Pyrazole and imidazole derivatives as dual orexin and kappa-opioid receptors modulators, compositions, and methods for treating neurological and psychiatric disorders

Abstract

The present disclosure is directed to substituted Pyrazole and Imidazole derivatives of compounds that are antagonists and / or modulators of orexin and kappa-opioid receptors, and which are useful in the treatment or prevention of neurological, psychiatric, cardiovascular and cancer disorders and diseases in which orexin and kappa-opioid receptors are involved or implicated. The disclosure is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin and kappa-opioid receptors are involved.

Description

[0001] PYRAZOLE 4IVD IMIDAZOLE DERIVATIVES AS DUAL OREXIN and KAPPA-OPIOID RECEPTORS MODULATORS, COMPOSITIONS, AND METHODS FOR TREATING NEUROLOGICAL AND PSYCHIATRIC DISORDERS

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Ser. No. 63 / 561 ,476 filed on March 5, 2024, which is incorporated in its entirety into this disclosure.

[0004] FELD OF THE INVENTION

[0005] This disclosure pertains to and provides compounds, compositions and methods for using dualacting orexin and kappa-opioid receptor antagonists and / or modulators to treat or ameliorate human and animal diseases as therapeutic agents. In particular, any pathological disorder in which both types of orexin and kappa-opioid receptors (OXiR, OX?R, KOR, respectively) are pharmacologically involved or implicated. In preferred embodiments, the compounds disclosed herein can be used to treat disorders in which particular of these receptors are primarily or solely (i.e., with respect to any one or more of these three receptors) involved or implicated including: 1) OXiR and KOR only; 2) OXiR, OX2R and KOR only; 3) OXiR and OX2R only; 4) OXiR only; 5) OX2R and KOR only; or, 6) KOR only. These important therapeutic applications include but are not limited to treating central nervous system (CNS) disorders, neurological, cardiovascular diseases including various cancers (e g., stomach cancer) that involve or are modulated by orexin and / or kappa-opioid receptors including but not limited to disorders that are responsive to orexin and / or kappa-opioid receptor antagonists, e.g., substance addiction and dependence, cognitive impairment, Alzheimer's disease (AD), posttraumatic stress disorder (PTSD), schizophrenia, panic, anxiety, autism, pain and depression.

[0006] STATEMENT REGARDING FEDERAL SUPPORT

[0007] This disclosure was made with partial government support under Federal

[0008] Award UF1DA054817 awarded by The National Institutes of Drug Abuse (NIDA) of NIH. The government has certain rights in the disclosure.

[0009] BACKGROUND OF THE DICLOSURE

[0010] The orexins (also known as hypocretins) are comprised of two excitatory hypothalamic neuropeptides: orexin A (OX-A; a 33 amino acid peptide) and orexin B (OX-B; a 28 amino acid peptide). They were simultaneously discovered in 1998 by two research groups searching for new signaling molecules, (1) Sakurai and co-workers (who named them orexin-A and -B) (Sakurai, T. et al, Cell 1998, 92, 573) and (2) de Lecea and co-workers (who named them hypocretin 1 and 2, respectively) (de Lecea, L. et al, Proc. Natl. Acad. Sci. U.S.A.1998, 95, 322.). These neuropeptides are endogenous ligands for two G protein-coupled receptors (GPCR) named OX1R and OX2R (also referred to as Hcrt1 and Hcrt2, respectively) and are derived proteolytically from the same precursor peptide called pre-pro-orexin polypeptide (Sakurai T., et al. The Journal of biological chemistry.1999; 274, 17771–17776). Though structurally related, the binding affinities of these endogenous ligands for the two GPCRs differ. Orexin A binds to OX1R with about 100-fold higher affinity than Orexin B, whilst both Orexin A and Orexin B bind to OX2R with the same affinity (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375). Soon after the discovery of orexin, modulation of the orexin signaling was originally considered for potential novel treatments of narcoleptic or insomniac patients since the role of orexin in regulation of sleep and wakefulness was well-studied and understood, and the discovery of small-molecule modulators of orexin signaling facilitated the development of this class of compounds. Narcoleptic patients show a diminished activity in hypothalamic orexin neurons thereby lowering the amounts of circulating orexin in the cerebrospinal fluid. In contrast, activation of orexin neurons maintains wakefulness and arousal. The effects of orexin signaling on feeding and energy homeostasis were also established earlier and found to be coordinated to the sleep-wake cycle (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375). More recent studies have established the role of orexin and / or kapp-opioid signaling in other key physiological pathways such as neuroendocrine functions (Inutsuka, A.; Yamanaka, A. Front. Endocrinol. 2013, 4:18. doi: 10.3389 / fendo.2013.00018), glucose metabolism (Tsuneki, H., et al., Endocrinology, 2016, 157, 4146–4157), stress-adaptive responses (Xiao, F., et al. Neuropharmacology, 2013, 67, 16–24), and addiction / reward-seeking (Aston-Jones, G., et al. Brain Res., 2010, 1314, 74–90). Small molecule orexin antagonists have been broadly categorized into three classes based on theiroverall receptor selectivity profiles: (1) DORA (dual-acting, or non-selective OX1R / OX2R antagonists), (2) SORA-1 (selective OX1R antagonists), and (3) SORA-2 (selective OX2R antagonists). It has been shown that while OX2R knockout mice and OX1R / OX2R double knockout mice both show a narcoleptic phenotype, the effect is very muted in OX1R knockouts (Wang C., et al. Neurosci., 2018, 11, 220. doi: 10.3389 / fnmol.2018.00220). Additionally, both DORA and SORA-2 compounds inhibit wakefulness, but SORA-1 compounds do not – thus suggesting that narcoleptic effects are mediated through OX2R or a combination of OX1R and OX2R, but not through OX1R alone. Thus, it is clear that the discovery and development of differentiated orexin antagonists is crucial to the advancement of this field but most importantly to the development of therapeutic agents for dysregulated biological processes that involve the orexin receptor; especially for non-sleep related indications such as substance addiction, anxiety, panic and PTSD. Kappa-Opioid Receptor OR): Opioid research has been the focus of numerous drug development efforts for CNS or neuropsychiatric disorders thru the modulation of endogenous -endorphins, dynorphins, and enkephalins, respectively. Morespecific (i.e., preferably) antagonists have shown potential utility in the treatment of stress-related mood-disorders including depression, anxiety, and drug-abuse. Stressful stimuli, endogenous ligand dynorphin. This stress-induced depressive disorder contributes to relapse ofdrug-seeking behavior, which has been shown to b . In contrast,stimulation nists such as opioids is known to show anti-nociceptive and analgesic effects. The simultaneous modulation of different molecular targets or receptors that are co-implicated in a common disease pathway or disorder, using a single molecular entity, could provide better overall efficacy compared to dosing with either a cocktail of medications or a single pill Formulated with multi-component agents. Potential advantages of dual target modulation approach over drug combinations or cocktails include but are not limited to: improved dosing regimen and compliance, reduced drug-drug interactions, simplified and predictable PK / PD relationships and one- dimensional DMPK and safety profiles, potentially synergistic efficacy, reduced potential for tolerance, and reduced regulatory hurdles. This Network Pharmacology approach could provide superior efficacy versus single-target agents to treat multifactorial and multi-etiological disease states such as CNS and / or neurological disorders, cancer, metabolic syndrome, cardiovascular disorders, and more specifically (i.e., preferred) conditions such as addiction disorders. Therefore, a measured but balanced simultaneous modulation of orexin and kappa-opioid receptors (OXR and (e.g., antagonist of OXR and partial antagonist or inverse agonist or agonist may provide unique, first in class and high efficacy new molecular entities as a therapeutic agent(s) for numerous dysregulated biological processes that involve orexin and / or kappa-opioid receptors. The compounds, compositions and methods provide solutions to such problems in the art. SUMMARY OF THE DISCLOSURE This disclosure addresses the aforementioned therapeutic needs by providing compounds of Formula I or II, in different embodiments: R4R2salts, solvates, adducts, polymorphs, and isomers thereof. Compounds of Formulas I or II, respectively, can be used to treat the conditions described herein, such as through modulations of orexin and / or kappa-opioid receptors. In some embodiments, the compounds provide a balanced simultaneous modulation of orexin and kappa-opioid receptors (OXR and of OXR and partial antagonist or inverse agonist or agonist Preferred compounds encompassed by Formulas I and / or II include Compounds 1-138 (see Tables 3 and 4). The present disclosure also provides compositions that comprise the above compounds or a pharmaceutically acceptable salt thereof. In another aspect of the disclosure, there is provided a method for treating CNS disorders such as, among others, substance addiction and dependence, posttraumatic stress disorder (PTSD), schizophrenia, panic, anxiety, pain, depression, cognitive impairment and Alzheimer’s disease (AD), and / or cancer (e.g., stomach cancer) in a subject in need or at risk thereof, the method comprising the step of administering to said subject a therapeutically effective amount of orexin and / or kappa-opioid receptor antagonists and / or modulators or a pharmaceutically acceptable salt thereof. In preferred embodiments, the compounds disclosed herein can be used to treat disorders in which only particular receptors are primarily or solely (i.e., with respect to any one or more other of these three receptors) involved or implicated including: 1) OX1R and KOR; 2) OX1R, OX2R and KOR; 3) OX1R and OX2R; 4) OX1R; 5) OX2R and KOR; or, 6) KOR. In certain embodiments of the disclosure, the antagonists and / or modulators or a pharmaceutically acceptable salt thereof could be Formulated to be administered periodically, for example every 3, 6 to 24 hours or weekly as deemed clinically beneficial. DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure pertains to a fused 6 and 5 membered ring system derivatives of Formula (I) and / or (II) wherein the fused 6 and 5 membered rings are as described in the full disclosure enabling structural descriptions, to pharmaceutically acceptable salts thereof, to their preparation, to pharmaceutical compositions containing one or more compounds of Formula (I) and / or (II), and to their use as pharmaceuticals and therapeutic agents, particularly to their use as orexin and / or kappa-opioid receptor antagonists and / or modulators. These novel agents as described by Formula (I) and / or (II) which are non-peptide modulators of human orexin and / or kappa-opioid receptors and are potentially useful in the treatment of disorders relating to orexinergic and kappa-opioid receptors dysfunctions; including but not limited for such disorders like substance addiction, anxiety, panic, cognitive dysfunctions, mood, or appetite, sleep, Alzheimer (AD), metabolic syndrome, hypertension, and / or cancer (e.g., stomach cancer); and especially these compounds could be of great therapeutic value in the treatment of anxiety disorders, pain, addiction disorders, and sleep disorders. In preferred embodiments, the compounds disclosed herein can be used to treat such disorders in which particular of the three receptors are primarily or solely (i.e., with respect to any one or more of the other of these three receptors) involved or implicated including: 1) OX1R and KOR; 2) OX1R, OX2R and KOR; 3) OX1R and OX2R only; 4) OX1R only; 5) OX2R and KOR; or, 6) KOR. As shown herein, this disclosure provides examples of compounds that affect, either exclusively or primarily, these combinations of OX1R, OX2R and KOR as determined using reliable, specific in vitro assays. For instance, Examples 1, 2, 25, 79, 83, 89, 94 and 136 have been shown to affect OX1R and KOR; Examples 10, 27, 28, 80, 81, 97, 106, 111, and 113 have been shown to affect OX1R, OX2R and KOR; Examples 3, 9, 16, 22, 37, 39 and 76 have been shown to affect OX1R and OX2R only; Examples 13, 14, 19, 33, 38, 40, 41, 42, 43 have been shown to primarily or only affect OX1R OX2R and KOR; Examples 23, 105, and 106 have been shown to primarily or only affect OX2R and KOR; and, Examples 30, 31, and 90 have been shown to primarily or only affect KOR. Compounds of categories 1-6 can be used to treat conditions and / or diseases that are primarily or solely (i.e., with respect to any one or more of the other of these three receptors) affected or caused by the activity of a particular combination of OX1R, OX2R and / or KOR. A first aspect of the disclosure relates to and provides compounds of the Formula (I) or (II), respectively: R4R2GMR9R8wherein: R1, includes E in which is Carbon (C) but not Nitrogen (N), and E is linked to J or D with a double bond, and R1is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1is heteroaryl, R1is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl (exemplary preferred R1groups are shown in Table 1); R2, R3, and R4are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R5’ = aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1- 4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1 and Z2, wherein R5’is defined herein; R8= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8connected to either R10, R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2= H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups; also wherein: fused or unfused ring system A-B-J-D-E is a five-membered heteroaryl, for example, imidazole (wherein A, J = Nitrogen while B, E, D = Carbon), pyrazole (when A, B = Nitrogen, while D, E, J = Carbon) fused or unfused with an additional ring systems; fused ring system B-J-M-G-K-L is an arrangement of these outlined variables to provide groups consisting of a 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6- membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5 or 6-membered cycloalkyl, and 5 or 6-membered heterocycloalkyl; wherein the preferred groups are: A = Nitrogen, such as in Imidazole or Pyrazole ring systems; B = Carbon or Nitrogen J = Carbon or Nitrogen D = Carbon E = Carbon, wherein R1 is as defined above; M = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N; G = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; K = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and, L = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N. In a more specific (i.e., preferred) embodiment, the disclosure provides a compound that has the Formula I-a and II-a, wherein the ring system (illustrated by A-B-J-D-E variables in Formula (I) or (II)) fused to the 6-membered ring is preferred as an imidazolo ring system as represented by embodiment Formula I-a or II-a, respectively, herein:

[0011] R4R2GMR9R8 R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1 is heteroaryl, R1 is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3- 7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4; R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R5’= aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R8= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8connected to either R10, R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9connected to either R6or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups; also wherein: fused ring system B-J-M-G-K-L is an arrangement of these outlined variables to provide groups consisting of a 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6- membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5 or 6-membered cycloalkyl, and 5 or 6-membered heterocycloalkyl; wherein the preferred groups are: M = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N; G = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; K = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and, L = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N. In a more specific (i.e., preferred) embodiment, the disclosure provides a compound that has the Formula I-b and II-b, wherein the ring system (illustrated by A-B-J-D-E variables in Formula (I) or (II)) to the 6-membered ring is preferred as a pyrazolo ring system as represented by embodiment Formula I-b or II-b, respectively, herein: R4 R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1 is heteroaryl, R1 is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3and R4is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5 replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R5’ = aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1- 4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6 connected to either R10 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R8 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8 connected to either R10, R11 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb(where Raand Rb= alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups; also wherein: fused ring system B-J-M-G-K-L is an arrangement of these outlined variables to provide groups consisting of a 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6- membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5 or 6-membered cycloalkyl, and 5 or 6-membered heterocycloalkyl; wherein the preferred groups are: M = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, N; G = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; K = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O; and, L = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

[0012] A further embodiment of the disclosure relates to preferred compounds wherein the imidazole fused six-membered ring is preferred as shown herein according to embodiment Formula I-a1 or II-a1, respectively: R4R25' wherein: R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1 is heteroaryl, R1 is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3- 7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4; R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R5’ = aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1- 4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R8 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8 connected to either R10, R11 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups; wherein the preferred groups are: L = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N. A further embodiment of the disclosure relates to compounds wherein the imidazole fused six-membered ring is preferred as shown herein according to embodiment Formula I-a2 or II-a2, respectively: R4R2R ' wherein: R1is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1is heteroaryl, R1is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R5’= aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R8 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8 connected to either R10, R11 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups. A further embodiment of the disclosure relates to preferred compounds wherein the imidazole fused six-membered ring is preferred as shown herein according to embodiment Formula I-a3 or II-a3, respectively: R4R2R R wherein: R1is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1is heteroaryl, R1is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R5’= aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R8= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8connected to either R10,R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2= H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups. A further embodiment of the disclosure relates to preferred compounds wherein the pyrazole fused six-membered ring is preferred as shown herein according to embodiments of Formulas I-b1 or II-b1, respectively: R4R2M wherein: R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1 is heteroaryl, R1 is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3- 7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4; R5= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R5’= aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R8= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8connected to either R10,R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently; wherein the preferred groups are: M = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N. A further embodiment of the disclosure relates to preferred compounds wherein the pyrazole fused six-membered ring is preferred as shown herein according to embodiments of Formulas I-b2 or II-b2, respectively: R4R R8R2O R910X R7Z1' wherein: R1is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1is heteroaryl, R1is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3and R4is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5 replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R5’ = aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R8= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8connected to either R10,R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups. A further embodiment of the disclosure relates to preferred compounds wherein the pyrazole fused six-membered ring is preferred as shown herein according to the embodiments of Formulas I-b3 or II-b3, respectively: R4R2O 2 R5' wherein: R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1 is heteroaryl, R1 is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3- 7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4; R5= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R5replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R5’ = aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R8= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8connected to either R10,R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9 connected to either R6 or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example to provide five membered pyrrolidine ring), CRaRb (where Ra and Rb = alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups. In a more specific (i.e., preferred) embodiment of the disclosure as it relates to compounds wherein the stereogenic centers and main scaffold rings are preferred as shown in the exemplification Formula as shown herein according to embodiments of Formulas I-a4, I-a5, I-a6, II-a4, II-a5, or II-a6, respectively: R5' R1is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1is heteroaryl, R1is preferably a 5 or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3- 7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4; R5is H or replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R5’ = aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1- 4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6 connected to either R10 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7 is H or replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R8 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8 connected to either R10, R11 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9connected to either R6or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10connected to R6or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11connected to R6as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12connected to R9as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example, to provide five membered pyrrolidine ring), CRaRb(where Raand Rb= alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; Z1, Z2 = H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups; and, L = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N. In a more specific (i.e., preferred) embodiment of the disclosure as it relates to compounds wherein the stereogenic centers and main scaffold rings are preferred as shown in the exemplification Formula as shown herein according to the embodiments of Formulas I-b4, I-b5, I-b6, II-b4, II-b5, or II-b6, respectively: R R44R R4R22O R2R5' R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl , phenyl, aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5 - 6 membered ring); or, when R1 is heteroaryl, R1 is preferably a 5 or 6-membered heteroaryl selected from the group of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3and R4is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5is H or replaced with the carbon bearing Y, Z1and Z2, wherein R5’is defined herein; R5’ = aromatic or aryl, heteroaryl (5 - 6 membered ring), substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems (5 - 6 membered ring); wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1- 4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, (C3-7)heterocycloalkyl; R6 = H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R6 connected to either R10 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7 H or is replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R8= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R8connected to either R10, R11or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, R9connected to either R6or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R10connected to R6or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R11connected to R6as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12= H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, or R12connected to R9as alkyl to form a (C1-3)alkyl bridge cyclic structure; X = CH2, O, nothing (i.e., absent; for example, to provide five membered pyrrolidine ring), CRaRb(where Raand Rb= alkyl, cycloalkyl, Fluoroalkyl); wherein the carbon atom at position 2 of the piperidine or pyrrolidine is preferred in absolute (S)-configuration; in contrast, the carbon atom at position 2 of the of the morpholine ring (when X = O, oxygen) is preferred in absolute (R)- configuration; Y = O, NH, nothing (i.e., absent such that R5’ is attached directly to the carbon bearing the Z1 and Z2 groups), CH2OR5’, CH2, NRa (wherein Ra = alkyl, cycloalkyl, heteroalkyl), or Y could be chosen as a preferred linker as a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl; and, Z1, Z2= H, F, (C1-4)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C2-7)cycloalkyl or independently chosen from one of these groups; wherein the preferred groups are:M = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and N.In some preferred embodiments, R1 of any formula of this disclosure (preferably anyof Formulas I, I-a, I-a1, I-a2, I-a3, I-a4, I-a5, I-a6, I-b1, I-b2, I-b3, I-b4, I-b5, I-b6, II, Ia, II-a1,II-a2, II-a3, II-a4, II-a5, II-a6, II-b1, II-b2, II-b3, II-b4, II-b5, and II-b6) can be selected from thegroups shown in Table 1 below:Table 1 Exemplary Preferred R1 compound number(s)) In some preferred embodiments, the group present at the Y position (i.e,. connected to thecarbon (C) that is connected to Z1Z2YR5 where, as indicated above, Y per se can be absent)can be selected from the groups shown in Table 2. In some embodiments, the group present at the Y position can be connected to that carbon through a nitrogen contained within a heterocyclic group (as shown below) or an oxygen (see, e.g., compounds 41, 46, 47, 54, 61,68). In some preferred embodiments, these preferred R1 and Y groups of Tables 1 and 2can be combined in the same compound of any of the formulas disclosed herein (preferably any of Formulas I, I-a, I-a1, I-a2, I-a3, I-a4, I-a5, I-a6, I-b1, I-b2, I-b3, I-b4, I-b5, I-b6, II, II-a, II-a1, II-a2, II-a3, II-a4, II-a5, II-a6, II-b1, II-b2, II-b3, II-b4, II-b5, and II-b6). Table 2 (exemplary compound number) ; Exemplary preferred compounds of the formulas of this disclosure including but not limited to Formulas I, II, II-a, and / or II-b and also being comprised within the subformulas which are included in the main Formulas (preferably any of Formulas I-a, I-a1, I-a2, I-a3, I- a4, I-a5, I-a6, I-b1, I-b2, I-b3, I-b4, I-b5, I-b6, II-a, II-a1, II-a2, II-a3, II-a4, II-a5, II-a6, II-b1, II- b2, II-b3, II-b4, II-b5, and II-b6), and in the exemplary preferred embodiments as shown in Table 3 below. Exemplary, preferred compounds of this disclosure are presented below as Examples 1-138. These compounds are shown in the Examples section of this disclosure and shown below. To the extent any of the Example number and / or structure of the compounds shown in this Table 3 contradict those presented in the working Examples section (Table 4), the numbering and / or structure presented in Table 4 controls. Table 3 Compound Structure Compound Structure Number Number 75 F NNN N N N N 8FFNN4 N NNNN O N N F 92 O N N N 99 Cl O NFFN N N Cl F FN 105 N N N N N ONNN N 113 Cl N N N N NNNN O N 121 N N N N N O NNN 128 N N N N N N N N N O N N 67 13ON 6 N N N N N N N Any embodiment given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, unless otherwise indicated. Isotopically labeled compounds have structures depicted by the Formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,11C,13C,14C,15N,18F,31P,32P,35S,36Cl,125I, respectively. The various herein, for example those into which radioactive isotopes, such as3H,13C, and14C, are present. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography or single- photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or labeled compound may be particularly preferred for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45,11-30. The disclosure also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726. Furthermore, multiple substituents on a piperidinyl or pyrrolidinyl ring can also be in either cis or trans relationship to each other with respect to the plane of the piperidinyl or the pyrrolidinyl ring. Such forms or geometric isomers, although not explicitly indicated in the Formulae described herein, are intended to be included within the scope of the present disclosure. With respect to the methods and compositions of the present disclosure, reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically. Pharmaceutically acceptable salts is used herein to refer to an agent or a compound according to the disclosure that is a therapeutically active, non- toxic base and acid salt form of the compounds. The acid addition salt form of a compound that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p- aminosalicylic, pamoic and the like (see, e.g., WO 01 / 062726, U.S. Pat. No. 8,492,416 B2, US 2017 / 0022208 A1, and US 2017 / 0253603 A2). Compounds containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt form, e.g., metal or amine salts, by treatment with appropriate organic and inorganic bases. Appropriate base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, e.g., lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, said salt forms can be converted into the free forms by treatment with an appropriate base or acid. Compounds and their salts can be in the form of a solvate, which is included within the scope of the present disclosure. Such solvates include for example hydrates, alcoholates and the like. Throughout this dislcosure, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components). The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise. The term “including” is used to mean “including but not limited to “Including” and “including but not limited to” are used interchangeably. The term “Substance Addiction” or “Substance Addiction Disorder” (SUD) can include addiction to a number of either stimulants (for example: including but not limited to cocaine, methamphetamines, nicotine, etc.) or depressants (for example: including but not limited to opioids, alcohol, etc.). The term “agent” is used herein to denote a chemical compound (such as an organic or a mixture of chemical compounds). Agents include, for example, agents that are known with respect to structure, and their orexin and / or kappa-opioid antagonist / modulators activities of such agents may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure. Where the term “=” is used to describe a subsitituent (e.g., R1), it is understood meant to indicate “is selected from the group consisting of”. Where the term “=” used with reference to multiple possible substituents, it should be understood to each of such possible substituents can be independently selected from the groups listed thereafter (e.g., “Z1, Z2 =” is meant to indicate “Z1 and Z2 are independently selected from the group consisting of” the groups listed). The term "aryl" as used herein means a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is a non-limiting (unless otherwise indicated) example of a monocyclic aromatic or aryl ring system. The term "heteroaryl" as used herein means a monocyclic or bicyclic aromatic or aryl ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement. In such a bicyclic aromatic or aryl ring system embodiment of "heteroaryl": both rings may be aromatic or aryl; and one or both rings may contain said heteroatom or heteroatom groups. Examples of heteroaryl rings include 2- furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3- pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2- triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g., 2- indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3- quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1- isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). The term "cycloalkyl or cycloalkenyl" refers to a monocyclic or fused or (C1-3)alkyl bridged bicyclic carbocyclic ring system that is not aromatic or aryl. Cycloalkenyl rings have one or more units of unsaturation. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantly and decalinyl. The compounds of the present disclosure also include prodrugs, analogs or derivatives. The term "prodrug" is a recognized art in the field and is intended to encompass compounds or agents which, under physiological conditions, are converted into orexin and kappa-opioid antagonists. A common method for making a prodrug is to select moieties which are hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal to an orexin and / or kappa-opioid antagonist (i.e., as an antagonist and / or modulator thereof). The present disclosure also includes isotopically labelled, especially2H (deuterium) labelled compounds of all Formulas, which compounds are identical to the compounds of any of the Formulas described herein except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. lsotopically labelled, especially2H (deuterium) labelled compounds of all Formulas and salts thereof are within the scope of the present disclosure. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In another aspects of embodiment of the disclosure, the compounds of all Formulas are not isotopically labelled. However, isotopically labelled compounds of all Formula could be prepared by anyone skilled in the art in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials. In some embodiments, this disclosure provides a composition comprising any one or more of such a compound, and / or pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. The disclosure further provides pharmaceutical compositions comprising one or more compounds of the disclosure together with a pharmaceutically acceptable carrier or excipient. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and at least one pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. In some embodiments, this disclosure provides a therapeutically effective amount of such a compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, this disclosure provides such a pharmaceutical composition further comprises at least one second therapeutic agent. The disclosure also provides pharmaceutical compositions comprising one or more compounds of this disclosure (or the like, such as a pharmaceutically acceptable salt thereof) (i.e., as an active agent, as a therapeutic agent), and one or more pharmaceutically acceptable carriers or excipients. A pharmaceutical composition contains a therapeutically effective amount of one or more of such compounds or the like (i.e., active agent(s)), or an appropriate fraction thereof. A composition can optionally contain an additional active agent. In some embodiments, a peptide product is at least about 90%, 95% or 98% pure. Pharmaceutically acceptable excipients and carriers include pharmaceutically acceptable substances, materials and vehicles. Non-limiting examples of types of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, absorption-delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweetening agents, flavoring agents, coloring agents, encapsulating materials and coating materials. The use of such excipients in pharmaceutical Formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e.g., vegetable oils such as olive oil and sesame oil), aqueous solvents (e.g., saline, buffered saline (e.g., phosphate-buffered saline [PBS]) and isotonic solutions (e.g., Ringer’s solution), and organic solvents (e.g., dimethyl sulfoxide and alcohols (e.g., ethanol, glycerol and propylene glycol)). Except insofar as any conventional excipient or carrier is incompatible with a peptide product, the disclosure encompasses the use of conventional excipients and carriers in Formulations containing a peptide product. See, e.g., Remington: The Science and Practice of Pharmacy, 2lst Ed., Lippincott Williams and Wilkins (Philadelphia, Pennsylvania) (2005); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et ah, Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Pre-Formulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida) (2004). The appropriateness of a particular Formulation can depend on various factors, such as the route of administration chosen. Potential routes of administration of a pharmaceutical composition comprising the compounds or the like disclosed herein can include, without limitation oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intra-arterial, intraperitoneal, intracavitary and topical), topical (including transdermal, transmucosal, intranasal (e.g., by nasal spray or drop), ocular (e.g., by eye drop), pulmonary (e.g., by oral or nasal inhalation), buccal, sublingual, rectal (e.g., by suppository), vaginal (e.g., by suppository), and / or other suitable route as would be known to those of ordinary skill in the art. In some embodiments, the compounds and compositions of this disclosure can be used as orexin receptor and / or -opioid receptor (or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, which is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene) antagonists and / or modulators. In preferred embodiments, the compounds and / or compositions disclosed herein can be antagonists for one or more orexin receptor antagonists, such as either one of OX1R or OX2R, or both OX1R or OX2R; and antagonists and / or modulators of KOR. The compounds and / or compositions disclosed herein can be selectively more antagonistic for one or more orexin receptor as compared to another orexin receptor, such as in being more or less antagonistic of OX1R or OX2R as compared to the other orexin receptor. Thus, the compounds and / or compositions of the same can be referred to herein as “Orexin Receptor Antagonists”. In some embodiments, the compounds may be antagonists and / or modulators of the -opioid receptor. In some embodiments, the compounds and / or compositions of this disclosure may be antagonists of one or more types of orexin receptors (i.e., Orexin Receptor Antagonist; i.e., for either or both of OX1R and / or OX2R) but not a KOR. In some preferred embodiments, for instance, one or more compounds of this disclosure, and / or a combination thereof, designed and preferred to provide the following characteristics as measured using standard in vitro cellular assays (e.g., those described in the Examples herein), for effective therapeutic efficacy: 1) OX1R Kb < 1000 nM, OX2R Kb > 500 nM, and KOR Ki < 1000 nM (OX2R + KOR; see, e.g., Examples 1, 2, 25, 79, 83, 89, 94 and 136); 2) OX1R Kb < 1000 nM, OX2R Kb < 1000 nM, and KOR Ki < 1000 nM (OX1R, OX2R and KOR; see, e.g., Examples 10, 27, 28, 80, 81, 97, 106, 111, and 113); 3) OX1R Kb < 1000 nM, OX2R Kb < 1000 nM, and KOR Ki > 1000 nM (OX1R and OX2R only; see, e.g., Examples 3, 9, 16, 22, 37, 39 and 76); 4) OX1R Kb < 1000 nM, OX2R Kb > 1000 nM, and KOR Ki > 1000 nM (OX1R only; see, e.g., Examples 13, 14, 19, 33, 38, 40, 41, 42, 43); 5) OX1R Kb > 1000 nM, OX2R Kb < 1000 nM, and KOR Ki < 1000 nM (OX2R and KOR, see, e.g., Examples 23, 105, and 106); and, 6) OX1R Kb > 1000 nM, OX2R Kb > 1000 nM, and KOR Ki < 1000 nM (KOR only, see, e.g., Examples 30, 31, and 90). In some embodiments, this disclosure provides methods of preventing or treating a condition associated with an orexin receptor (i.e., as an Orexin Receptor Antagonist) and / or one or more -opioid receptors. For in vivo assays, the compounds and / or compositions of this disclosure may be tested using an animal model such as the rat by measuring primary dependent measures (e.g., such as but not limited to the time to obtain first drug injection, total drug injections taken, rate of drug intake, and total inactive lever presses), the progressive ratio (e.g., such as but not limited to time to obtain first drug injection, breakpoints, final ratio completed, and total active and inactive lever presses), and reinstatement (e.g., such as but not limited to time to first lever press as well as total active and inactive lever presses). These tests and in-vivo assessments are designed, planned and expected to demonstrate disclosures of compounds therapeutic utility and in vivo efficacy – towards attenuation of intake and motivation towards illicit drugs of abuse using techniques known to those of ordinary skill in the art (e.g., Brain Research 1731 (2020), edited by James, et al. (see, e.g., Brodnik, et al. Article 145894);Gentile, et al. Addict Biol 2018, 23(1):247-255; Brodnik, et al. Behav Brain Res. 2015 September 15; 291: 377–384, doi:10.1016 / j.bbr.2015.05.051). Other testing methods may also be suitable as would be understood by those of ordinary skill in the art. In some embodiments, this disclosure provides methods of preventing or treating a condition selected from the group consisting of a central nervous system (CNS) disorder, substance addiction, dependence, panic, anxiety, depression, posttraumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer disease (AD) in a subject in need thereof, by administering to the subject any of such one or more compounds and / or composition comprising one or more of such compounds, or pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the methods can include administering a composition comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the composition comprises a pharmaceutically acceptable salt or isotope of such a compound. In some embodiments, the composition can comprise an unlabeled form of the compound or an isotopically labeled form of the compound in which the compound has a structure depicted by the Formula wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number. In some embodiments, this disclosure provides for the use of a compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, disclosed herein in the preparation of a medicament for preventing and / or treating a condition selected from the group consisting of a central nervous system (CNS) disorder, substance addiction, dependence, panic, anxiety, depression, posttraumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer disease (AD) in a subject in need thereof. Substance addiction, for instance, can include addiction of a person to one or more of an opioids (e.g., such as but not limited to heroin, morphine, oxycodone (e.g., OxyContin, Percocet), fentanyl, and / or hydrocodone (e.g., Vicodin)), one or more stimulants (e.g., amphetamine (e.g., Adderall, Ritalin), cocaine, crack cocaine, methamphetamine, one or more sedatives and / or tranquilizers (e.g., such as but not limited to benzodiazepines (e.g., Valium, Xanax, Klonopin) or barbituates (e.g., Nembutal, Luminal, phenobarbital), or other addictive substance(s) as may be known to those of ordinary skill in the art. In some embodiments, the use can include a composition comprises a therapeutically effective amount of the compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, such use can comprise a composition a pharmaceutically acceptable salt or isotope of the compound. In some embodiments, such use can comprise a composition comprises an unlabeled form of the compound or an isotopically labeled form of the compound in which the compound has a structure depicted by the Formula wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number. This disclosure also provides intermediates of the compounds disclosed herein as well as methods for preparing the same. In some embodiments, such methods for preparing can include using any of the intermediates disclosed herein. Other embodiments are also contemplated here as would be understood by those of ordinary skill in the art. The term “therapeutically effective amount” refers to an amount of a compound that, when administered to a subject, is sufficient to prevent, reduce the risk of developing, delay the onset of, slow the progression of or cause regression of the medical condition being treated, or to alleviate to some extent the medical condition or one or more symptoms or complications of that condition, at least in some fraction of the subjects taking that compound. The term “therapeutically effective amount” also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, organ or human which is sought by a medical doctor or clinician. The terms “treat,” “treating” and “treatment” include alleviating, ameliorating, inhibiting the progress of, reversing or abrogating a medical condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating or eradicating one or more causes of the condition. Reference to “treatment” of a medical condition includes prevention of the condition. The terms “prevent”, “preventing” and “prevention” include precluding, reducing the risk of developing and delaying the onset of a medical condition or one or more symptoms or complications associated with the condition. The term “medical conditions” (or “conditions” for brevity) includes diseases and disorders. The terms “diseases” and “disorders” are used interchangeably herein. Throughout this disclosure the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components). The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise. The symbol “=” when used in describing a Formula means “is”. The term “including” is used to mean “including but not limited to “Including” and “including but not limited to” are used interchangeably. The term “agent” is used herein to denote a chemical compound (such as an organic or a mixture of chemical compounds). Agents include, for example, agents that are known with respect to structure, and their orexin antagonist activities of such agents may render them suitable as “therapeutic agents” in the methods and compositions disclosed herein. In addition, those of ordinary skill in the art recognize that it is common to use the following abbreviations: Me: methyl Et: ethyl t-Bu: tert-butyl Ar: aryl Ph: phenyl BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Bn: benzyl Ac: acetyl Boc: tert-butyloxy carbonyl BSA: bovine serum albumin CbzCl: benzylchloroformate CDI: carbonyl diimidazole DCM: dichloromethane DCE: dichloroethane DEAD: diethylazodicarboxylate DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide CH2Cl2: dichloromethane EDC: N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide Et3N: triethylamine EtOAc: ethyl acetate EtOH: ethanol HCl: hydrogen chloride HOAt: 1-hydroxy-7-aza-10-benzotriazole HOBT: hydroxybenzotriazole hydrate LCMS: Liquid Chromatography Mass Spectrometry HPLC: High Performance Liquid Chromatography Hunig's base: N,N-diisopropylethylamine MeOH: methanol MgS04: magnesium sulfate MTBE: methyl tert-butyl ether NaHCO3: sodium bicarbonate Na2CO3: sodium carbonate K2CO3: potassium carbonate NaOH: sodium hydroxide NMM: N-methylmorpholine Pt02: Platinum oxide Pd: Palladium Pd / C: Palladium over carbon PyClu: 1-(chloro-1 pyrrolidinylmethylene)pyrrolidiniumhexafluorophosphate RT or rt: room temperature SOCl2: thionyl chloride THF: tetrahydrofuran TFA: trifluoroacetic acid X-Phos: 2-(dicyclohexyl-phosphino)-2',4',6'-triisopropylbiphenyl HATU: (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate NMR: Nuclear Magnetic Resonance ESI: Electrospray Ionization MS: Mass spectrometry reaction Thus, in some embodiments, this disclosure provides compounds of the Formulas shown below, compositions comprising the same, methods for making (e.g., as in the Examples section) and using the same (e.g., to treat disease conditions): R4R9R8R2R10X R7Z1' , , R4R9R8R2GMR10X R7Z1Z2R5 R10XR8Z1R10 XR8Z1R10 XR8Z1Z2Z2Z2R5' or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein, if present: R1 includes E as Carbon (C) but not Nitrogen (N), and in Formula I E is linked to J or D with a double bond or in Formula II E is linked to A or D with a double bond, and R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl that is optionally a 5- or 6 membered heteroaryl, substituted aromatic or aryl, and, substituted heteroaryl that is optionally a 5- or 6-membered heteroaryl; wherein if R1 is heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl (see, e.g., the preferred embodiments shown in Table 1); R2, R3, and R4are independently selected from the group consisting of H, alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and halogen that is optionally F, Cl, or Br; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4; R5is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R5replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is as defined herein; R5’ is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally comprising a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and (C3-7)heterocycloalkyl; R6is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R6 connected to either R10 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R8 connected to either R10, R11 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R9 connected to either R6 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X is selected from the group consisting of absent (to provide five membered pyrrolidine ring), CH2, O, and CRaRb where Ra and Rb are selected from the group consisting of alkyl, cycloalkyl, and fluoroalkyl; and wherein: the carbon atom at position 2 of the piperidine or pyrrolidine is optionally in absolute (S)- configuration; or, the carbon atom at position 2 of the of the morpholine ring wherein X is oxygen and optionally in absolute (R)-configuration; Y is absent such that R5’ is attached directly to the carbon bearing the Z1and Z2groups, or selected from the group consisting of O; NH; CH2OR5’; CH2; NRawherein Rais selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; and a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl (see, e.g., the preferred embodiments shown in Table 2); and, Z1 and Z2 are independently selected from the group consisting of H, F, (C1-4)alkyl, (C1- 3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C2-7)cycloalkyl; and wherein: fused or unfused ring system A-B-J-D-E is a five-membered heteroaryl optionally imidazole wherein A and J are Nitrogen while B, E, D are Carbon; pyrazole wherein A and B are Nitrogen while D, E, and J are Carbon; optionally fused or unfused with one or more additional ring systems; the fused ring system B-J-M-G-K-L is an arrangement of these outlined variables to provide groups consisting of a 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5 or 6-membered cycloalkyl, and 5 or 6-membered heterocycloalkyl; and wherein, optionally: A is Nitrogen, optionally an Imidazole or Pyrazole; B is Carbon or Nitrogen; J is Carbon or Nitrogen; D is Carbon; E is Carbon, wherein R1 is as defined above; M is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; G is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; K is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; and, L is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In preferred embodiments, the intermediates, reaction conditions and the like used to produce the compounds are described in detail in the Examples section, which is not reproduced in detail here but will be understood by those of skill in the art therefrom as if the same was reproduced in describing this preferred aspect (i.e., incorporated herein). This disclosure also provides methods for manufacturing a pharmaceutical composition comprising combining at least one compound of this disclosure with at least one pharmaceutically acceptable excipient. Methods for making such combinations (i.e., at least one compound or the like and at least one pharmaceutical composition) are generally known in the art and are therefore not described in detail within this aspect, but are incorporated herein. Thus, this disclosure, in preferred embodiments, provides a compound of any of Examples 1-138 (see Tables 3 and 4), and / or a combination thereof, and / or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the compound is unlabeled or isotopically. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound disclosed herein, and / or a combination thereof, and / or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and at least one pharmaceutically acceptable carrier, adjuvant and / or vehicle. In preferred embodiments, the pharmaceutical composition comprieses a therapeutically effective amount of the compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, and / or combination thereof. In some embodiments, the composition further comprises at least one second therapeutic agent. In some preferred embodiments, this disclosure provides methods for antagonizing and / or modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a cell, comprising the step of exposing the cell to a compound and / or composition of this disclosure, optionally wherein said method is in vitro. In some preferred embodiments, the methods for modulating at least one orexin receptor and / or at least one kappa- opioid receptor in a subject in need thereof, comprising the step of administering to the subject a compound and / or composition of this disclosure. In some preferred embodiments, the method of treating a condition is selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, posttraumatic stress disorders (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer diseases (AD), a central nervous system (CNS) disorder, and cancer in a subject in need thereof, comprising the step of administering to the subject a compound and / or composition of this disclosure. In some preferred embodiments, the substance corresponding to the substance addiction or substance dependence is selected from the group consisting of one or more opioids, optionally heroin, morphine, oxycodone, fentanyl, and hydrocodone; one or more stimulants optionally selected from the group consisting of amphetamine, cocaine, crack cocaine, and methamphetamine; one or more sedatives and / or tranquilizers, benzodiazepine, and barbituates. In some embodiments, the compound antagonize at least one orexin receptor and / or antagonize or modulate at least one kappa-opioid receptor. In preferred embodiments, the compound antagonizes one or more orexin receptor(s) and / or kappa-opioid receptor wherein the combination or receptor is selected from the group consisting of orexin receptor OX1R and KOR; orexin receptor OX1R, orexin receptor OX2R and KOR; orexin receptor OX1R and orexin receptor OX2R only; orexin receptor OX1R; orexin receptor OX2R and KOR; and, KOR. In some preferred embodiments, this disclosure provides methods for manufacturing a compound or composition of any preceding claim using at least one applicable combination of acid intermediates, amine intermediates, and methods presented herein or as may be otherwise available to those of ordinary skill in the art. In some preferred embodiments, this disclosure provides novel intermediates that can be used to produce the compounds disclosed herein (preferably any of compounds 1-138). In some preferred embodiments, the intermediate is a carboxylic acid-containing intermediate can be selected from the group consisting of:

[0013] can be selected from the group consisting of: Certain of these carboxylic acid-containing intermediates and certain of these secondary amine- containing intermediates can be combined to produce the compounds of this disclosure as shownin the Examples herein (see, e.g., Section I thereof). Other combinations of intermediates canalso be utilized as would be understood by those of ordinary skill in the art.All references cited within this disclosure are hereby incorporated by reference in theirentirety. Certain embodiments are further described in the following examples. These embodiments are provided as examples only and are not intended to limit the scope of the claims in any way. EXAMPLES The following intermediates have prepared and can be used to synthesize compoundsencompassed by the formulas disclosed herein:1. Carboxylic Containing Intermediates prepared – Carboxylic Acids Group 2. Secondary Amine Containing Intermediates prepared – Amine Group

[0014] I. General Synthetic Methods and Procedures That Can Be Used to PrepareCompounds Encompassed by the Formulas Disclosed Herein General: All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen. Compounds were purified by flash column chromatography on silica gel or bypreparative HPLC. Compounds described inthe disclosure are characterized by LC-MS data (retention time tR is given in min; molecularweight obtained from the mass spectrum is given in g / mol) using the conditions listed below. LC-MS under acidic conditions Method A: Agilent 1100 series with mass spectrometry detection (MS: Agilent single quadrupole). Column: Zorbax SB (3.5 µm, 4.6 x 150 mm). Conditions: MeCN (0.1% FA) [gradient eluent A]; water (0.1% FA) [gradient eluent B]. Gradient: 95% B + 5% B over 5 min (flow: 0.8 ml / min). Detection: UV 280 / 254 nm + MS. Method B: Agilent 1100 series with mass spectrometry detection (MS: Agilent single quadrupole). Column: X-Bridge C18 (3.5 µm, 4.6 x 150 mm). Conditions: MeCN (0.1% FA) [gradient eluent A]; water (0.1% FA) [gradient eluent B]. Gradient: 95% B + 5% B over 5 min (flow: 0.8 ml / min). Detection: UV 280 / 254 nm + MS. In general, the compounds of this disclosure may be prepared by methods known to those skilled in the art and contemporary technologies in the field. Schemes 1-4 below illustrate synthetic routes to the compounds of the present disclosure. Other equivalent schemes, which will be readily apparent to the ordinary skilled synthetic organic or medicinal chemist may alternatively be used to synthesize various portions of the molecules as illustrated by the general schemes described herein. 3. Example of Synthesis of Carboxylic Containing Intermediates – Carboxylic Acids Group Cl N N Cl Step g, 2.31 mmol) was dissolved in Acetone (10.0 mL). The K2CO3(0.96 g, 6.9 mmol) was added, followed by 1-Bromo-2-Chloro-ethane (0.1 mL, 11.6 mmol). The rxn mixture was heated at 55oC for 16 h. LCMS data shows desired product formation m / z 279.0 and minor amount of side product formation. The rxn mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 0.6 g of liquid product was isolated (Yield 93.2 %). MS (ESI) mass calcd. for C14H15ClN2O2, 278.7; m / z found 279.0 [M+H]+. Step 2: Synthesis of HBS-037-040: Compound HBS-037-036 (0.55 g, 1.97 mmol) was dissolved in Dry THF (6.0 mL). The DIBAL (12.0 mL, 1.0 M solution, 11.8 mmol) was added, under ice cooling bath. The rxn mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data shows desired product formation m / z 237.0. The rxn mixture was quenched with 1.0 N aq. NaOH solution and diluted with ethyl acetate (10.0 mL). The rxn mixture was filtered through celite bed and washed with ethyl acetate (10.0 mL x 3). The EtOAc layer was separated and washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product 0.4 g (Yield 85.6 %). MS (ESI) mass calcd. for C12H13ClN2O, 236.7; m / z found 237.0 [M+H]+. Step 3: Synthesis of HBS-037-042: Compound HBS-037-040 (0.47 g, 1.97 mmol) was dissolved in Dry DMF (12.0 mL). The NaH (0.12 g, 2.96 mmol) was added under ice cooling. The rxn mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data shows desired product formation m / z 201.1. The rxn mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 0.26 g of solid product was obtained (Yield 65.3 %). MS (ESI) mass calcd. for C12H12N2O, 200.2; m / z found 201.1 [M+H]+. Step 4: Synthesis of HBS-037-043: Compound HBS-037-042 (0.25 g, 1.25 mmol) was dissolved in DCM (5.0 mL). The NBS (0.24 g, 1.37 mmol) was added, and rxn mixture was stirred at room temperature for 16 h. LCMS data shows desired product formation m / z 280.9. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 0.29 g of liquid product was obtained (Yield 81.7 %). MS (ESI) mass calcd. for C12H11BrN2O, 279.1; m / z found 280.9 [M+H]+. Step 5: Synthesis of HBS-037-054: Compound HBS-037-043 (0.025 g, 0.09 mmol) was dissolved in anhydrous THF (1.0 mL) under N2atm. The reaction mixture was cooled at -78.0oC temperature and n-BuLi (0.12 mL, 1.6 M) was added into the rxn mixture. The rxn mixture was stirred at -78.0oC temperature for 30.0 min. The dry CO2gas bubbled through the rxn mixture at -65oC and the rxn mixture was gradually warmed at room temperature. The LCMS data shows desired product formation m / z 245, debrominated side product (m / z 201) and some unknown product formation. The rxn mixture was quenched by water and extracted with ethyl acetate. The ethyl acetate layer was separated and debrominated product was recovered. The aq. Layer was acidified with 1 M HCl solution and evaporated to dryness to obtain 0.022 g of solid product. MS (ESI) mass calcd. for C13H12N2O3, 244.3; m / z found 245.0 [M+H]+,1H NMR (400 MHz,CHLOROFORM-d - 4.15 (m, 2 H) 4.16 - 4.25 (m, 2 H) 5.03 - 5.10 (s, 2 H) 7.32 - 7.40(m, 3 H) 7.60 - 7.69 (m, 2 H) OO O OACNN 1.0 N NaOH N NBS O+OOHO in DMSO (5.0 mL). The NBS (0.51 g, 2.86 mmol) was added and rxn mixture was stirred at ambient temperature for 24 h. LCMS shows product formation m / z 270.9. The rxn mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl actetate layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.42 g of product was obtained (Yield 59.7 %). MS (ESI) mass calcd. for C11H11BrO3, 271.1; m / z found 270.9 [M+H]+. Step 2: Synthesis of HBS-037-192: Compound HBS-037-191 (0.42 g, 1.55 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). The 2-amino-pyridine (0.15 g, 1.55 mmol) was added and rxn mixture was stirred at 80oC for 1 h. LCMS shows product formation m / z 267.1. The rxn mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.24 g of product was obtained (Yield 58.0 %). MS (ESI) mass calcd. for C16H14N2O2, 266.3; m / z found 267.1 [M+H]+. Step 3: Synthesis of HBS-037-193: Compound HBS-037-192 (0.24 g, 0.9 mmol) was dissolved in MeOH (5.0 mL). The 1.0 N aq. NaOH solution (4.51 mL, 4.51 mmol) was added and rxn mixture was stirred at 60oC temperature for 3 h. LCMS shows product formation m / z 239. The rxn mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (10.0 mL x 3) to obtain 0.2 g of solid product. MS (ESI) mass calcd. for C14H10N2O2, 238.2; m / z found 239.1 [M+H]+,1H NMR (400 MHz, CHLOROFORM-d J=6.93 Hz, 1 H) 7.33 - 7.48 (m, 4 H) 7.70 -7.78 (m, 3 H) 9.41 (d, J=7.04 Hz, 1 H). N 1.0 N NaOH N O Step 1: Synthesis of HBS-037-163: 2-Phenyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (0.2 g, 0.75 mmol) was dissolved in MeOH (6.0 mL). The 1.0 N aq. NaOH solution (3.8 mL, 3.8 mmol) was added and rxn mixture was stirred at 60 oC temperature for 24 h. LCMS shows product formation m / z 239.1. The rxn mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 1.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (10.0 mL x 3) to obtain 0.18 g of solid product. MS (ESI) mass calcd. for C14H10N2O2, 238.2; m / z found 239.1 [M+H]+, 1H NMR (400 MHz, CHLOROFORM- d) ppm 6.90 - 7.03 (m, 1 H) 7.27 - 7.47 (m, 4 H) 7.75 – 7.78 (ddd, J=4.86, 3.21, 1.54 Hz, 2 H) 8.18 - 8.28 (dd, J=8.99, 0.70 Hz, 1 H) 8.49 – 8.56 (dd, J=6.90, 0.73 Hz, 1 H). HOBOH g, 6.17 mmol) was dissolved in ethanol (20.0 mL). The catalytic amount of conc. sulfuric acid (0.5 mL) was added and rxn mixture was refluxed for 16 h. The LCMS data shows product formation m / z 191.1. The rxn mixture was concentrated under reduced pressure and neutralized with saturate aq. solution of sodium bicarbonate. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave product. The 1.2 g of product was obtained (Yield Quant.) MS (ESI) mass calcd. for C10H10N2O2, 190.2; m / z found 191.1 [M+H]+. Step 2: Synthesis of HBS-039-014: The HBS-039-013 (1.17 g, 6.17 mmol) was dissolved in DCM (25.0 mL). The NBS (1.1 g, 6.17 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 271.0. The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.5 g of product was obtained (Yield 90.4 %). MS (ESI) mass calcd. for C10H9BrN2O2, 269.1; m / z found 271.0 [M+H]+. Step 3: Synthesis of HBS-039-015: The HBS-039-014 (0.2 g, 0.74 mmol) was dissolved in mixture of Dioxane / water (8.0:2.0 v / v mL). The phenylboronic acid (0.11 g, 0.89 mmol) and K2CO3 (0.3 g, 2.23 mmol) were added followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.07 mmol). The rxn mixture was stirred at 80oC temperature under N2 atm. for 5 h. The LCMS data shows product formation m / z 267. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.2 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C16H14N2O2, 266.3; m / z found 267.1 [M+H]+. Step 4: Synthesis of HBS-039-018: HBS-039-015 (0.2 g, 0.74 mmol) was dissolved in MeOH (6.0 mL). The 1.0 N aq. solution of NaOH (3.7 mL, 3.7 mmol) was added and rxn mixture was stirred at 60oC temperature for 16 h. The LCMS data shows product formation m / z 239.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 1.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.16 g of solid product (Yield 92.6 %). MS (ESI) mass calcd. for C14H10N2O2, 238.2; m / z found 239.1 [M+H]+. BHO OHPd(dppf)Cl N N O r N BDCM , K CO ,O N N O OH mmol) was dissolved in DCM (20.0 mL). The NBS (1.0 g, 5.78 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 271.0. The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.4 g of product was obtained (Yield 98.9 %). MS (ESI) mass calcd. for C10H9BrN2O2, 269.1; m / z found 271.0 [M+H]+. Step 2: Synthesis of HBS-039-017: Compound HBS-039-016 (0.2 g, 0.74 mmol) was dissolved in mixture of Dioxane / water (8.0:2.0 v / v mL). The phenylboronic acid (0.11 g, 0.89 mmol) and K2CO3 (0.3 g, 2.23 mmol) were added followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.07 mmol). The rxn mixture was stirred at 80oC temperature under N2 atm. for 5 h. The LCMS data shows product formation m / z 267.1. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.2 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C16H14N2O2, 266.3; m / z found 267.1 [M+H]+. Step 3: Synthesis of HBS-039-019: Compound HBS-039-017 (0.2 g, 0.74 mmol) was dissolved in MeOH (6.0 mL). The 1.0 N aq. solution of NaOH (3.7 mL, 3.7 mmol) was added and rxn mixture was stirred at 60oC temperature for 16 h. The LCMS data shows product formation m / z 239.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 1.0 M HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.11 g of solid product (Yield 62.1 %). MS (ESI) mass calcd. for C14H10N2O2, 238.2; m / z found 239.1 [M+H]+. N N N Step 1: dissolved in DCM (20.0 mL). The NBS (3.1 g, 17.17 mmol) was added and rxn mixture was stirred at 35oC temperature for 48 h. LCMS shows product formation m / z 272.0. The rxn mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl actetate layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 3.75 g of product was obtained (Yield 88.6 %). MS (ESI) mass calcd. for C11H11BrO3, 271.1; m / z found 272.0 [M+H]+. Step 2: Synthesis of HBS-039-135: Compound HBS-039-130 (0.25 g, 0.92 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). The pyrazine-2-amine (0.088 g, 0.92 mmol) was added and rxn mixture was stirred at 80oC for 24 h. LCMS shows product formation m / z 268.1. The rxn mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.13 g of product was obtained (Yield 51.5 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.1 [M+H]+. Step 3: Synthesis of HBS-039-139: Compound HBS-039-135 (0.12 g, 0.45 mmol) was dissolved in MeOH (2.5 mL). The 1.0 N aq. NaOH solution (2.24 mL, 2.24 mmol) was added and rxn mixture was stirred at 60oC temperature for 3 h. LCMS shows product formation m / z 240.0. The rxn mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (1.0 mL x 3) to obtain 0.11 g of solid product. MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.0 [M+H]+. O O O NH O % Step 1: was dissolved in anhydrous THF (5.0 mL). The n-BuLi (5.2 mL, 8.32 mmol) was added at -78oC temperature and rxn mixture was stirred at -78oC temperature for 1 h. The ethyl chloroformate (1.59 mL, 16.7 mmol) was added at -78oC temperature and rxn mixture was gradually warmed to ambient temperature. The LCMS data shows product formation m / z 193.0. The rxn mixture was diluted with aq. NH4Cl solution and product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The 0.8 g of crude product was obtained (Yield Quant.). MS (ESI) mass calcd. for C11H9FO2, 192.19; m / z found 193.0 [M+H]+. Step 2: Synthesis of HBS-039-148: Compound HBS-039-147 (0.4 g, 2.08 mmol) and 1- Aminopyridinium iodide (0.46 g, 2.08 mmol) were dissolved in anhydrous DMF (5.0 mL). The anhydrous K2CO3(0.72 g, 5.2 mmol) was added, and reaction mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 285.1. The reaction mixture was diluted with water and ppts were filtered. The drying of ppts gave crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.4 g of product was obtained (Yield 67.6 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.1 [M+H]+. Step 3: Synthesis of HBS-039-150: Compound HBS-039-148 (0.4 g, 1.41 mmol) was dissolved in MeOH (7.0 mL). The 1.0 N aq. NaOH solution (7.0 mL, 7.0 mmol) was added, and reaction mixture was refluxed for 8 h. LCMS shows product formation m / z 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.35 g of solid product (Yield 97.5 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. O NH N O Cl I O O O OH % Step 1: was dissolved in anhydrous THF (10.0 mL). The n-BuLi (10.4 mL, 16.65 mmol) was added at -78oC temperature and rxn mixture was stirred at -78oC temperature for 1 h. The ethyl chloroformate (3.8 mL, 40.0 mmol) was added at -78oC temperature and rxn mixture was gradually warmed to ambient temperature. The LCMS data shows product formation m / z 193.0. The rxn mixture was diluted with aq. NH4Cl solution and product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The 1.6 g of crude product was obtained (Yield Quant.). MS (ESI) mass calcd. for C11H9FO2, 192.19; m / z found 193.0 [M+H]+. Step 2: Synthesis of HBS-039-189: Compound HBS-039-188 (1.6 g, 8.33 mmol) and 1- Aminopyridinium iodide (1.85 g, 8.33 mmol) were dissolved in anhydrous DMF (15.0 mL). The anhydrous K2CO3(2.88 g, 20.81 mmol) was added, and reaction mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 285.1. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 1.56 g of product was obtained (Yield 66.0 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.1 [M+H]+. Step 3: Synthesis of HBS-039-192: 189 (1.56 g, 5.5 mmol) was dissolved in MeOH (10.0 mL). The 1.0 N aq. NaOH solution (16.5 mL, 16.5 mmol) was added, and reaction mixture was refluxed for 12 h. LCMS shows product formation m / z 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 1.3 g of solid product (Yield 92.3 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. F F F OO O O+ N NH % Step dissolved in DCM (20.0 mL). The NBS (1.8 g, 11.1 mmol) and TsOH.H2O (0.38 g, 2.0 mmol) were added and reaction mixture was stirred at ambient temperature for 24 h. LCMS shows product formation m / z 272.0. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 2.1 g of product was obtained (Yield 70.0 %). MS (ESI) mass calcd. for C11H11BrO3, 271.1; m / z found 272.0 [M+H]+. Step 2: Synthesis of HBS-054-010: Compound HBS- (1.5 g, 5.56 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). The 2-amino-5-fluoropyridine (1.9 g, 16.67 mmol) was added and reaction mixture was stirred at 80oC for 16 h. LCMS shows product formation m / z 285.0. The reaction mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 1.2 g of product was obtained (Yield 75.0 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.0 [M+H]+. Step 3: Synthesis of HBS-054-014: Compound HBS-054-010 (1.2 g, 4.22 mmol) was dissolved in MeOH (12.0 mL). The 1.0 N aq. NaOH solution (8.44 mL, 8.5 mmol) was added, and reaction mixture was stirred at 60oC temperature for 12 h. LCMS shows product formation m / z 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.92 g of solid product (Yield 84.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. OON NH2O % Step 1: g, 7.14 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). The 2-amino-pyridine (2.0 g, 21.4 mmol) was added followed by CBr4(4.7 g, 14.27 mmol) and reaction mixture was stirred at 80oC for 16 h. LCMS shows product formation m / z 285.0. The reaction mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 1.9 g of product was obtained (Yield 95.0 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.0 [M+H]+. Step 2: Synthesis of HBS-054-015: Compound HBS-054-011 (1.5 g, 5.28 mmol) was dissolved in MeOH (15.0 mL). The 1.0 N aq. NaOH solution (10.6 mL, 10.56 mmol) was added, and reaction mixture was stirred at 60oC temperature for 12 h. LCMS shows product formation m / z 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 1.07 g of solid product (Yield 79.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. N NH2O OH % Step 1: Synthesis of HBS-054-012: Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (1.5 g, 7.14 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). The 2-amino-pyridine (2.0 g, 21.4 mmol) was added followed by CBr4(4.7 g, 14.27 mmol) and reaction mixture was stirred at 80oC for 4 h. LCMS shows product formation m / z 285.0. The reaction mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 1.83 g of product was obtained (Yield 90.0 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.0 [M+H]+. Step 2: Synthesis of HBS-054-016: Compound HBS-054-012 (1.5 g, 5.28 mmol) was dissolved in MeOH (15.0 mL). The 1.0 N aq. NaOH solution (10.6 mL, 10.56 mmol) was added, and reaction mixture was stirred at 60oC temperature for 12 h. LCMS shows product formation m / z 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 1.1 g of solid product (Yield 81.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. F % Step 1: dissolved in anhydrous acetonitrile (20.0 mL). The 2-amino-4-fluoropyridine (2.6 g, 23.4 mmol) was added followed by CBr4 (5.2 g, 15.6 mmol) and reaction mixture was stirred at 80oC for 16 h. LCMS shows product formation m / z 285.0. The reaction mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.9 g of product was obtained (Yield 41.0 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.0 [M+H]+. Step 2: Synthesis of HBS-054-021: Compound HBS-054-020 (0.9 g, 3.17 mmol) was dissolved in MeOH (10.0 mL). The 1.0 N aq. NaOH solution (6.3 mL, 6.34 mmol) was added, and reaction mixture was stirred at 60oC temperature for 12 h. LCMS shows product formation m / z 257.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.37 g of solid product (Yield 41.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. OO O OPd (db N N HO OHa) N O O % mmol) was dissolved in DCM (80.0 mL). The NBS (3.4 g, 18.94 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 270.0. The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 5.1 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C10H9BrN2O2, 269.1; m / z found 270.0 [M+H]+. Step 2: Synthesis of HBS-054-035: Compound HBS-054-028 (1.5 g, 5.6 mmol) and 4- fluorophenylboronic acid (1.2 g, 8.4 mmol) were dissolved in mixture of Dioxane / water (24.0:6.0 v / v mL). The anhydrous Cs2CO3 (3.8 g, 11.75 mmol) was added followed by Pd2(dba)3 (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The rxn mixture was stirred at 80oC temperature under N2 atm. for 12 h. The LCMS data shows product formation m / z 285.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi- flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.4 g of product was obtained (Yield 85.0 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.0 [M+H]+. Step 3: Synthesis of HBS-054-039: Compound HBS-054-035 (1.4 g, 4.93 mmol) was dissolved in MeOH (15.0 mL). The 1.0 N aq. solution of NaOH (10.0 mL, 9.86 mmol) was added and rxn mixture was refluxed for 12 h. The LCMS data shows product formation m / z 257.0. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.56 g of solid product (Yield 45.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. OO O OHOPd (dba) N N BOHO N O OH % mmol) was dissolved in DCM (80.0 mL). The NBS (3.4 g, 18.94 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 270.0. The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 5.1 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C10H9BrN2O2, 269.1; m / z found 270.0 [M+H]+. Step 2: Synthesis of HBS-054-036: Compound HBS-054-028 (1.5 g, 5.6 mmol) and 2- fluorophenylboronic acid (1.2 g, 8.4 mmol) were dissolved in mixture of Dioxane / water (24.0:6.0 v / v mL). The anhydrous Cs2CO3(3.8 g, 11.75 mmol) was added followed by Pd2(dba)3(0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The rxn mixture was stirred at 80oC temperature under N2atm. for 12 h. The LCMS data shows product formation m / z 285.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi- flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.2 g of product was obtained (Yield 75.0 %). MS (ESI) mass calcd. for C16H13FN2O2, 284.29; m / z found 285.0 [M+H]+. Step 3: Synthesis of HBS-054-040: Compound HBS-054-036 (1.2 g, 4.22 mmol) was dissolved in MeOH (15.0 mL). The 1.0 N aq. solution of NaOH (8.4 mL, 8.44 mmol) was added and rxn mixture was refluxed for 12 h. The LCMS data shows product formation m / z 257.0. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.7 g of solid product (Yield 65.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. OO O OHO OHPd (dba)N N N NO 1.0 N NaOH O NBS B X-Phos, Cs aq. N Br CO , OH % (2.4 g, was . g, was rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 256.0. The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 3.5 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C9H7BrN2O2, 255.07; m / z found 256.0 [M+H]+. Step 2: Synthesis of HBS-054-037: Compound HBS-054-033 (1.5 g, 5.9 mmol) and 4- fluorophenylboronic acid (1.2 g, 8.86 mmol) were dissolved in mixture of Dioxane / water (24.0:6.0 v / v mL). The anhydrous Cs2CO3(4.0 g, 12.39 mmol) was added followed by Pd2(dba)3(0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The rxn mixture was stirred at 80oC temperature under N2atm. for 12 h. The LCMS data shows product formation m / z 271.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi- flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.24 g of product was obtained (Yield 78.0 %). MS (ESI) mass calcd. for C15H11FN2O2, 270.26; m / z found 271.0 [M+H]+. Step 3: Synthesis of HBS-054-041: Compound HBS-054-037 (1.2 g, 4.59 mmol) was dissolved in MeOH (15.0 mL). The 1.0 N aq. solution of NaOH (9.2 mL, 9.18 mmol) was added and rxn mixture was refluxed for 12 h. The LCMS data shows product formation m / z 257.0. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 1.0 g of solid product (Yield 85.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+.O O O OHO OHPd (dba)N NNB Br B X-Phos, Cs CO , ON N1.0 N NaOH aq. O N S N OH % (2.4 g, was . g, was rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 256.0. The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 3.5 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C9H7BrN2O2, 255.07; m / z found 256.0 [M+H]+. Step 2: Synthesis of HBS-054-038: Compound HBS-054-033 (1.5 g, 5.9 mmol) and 2- fluorophenylboronic acid (1.2 g, 8.86 mmol) were dissolved in mixture of Dioxane / water (24.0:6.0 v / v mL). The anhydrous Cs2CO3 (4.0 g, 12.39 mmol) was added followed by Pd2(dba)3 (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The rxn mixture was stirred at 80oC temperature under N2atm. for 12 h. The LCMS data shows product formation m / z 271.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi- flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.4 g of product was obtained (Yield 86.0 %). MS (ESI) mass calcd. for C15H11FN2O2, 270.26; m / z found 271.0 [M+H]+. Step 3: Synthesis of HBS-054-042: Compound HBS-054-038 (1.4 g, 5.18 mmol) was dissolved in MeOH (15.0 mL). The 1.0 N aq. solution of NaOH (10.4 mL, 10.36 mmol) was added and rxn mixture was refluxed for 12 h. The LCMS data shows product formation m / z 257.0. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 1.0 g of solid product (Yield 85.0 %). MS (ESI) mass calcd. for C14H9FN2O2, 256.23; m / z found 257.0 [M+H]+. F3C F3C OOCF3CBr4, % in anhydrous acetonitrile (20.0 mL). The 2-amino-4-(trifluoromethyl)pyridine (3.8 g, 23.4 mmol) was added followed by CBr4(5.2 g, 15.6 mmol) and reaction mixture was stirred at 80oC for 16 h. LCMS shows product formation m / z 335.0. The reaction mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 1.0 g of product was obtained (Yield 38.0 %). MS (ESI) mass calcd. for C17H13F3N2O2, 334.29; m / z found 335.0 [M+H]+. Step 2: Synthesis of HBS-054-080: Compound 076 (1.0 g, 2.99 mmol) was dissolved in MeOH (10.0 mL). The 1.0 N aq. NaOH solution (6.0 mL, 6.0 mmol) was added, and reaction mixture was refluxed for 12 h. LCMS shows product formation m / z 307.0. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (5.0 mL x 3) to obtain 0.3 g of solid product (Yield 33.0 %). MS (ESI) mass calcd. for C15H9F3N2O2, 306.24; m / z found 307.0 [M+H]+. F O F O F Cl Step 1: Synthesis of HBS-054-061: Methyl 4-(4-fluorophenyl)-2,4-dioxobutanoate (2.2 g, 10.68 mmol) was dissolved in anhydrous THF (40.0 mL). The hydrazine monohydrate (0.56 g, 11.21 mmol) was added. The reaction mixture was heated at reflux for 3 h. LCMS data shows desired product formation m / z 221.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 1.2 g of product was isolated (Yield 51.0 %). MS (ESI) mass calcd. for C11H9FN2O2, 220.2; m / z found 221.0 [M+H]+. Step 2: Synthesis of HBS-054-062: Compound HBS-054-061 (0.64 g, 2.91 mmol) was dissolved in Acetone (15.0 mL). The K2CO3 (0.8 g, 5.82 mmol) was added, followed by 1-Bromo-2-Chloro- ethane (0.5 g, 3.49 mmol). The reaction mixture was heated at 55oC for 16 h. LCMS data shows desired product formation m / z 283.0 and minor amount of side product formation. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 0.7 g of product was isolated (Yield 85.0 %). MS (ESI) mass calcd. for C13H12ClFN2O2, 282.7; m / z found 283.0 [M+H]+. Step 3: Synthesis of HBS-054-064: Compound HBS-054-062 (0.7 g, 2.48 mmol) was dissolved in dry THF (10.0 mL). The 2.0 M LAH solution in THF (1.24 mL, 2.48 mmol) was added, under ice cooling bath. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data shows desired product formation m / z 255.0. The reaction mixture was quenched with 1.0 N aq. NaOH solution and diluted with ethyl acetate (10.0 mL). The reaction mixture was filtered through celite bed and washed with ethyl acetate (10.0 mL x 3). The organic layer was separated and washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product 0.6 g (Yield 95.0 %). MS (ESI) mass calcd. for C12H12ClFN2O, 254.69; m / z found 255.0 [M+H]+. Step 4: Synthesis of HBS-054-065: Compound HBS-054-064 (0.6 g, 2.36 mmol) was dissolved in dry DMF (5.0 mL). The NaH (0.11 g, 4.72 mmol) was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data shows desired product formation m / z 219.0. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 0.46 g of solid product was obtained (Yield 88.0 %). MS (ESI) mass calcd. for C12H11FN2O, 218.23; m / z found 219.0 [M+H]+. Step 5: Synthesis of HBS-054-071: Compound HBS-054-065 (0.46 g, 2.11 mmol) was dissolved in DCM (7.0 mL). The NBS (0.41 g, 2.32 mmol) was added, and reaction mixture was stirred at room temperature for 16 h. LCMS data shows desired product formation m / z 298.0. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 0.25 g of product was obtained (Yield 40.0 %). MS (ESI) mass calcd. for C12H10BrFN2O, 297.12; m / z found 298.0 [M+H]+. Step 6: Synthesis of HBS-054-088: Compound HBS-054-071 (1.15 g, 3.85 mmol) was dissolved in anhydrous THF (20.0 mL) under N2 atm. The reaction mixture was cooled at -78.0oC temperature and 1.6 M n-BuLi in Hexane (4.81 mL, 7.7 mmol) was added into the reaction mixture. The reaction mixture was stirred at -78.0oC temperature for 30.0 min. The dry CO2 gas bubbled through the reaction mixture at -65oC and the reaction mixture gradually warmed at room temperature. The LCMS data shows desired product formation m / z 263.0, debrominated side product and some unknown product formation. The reaction mixture was quenched by water and extracted with ethyl acetate. The ethyl acetate layer was separated and debrominated product was recovered. The aq. Layer was acidified with 2 M HCl solution to obtain the ppts. The ppts were filtered and dried to obtain 0.6 g of solid product (Yield 60.0 %). MS (ESI) mass calcd. for C13H11FN2O3, 262.24; m / z found 263.0 [M+H]+. O O O O O O O O O O OClO% added dropwise in NaOMe solution (1.25 g Na in 25.0 mL of Methanol). The rxn mixture was stirred at ambient temperature for 30.0 min. The Diethyl oxalate (5.81 g, 39.81 mmol) solution in anhydrous Methanol (25.0 mL) was added and reaction mixture was stirred at ambient temperature for 16 h. LCMS data shows desired product formation m / z 225.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in cold water and acidified with 2.0 M aq. HCl solution. The ppts were filtered and dried to obtain 8.62 g of crude product. MS (ESI) mass calcd. for C11H9FO4, 224.19; m / z found 225.0 [M+H]+. Step 2: Synthesis of HBS-039-200: Compound HBS-039-198 (8.62 g, 36.19 mmol) was dissolved in IPA (100.0 mL). The hydrazine monohydrate (2.1 mL, 43.4 mmol) was added, and reaction mixture was heated at reflux for 3 h. LCMS data shows desired product formation m / z 221.0. and hydrolyzed side product m / z 207.0. The reaction mixture was cooled at ambient temperature to obtain ppts. The ppts were filtered to obtain 7.19 g of crude product. (Yield 90.2 %). MS (ESI) mass calcd. for C11H9FN2O2, 220.2; m / z found 221.0 [M+H]+and mass calcd. for C10H7FN2O2, 206.17; m / z found 207.0 [M+H]+. Step 3: Synthesis of HBS-055-002: Compound HBS-039-200 crude (7.19 g, 32.65 mmol) was dissolved in anhydrous Methanol (100.0 mL). The conc. Sulfuric acid (4.0 mL) was added, and reaction mixture was heated at reflux for 24 h. LCMS data shows desired product formation m / z 221.0. The reaction mixture was cooled at ambient temperature and neutralized with aq. saturated solution of sodium bicarbonate to obtain ppts. The ppts were filtered and dried to obtain 7.19 g of solid product. (Yield Quant.). MS (ESI) mass calcd. for C11H9FN2O2, 220.2; m / z found 221.0 [M+H]+. Step 4: Synthesis of HBS-055-004: Compound HBS-055-002 (7.19 g, 32.65 mmol) was dissolved in Acetone (100.0 mL). The K2CO3 (13.53 g, 97.95 mmol) was added, followed by 1- Bromo-2-Chloro-ethane (13.5 mL, 163.3 mmol). The reaction mixture was heated at 65oC for 24 h. LCMS data shows desired product formation m / z 283.0. The reaction mixture was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 2.85 g of product was isolated (Yield 30.9 %). MS (ESI) mass calcd. for C13H12ClFN2O2, 282.7; m / z found 283.0 [M+H]+. Step 5: Synthesis of HBS-055-007: Compound HBS-055-004 (2.85 g, 10.1 mmol) was dissolved in dry THF (25.0 mL). The reaction mixture was cooled at 0oC temperature in the ice bath. The 1.0 M DIBAL solution in Hexane (25.2 mL, 25.2 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data shows desired product formation m / z 255.1. The reaction mixture was quenched with aq. NH4Cl solution and diluted with ethyl acetate (100.0 mL). The reaction mixture was filtered through celite bed and washed with ethyl acetate. The organic layer was separated and washed with brine. The organic layer was dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product 2.57 g (Yield Quant.). MS (ESI) mass calcd. for C12H12ClFN2O, 254.69; m / z found 255.0 [M+H]+. Step 6: Synthesis of HBS-055-008: Compound HBS-055-007 (2.57 g, 10.1 mmol) was dissolved in dry DMF (20.0 mL). The 60.0 % NaH (0.81 g, 20.2 mmol) in mineral oil was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 h. LCMS data shows desired product formation m / z 219.1. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 1.17 g of solid product was obtained (Yield 53.2 %). MS (ESI) mass calcd. for C12H11FN2O, 218.23; m / z found 219.1 [M+H]+. Step 7: Synthesis of HBS-055-010: Compound HBS-055-008 (1.17 g, 5.36 mmol) was dissolved in DCM (15.0 mL). The NBS (1.05 g, 5.9 mmol) was added, and reaction mixture was stirred at ambient temperature for 16 h. LCMS data shows desired product formation m / z 299.0. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile Phase: EtOAc:Hexane, gradient. The 1.27 g of product was obtained (Yield 79.7 %). MS (ESI) mass calcd. for C12H10BrFN2O, 297.12; m / z found 299.0 [M+H]+. Step 8: Synthesis of HBS-055-013: Compound HBS-055-010 (1.27 g, 4.27 mmol) was dissolved in anhydrous THF (15.0 mL) under N2 atm. The reaction mixture was cooled at -78.0oC temperature. The 1.6 M n-BuLi in Hexane (5.33 mL, 8.54 mmol) was added and reaction mixture was stirred at -78.0oC temperature for 30.0 min. The dry CO2 gas bubbled through the reaction mixture at -65oC temperature and the reaction mixture gradually warmed at room temperature. The LCMS data shows desired product formation m / z 263.1, debrominated side product and some unknown product formation. The reaction mixture was quenched by water and extracted with ethyl acetate. The ethyl acetate layer was separated and debrominated product was recovered. The aq. Layer was acidified with 2 M HCl solution to obtain the ppts. The ppts were filtered and dried to obtain 0.84 g of solid product (Yield 75.0 %). MS (ESI) mass calcd. for C13H11FN2O3, 262.24; m / z found 263.1 [M+H]+. HO OH B O Br N N O OBr BrO O O O % % 6.40 mmol) was dissolved in anhydrous Acetonitrile (15.0 mL). The anhydrous K2CO3 (3.54 g, 25.62 mmol) was added, and reaction mixture was stirred at ambient temperature for 15.0 min. The 1,3- dibromo propane (0.72 mL, 7.05 mmol) was added, and reaction mixture was heated at reflux for 6 h. The LCMS data shows product formation m / z 197.1. The reaction mixture cooled at ambient temperature and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.03 g of product was obtained (Yield 81.97 %). MS(ESI) mass calcd. for C9H12N2O3, 196.20; m / z found 197.1 [M+H]+.Step 2: Synthesis of HBS-055-192: Compound HBS-055-191 (1.03 g, 5.25 mmol) was dissolved in DCM (15.0 mL). The NBS (0.93 g, 5.25 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 275.0. The reaction mixture was diluted with water and the product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 1.44 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C9H11BrN2O3, 275.1; m / z found 275.0 [M+H]+. Step 3: Synthesis of HBS-055-194: HBS-055-192 (0.4 g, 1.45 mmol) and Phenylboronic acid (0.27 g, 2.18 mmol) were dissolved in mixture of Dioxane / water (9:1 v / v mL). The anhydrous K2CO3(0.6 g, 4.36 mmol) was added followed by Pd(dppf)Cl2.DCM2(0.06 g, 0.073 mmol). The rxn mixture was stirred at 100oC temperature under N2atm. for 6 h. The LCMS data shows product formation m / z 273.1. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.37 g of product was obtained (Yield 94.7 %). MS (ESI) mass calcd. for C15H16N2O3, 272.3; m / z found 273.1 [M+H]+. Step 4: Synthesis of HBS-055-197: HBS-055-194 (0.37 g, 1.38 mmol) was dissolved in MeOH (5.0 mL). The 1.0 N aq. solution of NaOH (4.1 mL, 4.1 mmol) was added and rxn mixture was refluxed for 6 h. The LCMS data shows product formation m / z 245.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.26 g of solid product (Yield 77.3 %). MS (ESI) mass calcd. for C13H12N2O3, 244.25; m / z found 245.1 [M+H]+. H O O O O N OH2H2O O O NaNO , TFAA, Dry Toluene O % % was dissolved in water (6.0 mL). Anhydrous NaNO2(0.79 g, 11.44 mmol) was added and rxn mixture was cooled at 0oC temperature in Ice bath. The 12.0 M aq. HCl (1.27 mL, 15.26 mmol) was added, and reaction mixture was gradually warmed at ambient temperature for 16 h. The LCMS data shows product formation m / z 161.1. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The 1.22 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C5H8N2O4, 160.13; m / z found 161.1 [M+H]+. Step 2: Synthesis of HBS-062-007: Compound HBS-062-005 (1.22 g, 7.63 mmol) was dissolved in anhydrous toluene (10.0 mL). The rxn mixture was cooled at 0oC temperature in the Ice bath. The anhydrous TFA (1.6 mL, 11.44 mmol) was added, and reaction mixture was gradually warmed at ambient temperature for 16 h. The LCMS data shows product formation m / z 143.1. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.02 g of product was obtained (Yield 94.1 %). MS (ESI) mass calcd. for C5H6N2O3, 142.11; m / z found 143.1 [M+H]+. Step 3: Synthesis of HBS-062-009: Compound HBS-062-007 (1.0 g, 7.18 mmol) was dissolved in Xylene (10.0 mL). The ethyl propiolate (0.95 mL, 9.33 mmol) was added, and reaction mixture was heated at 120oC temperature for 6 h. The LCMS data shows product formation m / z 197.1. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.0 g of product was obtained (Yield 71.0 %). MS (ESI) mass calcd. for C9H12N2O3, 196.20; m / z found 197.1 [M+H]+. Step 4: Synthesis of HBS-062-010: HBS-062-009 (1.0 g, 5.1 mmol) was dissolved in DCM (15.0 mL). The NBS (1.0 g, 5.61 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 275.0. The reaction mixture was diluted with water and the product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 1.4 g of product was obtained (Yield 99.7 %). MS (ESI) mass calcd. for C9H11BrN2O3, 275.1; m / z found 275.0 [M+H]+. Step 5: Synthesis of HBS-052-011: Compound HBS-062-010 (0.4 g, 1.45 mmol) and Phenylboronic acid (0.27 g, 2.18 mmol) were dissolved in mixture of Dioxane / water (9:1 v / v mL). The anhydrous K2CO3 (0.6 g, 4.36 mmol) was added followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.073 mmol). The rxn mixture was stirred at 100oC temperature under N2 atm. for 6 h. The LCMS data shows product formation m / z 273.1. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.39 g of product was obtained (Yield 95.5 %). MS (ESI) mass calcd. for C15H16N2O3, 272.3; m / z found 273.1 [M+H]+. Step 6: Synthesis of HBS-062-013: Compound HBS-062-011 (0.39 g, 1.43 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. solution of NaOH (4.3 mL, 4.3 mmol) was added and rxn mixture was refluxed for 6 h. The LCMS data shows product formation m / z 245.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.23 g of solid product (Yield 65.8 %). MS (ESI) mass calcd. for C13H12N2O3, 244.25; m / z found 245.1 [M+H]+. O OHOBOHBr O O O % % Step mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled at 0oC temperature in Ice bath. The NBS (1.38 g, 7.73 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 236.0. The reaction mixture was diluted with aq. saturated solution of NaHCO3. The product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: DCM:Methanol gradient. The 0.62 g of product was obtained (Yield 41.1 %). MS (ESI) mass calcd. for C6H8BrN3O2, 234.05; m / z found 236.0 [M+H]+. Step 2: Synthesis of HBS-062-021: Compound HBS-062-019 (0.62 g, 2.65 mmol) and 1,1,3,3- Tetraethoxy propane (0.76 mL, 3.18 mmol) were dissolved in anhydrous Acetic acid (10.0 mL). The reaction mixture was heated at 70oC temperature for 24 h. The LCMS data shows product formation m / z 272.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with aq. saturated solution of NaHCO3. The ppts were filtered and dried to obtain 0.3 g of product (Yield 41.9 %). MS (ESI) mass calcd. for C9H8BrN3O2, 270.08; m / z found 272.0 [M+H]+. Step 3: Synthesis of HBS-062-024: Compound HBS-062-021 (0.3 g, 1.11 mmol) and Phenylboronic acid (0.2 g, 1.67 mmol) were dissolved in mixture of Dioxane / water (7:1 v / v mL). The anhydrous K2CO3(0.46 g, 3.33 mmol) was added followed by Pd(dppf)Cl2.DCM2(0.045 g, 0.056 mmol). The rxn mixture was stirred at 100oC temperature under N2atm. for 4 h. The LCMS data shows product formation m / z 268.1. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.25 g of product was obtained (Yield 84.2 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.1 [M+H]+. Step 4: Synthesis of HBS-062-027: Compound HBS-062-024 (0.25 g, 0.94 mmol) was dissolved in MeOH (6.0 mL). The 1.0 N aq. solution of NaOH (1.9 mL, 1.87 mmol) was added and rxn mixture was refluxed for 8 h. The LCMS data shows product formation m / z 240.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.11 g of solid product (Yield 49.2 %). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.1 [M+H]+. NH2O O O N I OH % Step in anhydrous THF (12.0 mL). The n-BuLi (7.2 mL, 11.53 mmol) was added at -78oC temperature and rxn mixture was stirred at -78oC temperature for 30.0 min. The ethyl chloroformate (1.4 mL, 14.41 mmol) was added at -78oC temperature and rxn mixture was gradually warmed to ambient temperature for 3 h. The LCMS data shows product formation m / z 177.1. The rxn mixture was diluted with aq. NH4Cl solution and product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: DCM:MeOH gradient. The 0.78 g of product was obtained (Yield 46.1 %). MS (ESI) mass calcd. for C9H8N2O2, 176.17; m / z found 177.1 [M+H]+. Step 2: Synthesis of HBS-062-023: Compound HBS-062-020 (0.75 g, 4.25 mmol) and 1- Aminopyridinium iodide (1.13 g, 5.11 mmol) were dissolved in anhydrous DMF (10.0 mL). The anhydrous K2CO3 (1.47 g, 10.63 mmol) was added, and reaction mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 269.1. The rxn mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: Ethyl acetate:Hexane gradient. The 0.48 g of product was obtained (Yield 42.1 %). MS (ESI) mass calcd. for C14H12N4O2, 268.27; m / z found 269.1 [M+H]+. Step 3: Synthesis of HBS-062-028: Compound HBS-062-023 (0.28 g, 1.04 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. NaOH solution (2.1 mL, 2.09 mmol) was added, and reaction mixture was refluxed for 6 h. LCMS shows product formation m / z 241.1. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.22 g of solid product (Yield 87.5 %). MS (ESI) mass calcd. for C12H8N4O2, 240.22; m / z found 241.1 [M+H]+. O NH Cl O O O N I N H % Step 1: dissolved in anhydrous THF (15.0 mL). The n-BuLi (14.6 mL, 23.3 mmol) was added at -78oC temperature and rxn mixture was stirred at -78oC temperature for 30.0 min. The ethyl chloroformate (2.2 mL, 23.3 mmol) was added at -78oC temperature and rxn mixture was gradually warmed to ambient temperature for 3 h. The LCMS data shows product formation m / z 176.1. The rxn mixture was diluted with aq. NH4Cl solution and product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: Ethyl acetate:Hexane gradient. The 1.29 g of product was obtained (Yield 38.0 %). MS (ESI) mass calcd. for C10H9NO2, 175.18; m / z found 176.1 [M+H]+. Step 2: Synthesis of HBS-062-025: Compound HBS-062-022 (0.5 g, 2.85 mmol) and 1- Aminopyridinium iodide (0.76 g, 3.43 mmol) were dissolved in anhydrous DMF (8.0 mL). The anhydrous K2CO3 (0.79 g, 5.71 mmol) was added, and reaction mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 268.1. The rxn mixture was diluted with water and the product was extracted with ethyl acetate. The combined ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: Ethyl acetate:Hexane and DCM:Methanol gradient . The 0.57 g of product was obtained (Yield 74.6 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.1 [M+H]+. Step 3: Synthesis of HBS-062-030: Compound HBS-062-025 (0.56 g, 2.1 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. NaOH solution (4.2 mL, 4.19 mmol) was added, and reaction mixture was refluxed for 4 h. LCMS shows product formation m / z 240.1. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.26 g of solid product (Yield 50.9 %). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.1 [M+H]+. O O O O Acetic acidN NO NBS, DCMN NOHOBOH+ Step 1: Synthesis of HBS-062-033: Ethyl 5-amino-1H-Pyrazole-4-carboxylate (1.0 g, 6.43 mmol) and 1,1,3,3-Tetraethoxy propane (1.85 mL, 7.72 mmol) were dissolved in anhydrous Acetic acid (8.0 mL). The reaction mixture was heated at 70oC temperature for 24 h. The LCMS data shows product formation m / z 192.1.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with aq. saturated solution of NaHCO3. The product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: DCM:Methanol gradient. The 0.98 g of product was obtained (Yield 79.7 %). MS (ESI) mass calcd. for C9H9N3O2, 191.19; m / z found 192.1 [M+H]+. Step 2: Synthesis of HBS-062-037: Compound HBS-062-033 (0.98 g, 5.13 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled at 0oC temperature in Ice bath. The NBS (1.0 g, 5.64 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 272.0. The reaction mixture was diluted with aq. saturated solution of NaHCO3. The product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave 1.38 g of crude product (Yield Quant.). MS (ESI) mass calcd. for C9H8BrN3O2, 270.08; m / z found 272.0 [M+H]+. Step 3: Synthesis of HBS-062-038: Compound HBS-062-037 (0.4 g, 1.48 mmol) and Phenylboronic acid (0.27 g, 2.22 mmol) were dissolved in mixture of Dioxane / water (8:1 v / v mL). The anhydrous K2CO3 (0.61 g, 4.44 mmol) was added followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.074 mmol). The rxn mixture was stirred at 100oC temperature under N2 atm. for 6 h. The LCMS data shows product formation m / z 268.1. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.32 g of product was obtained (Yield 80.1 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.1 [M+H]+. Step 4: Synthesis of HBS-062-041: Compound HBS-062-038 (0.32 g, 1.19 mmol) was dissolved in MeOH (5.0 mL). The 1.0 N aq. solution of NaOH (2.4 mL, 2.37 mmol) was added and rxn mixture was refluxed for 6 h. The LCMS data shows product formation m / z 240.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.18 g of solid product (Yield 65.9 %). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.1 [M+H]+.

[0015] NO EtONON NO N H, HNNBS + Sn Step- g, 6.17 mmol) was dissolved in ethanol (20.0 mL). The catalytic amount of conc. sulfuric acid (0.5 mL) was added and rxn mixture was refluxed for 16 h. The LCMS data shows product formation m / z 191.1. The rxn mixture was concentrated under reduced pressure and neutralized with saturate aq. solution of sodium bicarbonate. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave product. The 1.2 g of product was obtained (Yield Quant.) MS (ESI) mass calcd. for C10H10N2O2, 190.2; m / z found 191.1 [M+H]+. Step-2: Synthesis 014: The HBS-039-013 (1.17 g, 6.17 mmol) was dissolved in DCM (25.0 mL). The NBS (1.1 g, 6.17 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 271.0. The rxn mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.5 g of product was obtained (Yield 90.4 %). MS (ESI) mass calcd. for C10H9BrN2O2, 269.1; m / z found 271.0 [M+H]+. Step 3: Synthesis of HBS-062-179: Compound HBS-039-014 (0.5 g, 1.86 mmol) and 2-(tributyl stannyl)-pyridine (1.36 g, 3.72 mmol) were dissolved in 1,4-Dioxane (10.0 mL). The Pd(PPh3)4(0.214 g, 0.18 mmol) was added, and reaction mixture was heated at 115oC temperature under N2atm. for 18 h. The LCMS data shows product formation m / z 268.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.35 g of product was obtained (Yield 70.5 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.0 [M+H]+. Step 4: Synthesis of HBS-062-182: Compound HBS-062-179 (0.35 g, 1.31 mmol) was dissolved in MeOH (5.0 mL). The 1.0 N aq. solution of NaOH (2.62 mL, 2.62 mmol) was added and rxn mixture was refluxed for 8 h. The LCMS data shows product formation m / z 240.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.31 g of product (Yield Quant.). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.1 [M+H]+. OO% % Step 1: Synthesis of HBS-062-033: Ethyl 5-amino-1H-Pyrazole-4-carboxylate (1.0 g, 6.43 mmol) and 1,1,3,3-Tetraethoxy propane (1.85 mL, 7.72 mmol) were dissolved in anhydrous Acetic acid (8.0 mL). The reaction mixture was heated at 70oC temperature for 24 h. The LCMS data shows product formation m / z 192.1.0. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was diluted with water and neutralized with aq. saturated solution of NaHCO3. The product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: DCM:Methanol gradient. The 0.98 g of product was obtained (Yield 79.7 %). MS (ESI) mass calcd. for C9H9N3O2, 191.19; m / z found 192.1 [M+H]+. Step 2: Synthesis of HBS-062-037: Compound HBS-062-033 (0.98 g, 5.13 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled at 0oC temperature in Ice bath. The NBS (1.0 g, 5.64 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 272.0. The reaction mixture was diluted with aq. saturated solution of NaHCO3. The product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave 1.38 g of crude product (Yield Quant.). MS (ESI) mass calcd. for C9H8BrN3O2, 270.08; m / z found 272.0 [M+H]+. Step 3: Synthesis of HBS-062-183: Compound HBS-062-037 (0.95 g, 3.52 mmol) and 2-(tributyl stannyl)-pyridine (1.94 g, 5.28 mmol) were dissolved in 1,4-Dioxane (12.0 mL). The Pd(PPh3)4 (0.41 g, 0.35 mmol) was added, and reaction mixture was heated at 115oC temperature under N2 atm. for 18 h. The 0.05 eq Pd(PPh3)4 was added to consume the starting material. The LCMS data shows product formation m / z 269.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.725 g of product was obtained (Yield 76.8 %). MS (ESI) mass calcd. for C14H12N4O2, 268.27; m / z found 269.0 [M+H]+. Step 4: Synthesis of HBS-062-186: Compound (0.73 g, 2.7 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. solution of NaOH (5.4 mL, 5.4 mmol) was added and rxn mixture was refluxed for 6 h. The LCMS data shows product formation m / z 241.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.52 g of product (Yield 80.2 %). MS (ESI) mass calcd. for C12H8N4O2, 240.22; m / z found 241.1 [M+H]+.

[0016] O O N+K CO O O Br Br NIS, DCMN NOSn mmol) was dissolved in anhydrous Acetonitrile (40.0 mL). The anhydrous K2CO3 (7.1 g, 51.24 mmol) was added, and reaction mixture was stirred at ambient temperature for 10.0 min. The 1,3- dibromo propane (1.43 mL, 14.1 mmol) was added, and reaction mixture was heated at reflux for 12 h. The LCMS data shows product formation m / z 197.1. The reaction mixture cooled at ambient temperature and filtered over celite. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 1.93 g of product was obtained (Yield 76.8 %). MS (ESI) mass calcd. for C9H12N2O3, 196.20; m / z found 197.1 [M+H]+. Step 2: Synthesis of HBS-062-178: Compound HBS-062-173 (1.9 g, 9.68 mmol) was dissolved in DCM (30.0 mL). The NIS (2.61 g, 11.62 mmol) was added and rxn mixture was stirred at ambient temperature for 30 h. The 0.6 eq of NIS was added to consume the starting material. The LCMS data shows product formation m / z 323.0. The reaction mixture was diluted with water and the product was extracted with DCM. The DCM layer was separated and washed with aq. sodium thiosulphate solution. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 3.12 g of product was obtained(Yield Quant.). MS (ESI) mass calcd. for C9H11IN2O3, 322.1; m / z found 323.0 [M+H]+.Step 3: Synthesis of HBS-062-189: Compound HBS-062-178 (1.0 g, 3.11 mmol) and 2-(tributyl stannyl)-pyridine (1.14 g, 3.11 mmol) were dissolved in 1,4-Dioxane (12.0 mL). The Pd(PPh3)4(0.36 g, 0.31 mmol) was added, and reaction mixture was heated at 120oC temperature under N2atm. for 30 h. The LCMS data shows product formation m / z 274.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient and EtOAc:Methanol (95:05, v / v mL) gradient. The 0.44 g of product was obtained (Yield 51.9 %). MS (ESI) mass calcd. for C14H15N3O3, 273.3; m / z found 274.0 [M+H]+. Step 4: Synthesis of HBS-062-192: Compound HBS-062-189 (0.44 g, 1.61 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. solution of NaOH (3.22 mL, 3.22 mmol) was added and rxn mixture was refluxed for 8 h. The LCMS data shows product formation m / z 246.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.31 g of product (Yield 78.5 %). MS (ESI) mass calcd. for C12H11N3O3, 245.23; m / z found 246.1 [M+H]+. N O N N % 0.55 g, Yield Quant. Step 1: Synthesis of HBS-062-199: 3-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.0 g, 3.72 mmol) and 2-(tributyl stannyl)-pyridine (1.5 g, 4.1 mmol) were dissolved in Dry DMF (12.0 mL). The Pd(PPh3)4(0.43 g, 0.37 mmol) was added, and reaction mixture was heated at 115-120oC temperature under N2atm. for 36 h. The 0.05 eq of Pd(PPh3)4was added to consume the starting material during the reaction. The LCMS data shows product formation m / z 268.1 and acid side product m / z 240.1. The reaction mixture was diluted with water and the product was extracted with DCM. The DCM layer was separated and washed with aq. sodium thiosulphate solution. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient and EtOAc:Methanol (95:05, v / v mL) gradient. The 0.61 g of product was obtained (Yield 61.4 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.1 [M+H]+and 0.1 g of acid side product was obtained (Yield 11.2 %). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.1 [M+H]+. Step 2: Synthesis of HBS-065-004: Compound HBS-062-199A (0.61 g, 2.28 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. solution of NaOH (4.6 mL, 4.56 mmol) was added and reaction mixture was refluxed for 8 h. The LCMS data shows product formation m / z 240.9. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The aq. layer was concentrated to obtain 0.55 g of product (Yield Quant.). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.9 [M+H]+. ON NO ON NNO N O % Step 1: stannyl)- pyridine (1.6 g, 4.36 mmol) were dissolved in Dry DMF (12.0 mL). The Pd(PPh3)4 (0.42 g, 0.36 mmol) was added, and reaction mixture was heated at 120oC temperature under N2atm. for 30 h. The 0.05 eq of Pd(PPh3)4was added to consume the starting material during the reaction. The LCMS data shows product formation m / z 274.0 and acid side product m / z 246.0. The reaction mixture was diluted with water and the product was extracted with DCM. The DCM layer was separated and washed with aq. sodium thiosulphate solution. The combined DCM layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient and DCM:Methanol gradient. The 0.26 g of product was obtained (Yield 26.3 %). MS (ESI) mass calcd. for C14H15N3O3, 273.29; m / z found 274.0 [M+H]+and 0.15 g of acid side product was obtained (Yield 16.8 %). MS (ESI) mass calcd. for C12H11N3O3, 245.23; m / z found 246.0 [M+H]+. Step 2: Synthesis of HBS-065-019: Compound HBS-065-011A (0.26 g, 0.96 mmol) was dissolved in MeOH (5.0 mL). The 1.0 N aq. solution of NaOH (1.9 mL, 1.91 mmol) was added and reaction mixture was refluxed for 3 h. The LCMS data shows product formation m / z 246.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and aq. layer was concentrated to obtain 0.23 g of total product (Yield 92.0 %). MS (ESI) mass calcd. for C12H11N3O3, 245.23; m / z found 246.1 [M+H]+. F F OO O O% in Chloroform (12.0 mL). The Bromine (0.13 mL, 2.59 mmol) solution in Chloroform (1.0 mL) was added and reaction mixture was stirred at ambient temperature for 2 h. LCMS shows product formation m / z 274.0. The reaction mixture was diluted with aq. saturated solution of NaHCO3and the product was extracted with Chloroform. The Chloroform layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave 0.7 g of crude product (Yield Quant.). MS (ESI) mass calcd. for C10H10BrNO3, 272.1; m / z found 274.0 [M+H]+. Step 2: Synthesis of HBS-065-051: Compound HBS-065-050 (0.7 g, 2.59 mmol) was dissolved in anhydrous Acetonitrile (8.0 mL). The 2-amino-5-fluoropyridine (0.29 g, 2.59 mmol) was added and reaction mixture was heated at reflux for 16 h. LCMS shows product formation m / z 286.1. The reaction mixture was diluted with aq. saturated solution of NaHCO3 and the product was extracted with Ethyl acetate. The combined Ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by combi-flash system, Mobile phase: DCM:Methanol gradient. The 0.39 g of product was obtained (Yield 52.8 %). MS (ESI) mass calcd. for C15H12FN3O2, 285.27; m / z found 286.1 [M+H]+. Synthesis of HBS-065-055: Compound HBS-065-051 (0.39 g, 1.37 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. NaOH solution (2.7 mL, 2.73 mmol) was added, and reaction mixture was heated at reflux for 12 h. LCMS shows product formation m / z 258.2. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.33 g of solid product (Yield 93.8 %). MS (ESI) mass calcd. for C13H8FN3O2, 257.22; m / z found 258.2 [M+H]+. Cl Cl OOCl % Step dissolved in anhydrous Acetonitrile (10.0 mL). The 2-amino-4-chloropyridine (0.67 g, 5.18 mmol) was added and reaction mixture was heated at reflux for 16 h. LCMS shows product formation m / z 302.0. The reaction mixture was diluted with aq. saturated solution of NaHCO3 and the product was extracted with Ethyl acetate. The combined Ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by combi-flash system, Mobile phase: DCM:Methanol gradient. The 0.8 g of product was obtained (Yield 51.2 %). MS (ESI) mass calcd. for C15H12ClN3O2, 301.73; m / z found 302.0 [M+H]+. Step 2: Synthesis of HBS-065-064: Compound HBS-065-062 (0.8 g, 2.65 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. NaOH solution (5.3 mL, 5.30 mmol) was added, and reaction mixture was heated at reflux for 8 h. LCMS shows product formation m / z 274.0. The reaction mixture was concentrated under reduced pressure. The crude was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (3.0 mL x 3) to obtain 0.46 g of solid product (Yield 63.4 %). MS (ESI) mass calcd. for C13H8ClN3O2, 273.67; m / z found 274.0 [M+H]+.O OAcetonitrile N N % in anhydrous Acetonitrile (12.0 mL). The 2-aminopyridine (0.49 g, 5.18 mmol) was added and the reaction mixture was heated at reflux for 16 h. LCMS shows product formation m / z 268.0. The reaction mixture was diluted with aq. saturated solution of NaHCO3and the product was extracted with Ethyl acetate. The combined Ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by combi-flash system, Mobile phase: DCM:Methanol gradient. The 0.7 g of product was obtained (Yield 50.6 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.0 [M+H]+. Step 2: Synthesis of HBS-065-076: Compound HBS-065-073 (0.7 g, 2.62 mmol) was dissolved in MeOH (6.0 mL). The 1.0 N aq. NaOH solution (5.2 mL, 5.24 mmol) was added, and reaction mixture was heated at reflux for 4 h. LCMS shows product formation m / z 240.0. The reaction mixture was concentrated under reduced pressure. The crude was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (3.0 mL x 3) to obtain 0.52 g of solid product (Yield 83.0 %). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.0 [M+H]+. N OHNON NO HO B OH N Conc. H SONNBS S Cl Step-1: Synthesis of HBS-065-106: The pyrazolo[1,5-a]pyridine-2-carboxylic acid (2.0 g, 12.34 mmol) was dissolved in Ethanol (40.0 mL). The catalytic amount of conc. sulfuric acid (0.1 mL) was added and rxn mixture was refluxed for 8 h. The LCMS data shows product formation m / z 191.1. The rxn mixture was concentrated under reduced pressure and neutralized with saturate aq. solution of sodium bicarbonate. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave product. The 2.2 g of product was obtained (Yield 93.7 %) MS (ESI) mass calcd. for C10H10N2O2, 190.2; m / z found 191.1 [M+H]+. Step 2: Synthesis of 108: Compound HBS-065-106 (2.2 g, 11.57 mmol) was dissolved in DCM (40.0 mL). The NBS (2.27 g, 12.73 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 270.9. The rxn mixture was diluted with aq. saturated solution of sodium bicarbonate. The product was extracted with DCM. The combined DCM layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave product. The crude product was purified by normal phase chromatography system, Mobile phase: EtOAc:Hexane gradient. The 3.11 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C10H9BrN2O2, 269.1; m / z found 270.9 [M+H]+. Step 3: Synthesis of HBS-065-125: Compound HBS-065-108 (0.4 g, 1.49 mmol) and 5- Chlorothiophene-2-boronic acid (0.48 g, 2.97 mmol) were dissolved in mixture of Dioxane / water (12:1 v / v mL). The anhydrous K2CO3 (0.41 g, 2.97 mmol) was added followed by Pd(dppf)Cl2.DCM2 (0.06 g, 0.074 mmol). The rxn mixture was stirred at 100oC temperature under N2 atm. for 24 h. The 5-Chlorothiophene-2-boronic acid and catalyst were added to consume the starting material during the reaction. The LCMS data shows product formation m / z 307.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.31 g of product was obtained (Yield 67.9 %). MS (ESI) mass calcd. for C14H11ClN2O2S, 306.77; m / z found307.0 [M+H]+. Step 4: Synthesis of HBS-065-127: Compound HBS-065-125 (0.31 g, 1.01 mmol) was dissolved in MeOH (5.0 mL). The 1.0 N aq. solution of NaOH (2.0 mL, 2.0 mmol) was added and reaction mixture was stirred at ambient temperature for 16 h. The LCMS data shows product formation m / z 278.9. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.24 g of solid product (Yield 83.4 %). MS (ESI) mass calcd. for C12H7ClN2O2S, 278.71; m / z found 278.9 [M+H]+. NNO Sn(n-But) Pd(PPh )N NN N N CsF, CuCl O OH 1.0 O N N aq. NaOH + O % and 2- (tributylstannyl)-pyrimidine (0.69 g, 1.86 mmol) were dissolved in anhydrous DMF (6.0 mL). The anhydrous CsF (0.85 g, 5.57 mmol) and CuCl (0.024 g, 0.24 mmol) were added followed by Pd(PPh3)4(0.11 g, 0.093 mmol). The rxn mixture was irradiated with microwave radiation at 120oC temperature for 50.0 min in microwave reactor. The LCMS data shows product formation m / z 269.2. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was diluted with water and extracted with Ethyl acetate. The combined Ethyl acetate layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.37 g of product was obtained (Yield 73.6 %). MS (ESI) mass calcd. for C14H12N4O2, 268.27; m / z found 269.2 [M+H]+. Step 2: Synthesis of HBS-065-159: Compound HBS-065-156 (0.37 g, 1.37 mmol) was dissolved in MeOH (8.0 mL). The 1.0 N aq. solution of NaOH (2.74 mL, 2.74 mmol) was added and reaction mixture was refluxed for 4 h. The LCMS data shows product formation m / z 241.1. The rxn mixture was concentrated under reduced pressure and diluted with water. The aq. layer was acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.25 g of solid product (Yield 76.7 %). MS (ESI) mass calcd. for C12H8N4O2, 240.22; m / z found 241.1 [M+H]+. N N 0.15 g, Yield 21.3 % 0.11 g, Yield 82.7 % Step 1: Synthesis of HBS-039-126: Ethyl benzoylacetate (0.5 g, 2.6 mmol) was dissolved in anhydrous acetonitrile (10.0 mL). The 2-amino-pyrimidine (0.55 g, 5.76 mmol) was added followed by CBr4(1.27 g, 3.84 mmol) and reaction mixture was stirred at 80oC for 48 h. The reagents were added to consume the starting material. LCMS shows product formation m / z 268.1. The reaction mixture was concentrated under reduced pressure to yield crude product. The crude product was purified by combi-flash system, Mobile phase: EtOAc:Hexane gradient. The 0.15 g of product was obtained (Yield 21.3 %). MS (ESI) mass calcd. for C15H13N3O2, 267.28; m / z found 268.1 [M+H]+. Step 2: Synthesis of HBS-039-132: Compound HBS-039-126 (0.15 g, 0.55 mmol) was dissolved in MeOH (2.5 mL). The 1.0 N aq. NaOH solution (2.77 mL, 2.76 mmol) was added, and reaction mixture was refluxed for 3 h. LCMS shows product formation m / z 240.1. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aq. HCl solution (pH = 5). The ppts were filtered and washed with water (2.0 mL x 3) to obtain 0.11 g of solid product (Yield 82.7 %). MS (ESI) mass calcd. for C13H9N3O2, 239.23; m / z found 240.1 [M+H]+. Synthesis of Secondary Amine Containing Intermediates – Amine Group HO 1. CDI, THF, H N N O N 0o2C to RTO F NNF in THF (30 mL). The solution was cooled in an ice bath for 1 h. CDI (1.09g, 6.72 mmol) was added and after 30 min the ice bath was removed, and the reaction was stirred at RT for 18 h. The hydroxyl amidine (0.694 g, 4.48 mmol) was added and stirring at RT continued. After 24 h observed only 36% conversion to the acyl intermediate by LCMS. Introduced sequentially HOBT (0.908 g, 6.72 mmol), EDC (1.09 g, 6.72 mmol), and TEA (3.11 mL, 22.3 mmol), and CH2Cl2(30 mL) and stirred at RT. LCMS showed conversion to the acyl intermediate was complete after 22 h with m / z 367. The acyl intermediate was isolated by extractive workup between EtOAc and water affording a viscous yellow oil (2.40 g). The oil was dissolved in DCM (15 mL), toluene (25 mL) was added, and the reaction was heated in an open flask to 100-120oC. LCMS showed the product with m / z 349. The reaction mix was dissolved in aq. sat. NaHCO3(aq). and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 1.14 g of white solid (Yield = 73.3 %). MS (ESI) mass calcd. for C17H21FN4O3, 348.2; m / z found 349.1 [M+H]+. Step 2: Synthesis of HBS-061-199: Compound HBS-061-186 (1.142 g, 3.28 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (4.1 mL, 16.4 mmol) was added and the reaction was stirred vigorously at 60oC for 42 h forming a suspension. LCMS showed complete conversion to product m / z 249. The reaction mixture was cooled to RT, filtered, and washed with hexanes to obtain a paste that adhered to the filter paper. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.807 g of powdery off white solid (Yield = 76.7 %). MS (ESI) mass calcd. for C12H13FN4O, 248.1; m / z found 249.1 [M+H]+. N Step 1: Synthesis of HBS-061-180: The carboxylic acid (1.993 g, 8.69 mmol) was dissolved in THF (40 mL). The solution was cooled in an ice bath for 1 h. CDI (1.42 g, 8.76 mmol) was added and after 15 min the ice bath was removed, and the reaction was stirred at RT for 6 h. The hydroxyl amidine (0.795 g, 5.80 mmol) was added and stirring at RT continued. After 72 h observed only 50% conversion to the acyl intermediate by LCMS. Introduced sequentially HOBT (1.17 g, 8.66 mmol), EDC (1.67 g, 8.71 mmol), and TEA (4.0 mL, 28.7 mmol), and CH2Cl2(40 mL) and stirred at RT. LCMS showed conversion to the acyl intermediate was complete after 22 h with m / z 349. The acyl intermediate was isolated by extractive workup between EtOAc and water affording a light-yellow oil (2.87 g). The oil was dissolved in CH2Cl2(25 mL), toluene (30 mL) was added, and the reaction was heated in an open flask to 100oC. LCMS showed the product formation m / z 331. The reaction mix was dissolved in aq. sat. NaHCO3and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexanes:EtOAc gradient. Obtained 1.65 g of colorless oil (Yield = 85.9 %). MS (ESI) mass calcd. for C17H22N4O3, 330.2; m / z found 331.1 [M+H]+. Step 2: Synthesis of HBS061-198: Compound HBS-061-180 (1.645 g, 4.98 mmol) was dissolved in anhydrous dioxane (30 mL). The 4.0 M HCl in dioxane (6.2 mL, 24.8 mmol) was added and the reaction was stirred vigorously at 60oC for 42 h. LCMS showed complete conversion to product m / z 231. The reaction mixture was cooled to RT, filtered, and washed with hexanes to obtain a paste that adhered to the filter paper. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 1.47 g of crusty beige solid (Yield = 97.1 %). MS (ESI) mass calcd. for C12H14N4O, 230.1; m / z found 231.1 [M+H]+. HN O O N HBS-061-140 General Synthesis of HBS-061-129: The alcohol (3.09 g, 14.3 mmol) was dissolved in anhydrous DCM (30 mL). DIPEA (3.75 mL, 21.5 mmol) and DMAP (2.63 g, 21.5 mmol) were added sequentially, and the mixture was stirred in an ice bath for 1 h. The p-TsCl (3.01 g, 15.8 mmol) was added in portions over 20 min and the ice bath were allowed to slowly warm to RT 24 h. The reagents were added to consume the starting material during the reaction. The LCMS data shows product formation m / z 314, 270. The reaction mixture was treated with water and the product was extracted with DCM. The DCM layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 3.21 g of crystalline white solid (Yield = 60.4 %). MS (ESI) mass calcd. for C18H27NO5S, 369.2; m / z found 314.1, 270.1 [M+H]+. Step 1: Synthesis of HBS-061-132: HBS-061-129 (1.034 g, 2.80 mmol) and the pyrazole (0.716 g, 3.36 mmol) were dissolved in anhydrous dioxane (20 mL). The Cs2CO3 (1.82 g, 5.58 mmol) was added, and the reaction mixture was heated to 70oC with vigorous stirring. LCMS showed high conversion to product as an 82:18 isomer mixture with m / z 411 after 40 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.39 g of the major isomer as a colorless oil (Yield = 33.7 %). MS (ESI) mass calcd. for C20H25F3N4O2, 410.2; m / z found 411.2 [M+H]+. Step 2: Synthesis of HBS-061-140: Compound HBS-061-132 (0.387 g, 0.943 mmol) was dissolved in anhydrous dioxane (7 mL). The 4.0 M HCl in dioxane (1.2 mL, 4.8 mmol) was added and the reaction was stirred vigorously at 50oC for 21 h. LCMS showed complete conversion to product m / z 311. The reaction mixture was cooled to RT and concentrated to afford a glass. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.38 g of a glass (Yield Quant.). MS (ESI) mass calcd. for C15H17F3N4, 310.2; m / z found 311.2 [M+H]+. HN N N ClCl Step 1: Synthesis of HBS-061-133: Compound HBS-061-129 (1.050 g, 2.84 mmol) and the pyrazole (0.612 g, 3.41 mmol) were dissolved in anhydrous dioxane (20 mL). The Cs2CO3(1.85 g, 5.68 mmol) was added, and the reaction mixture was heated to 70oC with vigorous stirring. LCMS showed high conversion to product as an 80:20 isomer mixture with m / z 377 after 40 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.35 g of the major isomer as a colorless oil (Yield = 32.3 %). MS (ESI) mass calcd. for C19H25ClN4O2, 376.2; m / z found 377.2 [M+H]+. Step 2: Synthesis of HBS-061-141: Compound HBS-061-133 (0.346 g, 0.918 mmol) was dissolved in anhydrous dioxane (7 mL). The 4.0 M HCl in dioxane (1.15 mL, 4.6 mmol) was added and the reaction was stirred vigorously at 50oC for 24 h followed by 3 h at 60oC. LCMS showed complete conversion to product m / z 277. The reaction mixture was cooled to RT, filtered, and washed with hexanes to afford 0.27 g of powdery white solid (Yield = 85.3 %). MS (ESI) mass calcd. for C14H17ClN4, 276.1; m / z found 277.1 [M+H]+. N O OHNCF3CF3 the pyrazole (0.612 g, 3.41 mmol) were dissolved in anhydrous dioxane (20 mL). The Cs2CO3 (1.78 g, 5.46 mmol) was added, and the reaction mixture was heated to 70oC with vigorous stirring. LCMS showed high conversion to product as an 88:12 isomer mixture with m / z 412 after 40 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.30 g of the major isomer as a colorless oil (Yield = 26.9 %). MS (ESI) mass calcd. for C19H24F3N5O2, 411.2; m / z found 412.1 [M+H]+. Synthesis of HBS-061-142: Compound HBS-061-134 (0.303 g, 0.736 mmol) was dissolved in anhydrous dioxane (7 mL). The 4.0 M HCl in dioxane (0.92 mL, 3.7 mmol) was added and the reaction was stirred vigorously at 50oC for 24 h followed by 3 h at 60oC. LCMS showed complete conversion to product m / z 312. Upon cooling a precipitate formed. The reaction mixture was filtered and washed with Hexane to afford 0.23 g of powdery white solid (Yield = 79.9%). MS (ESI) mass calcd. for C14H16F3N5, 311.1; m / z found 312.2 [M+H]+. OH O g, was CH2Cl2(32 mL). DIPEA (3.92 mL, 22.5 mmol) and DMAP (2.75 g, 22.5 mmol) were added sequentially, and the mixture was stirred in an ice bath for 1 h. p-TsCl (3.43 g, 15.8 mmol) was added in portions over 10 min and the ice bath were allowed to slowly warm to RT. After 24 h at RT LCMS showed complete conversion to product with m / z 300, 256. The reaction mixture was treated with water and the product was extracted with DCM. The DCM layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 4.91 g of colorless oil (Yield = 92.0 %). MS (ESI) mass calcd. for C17H25NO5S, 355.2; m / z found 300.0, 256.0 [M+H]+. HN Step 1: Synthesis of HBS-061-146: Compound HBS-061-169 (1.533 g, 4.31 mmol) and the pyrazole (0.750 g, 5.17 mmol) were dissolved in anhydrous dioxane (30 mL). The Cs2CO3 (2.81 g, 5.17 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product as an 83:17 isomer mixture with m / z 329 after 24 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 1.06 g of the major isomer as a colorless oil (Yield = 75.0 %). MS (ESI) mass calcd. for C18H24N4O2, 328.2; m / z found 329.2 [M+H]+. Step 2: Synthesis of HBS-061-153: Compound HBS-061-146 (1.061 g, 3.23 mmol) was dissolved in anhydrous dioxane (12 mL). The 4.0 M HCl in dioxane (4.04 mL, 16.2 mmol) was added and the reaction was stirred vigorously at 60oC for 18 h. LCMS showed complete conversion to product m / z 229. The reaction mixture was cooled to RT, filtered, and washed with hexanes to afford 0.97 g of powdery white solid (Yield = 100 %). MS (ESI) mass calcd. for C13H16N4, 228.1; m / z found 229.1 [M+H]+. N Cl CF3 THF (10 mL). The 60 % NaH (0.42 g, 10.5 mmol) was added in one portion and after 15 minutes the chloropyrimidine (1.28 g, 7.00 mmol) was added as a solution in DMF (6 mL). The reaction mixture was heated to 70oC. LCMS showed product formation after 3 h with m / z 292, 248. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.13 g of the product as a colorless oil (Yield = 5.3 %). MS (ESI) mass calcd. for C15H20F3N3O3, 347.2; m / z found 292.0, 248.1 [M+H]+. Step 2: Synthesis of HBS-061-170: Compound HBS-061-167 (0.129 g, 0.371 mmol) was dissolved in anhydrous dioxane (2 mL). The 4.0 M HCl in dioxane (0.47 mL, 1.88 mmol) was added and the reaction was stirred vigorously at RT for 96 h forming a suspension. LCMS showed complete conversion to product m / z 248. The reaction mixture was filtered and washed with hexanes to afford 67 mg of white solid (yield = 63.5%). MS (ESI) mass calcd. for C10H12F3N3O, 247.1; m / z found 248.1 [M+H]+. Cl Step 1: Synthesis of HBS-061-185: Compound HBS-061-169 (0.695 g, 1.96 mmol) and the pyrazole (0.422 g, 2.35 mmol) were dissolved in anhydrous dioxane (15 mL). The Cs2CO3(1.27 g, 3.90 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product with isomer mixture m / z 363 after 42 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.18 g of the major isomer as a colorless oil (Yield = 24.9%). MS (ESI) mass calcd. for C18H23ClN4O2, 362.2; m / z found 363.1 [M+H]+. Step 2: Synthesis of HBS-061-192: Compound HBS-061-185 (0.177 g, 0.488 mmol) was dissolved in anhydrous dioxane (10 mL). The 4.0 M HCl in dioxane (1.22 mL, 4.88 mmol) was added and the reaction was stirred vigorously at 60oC for 64 h. LCMS showed complete conversion to product m / z 263. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.16 g of white solid (Yield = 97.7 %). MS (ESI) mass calcd. for C13H15ClN4, 262.1; m / z found 263.1 [M+H]+. HN NCl Step and the pyrazole (0.427 g, 2.38mmol) were dissolved in anhydrous dioxane (20 mL). The Cs2CO3(1.29 g, 3.96 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product with m / z 363 after 64 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.64 g of the product as a colorless oil (Yield = 89.3 %). MS (ESI) mass calcd. for C18H23ClN4O2, 362.2; m / z found 363.1 [M+H]+. Step 2: Synthesis of HBS-061-179: Compound HBS-061-176 (0.642 g, 1.77 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.21 mL, 8.84 mmol) was added and the reaction was stirred vigorously at 60oC for 18 h. LCMS showed complete conversion to product m / z 263. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.54 g of powdery white solid (Yield = 91.6 %). MS (ESI) mass calcd. for C13H15ClN4, 262.1; m / z found 263.1 [M+H]+. HN N Step 1: Synthesis of HBS-066-001: HBS-061-169 (0.614 g, 1.73 mmol) and the pyrazole (0.441 g, 2.07 mmol) were dissolved in anhydrous dioxane (20 mL). The Cs2CO3 (1.12 g, 3.44 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product as an 88:12 isomer mixture with m / z 397 after 64 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexanes:EtOAc gradient. Obtained 0.51 g of the major isomer as a waxy white solid (Yield = 74.9 %). MS (ESI) mass calcd. for C19H23F3N4O2, 396.2; m / z found 397.1 [M+H]+. Step 2: Synthesis of HBS-066-005: Compound HBS-066-001 (0.513 g, 1.29 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (1.62 mL, 6.48 mmol) was added and the reaction was stirred vigorously at 60oC for 90 h. LCMS showed complete conversion to product m / z 297. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.36 g of powdery white solid (Yield = 76.0 %). MS (ESI) mass calcd. for C14H15F3N4, 296.1; m / z found 297.1 [M+H]+. OH O H2N NEDC.HCl,H2NF OH N O F Step 1: Synthesis of HBS-061-186: The carboxylic acid (1.720 g, 7.50 mmol) was dissolved in CH2Cl2(40 mL). Introduced sequentially the hydroxyl amidine (0.771 g, 5.00 mmol), HOBT (1.35 g, 10.0 mmol), EDC (1.917 g, 10.0 mmol), and TEA (3.50 mL, 25.0 mmol), and stirred at RT. LCMS showed conversion to the acyl intermediate was complete after 24 h with m / z 366. The acyl intermediate was isolated by extractive workup between EtOAc and water affording a viscous yellow oil (2.44 g). The oil was dissolved in DCM (20 mL), toluene (30 mL) was added, and the reaction was heated in an open flask to 100oC. LCMS showed complete conversion after 21 h forming product with m / z 348, 292, 248. Upon cooling the reaction mix was dissolved in EtOAc and extracted with aq. sat. NaHCO3. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.717 g of colorless oil (Yield = 41.0 %). MS (ESI) mass calcd. for C18H22FN3O3, 347.2; m / z found 348.1, 292.0, 248.0 [M+H]+. Step 2: Synthesis of HBS-066-011 / HBS-066-022: Compound HBS-066-008 (0.717 g, 2.06 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (3.29 mL, 13.2 mmol) was added and the reaction was stirred vigorously at 60oC for 72 h. LCMS showed complete conversion to product m / z 248. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.53 g of powdery white solid (Yield = 90.2 %). MS (ESI) mass calcd. for C13H14FN3O, 247.1; m / z found 248.1 [M+H]+. N CF HN3N CF3 the pyrazole (0.392 g, 1.85 mmol) were dissolved in anhydrous dioxane (20 mL). The Cs2CO3(1.00 g, 3.07 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product with m / z 396 after 48 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.47 g of the product as a colorless oil (Yield = 77.7 %). MS (ESI) mass calcd. for C20H24F3N3O2, 395.2; m / z found 396.1 [M+H]+. Step 2: Synthesis of HBS-066-013: Compound HBS-066-010 (0.473 g, 1.20 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (1.50 mL, 6.00 mmol) was added and the reaction was stirred vigorously at 60oC for 66 h. LCMS showed complete conversion to product m / z 296. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.37 g of powdery white solid (Yield = 84.0 %). MS (ESI) mass calcd. for C15H16F3N3, 295.1; m / z found 296.1 [M+H]+. N3 Synthesis of HBS-066-019: HBS-061-169 (1.179 g, 3.32 mmol) was dissolved in anhydrous DMF (20 mL). The NaN3 (0.323 g, 4.97 mmol) was added, and the reaction mixture was heated to 70oC with vigorous stirring. LCMS showed high conversion to product with m / z 171, 127 after 24 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.630 g of the product as a colorless oil (Yield = 83.9 %). MS (ESI) mass calcd. for C10H18N4O2, 226.2; m / z found 171.1, 127.1 [M+H]+. Step 1: Synthesis of HBS066-017: Compound HBS-066-019 (0.177 g, 0.782 mmol) was dissolved in a mixture of toluene and t-BuOH (4:1 v / v mL). Added sequentially the acetylene (0.103 mL, 0.938 mmol), CuI (15 mg, 0.078 mmol), and DIPEA (0.272 mL, 1.56 mmol). The reaction mixture was stirred vigorously at RT. LCMS showed high conversion to product with m / z 329.0 after 42 h. The reaction mixture was evaporated, and the crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.159 g of the product as a white solid (Yield = 62.0 %). MS (ESI) mass calcd. for C18H24N4O2, 328.2; m / z found 329.2 [M+H]+. Step 2: Synthesis of HBS-066-021: Compound HBS-066-017 (0.159 g, 0.484 mmol) was dissolved in anhydrous dioxane (10 mL). The 4.0 M HCl in dioxane (0.81 mL, 3.24 mmol) was added and the reaction was stirred vigorously at 60oC for 72 h forming a suspension. LCMS showed complete conversion to product m / z 229. The reaction mixture was cooled to RT, filtered, and washed with Hexane. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.14 g of off white waxy solid (yield = 95.3%). MS (ESI) mass calcd. for C13H16N4, 228.1; m / z found 229.1 [M+H]+. F F g, was dissolved in a mixture of toluene and t-BuOH (6:1.5, v / v mL). Added sequentially the acetylene (0.200 g, 1.66 mmol), CuI (28 mg, 0.147 mmol), and DIPEA (0.485 mL, 2.78 mmol). The reaction mixture was stirred vigorously at RT. LCMS showed incomplete conversion to product after 42 h. Heated to 60oC to achieve high conversion after 2.5 h forming product with m / z 347. The reaction mixture was evaporated, and the crude product was purified by column chromatography, mobile phase: hexanes / EtOAc gradient. Obtained 0.32 g of the product as a white solid (Yield = 66.6 %). MS (ESI) mass calcd. for C18H23FN4O2, 346.2; m / z found 347.1 [M+H]+. Step 2: Synthesis of HBS-066-028: Compound HBS-066-024 (0.321 g, 0.927 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.32 mL, 9.27 mmol) was added and the reaction was stirred vigorously at 60oC for 42 h. LCMS showed complete conversion to product m / z 247. The reaction mixture was cooled to RT, filtered, and washed with hexanes to obtain a white waxy solid that adhered to the filter paper. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.32 g of white waxy solid (Yield Quant.). MS (ESI) mass calcd. for C13H15FN4, 246.1; m / z found 247.1 [M+H]+. 10 mol% CuI Cl Step 1: Synthesis of HBS-066-025: Compound HBS-066-019 (0.315 g, 1.39 mmol) was dissolved in a mixture of toluene and t-BuOH (6:1.5, v / v mL). Added sequentially the acetylene (0.228 g, 1.67 mmol), CuI (28 mg, 0.147 mmol), and DIPEA (0.485 mL, 2.78 mmol). The reaction mixture was stirred vigorously at RT. LCMS showed incomplete conversion to product after 42 h. Heated to 60oC to achieve high conversion after 2.5 h forming product with m / z 363. The reaction mixture was evaporated, and the crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.312 g of the product as a white solid (Yield = 61.8 %). MS (ESI) mass calcd. for C18H23ClN4O2, 362.2; m / z found 363.1 [M+H]+. Step 2: Synthesis of HBS-066-029: Compound HBS-066-025 (0.31 g, 0.860 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.15 mL, 8.60 mmol) was added and the reaction was stirred vigorously at 60oC for 42 h forming a suspension. LCMS showed complete conversion to product m / z 263. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.260 g of white solid (Yield = 90.1 %). MS (ESI) mass calcd. for C13H15ClN4, 262.1; m / z found 263.1 [M+H]+. HN N Cs2CO3N ClCl Step 1: Synthesis of HBS-066-032: HBS-061-169 (1.01 g, 2.83 mmol) and the pyrazole (0.607 g, 3.40 mmol) were dissolved in anhydrous dioxane (25 mL). The Cs2CO3 (1.85 g, 5.68 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product as a 92:8 isomer mixture with m / z 362 after 24 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.518 g of the major isomer as a colorless oil (Yield = 50.5 %). MS (ESI) mass calcd. for C19H24ClN3O2, 361.2; m / z found 362.1 [M+H]+. Step 2: Synthesis of HBS-066-035 / HBS-066-044: Compound HBS-066-032 (0.518 g, 1.43 mmol) was dissolved in anhydrous dioxane (30 mL). The 4.0 M HCl in dioxane (3.58 mL, 14.3 mmol) was added and the reaction was stirred vigorously at 60oC for 66 h forming a suspension. LCMS showed complete conversion to product m / z 262. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.395 g of powdery white solid (Yield = 82.4 %). MS (ESI) mass calcd. for C14H16ClN3, 261.1; m / z found 262.1 [M+H]+. HN N Step 1: Synthesis of HBS066-034: HBS-061-169 (0.499 g, 1.40 mmol) and the pyrazole (0.243 g, 1.68 mmol) were dissolved in anhydrous dioxane (12 mL). The Cs2CO3(0.915 g, 2.81 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product with isomer mixture m / z 328 after 90 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. TLC (95:5, DCM, MeOH) showed the isomers separating. The crude product was purified by column chromatography, mobile phase: DCM:MeOH gradient. Obtained 0.253 g of the major isomer as a yellow oil (Yield = 55.0 %). MS (ESI) mass calcd. for C19H25N3O2, 327.2; m / z found 328.2 [M+H]+. Step 2: Synthesis of HBS-066-039: Compound HBS-066-034 (0.253 g, 7.73 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (1.93 mL, 4.88 mmol) was added and the reaction was stirred vigorously at 60oC for 27 h forming a suspension. LCMS showed complete conversion to product m / z 228. The reaction mixture was cooled to RT, filtered, and washed with Hexane. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.168 g of white crystalline wax (Yield = 72.4 %). MS (ESI) mass calcd. for C14H17N3, 227.1; m / z found 228.1 [M+H]+. HN N Cs2CO3F Step 1: Synthesis of HBS-066-036: Compound HBS-061-169 (0.978 g, 2.75 mmol) and the pyrazole (0.545 g, 3.02 mmol) were dissolved in anhydrous dioxane (25 mL). The Cs2CO3 (1.79 g, 5.49 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product as a 96:4 isomer mixture with m / z 364 after 64 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.682 g of the major isomer as a colorless oil (Yield = 68.2 %). MS (ESI) mass calcd. for C19H23F2N3O2, 363.2; m / z found 364.2 [M+H]+. Step 2: Synthesis of HBS-066-042: Compound HBS-066-036 (0.682 g, 1.88 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.35 mL, 9.40 mmol) was added and the reaction was stirred vigorously at 60oC for 66 h forming a suspension. LCMS showed complete conversion to product m / z 264. The reaction mixture was cooled to RT, filtered, and washed with hexanes to obtain a film that adhered to the filter paper. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.55 g of off-white wax (Yield = 87.2 %). MS (ESI) mass calcd. for C14H15F2N3, 263.1; m / z found 264.2 [M+H]+.HN NCs2CO3N N Cl Step 1: Synthesis of HBS-066-037: Compound HBS-061-169 (0.963 g, 2.71 mmol) and the pyrazole (0.532 g, 2.98 mmol) were dissolved in anhydrous dioxane (25 mL). The Cs2CO3 (1.76 g, 5.40 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product with m / z 362 after 64 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.65 g of the major isomer as a yellow oil (Yield = 66.4 %). MS (ESI) mass calcd. for C19H24ClN3O2, 361.2; m / z found 362.1 [M+H]+. Step 2: Synthesis of HBS-066-043: Compound HBS066-037 (0.651 g, 1.80 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.25 mL, 9.00 mmol) was added and the reaction was stirred vigorously at 60oC for 66 h forming a suspension. LCMS showed complete conversion to product m / z 262. The reaction mixture was cooled to RT, filtered, and washed with hexanes to obtain a film that adhered to the filter paper. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.54 g of beige wax (Yield = 88.9 %). MS (ESI) mass calcd. for C14H16ClN3, 261.1; m / z found 262.1 [M+H]+. HN N Cs2CO3N N F Step 1: Synthesis of HBS-066-046: Compound HBS-061-169 (1.355 g, 3.81 mmol) and the pyrazole (0.680 g, 4.19 mmol) were dissolved in anhydrous dioxane (40 mL). The Cs2CO3 (2.48 g, 7.61 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product with isomer mixture m / z 346 after 48 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. TLC (95:5 DCM,MeOH) showed the isomers separating. The crude product was purified by column chromatography, mobile phase: DCM:MeOH gradient. Obtained 0.63 g of the major isomer as a yellow oil (Yield = 47.9 %). MS (ESI) mass calcd. for C19H24FN3O2, 345.2; m / z found 346.2 [M+H]+. Step 2: Synthesis of HBS-066-050: Compound HBS-066-046 (0.61 g, 1.78 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.22 mL, 8.88 mmol) was added and the reaction was stirred vigorously at 60oC for 68 h forming a suspension. LCMS showed complete conversion to product m / z 246. The reaction mixture was cooled to RT, filtered, and washed with Hexane to afford 0.478 g of white solid (Yield = 84.5%). MS (ESI) mass calcd. for C14H16FN3, 245.1; m / z found 246.2 [M+H]+.

[0017] HN N Cs2CO3 Step 1: Synthesis of HBS-066-047: Compound HBS-061-169 (0.858 g, 2.41 mmol) and the pyrazole (0.564 g, 2.66 mmol) were dissolved in anhydrous dioxane (25 mL). The Cs2CO3 (1.57 g, 4.82 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product as a 92:8 isomer mixture with m / z 396 after 64 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography, mobile phase: hexanes / EtOAc gradient. Obtained 0.70 g of the major isomer as a colorless oil (Yield = 73.8 %). MS (ESI) mass calcd. for C20H24F3N3O2, 395.2; m / z found 396.2 [M+H]+. Step 2: Synthesis of HBS-066-053: Compound HBS-066-047 (0.704 g, 1.78 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.20 mL, 8.80 mmol) was added and the reaction was stirred vigorously at 60oC for 72 h. LCMS showed complete conversion to product m / z 296. The reaction mixture was cooled to RT, filtered, and washed with Hexane. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.59 g of off white crusty solid (Yield = 90.1 %). MS (ESI) mass calcd. for C15H16F3N3, 295.1; m / z found 296.2 [M+H]+. HN N Cs2CO3S Cl Step 1: Synthesis of HBS-066-048: HBS061-169 (0.866 g, 2.44 mmol) and the pyrazole (0.495 g, 2.68 mmol) were dissolved in anhydrous dioxane (25 mL). The Cs2CO3 (1.59 g, 4.88 mmol) was added, and the reaction mixture was heated to 100oC with vigorous stirring. LCMS showed high conversion to product with isomer mixture m / z 368 after 64 h. The reaction mixture was cooled to RT, treated with water, and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and evaporated. TLC (2:1 Hexane:EtOAc) showed the isomers separating. The crude product was purified by column chromatography, mobile phase: Hexane:EtOAc gradient. Obtained 0.670 g of the major isomer as a colorless oil (Yield = 74.7 %). MS (ESI) mass calcd. for C17H22ClN3O2S, 367.1; m / z found 368.1 [M+H]+. Step 2: Synthesis of HBS-066-054: Compound HBS-066-048 (0.670 g, 1.82 mmol) was dissolved in anhydrous dioxane (20 mL). The 4.0 M HCl in dioxane (2.30 mL, 9.20 mmol) was added and the reaction was stirred vigorously at 60oC for 72 h. LCMS showed complete conversion to product m / z 268. The reaction mixture was cooled to RT, filtered, and washed with Hexane to obtain a crusty solid that adhered to the filter paper. The sample was dissolved in MeOH, concentrated, and dried in a vacuum oven to afford 0.53 g of off white crusty solid (Yield = 85.9 %). MS (ESI) mass calcd. for C12H14ClN3S, 267.1; m / z found 268.1 [M+H]+. CF3H 4.0 M HCl H NH2DMSON N in Dioxane N N NN CF3 (S)-1-Boc-2-(aminomethyl)-pyrrolidine (0.36 g, 1.81 mmol) were dissolved in Dry DMSO (5.0 mL). The DIPEA (1.6 mL, 9.1 mmol) was added and rxn mixture was stirred at 100oC temperature for 4 h. TLC shows product formation. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The desired liquid product was isolated 0.24 g (Yield 39.0 %). MS (ESI) mass calcd. for C16H22F3N3O2, 345.0; m / z found 346.1 [M+H]+. Synthesis of HBS-037-069: HBS-037-067 (0.24 g, 0.71 mmol) were dissolved in Dry Dioxane (3.0 mL). The 4.0 M HCl solution in dioxane (1.77 mL, 7.08 mmol) was added and rxn mixture was stirred at 50oC temperature for 4 h. LCMS shows product formation m / z 246. The rxn mixture was concentrated under reduced pressure to obtain solid product (0.19 g, Yield 78.4 %). MS (ESI) mass calcd. for C11H14F3N3, 245.2; m / z found 246.0 [M+H]+,1H NMR (400 MHz,CHLOROFORM-d - 2.01 (m, 1 H) 2.01 - 2.15 (m, 1 H) 2.15 - 2.28 (m, 1 H) 2.36 (brs, 1 H) 3.25 - 3.46 (br s, 1 H) 3.48 (br s, 1 H) 4.04 (br s, 2 H) 4.31 (br s, 1 H) 7.47 (br s, 1 H) 7.86 (br s, 1 H) 8.19 (br s, 1 H) 9.41 - 10.42 (br s, 1 H). H H Step 1: Synthesis of HBS-037-070: 2-Chloro-5-ethyl-pyrimidine (0.2 g, 1.37 mmol) and (S)-1- Boc-2-(aminomethyl)-pyrrolidine (0.28 g, 1.37 mmol) were dissolved in Dry DMF (5.0 mL). The Cs2CO3 (0.89 g, 2.75 mmol) was added and rxn mixture was stirred at 120oC temperature for 24 h. TLC shows product formation. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The desired liquid product was isolated 0.27 g (Yield 64.2 %). MS (ESI) mass calcd. for C16H26N4O2, 306.4; m / z found 307.1 [M+H]+. Step 2: Synthesis of HBS-037-074: HBS-037-070 (0.27 g, 0.88 mmol) were dissolved in Dry Dioxane (3.0 mL). The 4.0 M HCl solution in dioxane (2.2 mL, 8.81 mmol) was added and rxn mixture was stirred at 60oC temperature for 4 h. LCMS shows product formation m / z 207. The rxn mixture was concentrated under reduced pressure to obtain solid product (0.31 g, Yield Quant.). MS (ESI) mass calcd. for C11H18N4, 206.3; m / z found 207.1 [M+H]+. H N N DMF N 20.0 % Pd-OH / C 2- yl]methanamine (0.35 g, 1.4 mmol) and 2-chloro-5-ethyl-pyrimidine (0.2 g, 1.4 mmol) were dissolved in Dry DMF (4.0 mL). The K2CO3 (0.39 g, 2.82 mmol) was added and rxn mixture was stirred at 120oC temperature for 6 h. TLC shows product formation. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by Combiflash chromatography system, Mobile phase: EtOAc:Hexane, gradient. The 0.33 g of product was obtained (Yield 65.4 %). MS (ESI) mass calcd. for C21H30N4O, 354.5; m / z found 355.2[M+H]+, 1H NMR (400 MHz, CHLOROFORM-d – 0.94 (d, J=8.0 Hz, 3 H) 1.16 (t, J=8.0Hz, 3 H) 1.25 - 1.47 (m, 2 H) 1.50 - 1.84 (m, 2 H) 2.05 – 2.25 (m, 1 H) 2.35 – 2.47 (q, J=8.0 Hz, 2 H) 2.47 – 2.60 (m, 1 H) 2.62 - 2.83 (m, 2 H) 3.33 - 3.46 (m, 2 H) 3.77 (s, 3 H) 3.78 - 3.85 (m, 2 H) 5.68 (br s, 1 H) 6.84 (d, J=8.66 Hz, 2 H) 7.24 - 7.31 (m, 2 H) 8.12 (s, 2 H). Step 2: Synthesis of HBS-037-101: HBS-037-095 (0.1 g, 0.3 mmol) was dissolved in MeOH (3.0 mL). The 20.0 % Pd-OH / C (30.0 mg) was added and rxn mixture was stirred at ambient temperature for 24 h. The TLC shows little amount of starting material and product formation. The 20.0 % Pd-OH / C (30.0 mg) was further added and rxn mixture was stirred at ambient temperature for another 24 h. The TLC shows completion of rxn. The LCMS data shows m / z 235 of product formation. The rxn mixture was filtered over celite and washed with MeOH. The filtrate was evaporated under reduced pressure to obtain 66.0 mg of crude product. The crude product is used in next step without purification. MS (ESI) mass calcd. for C13H22N4, 234.3; m / z found 235.2 [M+H]+. CF3H N Pd / C NH2DMF N H2, 16 h N CF3 2- yl]methanamine (0.32 g, 1.29 mmol) and 2-chloro-5-trifluoromethyl-pyridine (0.23 g, 1.29 mmol) were dissolved in Dry DMF (5.0 mL). The K2CO3(0.36 g, 2.58 mmol) was added and rxn mixture was stirred at 120oC temperature for 4 h. TLC shows product formation and LCMS shows m / z 394 of product formation. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combiflash chromatography system, Mobile phase: DCM:MeOH (90:10 v / v mL). The product band was isolated. The 0.41 g of pure product was obtained with m / z 394 (Yield 81.4 %). MS (ESI) mass calcd. For C21H26F3N3O, 393.5;m / z found 394.1 [M+H]+, 1H NMR (400 MHz, CHLOROFORM-d J=7.04 Hz, 3 H)1.19 - 1.46 (m, 2 H) 1.54 - 1.65 (m, 1 H) 1.65 - 1.83 (m, 1 H) 2.07 - 2.22 (m, 1 H) 2.50 - 2.65 (m, 1 H) 2.65 - 2.80 (m, 2 H) 3.20 - 3.38 (m, 2 H) 3.78 (s, 3 H) 3.79 - 3.84 (m, 2 H) 5.67 (br s, 1 H) 6.32 (d, J=8.80 Hz, 1 H) 6.80 - 6.89 (m, 2 H) 7.15 - 7.29 (m, 2 H) 7.49 (dd, J=8.80, 2.35 Hz, 1 H) 8.28 - 8.32 (m, 1 H) Step 2: Synthesis of HBS-037-110: HBS-037-106 (0.02 g, 0.5 mmol) was dissolved in MeOH (5.0 mL). The 10.0 % Pd / C (60.0 mg) was added and rxn mixture was stirred at ambient temperature for 24 h under H2 atm. The TLC shows completion of rxn. The LCMS data shows m / z 274 of product formation. The rxn mixture was filtered over celite and washed with MeOH. The filtrate was evaporated under reduced pressure to obtain 0.16 g of crude product. MS (ESI) mass calcd. for C13H18F3N3, 273.3; m / z found 274.1 [M+H]+. Cl N O 4.0 M HCl OH NaH in Dioxane NN NN O N N N Dry DMF (4.0 mL). The NaH (0.08 g, 2.0 mmol) was added under ice cooling. The 2-Chloro-5-Ethyl- Pyrimidine (0.2 g, 1.5 mmol) was added under cooling and rxn mixture was gradually warmed at room temperature under stirring for 3 h. The LCMS shows product formation m / z 308.2. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate three times. The EtOAc layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.3 g of pure product was obtained (Yield Quantitative). MS (ESI) mass calcd. for C16H25N3O3, 307.4; m / z found 308.2 [M+H]+. Step 2: Synthesis of HBS-037-154: HBS-037-152 (0.3 g, 0.99 mmol) were dissolved in Dry Dioxane (4.0 mL). The 4.0 M HCl solution in dioxane (2.48 mL, 9.9 mmol) was added and rxn mixture was stirred at 60oC temperature for 4 h. LCMS shows product formation m / z 208.1. The rxn mixture was concentrated under reduced pressure to obtain 0.32 g of liquid product. MS (ESI) mass calcd. for C11H17N3O, 207.3; m / z found 208.1 [M+H]+. Cl OH O 4.0 M HCl NNaHCF3 Dry DMF (4.0 mL). The NaH (0.08 g, 2.0 mmol) was added followed by 2-Chloro-5- trifluoromethylpyridine (0.27 g, 1.5 mmol). The rxn mixture was heated at 70oC temperature for 3 h. The LCMS shows product formation m / z 347.1. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate three times. The EtOAc layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc: Hexane gradient. The 0.3 g of pure product was obtained (Yield 86.0 %). MS (ESI) mass calcd. for C16H21F3N2O3, 346.3; m / z found 347.1 [M+H]+. Step 1: Synthesis of HBS-037-155: HBS-037-153 (0.3 g, 0.86 mmol) were dissolved in Dry Dioxane (2.0 mL). The 4.0 M HCl solution in dioxane (2.14 mL, 8.6 mmol) was added and rxn mixture was stirred at 60oC temperature for 4 h. LCMS shows product formation m / z 247.1. The rxn mixture was filtered and washed with Hexane (5.0 mL x 3) to obtain the 0.27 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C11H13F3N2O, 246.2; m / z found 247.1 [M+H]+,1H NMR(400 MHz, CHLOROFORM-d - 1.99 (m, 1 H) 1.99 - 2.08 (m, 1 H) 2.08 - 2.17 (m, 1H) 2.17 - 2.29 (m, 1 H) 3.32 - 3.49 (m, 2 H) 3.96 - 4.09 (m, 1 H) 4.60 - 4.77 (m, 2 H) 7.00 (d, J=8.73 Hz, 1 H) 7.77 (dd, J=8.73, 2.35 Hz, 1 H) 8.37 - 8.42 (m, 1 H) 9.74 (br s, 1 H) 10.32 (br s, 1 H). Cl OS OHN OHNO O S NDMF Step 1: Synthesis of HBS-039-033: The N-Boc-L-Prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.9 mL, 4.97 mmol) was added followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled in ice bath and p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256, 300. The rxn mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.88 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.5; m / z found 300.1, 256.1 [M+H]+. Step 2: Synthesis of HBS-039-034: HBS-039-033 (0.88 g, 2.48 mmol) and 3-Phenyl-1H- Pyrazole (0.43 g, 2.98 mmol) were dissolved in Dry DMF (5.0 mL). The Cs2CO3(1.61 g, 4.96 mmol) was added and the rxn mixture was stirred at 70oC temperature for 4 h. The LCMS shows product formation m / z 328. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.73 g of pure product was obtained (Yield 89.5 %). MS (ESI) mass calcd. for C19H25N3O2, 327.4; m / z found 328.3 [M+H]+. Step 3: Synthesis of HBS-039-036: HBS-039-034 (0.73 g, 2.24 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in dioxane (2.8 mL, 11.2 mmol) was added and rxn mixture was stirred at 50oC temperature for 16 h. LCMS shows product formation m / z 228. The rxn mixture was filtered and washed with Hexane (5.0 mL x 3) to obtain the 0.53 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C14H17N3, 227.1; m / z found 228.2 [M+H]+,1H NMR (400MHz, CHLOROFORM-d - 1.94 (m, 1 H) 1.94 - 2.05 (m, 1 H) 2.06 - 2.15 (m, 1 H) 2.16– 2.35 (m, 1 H) 3.21 - 3.45 (m, 2 H) 4.33 (br s, 1 H) 4.86 (dd, J=14.82, 3.96 Hz, 1 H) 5.07 (br dd, J=14.67, 8.66 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 7.34 - 7.48 (m, 3 H) 7.76 - 7.87 (m, 2 H) 8.44 (d, J=2.49 Hz, 1 H) 9.51 - 10.12 (br, 1 H). Cl H NH24.0 M HCl H Pd2(dba)3, X-phos N N in Dioxane N N F and 2-Chloro-5-fluoro pyridine (0.033 g, 0.25 mmol) were dissolved in Dioxane (3.0 mL). The anhydrous t-BuOK (0.042 g, 0.37 mmol) was added followed by Pd2(dba)3 (0.023 g, 0.025 mmol) and X-Phos (0.012 g, 0.025 mmol). The rxn mixture was stirred at 110oC temperature under N2 atm. for 4 h. The LCMS data shows product formation m / z 296.0. The rxn mixture was filtered over celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.032 g of product wasobtained (Yield 86.8 %). MS (ESI) mass calcd. for C15H22FN3O2, 295.35; m / z found 296.0 [M+H]+. Step 2: Synthesis of HBS-039-120: Compound HBS-039-118 (0.032 g, 0.11 mmol) was dissolved in Dry Dioxane (1.0 mL). The 4.0 M HCl solution in dioxane (0.27 mL, 1.1 mmol) was added and rxn mixture was stirred at ambient temperature for 16 h. LCMS shows product formation m / z 196.1. The rxn mixture was concentrated under reduced pressure to obtain the 0.033 g of product (Yield Quant.). MS (ESI) mass calcd. for C10H14FN3, 195.24; m / z found 196.1 [M+H]+. Br O OH 4.0 M HCl N N NaH N N Br Dioxane O + N Br% DMF (2.0 mL). The NaH (0.12 g, 2.98 mmol) was added at 0oC temperature. The rxn mixture was stirred at 0oC temperature for 30.0 min. The 2-Bromo-5-fluoro-pyridine (0.26 g, 1.49 mmol) solution in DMF (1.0 mL) was added at 0oC temperature. The rxn mixture was gradually warmed at ambient temperature and heated at 70oC temperature for 3 h. The LCMS shows product formation m / z 357.1. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.25 g of product was obtained (Yield 70.4 %). MS (ESI) mass calcd. for C15H21BrN2O3, 357.24; m / z found 357.1 [M+H]+. Step 2: Synthesis of HBS-039-137: Compound HBS-039-131 (0.25 g, 0.7 mmol) was dissolved in Dry Dioxane (5.0 mL). The 4.0 M HCl solution in dioxane (1.74 mL, 7.0 mmol) was added and rxn mixture was stirred at 50oC temperature for 6 h. LCMS shows product formation m / z 257. The rxn mixture was filtered and dried to obtain the 0.2 g of product (Yield 86.6 %). MS (ESI) mass calcd. for C10H13BrN2O, 257.13; m / z found 257.0 [M+H]+. Cl 4.0 M HCl CF3 - was dissolved in anhydrous DMF (5.0 mL). The NaH (0.14 g, 3.48 mmol) was added at 0oC temperature and reaction mixture was stirred for 15.0 min. The 2-chloro-5-trifluoromethylpyridine (0.32 g, 1.74 mmol) was added and the reaction mixture was gradually warmed at ambient temperature. The reaction mixture was heated at 80oC for 8 h. LCMS shows product formation m / z 361.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The EtOAc layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.2 g of product was obtained (Yield 48.0 %). MS (ESI) mass calcd. for C17H23F3N2O3, 360.37; m / z found 361.2 [M+H]+. Step 2: Synthesis of HBS-039-160: Compound HBS-039-144 (0.2 g, 0.56 mmol) was dissolved in anhydrous Dioxane (5.0 mL). The 4.0 M HCl in Dioxane (1.39 mL, 5.58 mmol) was added and the reaction was heated at 50oC temperature for 3 h. LCMS shows product formation m / z 261.1. The reaction mixture was concentrated under reduced pressure to obtain 0.16 g of product (Yield 86.1 %). MS (ESI) mass calcd. for C12H15F3N2O, 260.26; m / z found 261.1 [M+H]+. Cl H HO S ON ONO O NDMFCF33 Step 1: Synthesis of HBS-039-166: The N-Boc-L-Prolinol (1.0 g, 4.97 mmol) was dissolved in DCM (15.0 mL). The DIPEA (1.72 mL, 9.94 mmol) was added followed by DMAP (1.21 g, 9.94 mmol). The rxn mixture was cooled at 0oC in Ice bath. The p-TsCl (1.04 g, 5.46 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 1.76 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.0 [M-Boc]+. Step 2: Synthesis of HBS-039-172: Compound HBS-039-166 (0.84 g, 2.36 mmol) and 3-[4- (trifluoromethyl)Phenyl]-1H-Pyrazole (0.5 g, 2.36 mmol) were dissolved in Dry DMF (10.0 mL). The anhydrous Cs2CO3 (1.53 g, 4.71 mmol) was added and the rxn mixture was stirred at 70oC temperature for 12 h. The LCMS shows product formation m / z 396.3. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.8 g of pure product was obtained (Yield 85.9 %). MS (ESI) mass calcd. for C20H24F3N3O2, 395.42; m / z found 396.3 [M+H]+. Step 3: Synthesis of HBS-039-176: Compound HBS-039-172 (0.8 g, 2.02 mmol) was dissolved in Dry Dioxane (20.0 mL). The 2.0 M HCl solution in Diethyl ether (4.1 mL, 8.1 mmol) was added and rxn mixture was stirred at 60oC temperature for 16 h. LCMS shows product formation m / z 296.1. The rxn mixture cooled and ppts were filtered. The ppts were dried to obtain the 0.6 g of solid product (Yield 89.4 %). MS (ESI) mass calcd. for C14H17N3, 227.1; m / z found 228.2 [M+H]+. Cl HN OH O S ONO O NCs2CO3F F Step 1: Synthesis of HBS-039-177: The N-Boc-L-Prolinol (1.0 g, 4.97 mmol) was dissolved in DCM (15.0 mL). The DIPEA (1.72 mL, 9.94 mmol) was added followed by DMAP (1.21 g, 9.94 mmol). The rxn mixture was cooled at 0oC in Ice bath. The p-TsCl (1.04 g, 5.46 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256.1, 300.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave 1.76 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.1, 300.1 [M-Boc]+. Step 2: Synthesis of HBS-039-178: Compound HBS-039-177 (1.0 g, 6.17 mmol) and 3-[4- fluorophenyl]-1H-Pyrazole (1.0 g, 6.17 mmol) were dissolved in Dry DMF (20.0 mL). The anhydrous Cs2CO3(4.0 g, 12.33 mmol) was added and the rxn mixture was stirred at 70oC temperature for 12 h. The LCMS shows product formation m / z 346.3. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 2.0 g of pure product was obtained (Yield 93.9 %). MS (ESI) mass calcd. for C19H24FN3O2, 345.41; m / z found 346.3 [M+H]+. Step 3: Synthesis of HBS-039-179: Compound HBS-039-178 (2.0 g, 5.79 mmol) was dissolved in Dry Dioxane (20.0 mL). The 2.0 M HCl solution in Diethyl ether (11.58 mL, 23.16 mmol) was added and rxn mixture was stirred at 60oC temperature for 16 h. LCMS shows product formation m / z 24621. The rxn mixture cooled and ppts were filtered. The ppts were dried to obtain 1.63 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C14H16FN3, 245.3; m / z found 246.2 [M+H]+. Cl OH O S OHN N N N O O Cs2CO3h Step 1: Synthesis of HBS-055-090: The N-Boc-L-Prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.9 mL, 4.97 mmol) was added followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled at 0oC in Ice bath. The p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256.1, 300.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave 0.88 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.1, 300.1 [M-Boc]+. Step 2: Synthesis of HBS-055-091: Compound HBS-055-090 (0.88 g, 2.48 mmol) and 2-(1H- pyrazol-4-yl)pyridine dihydrochloride (0.6 g, 2.73 mmol) were dissolved in Dry DMF (10.0 mL). The anhydrous Cs2CO3(1.61 g, 4.97 mmol) was added and the rxn mixture was stirred at 70oC temperature for 16 h. The LCMS shows product formation m / z 329.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.82 g of pure product was obtained (Yield 81.5 %). MS (ESI) mass calcd. for C18H24N4O2, 328.41; m / z found 329.2 [M+H]+. Step 3: Synthesis of HBS-055-092: Compound HBS-055-091 (0.82 g, 2.48 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (2.5 mL, 9.94 mmol) was added and rxn mixture was stirred at 50oC temperature for 12 h. LCMS shows product formation m / z 229.2. The rxn mixture cooled and ppts were filtered. The ppts were dried to obtain 0.75 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C13H16N4, 228.29; m / z found 229.1 [M+H]+. Cl OH O S O HN O O N N h HBS-055-097 0.75 g, Yield Quant. Step 1: Synthesis of HBS-055-093: The N-Boc-L-Prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.9 mL, 4.97 mmol) was added followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled at 0oC in Ice bath. The p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256.1, 300.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.88 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.1, 300.1 [M-Boc]+. Step 2: Synthesis of HBS-055-094: Compound HBS-055-093 (0.88 g, 2.48 mmol) and 2-(1H- pyrazol-3-yl)pyridine (0.43 g, 2.98 mmol) were dissolved in Dry DMF (10.0 mL). The anhydrous Cs2CO3(1.62 g, 4.97 mmol) was added and the rxn mixture was stirred at 70oC temperature for 12 h. The LCMS shows product formation m / z 329.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.81 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C18H24N4O2, 328.41; m / z found 329.2 [M+H]+. Step 3: Synthesis of HBS-055-097: Compound HBS-055-094 (0.81 g, 2.48 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (2.5 mL, 9.93 mmol) was added and rxn mixture was stirred at 50oC temperature for 12 h. LCMS shows product formation m / z 229.2. The rxn mixture cooled and ppts were filtered. The ppts were dried to obtain 0.75 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C13H16N4, 228.29; m / z found 229.1 [M+H]+. Cl HN N OH O S OO O N h Step 1: Synthesis of HBS-055-095: The N-Boc-L-Prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.9 mL, 4.97 mmol) was added followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled at 0oC in Ice bath. The p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256.1, 300.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.88 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.1, 300.1 [M-Boc]+. Step 2: Synthesis of HBS-055-096: Compound HBS-055-095 (0.88 g, 2.48 mmol) and 4-Phenyl- 1H-pyrazole (0.72 g, 4.97 mmol) were dissolved in Dry DMF (10.0 mL). The anhydrous Cs2CO3(1.62 g, 4.97 mmol) was added and the rxn mixture was stirred at 70oC temperature for 16 h. The LCMS shows product formation m / z 328.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.6 g of pure product was obtained (Yield 73.8 %). MS (ESI) mass calcd. for C19H25N3O2, 327.42; m / z found 328.2 [M+H]+. Step 3: Synthesis of HBS-055-098: Compound HBS-055-096 (0.6 g, 1.83 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (1.83 mL, 7.33 mmol) was added and rxn mixture was stirred at 50oC temperature for 12 h. LCMS shows product formation m / z 228.2. The rxn mixture cooled and ppts were filtered. The ppts were dried to obtain 0.48 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C14H17N3, 227.31; m / z found 228.2 [M+H]+. Cl OH O S OHN N O O N F F Step 1: Synthesis of HBS-055-102: The N-Boc-L-Prolinol (0.5 g, 2.48 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.9 mL, 4.97 mmol) was added followed by DMAP (0.61 g, 4.97 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.52 g, 2.73 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256.1, 300.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.88 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.1, 300.1 [M-Boc]+. Step 2: Synthesis of HBS-055-103: Compound HBS-055-102 (0.88 g, 2.48 mmol) and 5-Fluoro- 2-(1H-pyrazole-4-yl)pyridine (0.7 g, 2.98 mmol) were dissolved in Dry DMF (10.0 mL). The anhydrous Cs2CO3 (2.64 g, 8.1 mmol) was added and the rxn mixture was stirred at 80oC temperature for 16 h. The LCMS shows product formation m / z 347.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.45 g of pure product was obtained (Yield 52.3 %). MS (ESI) mass calcd. for C18H23FN4O2, 346.4; m / z found 347.2 [M+H]+. Step 3: Synthesis of HBS-055-109: Compound HBS-055-103 (0.45 g, 1.3 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (1.3 mL, 5.2 mmol) was added and rxn mixture was stirred at 50oC temperature for 6 h. LCMS shows product formation m / z 246.28. The rxn mixture cooled and ppts were filtered. The ppts were dried to obtain 0.21 g of solid product (Yield 50.6 %). MS (ESI) mass calcd. for C13H15FN4, 246.28; m / z found 247.1 [M+H]+. 2.0 M BH3.Me2S Cl in THF NaH O CF3h 3 - - Heptane-3-carboxylic acid (0.5 g, 2.1 mmol) was dissolved in Dry THF (10.0 mL). The 2.0 M BH3.Me2S (2.1 mL, 4.14 mmol) was added at 0oC temperature. The rxn mixture gradually warmed at ambient temperature for 16 h. The LCMS shows product formation m / z 172.1, 250.1. The rxn mixture was quenched with Methanol. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.47 g of crude product. (Yield Quant.). MS (ESI) mass calcd. for C12H21NO3, 227.3; m / z found 172.1, 250.1 [M+Na]+. Step 2: Synthesis of HBS-055-123: Compound HBS-055-120 (0.47 g, 2.1 mmol) was dissolved in Dry THF (10.0 mL). The NaH (0.166 g, 4.14 mmol) was added at 0oC temperature. The 2- Chloro-5-trifluoromethylpyridine (0.45 g, 2.48 mmol) was added and reaction mixture was gradually heated at reflux temperature for 16 h. The LCMS shows product formation m / z 373.1. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.5 g of pure product was obtained (Yield 64.9 %). MS (ESI) mass calcd. for C18H23F3N2O3, 372.38; m / z found 373.1 [M+H]+. Step 3: Synthesis of HBS-055-127: Compound HBS-055-123 (0.5 g, 1.34 mmol) was dissolved in Dioxane (10.0 mL). The 4.0 M HCl solution in dioxane (1.34 mL, 5.37 mmol) was added and rxn mixture was stirred at 50oC temperature for 16 h. LCMS shows product formation m / z 273.1. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.41 g of solid product (Yield 88.4 %). MS (ESI) mass calcd. for C13H15F3N2O, 272.27; m / z found 273.1 [M+H]+. Cl OH O S OHN O O N F F Step 1: Synthesis of HBS-055-140: The N-Boc-L-Prolinol (0.25 g, 1.24 mmol) was dissolved in DCM (5.0 mL). The DIPEA (0.43 mL, 2.48 mmol) was added followed by DMAP (0.3 g, 2.48 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.26 g, 1.34 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256.1, 300.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.44 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.1, 300.1 [M-Boc]+. Step 2: Synthesis of HBS-055-141: Compound HBS-055-140 (0.44 g, 1.24 mmol) and 5-Fluoro- 2-(1H-pyrazole-3-yl)pyridine (0.24 g, 1.49 mmol) were dissolved in Dry DMF (8.0 mL). The anhydrous Cs2CO3 (1.21 g, 3.73 mmol) was added and the rxn mixture was stirred at 70oC temperature for 16 h. The LCMS shows product formation m / z 347.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.42 g of pure product was obtained (Yield 97.2 %). MS (ESI) mass calcd. for C18H23FN4O2, 346.4; m / z found 347.2 [M+H]+. Step 3: Synthesis of HBS-055-143: Compound HBS-055-141 (0.42 g, 1.21 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (1.21 mL, 4.83 mmol) was added and rxn mixture was stirred at 50oC temperature for 12 h. LCMS shows product formation m / z 247.1. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.38 g of solid product (Yield 98.6 %). MS (ESI) mass calcd. for C13H15FN4, 246.28; m / z found 247.1 [M+H]+. 2.0 M BH Cl HN OH3.Me2S OSO in THFOH OO N F Step 1: Synthesis of HBS-055-131: (1S,3S,5S)-2-(Tert-butoxy carbonyl)-2-azabicyclo [3.1.0] Heptane-3-carboxylic acid (1.0 g, 4.4 mmol) was dissolved in Dry THF (10.0 mL). The 2.0 M BH3.Me2S (4.4 mL, 8.8 mmol) was added at 0oC temperature. The rxn mixture gradually warmed at ambient temperature for 16 h. The LCMS shows product formation m / z 158.1. The rxn mixture was quenched with Methanol. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.94 g of crude product. (Yield Quant.). MS (ESI) mass calcd. for C11H19NO3, 213.27; m / z found 158.1 [M-Boc]+. Step 2: Synthesis of HBS-055-139: Compound HBS-055-131 (0.25 g, 1.17 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.4 mL, 2.34 mmol) was added followed by DMAP (0.24 g, 2.34 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.25 g, 1.29 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 268.1, 312.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave 0.4 g of product (Yield Quant.). MS (ESI) mass calcd. for C18H25NO5S, 367.46; m / z found, 268.1, 312.1 [M-Boc]+. Step 3: Synthesis of HBS-055-142: Compound HBS-055-139 (0.4 g, 1.1 mmol) and 3-(4-Fluoro- phenyl)-1H-pyrazole (0.2 g, 1.21 mmol) were dissolved in Dry DMF (8.0 mL). The anhydrous Cs2CO3 (1.1 g, 3.3 mmol) was added and reaction mixture was stirred at 70oC temperature for 16 h. The LCMS shows product formation m / z 358.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.24 g of pure product was obtained (Yield 61.5 %). MS (ESI) mass calcd. for C20H24FN3O2, 357.42; m / z found 358.2 [M+H]+. Step 4: Synthesis of HBS-055-147: Compound HBS-055-141 (0.24 g, 0.68 mmol) was dissolved in Dry Dioxane (5.0 mL). The 4.0 M HCl solution in Dioxane (1.35 mL, 2.71 mmol) was added and rxn mixture was stirred at 50oC temperature for 16 h. LCMS shows product formation m / z 258.1. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.19 g of solid product (Yield 95.5 %). MS (ESI) mass calcd. for C15H16FN3, 257.31; m / z found 258.1 [M+H]+.OH ClHN OS OO O N F NDIPNS Cs CONNN+ EA, DMAP 2 3O O + h F Step 1: Synthesis of HBS-055-154: (S)-1-(tert-Butoxycarbonyl)-2-azetidinemethanol (0.5 g, 2.67 mmol) was dissolved in DCM (10.0 mL). The DIPEA (0.93 mL, 5.34 mmol) was added followed by DMAP (0.65 g, 5.34 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.56 g, 2.94 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 242.1, 286.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.91 g of product (Yield Quant.). MS (ESI) mass calcd. for C16H23NO5S, 341.42; m / z found, 242.1, 286.1 [M-Boc]+. Step 2: Synthesis of HBS-055-155: Compound HBS-055-154 (0.91 g, 2.67 mmol) and 3-(4- Fluorophenyl)-1H-pyrazole (0.48 g, 0.48 mmol) were dissolved in Dry DMF (10.0 mL). The anhydrous Cs2CO3(2.61 g, 8.01 mmol) was added, and reaction mixture was stirred at 70oC temperature for 16 h. The LCMS shows product formation m / z 332.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.89 g of pure product was obtained (Yield Quant.). MS (ESI) mass calcd. for C18H22FN3O2, 331.38; m / z found 332.2 [M+H]+. Step 3: Synthesis of HBS-055-158: Compound HBS-055-155 (0.89 g, 2.67 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (2.7 mL, 10.68 mmol) was added and rxn mixture was stirred at 50oC temperature for 16 h. LCMS shows product formation m / z 232.1. The rxn mixture was cooled and concentrated under reduced pressure to obtain 0.72 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C13H14FN3, 231.27; m / z found 232.1 [M+H]+.OH ClHN OS OO N F N+ DIPEA, DMAPNO S Cs2CO3 NNNN O O + h F g, 1.33 mmol) was dissolved in DCM (8.0 mL). The DIPEA (0.47 mL, 2.67 mmol) was added followed by DMAP (0.33 g, 2.67 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.28 g, 1.47 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 242.1, 286.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.46 g of product (Yield Quant.). MS (ESI) mass calcd. for C16H23NO5S, 341.42; m / z found, 242.1, 286.1 [M-Boc]+. Step 2: Synthesis of HBS-055-157: Compound HBS-055-156 (0.46 g, 1.33 mmol) and 5-fluoro- 2-(1H-pyrazole-3-yl)pyridine (0.26 g, 1.60 mmol) were dissolved in Dry DMF (10.0 mL). The anhydrous Cs2CO3(1.31 g, 4.0 mmol) was added, and reaction mixture was stirred at 70oC temperature for 16 h. The LCMS shows product formation m / z 333.1. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.44 g of pure product was obtained (Yield Quant.). MS (ESI) mass calcd. for C17H21FN4O2, 332.37; m / z found 333.1 [M+H]+. Step 3: Synthesis of HBS-055-162: Compound HBS-055-157 (0.44 g, 1.34 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (1.34 mL, 5.34 mmol) was added and rxn mixture was stirred at 40oC temperature for 16 h. LCMS shows product formation m / z 233.1. The rxn mixture cooled and concentrated under reduced pressure to obtain 0.41 g of product (Yield Quant.). MS (ESI) mass calcd. for C12H13FN4, 232.26; m / z found 233.1 [M+H]+. Cl HN OH O S OO O N DIPNSCs2CO3F N EA, DMAP O O +NNN NF in DCM (10.0 mL). The DIPEA (0.4 mL, 2.34 mmol) was added followed by DMAP (0.24 g, 2.34 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.25 g, 1.29 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 268.1, 312.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.43 g of product (Yield Quant.). MS (ESI) mass calcd. for C18H25NO5S, 367.46; m / z found, 268.1, 312.1 [M-Boc]+. Step 2: Synthesis of HBS-055-169: Compound HBS-055-168 (0.43 g, 1.17 mmol) and 5-fluoro- 2-(1H-pyrazol-3-yl)pyridine (0.23 g, 1.41 mmol) were dissolved in Dry DMF (8.0 mL). The anhydrous Cs2CO3(1.15 g, 3.52 mmol) was added, and reaction mixture was stirred at 70oC temperature for 16 h. The LCMS shows product formation m / z 359.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.23 g of pure product was obtained (Yield 53.8 %). MS (ESI) mass calcd. for C19H23FN4O2, 358.41; m / z found 359.2 [M+H]+. Step 3: Synthesis of HBS-055-170: Compound HBS-055- g, 0.63 mmol) was dissolved in Dry Dioxane (6.0 mL). The 4.0 M HCl solution in Dioxane (0.63 mL, 2.52 mmol) was added and rxn mixture was stirred at 50oC temperature for 16 h. LCMS shows product formation m / z 259.1. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.19 g of solid product (Yield 90.95 %). MS (ESI) mass calcd. for C14H15FN4, 258.29; m / z found 259.1 [M+H]+. O O Cl O NaH O Step 1: Synthesis of HBS-055-179: The (R)-3-hydroxymethyl-4-Boc-morpholine (0.5 g, 2.3 mmol) was dissolved in Dry THF (10.0 mL). The NaH (0.14 g, 3.45 mmol) was added at 0oC temperature. The 2-Chloro-5-trifluoromethylpyridine (0.5 g, 2.76 mmol) was added and the reaction mixture was gradually heated at reflux temperature for 16 h. The LCMS shows two product formation m / z 363.1 and m / z 263.1. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient and DCM:MeOH gradient. The 0.39 g of pure product A was obtained (Yield 46.8 %) and 0.12 g of deboc product B was obtained (Yield 19.9 %). MS (ESI) mass calcd. for C16H21F3N2O4, 362.34; m / z found 363.1 [M+H]+and MS (ESI) mass calcd. for C11H13F3N2O2, 262.23; m / z found 263.1 [M+H]+Step 2: Synthesis of HBS-055-180: Compound HBS-055-179A (0.39 g, 1.08 mmol) was dissolved in Dioxane (6.0 mL). The 4.0 M HCl solution in dioxane (1.1 mL, 4.31 mmol) was added and rxn mixture was stirred at 50oC temperature for 16 h. LCMS shows product formation m / z 263.0. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.33 g of pure product (Yield 91.5 %). MS (ESI) mass calcd. for C11H13F3N2O2, 262.23; m / z found 263.0 [M+H]+. Cl OS OHN N DIPEA, DMAPNO N Cs O2CO3h Step 1: Synthesis of HBS-062-054: Compound HBS-062-051 (0.9 g, 4.18 mmol) was dissolved in DCM (15.0 mL). The DIPEA (1.1 mL, 6.27 mmol) was added followed by DMAP (0.77 g, 6.27 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.88 g, 4.6 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 270.1, 314.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 1.54 g of product (Yield Quant.). MS (ESI) mass calcd. for C18H27NO5S, 369.48; m / z found, 270.1, 314.1 [M-Boc]+. Step 2: Synthesis of HBS-062-055: Compound HBS-062-054 (1.54 g, 4.17 mmol) and 2-(1H- pyrazol-3-yl)pyridine (0.61 g, 4.17 mmol) were dissolved in Dry DMF (12.0 mL). The anhydrous Cs2CO3(4.1 g, 12.5 mmol) was added, and reaction mixture was stirred at 70oC temperature for 12 h. The LCMS shows product formation m / z 343.2 and other other side products. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.12 g of pure product was obtained (Yield 8.41 %). MS (ESI) mass calcd. for C19H26N4O2, 342.44; m / z found 343.2 [M+H]+. Step 3: Synthesis of HBS-062-063: Compound HBS-062-055 (0.12 g, 0.35 mmol) was dissolved in Dry Dioxane (5.0 mL). The 4.0 M HCl solution in Dioxane (0.4 mL, 1.75 mmol) was added and rxn mixture was stirred at 50oC temperature for 6 h. LCMS shows product formation m / z 243.1. The rxn mixture was cooled and solvent was concentrated to obtain 0.067 g of solid product (Yield 60.7 %). MS (ESI) mass calcd. for C14H18N4, 242.32; m / z found 243.1 [M+H]+. Cl OH 2.0 M BH3.Me2S OH i NaH O N n THF N + N h 0.46 g, Yield 75.4 %Step 1: Synthesis of HBS-062-051: N-Boc-alpha-methyl-L-proline (4.0 g, 17.44 mmol) was dissolved in Dry THF (20.0 mL). The 2.0 M BH3.Me2S (17.4 mL, 34.9 mmol) was added at 0oC temperature. The rxn mixture gradually warmed at ambient temperature for 16 h. The LCMS shows product formation m / z 160.1. The rxn mixture was quenched with Methanol. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 3.75 g of crude product. (Yield Quant.). MS (ESI) mass calcd. for C11H21NO3, 215.29; m / z found 160.1 [M- Boc]+. Step 2: Synthesis of HBS-062-060: Compound HBS-062-051 (0.9 g, 4.18 mmol) was dissolved in Dry DMF (10.0 mL). The NaH (0.25 g, 6.27 mmol) was added at 0oC temperature. The 2- Chloro-5-trifluoromethylpyridine (0.76 g, 4.18 mmol) was added and the reaction mixture was gradually heated at reflux temperature for 5 h. The LCMS shows product formation m / z 361.1. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.66 g of product was obtained (Yield 43.8 %). MS (ESI) mass calcd. for C17H23F3N2O3, 360.37; m / z found 361.1 [M+H]+. Step 3: Synthesis of HBS-062-065: Compound HBS-062-060 (0.66 g, 1.83 mmol) was dissolved in Dioxane (8.0 mL). The 4.0 M HCl solution in dioxane (1.83 mL, 7.33 mmol) was added and rxn mixture was stirred at 50oC temperature for 16 h. LCMS shows product formation m / z 261.1. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.46 g of pure product (Yield 75.4 %). MS (ESI) mass calcd. for C12H15F3N2O, 260.26; m / z found 261.1 [M+H]+. OH Cl O 4.0 M HCl N+NNaHN Dioxane N O CF3 7- carboxylate (0.2 g, 0.88 mmol) was dissolved in Dry DMF (6.0 mL). The NaH (0.052 g, 1.32 mmol) was added at 0oC temperature. The 2-Chloro-5-trifluoromethylpyridine (0.24 g, 1.32 mmol) was added and the reaction mixture was gradually heated at 75oC temperature for 8 h. The LCMS shows product formation m / z 373.1. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.33 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C18H23F3N2O3, 372.38; m / z found 373.1 [M+H]+. Step 2: Synthesis of HBS-062-116: Compound HBS-062-114 (0.33 g, 0.88 mmol) was dissolved in Dioxane (5.0 mL). The 4.0 M HCl solution in dioxane (0.88 mL, 3.52 mmol) was added and rxn mixture was stirred at 50oC temperature for 8 h. LCMS shows product formation m / z 273.1. The rxn mixture was cooled and concentrated under reduced pressure to obtain 0.28 g of pure product (Yield 92.2 %). MS (ESI) mass calcd. for C13H15F3N2O, 272.27; m / z found 273.1 [M+H]+.

[0018] Cl OH 2.0 M BH3.Me2S OH i NaH O N n THF N + N N N 3 h Step 1: Synthesis of HBS-062-134: N-Boc-alpha-methyl-L-proline (5.0 g, 21.81 mmol) was dissolved in Dry THF (20.0 mL). The 2.0 M BH3.Me2S (21.8 mL, 43.62 mmol) was added at 0oC temperature. The rxn mixture gradually warmed at ambient temperature for 16 h. The LCMS shows product formation m / z 160.0. The rxn mixture was quenched with Methanol. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The EtOAc layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent gave 4.3 g of crude product. (Yield Quant.). MS (ESI) mass calcd. for C11H21NO3, 215.29; m / z found 160.1 [M-Boc]+. Step 2: Synthesis of HBS-062-138: Compound HBS-062-134 (0.5 g, 2.32 mmol) was dissolved in Dry THF (6.0 mL). The NaH (0.14 g, 3.49 mmol) was added at 0oC temperature. The 2-Chloro- 5-trifluoromethylpyrazine (0.3 mL, 2.32 mmol) was added and the reaction mixture was gradually heated at reflux temperature for 6 h. The LCMS shows product formation m / z 262.1, 306.0. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.44 g of product was obtained (Yield 52.4 %). MS (ESI) mass calcd. for C16H22F3N3O3, 361.36; m / z found 262.1, 306.0 [M-Boc]+. Step 3: Synthesis of HBS-062-142: Compound HBS-062-138 (0.44 g, 1.22 mmol) was dissolved in Dioxane (5.0 mL). The 4.0 M HCl solution in dioxane (1.52 mL, 6.1 mmol) was added and rxn mixture was stirred at 50oC temperature for 8 h. LCMS shows product formation m / z 262.1. The rxn mixture was cooled and concentrated under reduced pressure to obtain 0.37 g of pure product (Yield 82.4 %). MS (ESI) mass calcd. for C11H14F3N3O, 261.24; m / z found 262.1 [M+H]+. D D Ru / C, H2D D O O TEA, DCM D N OH + 24 h mmol) were dissolved in D2O (5.0 mL). The Ru / C, 5 wt.% (0.058 g, 10 % w / w) was added and reaction mixture was stirred under hydrogen atm at 70oC temperature for 6 h. LCMS shows product formation m / z 118.1. The rxn mixture was filtered over celite bed and washed with D2O. The reaction mixture pH was adjusted to pH 6.5 using HCl. The Dowex X-8 [H+] resin was added and aq. layer filtered and washed with 25 % aq. ammonia solution. The aq. layer was concentrated under reduced pressure to obtain 0.59 g of crude product. (Yield Quant.). MS (ESI) mass calcd. for C5H6D3NO2, 118.15; m / z found 118.1 [M+H]+. Step 2: Synthesis of HBS-062-155: Compound HBS-062-150 (0.59 g, 5.0 mmol) was dissolved in DCM (15.0 mL). The triethyl amine (0.76 mL, 5.5 mmol) was added followed by Di-tert-butyl- dicarbonate (1.2 g, 5.5 mmol). The rxn mixture was stirred at ambient temperature for 16 h. The LCMS shows product formation m / z 162.0. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent and aq. layer extracted gave 0.95 g combined product. (Yield 87.1 %). MS (ESI) mass calcd. for C10H14D3NO4, 218.26; m / z found 162.0 [M-tButyl]+. Step 3: Synthesis of HBS-062-156: Compound HBS-062-155 (0.95 g, 4.35 mmol) was dissolved in Dry THF (10.0 mL). The 2.0 M BH3.Me2S (4.3 mL, 8.70 mmol) was added at 0oC temperature. The rxn mixture gradually warmed at ambient temperature for 16 h. The LCMS shows product formation m / z 148.1. The rxn mixture was quenched with Methanol. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The EtOAc layers were separated and dried over anhydrous Na2SO4.The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.8 g of product was obtained. (Yield 90.0 %). MS (ESI) mass calcd. for C10H16D3NO3, 204.28; m / z found 148.1 [M-tButyl]+. Step 4: Synthesis of HBS-062-163: Compound HBS-062-156 (0.4 g, 1.96 mmol) was dissolved in Dry THF (10.0 mL). The NaH (0.12 g, 2.49 mmol) was added at 0oC temperature. The 2- Chloro-5-trifluoromethylpyridine (0.53 g, 2.94 mmol) was added and the reaction mixture was gradually heated at reflux temperature for 6 h. The LCMS shows product formation m / z 350.1. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.6 g of product was obtained (Yield 87.7 %). MS (ESI) mass calcd. for C16H18D3F3N2O3, 349.36; m / z found 350.1 [M+H]+. Step 5: Synthesis of HBS-062-166: Compound HBS-062-163 (0.6 g, 1.72 mmol) was dissolved in Dioxane (8.0 mL). The 4.0 M HCl solution in dioxane (2.15 mL, 8.59 mmol) was added and rxn mixture was stirred at 55oC temperature for 8 h. LCMS shows product formation m / z 250.1. The rxn mixture was cooled at ambient temperature. The ppts were filtered and dried to obtain 0.49 g of pure product (Yield 88.5 %). MS (ESI) mass calcd. for C11H10D3F3N2O, 249.25; m / z found 250.1 [M+H]+. O Cl S D D 4.0 M HCl in DCM (15.0 mL). The DIPEA (0.51 mL, 2.94 mmol) was added followed by DMAP (0.36 g, 2.94 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.41 g, 2.15 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 24 h. The LCMS shows product formation m / z 258.1, 302.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.7 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H22D3NO5S, 358.47; m / z found, 258.1, 302.1 [M-Boc]+. Step 2: Synthesis of HBS-062-169: Compound HBS-062-167 (0.7 g, 1.96 mmol) and 3-phenyl- 1H-pyrazol (0.34 g, 2.35 mmol) were dissolved in Dry 1,4-Dioxane (10.0 mL). The anhydrous Cs2CO3(1.6 g, 4.9 mmol) was added, and reaction mixture was stirred at reflux temperature for 24 h. The LCMS shows product formation m / z 331.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.58 g of pure product was obtained (Yield 89.6 %). MS (ESI) mass calcd. for C19H22D3N3O2, 330.44; m / z found 331.2 [M+H]+. Step 3: Synthesis of HBS-062-172: Compound HBS-062-169 (0.58 g, 1.76 mmol) was dissolved in Dry Dioxane (8.0 mL). The 4.0 M HCl solution in Dioxane (2.2 mL, 8.78 mmol) was added and rxn mixture was stirred at 55oC temperature for 8 h. LCMS shows product formation m / z 231.1. The rxn mixture was cooled and solvent was concentrated to obtain 0.47 g of solid product (Yield Quant.). MS (ESI) mass calcd. for C14H14D3N3, 230.32; m / z found 231.1 [M+H]+. O Cl S DDFD DF in DCM (15.0 mL). The DIPEA (0.64 mL, 3.67 mmol) was added followed by DMAP (0.45 g, 3.67 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (0.56 g, 2.94 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 24 h. The LCMS shows product formation m / z 259.1, 303.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 0.82 g of product (Yield 93.7 %). MS (ESI) mass calcd. for C17H22D3NO5S, 358.47; m / z found, 259.1, 303.1 [M-Boc]+. Step 2: Synthesis of HBS-062-194: Compound HBS-062-190 (0.8 g, 2.23 mmol) and 3-(4- fluorophenyl)-1H-pyrazol (0.43 g, 2.68 mmol) were dissolved in Dry 1,4-Dioxane (12.0 mL). The anhydrous Cs2CO3(1.81 g, 5.58 mmol) was added, and reaction mixture was stirred at reflux temperature for 24 h. The LCMS shows product formation m / z 349.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.62 g of pure product was obtained (Yield 79.7 %). MS (ESI) mass calcd. for C19H21D3FN3O2, 348.43; m / z found 349.2 [M+H]+. Step 3: Synthesis of HBS-062-197: Compound HBS-062-194 (0.62 g, 1.78 mmol) was dissolved in Dry Dioxane (8.0 mL). The 4.0 M HCl solution in Dioxane (1.8 mL, 7.12 mmol) was added and rxn mixture was stirred at 55oC temperature for 8 h. LCMS shows product formation m / z 249.2. The rxn mixture was cooled and ppts were filtered. The drying of ppts gave 0.49 g of solid product (Yield 96.7 %). MS (ESI) mass calcd. for C14H13D3FN3, 248.31; m / z found 249.2 [M+H]+. NCF3HN O CF3 in DCM (15.0 mL). The DIPEA (1.3 mL, 7.45 mmol) was added followed by DMAP (0.91 g, 7.45 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (1.04 g, 5.46 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 256.0, 300.0. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave 1.76 g of product (Yield Quant.). MS (ESI) mass calcd. for C17H25NO5S, 355.45; m / z found, 256.0, 300.0 [M-Boc]+. Step 2: Synthesis of HBS-065-040: Compound HBS-065-037 (1.76 g, 4.97 mmol) and 2-(1H- pyrazole-4-yl-5-(trifluoromethyl)pyridine hydrochloride (1.42 g, 4.97 mmol) were dissolved in Dry 1,4-Dioxane (25.0 mL). The anhydrous Cs2CO3(3.24 g, 9.94 mmol) was added, and reaction mixture was stirred at reflux temperature for 24 h. The LCMS shows product formation m / z 397.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 1.0 g of pure product was obtained (Yield 50.8 %). MS (ESI) mass calcd. for C19H23F3N4O2, 396.41; m / z found 397.2 [M+H]+. Step 3: Synthesis of HBS-065-043: Compound HBS-065-040 (1.0 g, 2.52 mmol) was dissolved in Dry Dioxane (15.0 mL). The 4.0 M HCl solution in Dioxane (2.52 mL, 10.1 mmol) was added and reaction mixture was stirred at 60oC temperature for 12 h. LCMS shows product formation m / z 297.1. The rxn mixture was cooled and ppts were filtered. The drying of ppts gave 0.81 g of solid product (Yield 87.0 %). MS (ESI) mass calcd. for C14H15F3N4, 296.29; m / z found 297.1 [M+H]+. CF3 pyrrolidine-1-carboxylate (0.25 g, 1.16 mmol) was dissolved in Dry THF (6.0 mL). The NaH (0.07 g, 1.74 mmol) was added at 0oC temperature. The 2-Chloro-5-trifluoromethylpyridine (0.25 g, 1.39 mmol) was added and the reaction mixture was gradually heated at reflux temperature for 6 h. The LCMS shows product formation m / z 361.2. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.42 g of product was obtained (Yield Quant.). MS (ESI) mass calcd. for C17H23F3N2O3, 360.37; m / z found 361.2 [M+H]+. Step 2: Synthesis of HBS-065-058: Compound HBS-065-056 (0.42 g, 1.17 mmol) was dissolved in Dioxane (8.0 mL). The 4.0 M HCl solution in dioxane (1.16 mL, 4.66 mmol) was added and rxn mixture was stirred at 60oC temperature for 12 h. LCMS shows product formation m / z 261.1. The reaction mixture was cooled at ambient temperature. The ppts were filtered and dried to obtain 0.31 g of pure product (Yield 79.8 %). MS (ESI) mass calcd. for C12H15F3N2O, 260.26; m / z found 261.1 [M+H]+. Cl OH N O 4.0 M HCl NNaO +HN Dioxane N H CF3 Step 1: Synthesis of HBS-065-065: Compound HBS-055-131 (0.5 g, 2.34 mmol) was dissolved in Dry THF (8.0 mL). The NaH (0.14 g, 3.51 mmol) was added at 0oC temperature. The 2-Chloro- 5-trifluoromethylpyridine (0.51 g, 2.81 mmol) was added and the reaction mixture was gradually heated at reflux temperature for 6 h. The LCMS shows product formation m / z 359.1. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.6 g of product was obtained (Yield 71.5 %). MS (ESI) mass calcd. for C17H21F3N2O3, 358.36; m / z found 359.1 [M+H]+. Step 2: Synthesis of HBS-065-067: Compound HBS-065-065 (0.6 g, 1.67 mmol) was dissolved in Dioxane (6.0 mL). The 4.0 M HCl solution in dioxane (1.67 mL, 6.7 mmol) was added and rxn mixture was stirred at 60oC temperature for 12 h. LCMS shows product formation m / z 259.0. The reaction mixture was cooled at ambient temperature and concentrated under reduced pressure to obtain 0.55 g of pure product (Yield Quant.). MS (ESI) mass calcd. for C12H13F3N2O, 258.24; m / z found 259.0 [M+H]+. 2.0 M BH Cl HN OH3.Me2S OH O S OO O N h Step 1: Synthesis of HBS-065-119: (1R,3S,5R)-2-[(Tert-butoxy) carbonyl]-2-azabicyclo [3.1.0] Hexane-3-carboxylic acid (2.0 g, 8.8 mmol) was dissolved in Dry THF (20.0 mL). The 2.0 M BH3.Me2S (8.8 mL, 17.6 mmol) was added at 0oC temperature. The rxn mixture gradually warmed at ambient temperature for 16 h. The LCMS shows product formation m / z 158.1. The rxn mixture was quenched with Methanol. The reaction mixture was diluted with water. The product was extracted with Ethyl acetate. The EtOAc layers were separated and dried over anhydrous Na2SO4.The evaporation of solvent gave 1.88 g of crude product. (Yield Quant.). MS (ESI) mass calcd. for C11H19NO3, 213.27; m / z found 158.1 [M-Boc]+. Step 2: Synthesis of HBS-065-123: Compound HBS-065-119 (1.86 g, 8.72 mmol) was dissolved in DCM (25.0 mL). The DIPEA (2.3 mL, 13.1 mmol) was added followed by DMAP (1.6 g, 13.1 mmol). The rxn mixture was cooled at 0oC in the Ice bath. The p-TsCl (2.0 g, 10.47 mmol) was added. The rxn mixture was stirred and gradually warmed to room temperature for 16 h. The LCMS shows product formation m / z 268.1, 312.1. The reaction mixture was diluted with water. The product was extracted with DCM. The DCM layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 2.76 g of product was obtained (Yield 86.12 %). MS (ESI) mass calcd. for C18H25NO5S, 367.46; m / z found, 268.1, 312.1 [M-Boc]+. Step 3: Synthesis of HBS-065-126: Compound HBS-065-123 (0.5 g, 1.36 mmol) and 2-(1H- Pyrazol-3-yl)pyridine (0.22 g, 1.5 mmol) were dissolved in 1,4-Dioxane (8.0 mL). The anhydrous Cs2CO3 (0.89 g, 2.72 mmol) was added, and reaction mixture was stirred at reflux for 16 h. The LCMS shows product formation m / z 341.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.12 g of pure product was obtained (Yield 24.8 %). MS (ESI) mass calcd. for C19H24N4O2, 340.42; m / z found 341.2 [M+H]+. Step 4: Synthesis of HBS-065-128: Compound HBS-065-126 (0.12 g, 0.33 mmol) was dissolved in Dry Dioxane (5.0 mL). The 4.0 M HCl solution in Dioxane (0.33 mL, 1.35 mmol) was added and rxn mixture was stirred at ambient temperature for 24 h. LCMS shows product formation m / z 241.1. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.093 g of solid product (Yield 87.9 %). MS (ESI) mass calcd. for C14H16N4, 240.3; m / z found 241.1 [M+H]+. N O HN N 4.0 M H N O N Cl Step 1: Synthesis of HBS-065-135: Compound HBS-065-123 (0.5 g, 1.36 mmol) and 2-(1H- Pyrazol-4-yl)pyridine (0.22 g, 1.5 mmol) were dissolved in 1,4-Dioxane (10.0 mL). The anhydrous Cs2CO3 (0.89 g, 2.72 mmol) was added, and reaction mixture was stirred at reflux for 16 h. The LCMS shows product formation m / z 341.2. The rxn mixture was cooled at ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined EtOAc layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by column chromatography, Mobile phase: EtOAc:Hexane gradient. The 0.46 g of pure product was obtained (Yield Quant.). MS (ESI) mass calcd. for C19H24N4O2, 340.42; m / z found 341.2 [M+H]+. Step 4: Synthesis of HBS-065-140: Compound HBS-065-135 (0.46 g, 1.36 mmol) was dissolved in Dry Dioxane (10.0 mL). The 4.0 M HCl solution in Dioxane (1.36 mL, 5.44 mmol) was added and rxn mixture was stirred at 55oC temperature for 8 h. LCMS shows product formation m / z 241.2. The rxn mixture was cooled and ppts were filtered. The ppts were dried to obtain 0.38 g of solid product (Yield 89.1 %). MS (ESI) mass calcd. for C14H16N4, 240.3; m / z found 241.2 [M+H]+. Cl H F % - - 2- yl]methanamine (0.1 g, 0.4 mmol) and 2-Chloro-5-Fluoro-pyrimidine (0.12 g, 0.81 mmol) were dissolved in Dry DMF (3.0 mL). The K2CO3(0.14 g, 1.01 mmol) was added and rxn mixture was stirred at 120oC temperature for 5 h. LCMS shows product formation m / z 345.2. The rxn mixture was diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.14 g of product was isolated (Yield Quant.). MS (ESI) mass calcd. for C19H25FN4O, 344.43; m / z found 345.2 [M+H]+. Step 2: Synthesis of HBS-037-170: Compound HBS-037-167 (0.14 g, 0.4 mmol) was dissolved in MeOH (4.0 mL). The 20.0 % Pd-OH / C (28.0 mg) was added and rxn mixture was stirred at ambient temperature for 24 h. The LCMS shows unreacted starting material and product formation. The 20.0 % Pd-OH / C (20.0 mg) was further added and rxn mixture was stirred at ambient temperature for another 24 h. The LCMS shows product formation m / z 225.1. The rxn mixture was filtered over celite and washed with MeOH. The filtrate was evaporated under reduced pressure to obtain 67.0 mg of crude product (Yield 74.0 %). The crude product is used in the next step without purification. MS (ESI) mass calcd. for C11H17FN4, 224.28; m / z found 225.1 [M+H]+. F % 2-Chloro-5-Fluoro-pyrimidine (0.2 g, 1.5 mmol) were dissolved in anhydrous DMF (4.0 mL). The K2CO3(0.35 g, 2.5 mmol) was added, and the reaction mixture was heated to 100oC temperature for 5 h. LCMS shows product formation m / z 297.0 and side product. The reaction mixture was cooled to ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.25 g of major product was obtained (Yield 84.8 %). MS (ESI) mass calcd. for C14H21FN4O2, 296.34; m / z found 297.0 [M+H]+. Step 2: Synthesis of HBS-037-172: Compound HBS-037-169 (0.25 g, 0.85 mmol) was dissolved in anhydrous dioxane (3.0 mL). The 4.0 M HCl in dioxane (2.1 mL, 8.47 mmol) was added and the reaction was stirred at 50oC temperature for 5 h. LCMS shows product formation m / z 197.0. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to obtain 0.2 of product (Yield 68.0 %). MS (ESI) mass calcd. for C9H13FN4, 196.22; m / z found 197.0 [M+H]+. Cl H 4.0 M HCl N NH2N NK2CO3 N Dioxane H N CF3 g, 0.93 mmol) and 2-Chloro-5-trifluoromethylpyridine (0.2 g, 1.11 mmol) were dissolved in anhydrous DMF (5.0 mL). The K2CO3(0.32 g, 2.32 mmol) was added, and the reaction mixture was heated to 120oC temperature for 5 h. LCMS shows product formation m / z 360.0. The reaction mixture was cooled to ambient temperature and diluted with water. The product was extracted with Ethyl acetate. The combined ethyl acetate layer was washed with water followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash chromatography system, Mobile phase: EtOAc:Hexane gradient. The 0.17 g of product was obtained (Yield 50.6 %). MS (ESI) mass calcd. for C17H24F3N3O2, 359.39; m / z found 360.0 [M+H]+. Step 2: Synthesis of HBS-037-200: Compound HBS-037-197 (0.17 mmol) was dissolved in anhydrous dioxane (5.0 mL). The 4.0 M HCl in dioxane (1.2 mL, 4.7 mmol) was added and the reaction was stirred at 50oC temperature for 5 h. LCMS shows product formation m / z 260.0. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to obtain 0.17 of product (Yield Quant.). MS (ESI) mass calcd. for C12H16F3N3, 259.27; m / z found 260.0 [M+H]+. General Experimental Procedures for Synthesis of Example Compounds: Method A: Acid Intermediate 1.0 eq. (0.1 mmol) was dissolved in anhydrous DCM (2.0 mL). The EDC.HCl 1.5 eq. (0.15 mmol) and HOBt 1.5 eq. (0.15 mmol) were added followed by Et3N 5.0 eq. (0.5 mmol). The rxn mixture was stirred at ambient temperature for 5.0 min. Amine Intermediate (0.1 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 h. The rxn mixture was diluted with DCM and washed with saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: Ethyl Acetate:Hexane or DCM:MeOH gradient. Method B: Acid Intermediate 1.0 eq. (0.1 mmol) and HATU 1.1 eq. (0.11 mmol) were dissolved in anhydrous DMF (1.5 mL). The DIPEA 4.0 eq. (0.4 mmol) was added and rxn mixture was stirred at ambient temperature for 5.0 min. Amine Intermediate (0.1 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 h. The rxn mixture was diluted with DCM and washed with saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4.The evaporation of solvent gave crude product. The crude product was purified by ISCO combi-flash system, Mobile phase: Ethyl Acetate:Hexane or DCM:MeOH gradient. 4. Preferred Compounds of the General Formulas Disclosed Herein: Preferred compounds of this disclosure are presented in Table 3 above and Table 4 below. The preferred compounds are encompassed by Compound Numbers 1-138. II. Biological Assays Experimental Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure: In vitro Orexin Antagonism measurement assay: Intracellular calcium measurements: Chinese hamster ovary (CHO) cells expressing the human orexin receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L- Glutamine) containing 300 µg / mL G418, 100 U / mL penicillin, 100 µg / mL streptomycin and 10 % heat inactivated fetal calf serum (FCS). The cells are seeded at 20'000 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2. Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH: water (1:1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA), NaHC03: 0.375g / L and 20 mM HEPES for use in the assay at a final concentration of 3 nM. Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHC03: 0.375g / L and 20 mM HEPES. On the day of the assay, 50 µL of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, NaHCO3: 0.375g / L, 5 mM probenecid (Sigma) and 3 µM of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well. The 384- well cell-plates are incubated for 50 min at 37° C in 5% CO2followed by equilibration at RT for 30 min before measurement. Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists are added to the plate in a volume of 10 µL / well, incubated for 120 min and finally 10 µL / well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 3 nM orexin-A with vehicle in place of antagonist. The IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined and may be normalized using the obtained IC50 value of an on-plate reference compound. Optimized conditions were achieved by adjustment of pipetting speed and cell splitting regime. Thecalculated IC50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. In the case where IC50values have been determined several times for the same compound, the geometric mean has been given. Antagonistic activities of example compounds are shown in Table 2. Human k-opioid (KOP) receptor (agonist radioligand) Binding assay Purpose: Evaluation of the affinity of compounds for the human k-opioid receptor in transfected RBL cells determined in a radioligand binding assay. Experimental protocol: protein) are incubated for 60 min at 22°C with 0.5 nM [3H]U-69593 in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 10 mM MgCl2 and 1 mM EDTA. Nonspecific binding M naloxone. Following incubation, the samples are filtered rapidly under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters are dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results are expressed as a percent inhibition of the control radioligand specific binding. The standard reference compound is U-50488, which is tested in each experiment at several concentrations to obtain a competition curve from which its IC50 is calculated. Results from these experiments are shown in Table 4. Table 4 Example of compounds reduced to practice with data (% Inhibition @ 1 uM), and selected compounds with IC50values) at Orexin type 1 (OX1R), Orexin type 2 (OX2R) Receptors and kappa-Opioid Receptors (kOR) Table Key: No.: Compound number; Column A: OX1R% Inhib.@ 1 uM; Column B: OX1R IC50, nM (Kb, nM); Column C: OX2R % Inhib.@ 1 uM; Column D: OX2R IC50, nM (Kb, nM); Column E: kOR % Inhib.@ 1 uM (against agonist binding); Column F: kOR IC50, nM (Ki, nM) (against agonist binding) Ex. Structure MW. No. A B C D E F LogP (g / mol) 2 6 5 0 9

[0019] 1 5 1

[0020] 5 6 6 0 3 8 2 4 2 3

[0021] 6 1 0 1 1 0 9

[0022] 1 0 9 4 2 2

[0023] 2 6 2 1 3 1 6

[0024] 3 7 5 9

[0025] 3 7 7 3

[0026] 2 5 5 4

[0027] 5 3 4 7

[0028] 5 8 5 4 5

[0029] 4 5 5 7 4

[0030] 5 5 1 9

[0031] 7 5 2

[0032] While certain embodiments have been described in terms of the preferred embodiments, it is understood that variations and modifications will occur to those skilled in the art. Therefore, it is intended that the appended claims cover all such equivalent variations that come within the scope of the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of a) Formula I or H:or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:R1 includes E as Carbon (C) but not Nitrogen (N), and in Formula I E is linked to J or D with a double bond or in Formula II E is linked to A or D with a double bond, and R9is selected from the group consisting of H, alkyl, alkoxy, cycloalkyi, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl that is optionally a 5- or 6 membered heteroaryl, substituted aromatic or aryl, and, substituted heteroaryl that is optionally a 5- or 6-membered heteroaryl; wherein if R1 is heteroaryl, Ri is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, or di-substituted, wherein the substituents aarree independently selected from the group consisting of (Ci-4)alky!, (Ci.4)alkoxy, halogen, (Ci.j)fluoroalkyl, (C1.3)fluoroalkoxy and (C^cycSoalkyl;R2, Rs, and R4are independently selected from the group consisting of H. alkyl, substituted alkyl, (Ci-^)alkyL (Ci.4)alkoxy, (Ci 3)fluoroalkyl, (Ci.3)fluoroalkoxy, (C^cycloalkyl, and halogen that is optionally F, Cl, or Br; wherein each of R2, Ra and R4is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, Ry and R4;R5is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R5replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is as defined herein; R5’ is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally comprising a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and (C3-7)heterocycloalkyl; R6is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is defined herein; R8is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R8connected to either R10, R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R9connected to either R6or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R10connected to R6or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R11connected to R6as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R12connected to R9as alkyl to form a (C1-3)alkyl bridge cyclic structure; X is selected from the group consisting of absent to optionally provide five membered pyrrolidine ring, CH2, O, and CRaRb where Ra and Rb are selected from the group consisting of alkyl, cycloalkyl, and Fluoroalkyl; and wherein:the carbon atom at position 2 of the piperidine or pyrrolidine is optionally in absolute (S)- configuration; or, the carbon atom at position 2 of the of the morpholine ring wherein X is oxygen and optionally in absolute (R)-configuration; Y is selected from the group consisting of absent to provide R5’ attached directly to the carbon bearing Z1and Z2groups; O; NH; CH2OR5’; CH2; NRawherein Rais selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; and a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and, Z1 and Z2 are independently selected from the group consisting of H, F, (C1-4)alkyl, (C1- 3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C2-7)cycloalkyl; and wherein: fused or unfused ring system A-B-J-D-E is a five-membered heteroaryl optionally imidazole wherein A and J are Nitrogen while B, E, D are Carbon; pyrazole wherein A and B are Nitrogen while D, E, and J are Carbon; optionally fused or unfused with one or more additional ring systems; the fused ring system B-J-M-G-K-L is an arrangements of these outlined variables to provide groups consisting of a 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5 or 6-membered cycloalkyl, and 5 or 6-membered heterocycloalkyl; and wherein, optionally: A is Nitrogen, optionally an Imidazole or Pyrazole; B is Carbon or Nitrogen; J is Carbon or Nitrogen; D is Carbon; E is Carbon, wherein R1 is as defined above; M is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N;G is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; K is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; and, L is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. b) Formula I-a or II-a: R4R2R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl that is optionally a 5- or 6 membered heteroaryl, substituted aromatic or aryl, and, substituted heteroaryl that is optionally a 5- or 6-membered heteroaryl; wherein if R1 is heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl;R2, R3, and R4are independently selected from the group consisting of H, alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, halogen that is optionally F, Cl, or Br; wherein each of R2, R3and R4is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R5 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is as defined herein; R5’ is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally comprising a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and (C3- 7)heterocycloalkyl; R6 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R6 connected to either R10 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R7 replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R8 connected to either R11 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R9 connected to either R6 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure;R12is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R12connected to R9as alkyl to form a (C1-3)alkyl bridge cyclic structure; X is selected from the group consisting of absent to optionally provide five membered pyrrolidine ring, CH2, O, and CRaRbwhere Raand Rbare selected from the group consisting of alkyl, cycloalkyl, and Fluoroalkyl; and wherein: the carbon atom at position 2 of the piperidine or pyrrolidine ring is optionally in absolute (S)-configuration; or, the carbon atom at position 2 of the of the morpholine ring wherein X is oxygen is optionally in absolute (R)-configuration; Y is selected from the group consisting of absent to provide R5’ attached directly to the carbon bearing Z1 and Z2 groups; O; NH; CH2OR5’; CH2; NRa wherein Ra is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; and a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl ; Z1 and Z2 are independently selected from the group consisting of H, F, (C1-4)alkyl, (C1- 3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C2-7)cycloalkyl; wherein: the fused ring system B-J-M-G-K-L is selected from arrangements of these outlined variables to provide groups consisting of a 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5 or 6-membered cycloalkyl, and 5 or 6-membered heterocycloalkyl; and preferably: M is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; G is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; K is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O, or absent to provide 5 – membered cycloalkyl, and heterocycloalkyl; and,L is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and, N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. c) Formula I-b or II-b: R4R2R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl that is optionally a 5- or 6 membered heteroaryl, substituted aromatic or aryl, and, substituted heteroaryl that is optionally a 5- or 6- membered heteroaryl; wherein if R1 is heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1- 3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3and R4is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4;R5is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R5replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is as defined herein; R5’ is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally comprising a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and (C3-7)heterocycloalkyl; R6is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R7replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is defined herein; R8is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R8connected to either R10, R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R9connected to either R6or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R10 connected to R6 or R11 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R11 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1- 3)fluoroalkyl, cycloalkyl, and R11 connected to R6 as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1- 3)fluoroalkyl, cycloalkyl, and R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure;X is selected from the group consisting of absent to optionally provide five membered pyrrolidine ring, CH2, O, and CRaRbwhere Raand Rbare selected from the group consisting of alkyl, cycloalkyl, and Fluoroalkyl; and wherein: the carbon atom at position 2 of the piperidine or pyrrolidine is optionally in absolute (S)-configuration; or, the carbon atom at position 2 of the of the morpholine ring wherein X is oxygen and optionally in absolute (R)-configuration; Y is selected from the group consisting of absent to provide R5’ attached directly to the carbon bearing Z1 and Z2 groups; O; NH; CH2OR5’; CH2; NRa wherein Ra is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; and a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl ; Z1 and Z2 are independently selected from the group consisting of H, F, (C1-4)alkyl, (C1- 3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C2-7)cycloalkyl; wherein: the fused ring system B-J-M-G-K-L is selected from arrangements of these outlined variables to provide groups consisting of a 6-membered aromatic, 6-membered aryl, 6-membered substituted aromatic, 6-membered substituted aryl, 6-membered substituted heteroaryl, 6-membered unsubstituted heteroaryl, 5 or 6-membered cycloalkyl, and 5 or 6-membered heterocycloalkyl; and preferably: M is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; G is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O; K is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and O, or absent to provide 5 – membered cycloalkyl, and heterocycloalkyl; and,L is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof d) Formula I-a4, I-a5, I-a6, II-a4, II-a5, or II-a6: R4R4R4R2R2R2R5'R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl that is optionally a 5- or 6 membered heteroaryl, substituted aromatic or aryl, and, substituted heteroaryl that is optionally a 5- or 6- membered heteroaryl; wherein if R1 is heteroaryl, R1 is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3and R4is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3and R4; R5is H or replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is as defined herein; R5’ is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally comprising a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and (C3-7)heterocycloalkyl; R6is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7is H or replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is defined herein; R8is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R8connected to either R10, R11or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R9is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R9connected to either R6or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R10connected to R6or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R12 connected to R9 as alkyl to form a (C1-3)alkyl bridge cyclic structure; X is selected from the group consisting of absent to optionally provide five membered pyrrolidine ring, CH2, O, and CRaRb where Ra and Rb are selected from the group consisting of alkyl, cycloalkyl, and Fluoroalkyl; and wherein:the carbon atom at position 2 of the piperidine or pyrrolidine is optionally in absolute (S)-configuration; or, the carbon atom at position 2 of the of the morpholine ring wherein X is oxygen and optionally in absolute (R)-configuration; Y is selected from the group consisting of absent to provide R5’ attached directly to the carbon bearing Z1and Z2groups; O; NH; CH2OR5’; CH2; NRawherein Rais selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; and a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and, Z1 and Z2 are independently selected from the group consisting of H, F, (C1-4)alkyl, (C1- 3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C2-7)cycloalkyl; and preferably: L is selected from the group consisting of Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, and, N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and / or, e) Formula I-b4, I-b5, I-b6, II-b4, II-b5, or II-b6: R4R4R2R O4R2R2R5'wherein: R1is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, aromatic or aryl, heteroaryl that is optionally a 5- or 6 membered heteroaryl, substituted aromatic or aryl, and, substituted heteroaryl that is optionally a 5- or 6-membered heteroaryl; wherein if R1is heteroaryl, R1is optionally a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-substituted, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; R2, R3, and R4 are independently selected from the group consisting of H, halogen (such as F, Cl, Br), alkyl, substituted alkyl, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy and (C3-7)cycloalkyl; wherein each of R2, R3 and R4 is independently and optionally substituted at each substitutable position with up to three (3) substituents independently selected from one, two, or all R2, R3 and R4; R5 is H or is replaced with the carbon bearing Y, Z1 and Z2, wherein R5’ is as defined herein; R5’ is selected from the group consisting of aromatic, aryl, heteroaryl, 5- or 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl or fused two heteroaryl ring systems, optionally comprising a 5- or 6-membered ring; wherein said aromatic, aryl or heteroaryl is unsubstituted, mono-, or di-substituted or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, (C3-7)cycloalkyl, and (C3-7)heterocycloalkyl; R6is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R6connected to either R10or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R7is H or is replaced with the carbon bearing Y, Z1and Z2, wherein R5’ is defined herein; R8 is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R8 connected to either R10, R11 or R12 as alkyl to form a (C1-3)alkyl bridge cyclic structure;R9is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R9connected to either R6or R12as alkyl to form a (C1-3)alkyl bridge cyclic structure; R10is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R10connected to R6or R11as alkyl to form a (C1-3)alkyl bridge cyclic structure; R12is selected from the group consisting of H, F, CH3, alkyl, substituted alkyl, (C1-3)fluoroalkyl, cycloalkyl, and R12connected to R9as alkyl to form a (C1-3)alkyl bridge cyclic structure; X is selected from the group consisting of absent to optionally provide five membered pyrrolidine ring, CH2, O, and CRaRb where Ra and Rb are selected from the group consisting of alkyl, cycloalkyl, and Fluoroalkyl; and wherein: the carbon atom at position 2 of the piperidine or pyrrolidine ring is optionally in absolute (S)-configuration; or, the carbon atom at position 2 of the of the morpholine ring wherein X is oxygen and optionally in absolute (R)-configuration; Y is selected from the group consisting of absent to provide R5’ attached directly to the carbon bearing Z1 and Z2 groups; O; NH; CH2OR5’; CH2; NRa wherein Ra is selected from the group consisting of alkyl, cycloalkyl, and heteroalkyl; and a 5 or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, and oxadiazolyl; and, Z1 and Z2 are independently selected from the group consisting of H, F, (C1-4)alkyl, (C1- 3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C2-7)cycloalkyl; and preferrably: M = Carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, N; or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

2. A compound of claim 1 selected from the group consisting of: 1 O 70 N N N NN NN N N F O78 O D N N D N N N D N O N NNN87FFN O N N N O N NCl 94 O N N ND Cl O 101 N D N N D NN 108 F N N N N NNNN Cl116 O N N N ONNN F123 O N N N O62F FN 131 N N N N N N N3. A compound of claim 1 in which the compound is unlabeled or isotopically.

4. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and at least one pharmaceutically acceptable carrier, adjuvant and / or vehicle.

5. The pharmaceutical composition of claim 3 comprising a therapeutically effective amount of the compound, pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, and / or combination thereof.

6. The pharmaceutical composition according to claim 3 or 4, wherein said composition further comprises at least one second therapeutic agent.

7. A method for antagonizing and / or modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a cell, comprising the step of exposing the cell to a compound and / or composition according to any one of claims 1-6, optionally wherein said method is in vitro.

8. A method for modulating at least one orexin receptor and / or at least one kappa-opioid receptor in a subject in need thereof, comprising the step of administering a compound and / or composition according to any one of claims 1-6.

9. A method of treating a condition selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, posttraumatic stress disorders (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer diseases (AD), a central nervous system (CNS) disorder, and cancer in a subject in need thereof, comprising the step of administering a compound and / or composition according to any one of claims 1-6.

10. The method of claim 9 wherein the substance corresponding to the substance addiction or substance dependence is selected from the group consisting of one or more opioids, optionally heroin, morphine, oxycodone, fentanyl, and hydrocodone; one or more stimulants optionally selected from the group consisting of amphetamine, cocaine, crack cocaine, and methamphetamine; one or more sedatives and / or tranquilizers, benzodiazepine, and barbituates.

10. The method of any one of claims 7-10 wherein the compound antagonizes at least one orexin receptor and / or antagonize or modulate at least one kappa-opioid receptor (KOR).

11. The method of claim 10 wherein the compound antagonizes one or more orexin receptor(s)and / or kappa-opioid receptor wherein the combination is selected from the group consisting of orexin receptor OX1R and KOR; orexin receptor OX1R, orexin receptor OX2R and KOR;orexin receptor OX1R and orexin receptor OX2R only; orexin receptor OX1R; orexin receptorOX2R and KOR; and, KOR.

12. A method for manufacturing a compound or composition of any preceding claim using at leastone applicable combination of acid intermediates, amine intermediates, and methods ofpresented herein.

13. A carboxylic acid-containing intermediate selected from the group consisting of:

14. A secondary amine-containing intermediate selected from the group consisting of: