selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 3 is selected from —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 3 is selected from —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , and —SO 2 R 62 . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 3 is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 3 is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , —NR 61a R 61b , and —SO 2 R 62 . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 3 is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 60 , —NR 61a R 61b , and —SO 2 R 62 . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 3 is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 3 is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , and —NR 61a R 61b . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 3 is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 3 is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 60 , and —NR 61a R 61b . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 3 is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 3 is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 60 , and —NR 61a R 61b . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 3 is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 3 is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 3 is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 3 is selected from hydrogen, —F, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 3 is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, and —CF 3 . In yet a further aspect, R 3 is selected from hydrogen, —F, methyl, and —CF 3 .

In a further aspect, R 3 is selected from hydrogen, halogen, and C1-C3 alkyl. In a still further aspect, R 3 is selected from hydrogen, —F, —Cl, methyl, and ethyl. In yet a further aspect, R 3 is selected from hydrogen, —F, —Cl, and methyl. In an even further aspect, R 3 is selected from hydrogen, —F, and methyl.

In a further aspect, R 3 is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 3 is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 3 is selected from hydrogen and methyl.

In a further aspect, R 3 is —F. In a still further aspect, R 3 is —Cl. In yet a further aspect, R 3 is methyl. In an even further aspect, R 3 is —CF 3 . In a still further aspect, R 3 is hydrogen.

In a further aspect, each of R 2 and R 3 is hydrogen.

i. R 4 Groups

In one aspect, each of R 4a , R 4b , R 4c , and R 4d , is independently selected from hydrogen and fluoro. In a further aspect, each of R 4a , R 4b , and R 4c is hydrogen, and wherein R 4d is fluoro. In a still further aspect, each of R 4a , R 4b , and R 4d is hydrogen, and wherein R 4c is fluoro. In yet a further aspect, each of R 4a , R 4c , and R 4c is hydrogen, and wherein R 4b is fluoro. In an even further aspect, each of R 4b , R 4c , and R 4d is hydrogen, and wherein R 4a is fluoro. In a still further aspect, each of R 4a and R 4b is hydrogen, and wherein each of R 4c and R 4d is fluoro. In yet a further aspect, each of R 4a and R 4c is hydrogen, and wherein each of R 4b and R 4d is fluoro. In an even further aspect, each of R 4a and R 4d is hydrogen, and wherein each of R 4b and R 4c is fluoro. In a still further aspect, each of R 4b and R 4c is hydrogen, and wherein each of R 4a and R 4d is fluoro. In yet a further aspect, each of R 4b and R 4d is hydrogen, and wherein each of R 4a and R 4c is fluoro. In an even further aspect, each of R 4c and R 4d is hydrogen, and wherein each of R 4a and R 4b is fluoro. In a still further aspect, each of R 4a , R 4b , R 4c , and R 4d is hydrogen. In yet a further aspect, each of R 4a , R 4b , R 4c , and R 4d is fluoro.

In a further aspect, each of R 2 , R 4a , R 4b , R 4c , and R 4d is hydrogen.

In a further aspect, each of R 3 , R 4a , R 4b , R 4c , and R 4d is hydrogen.

In a further aspect, each of R 2 , R 3 , R 4a , R 4b , R 4c , and R 4d is hydrogen.

j. R 5 Groups

In one aspect, R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 . In a further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 . In a yet further aspect, R 5 , when present, is selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a yet further aspect, R 5 , when present, is selected from —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 5 , when present is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , and —NR 21a R 21b . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , and —NR 21a R 21b . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 20 , and —NR 21a R 21b . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a still further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, and —CF 3 . In an even further aspect, R 5 , when present, is selected from hydrogen, —F, methyl, and —CF 3 .

In a further aspect, R 5 , when present, is selected from hydrogen, halogen, and C1-C3 alkyl. In a still further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, methyl, and ethyl. In an even further aspect, R 5 , when present, is selected from hydrogen, —F, —Cl, and methyl. In a yet further aspect, R 5 , when present, is selected from hydrogen, —F, and methyl.

In a further aspect, R 5 , when present, is selected from hydrogen and C1-C3 alkyl. In still further aspect, R 5 , when present, is selected from hydrogen, methyl, and ethyl. In an even further aspect, R 5 , when present, is selected from hydrogen and methyl.

In a further aspect, R 5 is —CN. In a further aspect, R 5 is —F. In a still further aspect, R 5 is —Cl. In an even further aspect, R 5 is methyl. In a still further aspect, R 5 is —CF 3 . In a yet further aspect, R 5 is hydrogen.

In a further aspect, R 5 , when present, and R 2 is hydrogen. In a still further aspect, R 5 , when present, and R 3 is hydrogen. In an even further aspect, each of R 4a , R 4b , R 4c , R 4d and R 5 , when present, is hydrogen. In a yet further aspect, each of R 2 , R 4a , R 4b , R 4c , R 4d , and R 5 , when present, is hydrogen. In a still further aspect, each of R 3 , R 4a , R 4b , R 4c , R 4d , and R 5 , when present, is hydrogen. In an even further aspect, each of R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , and R 5 , when present, is hydrogen.

k. R 6 Groups

In one aspect, R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 30 , —NR 31a R 31b , —SO 2 R 32 , and —(C═O)R 33 . In a further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 . In a still further aspect, R 6 , when present, is selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , and —NR 21a R 21b . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , and —NR 21a R 21b . In a still further aspect, R 6 , when present, s selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 20 , and —NR 21a R 21b . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In yet a further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, and —CF 3 . In a yet further aspect, R 6 , when present, is selected from hydrogen, —F, methyl, and —CF 3 .

In a further aspect, R 6 , when present, is selected from hydrogen, halogen, and C1-C3 alkyl. In a still further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, methyl, and ethyl. In yet a further aspect, R 6 , when present, is selected from hydrogen, —F, —Cl, and methyl. In an even further aspect, R 6 , when present, is selected from hydrogen, —F, and methyl.

In a further aspect, R 6 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 6 is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 6 , when present, is selected from hydrogen and methyl.

In a further aspect, R 6 , when present, is —F. In a still further aspect, R 6 , when present, is —Cl. In yet a further aspect, R 6 , when present, is methyl. In an even further aspect, R 6 , when present, is —CF 3 . In still a further aspect, R 6 , when present, is hydrogen.

In a further aspect, each of R 2 and R 6 , when present, is hydrogen.

In a further aspect, each of R 3 and R 6 , when present, is hydrogen.

In a further aspect, each of R 5 and R 6 , when present, is hydrogen.

In a further aspect, each of R 4a , R 4b , R 4c , R 4d , and R 6 , when present, is hydrogen.

In a further aspect, each of R 2 , R 4a , R 4b , R 4c , R 4d , R 5 , and R 6 , when present, is hydrogen.

In a further aspect, each of R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , and R 6 , when present, is hydrogen.

In a further aspect, each of R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , and R 6 , when present, is hydrogen.

l. R 7 Groups

In one aspect, R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 40 , —NR 41a R 41b , —SO 2 R 42 , and —(C═O)R 43 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , —SO 2 R 22 , and —(C═O)R 23 . In a still further aspect, R 7 , when present, is selected from —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CH 2 CH 3 , —(C═O)CH 2 F, —(C═O)CH 2 Cl, —(C═O)CH 2 CH 2 F, —(C═O)CH 2 CH 2 Cl, —(C═O)CHF 2 , —(C═O)CF 3 , —(C═O)CHCl 2 , —(C═O)CCl 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 . In a still further aspect, R 7 , when present, is selected from —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , —SO 2 —N(CH 3 ) 2 , —(C═O)CH 3 , —(C═O)CF 3 , —(C═O)NH 2 , —(C═O)NHCH 3 , and —(C═O)N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 20 , —NR 21a R 21b , and —SO 2 R 22 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CH 2 F, —SO 2 CHF 2 , —SO 2 CF 3 , —SO 2 -cyclopropyl, —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SO 2 CH 3 , —SO 2 CF 3 , —SO 2 —NH 2 , —SO 2 —NHCH 3 , and —SO 2 —N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, —CN, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , and —NR 21a R 21b . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, —CN, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, —CN, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —CN, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, —OR 20 , and —NR 21a R 21b . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CF 3 , cyclopropyl, —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, —OR 20 , and —NR 21a R 21b . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —O-cyclopropyl, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CF 3 , —OH, —OCH 3 , —OCF 3 , —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, and —CF 3 . In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, methyl, and —CF 3 .

In a further aspect, R 7 , when present, is selected from hydrogen, halogen, and C1-C3 alkyl. In a still further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, methyl, and ethyl. In a yet further aspect, R 7 , when present, is selected from hydrogen, —F, —Cl, and methyl. In an even further aspect, R 7 , when present, is selected from hydrogen, —F, and methyl.

In a further aspect, R 7 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 7 , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, R 7 , when present, is selected from hydrogen and methyl.

In a further aspect, R 7 , when present, is —F. In a still further aspect, R 7 , when present, is —Cl. In a yet further aspect, R 7 , when present, is methyl. In an even further aspect, R 7 , when present, is —CF 3 . In a still further aspect, R 7 , when present, is hydrogen.

In a further aspect, each of R 2 and R 7 , when present, is hydrogen.

In a further aspect, each of R 3 and R 7 , when present, is hydrogen.

In a further aspect, each of R 4a , R 4b , R 4c , R 4d , and R 7 , when present, is hydrogen.

In a further aspect, each of R 5 and R 7 , when present, is hydrogen.

In a further aspect, each of R 6 and R 7 , when present, is hydrogen.

In a further aspect, each of R 2 , R 4a , R 4b , R 4c , R 4d , R 5 , R 6 , and R 7 , when present, is hydrogen.

In a further aspect, each of R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , R 6 , and R 7 , when present, is hydrogen.

In a further aspect, each of R 2 , R 3 , R 4a , R 4b , R 4c , R 4d , R 5 , R 6 , and R 7 , when present, is hydrogen.

m. R 8 Groups

In one aspect, R 8 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl.

In a further aspect, R 8 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 8 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 8 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 8 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 8 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 8 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 8 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 8 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 8 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 8 , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 8 , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 8 , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, R 8 , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 8 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 8 , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, R 8 , when present, is selected from hydrogen and methyl.

In a further aspect, R 8 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl.

In a further aspect, R 8 is F.

In a further aspect, each of R 8 and R 9 , when present, is hydrogen. In a further aspect, —CR 8 R 9 is selected from —CHF and —CF 2 . In a further aspect, —CR 8 R 9 is —CHF. In a further aspect, —CR 8 R 9 is —CF 2 .

n. R 9 Groups

In one aspect, R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl.

In a further aspect, R 9 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 9 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl.

In yet a further aspect, R 9 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 9 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 9 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 9 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 9 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 9 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 9 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 9 , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 9 , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 9 , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 9 , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 9 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 9 , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 9 , when present, is selected from hydrogen and methyl.

In a further aspect, R 9 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 9 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 9 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 9 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 9 , when present, is selected from hydrogen, —CF 3 , and cyclopropyl. In yet a further aspect, R 9 , when present, is hydrogen.

In a further aspect, R 9 , when present, is selected from halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 9 , when present, is selected from —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 9 , when present, is selected from —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 9 , when present, is selected from —F, —Cl, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 9 , when present, is selected from —F, —Cl, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, methyl, and —CF 3 . In yet a further aspect, R 9 , when present, is selected from hydrogen, —F, methyl, and —CF 3 .

In a further aspect, R 9 , when present, is selected from hydrogen, halogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, methyl, and cyclopropyl. In an even further aspect, R 9 , when present, is selected from hydrogen, —F, methyl, and cyclopropyl.

In a further aspect, R 9 , when present, is selected from hydrogen, halogen, and C1-C3 alkyl. In a still further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, methyl, and ethyl. In yet a further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, and methyl. In an even further aspect, R 9 , when present, is selected from hydrogen, —F, and methyl.

In a further aspect, R 9 , when present, is selected from hydrogen, halogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 9 , when present, is selected from hydrogen, —F, —Cl, —CF 3 , and cyclopropyl. In yet a further aspect, R 9 , when present, is selected from hydrogen, —F, —CF 3 , and cyclopropyl. In an even further aspect, R 9 , when present, is hydrogen.

In a further aspect, R 9 is F.

In a further aspect, each of R 8 and R 9 , when present, is hydrogen. In a further aspect, —CR 8 R 9 is selected from —CHF and —CF 2 . In a further aspect, —CR 8 R 9 is —CHF. In a further aspect, —CR 8 R 9 is —CF 2 .

o. R 10 Groups

In one aspect, each of R 10a and R 10b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, each of R 10a and R 10b is independently selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, each of R 10a and R 10b is independently selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 10a and R 10b is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 10a and R 10b is independently selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 10a and R 10b is independently selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 10a and R 10b is independently selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 10a and R 10b is independently selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 10a and R 10b is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 10a and R 10b is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 10a and R 10b is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 10a and R 10b is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 10a and R 10b is independently selected from hydrogen and methyl.

In a further aspect, each of R 10a and R 10b is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 10a and R 10b is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 10a and R 10b is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 10a and R 10b is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 10a and R 10b is independently selected from hydrogen, —CF 3 , and cyclopropyl. In yet a further aspect, each of R 10a and R 10b is hydrogen.

In a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 10a is hydrogen and R 10b is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 10a is hydrogen and R 10b is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 10a is hydrogen and R 10b is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 10a is hydrogen and R 10b is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 10a is hydrogen and R 10b is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 10a is hydrogen and R 10b is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 10a is hydrogen and R 10b is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen and methyl.

In a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 10a is hydrogen and R 10b is selected from hydrogen, —CF 3 , and cyclopropyl.

p. R 12 Groups

In one aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl.

In a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen and methyl.

In a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from m hydrogen, —F, —Cl, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, methyl, and —CF 3 . In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, methyl, and —CF 3 .

In a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, and —CF 3 . In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, and —CF 3 .

In a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, halogen, and C1-C3 alkyl. In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, methyl, and ethyl. In yet a further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, —Cl, and methyl.

In an even further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is independently selected from hydrogen, —F, and methyl. In a still further aspect, each occurrence of R 12a , R 12a , R 12a , and R 12a , when present, is hydrogen.

q. R 20 Groups

In one aspect, R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a further aspect, R 20 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 20 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 20 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 20 , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 20 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 20 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 20 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 20 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 20 , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 20 , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 20 , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, R 20 , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 20 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 20 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 20 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 20 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 20 , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 20 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 20 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 20 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 20 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 20 , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 20 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 20 , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, R 20 , when present, is selected from hydrogen and methyl. In an even further aspect, R 20 , when present, is hydrogen.

r. R 21 Groups

In one aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 21a and R 21b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R 21a and R 21b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 21a , when present, is hydrogen and R 21b , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R 21a and R 21b , when present, is hydrogen.

In a further aspect, R 21a and R 21b , when present, are optionally covalently bonded and, together with the nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, R 21a and R 21b , when present, are covalently bonded, and together with the nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, and pyrrolyl. In a yet further aspect, R 21a and R 21b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, and pyrazolidinyl. In an even further aspect, R 21a and R 21b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from imidazolyl, pyrazolyl, and pyrrolyl. In a still further aspect, R 21a and R 21b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a pyrrolidinyl. In a yet further aspect, R 21a and R 21b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a piperidinyl.

s. R 22 Groups

In one aspect, R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 24a R 24b . In a further aspect, R 22 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 22 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 24a R 24b . In a still further aspect, R 22 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a yet further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 22 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 22 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CC 3 , and cyclopropyl. In an even further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 22 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 22 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 22 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 22 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 22 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 22 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 22 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 22 , when present, is selected from methyl, ethyl, and cyclopropyl. In a yet further aspect, R 22 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 22 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 22 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 22 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 22 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 22 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 22 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 22 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 2 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a yet further aspect, R 22 , when present, is —CF 3 .

In a further aspect, R 22 , when present, is C1-C3 alkyl. In a still further aspect, R 22 is selected from methyl, and ethyl. In a yet further aspect, R 22 , when present, is methyl.

t. R 23 Groups

In one aspect, R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 25a R 25b . In a further aspect, R 23 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 23 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In further aspect, R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 24a R 24b . In a still further aspect, R 23 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a yet further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 23 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 23 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 23 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 23 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 23 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 23 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 23 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 23 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 23 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 23 , when present, is selected from methyl, ethyl, and cyclopropyl. In a yet further aspect, R 23 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 23 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 23 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 23 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 23 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 23 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 23 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 23 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 23 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 23 , when present, is —CF 3 .

In a further aspect, R 23 , when present, is C1-C3 alkyl. In a still further aspect, R 23 , when present, is selected from methyl, and ethyl. In a yet further aspect, R 23 , when present, is methyl.

u. R 24 Groups

In one aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 24a and R 24b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R 24a and R 24b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 24a , when present, is hydrogen and R 24b , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, R 24a , when present, is hydrogen and R 24b is selected from hydrogen and methyl. In an even further aspect, each of R 24a and R 24b , when present, is hydrogen.

v. R 25 Groups

In one aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 25a and R 25b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R 25a and R 25b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, R 25a , when present, is hydrogen and R 25b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 25a and R 25b , when present, is hydrogen.

w. R 30 Groups

In one aspect, R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a further aspect, R 30 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 30 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 30 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 30 , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 30 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 30 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 30 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a still further aspect, R 30 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a yet further aspect, R 30 , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 30 , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 30 , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, R 30 , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 30 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 30 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 30 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 30 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 30 , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 30 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 30 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 30 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 30 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 30 , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 30 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 30 , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, R 30 , when present, is selected from hydrogen and methyl. In an even further aspect, R 30 , when present, is hydrogen.

x. R 31 Groups

In one aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In still a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 31a and R 31b , when present, is independently selected from hydrogen and methyl. In an even further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 31a , when present, is hydrogen and R 31b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 31a and R 31b , when present, is hydrogen.

In a further aspect, R 31a and R 31b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, R 31a and R 31b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, and pyrrolyl. In yet a further aspect, R 31a and R 31b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, and pyrazolidinyl. In an even further aspect, R 31a and R 31b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from imidazolyl, pyrazolyl, and pyrrolyl. In a still further aspect, R 31a and R 31b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a pyrrolidinyl. In yet a further aspect, R 31a and R 31b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a piperidinyl.

y. R 32 Groups

In one aspect, R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 34a R 34b . In a further aspect, R 32 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 32 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 34a R 34b . In a still further aspect, R 32 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In yet a further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 32 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 32 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 32 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 32 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 32 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 32 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 32 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 32 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 32 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 32 , when present, is selected from methyl, ethyl, and cyclopropyl. In yet a further aspect, R 32 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 32 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 32 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 32 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 32 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 32 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 32 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 32 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 32 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 32 , when present, is —CF 3 .

In a further aspect, R 32 , when present, is C1-C3 alkyl. In a still further aspect, R 32 , when present, is selected from methyl, and ethyl. In yet a further aspect, R 32 , when present, is methyl.

z. R 33 Groups

In one aspect, R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 35a R 35b . In a further aspect, R 33 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In a yet further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 33 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 34a R 34b . In a still further aspect, R 33 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a yet further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 33 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 33 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 33 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 33 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 33 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 33 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 33 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. R 33 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 33 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 33 , when present, is selected from methyl, ethyl, and cyclopropyl. In a yet further aspect, R 33 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 33 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 33 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 33 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 33 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 33 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 33 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 33 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 33 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 33 , when present, is —CF 3 .

In a further aspect, R 33 , when present, is C1-C3 alkyl. In a still further aspect, R 33 , when present, is selected from methyl, and ethyl. In a yet further aspect, R 33 , when present, is methyl.

aa. R 34 Groups

In one aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 34a and R 34b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 34a and R 34b , when present, is independently selected from hydrogen and methyl. In an even further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 34a , when present, is hydrogen and R 34b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 34a and R 34b , when present, is hydrogen.

bb. R 35 Groups

In one aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 35a and R 35b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen, methyl, and ethyl. In a yet further aspect, each of R 35a and R 35b , when present, is independently selected from hydrogen and methyl. In an even further aspect, R 35a is hydrogen and R 35b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In a yet further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a yet further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In a yet further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In a yet further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen, methyl, and ethyl. In a yet further aspect, R 35a , when present, is hydrogen and R 35b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 35a and R 35b , when present, is hydrogen.

cc. R 40 Groups

In one aspect, R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a further aspect, R 40 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 40 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 40 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 40 , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 40 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 40 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 40 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 40 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 40 , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 40 , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 40 , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 40 , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 40 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 40 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 40 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 40 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 40 , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 40 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 40 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 40 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 40 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 40 , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 40 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 40 , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 40 , when present, is selected from hydrogen and methyl. In an even further aspect, R 40 , when present, is hydrogen.

dd. R 41 Groups

In one aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 41a and R 41b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 41a is hydrogen and R 41b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 41a , when present, is hydrogen and R 41b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 41a and R 41b , when present, is hydrogen.

In a further aspect, R 41a and R 41b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, R 41a and R 41b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, and pyrrolyl. In yet a further aspect, R 41a and R 41b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, and pyrazolidinyl. In an even further aspect, R 41a and R 41b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from imidazolyl, pyrazolyl, and pyrrolyl. In a still further aspect, R 41a and R 41b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a pyrrolidinyl. In yet a further aspect, R 41a and R 41b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a piperidinyl.

ee. R 42 Groups

In one aspect, R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 44a R 44b . In a further aspect, R 42 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 42 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 44a R 44b . In a still further aspect, R 42 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In yet a further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 42 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 42 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 42 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 42 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 42 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 42 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 42 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 42 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 42 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 42 , when present, is selected from methyl, ethyl, and cyclopropyl. In yet a further aspect, R 42 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 42 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 42 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 42 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 42 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 42 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 42 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 42 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 42 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 42 , when present, is —CF 3 .

In a further aspect, R 42 , when present, is C1-C3 alkyl. In a still further aspect, R 42 , when present, is selected from methyl, and ethyl. In yet a further aspect, R 42 , when present, is methyl.

ff. R 43 Groups

In one aspect, R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 45a R 45b . In a further aspect, R 43 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 43 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 44a R 44b . In a still further aspect, R 43 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In yet a further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 43 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 43 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 43 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 43 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 43 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 43 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 43 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 43 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 43 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 43 , when present, is selected from methyl, ethyl, and cyclopropyl. In yet a further aspect, R 43 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 43 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 43 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 43 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 43 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 43 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 43 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 43 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 43 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 43 , when present, is —CF 3 .

In a further aspect, R 43 , when present, is C1-C3 alkyl. In a still further aspect, R 43 , when present, is selected from methyl, and ethyl. In yet a further aspect, R 43 , when present, is methyl.

gg. R 44 Groups

In one aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 44a and R 44b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 44a and R 4b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 44a and R 44b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 44a is hydrogen and R 44b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 44a , when present, is hydrogen and R 44b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 44a and R 44b , when present, is hydrogen.

hh. R 45 Groups

In one aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 45a and R 45b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 45a and R 45b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 45a is hydrogen and R 45b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 45a , when present, is hydrogen and R 45b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 45a and R 45b , when present, is hydrogen.

ii. R 50 Groups

In one aspect, R 50 , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 50 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 50 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 50 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 50 , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 50 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 50 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 50 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 50 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 50 , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 50 , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 50 , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 50 , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 50 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 50 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 50 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 50 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 50 , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 50 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 50 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 50 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 50 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 50 , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 50 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 50 , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 50 , when present, is selected from hydrogen and methyl. In an even further aspect, R 50 , when present, is hydrogen.

jj. R 51 Groups

In one aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 51a and R 51b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 51a is hydrogen and R 51b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 51a , when present, is hydrogen and R 51b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 51a and R 51b , when present, is hydrogen.

In a further aspect, R 51a and R 51b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, R 51a and R 51b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, and pyrrolyl. In yet a further aspect, R 51a and R 51b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, and pyrazolidinyl. In an even further aspect, R 51a and R 51b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from imidazolyl, pyrazolyl, and pyrrolyl. In a still further aspect, R 51a and R 51b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a pyrrolidinyl. R 51a and R 51b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a piperidinyl.

kk. R 52 Groups

In one aspect, R 52 , when present, is independently selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 54a R 54b . In a further aspect, R 52 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 52 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 52 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 54a R 54b . In a still further aspect, R 52 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In yet a further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 52 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 52 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 52 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 52 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 52 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 52 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 52 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 52 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 52 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 52 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 52 , when present, is selected from methyl, ethyl, and cyclopropyl. In a yet further aspect, R 52 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 52 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 52 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 52 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 52 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 52 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 52 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 52 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 52 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 52 , when present, is —CF 3 .

In a further aspect, R 52 , when present, is C1-C3 alkyl. In a still further aspect, R 52 , when present, is selected from methyl, and ethyl. In an even further aspect, R 52 , when present, is methyl.

II. R 53 Groups

In one aspect, R 53 , when present, is independently from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 55a R 55b . In a further aspect, R 53 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 53 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 53 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 54a R 54b . In a still further aspect, R 53 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In yet a further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 53 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 53 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 53 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 53 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 53 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 53 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 53 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 53 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 53 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 53 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 53 , when present, is selected from methyl, ethyl, and cyclopropyl. In yet a further aspect, R 53 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 53 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 53 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 53 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 53 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 53 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 53 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 53 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 53 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 53 , when present, is —CF 3 .

In a further aspect, R 53 , when present, is C1-C3 alkyl. In a still further aspect, R 53 , when present, is selected from methyl, and ethyl. In yet a further aspect, R 53 , when present, is methyl.

mm. R 54 Groups

In one aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 54a and R 54b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In yet a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 54a and R 54b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 54a is hydrogen and R 54b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 54a , when present, is hydrogen and R 54b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 54a and R 54b , when present, is hydrogen.

nn. R 55 Groups

In one aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle

In a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 55a and R 55b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of Rss 55a and R 55b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 55a and R 55b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 55a is hydrogen and R 55b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, Rssa, when present, is hydrogen and R 55b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 55a , when present, is hydrogen and R 55b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 55a and R 55b , when present, is hydrogen.

oo. R 60 Groups

In one aspect, R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a further aspect, R 60 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 60 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 60 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 60 , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 60 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 60 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 60 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 60 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 60 , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 60 , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 60 , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 60 , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 60 , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 60 , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 60 , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 60 , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 60 , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 60 , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 60 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 60 , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 60 , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 60 , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 60 , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 60 , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 60 , when present, is selected from hydrogen and methyl. In an even further aspect, R 60 , when present, is hydrogen.

pp. R 61 Groups

In one aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle.

In a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, and —CF 3 .

In a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen and —CF 3 .

In a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen and C1-C3 alkyl. In a still further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 61a and R 61b , when present, is independently selected from hydrogen and methyl.

In a further aspect, R 61a is hydrogen and R 61b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In yet a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In an even further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, ethyl, and cyclopropyl. In yet a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, and cyclopropyl.

In a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, and —CF 3 .

In a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen and —CF 3 .

In a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen and C1-C3 alkyl. In a still further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 61a , when present, is hydrogen and R 61b , when present, is selected from hydrogen and methyl. In an even further aspect, each of R 61a and R 61b , when present, is hydrogen.

In a further aspect, R 61a and R 61b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, R 61a and R 61b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, imidazolyl, pyrazolyl, and pyrrolyl. In yet a further aspect, R 61a and R 61b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from pyrrolidinyl, piperidinyl, azepanyl, imidazolidinyl, and pyrazolidinyl. In an even further aspect, R 61a and R 61b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a heterocycle selected from imidazolyl, pyrazolyl, and pyrrolyl. In a still further aspect, R 61a and R 61b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a pyrrolidinyl. In yet a further aspect, R 61a and R 61b , when present, are covalently bonded, and together with nitrogen atom to which they are attached, comprise a piperidinyl.

qq. R 62 Groups

In one aspect, R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 64a R 64b . In a further aspect, R 62 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 62 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 64a R 64b . In a still further aspect, R 62 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In yet a further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 62 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 62 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 62 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 62 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 62 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 62 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 62 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 62 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 62 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 62 , when present, is selected from methyl, ethyl, and cyclopropyl. In yet a further aspect, R 62 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 62 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 62 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 62 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 62 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 62 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 62 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 62 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 62 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 62 , when present, is —CF 3 .

In a further aspect, R 62 , when present, is C1-C3 alkyl. In a still further aspect, R 62 , when present, is selected from methyl, and ethyl. In yet a further aspect, R 62 , when present, is methyl.

rr. R 63 Groups

In one aspect, R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, cyclopropyl, and, —NR 65a R 65b . In a further aspect, R 63 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , cyclopropyl, —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In a still further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In yet a further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl, —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 63 , when present, is selected from methyl, —CF 3 , cyclopropyl, and —NHCH 3 .

In a further aspect, R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and, —NR 64a R 64b . In a still further aspect, R 63 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH(CH 2 ) 2 CH 3 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —N(CH 3 )(CH 2 ) 2 CH 3 , —N(CH 3 )CH(CH 3 ) 2 , and —N(CH 2 CH 3 ) 2 . In yet a further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —NHCH 3 , and —N(CH 3 ) 2 . In an even further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , —NHCH 3 , and —N(CH 3 ) 2 . In a still further aspect, R 63 , when present, is selected from methyl, —CF 3 , and —NHCH 3 .

In a further aspect, R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 63 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 63 , when present, is selected from methyl, —CF 3 , and cyclopropyl.

In a further aspect, R 63 , when present, is selected from C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, R 63 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, R 63 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, R 63 , when present, is selected from —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, R 63 , when present, is selected from —CF 3 and cyclopropyl.

In a further aspect, R 63 , when present, is selected from C1-C3 alkyl, and cyclopropyl. In a still further aspect, R 63 , when present, is selected from methyl, ethyl, and cyclopropyl. In yet a further aspect, R 63 , when present, is selected from methyl, and cyclopropyl.

In a further aspect, R 63 , when present, is selected from C1-C3 alkyl, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 63 , when present, is selected from methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 63 , when present, is selected from methyl, —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 63 , when present, is selected from methyl and —CF 3 .

In a further aspect, R 63 , when present, is selected from C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In a still further aspect, R 63 , when present, is selected from —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , and —CH 2 CCl 3 . In yet a further aspect, R 63 , when present, is selected from —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , and —CCl 3 . In an even further aspect, R 63 , when present, is selected from —CH 2 F, —CHF 2 , and —CF 3 . In a still further aspect, R 63 , when present, is —CF 3 .

In a further aspect, R 63 , when present, is C1-C3 alkyl. In a still further aspect, R 63 , when present, is selected from methyl, and ethyl. In yet a further aspect, R 63 , when present, is methyl.

ss. R 64 Groups

In one aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle

In a further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl; or wherein R 64a and R 64b , when present, are optionally covalently bonded and, together with nitrogen atom to which they are attached, comprise a 3- to 6-membered heterocycle. In a still further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, methyl, ethyl, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, methyl, —CF 3 , and cyclopropyl.

In a further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, and cyclopropyl. In a still further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CH 2 CH 2 F, —CH 2 CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CHCl 2 , —CH 2 CCl 3 , and cyclopropyl. In yet a further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, —CH 2 F, —CH 2 Cl, —CHF 2 , —CF 3 , —CHCl 2 , —CCl 3 , and cyclopropyl. In an even further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , and cyclopropyl. In a still further aspect, each of R 64a and R 64b , when present, is independently selected from hydrogen, —CF 3 and cyclopropyl.

In a further aspect, each of R 64a and R 64b , wh