Substituted pyrazoles and imidazoles as orexin receptor antagonists, compositions, and methods for treating neurological and psychiatric disorders

Abstract

The present disclosure relates to derivatives of compounds having substituted imidazole and pyrazole ring systems that are orexin receptor antagonists and useful for the treatment and prevention of neurological and psychiatric disorders and diseases involving or associated with orexin receptors. 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 involving orexin receptors.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 400,894, filed August 25, 2022, the entire contents of which are incorporated herein by reference.

[0002] Federally funded research This invention was made with government support under Cooperative Agreement Research Grant No. UF1DA054817 awarded by the National Institute on Drug Abuse. The federal government has certain rights in this invention.

[0003] The present disclosure relates to and provides compounds, compositions, and methods for making orexin antagonists, as well as methods for using orexin antagonists as therapeutic agents to treat or ameliorate human and animal diseases, particularly any pathological disorder in which both orexin receptors are pharmacologically implicated or associated. Important therapeutic applications include, but are not limited to, the treatment of central nervous system (CNS) disorders and neurological diseases in which orexin receptors are implicated or modulated; such disorders include, but are not limited to, disorders responsive to orexin receptor antagonists, such as substance addiction and dependency, cognitive impairment, Alzheimer's disease (AD), post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety, autism, pain, and depression. [Background technology]

[0004] Orexins (also known as hypocretins) comprise 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 discovered by two research groups searching for novel signaling molecules: (1) Sakurai and coworkers (who named them orexin-A and -B) (Sakurai, T. et al., Cell 1998, 92, 573), and (2) de Lecea and coworkers, who named them hypocretin 1 and hypocretin 2, respectively (de Lecea, L. et al., Proc. Natl. Acad. Sci. USA 1998, 95, 322); These neuropeptides were discovered simultaneously in 1998 by Kodadek and Cai. These neuropeptides are endogenous ligands for two G protein-coupled receptors (GPCRs), OX1R and OX2R (also known as Hcrt1 and Hcrt2, respectively), and are derived by proteolysis from the same precursor peptide, the prepro-orexin polypeptide (Sakurai T. et al., The Journal of Biological Chemistry, 1999;274, 17771-17776). Although these endogenous ligands are structurally related, they have different binding affinities for the two GPCRs. Orexin A binds to OX1R with approximately 100-fold higher affinity than orexin B, whereas both orexin A and orexin B bind to OX2R with similar affinity (Kodadek, T.; Cai, D., Mol. BioSyst., 2010,6,1366-1375). Shortly after the discovery of orexins, modulation of orexin signaling was first explored as a potential novel therapeutic approach for patients with narcolepsy or insomnia; this is because the role of orexins in regulating sleep and wakefulness is well-studied and understood, and the discovery of small molecule modulators of orexin signaling has facilitated the development of this class of compounds. Patients with narcolepsy exhibit reduced activity of hypothalamic orexin neurons, which reduces the amount of circulating orexins in the cerebrospinal fluid. In contrast, activation of orexin neurons maintains wakefulness and alertness. The effects of orexin signaling on feeding and energy homeostasis have also been previously documented and shown to be coordinated with the sleep-wake cycle (Kodadek, T.; Cai, D. Mol. BioSyst., 2010, 6, 1366-1375).More recent studies have revealed roles for orexin signaling in other key physiological pathways, such as neuroendocrine function (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 adaptation 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 classified into three classes based on their overall receptor selectivity profiles: That is, (1) DORA (dual-acting or non-selective OX1R / OX2R antagonists), (2) SORA-1 (selective OX1R antagonist), and (3) SORA-2 (selective OX2R antagonist). Both OX2R knockout mice and OX1R / OX2R double knockout mice exhibit a sleep-inducing phenotype, but the effect is significantly weaker in OX1R knockout mice (Wang C et al., Neurosci., 2018, 11, 220. doi:10.3389 / fnmol2018.00220). Furthermore, both DORA and SORA-2 compounds disrupt wakefulness, whereas SORA-1 compounds do not; this suggests that the sleep-inducing effect is mediated by OX2R or a combination of OX1R and OX2R, but not by OX1R alone. Therefore, the discovery and development of selective orexin antagonists is crucial for advancement in this field, but more importantly, it is clear that the development of therapeutics for dysregulated biological processes involving orexin receptors, particularly for sleep-related conditions (e.g., substance addiction). Summary of the Invention

[0005] The present disclosure provides compounds of formula I and II: [ka] The present invention addresses the aforementioned therapeutic needs and / or other needs by providing a compound of the formula: The variants are defined herein, and include any pharmaceutically acceptable salts, solvates, adducts, polymorphs, and isomers thereof, as well as compositions comprising the same. Compounds of Formula I and / or II (and / or preferred embodiments thereof) and compositions comprising the same can be used to treat conditions as described herein (e.g., via their activity as orexin receptor antagonists). The compounds and / or compositions disclosed herein can be antagonists of one or more orexin receptors (e.g., either OX1R or OX2R, or both OX1R and OX2R). The compounds and / or compositions disclosed herein can be selectively more antagonistic to one or more orexin receptors compared to another orexin receptor (e.g., generally less antagonistic to OX1R or OX2R compared to the other orexin receptor). Thus, the compounds and / or compositions can be referred to herein as "orexin receptor antagonists."

[0006] In some embodiments, the present invention also provides compositions comprising the above-described compounds or pharmaceutically acceptable salts thereof. In another aspect of the present invention, methods are provided for treating CNS disorders, particularly CNS disorders such as substance addiction and dependence, post-traumatic stress disorder (PTSD), schizophrenia, panic, anxiety and depression, pain, cognitive impairment, and Alzheimer's disease (AD), in a subject in need of treatment or at risk for the disorder, comprising administering to the subject a therapeutically effective amount of an orexin receptor antagonist or a pharmaceutically acceptable salt thereof. In certain embodiments of the present invention, the orexin receptor antagonist or a pharmaceutically acceptable salt thereof can be formulated for periodic administration, e.g., every 3 hours, every 6 to 24 hours, as deemed clinically beneficial. Other aspects and embodiments are contemplated as would be understood by one of ordinary skill in the art. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present disclosure provides derivatives of the fused 6- and 5-membered ring systems of formulas (I) and (II), pharmaceutically acceptable salts thereof, compositions thereof, and methods of preparing and using the same, wherein the fused 6- and 5-membered rings are structurally described. In some embodiments, the present disclosure describes pharmaceutical compositions comprising one or more compounds of formulas (I) and (II), their preparation, and their use as pharmaceuticals and therapeutic agents, particularly (i.e., in preferred embodiments) as orexin receptor antagonists. These novel chemical entities, such as those represented by formulas (I) and (II), are nonpeptide antagonists of human orexin receptors and are potentially useful in treating disorders associated with dysfunction of orexinergic function, including, but not limited to, the treatment of disorders such as substance abuse (e.g., cocaine, opioids, alcohol), anxiety, panic, cognitive dysfunction, mood or appetite, sleep, Alzheimer's disease (AD), metabolic syndrome, pain, and / or hypertension. In preferred embodiments, the compounds disclosed herein are of therapeutic value in the treatment of anxiety disorders, abuse disorders, and / or sleep disorders.

[0008] In some embodiments, the present disclosure provides compounds of formula (I) and (II): [ka] provides a compound of where: R1 contains E which is a carbon (C) but not a nitrogen (N), and E is connected to J or D by a double bond; R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) As the alkyl that forms the cyclic structure of the alkyl bridge, R 10 or R 11 or R 13 is connected to one of the R5 and R6 together join to form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R7 is H, CH3, alkyl, substituted alkyl, (C 1~3) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 or R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; wherein in some embodiments, R 11 and R 12 can form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R 13 and R14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 or R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is an aromatic or aryl (including, but not limited to, a heteroaryl (e.g., preferably a 5- or 6-membered ring)), a substituted aromatic or aryl, a substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; and wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0009] In some preferred embodiments, the present disclosure provides compounds of formula Ia and II-a: [ka] wherein the ring systems represented by the variable ABJED of formulas (I) and (II) fused to the six-membered ring are preferred imidazolo ring systems as shown in the embodiments of formulas Ia and II-a herein; where R1 contains E which is a carbon (C) but not a nitrogen (N), and E is connected to J or D by a double bond; R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) As the alkyl that forms the cyclic structure of the alkyl bridge, R 10 or R 11 or R 13 is connected to one of the R5 and R6 together join to form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 or R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; wherein in some embodiments, R11 and R 12 can form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 or R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is an aromatic or aryl (including, but not limited to, a heteroaryl (e.g., preferably a 5- or 6-membered ring)), a substituted aromatic or aryl, a substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; and wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0010] In some preferred embodiments of Formula I (e.g., preferably Formula Ia) and Formula II (e.g., preferably Formula IIa), W is CH2; and R7, R8, R 13 , and R 14 is H; Substituents R7, R8, R 13 , and R 14are directly linked to the carbon having [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0011] In some preferred embodiments of Formula I (e.g., preferably Formula Ia) and Formula II (e.g., preferably Formula IIa), W is absent (i.e., non-existent); [ka] (all other groups included are defined herein).

[0012] In some preferred embodiments, the present disclosure also provides compounds of Formula I (e.g., preferably Formula Ia) and II (e.g., preferably Formula IIa), which include: a fused ring system ABJDE of five-membered heteroaryls (e.g., imidazole (where A, J are nitrogen while B, E, D are carbon) or pyrazole (where A, B are nitrogen while D, E, J are carbon)), which may or may not be fused to a further ring system; fused ring system ABJDE; 6-membered aromatic or aryl, substituted aromatic or aryl, substituted or unsubstituted heteroaryl, cycloalkyl, or heterocycloalkyl fused ring systems BJMGKL; where A, B, J, D, E, M, G, K and L are preferably as shown below: A is nitrogen or carbon; B is carbon or nitrogen; J is carbon or nitrogen; D is carbon; E is carbon, where R4 is defined above; M is carbon, CH, CHR, CHR, CR, CR, CR, CR, O, or N; G is carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, or O; K is carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR 4、 or O; and L is carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, or N.

[0013] In some preferred embodiments, the present disclosure provides compounds of formula Ib or II-b: [ka] wherein the ring system represented by the variables ABJDE of formulas (I) and (II) is fused to a six-membered ring, preferably a pyrazolo ring system, as shown in the embodiments of formula Ib or II-b herein; where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (such as, but not limited to, F, Cl, Br), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) As the alkyl that forms the cyclic structure of the alkyl bridge, R 10 or R 11 or R 13 is connected to one of the following: R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 and R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 and R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0014] In some preferred embodiments, the present disclosure provides compounds of formula Ib or II-b, where W is CH2, R7, R8, R 13 , R 14 is H, (as above) the substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0015] In some preferred embodiments, the present disclosure provides compounds of formula Ib or II-b, wherein W is absent (i.e., absent), [ka] (all other groups included are defined herein).

[0016] In other preferred embodiments, the present disclosure provides compounds wherein the imidazole-fused 6-membered ring of the compound has the formula (I-a1) and (II-a1): [ka] is an imidazole-fused six-membered ring as provided herein according to the embodiment shown in where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (such as, but not limited to, F, Cl, Br), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge10 or R 11 or R 13 It is connected to one of R5 and R6 linked together can form a spiro moiety such as cyclopropyl or cyclobutyl; R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 and R 12 (C 1~3) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 and R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0017] In some preferred embodiments, the present disclosure provides compounds of formula Ia or II-a1, where W is CH2, R7, R8, R 13 , R 14 is H, The substituents R, R, R as defined herein 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0018] In some preferred embodiments, the present disclosure provides compounds of formula Ib or II-b, Here W does not exist (i.e., is non-existent); [ka] (all other groups included are defined herein).

[0019] In some preferred embodiments, the disclosure provides compounds wherein the imidazole-fused 6-membered ring is represented by formulas (I-a2) and (II-a2): [ka] Preferably, the present invention is as described herein according to the embodiment shown in where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (such as, but not limited to, F, Cl, Br), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 and R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 and R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C3~7 ) heterocycloalkyl.

[0020] In some preferred embodiments, the present disclosure provides compounds of formula I-a2 or II-a2, where W is CH2, R7, R8, R 13 , R 14 are H, respectively, Substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0021] In some preferred embodiments, the present disclosure provides compounds of formula I-a2 or II-a2, where W does not exist (i.e., is non-existent), [ka] (all other groups included are defined herein).

[0022] In some preferred embodiments, the disclosure provides compounds wherein the imidazole-fused six-membered ring is represented by formulas (I-a3) and (II-a3): [ka] Preferably, the present invention is as described herein according to the embodiment shown in where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (such as, but not limited to, F, Cl, Br), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge10 or R 11 or R 13 connected to one of the following: R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 and R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 and R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0023] In some preferred embodiments, the present disclosure provides compounds of formula (I-a3) or (II-a3), where W is CH2, R7, R8, R 13 , R 14 is H, Substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0024] In some preferred embodiments, the present disclosure provides compounds of formula I-a3 or II-a3, where W does not exist (i.e., is non-existent), [ka] (all other groups included are defined herein).

[0025] In another preferred embodiment, the present disclosure provides compounds wherein the pyrazole-fused 6-membered ring is represented by formulas (I-b1) and (II-b1): [ka] Preferably, the present invention is as described herein according to the embodiment shown in where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (such as, but not limited to, F, Cl, Br), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) As the alkyl that forms the cyclic structure of the alkyl bridge, R 10 or R 11 or R 13 is connected to one of the R5 and R6 linked together can form a spiro moiety such as cyclopropyl or cyclobutyl; R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 and R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 and R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0026] In some preferred embodiments, the present disclosure provides compounds of formula (I-b1) or (II-b1), where W is CH2, R7, R8, R 13 , R 14 are H, respectively, Substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0027] In some preferred embodiments, the present disclosure provides compounds of formula (I-b1) or (II-b1), where W does not exist (i.e., is non-existent), [ka] (all other groups included are defined herein).

[0028] In some preferred embodiments, the disclosure provides compounds wherein the pyrazole-fused 6-membered ring has the formulas (I-b2) and (II-b2): [ka] Preferably, the present invention is as described herein according to the embodiment shown in where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (such as, but not limited to, F, Cl, Br), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) As the alkyl that forms the cyclic structure of the alkyl bridge, R 10 or R 11 or R 13 is connected to one of the R5 and R6 linked together can form a spiro moiety such as cyclopropyl or cyclobutyl; R7 is H, CH3, alkyl, substituted alkyl, (C 1~3) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 and R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 and R 14 (C 1~3) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0029] In some preferred embodiments, the disclosure provides compounds of formula Ib2 or IIb2, where W is CH2, R7, R8, R 13 , R 14 are H, respectively, Substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0030] In some preferred embodiments, the disclosure provides compounds of Formula Ib2 or IIb2, wherein W is absent (i.e., absent); [ka] A seven-membered ring system is provided as shown below (all other groups are defined herein).

[0031] In some preferred embodiments, the present disclosure provides compounds wherein the pyrazole-fused 6-membered ring is represented by formulas (I-b3) and (II-b3): [ka] Preferably, the present invention is as described herein according to the embodiment shown in where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, aromatic or aryl (e.g., phenyl), heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (such as, but not limited to, F, Cl, Br), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) As the alkyl that forms the cyclic structure of the alkyl bridge, R 10 or R 11 or R 13 is connected to one of the R5 and R6 linked together can form a spiro moiety such as cyclopropyl or cyclobutyl; R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 and R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 and R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0032] In some preferred embodiments, the present disclosure provides compounds of formula (I-b3) or (II-b3), where W is CH2, R7, R8, R 13 , R 14 are H, respectively, Substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0033] In some preferred embodiments, the present disclosure provides compounds of formula (I-b3) or (II-b3), wherein W is absent (i.e., non-existent); [ka] A seven-membered ring system is provided as shown below (all other groups are defined herein).

[0034] In some preferred embodiments, the disclosure provides compounds wherein the pyrazole-fused 6-membered ring has the formula (I-b4) and (II-b4): [ka] Preferably, the present invention is as described herein according to the embodiment shown in where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl group, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three substituents independently selected from one, two, or all of R2, R3, and R4; R5 and R6 are H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 It is connected to one of R5 and R6 linked together can form a spiro moiety such as cyclopropyl or cyclobutyl; R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to either of the following; R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to either of the following; R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; or R 11 and R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 13 and R 14 is selected from the group consisting of H, CH3, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 or R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15is selected from the group consisting of aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring) or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0035] In some preferred embodiments, the present disclosure provides compounds of formula (I-b4) or (II-b4), where W is CH2, R7, R8, R 13 , R 14 are H, respectively, Substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] The present invention provides a 5-5 bridged bicyclic ring system as shown in

[0036] In some preferred embodiments, the present disclosure provides compounds of formula (I-b4) or (II-b4), wherein W is absent (i.e., non-existent); [ka] A seven-membered ring system is provided as shown below (all other groups are defined herein).

[0037] In some particularly preferred embodiments, the present disclosure provides compounds wherein the stereocenters and main backbone rings are represented by formulas (I-a5), (I-b5), (II-a5), and (II-b5): [ka] 1. According to the embodiment shown in where Variables or substituents (i.e., R1-R 15 ) are as defined above and above.

[0038] In some preferred embodiments, the present disclosure provides compounds wherein the stereocenters and main backbone rings are represented by formulas (I-a6), (I-b6), (II-a6), and (II-b6): [ka] Preferably, the compound is represented by the exemplary formula described herein according to the embodiment shown in where Variables or substituents (i.e., R1-R 15 ) are as defined above and above.

[0039] In some preferred embodiments, the present disclosure provides a compound of formula I-a7, I-a8, I-a9, II-a7, II-a8, or II-a9: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently selected from H, halogen (F, Cl, Br, etc.), alkyl groups, substituted alkyls, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three substituents independently selected from one, two, or all of R2, R3, and R4; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted 5-6 membered heteroaryl or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0040] In some preferred embodiments, the present disclosure provides compounds of formula I-b7, I-b8, I-b9, I-b10, II-b7, II-b8, II-b9, and II-b10: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, having any of: where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, and substituted 5-6 membered heteroaryl; When 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are each independently H, halogen (optionally F, Cl, or Br), an alkyl group, a substituted alkyl group, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three substituents independently selected from one, two, or all of R2, R3, and R4; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl and a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl.

[0041] In some preferred embodiments, the present disclosure provides compounds of formula I-b11, I-b12, I-b13, I-b14, II-b11, II-b12, II-b13, and II-b14: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, having any of: where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, and substituted 5-6 membered heteroaryl; When 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 each independently represent H, halogen (F, Cl, or Br), an alkyl group, a substituted alkyl group, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three substituents independently selected from one, two, or all of R2, R3, and R4; R 12 is H, CH3, alkyl, substituted alkyl, (C 1~3) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 15 is selected from the group consisting of aromatic, aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic, substituted aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0042] In a most preferred embodiment, the present disclosure provides exemplary compounds of Formula I and / or Formula II as shown in Table 1.

[0043] Any embodiment shown herein is also intended to represent unlabeled and isotopically labeled forms of the compound, unless otherwise specified. Isotopically labeled compounds have the structure of the chemical formula shown 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 the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine (H, H, C, C, C, N, F, P, P, S, Cl, I, etc.). The present disclosure also includes various isotopically labeled compounds as defined herein, for example, compounds into which radioactive isotopes (H, C, and C, etc.) are incorporated. Such isotopically labeled compounds are useful for metabolic studies (preferably with C), kinetic studies (e.g., with H or H), detection or imaging techniques (including drug or substrate tissue distribution assays) such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), or radioisotope treatment of patients. In particular, F or a labeled compound thereof may be particularly preferred for PET or SPECT studies. The isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the procedures shown in the schemes or those disclosed in the Examples and preparation methods below, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0044] Many of the compounds disclosed herein that are useful in the methods and compositions of the present disclosure possess at least one stereocenter in their structure. This stereocenter may exist in either the R or S configuration, and the R and S designations are used in accordance with the rules set forth in Pure Appl. Chem. (1976), 45, 11-30. Accordingly, the compounds of the present disclosure also include all stereoisomeric forms, such as optical and diastereoisomeric forms of the compounds, or mixtures thereof, including all possible mixtures of stereoisomers. See, for example, WO 01 / 062726. Furthermore, in some embodiments, multiple substituents contained in a piperidinyl or pyrrolidinyl ring may also exist in either a cis or trans relationship relative to the plane of the piperidinyl or pyrrolidinyl ring. Such geometric isomeric forms, although not explicitly depicted in the chemical formulas depicted herein, are intended to be included within the scope of the present disclosure. With respect to the methods and compositions of the present disclosure, unless a particular isomeric form is specifically referred to, a reference to a single compound or compounds is intended to include the compound in each of its possible isomeric forms and mixtures thereof.

[0045] As used herein, the expression "pharmaceutically acceptable salts" refers to chemical entities or compounds according to the present disclosure in the form of therapeutically active, non-toxic base and acid salts of said compounds. Acid addition salt forms of compounds that exist in their free form as bases can be obtained by treating the free base form with a suitable acid (such as an inorganic acid, e.g., a hydrogen halide (such as hydrogen chloride or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, or an organic acid (e.g., acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, or the like); see, e.g., WO 01 / 062726, U.S. Patent No. 8,492,416 B2, U.S. Patent No. 2017 / 0022208 A1, and U.S. Patent No. 2017 / 0253603 A2).

[0046] The compounds of the present disclosure that contain acidic protons can be converted into their therapeutically effective non-toxic base addition salt forms, such as metal salts or amine salts, by treating with suitable organic and inorganic bases.Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts (e.g., lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc.), salts with organic bases, and salts with amino acids (e.g., arginine, lysine, etc.).Conversely, the salt forms can be converted into free forms by treating with suitable bases or acids.The compounds of the present disclosure and their salts can be in the form of solvates, which are included in the scope of this specification (e.g., hydrates, alcoholates, etc.).

[0047] The term "aryl" as used herein means a monocyclic or bicyclic carbocyclic aromatic or aryl ring system. Phenyl is a non-limiting example of a monocyclic aromatic or aryl ring system (unless otherwise specified).

[0048] As used herein, the term "heteroaryl" refers to a monocyclic or bicyclic aromatic or aryl ring system having one to three heteroatoms or heteroatomic groups in each ring selected from O, N, NH, or S in a chemically stable arrangement. In such bicyclic aromatic or aryl ring system embodiments of "heteroaryl," both rings may be aromatic or aryl, and either or both rings may contain the heteroatom or heteroatom group. Non-limiting examples of heteroaryl rings (unless otherwise specified) 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- Examples include 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).

[0049] As used herein, the term "cycloalkyl or cycloalkenyl" refers to a monocyclic or fused, or (C 1~3 ) refers to an alkyl-bridged bicyclic carbocyclic ring system that is neither aromatic nor aryl. The cycloalkenyl ring has one or more units of unsaturation. Preferred cycloalkyl or cycloalkenyl groups include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl, and decalinyl.

[0050] In some embodiments, the compounds of the present disclosure may be in the form of prodrugs, analogs, and / or derivatives. The term "prodrug" is understood by those skilled in the art and is intended to include compounds or chemicals that are converted to orexin antagonists under physiological conditions. A common method for making prodrugs is by selecting a moiety that is hydrolyzed or metabolized under physiological conditions to yield the desired compound or chemical. In other embodiments, the prodrug is converted to an orexin antagonist by enzymatic or chemical activity in the host animal.

[0051] The compounds of the present disclosure also include isotopically labeled compounds, particularly compounds labeled with 2H (deuterium); that is, compounds identical to the compounds of any formula described herein, except that one or more atoms are replaced by atoms having the same atomic number but different atomic masses from those normally found in nature. Isotopically labeled compounds of all formulas, particularly 2H (deuterium) labeled compounds, and salts thereof, are within the scope of the present invention. The replacement of hydrogen with 2H (deuterium) can provide stronger metabolic stability, for example, prolonged in vivo half-life or reduced required dose; and / or reduce the inhibition of cytochrome P450 enzymes, for example, improving safety profiles. In another aspect of the present embodiment, compounds of all formulas are not isotopically labeled. However, by using appropriate isotopic modifications of suitable reagents or starting materials, those skilled in the art can prepare isotopically labeled compounds of all formulas disclosed herein by methods similar to those described herein below.

[0052] In some embodiments, the present disclosure provides compositions comprising one or more of such compounds, and / or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, isomers, or combinations thereof. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combinations thereof; and at least one pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a therapeutically effective amount of such a compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combinations thereof. In some embodiments, the present disclosure provides such pharmaceutical compositions further comprising at least one second therapeutic agent. The present disclosure also provides pharmaceutical compositions comprising one or more compounds (such as, for example, pharmaceutically acceptable salts thereof) of the present disclosure (i.e., as active agents, as therapeutic agents) and one or more pharmaceutically acceptable carriers or excipients. Pharmaceutical compositions contain a therapeutically effective amount of one or more such compounds (i.e., active agents), or an appropriate fraction thereof. The composition may optionally contain additional active agents. In some embodiments, the 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, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, solvents, isotonicity agents, buffers, pH adjusters, absorption delaying agents, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, coloring agents, encapsulating materials, and coating materials. The use of such excipients in pharmaceutical formulations is known in the art.Conventional vehicles and carriers include, but are not limited to, 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 the peptide product, the present disclosure encompasses the use of conventional excipients and carriers in formulations comprising the peptide product. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA (2005); Handbook of Pharmaceutical Excipients, 5th ed., Rowe et al., 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 may depend on various factors, such as the chosen route of administration.Potential routes of administration of pharmaceutical compositions comprising compounds disclosed herein and the like can include, but are not limited to, oral, parenteral (including intradermal, subcutaneous, intramuscular, intravascular, intravenous, intraarterial, intraperitoneal, intracavity, and topical), topical (including transdermal), transmucosal, intranasal (e.g., via nasal spray or nasal drops), ophthalmic (e.g., via eye drops), pulmonary (e.g., via oral or nasal inhalation), buccal, sublingual, rectal (e.g., via suppository), vaginal (e.g., via suppository), and / or other suitable routes known to one of skill in the art.

[0053] In some embodiments, the compounds and compositions disclosed herein can be used as orexin receptor antagonists. In preferred embodiments, the compounds and / or compositions disclosed herein can be antagonists of one or more orexin receptors (e.g., either OX1R or OX2R, or both OX1R and OX2R). The compounds and / or compositions disclosed herein can be selectively more antagonistic to one or more orexin receptors compared to other orexin receptors (e.g., generally less antagonistic to OX1R or OX2R compared to other orexin receptors). Thus, the compounds and / or compositions can be referred to herein as "orexin receptor antagonists." In some embodiments, the compounds can be antagonists of the κ-opioid receptor (or kappa-opioid receptor [which is a G-protein-coupled receptor encoded by the OPRK1 gene in humans]; abbreviated as KOR or KOP, and ketazocine is its ligand). In some embodiments, compounds and / or compositions of the present disclosure may be antagonists of one or more orexin receptors (i.e., orexin receptor antagonists), but are not antagonists of KOR. In some embodiments, for example, one or more compounds of the present disclosure and / or combinations thereof are designed to, and preferably have, the following properties when measured using standards in in vitro cellular assays for effective therapeutic efficacy (e.g., assays described in the Examples herein): (1) OX1R Kb < 30nM, OX2R Kb > 1000nM, KOR Ki < 500nM; (2) OX1R Kb < 30nM, OX2R Kb > 30nM, KOR Ki < 500nM; or (3) OX1R Kb < 30 nM, OX2R Kb > 1000 nM, KOR Ki > 1000 nM. In some embodiments, the present disclosure provides a method for preventing or treating a condition associated with an orexin receptor and / or one or more κ-opioid receptors (i.e., a method for preventing or treating as an orexin receptor antagonist). For in vivo assays, the compounds and / or compositions of the present disclosure may be tested using animal models (such as rats) by measuring primary dependent measures (e.g., including, but not limited to, time of first drug injection, total drug injection administered, drug intake rate, and total lever press failures), progression ratios (e.g., including, but not limited to, time of first drug injection, breakpoint, final ratio at completion, and total lever presses and lever press failures), and state reinstatement (e.g., including, but not limited to, time of first drug injection, and total lever presses and lever press failures). These tests and in vivo evaluations are designed, planned, and predicted using techniques known to those skilled in the art for the purpose of demonstrating the therapeutic utility and in vivo efficacy of compounds (which are directed toward reducing intake and reducing motivation for illicit drug abuse) (see, e.g., Brain Research 1731 (2020), edited by James et al. (see, e.g., Brodnik et al., Editorial 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.201 5.05.051). Other suitable test methods will be understood by those skilled in the art.

[0054] In some embodiments, the present disclosure provides a method for preventing or treating a condition selected from the group consisting of central nervous system (CNS) disorders, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD) in a subject in need thereof by administering to the subject one or more such compounds and / or a composition comprising one or more of such compounds, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, the method can include administering a therapeutically effective amount of a composition comprising the compound, a 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 include an unlabeled form of the compound or an isotopically labeled form of the compound, wherein one or more atoms are replaced by an atom having a selected atomic mass or mass number. In some embodiments, the disclosure provides the use of a compound disclosed herein, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, in the preparation of a therapeutic medicament for preventing and / or treating a condition selected from the group consisting of central nervous system (CNS) disorder, substance addiction, dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, and Alzheimer's disease (AD) in a subject in need thereof.Examples of substance addictions can include a person's addiction to one or more opioids (e.g., but not limited to, heroin, morphine, oxycodone (e.g., OxyContin, Percocet), fentanyl and / or hydrocodone (e.g., Vicodin)), one or more stimulants (e.g., amphetamines (e.g., Adderall, Ritalin), cocaine, crack cocaine, methamphetamine), one or more sedatives and / or tranquilizers (e.g., but not limited to, benzodiazepines (e.g., Valium, Xanax, Klonopin) or barbiturates (e.g., Nembutal, Luminal, Phenobarbital)), or other addictive drugs as known to those skilled in the art. In some embodiments, the use can include a composition comprising a therapeutically effective amount of the compound, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof. In some embodiments, such uses may include compositions of pharmaceutically acceptable salts or isotopes of the compounds. In some embodiments, such uses may include compositions comprising unlabeled or isotopically labeled forms of the compounds, where the compounds have the structure shown in the formula, where one or more atoms are replaced by atoms having selected atomic masses or mass numbers. The present disclosure also provides intermediates of the compounds disclosed herein, as well as methods for preparing the same. In some embodiments, such preparations may include using any of the intermediates disclosed herein. Other embodiments are also contemplated as would be understood by one skilled in the art.

[0055] The present disclosure provides various aspects and embodiments of the compounds, compositions, and methods of preparing and using the same. In preferred embodiments, the present disclosure provides the following embodiments:

[0056] [Embodiment 1] Chemical formula (I) or (II): [ka] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; where R1 includes E, which is a carbon (C) but not a nitrogen (N), and E is connected to J or D by a double bond; R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Alternatively, 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three independently selected substituents of one, two, or all of R2, R3, and R4; R5 and R6 are independently H, CH3, alkyl, substituted alkyl, (C 1~3) selected from the group consisting of fluoroalkyl, cycloalkyl; R6 is (C 1~3 ) As the alkyl that forms the cyclic structure of the alkyl bridge, R 10 or R 11 or R 13 is connected to one of the R5 and R6 linked together form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R7 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R7 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R8 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R8 is (C 1~3 ) R as alkyl to form a cyclic structure of alkyl bridge 10 or R 11 or R 13 connected to one of the following: R9 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, cycloalkyl; R9 is (C 1~3 ) R6 or R as alkyl forming the cyclic structure of the alkyl bridge 11 connected to one of the following: R 10 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 11 and R 12 are independently H, CH3, alkyl, substituted alkyl, (C 1~3) selected from the group consisting of fluoroalkyl, cycloalkyl; R 11 or R 12 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; wherein in some embodiments, R 11 and R 12 can form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R 13 and R 14 are independently selected from the group consisting of H, CH, alkyl, substituted alkyl (e.g., fluoroalkyl), and cycloalkyl; R 13 or R 14 (C 1~3 ) linked to either R7 or R8 as an alkyl forming a cyclic structure of the alkyl bridge; R 15 is an aromatic or aryl (including, but not limited to, a heteroaryl (e.g., preferably a 5- or 6-membered ring)), a substituted aromatic or aryl, a substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; and wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl; (a) W is CH2, and R7, R8, R 13 , R 14 (each of which is H); Substituents R7, R8, R 13 , and R 14 The carbon bearing [ka] providing a 5-5 bridged bicyclic ring system as shown in or (b) W is non-existent, [ka] provides a seven-membered ring system shown in where The fused ring system ABJDE is a 5-membered heteroaryl, optionally imidazole (where A and J are nitrogen while B, E, and D are carbon) or pyrazole (where A and B are nitrogen and D, E, and J are carbon); a fused ring system fused to a further ring system or not fused to a further ring system; The fused ring system BJMGKL is a 6-membered aromatic or aryl, substituted aromatic or aryl, substituted or unsubstituted heteroaryl, cycloalkyl, heterocycloalkyl; A is nitrogen or carbon; B is carbon or nitrogen; J is carbon or nitrogen; D is carbon; E is carbon; M is selected from the group consisting of carbon, CH, CHR, CHR, CR, CR, CR, CR, O, and N; G is selected from the group consisting of carbon, CH, CHR, CHR, CR, CR, CR, CR, and O; K is selected from the group consisting of carbon, CH, CHR, CHR, CR, R, CR, CR, CR, and O; L is selected from the group consisting of carbon, CH, CHR2, CHR3, CR2R3, CR2, CR3, CR4, O, and N.

[0057] [Embodiment 2] Formula I-a7, Formula I-a8, Formula I-a9, Formula II-a7, Formula II-a8, or Formula II-a9: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); When R1 is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are independently selected from H, halogen (F, Cl, Br, etc.), alkyl groups, substituted alkyls, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three substituents independently selected from one, two, or all of R2, R3, and R4; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted 5-6 membered heteroaryl or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0058] [Embodiment 3] Formula I-b7, Formula I-b8, Formula I-b9, Formula I-b10, Formula II-b7, Formula II-b8, Formula II-b9 and Formula II-b10: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, and substituted 5-6 membered heteroaryl; When 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 are each independently H, halogen (optionally F, Cl, or Br), an alkyl group, a substituted alkyl group, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three substituents independently selected from one, two, or all of R2, R3, and R4; R 15 is selected from the group consisting of aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl and a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C3~7 ) cycloalkyl, (C 3~7 ) heterocycloalkyl.

[0059] [Embodiment 4] Formula I-b11, Formula I-b12, Formula I-b13, Formula I-b14, Formula II-b11, Formula II-b12, Formula II-b13 and Formula II-b14: [ka] or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; where When E in R1 is carbon (C) and not nitrogen (N), and E is connected to J or D by a double bond, then R1 is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, and substituted 5-6 membered heteroaryl; When 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; R2, R3, and R4 each independently represent H, halogen (F, Cl, or Br), an alkyl group, a substituted alkyl group, (C 1~4 ) alkyl, (C 1~4 ) alkoxy, (C1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy and (C 3~7 ) cycloalkyl; wherein each of R2, R3, and R4 is independently and optionally substituted at each substitutable position with up to three substituents independently selected from one, two, or all of R2, R3, and R4; R 12 is H, CH3, alkyl, substituted alkyl, (C 1~3 ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R 15 is selected from the group consisting of aromatic, aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic, substituted aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl or a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C 1~4 ) alkyl, (C 1~4 ) alkoxy, halogen, (C 1~3 ) fluoroalkyl, (C 1~3 ) fluoroalkoxy, (C 3~7 ) cycloalkyl, and (C 3~7 ) heterocycloalkyl.

[0060] [Embodiment 5] [ka] TIFF2025529901000042.tif224159TIFF2025529901000043.tif238159TIFF2025529901000044.tif215159TIFF2025529901000045.tif242158TIFF2025529901000046.tif242157TIFF2025529901000047.tif238159, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

[0061] [Embodiment 6] (particularly preferred embodiment) [ka] TIFF2025529901000049.tif195159, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

[0062] [Embodiment 7] 1. A pharmaceutical composition comprising: A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and an acceptable carrier, adjuvant or vehicle; Including, Pharmaceutical compositions.

[0063] [Embodiment 8] 7. The pharmaceutical composition of embodiment 6, comprising a therapeutically effective amount of the compound, a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

[0064] [Embodiment 9] 9. The pharmaceutical composition according to embodiment 7 or 8, wherein the composition further comprises at least one second therapeutic agent.

[0065] [Embodiment 10] A method of antagonizing at least one orexin receptor in a cell, comprising exposing the cell to a compound and / or composition according to any preceding paragraph, optionally an in vitro method.

[0066] [Embodiment 11] A method of antagonizing at least one orexin receptor, comprising administering a compound and / or composition according to any preceding item in a subject in need thereof.

[0067] [Embodiment 12] A method of treating a condition selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer's disease (AD), and central nervous system (CNS) disorders, comprising administering to a subject in need thereof a compound and / or composition according to any preceding paragraph.

[0068] [Embodiment 13] 13. The method of embodiment 12, wherein the substance corresponding to the substance addiction or substance dependence is: 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, benzodiazepines, and barbiturates, The method is selected from the group consisting of:

[0069] [Embodiment 14] The method of any one of embodiments 10-13, wherein the compound is an orexin receptor antagonist.

[0070] [Embodiment 15] 15. The method of any one of embodiments 10 to 14, wherein the compound is an antagonist of orexin receptor 1 (OX1R) or orexin receptor 2 (OX2R), or an antagonist of both OX1R and OX2R; Optionally, wherein the compound is an antagonist of a κ-opioid receptor; and / or the following as measured in an in vitro cell assay: (1)OX1R Kb < 30nm, OX2R Kb > 1000nm, KOR Ki <500nm; (2)OX1R Kb < 30nm, OX2R Kb > 30nm, KOR Ki <500nm; or (3)OX1R Kb < 30nm, OX2R Kb > 1000nm, KOR Ki > 1000nm, A method for characterizing

[0071] [Embodiment 16] 16. The method of any one of embodiments 10 to 15, A method comprising administering to said patient a therapeutically effective amount of a compound and / or composition of the preceding paragraph.

[0072] [Embodiment 17] 17. The method of any one of embodiments 10 to 16, A method comprising administering at least one unlabeled and / or at least one isotopically labeled form of the compound of any preceding item, and / or a composition comprising same.

[0073] [Embodiment 18] A method for preparing a compound of embodiment 1, comprising combining at least two intermediates to prepare said compound. In a preferred embodiment, the intermediates, reaction conditions, etc. used in preparing said compound are described in detail in the Examples section and will not be described in detail here, but one skilled in the art will understand from the above description that the same content is reproduced in the description of this preferred embodiment (i.e., incorporated herein).

[0074] [Embodiment 19] A method for producing the pharmaceutical composition of embodiment 1, comprising combining at least one compound of embodiment 1 with at least one pharmaceutically acceptable excipient. Methods for making such combinations (i.e., at least one compound, etc., and at least one pharmaceutical composition) are well known in the art and therefore are incorporated herein without further details for this embodiment.

[0075] The term "therapeutically effective amount" refers to an amount of compound that, when administered to a subject, is sufficient to prevent, reduce the risk of, delay the onset of, slow the progression of, or reverse the condition being treated, or to alleviate to some extent the condition or one or more symptoms or complications of the condition, in at least some of the subjects receiving the compound. The term "therapeutically effective amount" also refers to an amount of compound sufficient to elicit the biological or medical response in a cell, tissue, organ, or human that a physician or clinician seeks to achieve. The terms "treat," "treating," and "treatment" include alleviating, ameliorating, and preventing the progression of a condition, regressing or eliminating a condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating, or eradicating one or more causes of the condition. "Treatment" of a condition includes prevention of the condition. The terms "prevent," "preventing," and "prevention" include preventing, reducing the risk of, and delaying the onset of, a condition or one or more symptoms or complications associated with the condition. The term "medical conditions" (or, for short, "conditions") includes diseases and disorders. The terms "diseases" and "disorders" are used synonymously herein.

[0076] It will be understood that throughout this specification, expressions such as "comprise" or its variations "comprises" or "comprising" are intended to include the specified integer (or component) or group of integers (or components), but not to exclude any other integer (or component) or group of integers (or components). The singular forms "a", "an", and "the" also include the plural unless the context clearly dictates otherwise. The symbol "=" when used to refer to a chemical formula means "is". The term "including" is used to mean "including but not limited to", The terms "including" and "including but not limited to" are used synonymously. As used herein, the term "chemical entity" refers to a chemical compound, such as an organic compound or a mixture of compounds. "Chemical entity" includes, for example, chemical entities known in terms of structure, and if such chemical entities have orexin antagonist activity, they may be suitable as "therapeutic agents" in the methods and compositions disclosed herein. Additionally, one of skill in the art will recognize that the following abbreviations are commonly used: 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-butyloxycarbonyl BSA: bovine serum albumin CbzCl: benzyl chloroformate CDI: carbonyldiimidazole DCM: dichloromethane DCE: dichloroethane DEAD: Diethyl azodicarboxylate DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide CH2Cl2: dichloromethane EDC: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide Et3N: Triethylamine EtOAc: ethyl acetate EtOH: Ethanol HCl: Hydrochloric acid 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 MgSO4: Magnesium sulfate MTBE: Methyl tert-butyl ether NaHCO3: Sodium bicarbonate Na2CO3: Sodium carbonate K2CO3: Potassium carbonate NaOH: Sodium hydroxide NMM: N-methylmorpholine PtO2: platinum oxide Pd: Palladium Pd / C: Palladium / activated carbon PyClu: 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate RT or rt: room temperature Rxn: reaction SOCl2: Thionyl chloride THF: tetrahydrofuran TFA: trifluoroacetic acid X-Phos: 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate NMR: nuclear magnetic resonance ESI: electrospray ionization MS: mass spectrometry reaction

[0077] All references cited in this disclosure are incorporated herein by reference in their entirety. Specific embodiments are further described in the following examples. These embodiments are offered by way of illustration only and are not intended to limit the scope of the claims in any way.

[0078] Example Example 1 In accordance with the present disclosure, the following intermediates were prepared and used in the synthesis of exemplary compounds claimed herein: 1. Prepared Carboxylic Acid Group-Containing Intermediate - Carboxylic Acid Group [ka] and 2. Prepared Secondary Amine-Containing Intermediates – Amine Group [ka]

[0079] I. General Synthetic Methods, Procedures and Experimental A. General method All temperatures are 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 a nitrogen atmosphere. Compounds were purified by flash column chromatography on silica gel or preparative HPLC. The compounds described in this disclosure were characterized by LC-MS data (retention time t R are expressed in min; molecular weights obtained by mass spectrometry are expressed in g / mol).

[0080] 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 for 5 min (flow rate: 0.8 ml / min). Detection: UV 280 / 254 nm + MS.

[0081] 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 for 5 min (Flow rate: 0.8 ml / min). Detection: UV 280 / 254 nm + MS.

[0082] In general, the compounds of the present disclosure can be prepared by methods known to those skilled in the art and modern techniques in the art. The following schemes 1 to 4 show synthetic routes for the compounds of the present disclosure. Other equivalent schemes that would be readily apparent to a synthetic organic chemist or medicinal chemist can also be used alternatively to synthesize various portions of the molecules as shown in the general schemes described herein.

[0083] B. Intermediate synthesis 1. Synthesis of intermediate HBS-037-054 [ka] Step 1: Synthesis of Compound HBS-037-036: Ethyl-3-phenyl-1H-pyrazole-5-carboxylate (0.5 g, 2.31 mmol) was dissolved in acetone (10.0 mL). K2CO3 (0.96 g, 6.9 mmol) was added, followed by 1-bromo-2-chloroethane (0.1 mL, 11.6 mmol). The reaction mixture was heated at 55 °C for 16 hours. LCMS data showed the m / z value (279.0) for the desired product and a small amount of by-product. The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). A liquid compound (0.6 g) was obtained (yield 93.2%). C 14 H 15 The calculated MS(ESI) mass for ClN2O2 is 278.7, [M+H] + The m / z value of was 279.0. Step 2: Synthesis of Compound HBS-037-040: Compound HBS-037-036 (0.55 g, 1.97 mmol) was dissolved in dry THF (6.0 mL). DIBAL (12.0 mL, 1.0 M solution, 11.8 mmol) was added in an ice-cooled bath. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data indicated an m / z value (237.0) for the formation of the desired product. The reaction mixture was quenched with 1.0 N aqueous NaOH solution and diluted with ethyl acetate (10.0 mL). The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate (10.0 mL x 3). The EtOAc layer was separated and washed with water, then brine. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 0.4 g of crude product (85.6% yield). 12 H 13 The calculated MS(ESI) mass for ClNO is 236.7, [M+H] + The m / z value of was 237.0. Step 3: Synthesis of compound HBS-037-043: Compound HBS-037-040 (0.47 g, 1.97 mmol) was dissolved in dry DMF (12.0 mL). NaH (0.12 g, 2.96 mmol) was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed an m / z value (201.1) for the formation of the desired product. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.26 g of the compound was obtained in a solid state (65.3% yield). C 12 H 12 The calculated MS(ESI) mass for NO is 200.2, [M+H] + The m / z value of was 201.1. Step 4: Synthesis of compound HBS-037-043: Compound HBS-037-042 (0.25 g, 1.25 mmol) was dissolved in DCM (5.0 mL). NBS (0.24 g, 1.37 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. LCMS data showed an m / z value (280.9) for the formation of the desired product. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Liquid compound HBS-037-043 was obtained (0.29 g, 81.7% yield). 12 H 11 The calculated MS(ESI) mass for BrNO is 279.1, [M+H] + The m / z value of was 280.9. Step 5: Synthesis of Intermediate HBS-037-054: Compound HBS-037-043 (0.025 g, 0.09 mmol) was dissolved in anhydrous THF (1.0 mL) under a nitrogen atmosphere. The reaction mixture was cooled to −78° C., and n-BuLi (0.12 mL, 1.6 M) was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 30 minutes. Dry CO gas was bubbled through the reaction mixture at −65° C., and the reaction mixture was allowed to warm gradually to room temperature. LCMS data indicated the m / z value (245) for the desired product, the m / z value (201) for a debrominated by-product, and some unknown product. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was separated, and the debrominated product was recovered. The aqueous layer was acidified with 1 M HCl solution and evaporated to dryness to give 0.022 g of solid product. 13 H 12 The calculated MS(ESI) mass for N2O3 was 244.3, [M+H] + The m / z value of was 245.0; 1 H NMR (400 MHz, chloroform-d) δ ppm 4.06 - 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).

[0084] 2. Synthesis of intermediate HBS-037-193 [ka] Step 1: Synthesis of compound HBS-037-191: Ethyl benzoylacetate (0.5 g, 2.6 mmol) was dissolved in DMSO (5.0 mL). NBS (0.51 g, 2.86 mmol) was added, and the reaction mixture was stirred at ambient temperature for 24 hours. LCMS showed m / z value (270.9) for the product formation. 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 crude product was obtained by evaporating the solvent. It was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 0.42 g of product was obtained (yield 59.7%). C11 H 11 The calculated MS(ESI) mass for BrO3 is 271.1, [M+H] + The m / z value of was 270.9. Step 2: Synthesis of compound HBS-037-192: Compound HBS-037-191 (0.42 g, 1.55 mmol) was dissolved in anhydrous acetonitrile (5.0 mL). 2-Aminopyridine (0.15 g, 1.55 mmol) was added, and the reaction mixture was stirred at 80° C. for 1 hour. LCMS showed m / z value (267.1) for the product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). Compound HBS-037-192 (0.24 g) was obtained (yield 58.0%). C 16 H 14 The calculated MS(ESI) mass for N2O2 was 266.3, [M+H] + The m / z value of was 267.1. Step 3: Synthesis of intermediate HBS-037-193: Compound HBS-037-192 (0.24 g, 0.9 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH solution (4.51 mL, 4.51 mmol) was added, and the reaction mixture was stirred at 60° C. for 3 hours. LCMS showed the m / z value of the product (239). The reaction mixture was concentrated under reduced pressure, and the solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (10.0 mL×3) to give 0.2 g of solid product. 14 H 10 The calculated MS(ESI) mass for N2O2 was 238.2, [M+H] + The m / z value of was 239.1; 1 H NMR (400 MHz, chloroform-d) δ ppm 7.04 (t, 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).

[0085] 3. Synthesis of intermediate HBS-037-163 [ka] Step 1: Synthesis of intermediate HBS-037-163: Compound C1 (synthesized according to the method reported in Journal of Medicinal Chemistry; 2011, 54(13), 4752-4772) (0.2 g, 0.75 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH solution (3.8 mL, 3.8 mmol) was added, and the reaction mixture was stirred at a temperature of 60 °C for 24 hours. LCMS showed m / z value (239.1) for the product formation. The reaction mixture was concentrated under reduced pressure, and the solid was dissolved in water and acidified with 1.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (10.0 mL x 3) to give 0.18 g of solid product. C 14 H 10 The calculated MS(ESI) mass for N2O2 was 238.2, [M+H] + The m / z value of was 239.1; 1 H NMR (400 MHz, chloroform-d) δ 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).

[0086] 4. Synthesis of Intermediate HBS-037-188 [ka] Step 1: Synthesis of compound HBS-037-187: tert-Butyl-1,4-diazepane-1-carboxylate (0.5 g, 2.5 mmol) and 2,5-dichlorobenzoxazole (0.47 g, 2.5 mmol) were dissolved in anhydrous DMF (10.0 mL). Triethylamine (1.0 mL, 7.5 mmol) was added, and the reaction mixture was heated at 70° C. for 16 hours. LCMS data showed an m / z value (352.1) for the product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). Yield: 0.88 g of product was isolated. 17 H 22 The calculated MS(ESI) mass for ClN3O3 is 351.8, [M+H] + The m / z value of was 352.1. Step 2: Synthesis of intermediate HBS-037-188: Compound HBS-037-187 (0.88 g, 2.5 mmol) was dissolved in anhydrous dioxane (10.0 mL). 4.0 M HCl in dioxane (6.2 mL, 25.0 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value of 252 for product formation. The reaction mixture was concentrated under reduced pressure to give the product (0.9 g, yield). 12 H 14 The calculated MS(ESI) mass for ClNO is 251.7, [M+H] + The m / z value of was 252.0.

[0087] 5. Synthesis of Intermediate HBS-039-002 [ka] Step 1: Synthesis of compound HBS-037-198: Intermediate C (0.029 g, 0.12 mmol) was dissolved in anhydrous DCM (2.5 mL). EDC·HCl (0.046 g, 0.24 mmol) and HOBt (0.032 g, 0.24 mmol) were added, followed by EtN (0.17 mL, 1.21 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes. Benzyl-(5R)-5-methyl-1,4-diazepane-1-carboxylate (0.03 g, 0.12 mmol) in DCM (2.0 mL) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value of 469.2 for the product. The reaction mixture was diluted with saturated NaHCO solution, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). The product was obtained in a solid state (0.055 g, 97.1% yield). 28 H 28 The calculated MS(ESI) mass for N4O3 is 468.55, [M+H] + The m / z value of was 469.2. Step 2: Synthesis of intermediate HBS-039-002: Compound HBS-037-198 (0.055 g, 0.11 mmol) was dissolved in ethyl acetate (3.0 mL). 20.0% Pd-OH / C (10.0 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at ambient temperature for 16 hours. LCMS data showed an m / z value (335.2) for product formation. The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give 37.1 mg of crude product. This crude product was used in the next step without further purification. 20 H 22 The calculated MS(ESI) mass for NO is 334.4, [M+H] + The m / z value of was 335.2.

[0088] 6. Synthesis of Intermediate HBS-039-011A / B [ka] Step 1: Synthesis of Compound HBS-039-007: Intermediate HBS-039-193 (0.029 g, 0.12 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.046 g, 0.24 mmol) and HOBt (0.032 g, 0.24 mmol) were added, followed by EtN (0.17 mL, 1.21 mmol). The reaction mixture was stirred at ambient temperature for 10.0 minutes. Benzyl-(5R)-5-methyl-1,4-diazepane-1-carboxylate (0.03 g, 0.12 mmol) in DCM (2.0 mL) was added to the reaction mixture, which was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value of 469.2 for the product. The reaction mixture was diluted with saturated NaHCO solution, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). The product HBS-039-007 was obtained (0.033 g, 58.3% yield). 28 H 28 The calculated MS(ESI) mass for N4O3 is 468.55, [M+H] + The m / z value of was 469.2. Step 2: Synthesis of Intermediate HBS-039-011A / B: Compound HBS-039-007 (0.033 g, 0.07 mmol) was dissolved in ethyl acetate (5.0 mL). 20.0% Pd-OH / C (10.0 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at ambient temperature for 16 hours. LCMS data showed an m / z value of 335.2 for the product and 339.2 for the over-reduction by-product. The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give 22.0 mg of crude product. This crude product was used in the next step without further purification. 20 H 22 The calculated MS(ESI) mass for NO is 334.4, [M+H] + The m / z value of was 335.2.

[0089] 7. Synthesis of Intermediate HBS-039-010 [ka] Step 1: Synthesis of Compound HBS-039-008: Intermediate HBS-037-071 (0.044 g, 0.18 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.046 g, 0.24 mmol) and HOBt (0.032 g, 0.24 mmol) were added, followed by EtN (0.17 mL, 1.21 mmol). After stirring the reaction mixture at ambient temperature for 10 minutes, a solution of benzyl-(5R)-5-methyl-1,4-diazepane-1-carboxylate (0.03 g, 0.12 mmol) in DCM (2.0 mL) was added to the reaction mixture, which was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value of 475.2 for the product. The reaction mixture was diluted with saturated NaHCO solution, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound HBS-039-008 was obtained (0.023 g, 26.7% yield). C 27 H 30 The calculated MS(ESI) mass for N4O4 is 474.55, [M+H] + The m / z value of was 475.2. Step 2: Synthesis of intermediate HBS-039-010: Compound HBS-039-008 (0.023 g, 0.048 mmol) was dissolved in ethyl acetate (5.0 mL). 20.0% Pd-OH / C (5.0 mg) was added, and the reaction mixture was stirred at ambient temperature under a hydrogen atmosphere for 16 hours. LCMS data showed an m / z value (341.2) for the product formation. The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give 14.0 mg of crude product. This crude product was used in the next step without further purification. 19 H 24 The calculated MS(ESI) mass for N4O2 was 340.4, [M+H] + The m / z value of was 341.2.

[0090] 8. Synthesis of Intermediate HBS-039-024 [ka] Step 1: Synthesis of compound HBS-039-013: Pyrazolo[1,5-a]pyridine-2-carboxylic acid (1.0 g, 6.17 mmol) was dissolved in ethanol (20.0 mL). A catalytic amount of concentrated sulfuric acid (0.5 mL) was added, and the reaction mixture was refluxed for 16 hours. LCMS data showed an m / z value (191.1) for the product formation. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and the product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous Na2SO4. 。 The product was obtained by evaporation of the solvent (yield 1.2 g). 10 H 10 The calculated MS(ESI) mass for N2O2 was 190.2, [M+H] + The m / z value of was 191.1. Step 2: Synthesis of compound HBS-039-014: Compound HBS-039-013 (1.17 g, 6.17 mmol) was dissolved in DCM (25.0 mL). NBS (1.1 g, 6.17 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (271.0) for product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Compound HBS-039-013 was obtained (1.5 g, 90.4% yield). C 10 The calculated MS(ESI) mass for H9BrN2O2 is 269.1, [M+H] + The m / z value of was 271.0. Step 3: Synthesis of compound HBS-039-015: Compound HBS-039-014 (0.2 g, 0.74 mmol) was dissolved in a mixture of dioxane / water (8.0:2.0 v / v mL). 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 reaction mixture was stirred at 80 °C for 5 hours under a nitrogen atmosphere. LCMS data indicated an m / z value of 267 for the product. The reaction mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Compound HBS-039-015 was obtained (yield). C 16 H 14 The calculated MS(ESI) mass for N2O2 was 266.3, [M+H] + The m / z value of was 267.1. Step 4: Synthesis of compound HBS-039-018: Compound HBS-039-015 (0.2 g, 0.74 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH (3.7 mL, 3.7 mmol) was added, and the reaction mixture was stirred at 60° C. for 16 hours. LCMS data showed an m / z value (239.1) for the product formation. The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 1.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 0.16 g of solid product HBS-039-018 (92.6% yield). 14 H 10 The calculated MS(ESI) mass for N2O2 was 238.2, [M+H] + The m / z value of was 239.1. Step 5: Synthesis of Compound HBS-039-022: Compound HBS-039-018 (0.025 g, 0.11 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.04 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol) were added, followed by EtN (0.15 mL, 1.1 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes. Benzyl-(5R)-5-methyl-1,4-diazepane-1-carboxylate (0.03 g, 0.11 mmol) in DCM (2.0 mL) was added to the reaction mixture, which was then stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value of 469.2 for the product. The reaction mixture was diluted with saturated NaHCO solution, and the product was extracted with DCM. The combined DCM layers were separated, dried over anhydrous NaSO, and then evaporated to give the crude product. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Yield: 0.049 g of product. 28 H 28 The calculated MS(ESI) mass for N4O3 was 468.6, [M+H] + The m / z value of was 469.2. Step 6: Synthesis of intermediate HBS-039-024: Compound HBS-039-022 (0.05 g, 0.11 mmol) was dissolved in EtOAc (3.0 mL). 20.0% Pd-OH / C (10.0 mg) was added, and the reaction mixture was stirred at ambient temperature under a hydrogen atmosphere for 16 hours. LCMS data showed an m / z value (335.2) for the product formation. The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give 0.03 g of crude product HBS-039-024. This crude product was used in the next step without further purification. 20 H 22 The calculated MS(ESI) mass for NO is 334.4, [M+H] + The m / z value of was 335.2.

[0091] 9. Synthesis of Intermediate HBS-039-025 [ka] Step 1: Synthesis of compound HBS-039-016: Imidazo[1,2-a]pyridine-2-carboxylic acid (1.0 g, 5.26 mmol) was dissolved in DCM (20.0 mL). NBS (1.0 g, 5.78 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (271.0) for product formation. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Pure HBS-039-016 (1.4 g) was obtained (98.9% yield). C 10 The calculated MS(ESI) mass for H9BrN2O2 is 269.1, [M+H] + The m / z value of was 271.0. Step 2: Synthesis of Compound HBS-039-017: Compound HBS-039-016 (0.2 g, 0.74 mmol) was dissolved in a mixture of dioxane / water (8.0:2.0 v / v mL). 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 reaction mixture was stirred at 80 °C for 5 h under a nitrogen atmosphere. LCMS data indicated an m / z value (267.1) for the product formation. The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Compound HBS-039-017 (0.2 g) was obtained (yield). 16 H 14 The calculated MS(ESI) mass for N2O2 was 266.3, [M+H] + The m / z value of was 267.1. Step 3: Synthesis of compound HBS-039-019: Compound HBS-039-017 (0.2 g, 0.74 mmol) was dissolved in MeOH (6.0 mL), 1.0 N aqueous NaOH solution (3.7 mL, 3.7 mmol) was added, and the reaction mixture was stirred at 60° C. for 16 hours. LCMS data showed an m / z value (239.1) for the product formation. The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 1.0 M HCl solution (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 0.11 g of solid product (62.1% yield). 14 H 10 The calculated MS(ESI) mass for N2O2 was 238.2, [M+H] + The m / z value of was 239.1. Step 4: Synthesis of Compound HBS-039-023: Compound HBS-039-017 (0.025 g, 0.11 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.04 g, 0.21 mmol) and HOBt (0.028 g, 0.21 mmol) were added, followed by EtN (0.15 mL, 1.1 mmol). The reaction mixture was stirred at ambient temperature for 10.0 minutes. Benzyl-(5R)-5-methyl-1,4-diazepane-1-carboxylate (0.03 g, 0.11 mmol) in DCM (2.0 mL) was added to the reaction mixture, which was then stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value of 469.2 for the product. The reaction mixture was diluted with saturated NaHCO solution. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The solvent was evaporated to give the crude product, which was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound HBS-039-023 was obtained as the product (yield: 0.049 g). 28 H 28 The calculated MS(ESI) mass for N4O3 was 468.6, [M+H] + The m / z value of was 469.2. Step 5: Synthesis of intermediate HBS-039-025: Compound HBS-039-023 (0.05 g, 0.11 mmol) was dissolved in EtOAc (3.0 mL). 20.0% Pd-OH / C (10.0 mg) was added, and the reaction mixture was stirred at ambient temperature under a hydrogen atmosphere for 16 hours. LCMS data showed an m / z value (339.2) for the product formation. The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give 0.03 g of crude product. This crude product was used in the next step without further purification. 20 H 26 The calculated MS(ESI) mass for NO is 338.5, [M+H] + The m / z value of was 339.2.

[0092] 10. Synthesis of intermediate HBS-039-055 [ka] Compound HBS-037-198 (0.11 g, 0.24 mmol) was dissolved in ethyl acetate (5.0 mL). 20.0% Pd-OH / C (25.0 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at ambient temperature for 16 hours. LCMS data showed an m / z value of 335.2 for the product and 339.2 for the over-reduction by-product. The reaction mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give 72.0 mg of crude product. This crude product was used in the next step as a mixture without further purification. 20 H 22 The calculated MS(ESI) mass for NO is 334.4, [M+H] + The m / z value of was 335.2.

[0093] 11. Synthesis of Intermediate HBS-039-080 [ka] Step 1: Synthesis of intermediate HBS-039-080: Compound HBS-039-007 (0.4 g, 0.84 mmol) was dissolved in ethyl acetate (10.0 mL). 20.0% Pd-OH / C (20.0 mg) was added, and the reaction mixture was stirred at ambient temperature under a hydrogen atmosphere for 16 hours. LCMS data indicated an m / z value of 335.2 for the formation of the major product. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give 0.25 g of crude product. This crude product was used in the next step without further purification. 20 H 22 The calculated MS(ESI) mass for NO is 334.4, [M+H] + The m / z value of was 335.2. [ka] Step 1: Synthesis of HBS-039-170: 2-Boc-hexahydro-pyrrolo[3,4-c]pyrrole (1.0 g, 4.71 mmol) was dissolved in IPA (15.0 mL). Anhydrous K2CO3 (0.97 g, 7.07 mmol) was added, followed by 2-chloro-4,6-dimethylpyrimidine (0.067 g, 4.71 mmol). The rxn mixture was stirred at a temperature of 80 °C for 12 hours. LCMS data indicates an m / z value (319.3) for product formation. The rxn mixture was filtered and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 1.16 g of product was obtained (77.3% yield). C 17 H 26 The calculated MS(ESI) mass for N4O2 was 318.41, and the m / z value for [M+H]+ was 319.3. Step 2: Synthesis of HBS-039-171: Compound HBS-039-170 (1.16 g, 3.64 mmol) was dissolved in anhydrous dioxane (15.0 mL). 2.0 M HCl in diethyl ether (7.3 mL, 14.6 mmol) was added, and the rxn mixture was stirred at 55° C. for 6 hours. LCMS data showed an m / z value (219.1) for product formation. The rxn mixture was cooled to ambient temperature and filtered to obtain the product (0.8 g, yield).12 H 18 The calculated MS(ESI) mass for N4 is 218.3, [M+H] + The m / z value of was 219.1.

[0094] [ka] Step 1: Synthesis of HBS-039-147: 1-Ethynyl-4-fluorobenzene (0.5 g, 4.16 mmol) was dissolved in anhydrous THF (5.0 mL). n-BuLi (5.2 mL, 8.32 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 1 hour. Ethyl chloroformate (1.59 mL, 16.7 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature. LCMS data showed an m / z value (193.0) for product formation. The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. 0.8 g of crude product was obtained (yield). C 11 The calculated MS(ESI) mass for H9FO2 was 192.19, and the m / z value for [M+H]+ was 193.0. 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). Anhydrous K2CO3 (0.72 g, 5.2 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (285.1) for product formation. The reaction mixture was diluted with water, and the precipitate was filtered. The precipitate was dried to obtain the crude product. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 0.4 g of product was obtained (67.6% yield). C 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.1. Step 3: Synthesis of HBS-039-150: Compound HBS-039-148 (0.4 g, 1.41 mmol) was dissolved in MeOH (7.0 mL). 1.0 N aqueous NaOH solution (7.0 mL, 7.0 mmol) was added, and the reaction mixture was refluxed for 8 hours. LCMS showed m / z value (257.0) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.35 g of solid product (97.5% yield). 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0095] [ka] Step 1: Synthesis of HBS-054-005: Ethyl benzoylacetate (2.13 g, 11.1 mmol) was dissolved in DCM (20.0 mL). NBS (1.8 g, 11.1 mmol) and TsOH·H2O (0.38 g, 2.0 mmol) were added, and the reaction mixture was stirred at ambient temperature for 24 hours. LCMS showed an m / z value (272.0) for the product formation. 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 crude product was obtained by evaporating the solvent. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 2.1 g of product was obtained (70.0% yield). C 11 H 11 The calculated MS(ESI) mass for BrO3 was 271.1, and the m / z value for [M+H]+ was 272.0. Step 2: Synthesis of HBS-054-010: Compound HBS-054-005 (1.5 g, 5.56 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Amino-5-fluoropyridine (1.9 g, 16.67 mmol) was added, and the reaction mixture was stirred at 80° C. for 16 hours. LCMS showed m / z value (285.0) for product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 1.2 g of product was obtained (75.0% yield). C 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.0. Step 3: Synthesis of HBS-054-014: Compound HBS-054-010 (1.2 g, 4.22 mmol) was dissolved in MeOH (12.0 mL). 1.0 N aqueous NaOH solution (8.44 mL, 8.5 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed m / z value (257.0) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl solution (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 0.92 g of solid product (84.0% yield). 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0096] [ka] Step 1: Synthesis of HBS-054-011: Ethyl 3-(4-fluorophenyl)-3-oxopropanoate (1.5 g, 7.14 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Aminopyridine (2.0 g, 21.4 mmol) was added, followed by CBr4 (4.7 g, 14.27 mmol), and the reaction mixture was stirred at 80° C. for 16 hours. LCMS showed an m / z value (285.0) for the product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 1.9 g of product was obtained (yield 95.0%). 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.0. Step 2: Synthesis of HBS-054-015: Compound HBS-054-011 (1.5 g, 5.28 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (10.6 mL, 10.56 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed an m / z value (257.0) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 1.07 g of solid product (79.0% yield). 14 The calculated MS(ESI) mass for H9FN2O2 was 56.23, with an m / z value of [M+H]+ of 257.0.

[0097] [ka] 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). 2-Aminopyridine (2.0 g, 21.4 mmol) was added, followed by CBr4 (4.7 g, 14.27 mmol), and the reaction mixture was stirred at 80° C. for 4 hours. LCMS showed an m / z value (285.0) for the product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 1.83 g of product was obtained (yield 90.0%). 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.0. Step 2: Synthesis of HBS-054-016: Compound HBS-054-012 (1.5 g, 5.28 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH solution (10.6 mL, 10.56 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed an m / z value (257.0) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 1.1 g of solid product (81.0% yield). 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0098] [ka] Step 1: Synthesis of HBS-054-020: Ethyl benzoylacetate (1.5 g, 7.81 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Amino-4-fluoropyridine (2.6 g, 23.4 mmol) was added, followed by CBr4 (5.2 g, 15.6 mmol), and the reaction mixture was stirred at 80° C. for 16 hours. LCMS showed m / z value (285.0) for product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 0.9 g of product was obtained (41.0% yield). C 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.0. Step 2: Synthesis of HBS-054-021: Compound HBS-054-020 (0.9 g, 3.17 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (6.3 mL, 6.34 mmol) was added, and the reaction mixture was stirred at 60° C. for 12 hours. LCMS showed an m / z value (257.0) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH=5). The precipitate was filtered and washed with water (5.0 mL×3) to give 0.37 g of solid product (41.0% yield). 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0099] [ka] Step 1: Synthesis of HBS-054-028: Ethyl imidazo[1,2-a]pyridine-2-carboxylate (3.6 g, 18.94 mmol) was dissolved in DCM (80.0 mL). NBS (3.4 g, 18.94 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (270.0) for product formation. The rxn mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 5.1 g of product. C 10 The calculated MS(ESI) mass for H9BrN2O2 was 269.1, and the m / z value for [M+H]+ was 270.0. 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 a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (3.8 g, 11.75 mmol) was added, followed by Pd(dba) (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The rxn mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. LCMS data indicated an m / z value (285.0) for product formation. The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 1.4 g of product was obtained (yield 85.0%). 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.0. Step 3: Synthesis of HBS-054-039: Compound HBS-054-035 (1.4 g, 4.93 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH (10.0 mL, 9.86 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data showed an m / z value (257.0) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.56 g of solid product (45.0% yield). C 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0100] [ka] Step 1: Synthesis of HBS-054-028: Ethyl imidazo[1,2-a]pyridine-2-carboxylate (3.6 g, 18.94 mmol) was dissolved in DCM (80.0 mL). NBS (3.4 g, 18.94 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (270.0) for product formation. The rxn mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 5.1 g of product. C 10 The calculated MS(ESI) mass for H9BrN2O2 was 269.1, and the m / z value for [M+H]+ was 270.0. 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 a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (3.8 g, 11.75 mmol) was added, followed by Pd(dba) (0.26 g, 0.28 mmol) and X-Phos (0.4 g, 0.84 mmol). The rxn mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. LCMS data indicated an m / z value (285.0) for product formation. The rxn mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 1.2 g of product was obtained (yield 75.0%). 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.0. Step 3: Synthesis of HBS-054-040: Compound HBS-054-036 (1.2 g, 4.22 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH (8.4 mL, 8.44 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data showed an m / z value (257.0) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.7 g of solid product (65.0% yield). C 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0101] [ka] Step 1: Synthesis of HBS-054-033: Pyrazolo[1,5-a]pyridine-2-carboxylic acid methyl ester (2.4 g, 13.6 mmol) was dissolved in DCM (54.0 mL). NBS (2.5 g, 14.3 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 h. LCMS data indicated an m / z value of 256.0 for product formation. The rxn mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 3.5 g of product was obtained. The calculated MS (ESI) mass for CHBrNO was 255.07, and the m / z value for [M+H] was 256.0. 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 a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (4.0 g, 12.39 mmol) was added, followed by Pd(dba) (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The rxn mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. LCMS data indicated an m / z value (271.0) for product formation. The rxn mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 1.24 g of product was obtained (yield 78.0%). 15 H 11 The calculated MS(ESI) mass for FN2O2 was 270.26, with an m / z value of [M+H]+ of 271.0. Step 3: Synthesis of HBS-054-041: Compound HBS-054-037 (1.2 g, 4.59 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH (9.2 mL, 9.18 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data showed an m / z value (257.0) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 1.0 g of solid product (85.0% yield). C 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0102] [ka] Step 1: Synthesis of HBS-054-033: Pyrazolo[1,5-a]pyridine-2-carboxylic acid methyl ester (2.4 g, 13.6 mmol) was dissolved in DCM (54.0 mL). NBS (2.5 g, 14.3 mmol) was added, and the rxn mixture was stirred at ambient temperature for 16 h. LCMS data indicated an m / z value of 256.0 for product formation. The rxn mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Yield: 3.5 g of product was obtained. The calculated MS (ESI) mass for CHBrNO was 255.07, and the m / z value for [M+H] was 256.0. 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 a mixture of dioxane / water (24.0:6.0 v / v mL). Anhydrous CsCO (4.0 g, 12.39 mmol) was added, followed by Pd(dba) (0.27 g, 0.29 mmol) and X-Phos (0.4 g, 0.88 mmol). The rxn mixture was stirred at 80 °C under a nitrogen atmosphere for 12 hours. LCMS data indicated an m / z value (271.0) for product formation. The rxn mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 1.4 g of product was obtained (yield 86.0%). 15 H 11 The calculated MS(ESI) mass for FN2O2 was 270.26, with an m / z value of [M+H]+ of 271.0. Step 3: Synthesis of HBS-054-042: Compound HBS-054-038 (1.4 g, 5.18 mmol) was dissolved in MeOH (15.0 mL). 1.0 N aqueous NaOH (10.4 mL, 10.36 mmol) was added, and the rxn mixture was refluxed for 12 hours. LCMS data showed an m / z value (257.0) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 1.0 g of solid product (85.0% yield). C 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0103] [ka] Step 1: Synthesis of HBS-055-001: 2-Boc-hexahydro-pyrrolo[3,4-c]pyrrole (0.2 g, 0.94 mmol) was dissolved in IPA (5.0 mL). Anhydrous K2CO3 (0.2 g, 1.41 mmol) was added, followed by 2-chloro-5-trifluoromethylpyridine (0.21 g, 1.13 mmol). The rxn mixture was refluxed for 16 hours. LCMS data showed an m / z value (319.3) for product formation. The rxn mixture was cooled and filtered through a Buchner funnel. The filtrate was concentrated to obtain the crude product. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.22 g of product was obtained (65.4% yield). C 17 H 22 The calculated MS(ESI) mass for F3N3O2 was 357.37, and the m / z value for [M+H]+ was 358.3. Step 2: Synthesis of HBS-055-003: Compound HBS-055-001 (0.22 g, 0.62 mmol) was dissolved in anhydrous dioxane (10.0 mL). 2.0 M HCl in diethyl ether (1.63 mL, 3.27 mmol) was added, and the rxn mixture was stirred at 55° C. for 8 hours. LCMS data showed an m / z value (258.1) for product formation. The rxn mixture was cooled to ambient temperature and filtered to obtain a solid product (0.2 g, 88.5% yield). 12 H 14 The calculated MS(ESI) mass for F3N3 was 257.25, with an m / z value of [M+H]+ of 258.1.

[0104] [ka] Step 1: Synthesis of HBS-054-076: Ethyl benzoylacetate (1.5 g, 7.81 mmol) was dissolved in anhydrous acetonitrile (20.0 mL). 2-Amino-4-(trifluoromethyl)pyridine (3.8 g, 23.4 mmol) was added, followed by CBr4 (5.2 g, 15.6 mmol), and the reaction mixture was stirred at 80° C. for 16 hours. LCMS showed an m / z value (335.0) for the product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash system (mobile phase: EtOAc:hexane gradient). 1.0 g of product was obtained (38.0% yield). C 17 H 13 The calculated MS(ESI) mass for F3N2O2 was 334.29, with an m / z value of [M+H]+ of 335.0. Step 2: Synthesis of HBS-054-080: Compound HBS-054-076 (1.0 g, 2.99 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (6.0 mL, 6.0 mmol) was added, and the reaction mixture was refluxed for 12 hours. LCMS showed m / z value (307.0) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 0.3 g of solid product (33.0% yield). 15 The calculated MS(ESI) mass for H9F3N2O2 was 306.24, with an m / z value of [M+H]+ of 307.0.

[0105] [ka] 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). Hydrazine monohydrate (0.56 g, 11.21 mmol) was added. The reaction mixture was heated at reflux for 3 hours. LCMS data indicated an m / z value (221.0) for the formation of the desired product. 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). 1.2 g of product was isolated (51.0% yield). C 11 The calculated MS(ESI) mass for H9FN2O2 was 220.2, and the m / z value for [M+H]+ was 221.0. Step 2: Synthesis of HBS-054-062: Compound HBS-054-061 (0.64 g, 2.91 mmol) was dissolved in acetone (15.0 mL). K2CO3 (0.8 g, 5.82 mmol) was added, followed by 1-bromo-2-chloroethane (0.5 g, 3.49 mmol). The reaction mixture was heated at 55 °C for 16 hours. LCMS data showed the m / z value (283.0) for the desired product and a small amount of by-product. The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.7 g of product was isolated (85.0% yield). C 13 H 12 The calculated MS(ESI) mass for ClFN2O2 was 282.7, and the m / z value for [M+H]+ was 283.0. 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). 2.0 M LAH in THF (1.24 mL, 2.48 mmol) was added in an ice-cooled bath. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed an m / z value (255.0) for the formation of the desired product. The reaction mixture was quenched with 1.0 N aqueous NaOH and diluted with ethyl acetate (10.0 mL). The reaction mixture was filtered through a celite bed and washed with ethyl acetate (10.0 mL x 3). The organic layer was separated and washed with water, then brine. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 0.6 g of crude product (95.0% yield). C 12 H 12 The calculated MS(ESI) mass for ClFN2O was 254.69, with an m / z value of [M+H]+ of 255.0. 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). 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 hours. LCMS data showed the m / z value (219.0) for the formation of the desired product. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.46 g of solid product was obtained (yield 88.0%). C 12 H 11 The calculated MS(ESI) mass for FN2O was 218.23, with an m / z value of [M+H]+ of 219.0. Step 5: Synthesis of HBS-054-071: Compound HBS-054-065 (0.46 g, 2.11 mmol) was dissolved in DCM (7.0 mL). NBS (0.41 g, 2.32 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. LCMS data showed an m / z value (298.0) for the formation of the desired product. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 0.25 g of product was obtained (40.0% yield). C 12 H 10 The calculated MS(ESI) mass for BrFN2O was 297.12, and the m / z value for [M+H]+ was 298.0. Step 6: Synthesis of HBS-054-088: Compound HBS-054-071 (1.15 g, 3.85 mmol) was dissolved in anhydrous THF (20 mL) under a nitrogen atmosphere. The reaction mixture was cooled to -78 °C, and 1.6 M n-BuLi in hexane (4.81 mL, 7.7 mmol) was added to the reaction mixture. The reaction mixture was stirred at -78 °C for 30 min. Dry carbon dioxide gas was bubbled through the reaction mixture at -65 °C, and the reaction mixture was allowed to warm gradually to room temperature. LCMS data indicated an m / z value (263.0) for the formation of the desired product, a debrominated by-product, and some unknown product. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was separated, and the debrominated product was collected. The aqueous layer was acidified with 2 M HCl solution to obtain a precipitate. The precipitate was filtered and dried to give 0.6 g of solid product (yield 60.0%). 13 H 11 The calculated MS(ESI) mass for FN2O3 was 262.24, and the m / z value for [M+H]+ was 263.0.

[0106] [ka] Step 1: Synthesis of HBS-039-188: 1-Ethynyl-2-fluorobenzene (1.0 g, 8.33 mmol) was dissolved in anhydrous THF (10.0 mL). n-BuLi (10.4 mL, 16.65 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 1 hour. Ethyl chloroformate (3.8 mL, 40.0 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature. LCMS data showed an m / z value (193.0) for product formation. The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. (Yield) 1.6 g of crude product was obtained. C 11 The calculated MS(ESI) mass for H9FO2 was 192.19, and the m / z value for [M+H]+ was 193.0. 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). Anhydrous K2CO3 (2.88 g, 20.81 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (285.1) for product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.56 g of product was obtained (66.0% yield). C 16 H 13 The calculated MS(ESI) mass for FN2O2 was 284.29, with an m / z value of [M+H]+ of 285.1. Step 3: Synthesis of HBS-039-192: Compound HBS-039-189 (1.56 g, 5.5 mmol) was dissolved in MeOH (10.0 mL). 1.0 N aqueous NaOH solution (16.5 mL, 16.5 mmol) was added, and the reaction mixture was refluxed for 12 hours. LCMS showed an m / z value (257.0) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (5.0 mL x 3) to give 1.3 g of solid product (92.3% yield). 14 The calculated MS(ESI) mass for H9FN2O2 was 256.23, and the m / z value for [M+H]+ was 257.0.

[0107] [ka] Step 1: Synthesis of HBS-055-009: 2-Boc-hexahydro-pyrrolo[3,4-c]pyrrole (0.3 g, 1.41 mmol) was dissolved in IPA (10.0 mL). Anhydrous K2CO3 (0.97 g, 7.07 mmol) was added, followed by 2,5-dichlorobenzoxazole (0.38 g, 1.99 mmol). The rxn mixture was stirred at a temperature of 80 °C for 16 hours. LCMS data indicates an m / z value (364.2) for product formation. The rxn mixture was filtered at room temperature and washed with ethyl acetate. The filtrate was concentrated to obtain the crude product. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.27 g of product was obtained (52.5% yield). C 18 H 22 The calculated MS(ESI) mass for ClN3O3 was 363.84, and the m / z value for [M+H]+ was 364.2. Step 2: Synthesis of HBS-055-011: Compound HBS-055-009 (0.27 g, 0.74 mmol) was dissolved in anhydrous dioxane (15.0 mL). 2.0 M HCl in diethyl ether (1.5 mL, 2.97 mmol) was added, and the rxn mixture was stirred at 55° C. for 6 hours. LCMS data showed an m / z value (264.1) for product formation. The rxn mixture was cooled to ambient temperature and filtered to obtain a solid product (0.25 g, yield). 13 H 14 The calculated MS(ESI) mass for ClNO was 263.7, and the m / z value for [M+H] was 264.1.

[0108] [ka] Step 1: Synthesis of HBS-039-198: To a solution of NaOMe (25.0 mL of methanol containing 1.25 g of Na) was added 2-fluoroacetophenone (5.0 g, 36.19 mmol) dropwise. The mixture was stirred at ambient temperature for 30.0 minutes. A solution of diethyl oxalate (5.81 g, 39.81 mmol) in anhydrous methanol (25.0 mL) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (225.0) for the formation of the desired product. The reaction mixture was concentrated under reduced pressure to give the crude product. This crude product was dissolved in cold water and acidified with 2.0 M aqueous HCl. The precipitate was filtered and dried to give 8.62 g of crude product. 11 The calculated MS(ESI) mass for H9FO4 was 224.19, and the m / z value for [M+H]+ was 225.0. Step 2: Synthesis of HBS-039-200: Compound HBS-039-198 (8.62 g, 36.19 mmol) was dissolved in IPA (100.0 mL). Hydrazine monohydrate (2.1 mL, 43.4 mmol) was added, and the reaction mixture was heated at reflux for 3 hours. LCMS data showed m / z value (221.0) for the desired product and m / z value (207.0) for the hydrolysis by-product. The reaction mixture was cooled to ambient temperature to obtain a precipitate. The precipitate was filtered to obtain 7.19 g of crude product (90.2% yield). C 11The calculated MS(ESI) mass for H9FN2O2 was 220.2, and the m / z value for [M+H]+ was 221.0; 10 The calculated mass for H7FN2O2 was 206.17, and the m / z value for [M+H]+ was 207.0. Step 3: Synthesis of HBS-055-002: The crude product of compound HBS-039-200 (7.19 g, 32.65 mmol) was dissolved in anhydrous methanol (100.0 mL). Concentrated sulfuric acid (4.0 mL) was added and the reaction mixture was heated at reflux for 24 hours. LCMS data showed an m / z value (221.0) for the formation of the desired product. The reaction mixture was cooled to ambient temperature and neutralized with saturated aqueous sodium bicarbonate to obtain a precipitate. The precipitate was filtered and dried to give 7.19 g of solid product (yield). C 11 The calculated MS(ESI) mass for H9FN2O2 was 220.2, and the m / z value for [M+H]+ was 221.0. Step 4: Synthesis of HBS-055-004: Compound HBS-055-002 (7.19 g, 32.65 mmol) was dissolved in acetone (100.0 mL). K2CO3 (13.53 g, 97.95 mmol) was added, followed by 1-bromo-2-chloroethane (13.5 mL, 163.3 mmol). The reaction mixture was heated at 65 °C for 24 hours. LCMS data indicates an m / z value (283.0) for the formation of the desired product. The reaction mixture was filtered, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 2.85 g of product was isolated (30.9% yield). C 13 H 12 The calculated MS(ESI) mass for ClFN2O2 was 282.7, and the m / z value for [M+H]+ was 283.0. 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 to 0° C. in an ice bath. 1.0 M DIBAL in hexane (25.2 mL, 25.2 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed an m / z value (255.1) for the formation of the desired product. The reaction mixture was quenched with aqueous NH4Cl and diluted with ethyl acetate (100.0 mL). The reaction mixture was filtered through a 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. Evaporation of the solvent gave 2.57 g of crude product (yield). C 12 H 12 The calculated MS(ESI) mass for ClFN2O was 254.69, with an m / z value of [M+H]+ of 255.0. 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). Mineral oil containing 60.0% NaH (0.81 g, 20.2 mmol) was added under ice cooling. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. LCMS data showed an m / z value (219.1) for the formation of the desired product. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.17 g of solid product was obtained (yield 53.2%). C 12 H 11 The calculated MS(ESI) mass for FN2O was 218.23, with an m / z value of [M+H]+ of 219.1. Step 7: Synthesis of HBS-055-010: Compound HBS-055-008 (1.17 g, 5.36 mmol) was dissolved in DCM (15.0 mL). NBS (1.05 g, 5.9 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (299.0) for the formation of the desired product. The crude product was obtained by evaporating the solvent. The crude product was purified by column chromatography (mobile phase: EtOAc:hexane gradient). 1.27 g of product was obtained (79.7% yield). C 12 H 10 The calculated MS(ESI) mass for BrFN2O was 297.12, with an m / z value of [M+H]+ of 299.0. 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 a nitrogen atmosphere. The reaction mixture was cooled to -78 °C. 1.6 M n-BuLi in hexane (5.33 mL, 8.54 mmol) was added, and the reaction mixture was stirred at -78 °C for 30.0 minutes. Dry carbon dioxide gas was bubbled through the reaction mixture at -65 °C, and the reaction mixture was allowed to warm gradually to room temperature. LCMS data indicated the m / z value (263.1) for the desired product, a debrominated by-product, and some unknown product. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was separated, and the debrominated product was collected. The aqueous layer was acidified with 2 M HCl solution to obtain a precipitate. The precipitate was filtered and dried to give 0.84 g of solid product (75.0% yield). 13 H 11 The calculated MS(ESI) mass for FN2O3 was 262.24, and the m / z value for [M+H]+ was 263.1.

[0109] [ka] Step 1: Synthesis of HBS-055-027: Intermediate HBS-039-192 (0.1 g, 0.39 mmol) was dissolved in anhydrous DCM (4.0 mL). EDC·HCl (0.11 g, 0.59 mmol) and HOBt (0.079 g, 0.59 mmol) were added, followed by DIPEA (0.34 mL, 1.95 mmol). The rxn mixture was stirred at ambient temperature for 10.0 minutes. A solution of benzyl-(5R)-5-methyl-1,4-diazepane-1-carboxylate (0.097 g, 0.39 mmol) in DCM (1.0 mL) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (487.2) for the product. The rxn mixture was diluted with a saturated solution of NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporating the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.1 g of product was obtained (yield 52.7%). 28 H 27 The calculated MS(ESI) mass for FN4O3 was 486.54, and the m / z value for [M+H]+ was 487.2. Step 2: Synthesis of HBS-055-028: Compound HBS-055-027 (0.1 g, 0.21 mmol) was dissolved in ethyl acetate (5.0 mL). 20.0% Pd-OH / C (10.0 mg) was added, and the rxn mixture was stirred under a hydrogen atmosphere at ambient temperature for 16 hours. LCMS data indicated an m / z value (353.2) for product formation. The rxn mixture was filtered through a celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to give 72.0 mg of crude product. This crude product was used in the next step without further purification. 20 H 21 The calculated MS(ESI) mass for FN4O was 352.41, with an m / z value of [M+H]+ of 353.2.

[0110] [ka] Step 1: Synthesis of HBS-055-113: Tert-butyl (7R)-7-methyl-1,4-diazepane-1-carboxylate (0.5 g, 2.33 mmol) and 2-chloro-5-trifluoromethylpyridine (0.47 g, 2.57 mmol) were dissolved in anhydrous DMF (10.0 mL). Anhydrous K2CO3 (0.64 g, 4.66 mmol) was added, and the reaction mixture was stirred at 100 °C for 8 hours. LCMS data showed an m / z value (360.1) for the product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Yield: 0.84 g of product. C 17 H 24 The calculated MS(ESI) mass for F3N3O2 was 359.39, with an m / z value of [M+H]+ of 360.1. Step 2: Synthesis of HBS-055-117: Compound HBS-055-113 (0.84 g, 2.33 mmol) was dissolved in anhydrous dioxane (10.0 mL). 4.0 M HCl in dioxane (2.33 mL, 9.32 mmol) was added, and the reaction mixture was stirred at 50° C. for 12 hours. LCMS data indicated an m / z value (259.27) for the product formation. The rxn mixture was cooled to ambient temperature and concentrated to give a solid product (0.75 g, 87.3% yield). 12 H 16 The calculated MS(ESI) mass for F3N3 was 259.27, with an m / z value of [M+H]+ of 260.1.

[0111] [ka] Step 1: Synthesis of HBS-062-029: Tert-butyl (7R)-7-methyl-1,4-diazepane-1-carboxylate (0.5 g, 2.33 mmol) and 2,5-dichlorobenzoxazole (0.53 g, 2.79 mmol) were dissolved in anhydrous DMF (8.0 mL). Anhydrous K2CO3 (0.64 g, 4.66 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 hours. LCMS data showed an m / z value (366.1) for the product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.4 g of product was obtained (46.9% yield). C 18 H 24 The calculated MS(ESI) mass for ClN3O3 was 365.85, and the m / z value for [M+H]+ was 366.1. Step 2: Synthesis of HBS-062-031: Compound HBS-062-029 (0.4 g, 1.09 mmol) was dissolved in anhydrous dioxane (10.0 mL). 4.0 M HCl in dioxane (0.82 mL, 3.28 mmol) was added, and the rxn mixture was stirred at 50° C. for 8 hours. LCMS data showed an m / z value (266.1) for product formation. The rxn mixture was cooled to ambient temperature and concentrated to give a solid product (0.32 g, 86.4% yield). 13 H 16 The calculated MS(ESI) mass for ClNO was 265.74, and the m / z value for [M+H] was 266.1.

[0112] [ka] Step 1: Synthesis of HBS-062-005: Morpholine-3-carboxylic acid (1.0 g, 7.63 mmol) was dissolved in water (6.0 mL). Anhydrous NaNO (0.79 g, 11.44 mmol) was added, and the mixture was cooled to 0 °C in an ice bath. 12.0 M aqueous HCl (1.27 mL, 15.26 mmol) was added, and the reaction mixture was allowed to warm gradually to ambient temperature for 16 h. LCMS data indicated an m / z value of 161.1 for the product. The reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporation of the solvent. Yield: 1.22 g. The calculated MS (ESI) mass for C5H8N2O4 was 160.13, and the m / z value for [M+H]+ was 161.1. 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 mixture was cooled to 0 °C in an ice bath. Anhydrous TFA (1.6 mL, 11.44 mmol) was added, and the reaction mixture was allowed to warm gradually to ambient temperature for 16 h. LCMS data indicated an m / z value of 143.1 for the product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 1.02 g of product was obtained (94.1% yield). The calculated MS (ESI) mass for C5H6N2O3 was 142.11, and the m / z value for [M+H]+ was 143.1. Step 3: Synthesis of HBS-062-009: Compound HBS-062-007 (1.0 g, 7.18 mmol) was dissolved in xylene (10.0 mL). Ethyl propiolate (0.95 mL, 9.33 mmol) was added, and the reaction mixture was heated at 120° C. for 6 hours. LCMS data showed an m / z value (197.1) for the product formation. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 1.0 g of product was obtained (71.0% yield). CH 12The calculated MS(ESI) mass for N2O3 was 196.20, and the m / z value for [M+H]+ was 197.1. Step 4: Synthesis of HBS-062-010: Compound HBS-062-009 (1.0 g, 5.1 mmol) was dissolved in DCM (15.0 mL). NBS (1.0 g, 5.61 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (275.0) for the product formation. The reaction mixture was diluted with water, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 1.4 g of product was obtained (99.7% yield). CH 11 The calculated MS(ESI) mass for BrN2O3 was 275.1, and the m / z value for [M+H]+ was 275.0. 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 a mixture of dioxane / water (9:1 v / v mL). Anhydrous K2CO3 (0.6 g, 4.36 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.073 mmol). Under a nitrogen atmosphere, the rxn mixture was stirred at 100 °C for 6 hours. LCMS data indicated an m / z value (273.1) for product formation. The rxn mixture was filtered through a 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 an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 0.39 g of product was obtained (95.5% yield). C 15 H 16 The calculated MS(ESI) mass for N2O3 was 272.3, and the m / z value for [M+H]+ was 273.1. Step 6: Synthesis of HBS-062-013: Compound HBS-062-011 (0.39 g, 1.43 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH (4.3 mL, 4.3 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data showed an m / z value (245.1) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.23 g of solid product (65.8% yield). C 13 H 12 The calculated MS(ESI) mass for N2O3 was 244.25, and the m / z value for [M+H]+ was 245.1.

[0113] [ka] Step 1: Synthesis of HBS-055-191: Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (1.0 g, 6.40 mmol) was dissolved in anhydrous acetonitrile (15.0 mL). Anhydrous K2CO3 (3.54 g, 25.62 mmol) was added, and the reaction mixture was stirred at ambient temperature for 15.0 minutes. 1,3-Dibromopropane (0.72 mL, 7.05 mmol) was added, and the reaction mixture was heated at reflux for 6 hours. LCMS data indicated an m / z value (197.1) for product formation. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 1.03 g of product was obtained (81.97% yield). CH 12 The calculated MS(ESI) mass for N2O3 was 196.20, and the m / z value for [M+H]+ was 197.1. Step 2: Synthesis of HBS-055-192: Compound HBS-055-191 (1.03 g, 5.25 mmol) was dissolved in DCM (15.0 mL). NBS (0.93 g, 5.25 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (275.0) for the product formation. The reaction mixture was diluted with water, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). (Yield) 1.44 g of product was obtained. CH 11 The calculated MS(ESI) mass for BrN2O3 was 275.1, and the m / z value for [M+H]+ was 275.0. Step 3: Synthesis of HBS-055-194: Compound HBS-055-192 (0.4 g, 1.45 mmol) and phenylboronic acid (0.27 g, 2.18 mmol) were dissolved in a mixture of dioxane / water (9:1 v / v mL). Anhydrous K2CO3 (0.6 g, 4.36 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.073 mmol). Under a nitrogen atmosphere, the rxn mixture was stirred at 100 °C for 6 hours. LCMS data indicated an m / z value (273.1) for product formation. The rxn mixture was filtered through a 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 an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 0.37 g of product was obtained (94.7% yield). C 15 H 16 The calculated MS(ESI) mass for N2O3 was 272.3, and the m / z value for [M+H]+ was 273.1. Step 4: Synthesis of HBS-055-197: Compound HBS-055-194 (0.37 g, 1.38 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH (4.1 mL, 4.1 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data showed an m / z value (245.1) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.26 g of solid product (77.3% yield). C 13 H 12 The calculated MS(ESI) mass for N2O3 was 244.25, and the m / z value for [M+H]+ was 245.1.

[0114] [ka] Step 1: Synthesis of HBS-062-020: 1-Ethynylpyrimidine (1.0 g, 9.61 mmol) was dissolved in anhydrous THF (12.0 mL). n-BuLi (7.2 mL, 11.53 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 30.0 min. Ethyl chloroformate (1.4 mL, 14.41 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature over 3 h. LCMS data showed an m / z value (177.1) for product formation. The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.78 g of product was obtained (46.1% yield). The calculated MS(ESI) mass for C9H8N2O2 was 176.17, and the m / z value for [M+H]+ was 177.1. 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). Anhydrous K2CO3 (1.47 g, 10.63 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (269.1) for product formation. The rxn mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient). 0.48 g of product was obtained (42.1% yield). The MS (ESI) mass calculated for C9H8N2O2 was C 14 H 12 The m / z value of N4O2 was 268.27 and [M+H]+ was 269.1. Step 3: Synthesis of HBS-062-028: Compound HBS-062-023 (0.28 g, 1.04 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (2.1 mL, 2.09 mmol) was added, and the reaction mixture was refluxed for 6 hours. LCMS showed m / z value (241.1) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.22 g of solid product (87.5% yield). 12 The calculated MS(ESI) mass for H8N4O2 was 240.22, and the m / z value for [M+H]+ was 241.1.

[0115] [ka] Step 1: Synthesis of HBS-062-022: 1-Ethynylpyridine (2.0 g, 19.4 mmol) was dissolved in anhydrous THF (15.0 mL). n-BuLi (14.6 mL, 23.3 mmol) was added at -78 °C, and the rxn mixture was stirred at -78 °C for 30.0 minutes. Ethyl chloroformate (2.2 mL, 23.3 mmol) was added at -78 °C, and the rxn mixture was gradually warmed to ambient temperature over 3 hours. LCMS data showed an m / z value (176.1) for product formation. The rxn mixture was diluted with aqueous NH4Cl, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient). 1.29 g of product was obtained (38.0% yield). C 10 The calculated MS(ESI) mass for H9NO2 was 175.18, and the m / z value for [M+H]+ was 176.1. 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). Anhydrous K2CO3 (0.79 g, 5.71 mmol) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. LCMS data showed an m / z value (268.1) for product formation. The rxn mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: ethyl acetate:hexane and DCM:methanol gradient). 0.57 g of product was obtained (74.6% yield). C 15 H 13 The calculated MS(ESI) mass for N3O2 was 267.28, and the m / z value for [M+H]+ was 268.1. Step 3: Synthesis of HBS-062-030: Compound HBS-062-025 (0.56 g, 2.1 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH solution (4.2 mL, 4.19 mmol) was added, and the reaction mixture was refluxed for 4 hours. LCMS showed m / z value (240.1) for the product formation. The reaction mixture was concentrated under reduced pressure. The solid was dissolved in water and acidified with 2.0 M aqueous HCl solution (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.26 g of solid product (50.9% yield). 13 The calculated MS(ESI) mass for H9N3O2 was 239.23, and the m / z value for [M+H]+ was 240.1.

[0116] [ka] Step 1: Synthesis of HBS-062-019: Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.44 mmol) was dissolved in DCM (15.0 mL). The reaction mixture was cooled to 0 °C in an ice bath. NBS (1.38 g, 7.73 mmol) was added, and the mixture was stirred at ambient temperature for 16 h. LCMS data showed an m / z value of 236.0 for the product formation. The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: DCM:methanol gradient). 0.62 g of product was obtained (41.1% yield). The calculated MS(ESI) mass for C6H8BrN3O2 was 234.05, and the m / z value for [M+H]+ was 236.0. Step 2: Synthesis of HBS-062-021: Compound HBS-062-019 (0.62 g, 2.65 mmol) and 1,1,3,3-tetraethoxypropane (0.76 mL, 3.18 mmol) were dissolved in acetic anhydride (10.0 mL). The reaction mixture was heated at 70 °C for 24 hours. LCMS data showed an m / z value (272.0) for product formation. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was diluted with water and neutralized with a saturated aqueous solution of NaHCO3. The precipitate was filtered and dried to give 0.3 g of product (41.9% yield). The calculated MS (ESI) mass for CHBrNO2 was 270.08, and the m / z value for [M+H]+ was 272.0. 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 a mixture of dioxane / water (7:1 v / v mL). Anhydrous K2CO3 (0.46 g, 3.33 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.045 g, 0.056 mmol). Under a nitrogen atmosphere, the rxn mixture was stirred at 100 °C for 4 hours. LCMS data indicated an m / z value (268.1) for product formation. The rxn mixture was filtered through a 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 an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 0.25 g of product was obtained (84.2% yield). C 15 H 13 The calculated MS(ESI) mass for N3O2 was 267.28, and the m / z value for [M+H]+ was 268.1. Step 4: Synthesis of HBS-062-027: Compound HBS-062-024 (0.25 g, 0.94 mmol) was dissolved in MeOH (6.0 mL). 1.0 N aqueous NaOH (1.9 mL, 1.87 mmol) was added, and the rxn mixture was refluxed for 8 hours. LCMS data showed an m / z value (240.1) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.11 g of solid product (49.2% yield). C 13 The calculated MS(ESI) mass for H9N3O2 was 239.23, and the m / z value for [M+H]+ was 240.1.

[0117] [ka] 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-tetraethoxypropane (1.85 mL, 7.72 mmol) were dissolved in acetic anhydride (8.0 mL). The reaction mixture was heated at 70 °C for 24 hours. LCMS data showed an m / z value (192.1.0) for the product formation. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was diluted with water and neutralized with a saturated aqueous solution of NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: DCM:methanol gradient). 0.98 g of product was obtained (79.7% yield). The calculated MS(ESI) mass for C9H9N3O2 was 191.19, and the m / z value for [M+H]+ was 192.1. 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 to 0 °C in an ice bath. NBS (1.0 g, 5.64 mmol) was added, and the mixture was stirred at ambient temperature for 16 h. LCMS data showed an m / z value of 272.0 for the product formation. The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 1.38 g of crude product (yield). The calculated MS (ESI) mass for CHBrNO2 was 270.08, and the m / z value for [M+H]+ was 272.0. 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 a mixture of dioxane / water (8:1 v / v mL). Anhydrous K2CO3 (0.61 g, 4.44 mmol) was added, followed by Pd(dppf)Cl2·DCM2 (0.06 g, 0.074 mmol). Under a nitrogen atmosphere, the rxn mixture was stirred at 100 °C for 6 hours. LCMS data indicated an m / z value (268.1) for product formation. The rxn mixture was filtered through a 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 an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 0.32 g of product was obtained (80.1% yield). C 15 H 13 The calculated MS(ESI) mass for N3O2 was 267.28, and the m / z value for [M+H]+ was 268.1. Step 4: Synthesis of HBS-062-041: Compound HBS-062-038 (0.32 g, 1.19 mmol) was dissolved in MeOH (5.0 mL). 1.0 N aqueous NaOH (2.4 mL, 2.37 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data showed an m / z value (240.1) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.18 g of solid product (65.9% yield). C 13 The calculated MS(ESI) mass for H9N3O2 was 239.23, and the m / z value for [M+H]+ was 240.1.

[0118] [ka] Step 1: Synthesis of HBS-062-091: Tert-butyl (7R)-7-methyl-1,4-diazepane-1-carboxylate (0.5 g, 2.33 mmol) and 2-chloro-4,6-dimethylpyrimidine (0.4 g, 2.8 mmol) were dissolved in anhydrous DMF (8.0 mL). Anhydrous K2CO3 (0.64 g, 4.66 mmol) was added, and the reaction mixture was stirred at 90 °C for 16 hours. LCMS data showed an m / z value (321.1) for the product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Yield: 0.75 g of product. C 17 H 28 The calculated MS(ESI) mass for N4O2 was 320.43, and the m / z value for [M+H]+ was 321.2. Step 2: Synthesis of HBS-062-092: Compound HBS-062-091 (0.75 g, 2.33 mmol) was dissolved in anhydrous dioxane (6.0 mL). 4.0 M HCl in dioxane (2.91 mL, 11.65 mmol) was added, and the rxn mixture was stirred at 50° C. for 8 hours. LCMS data showed an m / z value (221.2) for product formation. The rxn mixture was cooled to ambient temperature and concentrated to give a solid product (0.69 g, 89.8% yield). 12 H 20 The calculated MS(ESI) mass for N4 was 220.31, with an m / z value of [M+H]+ of 221.2.

[0119] [ka] Step 1: Synthesis of HBS-062-111: Tert-butyl (7R)-7-methyl-1,4-diazepane-1-carboxylate (0.73 g, 3.4 mmol) and 2-iodo-5-methoxypyridine (0.8 g, 3.4 mmol) were dissolved in anhydrous 1,4-dioxane (2.0 mL). Anhydrous t-BuOK (0.95 g, 8.5 mmol) was added, and the reaction mixture was stirred under a nitrogen atmosphere. Pd2(dba)3 (0.16 g, 0.17 mmol) and X-Phos (0.16 g, 0.34 mmol) were added, and the rxn mixture was heated at reflux for 24 hours. The addition of these reagents consumed the starting material, driving the reaction to completion. LCMS data indicated an m / z value (322.1) for the product. The reaction mixture was filtered through Celite. The filtrate was concentrated to give the crude product. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:methanol gradient). 0.18 g of product was obtained (yield 16.5%). 17 H 27 The calculated MS(ESI) mass for N3O3 was 321.41, with an m / z value of [M+H]+ of 322.2. Step 2: Synthesis of HBS-062-119: Compound HBS-062-111 (0.18 g, 0.56 mmol) was dissolved in anhydrous dioxane (4.0 mL). 4.0 M HCl in dioxane (0.7 mL, 2.8 mmol) was added, and the rxn mixture was stirred at 50° C. for 8 hours. LCMS data showed an m / z value (222.2) for product formation. The rxn mixture was cooled to ambient temperature and concentrated to give the product (0.18 g, yield). C 12 H 19 The calculated MS(ESI) mass for N3O was 221.30, and the m / z value for [M+H]+ was 222.2.

[0120] [ka] Step 1: Synthesis of HBS-062-135: Tert-butyl (7R)-7-methyl-1,4-diazepane-1-carboxylate (0.5 g, 2.33 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (0.35 mL, 2.8 mmol) were dissolved in anhydrous DMF (8.0 mL). Anhydrous K2CO3 (0.64 g, 4.66 mmol) was added, and the reaction mixture was heated at 90 °C for 12 hours. LCMS data showed an m / z value (305.0) for product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.74 g of product was obtained (88.1% yield). C 16 H 23 The calculated MS(ESI) mass for F3N4O2 is 360.37, [MtButyl] + The m / z value of was 305.0. Step 2: Synthesis of HBS-062-136: Compound HBS-062-135 (0.74 g, 2.05 mmol) was dissolved in anhydrous dioxane (10.0 mL). 4.0 M HCl in dioxane (2.6 mL, 10.25 mmol) was added, and the reaction mixture was stirred at 50° C. for 8 hours. LCMS data showed an m / z value (261.0) for the product formation. The rxn mixture was cooled to ambient temperature and concentrated to give a solid product (0.76 g, 91.3% yield). 11 H 15 The calculated MS(ESI) mass for F3N4 was 260.26, with an m / z value of [M+H]+ of 261.0.

[0121] [ka] 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-tetraethoxypropane (1.85 mL, 7.72 mmol) were dissolved in acetic anhydride (8.0 mL). The reaction mixture was heated at 70 °C for 24 hours. LCMS data showed an m / z value (192.1.0) for the product formation. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was diluted with water and neutralized with a saturated aqueous solution of NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: DCM:methanol gradient). 0.98 g of product was obtained (79.7% yield). The calculated MS(ESI) mass for C9H9N3O2 was 191.19, and the m / z value for [M+H]+ was 192.1. 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 to 0 °C in an ice bath. NBS (1.0 g, 5.64 mmol) was added, and the mixture was stirred at ambient temperature for 16 h. LCMS data showed an m / z value of 272.0 for the product. The reaction mixture was diluted with saturated aqueous NaHCO3. The product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 1.38 g of crude product (yield). The calculated MS (ESI) mass for CHBrNO2 was 270.08, and the m / z value for [M+H]+ was 272.0. Step 3: Synthesis of HBS-062-183: Compound HBS-062-037 (0.95 g, 3.52 mmol) and 2-(tributylstannyl)-pyridine (1.94 g, 5.28 mmol) were dissolved in 1,4-dioxane (12.0 mL). Pd(PPh3)4 (0.41 g, 0.35 mmol) was added, and the reaction mixture was heated at 115 °C for 18 hours under a nitrogen atmosphere. 0.05 equivalents of Pd(PPh3)4 were added to consume the starting material. LCMS data showed an m / z value (269.0) for product formation. The rxn mixture was filtered through a bed of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 0.725 g of product was obtained (76.8% yield). 14 H 12 The calculated MS(ESI) mass for N4O2 was 268.27, and the m / z value for [M+H]+ was 269.0. Step 4: Synthesis of HBS-062-186: Compound HBS-062-183 (0.73 g, 2.7 mmol) was dissolved in MeOH (8.0 mL). 1.0 N aqueous NaOH (5.4 mL, 5.4 mmol) was added, and the rxn mixture was refluxed for 6 hours. LCMS data showed an m / z value (241.1) for product formation. The rxn mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was acidified with 2.0 M aqueous HCl (pH = 5). The precipitate was filtered and washed with water (2.0 mL x 3) to give 0.52 g of product (80.2% yield). C 12 The calculated MS(ESI) mass for H8N4O2 was 240.22, and the m / z value for [M+H]+ was 241.1.

[0122] IV. Synthesis of Example Compounds A. Compound Example 1 [ka] Synthesis of Compound Example 1: Intermediate HBS-037-163 (0.025 g, 0.1 mmol) was dissolved in anhydrous DCM (2.5 mL). EDC·HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, followed by EtN (0.15 mL, 1.1 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes. Intermediate HBS-037-188 (0.038 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (472.2) for product formation. The reaction mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). (Yield) 0.05 g of product was obtained. 26 H 22 The calculated MS(ESI) mass for ClNO2 is 471.9 [M+H] + The m / z value of was 472.2.

[0123] B. Compound example 2 [ka] Synthesis of Compound Example 2: HBS-037-054 (0.026 g, 0.1 mmol) was dissolved in anhydrous DCM (2.5 mL). EDC·HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, followed by EtN (0.15 mL, 1.1 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes. HBS-037-188 (0.038 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value of 478.2 for the product formation. The reaction mixture was diluted with saturated NaHCO3 solution, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Pure Compound Example 2 was obtained (0.019 g, 37.9% yield). 25 H 24 The calculated MS(ESI) mass for ClNO3 is 477.9, [M+H] + The m / z value of was 478.2.

[0124] C. Compound example 3 [ka] Synthesis of Compound Example 3: Intermediate HBS-037-193 (0.025 g, 0.1 mmol) was dissolved in anhydrous DCM (2.5 mL). EDC·HCl (0.04 g, 0.21 mmol) and HOBt (0.03 g, 0.21 mmol) were added, followed by EtN (0.15 mL, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes. HBS-037-188 (0.038 g, 0.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (472.2) for product formation. The reaction mixture was diluted with saturated NaHCO3 solution, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Pure Compound Example 3 was obtained (0.034 g, 68.6% yield). 26 H 22 The calculated MS(ESI) mass for ClNO2 was 471.9, [M+H] + The m / z value of was 472.2.

[0125] D. Compound example 4 [ka] Synthesis of Compound Example 4: HBS-039-002 (0.037 g, 0.11 mmol) was dissolved in anhydrous DMF (2.5 mL). Triethylamine (0.046 mL, 0.33 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.021 g, 0.11 mmol). The reaction mixture was stirred at 60° C. for 16 hours. LCMS data indicated an m / z value of 486 for the product. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. It was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). Pure Compound Example 4 was obtained (0.038 g, 69.9% yield). C27 H 24 The calculated MS(ESI) mass for ClNO2 was 485.96, [M+H] + The m / z value of was 486.0.

[0126] E. Compound Example 5 and Compound Example 6 [ka] Synthesis of Compound Example 5 and Compound Example 6: Intermediate HBS-039-011A / B (0.022 g, 0.07 mmol) was dissolved in anhydrous DMF (2.5 mL). Triethylamine (0.03 mL, 0.2 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.012 g, 0.07 mmol). The reaction mixture was stirred at 60° C. for 16 hours. LCMS data indicated the formation of a mixture of two products (m / z values ​​486 and 490). The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water and then brine. The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a crude product mixture of Compound Example 5 and Compound Example 6. This mixture was purified using an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient) and a prep-TLC plate (mobile phase: EtOAc:hexane (60:40, v / v mL)). 0.0053 g of the product of Compound Example 5 (m / z value, 486.2) was obtained (16.7% yield); and 0.014 g of the product of Compound Example 6 (m / z value, 490.2) was obtained (44.1% yield). 27 H 24 The calculated MS(ESI) mass for ClNO2 was 485.96, [M+H] + The m / z value of C was 486.2; 27 H 28 The calculated MS(ESI) mass for ClNO2 was 490.0, [M+H] + The m / z value of was 490.2.

[0127] F. Compound Example 7 [ka] Synthesis of Compound Example 7: HBS-039-010 (0.014 g, 0.04 mmol) was dissolved in anhydrous DMF (2.5 mL). Triethylamine (0.017 mL, 0.12 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.008 g, 0.042 mmol). The reaction mixture was stirred at 60° C. for 16 hours. LCMS data indicated an m / z value (492.2) for the product. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by ISCO combiflash chromatography (mobile phase: EtOAc:hexane gradient). Pure Compound Example 7 was obtained (12.4 mg, 60.4% yield). 26 H 26 The calculated MS(ESI) mass for ClNO3 is 491.97, [M+H] + The m / z value of was 492.2.

[0128] G. Compound example 8 [ka] Synthesis of Compound Example 8: Intermediate HBS-039-024 (0.032 g, 0.1 mmol) was dissolved in anhydrous DMF (2.5 mL). Triethylamine (0.04 mL, 0.29 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.018 g, 0.1 mmol). The reaction mixture was stirred at 60° C. for 16 hours. LCMS data indicated an m / z value (486.2) for the product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. The crude product was purified by prep-TLC plate (mobile phase: EtOAc:hexane (50:50 v / v mL)). Pure Compound Example 8 was obtained (0.032 g, 68.8% yield). C 27 H24 The calculated MS(ESI) mass for ClNO2 was 485.96, [M+H] + The m / z value of was 486.2.

[0129] H. Compound Example 9 [ka] Synthesis of Compound Example 9: Intermediate HBS-039-025 (0.017 g, 0.05 mmol) was dissolved in anhydrous DMF (2.5 mL). Triethylamine (0.021 mL, 0.15 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.009 g, 0.05 mmol). The reaction mixture was stirred at 60° C. for 16 hours. LCMS data indicated an m / z value (490.2) for the product formation. The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporating the solvent. It was purified by prep-TLC plate (mobile phase: EtOAc:hexane (80:20 v / v mL)). Compound Example 9 was obtained (0.009 g, 35.7% yield). C 27 H 28 The calculated MS(ESI) mass for ClNO2 was 490.0, [M+H] + The m / z value of was 490.2.

[0130] I. Compound example 10 [ka] Synthesis of Compound Example 10: Intermediate HBS-039-055 (0.07 g, 0.22 mmol) was dissolved in anhydrous DMF (3.0 mL). DIPEA (0.11 mL, 0.65 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.049 g, 0.26 mmol). The reaction mixture was stirred at 60° C. for 8 hours. LCMS data indicated the formation of two products: m / z 486.2 (major product) and m / z 490.2 (minor product). The reaction mixture was diluted with water, and the product was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and then brine. The organic layer was separated and dried over anhydrous sodium sulfate. The crude product mixture was obtained by evaporation of the solvent. The crude product mixture was purified using an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 0.054 g of the product of Compound Example 4 was obtained (yield 51.6%); and 0.015 g of the product of Compound Example 10 was obtained (yield 14.1%). 27 H 24 The calculated MS(ESI) mass for ClNO2 was 485.96, [M+H] + The m / z value of C was 486.2; 27 H 28 The calculated MS(ESI) mass for ClNO2 was 490.0, [M+H] + The m / z value of was 490.2.

[0131] J. Compound Example 11 [ka] Synthesis of Compound Example 11: HBS-039-010 (0.02 g, 0.06 mmol), 3-bromo-6-methoxy-pyridazine (0.024 g, 0.13 mmol), and CsCO (0.058 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc) (0.003 g, 0.012 mmol) and BINAP (0.015 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours. LCMS data indicated an m / z value (449.3) for the product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product, which was purified by prep-TLC plate (mobile phase: EtOAc:hexane, (70:30 v / v mL)). Compound Example 11 was obtained (0.004 g, yield 18.2%). 24 H 28 The calculated MS(ESI) mass for N6O3 is 448.5, [M+H] + The m / z value of was 449.3.

[0132] K. Compound Example 12 [ka] Synthesis of Compound Example 12: HBS-039-010 (0.02 g, 0.06 mmol), 2-bromo-5-methoxy-pyridine (0.022 g, 0.12 mmol), and t-BuOK (0.02 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc) (0.003 g, 0.012 mmol) and BINAP (0.015 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 5 hours. LCMS data indicates an m / z value (448.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by prep-TLC plate (mobile phase: EtOAc:hexane, (50:50 v / v mL)). Compound Example 12 was obtained (0.005 g, yield 19.8%). 25 H 29 The calculated MS(ESI) mass for N5O3 is 447.5, [M+H] + The m / z value of was 448.3.

[0133] L. Compound Example 13 [ka] Synthesis of Compound Example 13: HBS-039-002 (0.02 g, 0.06 mmol), 3-bromo-6-methoxy-pyridazine (0.023 g, 0.12 mmol), and t-BuOK (0.017 g, 0.15 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc) (0.003 g, 0.012 mmol) and X-Phos (0.011 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours. The reaction progress was monitored by LCMS, and reagents were added twice to consume the starting material. LCMS data indicates an m / z value (443.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by prep-TLC plate (mobile phase: EtOAc:hexane, (35:65 v / v mL)). Compound Example 13 was obtained (0.011 g, yield 42.6%). 25 H 26 The calculated MS(ESI) mass for N6O2 is 442.5, [M+H] + The m / z value of was 443.3.

[0134] M. Compound Example 14 [ka] Synthesis of Compound Example 14: HBS-039-002 (0.02 g, 0.06 mmol), 2-bromo-5-methoxy-pyridine (0.022 g, 0.12 mmol), and t-BuOK (0.017 g, 0.15 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(OAc) (0.003 g, 0.012 mmol) and X-Phos (0.011 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 16 hours. LCMS data indicated an m / z value (442.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate, and the filtrate was concentrated to give the crude product, which was purified by prep-TLC plate (mobile phase: EtOAc:hexane, (40:60 v / v mL)). Compound Example 14 was obtained (0.009 g, yield 33.3%). 26 H 27 The calculated MS(ESI) mass for N5O2 is 441.5, [M+H] + The m / z value of was 442.3.

[0135] N. Compound Example 15 [ka] Synthesis of Compound Example 15: HBS-039-002 (0.02 g, 0.06 mmol), 5-iodo-2-methoxy-pyridine (0.028 g, 0.12 mmol), and CsCO (0.058 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(dba) (0.011 g, 0.012 mmol) and X-Phos (0.011 g, 0.024 mmol) were added. The reaction mixture was stirred at 110 °C for 6 hours. The reaction progress was monitored by LCMS, and reagents were added twice to consume the starting material. LCMS data indicates an m / z value (442.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient) to give Compound Example 15 (0.01 g, 37.8% yield). 26 H 27The calculated MS(ESI) mass for N5O2 is 441.5, [M+H] + The m / z value of was 442.3.

[0136] O. Compound Example 16 [ka] Synthesis of Compound Example 16: HBS-039-010 (0.02 g, 0.06 mmol), 5-iodo-2-methoxy-pyridine (0.04 g, 0.18 mmol), and CsCO (0.057 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(dba) (0.011 g, 0.011 mmol) and X-Phos (0.011 g, 0.023 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The progress of the reaction was monitored by LCMS, and reagents were added twice to consume the starting material. LCMS data indicates an m / z value (448.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 16 was obtained (0.005 g, 19.3% yield). 25 H 29 The calculated MS(ESI) mass for N5O3 is 447.5, [M+H] + The m / z value of was 448.3.

[0137] P. Compound example 17 [ka] Synthesis of Compound Example 17: HBS-039-002 (0.02 g, 0.06 mmol), 2-chloro-5-trifluoromethylpyridine (0.022 g, 0.12 mmol), and CsCO (0.058 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(dba) (0.006 g, 0.012 mmol) and X-Phos (0.006 g, 0.012 mmol) were added. The reaction mixture was stirred at 100 °C for 24 hours. The reaction progress was monitored by LCMS, and reagents were added twice to consume the starting material. LCMS data indicates an m / z value (480.2) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 17 was obtained (0.01, yield 36.5%). 26 H 24 The calculated MS(ESI) mass for FNO is 479.5, [M+H] + The m / z value of was 480.2.

[0138] Q. Compound Example 18 [ka] Synthesis of Compound Example 18: HBS-039-010 (0.017 g, 0.05 mmol) and 2-chloro-5-trifluoromethylpyridine (0.018 g, 0.1 mmol) were dissolved in anhydrous DMF (2.0 mL). K2CO3-free (0.021 g, 0.15 mmol) was added, and the reaction mixture was stirred at 115 °C for 16 hours. LCMS data showed an m / z value (486.3) for product formation. The reaction mixture was concentrated under airflow to give the crude product, which was purified using an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 18 was obtained (0.014 g, 58.5% yield). C 25 H 26 The calculated MS(ESI) mass for F3N5O2 is 485.5, [M+H] + The m / z value of was 486.3.

[0139] R. Compound Example 19 [ka] Synthesis of Compound Example 19: HBS-039-080 (0.02 g, 0.06 mmol) and 2-chloro-5-trifluoromethylpyridine (0.022 g, 0.12 mmol) were dissolved in anhydrous DMF (2.0 mL). Anhydrous K2CO3 (0.025 g, 0.18 mmol) was added, and the reaction mixture was stirred at 115 °C for 16 hours. LCMS data showed an m / z value (480.2) for product formation. The reaction mixture was concentrated under airflow to give the crude product, which was purified using an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 19 was obtained (0.01 g, 35.5% yield). C 25 H 24 The calculated MS(ESI) mass for FNO is 479.5, [M+H] + The m / z value of was 480.2.

[0140] S. Compound example 20 [ka] Synthesis of Compound Example 20: HBS-039-080 (0.02 g, 0.06 mmol), 2-bromo-5-methoxy-pyridine (0.034 g, 0.18 mmol), and t-BuOK (0.02 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.006 g, 0.01 mmol) were added, and the reaction mixture was stirred at 110 °C for 24 hours. The reaction progress was monitored by LCMS, and reagents were added twice to consume the starting material. LCMS data indicates an m / z value (442.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 20 was obtained (0.007 g, 26.8% yield). 26 H 27 The calculated MS(ESI) mass for N5O2 is 441.5, [M+H]+ The m / z value of was 442.3.

[0141] T. Compound Example 21 [ka] Synthesis of Compound Example 21: HBS-039-080 (0.02 g, 0.06 mmol), 2-bromo-5-methoxy-pyridazine (0.034 g, 0.18 mmol), and t-BuOK (0.02 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd2(dba)3 (0.011 g, 0.012 mmol) and X-Phos (0.006 g, 0.012 mmol) were added, and the reaction mixture was stirred at 110 °C for 24 hours. The reaction progress was monitored by LCMS, and reagents were added twice to consume the starting material. LCMS data indicates an m / z value (443.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient) to give Compound Example 21 (0.015 g, 56.2% yield). 25 H 26 The calculated MS(ESI) mass for N6O2 is 442.5, [M+H] + The m / z value of was 443.3.

[0142] U. Compound example 22 [ka] Synthesis of Compound Example 22: HBS-039-080 (0.02 g, 0.06 mmol), 5-iodo-2-methoxy-pyridine (0.04 g, 0.18 mmol), and t-BuOK (0.02 g, 0.18 mmol) were suspended in 1,4-dioxane (2.0 mL). Pd(dba) (0.011 g, 0.012 mmol) and X-Phos (0.006 g, 0.012 mmol) were added, and the reaction mixture was stirred at 110 °C for 24 hours. The reaction progress was monitored by LCMS, and reagents were added twice to consume the starting material. LCMS data indicates an m / z value (442.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient) to give Compound Example 22 (0.02 g, 74.6% yield). 26 H 27 The calculated MS(ESI) mass for N5O2 is 441.5, [M+H] + The m / z value of was 442.3.

[0143] V. Compound Example 23 [ka] Synthesis of Compound Example 23: HBS-039-080 (0.025 g, 0.075 mmol), 2-chloro-5-fluoro-pyridine (0.02 g, 0.15 mmol), and t-BuOK (0.025 g, 0.22 mmol) were suspended in 1,4-dioxane (2.5 mL). Pd2(dba)3 (0.014 g, 0.015 mmol) and X-Phos (0.007 g, 0.015 mmol) were added, and the reaction mixture was stirred at 110 °C for 6 hours. LCMS data indicated an m / z value of 430.3 for the product. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 23 was obtained (0.017 g, yield 51.9%). 25 H 24The calculated MS(ESI) mass for FNO is 429.5, [M+H] + The m / z value of was 430.3.

[0144] W. Compound Example 24 [ka] Synthesis of Compound Example 24: HBS-039-002 (0.025 g, 0.075 mmol), 2-chloro-5-fluoro-pyridine (0.02 g, 0.15 mmol), and t-BuOK (0.025 g, 0.22 mmol) were suspended in 1,4-dioxane (3.0 mL). Pd2(dba)3 (0.014 g, 0.015 mmol) and X-Phos (0.007 g, 0.015 mmol) were added. The reaction mixture was stirred at 110 °C for 6 hours. LCMS data indicated an m / z value (430.3) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 24 was obtained (0.019 g, yield 59.8%). 25 H 24 The calculated MS(ESI) mass for FNO is 429.5, [M+H] + The m / z value of was 430.3.

[0145] X. Compound Example 25 [ka] Synthesis of Compound Example 25: HBS-039-010 (0.025 g, 0.073 mmol), 2-bromo-5-fluoro-pyridine (0.026 g, 0.15 mmol), and t-BuOK (0.021 g, 0.18 mmol) were suspended in 1,4-dioxane (2.5 mL). Pd2(dba)3 (0.007 g, 0.007 mmol) and X-Phos (0.004 g, 0.007 mmol) were added, and the reaction mixture was stirred at 110 °C for 6 hours. LCMS data indicated an m / z value of 436.3 for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated to give the crude product. The crude product was purified by an ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). Compound Example 25 was obtained (0.026 g, yield 83.5%). 24 H 26 The calculated MS(ESI) mass for FN5O2 is 435.5, [M+H] + The m / z value of was 436.3.

[0146] [ka] Synthesis of Compound Example 26: Intermediate HBS-054-014 (0.025 g, 0.1 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.028 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added, followed by DIPEA (0.07 mL, 0.4 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-039-171 (0.031 g, 0.11 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (457.0) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). (Yield) 0.045 g of product was obtained. 26 H 25The calculated MS(ESI) mass for FN6O was 456.5, and the m / z value for [M+H]+ was 457.0. Note: Compound Examples 27 to 34 were prepared using the corresponding acid and amine intermediates HBO-039-171 via a similar coupling method.

[0147] [Table 1]

[0148] [ka] Synthesis of Compound Example 35: Intermediate HBS-054-014 (0.015 g, 0.059 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.017 g, 0.088 mmol) and HOBt (0.012 g, 0.088 mmol) were added, followed by DIPEA (0.04 mL, 0.18 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-055-003 (0.019 g, 0.064 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (457.0) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.023 g of product was obtained (yield 79.0%). 26 H 21 The calculated MS(ESI) mass for F4N5O was 495.47, with an m / z value of [M+H]+ of 496.0. Note: Example compound 36 was prepared using a similar coupling method using the corresponding acid and amine intermediates.

[0149] [Table 2]

[0150] [ka] Synthesis of Compound Example 37: Intermediate HBS-054-080 (0.02 g, 0.07 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.019 g, 0.1 mmol) and HOBt (0.013 g, 0.1 mmol) were added, followed by DIPEA (0.034 mL, 0.2 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-039-171 (0.021 g, 0.072 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (507.0) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.02 g of product was obtained (yield 61.0%). 27 H 25 The calculated MS(ESI) mass for F3N6O was 506.52, and the m / z value for [M+H]+ was 507.03.

[0151] [ka] Synthesis of Compound Example 39: Intermediate HBS-054-088 (0.025 g, 0.095 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.027 g, 0.14 mmol) and HOBt (0.019 g, 0.14 mmol) were added, followed by DIPEA (0.05 mL, 0.29 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-039-171 (0.031 g, 0.11 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (463.0) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.027 g of product was obtained (yield 61.0%). 25 H 27 The calculated MS(ESI) mass for FN6O2 was 462.52, with an m / z value of [M+H]+ of 463.0. Note: Compound Example 41, Compound Example 42, and Compound Example 43 were prepared using similar coupling methods using the corresponding acid and amine intermediates.

[0152] [Table 3]

[0153] [ka] Synthesis of Compound Example 44: Intermediate HBS-039-192 (0.025 g, 0.098 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.025 g, 0.15 mmol) and HOBt (0.02 g, 0.15 mmol) were added, followed by DIPEA (0.17 mL, 0.98 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-039-171 (0.029 g, 0.098 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (457.3) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). (Yield) 0.045 g of product was obtained. 26 H 25 The calculated MS(ESI) mass for FN6O was 456.51, with an m / z value of [M+H]+ of 457.3. Note: Compound Example 45 and Compound Example 44 were prepared using similar coupling methods using the corresponding acid and amine intermediates.

[0154] [Table 4]

[0155] [ka] Synthesis of Compound Example 47: Intermediate HBS-039-192 (0.02 g, 0.078 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.022 g, 0.12 mmol) and HOBt (0.016 g, 0.12 mmol) were added, followed by DIPEA (0.14 mL, 0.78 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-055-011 (0.026 g, 0.078 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (502.2) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: EtOAc:hexane gradient). 0.039 g of product was obtained (yield). 27 H 21 The calculated MS(ESI) mass for ClFN5O2 was 501.94, and the m / z value for [M+H]+ was 502.2. Note: Compound HBO-12240 was prepared using a similar coupling method using the corresponding acid and amine intermediates.

[0156] [Table 5]

[0157] [ka] Synthesis of Compound Example 49: Intermediate HBS-055-013 (0.02 g, 0.076 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.022 g, 0.11 mmol) and HOBt (0.015 g, 0.11 mmol) were added, followed by DIPEA (0.13 mL, 0.76 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-039-171 (0.022 g, 0.076 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (463.3) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0168 g of product was obtained (yield 47.6%). 25 H 27 The calculated MS(ESI) mass for FN6O2 was 462.52, with an m / z value of [M+H]+ of 463.3. Note: Compound Example 50 and Compound Example 51 were prepared using similar coupling methods using the corresponding acid and amine intermediates.

[0158] [Table 6]

[0159] [ka] Synthesis of Compound Example 52: Intermediate HBS-055-028 (0.02 g, 0.057 mmol) was dissolved in anhydrous acetonitrile (2.0 mL). Anhydrous Cs2CO3 (0.037 g, 0.11 mmol) was added, followed by 2,5-dichloro-1,3-benzoxazole (0.016 g, 0.085 mmol). The reaction mixture was heated at reflux for 6 hours. LCMS data indicates an m / z value (504.2) for product formation. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient). 22.2 g of product was obtained (77.2% yield). C 27 H 23 The calculated MS(ESI) mass for ClFN5O2 was 503.96, and the m / z value for [M+H]+ was 504.2.

[0160] [ka] Synthesis of Compound Example 53: Intermediate HBS-055-028 (0.02 g, 0.057 mmol) was dissolved in anhydrous DMF (2.0 mL). Anhydrous Cs2CO3 (0.037 g, 0.11 mmol) was added, followed by 2-chloro-5-trifluoromethylpyridine (0.016 g, 0.089 mmol). The reaction mixture was heated at 100 °C for 16 hours. LCMS data indicated an m / z value (498.2) for product formation. The reaction mixture was diluted with water, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporation of the solvent. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient) to give 17.2 mg of pure product (60.5% yield). C 26 H 23 The calculated MS(ESI) mass for F4N5O2 was 497.49, and the m / z value for [M+H]+ was 498.2.

[0161] [ka] Synthesis of Compound Example 54: Intermediate HBS-055-028 (0.02 g, 0.057 mmol) was dissolved in anhydrous DMF (2.0 mL). Anhydrous Cs2CO3 (0.037 g, 0.11 mmol) was added, followed by 2-chloro-4,6-dimethylpyrimidine (0.018 g, 0.086 mmol). The reaction mixture was heated at 100 °C for 16 hours. LCMS data indicated an m / z value (459.3) for product formation. The reaction mixture was diluted with water, and the product was extracted with DCM. The combined DCM layers were separated and dried over anhydrous sodium sulfate. The crude product was obtained by evaporation of the solvent. The crude product was purified by an ISCO combiflash chromatography system (mobile phase: EtOAc:hexane gradient) to give 21.1 mg of pure product (80.7% yield). 26 H 27 The calculated MS(ESI) mass for FN6O was 458.53, and the m / z value for [M+H]+ was 459.3. Note: Compounds 54 and 55 were prepared using the corresponding acid and amine intermediates via the general EDC·HCl, HOBt·HO coupling method.

[0162] [Table 7]

[0163] [ka] Synthesis of Compound Example 57: Intermediate HBS-062-013 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.42 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-062-031 (0.028 g, 0.082 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (492.1) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.023 g of product was obtained (yield 56.1%). 26 H 26 The calculated MS(ESI) mass for ClN5O3 was 491.97, and the m / z value for [M+H]+ was 492.1. Note: Example compound 58 was prepared using a similar coupling method.

[0164] [Table 8]

[0165] [ka] Synthesis of Compound Example 59: Intermediate HBS-055-197 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.12 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.41 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-062-031 (0.028 g, 0.082 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (492.1) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.037 g of product was obtained (yield 91.9%). 26 H 26 The calculated MS(ESI) mass for ClN5O3 was 491.97, and the m / z value for [M+H]+ was 492.1. Note: Example compound 60 was prepared using a similar coupling method.

[0166] [Table 9]

[0167] [ka] Synthesis of Compound Example 61: Intermediate HBS-062-028 (0.02 g, 0.083 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.42 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-062-031 (0.028 g, 0.083 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (488.1) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0347 g of product was obtained (yield 85.5%). 25 H 22 The calculated MS(ESI) mass for ClN7O2 was 487.94, with an m / z value of [M+H]+ of 488.1. Note: Example compound 62 was prepared using a similar coupling method using the following intermediates:

[0168] [Table 10]

[0169] [ka] Synthesis of Compound Example 63: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.06 mL, 0.33 mmol) was added, and the rxn mixture was stirred at ambient temperature for 5.0 minutes. To the rxn mixture was added intermediate HBS-062-031 (0.028 g, 0.084 mmol). The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (487.1) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: DCM:MeOH gradient). (Yield) 0.041 g of product was obtained. 26 H 23 The calculated MS(ESI) mass for ClN6O2 was 486.95, and the m / z value for [M+H]+ was 487.1. Note: Example compound 64 was prepared using a similar coupling method using the following intermediates:

[0170] [Table 11]

[0171] [ka] Synthesis of Compound Example 65: Intermediate HBS-062-027 (0.02 g, 0.084 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.42 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. To the rxn mixture was added intermediate HBS-062-031 (0.028 g, 0.084 mmol). The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (487.1) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0375 g of product was obtained (yield 92.1%). 26 H 23 The calculated MS(ESI) mass for ClN6O2 was 486.95, and the m / z value for [M+H]+ was 487.1. Note: Example compound 66 was prepared using a similar coupling method using the following intermediates:

[0172] [Table 12]

[0173] [ka] Synthesis of Compound Example 67: Intermediate HBS-062-041 (0.02 g, 0.084 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.42 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-062-031 (0.028 g, 0.084 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (487.1) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0336 g of product was obtained (yield 82.5%). 26 H 23 The calculated MS(ESI) mass for ClN6O2 was 486.95, and the m / z value for [M+H]+ was 487.1. Note: Example compound 68 was prepared using a similar coupling method using the following intermediates:

[0174] [Table 13]

[0175] [ka] Synthesis of Compound Example 69: HBS-039-019 (0.02 g, 0.084 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.42 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. To the rxn mixture was added intermediate HBS-062-092 (0.028 g, 0.084 mmol). The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (441.2) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0343 g of product was obtained (yield 92.7%). 26 H 28 The calculated MS(ESI) mass for NO was 440.54, and the m / z value for [M+H] was 441.2. Note: Compound Example 70, Compound Example 71, Compound Example 72, Compound Example 73, and Compound Example 74 were prepared using a similar coupling method using the following intermediates.

[0176] [Table 14]

[0177] [ka] Synthesis of Compound Example 75: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.06 mL, 0.33 mmol) was added, and the rxn mixture was stirred at ambient temperature for 5.0 minutes. To the rxn mixture was added intermediate HBS-062-092 (0.028 g, 0.084 mmol). The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (442.2) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: DCM:MeOH gradient). (Yield) 0.037 g of product was obtained. 25 H 27 The calculated MS(ESI) mass for N7O was 441.53, and the m / z value for [M+H]+ was 442.2.

[0178] [ka] Synthesis of Compound Example 76: Intermediate HBS-062-013 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.41 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-062-119 (0.027 g, 0.082 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (448.2) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0294 g of product was obtained (yield 80.2%). 25 H 29The calculated MS(ESI) mass for N5O3 was 447.53, and the m / z value for [M+H]+ was 448.2. Note: Compound Example 77, Compound Example 78, Compound Example 79, and Compound Example 80 were prepared using a similar coupling method using the following intermediates.

[0179] [Table 15]

[0180] [ka] Synthesis of Compound Example 81: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.06 mL, 0.33 mmol) was added, and the rxn mixture was stirred at ambient temperature for 5.0 minutes. To the rxn mixture was added intermediate HBS-062-119 (0.028 g, 0.084 mmol). The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (442.2) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0342 g of product was obtained (yield 92.3%). 25 H 26 The calculated MS(ESI) mass for N6O2 was 442.51, and the m / z value for [M+H]+ was 443.4.

[0181] [ka] Synthesis of Compound Example 82: Intermediate HBS-062-013 (0.02 g, 0.082 mmol) was dissolved in anhydrous DCM (2.0 mL). EDC·HCl (0.024 g, 0.13 mmol) and HOBt (0.017 g, 0.13 mmol) were added, followed by EtN (0.06 mL, 0.42 mmol). The rxn mixture was stirred at ambient temperature for 5.0 minutes. To the rxn mixture was added intermediate HBS-062-136 (0.03 g, 0.082 mmol). The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicates an m / z value (487.2) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by ISCO combi-flash system (mobile phase: DCM:MeOH gradient). 0.0348 g of product was obtained (yield 87.4%). 24 H 25 The calculated MS(ESI) mass for F3N6O2 was 486.49, and the m / z value for [M+H]+ was 487.2. Note: Compound Example 83, Compound Example 84, Compound Example 85, Compound Example 86, Compound Example 87, Compound Example 88, Compound Example 89, Compound Example 90, and Compound Example 91 were prepared using a similar coupling method using the following intermediates:

[0182] [Table 16]

[0183] [ka] Synthesis of Compound Example 87: Intermediate HBS-062-030 (0.02 g, 0.084 mmol) and HATU (0.038 g, 0.1 mmol) were dissolved in anhydrous DMF (1.5 mL). DIPEA (0.07 mL, 0.4 mmol) was added, and the rxn mixture was stirred at ambient temperature for 5.0 minutes. Intermediate HBS-062-136 (0.034 g, 0.084 mmol) was added to the rxn mixture. The rxn mixture was stirred at ambient temperature for 16 hours. LCMS data indicated an m / z value (482.2) for product formation. The rxn mixture was diluted with DCM and washed with a saturated solution of NaHCO3. The DCM layer was separated and dried over anhydrous Na2SO4. The crude product was obtained by evaporation of the solvent. The crude product was purified by an ISCO combi-flash system (mobile phase: ethyl acetate:hexane gradient). (Yield) 0.04 g of product was obtained. 24 H 22 The calculated MS(ESI) mass for F3N7O was 481.47, with an m / z value of [M+H]+ of 482.2. NOTE: Compound Example 92, Compound Example 93, Compound Example 94, Compound Example 95, Compound Example 96, Compound Example 97, Compound Example 98, Compound Example 99, Compound Example 100, and Compound Example 101 were prepared by general coupling methods (EDC·HCl or HATU) using the following intermediates:

[0184] [Table 17]

[0185] Example 2 A. Biological Assays The antagonist activity of each exemplary compound against both orexin receptors was measured using an in vitro assay (intracellular calcium measurement) as described herein (i.e., for the purpose of identifying orexin receptor antagonists). Those skilled in the art will appreciate that other assays may also be used to identify orexin receptor antagonists. Chinese hamster ovary (CHO) cells expressing human orexin-1 receptor and human orexin-2 receptor, respectively, were grown in a medium (Ham's F-12 supplemented 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 were seeded at 20,000 cells / well into a black-bottomed, clear, 384-well sterile plate (Greiner). The seeded plate was incubated overnight at 37°C and 5% CO2. The agonist, human orexin-A, was prepared as a 1 mM stock solution (MeOH:water = 1:1) and diluted in HBSS containing 0.1% bovine serum albumin (BSA), 0.375 g / L NaHCO3, and 20 mM HEPES to a final concentration of 3 nM for the assay.

[0186] Antagonists were prepared as 10 mM stock solutions (DMSO) and then diluted in DMSO into 384-well plates. This dilution was then added to HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3 (0.375 g / L), and HEPES (20 mM). On the day of the assay, 50 μL of staining buffer (HBSS containing 1% FCS, HEPES (20 mM), NaHCO3 (0.375 g / L), 5 mM probenecid (Sigma), and 3 μM fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO with 10% Pluronic)) was added to each well. The 384-well cell plate was incubated at 37°C and 5% CO2 for 50 minutes, then equilibrated to room temperature for 30 minutes before measurement. Potential orexin receptor antagonists were added to the plate at 10 μL / well in a fluorescence imaging plate reader (FLIPR Tetra, Molecular Devices) and incubated for 120 min, followed by the final addition of 10 μL / well of agonist. Fluorescence in each well was measured at 1-second intervals, and the height of each fluorescence peak was compared to that elicited by 3 nM orexin-A containing vehicle instead of antagonist. IC 50 The IC value (the compound concentration required to inhibit the agonist response by 50%) was measured and compared with the IC obtained for the on-plate reference compound. 50 The values ​​were normalized using the calculated IC. Optimized conditions were achieved by adjusting the pipetting speed and cell splitting regime. 50 Values ​​will vary from day to day and from cell assay to cell assay, but such variations are known to those skilled in the art. 50 If values ​​are measured multiple times, IC 50 The geometric mean of the values ​​is obtained. The antagonist activity of exemplary compounds is shown in Table 1.

[0187] [Table 18] TIFF2025529901000156.tif191135TIFF2025529901000157.tif191124

[0188] While specific embodiments have been described with reference to preferred embodiments, those skilled in the art will recognize that variations and modifications thereof exist, and it is therefore intended that the appended claims cover all such equivalent variations that fall within the scope of the claims.

Claims

1. Chemical formula (I) or (II): 【Chemical 1】 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; where R １ contains E which is a carbon (C) but not a nitrogen (N), and E is connected to J or D by a double bond; R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); Or, R １ When is heteroaryl, R １ 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , and R ４ are independently H, halogen (F, Cl, Br, etc.), alkyl, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted by one, two, or all up to three independently selected substituents of R ５ and R ６ are independently H, CH ３ , alkyl, substituted alkyl, (C １～３ ) selected from the group consisting of fluoroalkyl, cycloalkyl; R ６ However, (C １～３ ) As the alkyl forming the cyclic structure of the alkyl bridge, R １０ or R １１ or R １３ is connected to one of the R ５ and R ６ are both linked together to form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R ７ But H, CH ３ , alkyl, substituted alkyl, (C １～３ ) selected from the group consisting of fluoroalkyl, cycloalkyl; R ７ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ or R １１ or R １３ connected to one of the following: R ８ But H, CH ３ , alkyl, substituted alkyl, (C １～３ ) selected from the group consisting of fluoroalkyl, cycloalkyl; R ８ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge １０ or R １１ or R １３ connected to one of the following: R ９ But H, CH ３ , alkyl, substituted alkyl, (C １～３ ) selected from the group consisting of fluoroalkyl, cycloalkyl; R ９ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ６ or R １１ connected to one of the following: R １０ But H, CH ３ , alkyl, substituted alkyl, (C １～３ ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R １１ and R １２ are independently H, CH ３ , alkyl, substituted alkyl, (C １～３ ) selected from the group consisting of fluoroalkyl, cycloalkyl; R １１ or R １２ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ７ or R ８ It is connected to one of In some embodiments, R １１ and R １２ can form a spiro moiety (such as, but not limited to, cyclopropyl and cyclobutyl); R １３ and R １４ are independently H, CH ３ , alkyl, substituted alkyl (e.g., fluoroalkyl), cycloalkyl; R １３ or R １４ (C １～３ ) R as alkyl forming the cyclic structure of the alkyl bridge ７ or R ８ connected to one of the following: R １５ is an aromatic or aryl (including, but not limited to, heteroaryl (e.g., preferably a 5- or 6-membered ring)), substituted aromatic or aryl, substituted heteroaryl (e.g., preferably a 5- or 6-membered ring), and a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; and wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; (c) W is CH ２ , and R ７ , R ８ , R １３ , R １４ (each of which is H); Substituent R ７ , R ８ , R １３ , and R １４ The carbons having the following may be directly linked; 【Chemistry 2】 providing a 5-5 bridged bicyclic ring system as shown in or (d) W is absent; 【Chemistry 3】 providing a seven-membered ring system shown in where the fused ring system A-B-J-D-E is a 5-membered heteroaryl, optionally imidazole (where A and J are nitrogen, while B, E, and D are carbon) or pyrazole (where A and B are nitrogen, and D, E, and J are carbon); the fused ring system is fused to a further ring system or is not fused to a further ring system; the fused ring system B-J-M-G-K-L is a 6-membered aromatic or aryl, substituted aromatic or aryl, substituted or unsubstituted heteroaryl, cycloalkyl, heterocycloalkyl; A is nitrogen or carbon; B is carbon or nitrogen; J is carbon or nitrogen; D is carbon; E is carbon; M is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; G is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O; K is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ and O; L is carbon, CH, CHR ２ , CHR ３ , C.R. ２ R ３ , C.R. ２ , C.R. ３ , C.R. ４ , O, and N; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

2. Chemical formula I-a7, chemical formula I-a8, chemical formula I-a9, chemical formula II-a7, chemical formula II-a8, or chemical formula II-a9: 【Chemistry 4】 10. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, thereof, wherein: where R １ In the formula (I), when E is a carbon (C) and not a nitrogen (N), and E is connected to J or D by a double bond, then R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl (5-6 membered ring), substituted aromatic or aryl, substituted heteroaryl (5-6 membered ring); R １ When is heteroaryl, it 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , and R ４ are independently H, halogen (F, Cl, Br, etc.), alkyl group, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted with up to three substituents independently selected from one, two, or all of: R １５ is selected from the group consisting of aromatic or aryl, heteroaryl, 5- to 6-membered heteroaryl, substituted aromatic or aryl, substituted 5- to 6-membered heteroaryl or a fused two heteroaryl ring system; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

3. Formula I-b7, Formula I-b8, Formula I-b9, Formula I-b10, Formula II-b7, Formula II-b8, Formula II-b9 and Formula II-b10: 【Chemistry 5】 10. The compound of claim 1 having the formula: where R １ In the formula (I), when E is a carbon (C) and not a nitrogen (N), and E is connected to J or D by a double bond, then R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl; R １ When is heteroaryl, R １ 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , R ４ are each independently H, halogen (optionally F, Cl, or Br), alkyl group, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted with up to three substituents independently selected from one, two, or all of: R １５ is selected from the group consisting of aromatic or aryl, heteroaryl, 5- to 6-membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5- to 6-membered heteroaryl, and a system of two fused heteroaryl rings; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, (C ３～７ ) heterocycloalkyl; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

4. Formula I-b11, Formula I-b12, Formula I-b13, Formula I-b14, Formula II-b11, Formula II-b12, Formula II-b13 and Formula II-b14: 【Chemistry 6】 10. The compound of claim 1 having the formula: where R １ In the formula (I), when E is a carbon (C) and not a nitrogen (N), and E is connected to J or D by a double bond, then R １ is selected from the group consisting of H, alkyl, alkoxy, cycloalkyl, phenyl, aromatic or aryl, heteroaryl, 5-6 membered heteroaryl, substituted aromatic or aryl, substituted heteroaryl, substituted 5-6 membered heteroaryl; R １ When is heteroaryl, R １ 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 the aromatic, aryl, or heteroaryl is unsubstituted, mono- or di-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; R ２ , R ３ , R ４ are each independently H, halogen (F, Cl, or Br); alkyl group, substituted alkyl, (C １～４ ) alkyl, (C １～４ ) alkoxy, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy and (C ３～７ ) cycloalkyl; Here, R ２ , R ３ and R ４ each independently and optionally at each substitutable position, R ２ , R ３ and R ４ substituted with up to three substituents independently selected from one, two, or all of: R １２ But H, CH ３ , alkyl, substituted alkyl, (C １～３ ) selected from the group consisting of fluoroalkyl, and cycloalkyl; R １５ is selected from the group consisting of aromatic, aryl, heteroaryl, 5- to 6-membered heteroaryl, substituted aromatic, substituted aryl, substituted heteroaryl, substituted 5- to 6-membered heteroaryl or a fused two heteroaryl ring system; wherein the aromatic, aryl or heteroaryl is unsubstituted, mono-, di- or tri-substituted; wherein the substituents are independently: (C １～４ ) alkyl, (C １～４ ) alkoxy, halogen, (C １～３ ) fluoroalkyl, (C １～３ ) fluoroalkoxy, (C ３～７ ) cycloalkyl, and (C ３～７ ) heterocycloalkyl; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

5. 10. A compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; 【Chemistry 7】 【change】 【change】 【change】 【change】 【change】 【change】 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

6. 6. The compound of claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; 【Chemistry 8】 【change】 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

7. 1. A pharmaceutical composition comprising: A compound according to any preceding claim, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof; and an acceptable carrier, adjuvant or vehicle; Including, Pharmaceutical compositions.

8. 8. The pharmaceutical composition of claim 7, comprising a therapeutically effective amount of the compound, its pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof.

9. 9. The pharmaceutical composition according to claim 7 or 8, wherein the composition further comprises at least one second therapeutic agent.

10. 10. A method of antagonizing at least one orexin receptor in a cell, optionally an in vitro method, comprising exposing said cell to a compound and / or composition according to any preceding claim.

11. 10. A method of antagonizing at least one orexin receptor, comprising administering a compound and / or composition according to any preceding claim in a subject in need thereof.

12. A method of treating a condition selected from the group consisting of substance addiction, substance dependence, panic, anxiety, depression, post-traumatic stress disorder (PTSD), neurodegeneration, autism, schizophrenia, pain, Alzheimer's disease (AD), and central nervous system (CNS) disorders, comprising administering to a subject in need thereof a compound and / or composition according to any preceding claim.

13. 13. The method of claim 12, wherein the substance corresponding to the substance addiction or substance dependence is: one or more opioids, optionally heroin, morphine, oxycodone, fentanyl, and hydrocodone; optionally one or more stimulants selected from the group consisting of amphetamine, cocaine, crack cocaine, and methamphetamine; one or more sedatives and / or tranquilizers, benzodiazepines, and barbiturates; selected from the group consisting of method.

14. 14. The method of any one of claims 10 to 13, wherein the compound is an orexin receptor antagonist.

15. 15. The method according to any one of claims 10 to 14, wherein: wherein the compound binds to orexin receptor 1 (OX １ R) or orexin receptor 2 (OX ２ R) antagonist, or OX １ R and OX ２ is an antagonist of both R; Optionally, where: the compound is an antagonist of the κ-opioid receptor; and / or as measured by in vitro cell assays: (1) OX １ R Kb < 30nm、OX ２ R Kb > 1000nm、KOR Ki <500nm; (2) OX １ R Kb < 30nm、OX ２ R Kb > 30nm、KOR Ki <500nm; or (3) OX １ R Kb < 30nm、OX ２ R Kb > 1000nm、KOR Ki > 1000nm、 Showing the characteristics of method.

16. 16. The method according to any one of claims 10 to 15, wherein: administering to a patient a therapeutically effective amount of a compound and / or composition of any preceding claim. method.

17. 17. The method according to any one of claims 10 to 16, wherein: administering at least one unlabeled and / or at least one isotopically labeled compound of any of the preceding claims, and / or a composition comprising the same; method.

18. 10. A method for making a compound of claim 1, comprising combining at least two intermediates to form said compound. method.

19. A method for preparing the pharmaceutical composition of any of claims 7 to 9, comprising combining at least one compound of claim 1 with at least one pharmaceutically acceptable excipient. method.

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