Tetrahydroquinoline derivatives for inhibiting CAV3.2-USP5 interaction

Abstract

The present application relates to various uses of thiazolidine derivative compounds of formula I in the treatment of diseases, disorders, or conditions that can be treated by inhibiting the interaction of the Cav3.2 T-type calcium channel (Cav3.2) with ubiquitin-specific peptidase 5 (USP5). For example, compounds of formula I are useful as analgesics in the treatment of pain. This application also relates to compounds of Formula I or pharmaceutically acceptable salts, hydrates and / or prodrugs thereof. JPEG2026508515000104.jpg43108

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of co-pending U.S. Provisional Patent Application No. 63 / 448,421, filed February 27, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] [Technical field] This application relates to tetrahydroquinoline derivatives, compositions containing them, and their use in therapy. More particularly, this application relates to five-membered ring-fused tetrahydroquinoline derivatives useful in the treatment of diseases, disorders, or conditions treatable by inhibiting the interaction between Cav3.2 voltage-gated T-type calcium channels and ubiquitin-specific peptidase 5 (USP5). [Background technology]

[0003] In primary afferent pain pathways, voltage-gated T-type calcium channels are thought to sustain neuronal firing and contribute to neurotransmitter release at afferent terminals in the dorsal horn of the spinal cord. A prominent T-type channel subtype expressed in peripheral afferent fibers is Cav3.2. Cav3.2 T-type calcium channels are important mediators of pain signaling, and their activity is not modulated in chronic pain states (Figure 1). 1 Reverse inhibition of these ion channels mediates analgesia in preclinical models. Aberrant upregulation of Cav3.2 is due to injury-induced increased expression of USP5, an enzyme that associates with these channels and increases their stability. 2~9 This leads to more Cav3.2 channels in pain-sensing neurons and therefore more pain. Depleting sensory neurons of Cav3.2 or preventing the interaction of USP5 with the channel by a penetrating decoy peptide protects against inflammatory, neuropathic, diabetic, and post-surgical pain in mice (Figure 2). 9 Using a high-throughput ELISA screen, we identified small organic molecules that can prevent USP5 interaction with the channel. 7(See Figure 3.) An initial screen of an active compound library at the Centre for Drug Research and Development (CDRD, University of British Columbia) yielded two hits (suramin and gossypetin) that were found to protect against diabetic, visceral, inflammatory, and neuropathic pain in mice. Therefore, inhibiting the interaction between Cav3.2 and USP5 may be a potential target for novel therapeutics.

[0004] US Patent No. 9,993,522 discloses the use of peptide inhibitors of the interaction between Cav3.2 and USP5 to inhibit Cav3.2 channel function.

[0005] WO 2004 / 098600 discloses tetrahydroquinoline derivatives as positive modulators of nicotinic acetylcholine receptors. WO 2004 / 072046 discloses tetrahydroquinoline derivatives for regulating liver-X receptors. WO 2016 / 014847 discloses tetrahydroquinoline derivative ligands for alpha-7 nicotinic acetylcholine receptors. WO 2016 / 014847 discloses tetrahydroquinoline derivatives for treating disorders associated with MDM2 activity.

[0006] WO 2011 / 009523 discloses a method for predicting the likelihood that a breast tumor patient will respond to treatment with an Eg5 inhibitor compound. Summary of the Invention

[0007] Compounds that inhibit or block the interaction between the Cav3.2 T-type calcium channel (Cav3.2) and ubiquitin-specific peptidase 5 (USP5) have been identified.

[0008] Thus, the present application provides a compound of formula (I):

[0009] [ka]

[0010] The compound of formula (I) X is selected from C, O, N, NH, S, S(O), and SO;

[0011] [ka]

[0012] is a single or double bond, provided that when X is C or N,

[0013] [ka]

[0014] is a double bond; A is phenyl and C 5~6 heteroaryl; R 1 is R 5 , OR 5 and NR 5 R 6 Selected from; R 2 H, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 heteroaryl, the latter ten groups being selected from OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6alkyl); R 3 H, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R 2 and R 3 together with the atoms between them, N, NH, N(C 1-6 alkyl), O, S, S(O), and SO2, and may contain one or two hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1-6 Alkyl and C 1-6 forming a 3- to 7-membered saturated or unsaturated ring optionally substituted by 1 to 4 substituents selected from haloalkyl; Each R 4 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OH, NH2, SH, SC 1~6 Alkyl, SC 1~6 Haloalkyl, OC 1~6 Alkyl, OC 1~6 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)H, C(O)C 1~6 Alkyl, C(O)C 1~6 Haloalkyl, CO2H, C(O)2C 1~6 Alkyl, C(O)C 1~6 Haloalkyl, CONH2, CONHC 1~6 Alkyl and CON(C 1~6 Alkyl)(C 1~6 alkyl); R 5 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylene R 7 and C 1~6 Haloalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), CONH2, CONH(C 1~6 alkyl), CON(C 1~6 Alkyl)(C 1~6 alkyl), SO2NH2, SO2NH(C 1~6 alkyl) and SO2N(C 1~6 Alkyl)(C 1~6 alkyl); R 6 is H, C 1~6 Alkyl and C 1~6 haloalkyl; or R 5 and R 6 together with the nitrogen atom between them, N, NR 8’ , O, S, S(O), and SO2, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~6 Alkylene NR 8 R 9 , C 1~6 Alkylene OR8 , C 1~6 Alkylene CO2R 8 , and C 1~6 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene forms a 3- to 12-membered heterocycloalkyl or heteroaryl ring optionally substituted by 1 to 4 substituents selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 7 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~10 Alkyl, OC 1~10 Haloalkyl, SC 1~10 Alkyl, SC 1~10 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)C 1~6 Alkyl, CO2C 1~6 Alkyl, C(O)NHC 1~6 Alkyl, C(O)N(C1~6 Alkyl)(C 1~6 alkyl), PO(OC 1~6 alkyl)(OC 1~6 alkyl), SO2C 1~6 Alkyl, SO2NH(C 1~6 alkyl), SO2N(C 1~6 Alkyl)(C 1~6 alkyl), NC 1~10 Alkyl SO2(C 1~6 alkyl), and NHSO2(C 1~6 alkyl); R 8 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylene R 10 and C 1~6 Haloalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 8’ are H, SO2NH2, SO2NH(C 1~6 alkyl), SO2N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)NH2, C(O)NH(C 1~6 alkyl), C(O)N(C 1~6 Alkyl)(C1~6 alkyl), C 1~6 Haloalkyl, C 1~6 Alkylene R 10 and C 1~6 Haloalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 9 is H, C 1~6 Alkyl and C 1~6 haloalkyl; R 10 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~10 Alkyl, OC 1~10 Haloalkyl, SC 1~10 Alkyl, SC 1~10 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)C 1~6 Alkyl, CO2C 1~6 Alkyl, C(O)NHC1~6 Alkyl, C(O)N(C 1~6 Alkyl)(C 1~6 alkyl), PO(OC 1~6 alkyl)(OC 1~6 alkyl), SO2C 1~6 Alkyl, SO2NH(C 1~6 alkyl), SO2N(C 1~6 Alkyl)(C 1~6 alkyl), NC 1~10 Alkyl SO2(C 1~6 alkyl), and NHSO2(C 1~6 alkyl); and n is selected from 0, 1, 2, 3, and 4; The present invention includes the compound, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0015] The present application includes a method for inhibiting the interaction between Cav3.2 T-type calcium channel (Cav3.2) and ubiquitin-specific peptidase 5 (USP5) in a cell, either in a biological sample or in a patient, the method comprising administering to the cell an effective amount of a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof.

[0016] The present application also includes a method for treating a disease, disorder, or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] The present application also includes a method for inhibiting Cav3.2 deubiquitination in a cell, either in a biological sample or in a patient, said method comprising administering to said cell an effective amount of a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof.

[0018] The present application also includes a method for treating a disease, disorder, or condition that can be treated by inhibiting Cav3.2 deubiquitination, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof.

[0019] In embodiments, the disease, disorder or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination is pain.

[0020] The present application also includes compositions comprising a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof and a carrier.

[0021] Other features and advantages of the present application will become apparent from the following detailed description. However, while presenting embodiments of the present application, the detailed description and specific examples are given by way of example only, and the scope of the claims should not be limited by these embodiments, but should be interpreted in the broadest possible manner consistent with the description as a whole.

[0022] Embodiments of the present application will now be described in more detail with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 shows (A) a graph showing the dose dependence of exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 on the biochemical interaction between USP5 and Cav3,2 assessed by ELISA, and (B) a graph showing the dose dependence of exemplary compounds (S,4R / S trans)I-51 (first four bars from the left), (R,4R / S trans)I-51 (fifth to eighth bars from the left), (R,4R / S trans)I-52 (ninth to twelfth bars from the left), and (S,4R / S trans)I-52 (thirteenth to sixteenth bars from the left) on the biochemical interaction between USP5 and Cav3,2 assessed by ELISA.

[0024] [Figure 2] Figure 2 is a molecular docking simulation showing the docking of an exemplary compound (4R / S trans) I-1 into the Cav3.2-III-IV linker-USP5 complex. The docking of the exemplary compound (4R / S trans) I-1 and the Cav3.2-III-IV linker sequence at three potential sites in USP5 is shown (arrows).

[0025] [Figure 3] Figure 3 is a molecular docking simulation showing the docking of an exemplary compound (4R / S trans) I-2 into the Cav3.2-III-IV linker-USP5 complex. The docking of the exemplary compound (4R / S trans) I-2 and the Cav3.2-III-IV linker sequence at two sites on USP5 is shown (arrows).

[0026] [Figure 4] 4A and 4B are graphs showing the effects of exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 on hERG and human Nav1.5 sodium channels. (A) shows the lack of effect of exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 on hERG1 tail current in tsA-201 cells. (B) shows the lack of effect of exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 on human Nav1.5 channels expressed in tsa-201 cells.

[0027] [Figure 5] Figure 5 is a graph showing the effect of an exemplary compound (4R / S trans)I-1 on formalin-induced nocifensive responses in mice, either via intrathecal delivery (top panel) or systemic (intraperitoneal) delivery (bottom panel).

[0028] [Figure 6]FIG. 6 is a graph showing the effect of an exemplary compound, (4R / S trans)I-2, on formalin-induced nocifensive responses in mice via intrathecal delivery.

[0029] [Figure 7] 7 is a graph showing the effect of an exemplary compound, (4R / S trans)I-40 (10 μg), on formalin-induced nocifensive responses in mice via intrathecal delivery. Left bar: vehicle. Right bar: (4R / S trans)I-40.

[0030] [Figure 8] 8 is a graph showing the effect of the exemplary compound (4R / S trans) I-1 on complete Freund's adjuvant (CFA)-induced thermal hypersensitivity. The upper graph shows the time course of the analgesic effect of the exemplary compound (4R / S trans) I-1 after intraperitoneal administration of different doses (3 mg / kg and 10 mg / kg) of the exemplary compound (4R / S trans) I-1 in CFA-treated wild-type mice. The top line of the four lines: phosphate-buffered saline (PBS) (20 μg / i.pl. (interphalangeal joint)), n=7. Second line: 10 mg / kg ip (4R / S trans) I-1, n=7; third line: 3 mg / kg ip (4R / S trans) I-1, n=7; and bottom line: control (PBS, 10 mL / kg ip (ip)), n=7. The bottom figure shows a comparison of the effect of 10 mg / kg ip exemplary compound (4R / S trans) I-1 on thermal withdrawal latencies in wild-type and Cav3.2 null mice. Left bar of each set of bars: before treatment (T0); right bar of each set of bars: after treatment (45 min).

[0031] [Figure 9]9 is a graph showing a comparison of the effects of 10 mg / kg i.p. exemplary compounds (4R / S trans)I-35 (top panel) and (4R / S trans)I-40 (bottom panel) on thermal escape latency in wild-type and Cav3.2 null mice. Left bar of each set of bars: baseline (B); second bar of each set of bars: pre-treatment (T0); right bar of each set of bars: post-treatment (10 mg / kg, i.p., 30 min).

[0032] [Figure 10] 10 is a graph showing the effect of exemplary compounds (4R / S trans)I-52 (top), (4R / S trans)I-49 (middle), and (4R / S trans)I-52 (bottom) on CFA-induced heat hypersensitivity. First bar of each graph: baseline (B), second bar of each graph: pre-treatment (T0), and third bar of each graph: exemplary compound, 3 mg / kg, i.p. (intraperitoneal), 30 minutes after treatment.

[0033] [Figure 11] 11 is a graph showing the effect of exemplary compounds (4R / S trans)I-2 (top left), (4R / S trans)I-40 (top right), (4R / S trans)I-1 (bottom left), and (4R / S trans)I-31 (bottom right) on CFA-induced heat hypersensitivity. For each graph, the left bar is baseline (B), the second bar is pre-treatment (T0), and the right bar is post-treatment.

[0034] [Figure 12] Figure 12 is a graph showing the effect of orally delivered exemplary compound (4R / S trans)I-31 on CFA-induced heat hypersensitivity (top panel) and the lack of effect of the exemplary compound (4R / S trans)I-31 on oral administration in Cav3.2 null mice (bottom panel). The top panel includes naproxen as a positive control.

[0035] [Figure 13]FIG. 13 is a graph showing the effect of an exemplary compound, (4R / S trans)I-40, on nerve injury-induced neuropathic pain in a repeated dosing regimen.

[0036] [Figure 14] Figure 14 is a graph showing a comparison of the effect of 10 mg / kg i.p. of the exemplary compound (4R / S trans)I-40 on mechanical hypersensitivity in mice with oxaliplatin-induced mechanical hypersensitivity. The bottom panel represents the baseline time point and time points T0 and T60 from the top panel, but shows all individual data points rather than simply the mean and SEM (standard error of the mean). DETAILED DESCRIPTION OF THE INVENTION

[0037] I. Definition Unless otherwise indicated, the definitions and embodiments set forth in this section and other sections are intended to be applicable to all embodiments and aspects of the present application described herein as appropriate as understood by one of ordinary skill in the art.

[0038] All features disclosed in this specification, including the claims, abstract, and drawings, and all steps in any disclosed method or process, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Each feature disclosed in this specification, including the claims, abstract, and drawings, may be replaced by an alternative feature serving the same, equivalent, or similar purpose, unless expressly specified otherwise.

[0039] As used herein, the terms "compound(s) of the application" or "compound(s) of the present application" and the like refer to compounds of Formula I or pharmaceutically acceptable salts and / or solvates thereof.

[0040] As used herein, the terms "composition(s) of the application" or "composition(s) of the present application" and the like refer to compositions, such pharmaceutical compositions, that include the compounds of the present application.

[0041] As used herein, the term "and / or" means that the listed items are present or used individually or in combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present. In reference to pharmaceutically acceptable salts and / or solvates thereof, the term "and / or" means that the compounds of the present application are present as individual salts and hydrates, as well as combinations of solvates, for example, of salts of the compounds of the present application.

[0042] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to refer to a particular embodiment including one compound, or two or more additional compounds.

[0043] In embodiments that include an "additional" or "second" component, such as an additional or second compound, as used herein, the second component is chemically distinct from the other component or the first component. The "third" component is distinct from the other, first, and second components, and further listed or "additional" components are similarly distinct.

[0044] As used in this application and the claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), and "including" (and any form of including, such as "contain" and "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0045] As used herein, the term "consisting of" and its derivatives are intended to be closed terms that specify the presence of specified features, elements, components, groups, integers, and / or steps, and exclude the presence of other unspecified features, elements, components, groups, integers, and / or steps.

[0046] As used herein, the term "consisting essentially of" is intended to specify the presence of the specified features, elements, components, groups, integers, and / or steps and those that do not materially affect the basic and novel characteristics of those features, elements, components, groups, integers, and / or steps.

[0047] As used herein, the term "suitable" means that the selection of a particular compound or conditions will depend on the particular synthetic operation being performed, the identity of the molecule being converted, and / or the particular use of the compound, but this selection will be within the ability of one of ordinary skill in the art. All process / method steps described herein should be performed under conditions sufficient to provide the indicated product. Those skilled in the art will understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, ratio of reactants, and whether the reaction should be carried out under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product, and this is within the skill of the art.

[0048] This specification presents several scientific terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0049] As used herein, the terms "about," "substantially," and "approximately" refer to a reasonable amount of deviation from the modified term so that the end result is not significantly altered. These terms of degree should be interpreted as including a deviation of at least ±5% from the modified term, unless this deviation negates the meaning of the word it modifies or the context suggests a different meaning to one of ordinary skill in the art.

[0050] As used herein, the term "alkyl," whether used alone or as part of another group, refers to a straight or branched chain saturated alkyl group. The possible number of carbon atoms in the recited alkyl group is indicated by the prefix "C n1~n2 For example, the term C 1~10 Alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0051] The term "alkylene," whether used alone or as part of another group, means a straight or branched chain saturated alkylene group, i.e., a saturated carbon chain containing substituents at both its termini. The possible number of carbon atoms in a given alkylene group is indicated by the prefix "C n1~n2 For example, the term C 1~6 Alkylene means an alkylene group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0052] As used herein, the term "cycloalkyl," whether used alone or as part of another group, refers to a cyclic group containing 3 to 20 atoms and at least one carbocyclic non-aromatic ring. Cycloalkyl groups can be saturated or unsaturated (i.e., contain one or more double bonds). The possible number of carbon atoms in a given cycloalkyl group is determined by the prefix "C." n1~n2 For example, the term C 3~10 Cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0053] As used herein, the term "heterocycloalkyl," whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring containing 3 to 20 atoms, in which one or more atoms are heteroatoms selected from O, S, SO, SO2, N, NH, and substituted N, and the remaining atoms are C. Heterocycloalkyl groups can be saturated or unsaturated (i.e., contain one or more double bonds). Heterocycloalkyl groups can be denoted by the prefix C. n1~n2When included within the prefix "heterocycloalkyl," this indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more, suitably 1 to 5, ring atoms are replaced with a heteroatom selected from O, S, SO, SO2, N, NH, and substituted N, and the remaining atoms are C. Heterocycloalkyl groups may be benzo-fused. When part of another group, "heterocycloalkyl" also refers to a cyclic group comprising at least one heterocycloalkyl group fused to one or more cyclic groups (e.g., heterocycloalkyl groups may be fused to aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups as defined herein).

[0054] As used herein, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and containing either 6, 9, or 10 carbon atoms, such as phenyl, indanyl, or naphthyl.

[0055] As used herein, the term "heteroaryl," whether used alone or as part of another group, refers to a cyclic group containing at least one aromatic heterocycle containing 5 to 20 atoms, in which one or more atoms are heteroatoms selected from O, S, N, NH, and substituted N, and the remaining atoms are C. A heteroaryl group may be denoted by the prefix C. n1~n2 When the prefix "" contains a substituted or unsubstituted aryl group, the prefix indicates the number of carbon atoms in the corresponding carbocyclic group where one or more, suitably 1 to 5, ring atoms are replaced by a heteroatom as defined above. Heteroaryl groups may be benzo-fused.

[0056] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups, contain one or more rings (i.e., are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused, or joined by bonds.

[0057] A first ring that is "fused" to a second ring means that the first ring and the second ring share two adjacent atoms between them.

[0058] A first ring that is "bridged" with a second ring means that the first ring and the second ring share two non-adjacent atoms between them.

[0059] A first ring that is "spirofused" to a second ring means that the first ring and the second ring share one atom between them.

[0060] The term "fluorosubstituted" means that one or more, including all, available hydrogens in the referenced group are replaced with fluoro.

[0061] As used herein, the terms "halo" or "halogen," whether used alone or as part of another group, refer to a halogen atom and include fluoro, chloro, bromo, and iodo.

[0062] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more available hydrogen atoms have been replaced by a halogen atom. Thus, for example, "C 1~6 "Haloalkyl" (or "C1-C6 haloalkyl") refers to a C1-C6 straight or branched chain alkyl group as defined above having one or more halogen substituents.

[0063] As used herein, the term "chloroalkyl" refers to a haloalkyl group as defined above where the halogen atom is chloro.

[0064] As used herein, the term "fluoroalkyl" refers to a haloalkyl group as defined above in which the halogen atom is fluoro.

[0065] As used herein, the term "haloalkylene" refers to an alkylene group as defined above in which one or more available hydrogen atoms have been replaced by a halogen atom. Thus, for example, "C 1~6"Haloalkylene" (or "C1-C6 haloalkylene") refers to a C1-C6 straight or branched chain alkylene group as defined above having one or more halogen substituents.

[0066] As used herein, the term "chloroalkylene" refers to a haloalkylene group as defined above where the halogen atom is chloro.

[0067] As used herein, the term "fluoroalkylene" refers to a haloalkylene group as defined above in which the halogen atom is fluoro.

[0068] As used herein, the term "substituted" means that the referenced atom contains at least one substituent other than a hydrogen atom.

[0069] As used herein, the term "substituent" refers to any chemical grouping, including groups containing carbon atoms and / or heteroatoms, that is compatible with the reaction conditions of the present methods.

[0070] When a group is substituted with one or more substituents, it is understood that the selection of these substituents is independent of one another, i.e., the one or more substituents may be the same or different.

[0071] As used herein, the term "tetrahydroquinoline" refers to a compound having the chemical formula and atomic number:

[0072] [ka]

[0073] As used herein, the tricyclic core structure of the compounds of Formula I has the following atomic numbers:

[0074] [ka]

[0075] For example, when X is O, the tricyclic core structure of compounds of Formula I is a "hexahydrofuro[3,2-c]quinoline" having the following chemical formula and atomic numbers:

[0076] [ka]

[0077] As used herein, the term "4R / S cis" in reference to compounds of Formula I of the present application means that the compounds of Formula I are a mixture of cis isomers of the compounds of Formula I (i.e., (3aR,4R,9bR) and (3aS,4S,9bS)), and have the following structure:

[0078] [ka]

[0079] As used herein, an "*" placed at the 3a, 4, and 9b positions of one cis isomer of a compound of Formula I of the present application means that the compound of Formula I is a mixture of both cis isomers described above. For example, the following structure means that the compound of Formula (I) is a mixture of (3aR,4R,9bR)-(I) and (3aS,4S,9bS)-(I) (e.g., (4R / S cis)-(I)):

[0080] [ka]

[0081] As used herein, the term "4S / S trans" in reference to the compound of Formula I of the present application means that the compound of Formula I is a mixture of the trans isomers of the compound of Formula I, i.e., (3aR,4R,9bR) and (3aS,4R,9bS), and has the following structure:

[0082] [ka]

[0083] As used herein, an "*" placed at the 3a, 4, and 9b positions of one trans isomer of a compound of Formula I of the present application means that the compound of Formula I is a mixture of both trans isomers described above. For example, the following structure means that the compound of Formula (I) is a mixture of (3aR,4S,9bR)-(I) and (3aS,4R,9bS)-(I) (e.g., (4R / S trans)-(I)).

[0084] [ka]

[0085] In the methods of the present application, it is common for compounds, including starting materials and products, to exist as mixtures of isomers. For example, when an R- or S-isomer is indicated as a product or starting material of a reaction, this means that the isomer is present in greater than about 80%, 85%, 90%, 95%, 98%, or 99% by weight, based on the total amount of R- and S-isomers.

[0086] The term "solvent" includes both a single solvent and a mixture containing two or more solvents.

[0087] The term "available," such as "available hydrogen atom" or "available atom," refers to an atom known to those of ordinary skill in the art to be substitutable by a substituent.

[0088] The term "optionally substituted" refers to a group, structure, or molecule that is either unsubstituted or substituted with one or more substituents.

[0089] As used herein, the term "protecting group" or "PG" and the like refers to a chemical moiety that protects or masks reactive portions of a molecule to prevent side reactions at those reactive portions of the molecule while manipulating or reacting different portions of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of an appropriate protecting group can be performed by one skilled in the art. Many conventional protecting groups are known to those skilled in the art and can be found, for example, in "Organic Chemistry" by McOmie, JFW Ed., Plenum Press, 1973, in Greene, T W and Wuts, P G M, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0090] The products of the methods of the present application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable methods.

[0091] Those skilled in the art will appreciate that when reaction steps herein are carried out in various solvents or solvent systems, said reaction steps may be carried out in suitable mixtures of solvents or solvent systems.

[0092] As used herein, the term "cell" refers to a single cell or multiple cells, including cells in either cell culture or in a subject.

[0093] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0094] The term "pharmaceutically acceptable" means compatible with the treatment of a subject.

[0095] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or other substance that enables a pharmaceutical composition to be formed, i.e., into a dosage form that can be administered to a subject.

[0096] The term "pharmaceutically acceptable salt" means either an acid addition salt or a base addition salt which is suitable or compatible with the treatment of a subject.

[0097] Acid addition salts suitable or compatible for the treatment of subjects are any non-toxic organic or inorganic acid addition salts of any basic compounds.

[0098] Suitable or compatible base addition salts for the treatment of subjects are any non-toxic organic or inorganic base addition salts of any acidic compounds.

[0099] As used herein, the term "solvate" refers to a complex formed between a compound and a solvent in which the compound is precipitated or produced. As used herein, the term "solvate" refers to a compound, or a salt of a compound, in which molecules of a suitable solvent are incorporated into the crystal lattice.

[0100] As used herein, the term "prodrug" means a compound, or a salt and / or solvate of a compound, that is converted into an active drug after administration.

[0101] The term "treating" or "treatment," as used herein and as well understood in the art, refers to an approach for obtaining effective or desired results, including clinical results. Effective or desired results include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of the disease, a stabilized (i.e., not worsening) state of the disease, prevention of the spread of the disease, delay or slowing of the progression of the disease, improvement or palliation of the disease state, reduction in recurrence of the disease, and remission (whether partial or total). "Treating" or "treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. As used herein, "treating" or "treatment" also includes prophylactic treatment. A treatment method comprises administering to a subject a therapeutically effective amount of one or more compounds of the present application, and may consist of a single dose, or alternatively, includes a series of doses.

[0102] "Ameliorating" a disease, disorder, or condition means reducing the severity and / or undesirable clinical symptoms of the disease, disorder, or condition and / or slowing or lengthening the time course of progression compared to if the disorder is not treated.

[0103] As used herein, the terms "prevention" or "prophylaxis," or synonyms thereof, refer to a reduction in the risk or likelihood of a patient suffering from a disease, disorder, or condition that can be treated by inhibiting the interaction between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin-specific peptidase 5 (USP5) in cells, or experiencing symptoms associated with a disease, disorder, or condition that can be treated by inhibiting the interaction between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin-specific peptidase 5 (USP5) in cells.

[0104] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a compound of the present application, or an amount of a compound, that is effective at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a disease, disorder, or condition treatable by inhibiting the interaction between Cav3.2 T-type calcium channel (Cav3.2) and ubiquitin-specific peptidase 5 (USP5), an effective amount is, for example, an amount that inhibits the interaction between Cav3.2 T-type calcium channel (Cav3.2) and ubiquitin-specific peptidase 5 (USP5) compared to the inhibition without administration of the compound. An effective amount may vary depending on factors such as the disease state, age, sex, and / or weight of the subject. The amount of a given compound that corresponds to such an amount will vary depending on various factors, such as the given drug or compound, pharmaceutical formulation, route of administration, type of disease, disorder, or condition, identity of the subject being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. An effective amount is an amount that results in an improvement or reduction in symptoms of any disease after treatment therewith. Where the condition is pain, an amount that is effective can, for example, cause a decrease in the sensation and / or duration of pain.

[0105] As used herein, the phrase "inhibition of the interaction between Cav3.2 T-type calcium channel (Cav3.2) and ubiquitin-specific peptidase 5 (USP5)" or "inhibition of the interaction between Cav3.2 and USP5" refers to inhibiting, blocking, and / or disrupting the interaction between a therapeutically relevant binding partner, such as USP5, and a Cav3.2 binding domain in a cell, said inhibition, blocking, and / or disruption causing a therapeutic effect in the cell.

[0106] As used herein, the phrase "inhibition of Cav3.2 deubiquitination" refers to inhibiting, blocking, and / or preventing the removal of ubiquitin from ubiquitin-bound Cav3.2. Inhibiting, blocking, and / or preventing the removal of ubiquitin causes a therapeutic effect in cells.

[0107] By "inhibition, blocking and / or interference" is intended any detectable inhibition, blocking and / or interference of a given activity or function in the presence of a compound compared to other conditions being the same except for the absence of the compound.

[0108] As used herein, the term "Cav3.2" is an isoform of a T-type calcium channel that contributes to the propagation and transmission of nociceptive information in afferent pain pathways.

[0109] As used herein, the term "USP5" or "ubiquitin-specific peptidase 5" refers to a deubiquitinating enzyme responsible for removing the ubiquitin group from ubiquitin-conjugated proteins.

[0110] As used herein, the term "administered" means administering to a cell, tissue, organ, or subject a therapeutically effective amount of a compound or composition of the present application.

[0111] As used herein, the term "drug" is intended to refer to any chemical compound or mixture of compounds capable of exerting a useful pharmacological effect.

[0112] When drawn perpendicularly across the bond

[0113] [ka]

[0114] indicates the point of covalent attachment of a chemical group.

[0115] II. Compounds of the Present Application The present applicants have identified a family of compounds that inhibit and / or block Cav3.2 T-type calcium channel (Cav3.2) function and / or expression levels by inhibiting, blocking and / or disrupting the interaction between Cav3.2 and ubiquitin-specific peptidase 5 (USP5).

[0116] Thus, the present application is a compound of formula (I).

[0117] [ka]

[0118] In the formula (I), X is selected from C, O, N, NH, S, S(O), and SO;

[0119] [ka]

[0120] is a single or double bond, provided that when X is C or N,

[0121] [ka]

[0122] is a double bond; A is phenyl and C 5~6 heteroaryl; R 1 is R 5 , OR 5 and NR 5 R 6 Selected from; R 2 H, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 heteroaryl, the latter ten groups being selected from OH, halo, CN, C 1~6Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 3 H, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R 2 and R 3 together with the atoms between them, N, NH, N(C 1-6 alkyl), O, S, S(O), and SO2, and may contain one or two hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1-6 Alkyl and C 1-6 forming a 3- to 7-membered saturated or unsaturated ring optionally substituted by 1 to 4 substituents selected from haloalkyl; Each R 4 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OH, NH2, SH, SC 1~6 Alkyl, SC 1~6 Haloalkyl, OC 1~6 Alkyl, OC 1~6 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)H, C(O)C 1~6 Alkyl, C(O)C 1~6 Haloalkyl, CO2H, C(O)2C 1~6 Alkyl, C(O)C 1~6 Haloalkyl, CONH2, CONHC 1~6 Alkyl and CON(C 1~6 Alkyl)(C 1~6 alkyl); R 5 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylene R 7 and C 1~6Haloalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), CONH2, CONH(C 1~6 alkyl), CON(C 1~6 Alkyl)(C 1~6 alkyl), SO2NH2, SO2NH(C 1~6 alkyl) and SO2N(C 1~6 Alkyl)(C 1~6 alkyl); R 6 is H, C 1~6 Alkyl and C 1~6 haloalkyl; or R 5 and R 6 together with the nitrogen atom between them, N, NR 8’ , O, S, S(O), and SO2, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R9 , C 1~6 Alkylene NR 8 R 9 , C 1~6 Alkylene OR 8 , C 1~6 Alkylene CO2R 8 , and C 1~6 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene forms a 3- to 12-membered heterocycloalkyl or heteroaryl ring optionally substituted by 1 to 4 substituents selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 7 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~10 Alkyl, OC 1~10 Haloalkyl, SC 1~10 Alkyl, SC 1~10 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6alkyl), C(O)C 1~6 Alkyl, CO2C 1~6 Alkyl, C(O)NHC 1~6 Alkyl, C(O)N(C 1~6 Alkyl)(C 1~6 alkyl), PO(OC 1~6 alkyl)(OC 1~6 alkyl), SO2C 1~6 Alkyl, SO2NH(C 1~6 alkyl), SO2N(C 1~6 Alkyl)(C 1~6 alkyl), NC 1~10 Alkyl SO2(C 1~6 alkyl), and NHSO2(C 1~6 alkyl); R 8 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylene R 10 and C 1~6 Haloalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 8’ are H, SO2NH2, SO2NH(C 1~6 alkyl), SO2N(C 1~6Alkyl)(C 1~6 alkyl), C(O)NH2, C(O)NH(C 1~6 alkyl), C(O)N(C 1~6 Alkyl)(C 1~6 alkyl), C 1~6 Haloalkyl, C 1~6 Alkylene R 10 and C 1~6 Haloalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 9 is H, C 1~6 Alkyl and C 1~6 haloalkyl; R 10 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~10 Alkyl, OC 1~10 Haloalkyl, SC 1~10 Alkyl, SC 1~10 Haloalkyl, NH(C 1~6 alkyl), N(C1~6 Alkyl)(C 1~6 alkyl), C(O)C 1~6 Alkyl, CO2C 1~6 Alkyl, C(O)NHC 1~6 Alkyl, C(O)N(C 1~6 Alkyl)(C 1~6 alkyl), PO(OC 1~6 alkyl)(OC 1~6 alkyl), SO2C 1~6 Alkyl, SO2NH(C 1~6 alkyl), SO2N(C 1~6 Alkyl)(C 1~6 alkyl), NC 1~10 Alkyl SO2(C 1~6 alkyl), and NHSO2(C 1~6 alkyl); and n is selected from 0, 1, 2, 3, and 4; The present invention includes the compound, or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0123] The present application provides a compound of formula (I):

[0124] [ka]

[0125] In the formula (I), X is selected from C, O, N, NH, S, S(O), and SO;

[0126] [ka]

[0127] is a single or double bond, provided that when X is C or N,

[0128] [ka]

[0129] is a double bond; A is phenyl and C 5~6 heteroaryl; R 1 is R 5 , OR 5 and NR 5 R 6 Selected from; R 2 H, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 heteroaryl, the latter ten groups being selected from OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 3 H, halo, C 1~6 Alkyl and C 1~6 haloalkyl; or R 2 and R 3 may optionally be N, NH, N(C 1-6 alkyl), O, S, S(O), and SO2, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1-6 Alkyl and C 1-6 forming a 3- to 7-membered saturated or unsaturated ring optionally substituted by 1 to 4 substituents selected from haloalkyl; Each R 4 Ha, Halo, C 1~6 Alkyl, C1~6 Haloalkyl, OH, NH2, SH, SC 1~6 Alkyl, SC 1~6 Haloalkyl, OC 1~6 Alkyl, OC 1~6 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)H, C(O)C 1~6 Alkyl, C(O)C 1~6 Haloalkyl, CO2H, C(O)2C 1~6 Alkyl, C(O)C 1~6 Haloalkyl, CONH2, CONHC 1~6 Alkyl and CON(C 1~6 Alkyl)(C 1~6 alkyl); R 5 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylene R 7 and C 1~6 Haloalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 6 is H, C 1~6Alkyl and C 1~6 haloalkyl; or R 5 and R 6 together with the nitrogen atom between them, N, NR 8’ , O, S, S(O), and SO2, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~6 Alkylene NR 8 R 9 , C 1~6 Alkylene OR 8 , C 1~6 Alkylene CO2R 8 , and C 1~6 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene forms a 3- to 12-membered heterocycloalkyl or heteroaryl ring optionally substituted by 1 to 4 substituents selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C 1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 7 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~10 Alkyl, OC 1~10 Haloalkyl, SC 1~10 Alkyl, SC 1~10 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)C 1~6 Alkyl, CO2C 1~6 Alkyl, C(O)NHC 1~6 Alkyl, C(O)N(C 1~6 Alkyl)(C 1~6 alkyl), PO(OC 1~6 alkyl)(OC 1~6 alkyl), SO2C 1~6 Alkyl, SO2NH(C 1~6 alkyl), SO2N(C 1~6 Alkyl)(C 1~6 alkyl), NC 1~10 Alkyl SO2(C 1~6 alkyl), and NHSO2(C 1~6 alkyl); R 8 is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylene R 10 and C 1~6 Haloalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~6 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylenephenyl, and C1~6 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, NH2, NH(C 1~6 alkyl) and N(C 1~6 Alkyl)(C 1~6 alkyl); R 9 is H, C 1~6 Alkyl and C 1~6 haloalkyl; R 10 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~10 Alkyl, OC 1~10 Haloalkyl, SC 1~10 Alkyl, SC 1~10 Haloalkyl, NH(C 1~6 alkyl), N(C 1~6 Alkyl)(C 1~6 alkyl), C(O)C 1~6 Alkyl, CO2C 1~6 Alkyl, C(O)NHC 1~6 Alkyl, C(O)N(C 1~6 Alkyl)(C 1~6 alkyl), PO(OC 1~6 alkyl)(OC 1~6 alkyl), SO2C 1~6 Alkyl, SO2NH(C 1~6 alkyl), SO2N(C 1~6 Alkyl)(C 1~6 alkyl), NC 1~10 Alkyl SO2(C 1~6 alkyl), and NHSO2(C 1~6 alkyl); and n is selected from 0, 1, 2, 3, and 4; The present invention also includes the compound or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0130] In some embodiments, the substituents in the compound of formula I are

[0131] [ka]

[0132] is attached at the C5 or C6 position of the tetrahydroquinoline core.

[0133] [ka]

[0134] is attached at the C6 or C7 position of the tetrahydroquinoline core.

[0135] [ka]

[0136] is attached at the C7 or C8 position of the tetrahydroquinoline core.

[0137] [ka]

[0138] is attached at C6 of the tetrahydroquinoline core.

[0139] In some embodiments, the substituents in the compound of formula I are

[0140] [ka]

[0141] is attached at the C5 or C6 position of the tetrahydroquinoline core structure, and optionally at the C8 or C9 position of the tricyclic core structure of the compound of Formula I. In some embodiments, the substituents in the compound of Formula I

[0142] [ka]

[0143] is attached at the C7 or C8 position of the tetrahydroquinoline core structure, and optionally at the C6 or C7 position of the tricyclic core structure of the compound of Formula I. In some embodiments, the substituents in the compound of Formula I

[0144] [ka]

[0145] is attached at the C6 position of the tetrahydroquinoline core structure and, optionally, at the C8 position of the tricyclic core structure of the compound of Formula I.

[0146] In some embodiments, the substituents in the compound of formula I are

[0147] [ka]

[0148] is attached at the C6 position of the tetrahydroquinoline core, and the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is a compound of formula IA or a pharmaceutically acceptable salt and / or solvate thereof.

[0149] [ka]

[0150] In the formula, A, X, R1 , R 2 , R 3 , R 4 and n is as defined in Formula I.

[0151] In some embodiments,

[0152] [ka]

[0153] is a single bond and X is selected from O, NH, S, S(O), and SO. In some embodiments,

[0154] [ka]

[0155] is a single bond and X is selected from S, S(O), and SO. In some embodiments,

[0156] [ka]

[0157] is a single bond and X is selected from O and NH. In some embodiments,

[0158] [ka]

[0159] is a single bond and X is O.

[0160] Thus, in some embodiments,

[0161] [ka]

[0162] is a single bond, X is O, and the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is a compound of formula IB or a pharmaceutically acceptable salt and / or solvate thereof.

[0163] [ka]

[0164] In the formula, A, R 1 , R 2 , R 3 , R 4 and n is as defined in Formula I.

[0165] In some embodiments, A is phenyl. Thus, in some embodiments, the compound of formula I, or a pharmaceutically acceptable salt and / or solvate thereof, is a compound of formula IC, or a pharmaceutically acceptable salt and / or solvate thereof:

[0166] [ka]

[0167] In the formula, X, R 1 , R 2 , R 3 , R 4 and n is as defined in Formula I.

[0168] In some embodiments,

[0169] [ka]

[0170] is a double bond and X is N or C. In some embodiments,

[0171] [ka]

[0172] is a double bond and X is N. In some embodiments,

[0173] [ka]

[0174] is a double bond and X is C.

[0175] In some embodiments,

[0176] [ka]

[0177] is a single bond, X is O, A is phenyl, and the compound of formula I or a pharmaceutically acceptable salt and / or solvate thereof is a compound of formula ID or a pharmaceutically acceptable salt and / or solvate thereof.

[0178] [ka]

[0179] In the formula, R 1 , R 2 , R 3 , R 4 and n is as defined in Formula I.

[0180] In some embodiments, A is C 5~6 In some embodiments, the C in A is heteroaryl. 5~6 Heteroaryl is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and triazinyl. 5~6Heteroaryl is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and triazinyl. 5~6 Heteroaryl is selected from pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, thiophenyl, pyridinyl, pyrimidinyl, and pyrazinyl. 5~6 Heteroaryl is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridinyl and pyrimidinyl.

[0181] In some embodiments, R 4 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OH, NH2, OH, SH, SC 1~4 Alkyl, SC 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 Haloalkyl, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)H, C(O)C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, CO2H, C(O)2C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, CONH2, CONHC 1~4 Alkyl and CON(C 1~4 Alkyl)(C 1~4 In some embodiments, R 4 are F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, OH, NH2, OH, SH, SC 1~4 Alkyl, SC 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 Haloalkyl, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4alkyl), C(O)H, C(O)C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, CO2H, C(O)2C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, CONH2, CONHC 1~4 Alkyl and CON(C 1~4 Alkyl)(C 1~4 alkyl).

[0182] In some embodiments, R 4 are F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, OH, NH2, SH, SC 1~4 Alkyl, SC 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 Haloalkyl, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)H, C(O)C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, CO2H, C(O)2C 1~4 Alkyl, C(O)C 1~4 Haloalkyl, CONH2, CONHC 1~4 Alkyl and CON(C 1~4 Alkyl)(C 1~4 In some embodiments, R 4 are F, Cl, C 1~4 Alkyl, C 1~2 Haloalkyl, OH, NH2, SH, SC 1~2 Alkyl, SC 1~2 Haloalkyl, OC 1~2 Alkyl, OC 1~2 Haloalkyl, NH(C 1~2 alkyl), N(C 1~2 Alkyl)(C 1~2 alkyl), C(O)H, C(O)C 1~2 Alkyl, C(O)C 1~2 Haloalkyl, CO2H, C(O)2C 1~2 Alkyl, C(O)C 1~2Haloalkyl, CONH2, CONHC 1~2 Alkyl and CON(C 1~2 Alkyl)(C 1~2 In some embodiments, R 4 are F, Cl, C 1~2 Alkyl, C 1~2 Fluoroalkyl, C 1~2 Chloroalkyl, OH, NH2, SH, SC 1~2 Alkyl, SC 1~2 Fluoroalkyl, SC 1~2 Chloroalkyl, OC 1~2 Alkyl, OC 1~2 Fluoroalkyl, OC 1~2 Chloroalkyl, NH(C 1~2 alkyl), N(C 1~2 Alkyl)(C 1~2 alkyl), C(O)H, C(O)C 1~2 Alkyl, C(O)C 1~2 Haloalkyl, CO2H, C(O)2C 1~2 Alkyl, C(O)C 1~2 Haloalkyl, CONH2, CONHC 1~2 Alkyl and CON(C 1~2 Alkyl)(C 1~2 In some embodiments, R 4 are F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, OC 1~2 Alkyl, OC 1~2 Fluoroalkyl and OC 1~2 In some embodiments, R 4is selected from F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CH2CClH2, CCl2H, CClH2, CH2CCl2H, CH2CCl3, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OCH(CH3)CH2CH3, OCH(CH3)3, OCF3, OCFH2, OCHF2, OCH2CF2H, OCH2CF3, OCH2CFH2, OCCl3, OCH2CClH2, OCCl2H, OCClH2, OCH2CCl2H, and OCH2CCl3. In some embodiments, R 4 is selected from F, Cl, CH3, CF3, CFH2, CHF2, CCl3, CH3, OCF3, OCFH2, OCHF2, and OCCl3. In some embodiments, R 4 is selected from F, Cl, CH3, and OCH3. In some embodiments, R 4 are F, Cl, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 In some embodiments, R 4 is selected from F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CH2CClH2, CCl2H, CClH2, CH2CCl2H, and CH2CCl3. In some embodiments, R 4 is selected from F, Cl, CH, CF, CFH, CHF, and CCl. In some embodiments, R 4 is selected from F, Cl and CH3.

[0183] In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 1 and 2. In some embodiments, n is 2. In some embodiments, n is 1. In some embodiments, n is 2 and each R 4is in the meta position relative to the point of attachment of A in the structure of the compound of Formula I. In some embodiments, n is 1 and R 4 is in the meta or para position relative to the point of attachment of A in the structure of the compound of Formula I. In some embodiments, n is 1 and R 4 is meta to the point of attachment of A in the structure of the compound of formula I.

[0184] In some embodiments, the group in the compound of formula I

[0185] [ka]

[0186] is selected from the following:

[0187] [ka]

[0188] [ka]

[0189] In some embodiments, R 2 H, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~7 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 heteroaryl, the latter eight groups being selected from OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4Alkyl)(C 1~4 In some embodiments, R 2 are H, F, Cl, Br, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 heteroaryl, the latter eight groups being selected from OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 2 are H, F, Cl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 heteroaryl, the latter eight groups being selected from OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0190] In some embodiments, R 2 C in 3~6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R 2 C in 3~6 Cycloalkyl is selected from cyclopropyl and cyclobutyl.

[0191] In some embodiments, R 2 C in 3~10 Heterocycloalkyl includes aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, dioxiranyl, azetidinyl, oxetanyl, 1,3-dioxolanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, isoxthiolidinyl, thiazole, thiazolidinyl ... In some embodiments, R is selected from azolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, dioxanyl, dithianyl, tetrahydrofuryl, azepanyl, oxepanyl, thiepanyl, diazepanyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. 2 C in 3~7 Heterocycloalkyl is selected from aziridinyl, oxiranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.

[0192] In some embodiments, R 2 C in 5~10Heteroaryl is selected from furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl and quinazolinyl.

[0193] In some embodiments, R 2 H, halo, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 3~6 Cycloalkyl, C 3~7 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 heteroaryl, the latter eight groups being selected from OH, F, Cl, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0194] In some embodiments, R 2 H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, R 2 are H, F, Cl, Br, and C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R 2is selected from H, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CH2CClH2, CCl2H, CClH2, CH2CCl2H, and CH2CCl3. In some embodiments, R 2 is selected from H, F, Cl, CH, CF, CFH, CHF, CCl, CClH, and CClH. 2 is selected from H, F, CH3, and CF3. In some embodiments, R 2 is H.

[0195] In some embodiments, R 3 H, halo, C 1~4 Alkyl and C 1~4 In some embodiments, R is selected from haloalkyl. 3 are H, F, Cl, Br, and C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R 3 is selected from H, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CH2CClH2, CCl2H, CClH2, CH2CCl2H, and CH2CCl3. In some embodiments, R 3 is selected from H, F, Cl, CH, CF, CFH, CHF, CCl, CClH, and CClH. 3 is selected from H, F, CH3, and CF3. In some embodiments, R 3 is H.

[0196] In some embodiments, R 2 and R 3 are both H. In some embodiments, R 2 and R3 are both H, and the compound of formula I, or a pharmaceutically acceptable salt and / or solvate thereof, is a compound of formula IE, IE(i), IE(ii) or IE(iii), or a pharmaceutically acceptable salt and / or solvate thereof:

[0197] [ka]

[0198] In the formula, R 1 , and R 4 and n is as defined in Formula I. In some embodiments, R 2 and R 3 together with the atoms between them, N, NH, N(C 1~4 alkyl), O, S, S(O), and SO2, and may contain one or two hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 and chloroalkyl, forming a 3- to 7-membered saturated or unsaturated ring which may be substituted by 1 to 4 substituents selected from chloroalkyl.

[0199] In some embodiments, R 2 and R 3 are combined with the atoms between them to form OH, F, Cl, CN, NO2, CHO, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, the 3- to 6-membered saturated or unsaturated ring is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, the 3- to 6-membered saturated or unsaturated ring is selected from cyclopropyl and cyclobutyl. Thus, in some embodiments, R 2 and R 3 are combined with the atoms between them to form OH, F, Cl, CN, NO2, CHO, C1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 It forms a cyclopropyl, cyclobutyl or cyclopentyl ring which may be substituted by 1 to 2 substituents selected from chloroalkyl.

[0200] In some embodiments, R 2 and R 3 together with the atoms between them, N, NH, N(C 1~4 alkyl), O, S, S(O), and SO2, and one or two hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 and chloroalkyl. In some embodiments, the 3- to 7-membered saturated or unsaturated ring containing one or two hetero moieties is selected from aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, azetidinyl, oxetanyl, theitanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, piperidinyl, tetrahydropyranyl, azepanyl, oxepanyl, and thiepanyl. In some embodiments, the 3- to 7-membered saturated or unsaturated ring containing one or two additional hetero moieties is selected from aziridinyl, oxiranyl, azetidinyl, and oxetanyl.

[0201] In some embodiments, R 1 is R 5 In some embodiments, R 1 is OR 5 In some embodiments, R 1 is NR 5 R 6 is.

[0202] In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkylene R7 and C 1~4 Haloalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)NH2, C(O)NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), SO2NH2, SO2NH(C 1~4 alkyl) and SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene R 7 , C 1~4 Fluoroalkylene R 7 and C 1~4 Chloroalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)NH2, C(O)NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), SO2NH2, SO2NH(C 1~4 alkyl) and SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene R 7 , and C 1~4 Fluoroalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)NH2, C(O)NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), SO2NH2, SO2NH(C 1~4 alkyl) and SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene R 7 , and C 1~4 Fluoroalkylene R 7 is selected from.

[0203] In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkylene R 7 and C 1~4 Haloalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene R 7 , C 1~4 Fluoroalkylene R 7 and C 1~4 Chloroalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene R 7 and C 1~4 Fluoroalkylene R 7 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0204] In some embodiments, R 7 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~4 Alkyl, OC 1~4 Haloalkyl, SC 1~4 Alkyl, SC 1~4 Haloalkyl, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)C 1~4 Alkyl, CO2C 1~4 Alkyl, C(O)NHC 1~4 Alkyl, C(O)N(C 1~4 Alkyl)(C 1~4 alkyl), PO(OC 1~4 alkyl)(OC 1~4 alkyl), SO2C 1~4 Alkyl, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), NC 1~4 Alkyl SO2(C 1~4 alkyl) and NHSO2(C1~4 In some embodiments, R 7 is OH, CHO, SH, NH2, CO2H, PO3H, SO2H, SO2NH2, NHSO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl, SC 1~4 Alkyl, SC 1~4 Haloalkyl, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)C 1~4 Alkyl, CO2C 1~4 Alkyl, C(O)NHC 1~4 Alkyl and C(O)N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 7 is OH, CHO, SH, NH2, CO2H, PO3H, SO2H, NHSO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl, SC 1~4 Alkyl, SC 1~4 Haloalkyl, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)C 1~4 Alkyl, CO2C 1~4 Alkyl, C(O)NHC 1~4 Alkyl and C(O)N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 7 is OH, CO2H, PO3H, SO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl, CO2C 1~4 Alkyl, SO2NH2, SO2NH(C 1~4 alkyl) and SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 7is OH, CO2H, PO3H, SO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl and CO2C 1~4 In some embodiments, R 7 are OH, CO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl and CO2C 1~4 In some embodiments, R 7 is OH, CO2H, PO3H, SO2H, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, OC 1~4 Chloroalkyl and CO2C 1~4 In some embodiments, R 7 are OH, CO2H, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, OC 1~4 Chloroalkyl and CO2C 1~4 In some embodiments, R 7 are OH, CO2H, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, CO2C 1~4 Alkyl, SO2NH2, SO2NH(C 1~4 alkyl) and SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 7 are OH, CO2H, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl and CO2C 1~4 alkyl.

[0205] In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C1~4 Alkylene CO2C 1~4 Alkyl, and C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)NH2, C(O)NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), SO2NH2, SO2NH(C 1~4 alkyl) and SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl, C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0206] In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 chloroalkyl, each alkyl being selected from OH, C 3~6 Cycloalkyl, C 4~6 Heterocycloalkyl, phenyl, C 5~6 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C4~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 chloroalkyl, each alkyl being selected from OH, C 3~6 Cycloalkyl, C 1~4 Alkylene C 4~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6 and the four groups may be substituted by one or two substituents selected from OH, F, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0207] In some embodiments, R 5 is H, C 1~4 Alkyl and C 1~4 fluoroalkyl, each alkyl being selected from OH, OH, F, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C1~4 C optionally substituted by 1 to 4 substituents selected from alkyl 1~4 In some embodiments, R 5 is C 1~4 Alkyl and C 1~4 fluoroalkyl, each alkyl being selected from OH and C 1~4 In some embodiments, R 5 is C 1~4 Alkyl and C 1~4 fluoroalkyl.

[0208] In some embodiments, R 5 is H.

[0209] In some embodiments, R 5 is C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene CO2C 1~4 Alkyl, C 1~4 Alkylene SO2NH2, C 1~4 AlkyleneSO2NH(C 1~4 alkyl) and C 1~4 Alkylene SO2N(C 1~4 Alkyl)(C 1~4 alkyl), and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene CO2C 1~4 Alkyl, C 1~4 Alkylene SO2NH2, C 1~4 AlkyleneSO2NH(C 1~4 alkyl) and C 1~4 Alkylene SO2N(C 1~4 Alkyl)(C 1~4 alkyl), and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10In some embodiments, R 5 is C 1~3 Alkylene OH, C 1~3 Alkylene COH, C 1~3 Alkylene OC 1~3 Alkyl, C 1~3 Alkylene CO2C 1~3 Alkyl, C 1~3 Fluoroalkylene OH, C 1~3 Fluoroalkylene COH,C 1~3 Fluoroalkylene OC 1~3 Alkyl, C 1~3 Fluoroalkylene CO2C 1~3 Alkyl, C 1~4 Alkylene SO2NH2, C 1~4 AlkyleneSO2NH(C 1~4 alkyl) and C 1~4 Alkylene SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is C 1~3 Alkylene OH, C 1~3 Alkylene COH, C 1~3 Alkylene OC 1~3 Alkyl, C 1~3 Alkylene CO2C 1~3 Alkyl, C 1~3 Fluoroalkylene OH, C 1~3 Fluoroalkylene COH,C 1~3 Fluoroalkylene OC 1~3 Alkyl, and C 1~3 Fluoroalkylene CO2C 1~3 In some embodiments, R 5 is C 1~3 Alkylene OH, C 1~3 Alkylene COH, C 1~3 Alkylene OC 1~3 Alkyl and C 1~3 Alkylene CO2C 1~3 alkyl.

[0210] In some embodiments, R5 is C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl, C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 5 is C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 It may be substituted with one or two substituents selected from heteroaryl.

[0211] In some embodiments, R 5 is C 2~3 Alkylene OH, C 2~3 Alkylene COH, C 2~3 Alkylene OC 1~3 Alkyl, C 2~3 Alkylene OC 1~3 Fluoroalkyl, C 2~3 Alkylene CO2C 1~3 Alkyl, C 2~3 Fluoroalkylene OH, C 2~3 Fluoroalkylene COH,C 2~3 Fluoroalkylene OC 1~3 Alkyl, C 2~3 Fluoroalkylene OC 1~3 Fluoroalkyl and C 2~3 Fluoroalkylene CO2C 1~3 In some embodiments, R 5 is C 1~3 Alkylene OH, C 1~3Alkylene COH, C 1~3 Alkylene OC 1~3 Alkyl, C 1~3 Alkylene CO2C 1~3 Alkyl, C 1~3 Fluoroalkylene OH, C 1~3 Fluoroalkylene COH,C 1~3 Fluoroalkylene OC 1~3 Alkyl, and C 1~3 Fluoroalkylene CO2C 1~3 In some embodiments, R 5 is C 1~3 Alkylene OH, C 1~3 Alkylene COH, C 1~3 Alkylene OC 1~3 Alkyl, C 1~3 Alkylene CO2C 1~3 alkyl.

[0212] In some embodiments, R 1 OR 5 If R 5 is H and R 1 is OH.

[0213] In some embodiments, R 1 OR 5 If R 5 is H, C 1~4 Alkyl and C 1~4 fluoroalkyl, each alkyl being selected from OH, OH, F, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 C optionally substituted by 1 to 4 substituents selected from alkyl 1~4 In some embodiments, R 1 OR 5 If R 5 is C 1~4Alkyl and C 1~4 fluoroalkyl, each alkyl being selected from OH and C 1~4 In some embodiments, R 1 OR 5 If R 5 is C 1~4 Alkyl and C 1~4 fluoroalkyl.

[0214] In some embodiments, R 1 NR 5 R 6 If R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl, C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 1 NR 5 R 6 If R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0215] In some embodiments, R 1 NR 5 R 6 If R 5 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 chloroalkyl, each alkyl being selected from OH, C 3~6 Cycloalkyl, C 4~6 Heterocycloalkyl, phenyl, C 5~6 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 4~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 1 is NHR 6 , N.R. 6 C 1~4 Alkyl and N(R 6 )C 1~4 fluoroalkyl, each alkyl being selected from OH, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 4~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6and heteroaryl, the latter four groups being OH, F, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0216] In some embodiments, R 1 is NHR 6 is.

[0217] In some embodiments, R 1 is N(R 6 )C 1~4 Alkyl and N(R 6 )C 1~4 fluoroalkyl, each alkyl being selected from OH, OH, F, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 C optionally substituted by 1 to 4 substituents selected from alkyl 1~4 In some embodiments, R 1 is NR 6 C 1~4 Alkyl and N(R 6 )C 1~4 fluoroalkyl, each alkyl being selected from OH and C 1~4 In some embodiments, R 1 is N(R 6 )C 1~4 Alkyl and N(R 6 )C 1~4 fluoroalkyl.

[0218] In some embodiments, R1 NR 5 R 6 If R 5 is C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~6 In some embodiments, R 1 is N(R 6 )C 1~4 Alkylene OH, N(R 6 )C 1~4 Alkylene COH, N(R6 )C 1~4 Alkylene OC 1~4 Alkyl, N(R 6 )C 1~4 Alkylene OC 1~4 Fluoroalkyl, N(R 6 )C 1~4 Alkylene CO2C 1~4 Alkyl, N(R 6 )C 1~4 Fluoroalkylene OH, N(R 6 )C 1~4 FluoroalkyleneCOH,N(R 6 )C 1~4 Fluoroalkylene OC 1~4 Alkyl, N(R 6 )C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and N(R 6 )C 1~4 Fluoroalkylene CO2C 1~4 In some embodiments, R 1 is N(R 6 )C 1~4 Alkylene OH, N(R 6 )C 1~4 Alkylene COH, N(R 6 )C 1~4 Alkylene OC 1~4 Alkyl, N(R 6 )C 1~4 Alkylene CO2C 1~4 Alkyl, N(R 6 )C 1~4 Fluoroalkylene OH, N(R 6 )C 1~4 FluoroalkyleneCOH,N(R 6 )C 1~4 Fluoroalkylene OC 1~4 Alkyl, and N(R 6 )C 1~4 Fluoroalkylene CO2C 1~4 In some embodiments, R 1 is N(R 6 )C 2~4 Alkylene OH, N(R 6 )C 2~4Alkylene COH, N(R 6 )C 2~4 Alkylene OC 1~4 Alkyl, N(R 6 )C 2~4 Alkylene CO2C 1~4 Alkyl, N(R 6 )C 2~4 Fluoroalkylene OH, N(R 6 )C 2~4 FluoroalkyleneCOH,N(R 6 )C 2~4 Fluoroalkylene OC 1~4 Alkyl and N(R 6 )C 2~4 Fluoroalkylene CO2C 1~4 In some embodiments, R 1 is N(R 6 )C3 alkylene OH, N(R 6 )C3 alkylene CO2H and N(R 6 )C3 alkylene CO2C 1~3 In some embodiments, R 1 is N(R 6 )C 1~4 Alkylene OH, N(R 6 )C 1~4 Alkylene COH, N(R 6 )C 1~4 Alkylene OC 1~4 Alkyl, N(R 6 )C 2~4 Alkylene CO2C 1~4 alkyl.

[0219] In some embodiments, R 6 is H, C 1~4 Alkyl and C 1~4 In some embodiments, R is selected from haloalkyl. 6 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R 6is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CH2CClH2, CCl2H, CClH2, CH2CCl2H, and CH2CCl3. In some embodiments, R 6 is selected from H, CH, CF, CFH, CHF, CCl, CClH, and CClH. In some embodiments, R 6 is selected from H, CH, and CF. In some embodiments, R 6 is H.

[0220] In some embodiments, R 1 is N(R 6 )C 1~4 Alkylene OH, N(R 6 )C 1~4 Alkylene COH, N(R 6 )C 1~4 Alkylene OC 1~4 Alkyl, N(R 6 )C 2~4 Alkylene CO2C 1~4 Alkyl, N(R 6 )C 2~4 Fluoroalkylene OH, N(R 6 )C 2~4 FluoroalkyleneCOH,N(R 6 )C 2~4 Fluoroalkylene OC 1~4 Alkyl and N(R 6 )C 2~4 Fluoroalkylene CO2C 1~4 alkyl, X is O, A is phenyl, and R 4 is selected from F, Cl, CH3, and OCH3. In some embodiments, R 1 is N(R 6 )C 1~4 Alkylene OH and N(R 6 )C 1~4 Alkylene CO2C 1~4 alkyl, X is O, A is phenyl, and R 4is selected from F, Cl, CH3, and OCH3. In some embodiments, R 1 is N(R 6 )C 2~4 Alkylene OH, N(R 6 )C 2~4 Alkylene COH, N(R 6 )C 2~4 Alkylene OC 1~4 Alkyl, N(R 6 )C 1~4 Alkylene OC 2~4 Fluoroalkyl, N(R 6 )C 2~4 Alkylene CO2C 1~4 Alkyl, N(R 6 )C 2~4 Fluoroalkylene OH, N(R 6 )C 2~4 FluoroalkyleneCOH,N(R 6 )C 2~4 Fluoroalkylene OC 1~4 Alkyl, N(R 6 )C 2~4 Fluoroalkylene OC 1~4 Fluoroalkyl and N(R 6 )C 2~4 Fluoroalkylene CO2C 1~4 alkyl, X is O, A is phenyl, and R 4 is selected from F, Cl, and CH. In some embodiments, R 1 is N(R 6 )C 2~4 Alkylene OH and N(R 6 )C 2~4 Alkylene CO2C 1~4 alkyl, X is O, A is phenyl, and R 4 is selected from F, Cl and CH3.

[0221] In some embodiments, R 1 is OH, A is phenyl, and R 4 is selected from F, Cl, and CH. In some embodiments, R 1 is OH, A is phenyl, and R 4is selected from F, Cl, CH3 and OCH3.

[0222] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8 , O, S, S(O), and SO2, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 AlkyleneNCO2R 8 , and C 1~4 AlkyleneC(O)R 8 R 9 and forming a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally substituted by 1 to 4 substituents selected from

[0223] Each alkyl and alkylene is OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C1~4 alkyl).

[0224] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8’ , O, S, S(O), and SO2, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO2, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 AlkyleneNCO2R 8 , and C 1~4 AlkyleneC(O)R 8 R 9 and each alkyl and alkylene forms a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally substituted by 1 to 4 substituents selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C1~4 Alkyl)(C 1~4 alkyl).

[0225] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8 and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 , and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene forms a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally substituted by one or two substituents selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C1~4 alkyl).

[0226] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene forms a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally substituted by one or two substituents selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4Alkyl)(C 1~4 alkyl).

[0227] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8 and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 , and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4alkyl).

[0228] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4alkyl).

[0229] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8 and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl, C 1~4 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 , and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0230] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl, C 1~4 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0231] In some embodiments, the 8- to 10-membered heterocycloalkyl ring is chosen from indolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.

[0232] In some embodiments, the 8- to 10-membered heterocycloalkyl ring is selected from the group consisting of OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl, C 1~4 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 , and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene may be substituted by one substituent selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4In some embodiments, the 8- to 10-membered heterocycloalkyl ring is optionally substituted with 1 to 4 substituents selected from OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl and C 1~4 It may be substituted by one substituent selected from haloalkyl.

[0233] In some embodiments, the 8- to 10-membered heterocycloalkyl ring is unsubstituted.

[0234] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8 and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl, C 1~4 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 , and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0235] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl, C 1~4 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 and C 1~4 AlkyleneC(O)NR 8 R 9 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0236] In some embodiments, the 5- to 6-membered heterocycloalkyl ring is selected from pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, piperidinyl, and piperazinyl. In some embodiments, the 5- to 6-membered heterocycloalkyl ring is selected from pyrrolidinyl and piperidinyl.

[0237] In some embodiments, R 5 and R 6 together with the nitrogen atom between them to form one additional NR 8 Contains hetero moieties, OH, F, Cl, CN, NO2, CHO, C 1~4 Alkyl and C 1~4 It forms a 5- to 6-membered heterocycloalkyl ring which may be substituted by 1 or 2 substituents selected from haloalkyl.

[0238] In some embodiments, R 5 and R 6 together with the nitrogen atom between them to form one additional NR 8’ Contains hetero moieties, OH, F, Cl, CN, NO2, CHO, C 1~4 Alkyl and C 1~4 It forms a 5- to 6-membered heterocycloalkyl ring which may be substituted by 1 or 2 substituents selected from haloalkyl.

[0239] In some embodiments, one additional NR 8The 5- to 6-membered heterocycloalkyl ring containing a hetero moiety is selected from pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl and piperazinyl.

[0240] In some embodiments, one additional NR 8’ The 5- to 6-membered heterocycloalkyl ring containing a hetero moiety is selected from pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, and piperazinyl. 5 and R 6 together with the nitrogen atom therebetween, form one additional NR selected from pyrazolidinyl and piperazinyl. 8’ Each of the hetero moieties is OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl and C 1~4 In some embodiments, one additional NR 8 The 5- to 6-membered heterocycloalkyl ring containing the hetero moiety is piperazinyl. 8’ The 5- to 6-membered heterocycloalkyl ring containing a hetero moiety is piperazinyl.

[0241] In some embodiments, one additional NR 8 The 5- to 6-membered heterocycloalkyl ring containing a hetero moiety is OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl and C 1~4 It may be further substituted with one or two substituents selected from haloalkyl.

[0242] In some embodiments, one additional NR 8’ The 5- to 6-membered heterocycloalkyl ring containing a hetero moiety is OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl and C 1~4 It may be further substituted with one or two substituents selected from haloalkyl.

[0243] Thus, in some embodiments, R 5 and R 6 are, together with the nitrogen atom between them, independently OH, F, Cl, CN, NO2, CHO, C 1~4 Alkyl, C 1~4 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 and C 1~4 AlkyleneC(O)NR 8 R 9 Indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, piperidinyl, piperazinyl, optionally substituted by one or two substituents selected from the group consisting of alkyl, C, 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4In some embodiments, R 5 and R 6 together with the nitrogen atom therebetween to form indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, piperidinyl, or piperazinyl, each of which independently represents OH, F, Cl, CN, NO, CHO, or C 1~4 Alkyl and C 1~4 In some embodiments, R 5 and R 6 together with the nitrogen atom therebetween to form tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, piperidinyl, and piperazinyl, each of which independently represents OH, F, Cl, CN, NO, CHO, C 1~4 Alkyl and C 1~4 It may be substituted by one or two substituents selected from haloalkyl.

[0244] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8 and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 , and C 1~4 AlkyleneC(O)NR 8 R 9and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~6 alkyl).

[0245] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~6 Alkyl, C 1~6 Haloalkyl, NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , SO2NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 and C 1~4 AlkyleneC(O)NR 8 R 9and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~6 alkyl).

[0246] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8 and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, C 1~4 Alkyl and C 1~4 In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8 and O, and may contain one or two additional hetero moieties selected from C 1~4 Alkyl and C 1~4 It forms a 5- to 10-membered heteroaryl ring which may be substituted with 1 or 2 substituents selected from haloalkyl.

[0247] In some embodiments, R 5 and R6 together with the nitrogen atom between them, N, NR 8’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, C 1~4 Alkyl and C 1~4 In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8’ and O, and may contain one or two additional hetero moieties selected from C 1~4 Alkyl and C 1~4 It forms a 5- to 10-membered heteroaryl ring which may be substituted with 1 or 2 substituents selected from haloalkyl.

[0248] In some embodiments, the 5- to 10-membered heteroaryl ring is chosen from pyrrole, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, azaindolyl, quinoline, and isoquinoline.

[0249] In some embodiments, R 8’ are H, SO2NH2, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)NH2, C(O)NH(C 1~4 alkyl), C(O)N(C 1~4 Alkyl)(C 1~4 alkyl), C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkylene R 10 and C 1~4 Haloalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 8’ are H, SO2NH2, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)NH2, C(O)NH(C 1~4 alkyl), C(O)N(C 1~4 Alkyl)(C 1~4 alkyl), C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 chloroalkyl, R 10 , C 1~4 Alkylene R 10 , C 1~4 Fluoroalkylene R 10 and C 1~4 Chloroalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0250] In some embodiments, R 8’ are H, SO2NH2, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)NH2, C(O)NH(C 1~4 alkyl), C(O)N(C 1~4 Alkyl)(C 1~4 alkyl), C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 chloroalkyl, C 1~4 Alkylene R 10 and C 1~4 Fluoroalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, C 5~6 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0251] In some embodiments, R 8 is H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkylene R 10 and C 1~4 Haloalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Haloalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 8 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene R 10 , C 1~4 Fluoroalkylene R 10 and C 1~4 Chloroalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 8 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene R 10 and C 1~4 Fluoroalkylene R 10 and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, C 5~6 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0252] In some embodiments, R 10 is OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C 3~6Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~10 Aryl, C 5~10 Heteroaryl, OC 1~4 Alkyl, OC 1~4 Haloalkyl, SC 1~4 Alkyl, SC 1~4 Haloalkyl, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)C 1~4 Alkyl, CO2C 1~4 Alkyl, C(O)NHC 1~4 Alkyl, C(O)N(C 1~4 Alkyl)(C 1~4 alkyl), PO(OC 1~4 alkyl)(OC 1~4 alkyl), SO2C 1~4 Alkyl, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), NC 1~4 Alkyl SO2(C 1~4 alkyl) and NHSO2(C 1~4 In some embodiments, R 10 is OH, CHO, SH, NH2, CO2H, PO3H, SO2H, SO2NH2, NHSO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl, SC 1~4 Alkyl, SC 1~4 Haloalkyl, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)C 1~4 Alkyl, CO2C 1~4 Alkyl, C(O)NHC 1~4 Alkyl and C(O)N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 10are OH, CO2H, PO3H, SO2H, SO2NH2, OC 1~4 Alkyl, OC 1~4 Haloalkyl, CO2C 1~4 Alkyl, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 10 In some embodiments, the haloalkyl in R is selected from fluoroalkyl and chloroalkyl. 10 haloalkyl in R is selected from fluoroalkyl and chloroalkyl; 10 are OH, CO2H, PO3H, SO2H, SO2NH2, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, OC 1~4 Chloroalkyl, CO2C 1~4 Alkyl, SO2NH(C 1~4 alkyl) and SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 10 are OH, CO2H, SO2NH2, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, OC 1~4 Chloroalkyl, CO2C 1~4 Alkyl, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 10 are OH, CO2H, SO2NH2, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, CO2C 1~4 Alkyl, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 10 is OH, CHO, SH, NH2, CO2H, PO3H, SO2H, NHSO2H, OC 1~4 Alkyl, OC 1~4Haloalkyl, SC 1~4 Alkyl, SC 1~4 Haloalkyl, NH(C 1~4 alkyl), N(C 1~4 Alkyl)(C 1~4 alkyl), C(O)C 1~4 Alkyl, CO2C 1~4 Alkyl, C(O)NHC 1~4 Alkyl and C(O)N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 10 is OH, CO2H, PO3H, SO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl and CO2C 1~4 In some embodiments, R 10 are OH, CO2H, OC 1~4 Alkyl, OC 1~4 Haloalkyl and CO2C 1~4 In some embodiments, R 10 In some embodiments, the haloalkyl in R is selected from fluoroalkyl and chloroalkyl. 10 haloalkyl in R is selected from fluoroalkyl and chloroalkyl; 10 is OH, CO2H, PO3H, SO2H, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, OC 1~4 Chloroalkyl and CO2C 1~4 In some embodiments, R 10 are OH, CO2H, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl, OC 1~4 Chloroalkyl and CO2C 1~4 In some embodiments, R 10 are OH, CO2H, OC 1~4 Alkyl, OC 1~4 Fluoroalkyl and CO2C 1~4 alkyl.

[0253] In some embodiments, R 8 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0254] In some embodiments, R 8 is H, C 1~4 Alkyl, C1~4 Fluoroalkyl and C 1~4 chloroalkyl, each alkyl being selected from OH, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, C 5~6 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0255] In some embodiments, R 8 is H, C 1~4 Alkyl and C 1~4 fluoroalkyl, each alkyl being selected from OH, OH, F, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 C optionally substituted by 1 to 4 substituents selected from alkyl 1~4 In some embodiments, R 8 is C 1~4 Alkyl and C 1~4 fluoroalkyl, each alkyl being selected from OH and C 1~4 In some embodiments, R 8 is C1~4 Alkyl and C 1~4 fluoroalkyl.

[0256] In some embodiments, R 8 is H.

[0257] In some embodiments, R 8 is C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 chloroalkyl, each alkyl being selected from OH, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~6 Heteroaryl may be optionally substituted by one or two substituents selected from OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 8 is C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 chloroalkyl, each alkyl being selected from OH and C 1~4 It is substituted by alkylenephenyl.

[0258] In some embodiments, R 8 is C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 chloroalkyl.

[0259] In some embodiments, R 8’ are SO2NH2, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), C 1~4 Alkylene SO2NH2, C1~4 AlkyleneSO2NH(C 1~4 alkyl), C 1~4 Alkylene SO2N(C 1~4 Alkyl)(C 1~4 alkyl), C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, and C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene is selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0260] In some embodiments, R 8’ are SO2NH2, SO2NH(C 1~4 alkyl), SO2N(C 1~4 Alkyl)(C 1~4 alkyl), C 1~4Alkylene SO2NH2, C 1~4 AlkyleneSO2NH(C 1~4 alkyl), C 1~4 Alkylene SO2N(C 1~4 Alkyl)(C 1~4 alkyl), C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl and C 1~4 Fluoroalkylene CO2C 1~4 In some embodiments, R 8’ are SO2NH2, SO2NH(CH3), SO2N(CH3)2, C 1~4 Alkylene SO2NH2, C 1~4 Alkylene SO2NH(CH3), C 1~4 Alkylene SO2N(CH3)2, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~3 Alkyl, C 1~4 Alkylene CO2C 1~3 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~3 Alkyl, and C 1~4 Fluoroalkylene CO2C 1~4 In some embodiments, R 8’ are SO2NH2, SO2NH(CH3), SO2N(CH3)2, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~3 Alkyl, C 1~4 Alkylene CO2C 1~3alkyl.

[0261] In some embodiments, R 8 is C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl, C 1~4 Fluoroalkylene CO2C 1~4 alkyl, each alkylene being selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 In some embodiments, R 8 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and C 1~4 Fluoroalkylene CO2C 1~4 In some embodiments, R 8 is C 2~4 Alkylene OH, C 2~4 Alkylene COH, C 2~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and C 1~4 Fluoroalkylene CO2C 1~4 In some embodiments, R 8 are C3 alkylene OH, C3 alkylene CO2H, and C3 alkylene CO2C 1~3 alkyl.

[0262] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, N, NR 8and O, and may contain one or two additional hetero moieties selected from 3H-indolyl, 2H-isoindolyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl; C 1~4 Alkyl and C 1~4 It forms an 8- to 10-membered heterocycloalkyl ring which may be substituted with 1 or 2 substituents selected from haloalkyl.

[0263] In some embodiments, R 5 and R 6 together with the nitrogen atom between them, NR 8 and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO, CHO, C 1~6 Alkyl and C 1~6 haloalkyl; and NR 8 R 9 , OR 8 , CO2R 8 , C(O)NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 1~4 Alkylene OR 8 , C 1~4 Alkylene CO2R 8 and C 1~4 AlkyleneC(O)NR 8 R 9 and R is substituted with at least one substituent selected from 8 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, C 1~4 Alkylene OH, C 1~4 Alkylene COH, C 1~4 Alkylene OC 1~4 Alkyl, C 1~4 Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and C 1~4 Fluoroalkylene CO2C 1~4 alkyl, and each alkyl and alkylene forms a 5- to 6-membered heterocycloalkyl ring selected from OH, C 3~6 Cycloalkyl, C 3~10 Heterocycloalkyl, phenyl, C 5~10 Heteroaryl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylenephenyl, and C 1~4 Alkylene C 5~10 and heteroaryl, the latter eight groups being OH, halo, CN, C 1~4 Alkyl, C 1~4 Fluoroalkyl, C 1~4 Chloroalkyl, NH2, NH(C 1~4 alkyl) and N(C 1~4 Alkyl)(C 1~4 alkyl).

[0264] In some embodiments, R 5 and R 6 together with the nitrogen atom between them to form one additional NR 8 Contains hetero moieties, OH, F, Cl, CN, NO2, CHO, C 1~4 Alkyl and C 1~4 forming a 5- to 6-membered heterocycloalkyl ring optionally substituted by 1 or 2 substituents selected from haloalkyl; R 8 is C 2~4 Alkylene OH, C 2~4 Alkylene COH, C 2~4 Alkylene OC 1~4 Alkyl, C 1~4Alkylene OC 1~4 Fluoroalkyl, C 1~4 Alkylene CO2C 1~4 Alkyl, C 1~4 Fluoroalkylene OH, C 1~4 Fluoroalkylene COH,C 1~4 Fluoroalkylene OC 1~4 Alkyl, C 1~4 Fluoroalkylene OC 1~4 Fluoroalkyl and C 1~4 Fluoroalkylene CO2C 1~4 In some embodiments, one additional NR 8 In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing the hetero moiety is piperazinyl. In some embodiments, A is phenyl and R 4 is selected from F, Cl and CH3.

[0265] In some embodiments, R 9 is H, C 1~4 Alkyl and C 1~4 In some embodiments, R is selected from haloalkyl. 9 is H, C 1~4 Alkyl, C 1~4 Fluoroalkyl and C 1~4 In some embodiments, R 9 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CH2CClH2, CCl2H, CClH2, CH2CCl2H, and CH2CCl3. In some embodiments, R 9 is selected from H, CH, CF, CFH, CHF, CCl, CClH, and CClH. In some embodiments, R 9 is selected from H, CH, and CF. In some embodiments, R 9 is H.

[0266] In some embodiments, R 1is selected from:

[0267] [ka]

[0268] [ka]

[0269] In some embodiments, the stereochemistry at carbons 9b, 3a, and 4 of the tricyclic core structure of the compounds of Formula I is either R or S. Thus, in some embodiments, the compounds of Formula I are racemates or stereoisomers, including enantiomers and diastereomers, or mixtures of stereoisomers, including mixtures of enantiomers, mixtures of diastereomers, or mixtures of enantiomers and diastereomers.

[0270] In some embodiments, the compound of Formula (I) is a cis isomer. In some embodiments, the cis isomer is selected from (3aR,4R,9bR) and (3aS,4S,9bS), a mixture thereof having the following structure, or a pharmaceutically acceptable salt and / or solvate thereof:

[0271] [ka]

[0272] During the ceremony, X,

[0273] [ka]

[0274] , A, R 1 , R 2 , R 3 , R 4 and n is as defined in formula (I).

[0275] In some embodiments, the compound of Formula (I) is a trans isomer. In some embodiments, the trans isomer is selected from (3aR,4S,9bR)-(I) and (3aS,4R,9bS)-(I), a mixture thereof, having the following structure, or a pharmaceutically acceptable salt and / or solvate thereof:

[0276] [ka]

[0277] During the ceremony, X,

[0278] [ka]

[0279] , A, R 1 , R 2 , R 3 , R 4 and n is as defined in formula (I). In some embodiments,

[0280] In some embodiments, the compound of Formula I is a mixture of enantiomers. In some embodiments, the compound of Formula (I) is a mixture of two cis isomers having the structures (3aR,4R,9bR) and (3aS,4S,9bS), as defined above (e.g., (4R / S cis)-(I)). In some embodiments, the compound of Formula (I) is a mixture of two trans isomers having the structures (3aR,4S,9bR) and (3aS,4R,9bS), as defined above (e.g., (4R / S trans)-(I)).

[0281] In some embodiments, the compound of Formula (I) has one of the following structures:

[0282] [ka]

[0283] or a pharmaceutically acceptable salt and / or solvate thereof During the ceremony: X,

[0284] JPEG2026508515000051.jpg731 , A, R 1 , R 2 , R 3 , R 4 and n is as defined in formula (I).

[0285] In embodiments, the compound of formula I is a compound selected from the list below, or a pharmaceutically acceptable salt and / or solvate thereof.

[0286] [Table 1-1]

[0287] [Table 1-2]

[0288] [Table 1-3]

[0289] [Table 1-4]

[0290] [Table 1-5]

[0291] [Table 1-6]

[0292] [Table 1-7]

[0293] [Table 1-8]

[0294] [Table 1-9]

[0295] [Table 1-10]

[0296] [Table 1-11]

[0297] [Table 1-12]

[0298] [Table 1-13]

[0299] [Table 1-14]

[0300] In embodiments, pharmaceutically acceptable salts of the compounds of Formula I and Formula II are acid addition salts or base addition salts. The selection of an appropriate salt may be made by one skilled in the art (see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0301] Acid addition salts suitable for or compatible with the treatment of subjects are any non-toxic organic or inorganic acid addition salts of any basic compounds. Basic compounds that form acid addition salts include, for example, compounds containing an amino group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In embodiments, mono- or di-acid salts are produced, and such salts exist as either hydrates, solvates, or substantially anhydrous. Acid addition salts are generally more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. The criteria for selecting an appropriate salt will be known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as, but not limited to, oxalates, may be used, for example, for experimental use or in isolating the compounds of the present application for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0302] Base addition salts suitable for or compatible with the treatment of subjects include non-toxic organic or inorganic base addition salts of any acidic compound. Acidic compounds that form base addition salts include, for example, compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxides, as well as ammonia. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of an appropriate salt can be useful, for example, to ensure that ester functional groups elsewhere in the compound, if any, are not hydrolyzed. The selection criteria for an appropriate salt will be known to those skilled in the art.

[0303] Solvates of the compounds of Formula I and Formula II include, for example, those formed with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvates are called hydrates), ethanol, and the like. Suitable solvents are physiologically acceptable at the administered dosage.

[0304] In embodiments of the present application, the compounds of Formula I and Formula II described herein may have at least one asymmetric center. When compounds have multiple asymmetric centers, they exist as diastereomers. It is to be understood that all such isomers and mixtures, in any ratio, are encompassed within the scope of the present application. It is further to be understood that while the stereochemistry of a compound may be as shown in any given compound listed herein, such a compound may contain a certain amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of a compound of the present application having alternating stereochemistry. When separated, any optical isomer, pure or partially pure optical isomer, or racemic mixture thereof, is intended to be encompassed within the scope of the present application.

[0305] The compounds of Formula I and Formula II may exist in different tautomeric forms, and any tautomeric forms that the compounds may form, as well as mixtures thereof, are intended to be included within the scope of this application.

[0306] The compounds of Formula I and Formula II may further exist in different polymorphic forms, and any resulting polymorphic form, or mixture thereof, is intended to be included within the scope of this application.

[0307] III. Methods and Uses of the Present Application The present applicants have identified a family of compounds that can inhibit and / or block Cav3.2 T-type calcium channel (Cav3.2) function and / or expression levels by inhibiting, blocking, and / or disrupting the interaction between Cav3.2 and ubiquitin-specific peptidase 5 (USP5). In embodiments, the compounds have been found to inhibit, block, and / or disrupt the interaction between Cav3.2 and ubiquitin-specific peptidase 5 (USP5). Thus, the compounds may be useful for inhibiting, blocking, and / or disrupting Cav3.2 deubiquitination.

[0308] Accordingly, the present application includes a method for inhibiting the interaction between Cav3.2 T-type calcium channel (Cav3.2) and ubiquitin-specific peptidase 5 (USP5) in a cell, either in a biological sample or in a patient, the method comprising administering to the cell an effective amount of a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof.

[0309] The present application also includes the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for inhibiting the interaction between Cav3.2 and USP5 in a cell, and the use of the compounds or compositions of the present application for the preparation of a medicament for inhibiting the interaction between Cav3.2 and USP5 in a cell. The present application further includes the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for use in inhibiting the interaction between Cav3.2 and USP5.

[0310] It has been found that the compounds of the present application can inhibit the interaction between Cav3.2 and USP5, and therefore the compounds of the present application are useful for treating diseases, disorders, or conditions by inhibiting the interaction between Cav3.2 and USP5. Therefore, the compounds of the present application are useful as pharmaceuticals. Therefore, the present application includes the compounds of the present application for use as pharmaceuticals.

[0311] The present application also includes a method for treating a disease, disorder, or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof.

[0312] The present application also includes the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for treating a disease, disorder, or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5 in a cell, and the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for the preparation of a medicament for treating a disease, disorder, or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5 in a cell. The present application further includes the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for use in the treatment of a disease, disorder, or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5.

[0313] The present application also includes a method for inhibiting Cav3.2 T-type calcium channel (Cav3.2) function and / or expression in cells, either in a biological sample or in a patient, by inhibiting the interaction between Cav3.2 and ubiquitin-specific peptidase 5 (USP5), the method comprising administering to the cells an effective amount of a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof.

[0314] The present application also includes the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for inhibiting Cav3.2 function and / or expression by inhibiting the interaction between Cav3.2 and USP5 in cells, and the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for the preparation of a medicament for inhibiting Cav3.2 function and / or expression by inhibiting the interaction between Cav3.2 and USP5 in cells. The present application further includes the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for use in inhibiting Cav3.2 function and / or expression by inhibiting the interaction between Cav3.2 and USP5 in cells.

[0315] The present application further includes a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof for use in inhibiting Cav3.2 function and / or expression by inhibiting the interaction between Cav3.2 and USP5. The present application also includes a method for treating a disease, disorder, or condition that is mediated or treatable by inhibiting Cav3.2 function and / or expression in a cell by inhibiting the interaction between Cav3.2 and USP5, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof.

[0316] The present application also includes the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for treating a disease, disorder, or condition treatable by inhibiting Cav3.2 function and / or expression by inhibiting the interaction between Cav3.2 and USP5 in a cell, as well as the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for the preparation of a medicament for treating a disease, disorder, or condition treatable by inhibiting Cav3.2 function and / or expression by inhibiting the interaction between Cav3.2 and USP5 in a cell. The present application further includes the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for use in the treatment of a disease, disorder, or condition treatable by inhibiting Cav3.2 function and / or expression by inhibiting the interaction between Cav3.2 and USP5.

[0317] Since USP5 is a deubiquitinase and the compounds of the present application have been found to inhibit the interaction between Cav3.2 and USP5, the compounds of the present application may be useful for inhibiting Cav3.2 deubiquitination. Accordingly, the present application also includes a method for inhibiting Cav3.2 deubiquitination in cells in either a biological sample or a patient, the method comprising administering to the cells an effective amount of a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof.

[0318] The present application also includes the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for inhibiting Cav3.2 deubiquitination in a cell, and the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for the formulation of a medicament for inhibiting Cav3.2 deubiquitination in a cell. The present application further includes the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for use in inhibiting Cav3.2 deubiquitination.

[0319] It has been found that the compounds of the present application can inhibit the interaction between Cav3.2 and the deubiquitinase USP5, and therefore the compounds of the present application are useful for treating diseases, disorders, or conditions by inhibiting Cav3.2 deubiquitination. Accordingly, the present application also includes a method for treating a disease, disorder, or condition that can be treated by inhibiting Cav3.2 deubiquitination, the method comprising administering a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0320] The present application also includes the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for treating a disease, disorder, or condition treatable by inhibiting Cav3.2 deubiquitination in a cell, as well as the use of the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for the formulation of a medicament for treating a disease, disorder, or condition treatable by inhibiting Cav3.2 deubiquitination in a cell. The present application further includes the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof for use in the treatment of a disease, disorder, or condition treatable by inhibiting Cav3.2 deubiquitination.

[0321] In embodiments, the disease, disorder, or condition treatable by inhibiting the interaction between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination is pain. Accordingly, the present application also includes a method for treating pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt and / or solvate thereof. The present application also includes the use of a compound of the present application, or a pharmaceutically acceptable salt and / or solvate thereof, for the treatment of pain, as well as the use of a compound of the present application, or a pharmaceutically acceptable salt and / or solvate thereof, for the preparation of a medicament for the treatment of pain. The present application further includes a compound of the present application, or a pharmaceutically acceptable salt and / or solvate thereof, for use in pain. In embodiments, the treatment is in an amount effective to improve at least one symptom of pain, e.g., particularly, reduction in sensation and duration, in a subject in need of such treatment.

[0322] In embodiments, the compounds of the present application are useful as analgesics in the treatment of pain.

[0323] In embodiments, the pain is acute pain or chronic pain.

[0324] In embodiments, chronic pain is any persistent or recurrent pain lasting for more than about 3 months. In embodiments, chronic pain is any persistent or recurrent pain lasting for more than about 6 months. In embodiments, chronic pain is selected from primary chronic pain, chronic cancer pain, chronic post-surgical pain and chronic post-traumatic pain, chronic neuropathic pain, orofacial pain, chronic visceral pain, and chronic musculoskeletal pain. In embodiments, chronic pain is selected from primary chronic pain, chronic neuropathic pain, chronic headache and orofacial pain, chronic visceral pain, and chronic musculoskeletal pain. In embodiments, chronic pain is selected from primary chronic pain, chronic neuropathic pain, and chronic visceral pain. In embodiments, chronic pain is selected from chronic neuropathic pain and chronic visceral pain.

[0325] In embodiments, the pain is nociceptive pain, inflammatory pain, or neuropathic pain. In embodiments, the pain is inflammatory pain or neuropathic pain. In embodiments, the pain is inflammatory pain. In embodiments, the pain is neuropathic pain.

[0326] In embodiments, the neuropathic pain is chronic neuropathic pain. In embodiments, the chronic neuropathic pain is central pain syndrome, complex regional pain syndrome, diabetic peripheral neuropathic pain, shingles, postherpetic neuralgia, chemotherapy-induced neuropathic pain, or trigeminal neuralgia. In embodiments, the chronic neuropathic pain is central pain syndrome, complex regional pain syndrome, diabetic peripheral neuropathic pain, shingles, postherpetic neuralgia, or trigeminal neuralgia. In embodiments, the chronic neuropathic pain is chemotherapy-induced neuropathic pain.

[0327] In embodiments, the central pain syndrome is pain associated with a disease, disorder, or condition associated with damage to the central system, in embodiments, the disease, disorder, or condition associated with damage to the central system is selected from one or more of multiple sclerosis and tumors.

[0328] In embodiments, the diabetic peripheral neuropathic pain is associated with diabetes. In embodiments, the diabetic peripheral neuropathic pain is associated with test injuries in the foot, leg, hand, or arm associated with diabetes. Thus, in embodiments, the pain is associated with diabetes.

[0329] In embodiments, the inflammatory pain is pain associated with an inflammation-related disease, disorder, or condition. In embodiments, the inflammation-related disease, disorder, or condition is selected from one or more of diabetes, cardiovascular disease (CVD), arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, menstrual pain, tendonitis, bursitis, skin-related conditions (such as psoriasis, eczema, burns, and dermatitis), and post-surgical inflammation. In embodiments, the inflammation-related disease, disorder, or condition is diabetes.

[0330] In embodiments, the arthritis is, but is not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, or juvenile arthritis.

[0331] In embodiments, the inflammation-related disease, disorder or condition is selected from one or more of inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.

[0332] In embodiments, the inflammation-related disease, disorder, or condition is selected from one or more of vascular disease, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, rheumatic fever, type 1 diabetes, neuromuscular junction diseases including myasthenia gravis, white matter diseases including multiple sclerosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like.

[0333] In embodiments, the inflammation-related disease, disorder or condition is an ocular disease, including, but not limited to, retinitis, retinal disease, uveitis, ocular photophobia, and acute injury to ocular tissue.

[0334] In embodiments, the inflammation-related disease, disorder or condition is pulmonary inflammation, including, but not limited to, that associated with viral infections and cystic fibrosis.

[0335] In embodiments, the inflammation-related disease, disorder or condition is a central nervous system disease such as cortical dementia, including Alzheimer's disease.

[0336] In embodiments, the inflammation-related disease, disorder or condition is selected from allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and central nervous system damage resulting from stroke, ischemia and trauma.

[0337] In further embodiments, the present application also includes a method for treating a disease, disorder, or condition mediated by or treatable by inhibition of the interaction between Cav3.2 and USP5 or inhibition of Cav3.2 deubiquitination, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application in combination with another known agent useful for treating a disease, disorder, or condition mediated by or treatable by inhibition of the interaction between Cav3.2 and USP5 or inhibition of Cav3.2 deubiquitination. The present application also includes the use of a compound of the present application in combination with a known agent useful for treating a disease, disorder, or condition mediated by or treatable by inhibition of the interaction between Cav3.2 and USP5 or inhibition of a Cav3.2 deubiquitinating protein, as well as the compound of the present application for treating a disease, disorder, or condition mediated by or treatable by inhibition of the interaction between Cav3.2 and USP5 or inhibition of Cav3.2 deubiquitination.

[0338] In a further embodiment, the disease, disorder or condition mediated or treatable by inhibition of the interaction between Cav3.2 and USP5 or inhibition of the Cav3.2 deubiquitinating protein is pain, and the compounds of the present application are administered in combination with one or more additional pain treatments.

[0339] In embodiments, an effective amount varies depending on factors such as the disease state, age, sex, and / or weight of the subject. In further embodiments, the amount of a given compound or compounds that corresponds to an effective amount will vary depending on factors such as the given drug or compound, pharmaceutical formulation, route of administration, type of disease, disorder, or condition, identity of the subject being treated, and the like, but can nevertheless be routinely determined by one of ordinary skill in the art.

[0340] In some embodiments, the compound is administered at least once a week. However, in other embodiments, the compound is administered to a subject about once every two weeks, three times a week, or three times a month. In other embodiments, the compound is administered about once a week to about once a day. In other embodiments, the compound is administered twice a day, three times a day, four times a day, five times a day, or six times a day. The length of treatment depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound, and / or a combination thereof. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment regimen. Dosage variations may be evident from the results obtained using standard diagnostic assays known in the art. In some cases, long-term administration may be necessary. For example, the compound is administered to a subject in an amount and for a duration sufficient to treat the subject.

[0341] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0342] The compounds of the present application are used either alone or in combination with other known agents useful for treating diseases, disorders, or conditions mediated or treatable by inhibition of the interaction between Cav3.2 and USP5 or inhibition of Cav3.2 deubiquitination. When used in combination with other agents useful for treating diseases, disorders, or conditions mediated or treatable by inhibition of the interaction between Cav3.2 and USP5 or inhibition of Cav3.2 deubiquitination, the compounds of Formula II are administered simultaneously with these agents. As used herein, "co-administration" of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of the administration depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other, if the pharmacokinetics are appropriate. Designing appropriate administration regimens is routine for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing both substances. Administration of a combination of agents to a subject other than simultaneously is a further embodiment of the present application. In embodiments, a compound of the present application is administered with another therapeutic agent either simultaneously or sequentially in separate unit dosage forms, or together in a unit dosage form. Thus, the present application provides a single unit dosage form comprising a compound of the present application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0343] The dosage of the compounds of the present application will vary depending on many factors, including the pharmacokinetic properties of the compound, the method of administration, the recipient's age, health, and weight, the nature and severity of symptoms, the frequency of treatment and type of concurrent treatment, if any, and the clearance rate of the compound in the treated subject. Those skilled in the art will be able to determine appropriate dosages based on these factors. In some embodiments, the compounds of the present application are initially administered at an appropriate dosage, which is adjusted as necessary depending on clinical response. Dosages are generally selected to maintain serum levels of the compounds of the present application between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. As a representative example, oral dosages of the compounds of the present application will range from about 1 mg / day to about 1000 mg / day, suitably between about 1 mg / day and about 500 mg / day, and more suitably between about 1 mg / day and about 200 mg / day for adults. For parenteral administration, a typical amount is about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For oral administration, a typical amount is about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For administration in the form of a suppository, a typical amount is about 0.1 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg.

[0344] IV. Compounds of the Present Application The present application includes compositions comprising the compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof and a carrier. The compositions of the present application are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Thus, the present application further includes pharmaceutical compositions comprising the compounds of the present application and a pharmaceutically acceptable carrier.

[0345] In embodiments, the pharmaceutical composition is used in the treatment of any of the diseases, disorders or conditions described herein.

[0346] The compounds of the present application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be appreciated by those skilled in the art. For example, the compounds of the present application may be administered orally, by inhalation, parenterally, buccal, sublingually, nasally, rectally, intravaginally, by patch, pump, topical, or transdermal administration, and pharmaceutical compositions formulated accordingly. In some embodiments, administration is by using a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and formulation of appropriate compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20th edition) and in The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19).

[0347] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may also be by continuous infusion over a selected period of time.

[0348] In some embodiments, the compounds of the present application are orally administered, for example, with an inert diluent or an absorbable edible carrier, or are enclosed in hard or soft shell gelatin capsules, or are compressed into tablets, or are directly mixed with dietary food.In some embodiments, the compounds are mixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like.For tablets, carriers used include lactose, corn starch, sodium citrate, and phosphate salts. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). In embodiments, tablets are coated by methods well known in the art. For tablets, capsules, pellets, or granules for oral administration, pH-sensitive enteric coatings, such as Eudragits™, designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include modified release, for example, immediate release and sustained release formulations. Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR, or XL), time-release or timed-release, controlled release (CR), or continuous release (CR or Contin), used as, for example, coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles, e.g., molecular sieve-type particles, or in the form of finely divided hollow particles agglomerated or held in a fibrous packet.Sustained-release compositions are formulated in which the active compound is protected by a differentially degradable coating, such as by liposomes or microencapsulation, multilayer coatings, etc. Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. For oral administration in capsule form, useful carriers or diluents include lactose and dried corn starch.

[0349] In some embodiments, lipid formulations for oral administration may take the form of, for example, a solution, syrup, or suspension, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oily phase formulated with an emulsifier and / or suspending agent. Optionally, specific sweeteners and / or flavorings and / or coloring agents are added. Such liquid formulations for oral administration are formulated by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0350] It is also possible to freeze-dry the compounds of the present application and use the resulting lyophilisates, for example, for the formulation of injectable products.

[0351] In some embodiments, the compounds of the present application are administered parenterally. For example, solutions of the compounds of the present application are formulated in water suitably mixed with a surfactant, such as hydroxypropylcellulose. In some embodiments, dispersions are formulated in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof, with or without alcohol, and oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the present application are typically prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the formulation isotonic. For ophthalmic administration, ointments or eyedrop solutions are delivered using ophthalmic delivery systems known in the art, such as applicators or eyedroppers. In some embodiments, such compositions comprise a mucomimetic such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, a preservative such as sorbic acid, EDTA or benzyl chromium chloride, and a conventional amount of diluent or carrier. For pulmonary administration, the diluent or carrier is selected to be appropriate so as to allow for the generation of an aerosol.

[0352] In some embodiments, the compounds of the present application are formulated for parenteral administration by injection, including conventional catheterization techniques or the use of an intravenous drip. Formulations for injection are, for example, presented in unit dosage form, for example, in ampoules or multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. Alternatively, the compounds of the present application are suitably in sterile powder form for reconstitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.

[0353] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, nasal drops, gels, and powders. For intranasal or inhalation administration, the compounds of the present application are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent, and are typically provided in single or multiple doses in a sterile form, for example, in the form of a cartridge or in a sealed container that is refilled for use with an atomizing device. Alternatively, the sealed container is an integrated dispensing device, such as a single-dose nasal inhaler or aerosol dispenser, equipped with a metering valve intended for disposal after use. When the dosage form includes an aerosol dispenser, it contains a propellant, for example, a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (e.g., made from gelatin) for use in an inhaler or insufflator are formulated, for example, containing a powder mix of the compound of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form can also be in the form of a pump-atomizer.

[0354] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the compounds are formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0355] Suppository forms of the compounds of the present application are useful for vaginal, urethral, ​​and rectal administration. Such suppositories are generally composed of a mixture of materials that are solid at room temperature but melt at body temperature. Materials commonly used to make such vehicles include, but are not limited to, theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, and mixtures of polyethylene glycols with various amounts of polyethylene glycol and fatty acid esters of polyethylene glycol. For further discussion of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0356] In some embodiments, the compounds of the present application are coupled to soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-palmitoyl-substituted polylysine. Furthermore, in some embodiments, the compounds of the present application are coupled to classes of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0357] Although the compounds of the present application, including their pharmaceutically acceptable salts and / or solvates, are suitably used alone, the compounds of the present application (active ingredients) will generally be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier. Depending on the method of administration, the pharmaceutical composition will contain from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight, of the active ingredient, and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of the pharmaceutically acceptable carrier, all weight percentages being based on the total composition.

[0358] IV. Methods for Preparing the Compounds of the Present Application The compounds of the present application can be prepared by a variety of synthetic methods. The selection of certain structural features and / or substituents may influence the selection of one method over another. The selection of a particular method for preparing a given compound of Formula I is within the expertise of one of ordinary skill in the art. Some starting materials for preparing the compounds of the present application are available from commercial chemical suppliers. For example, other starting materials described below are readily prepared from available precursors using straightforward transformations well known in the art.

[0359] Compounds of Formula I can be prepared by the methods illustrated in the following schemes. In the structural formulas shown below, unless otherwise specified, the variables are as defined in Formula I. Those skilled in the art will recognize that many of the reactions shown in the schemes below are oxygen and water sensitive and will be aware that reactions are carried out under an anhydrous, inert atmosphere, if necessary. Reaction temperatures and times are provided for illustrative purposes only and can be varied to optimize yields, as will be understood by those skilled in the art.

[0360] Thus, in some embodiments, compounds of Formula I are prepared as shown in Schemes 1 and 2.

[0361] In some embodiments, a compound of Formula I, where X is O, is prepared as shown in Scheme 1 by dissolving an amine compound of Formula A with a compound of Formula B in a 1:1 molar equivalent ratio in a solvent such as acetonitrile under an inert atmosphere, such as N, adding a suitable acid, such as trifluoroacetic acid, and stirring the reaction mixture at a suitable temperature and for a period of time, such as at room temperature for about 1 to about 4 hours, or about 2 hours. The reaction mixture is then cooled to a suitable temperature, such as 0°C, and a suitable acid, such as trifluoroacetic acid, is added in an amount of about 0.9 molar equivalents, followed by 2,3-dihydrofuran (e.g., 1.2 equivalents) after a suitable period of time, such as about 5 to 10 minutes, and the reaction mixture is stirred vigorously at a suitable temperature and for a period of time, such as at about 0°C for about 30 minutes, and then stirred at room temperature for about 16 hours to provide both the cis and trans isomers of the compound of Formula I. The cis and trans mixture of the compound of Formula I is purified by methods known in the art, such as silica gel flash chromatography, using suitable elution conditions, such as a 0-30% ethyl acetate gradient in hexane, to obtain the desired isomer.

[0362] [ka]

[0363] Compounds of formula I may be further converted to other compounds of formula I by methods known in the art. In some embodiments, R 1 OC 1~6 The compound of formula I, wherein R is an alkyl group, 1 is converted to a compound of formula I, where R is OH. 1 OC 1~6 A compound of formula I, which is alkyl (e.g., prepared by Scheme 1), is dissolved in a suitable solvent, such as MeOH:THF:HO (2:2:1), to which is added a suitable base, such as LiOH, at a suitable temperature, such as room temperature, and allowed to react for a suitable time, such as overnight, to give R 1 is obtained a compound of formula I wherein is OH.

[0364] In some embodiments, according to Scheme 2, R 1 NR5 R 6 A compound of formula I, wherein R 1 is prepared from a compound of formula I where R 1 A compound of formula I, wherein R is OH, is reacted with an amino compound of formula C under suitable amide bond forming conditions, such as in the presence of diisopropylethylamine and a suitable base, such as azabenzotriazole tetramethyluronium hexafluorophosphate (HATU), in a suitable solvent, such as dimethylformamide, to form R 1 NR 5 R 6 to obtain a compound of formula I, wherein R 1 NR 5 R 6 The crude mixture of compounds of formula I, which is is purified by methods known in the art such as silica gel flash chromatography using appropriate elution conditions such as a gradient of 0-10% MeOH in DCM.

[0365] [ka]

[0366] The formation of a desired compound salt is carried out using standard techniques, for example, treating a neutral compound with an acid or base in a suitable solvent and isolating the formed salt by filtration, extraction, or any other suitable method.

[0367] The formation of solvates will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an anti-solvent. The solvate is usually dried or azeotroped at ambient temperature. Selection of appropriate conditions for forming a particular solvate can be performed by one of ordinary skill in the art. Examples of suitable solvents are ethanol, water, and the like. When water is the solvent, the molecule is called a "hydrate." The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an anti-solvent. The solvate is usually dried or azeotroped at ambient temperature. Selection of appropriate conditions for forming a particular solvate can be performed by one of ordinary skill in the art.

[0368] Amide bond formation conditions include any known method of coupling a carboxylic acid with an amine that is compatible with the intermediates and products shown in the schemes above or that can be used to prepare the compounds of the present application. Known methods for preparing amides by coupling a carboxylic acid with an amine include either the use of a coupling reagent or prior conversion of the carboxylic acid to an activated derivative. Coupling reagents include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexyldicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), benzotriazole tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), and benzotriazol-1-yloxytripyrrolidinophosphonium. Examples of suitable peptide coupling reagents include, but are not limited to, any of the known peptide coupling reagents such as hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), and propanephosphoric anhydride.

[0369] In some embodiments, racemization of the carboxylic acid enantiomer occurs during amide bond formation with coupling reagents, and in some embodiments, racemization is avoided using "racemization suppressing" additives such as the triazoles 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), and ethyl cyanohydroxyiminoacetate (Oxyma).

[0370] Nucleophilic substitution reaction conditions include any known method for the reaction of a nucleophile to displace a leaving group to form a bond compatible with the intermediates and products shown in the schemes above or that may be used to prepare the compounds of the present application. In some embodiments, such conditions include combining the reactants in a suitable solvent in the presence of a base.

[0371] Conversion of a group or substituent to another group or substituent by chemical manipulation can be performed on any intermediate or final product on the synthetic route to the final product, with the types of possible transformations being limited only by the inherent incompatibility of other functionality carried by the molecule at that stage with the conditions or reagents used in the transformation. Such inherent incompatibilities, and how to circumvent them by performing the appropriate transformations and synthetic steps in the proper order, will be readily apparent to those skilled in the art. While exemplary transformations are provided herein, it should be understood that the desired transformations are not limited to the general groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are provided in "Comprehensive Organic Transformations—A Guide to Functional Group Preparations" by R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, such as "Advanced Organic Chemistry," March, 4th ed., McGraw Hill (1992) or "Organic Synthesis," by Smith, McGraw Hill, (1994).

[0372] Purification techniques for intermediates and final products include, for example, column or spinning plate normal and reverse phase chromatography, recrystallization, upstream and liquid-liquid or solid-liquid extraction, and will be readily understood by those skilled in the art.

[0373] Generally, the reaction is carried out in a suitable inert organic solvent at a temperature and for a time period that optimizes the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and the like.

[0374] The products of the methods of the present application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable methods.

[0375] It should be understood that throughout the processes described herein, suitable protecting groups are added to, and subsequently removed from, various reactants and intermediates, where appropriate, in a manner that would be readily understood by one skilled in the art. Conventional procedures for the use of such protecting groups and examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M.Wuts, Wiley-Interscience, New York, (1999).

[0376] Those skilled in the art will appreciate that when reaction steps herein are carried out in various solvents or solvent systems, said reaction steps may be carried out in suitable mixtures of solvents or solvent systems.

[0377] A particular enantiomer or diastereomer of a compound of the present application may be obtained by using the corresponding single enantiomer or diastereomer of the corresponding starting material. [Example]

[0378] The following non-limiting examples are illustrative of the present application.

[0379] A. Preparation of Exemplary Compounds of the Present Application Example 1: Synthesis of (4R / S trans)I-1, (4R / S trans)I-8, and (4R / S trans)I-58

[0380] [ka]

[0381] Step 1: 2-(4R / S trans)-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)ethyl acetate ((4R / S trans)I-58) Procedure: In a 100 mL round-bottom flask, 2-(4-aminophenyl)ethyl acetate (1 g; 5.58 mmol) and m-tolualdehyde (670.4 mg; 1 equiv.) were dissolved in acetonitrile (20 mL) under N2. Trifluoroacetic acid (0.1 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C. Trifluoroacetic acid (0.9 equiv.) was added, and the reaction mixture was stirred at 0 °C for 5 min. 2,3-Dihydrofuran (1.2 equiv.) was added, and the resulting mixture was stirred vigorously at 0 °C for 30 min, then at room temperature for 16 h. The reaction mixture was quenched with NaHCO3 solution. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude mixture was purified by silica gel flash chromatography (0-30% ethyl acetate in hexanes gradient) to give the desired isomer. The compound was isolated as an off-white solid (0.65 g; 33% yield). 1 H NMR(400MHz,CDCl3):δ 7.33(d,J=2.1Hz,1H),7.30~7.22(m,4H),7.20~7.16(m,1H),7.08(dd,J=8.2,2.1Hz,1 H),6.61(d,J=8.2Hz,1H),4.61(d,J=5.1Hz,1H),4.16(q,J=7.1Hz,3H),4.05(td,J=8. 4,6.1Hz,1H),3.88~3.82(m,1H),3.77(d,J=11.2Hz,1H),3.54(d,J=1.9Hz,2H),2.50~ 2.44(m,1H),2.41(s,3H),2.09~1.99(m,1H),1.84~1.67(m,1H),1.28(t,J=7.1Hz,3H); 13 C{ 1H} NMR(101MHz,CDCl3):δ 172.13,144.46,141.58,138.39,131.90,129.86,128.90,128.53,125.39,123.80,120 .07,114.89,76.17,65.25,60.67,57.81,43.29,40.61,28.87,21.47,14.23;HRMS(ESI) m / z [M+H] + C 22 H 26 NO3 calculated value 352.1913, actual value 352.1907.

[0382] Step 2: 2-(4R / S trans))-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)ethyl acetate ((4R / S trans)I-8). Procedure: To a stirred solution of ethyl 2-(4R / S trans)-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)acetate (200 mg; 0.575 mL) in MeOH:THF:HO (2:2:1, 5 mL) was added LiOH (27.6 mg; 2 equiv.) at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated, redissolved in water, and acidified with 1N HCl solution (pH ∼3). The precipitate was filtered and washed with HO. The white precipitate was dried to give the free acid (165 mg; 90% yield); 1 H NMR(400MHz,CDCl3):δ 7.32(d,J=2.1Hz,1H),7.28~7.19(m,3H),7.17(d,J=7.4Hz,1H),7.05(dd,J =8.2,2.1Hz,1H),6.59(d,J=8.2Hz,1H),4.60(d,J=5.0Hz,1H),4.03(td,J=8 .3,6.2Hz,1H),3.84(td,J=9.0,5.9Hz,1H),3.72(d,J=11.1Hz,1H),3.54(s ,2H),2.47~2.41(m,1H),2.39(s,3H),2.15~1.92(m,1H),1.76~1.68(m,1H); 13 C{ 1H} NMR(101MHz,CDCl3):δ 177.62,144.64,141.54,138.36,132.07,130.04,128.91,128.53,125.40,123. 08,119.94,114.96,76.16,65.16,57.66,43.20,40.30,28.79,21.48;HRMS(ESI) m / z[M+H] + C 20 H 22 NO3 calculated value 324.1600, actual value 324.1592.

[0383] Step 3: Methyl 3-(2-(4R / S trans)-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)acetamido)propanoate ((4R / S trans)I-1) Procedure: To a stirred solution of 2-(4R / S trans)-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)acetic acid (165 mg, 0.51 mmol) and methyl 3-aminopropanoate hydrochloride (85.5 mg; 1.2 equiv.) in dimethylformamide (4 mL) was added diisopropylethylamine (0.31 mL, 3.5 equiv.) at 0 °C. After 30 min, HATU (252 mg; 1.3 equiv.) was added. The reaction mixture was allowed to stir at room temperature overnight. After completion of the reaction, cold water was added to it. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude residue. The crude mixture was purified by silica gel flash chromatography (0-10% MeOH gradient in DCM). (4R / S trans) I-1 was isolated as a white solid (120 mg; 58% yield); 1H NMR (600MHz, CDCl3): δ 7.29~7.19(m,4H),7.15(d,J=7.5Hz,1H),6.98(dd,J=8.2,2.1Hz,1H),6.60(d,J=8.2Hz,1H) ,5.99(d,J=6.4Hz,1H),4.56(d,J=5.1Hz,1H),4.01(td,J=8.4,6.1Hz,1H),3.82(td,J=9.0, 6.0Hz,1H),3.72(d,J=11.1Hz,1H),3.65(s,3H),3.49~3.40(m,4H),2.50(td,J=6.3,2.6Hz, 2H),2.46~2.42(m,1H),2.38(s,3H),2.01(dtd,J=14.1,8.5,6.2Hz,1H),1.76~1.67(m,1H); 13 C{ 1 H} NMR (151MHz, CDCl3): δ 172.60,171.76,144.71,141.38,138.39,132.19,129.97,128.93,128.83,128.53,125.33,124.05 ,120.43,115.26,76.02,65.20,57.72,51.67,43.21,42.94,35.10,33.89,28.81,21.43;HRMS(ESI) m / z[M+H] + C 24 H 29 The calculated value of N2O4 is 409.2127 and the measured value is 409.2104.

[0384] Example 2: Synthesis of (4R / S trans)I-2

[0385]

change

[0386] To a stirred solution of methyl 3-(2-(4R / S trans))-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)acetamido)propanoate ((4R / S trans)I-1) (60 mg, 0.146 mmol) in THF:MeOH (1:1, 5 mL) was added sodium borohydride (55.5 mg; 10 equiv.) in portions at 0 °C. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was quenched with methanol. The solvent was evaporated and redissolved in DCM. The organic layer was washed with water and brine. The organic layer was concentrated and purified by silica gel flash chromatography (0-10% MeOH gradient in DCM). (4R / S trans)I-2 was isolated as a white solid (33 mg; 59% yield). 1 H NMR(600MHz,MeOD):δ 7.84(t,J=5.8Hz,1H),7.27(d,J=1.7Hz,1H),7.25~7.20(m,3H),7.15~7.11(m,1H),7.01(dd, J=8.3,2.1Hz,1H),6.67(d,J=8.2Hz,1H),4.55(d,J=5.0Hz,1H),3.96(td,J=8.4,6.2Hz,1H),3 .79(ddd,J=9.4,8.4,5.9Hz,1H),3.63(d,J=11.1Hz,1H),3.54(t,J=6.3Hz,2H),3.38(s,2H),3 .32~3.29(m,1H),3.27~3.22(m,2H),2.40~2.33(m,4H),2.03~1.97(m,1H),1.74~1.65(m,3H); 13 C NMR(151MHz,MeOD):δ 173.70,173.61,145.25,141.74,137.89,131.32,129.36,128.65,128.20,128.03,125.15,123.98,119.25,114. 83,76.34,64.56,58.99,57.37,42.98,41.90,41.85,36.30,36.17,31.76,31.74,28.25,20.09,14.03;HRMS(ESI) m / z[M+H] + C 23 H 29 N2O3 calculated value 381.2178, measured value 381.2155.

[0387] In a similar manner, the following additional compounds were prepared: (4R / S trans)I-3, (4R / S cis)I-4, (4R / S cis)I-5, (4R / S cis)I-6, (4R / S cis)I-7, I-9, I-10, I-11, (4R / S cis)I-12, I-13, (4R / S cis)I-14, I-15, I-16, I-17, (4R / S cis)I-18, I-19, I-20, I-21, (4R / S trans)I-22, (4R / S trans)I-23, (4R / S trans)I-24. TFA, (4R / S cis)I-8, (4R / S cis)I-1, (4R / S trans)I-27, (4R / S trans)I-28, (4R / S trans)I-29, (4R / S trans)I-30, (4R / S trans)I-31, I-32, (4R / S trans)I-33, (4R / S cis)I-33, (4R / S trans)I-35, (4R / S cis)I-35, I-37, (4R / S trans)I-38, (4R / S trans)I-39, (4R / S trans)I-40, (4R / S trans)I-41, (4R / S trans)I-42, (4R / S trans)I-43, (4R / S trans)I-44, (4R / S trans)I-45, (4R / S trans)I-46, (4R / S trans)I-49, (4R / S trans)I-50, (S, 4R / S trans)I-51, (R, 4R / S trans)I-51, (R, 4R / S trans)I-52, (S, 4R / S trans)I-52, and (R, 4R / S trans)I-53.

[0388] B: Biology Example 3 Biological assays a) Subarachnoid drug treatment Intrathecal (it) injections were performed in fully conscious mice according to previously described procedures (Gadotti et al., 2013, Gadotti et al., 2015). The dorsal fur of the mice was shaved 24 hours before injection. The animals were manually fastened, the spine arched, and a 30-gauge needle attached to a 25 μl Hamilton® microsyringe (Hamilton, Birmingham, UK) with PE20 polyethylene tubing was inserted into the subarachnoid space between the L4 and L5 vertebrae. Placement of the needle tip was confirmed by the animal's characteristic tail flick response, indicating correct needle placement. A 10 μl i.t. injection was delivered over a minimum of 5 seconds.

[0389] b) Formalin-induced pain assay Formalin-induced pain assays were performed as originally described (Huskaar et al., 1985) and previously described by the present applicant (Gadotti et al., 2013; Gadotti et al., 2015). Mice were always allowed to acclimate to the laboratory for at least 60 min before the experiment. Mice received a 20 μl volume of formalin solution (2.5%) prepared in phosphate-buffered saline (PBS) via intraplantar injection (i.p.) into the ventral surface of the right hind paw. Immediately after formalin injection, mice were individually placed into an observation chamber, and the time spent licking or biting the injected paw was recorded and considered as a nociceptive defense response. The nociceptive response of each animal was scored separately from 0 to 5 min (neuron differentiation phase) and 15 to 30 min (inflammatory phase). Exemplary and test compounds were administered intraspinal (it) 20 minutes before mice received formalin and their effects on both the nociceptive and inflammatory phases of the formalin test were analyzed. Screening of active compounds in a 384-well plate format

[0390] c) Screening and Cav3.2-USP5 ELISA A NeutrAvidin®-coated black 384-well plate (Thermoscientific) was preincubated with 60 μl of blocking buffer (Tris-BSA 1%) for 1 hour at room temperature. The plate was washed three times with 60 μl of Tris pH 7.5 buffer for 7 minutes each, and then 25 μl of Tris pH 7.5 buffer was added to the wells. Next, 0.0039 μg / μl of biotinylated Cav3.2-III-IV linker peptide in 15 μl of Tris buffer was added to the wells for 1 hour at room temperature. Then, 0.00078 μg / μl of USP5 human long isoform recombinant protein (Enzo Life Sciences) in 15 μl of Tris pH 7.5 buffer was added to all wells except the negative control wells for 1 hour at room temperature. After washing the wells three times for 7 minutes with 60 μl of Tris pH 7.5 buffer, 40 μl of anti-USP5 polyclonal antibody in blocking buffer (Tris-BSA 1%, 1:5000 dilution, 1 hour at room temperature) was added. Then, the wells were washed three times for 7 minutes with 60 μl of wash buffer Tris-tween-0.05% and 40 μl of anti-rabbit HRP-conjugated secondary antibody in blocking buffer, 1:10,000 dilution, was added. After washing three times for 7 minutes with wash buffer Tris-tween-0.05%, 27 μl of QuantaBlu® (ThermoScientific) substrate + 3 μl of stabilizer (9:1) was added for 10 minutes. Thirty microliters of QuantaBlu stop solution was added, and relative fluorescence units (RFU) readings (excitation / emission: 325 / 420 nm) were taken using the automatic setting of a SpectraMax Gemini XS microplate reader with 10 readings per well. The resulting raw data were converted to percentage inhibition, and signal-to-noise (S / N) values ​​were calculated. The net negative control values ​​for each drug (drug + Cav3.2-III-IV linker) were subtracted from the net values ​​(drug + Cav3.2-III-IV linker + USP5). Dose-response curves were performed by adding increasing amounts of compound.

[0391] d) USP5 / Cav3.2 interaction docking simulation Molecular docking simulations were performed as described by Garcia-Caballero et al. (2022).

[0392] Results and Discussion A series of tetrahydroquinolines was synthesized and tested for their ability to disrupt the interaction between the deubiquitinase USP5 and the Cav3.2 calcium channel domain III-IV linker region. At a screening concentration of 10 μM, a clear structure-activity relationship was observed among the exemplary compounds, with some compounds completely inhibiting the interaction and others having a lesser effect. Table 1 shows the % inhibition of exemplary compounds of Formula I in the Cav3.2-USP5 ELISA assay described above.

[0393] [Table 1-15]

[0394] [Table 1-16]

[0395] [Table 1-17]

[0396] [Table 1-18]

[0397] [Table 1-19]

[0398] [Table 1-20]

[0399] [Table 1-21]

[0400] [Table 1-22]

[0401] [Table 1-23]

[0402] Two potent exemplary compounds, (4R / S trans)I-1 and (4R / S trans)I-2, were further analyzed. Dose-response curves were compiled revealing blocking affinities in the 100 nM range. Table 2 shows the affinities (log C, respectively) of exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 for Cav3.2-USP5 in vitro interaction. 50 Figure 1 shows the dose-dependence of the effects of exemplary compounds (4R / S trans) I-1 and (4R / S trans) I-2 on the biochemical interaction between USP5 and Cav3.2 assessed by ELISA.

[0403] [Table 2]

[0404] FIG. 3 shows the dose-dependence of the effect of the exemplary compound (4R / S trans)I-1 on the biochemical interaction between USP5 and Cav3.2 assessed by ELISA.

[0405] Molecular docking simulations of exemplary compounds with the Cav3.2-III-IV linker-USP5 complex were performed. Figure 2 shows the docking of exemplary compound (4R / S trans) I-1 with the Cav3.2-III-IV linker-USP5 complex. Figure 2 shows the docking of exemplary compound (4R / S trans) I-1 at three potential sites in the USP5 and Cav3.2-III-IV linker sequences. Figure 3 shows the docking of exemplary compound (4R / S trans) I-2 with the Cav3.2-III-IV linker-USP5 complex. Figure 3 shows the docking of exemplary compound (4R / S trans) I-2 at two sites in the USP5 and Cav3.2-III-IV linker sequences. Thus, the molecular docking simulations revealed three potential high-affinity interaction sites for the exemplary compounds of the present application on the Cav3.2-USP5 protein complex.

[0406] Both exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 were tested for possible off-target effects on hERG and human Nav1.5 sodium channels. At a concentration of 5 μM, neither compound exhibited inhibitory effects, thus eliminating general concerns regarding cardiovascular safety. Figure 4A shows the lack of effect of exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 on hERG1 tail currents in tsA-201 cells. Figure 4B shows the lack of effect of exemplary compounds (4R / S trans)I-1 and (4R / S trans)I-2 on human Nav1.5 channels expressed in tsa-201 cells.

[0407] Both compounds were also tested for in vivo activity in the formalin model of acute inflammatory pain. When delivered intrathecally, both compounds mediated a dose-dependent shortening of the duration of formalin-induced nocifensive responses in both phases I and II, demonstrating potent analgesic effects. The illustrative compound (4R / S trans)I-1, administered intraperitoneally, also demonstrated dose-dependent inhibition of both phases of formalin-induced nocifensive responses.

[0408] Figure 5 shows the effect of the exemplary compound (4R / S trans) I-1 on formalin-induced nocifensive responses in mice, either via intrathecal or systemic delivery. Intrathecal or intraperitoneal delivery of the compound resulted in a shortening of the duration of both phases of the formalin-induced nocifensive response in wild-type mice. Specifically, Figure 5 shows the effect of the exemplary compound (4R / S trans) I-1 on phases I (left panel) and II (right panel) of the formalin-induced nocifensive response in mice. Formalin injection into the hind paw mediated nocifensive responses (licking and biting of the paw). There was an initial phase reflecting the acute response to formalin injection, followed by a quiescent period and a second phase of nocifensive behavior reflecting inflammatory pain. The duration of the response reflected the amount of pain. In both phases, the reaction time was dose-dependently shortened by intrathecal delivery of the exemplary compound (4R / S trans) I-1. Thus, the exemplary compound (4R / S trans) I-1 is analgesic in a mouse model of acute inflammatory pain. The same doses were then used in a chronic inflammatory pain assay (i.e., CFA).

[0409] 6 shows the effect of the exemplary compound (4R / S trans)I-2 on formalin-induced nocifensive responses in mice via intrathecal delivery. Administration of the exemplary compound (4R / S trans)I-2 resulted in a shortening of the duration of both phases of the formalin-induced nocifensive responses in wild-type mice.

[0410] Further testing was performed with additional exemplary compounds of the present application. Figure 1B shows the effects of exemplary compounds (S, 4R / S trans) I-51 (first four columns from the left), (R, 4R / S trans) I-51 (fifth to eighth columns from the left), (R, 4R / S trans) I-52 (ninth to twelfth columns from the left), and (S, 4R / S trans) I-52 (thirteenth to sixteenth columns from the left) on the biochemical interaction between USP5 and Cav3.2 as assessed by ELISA.

[0411] Figure 7 shows the effect of an exemplary (4R / S trans)I-40 on formalin-induced acute inflammatory pain. The compound was delivered intrathecally and resulted in a shortening of the duration of both phases of the formalin-induced nocifensive response in wild-type mice.

[0412] Example 4: Paw Withdrawal Latency Paw withdrawal latency (unit: seconds) was used to assess thermal hyperalgesia in the complete Freund's adjuvant (CFA) model using a Hargreaves apparatus. Animals were individually placed in a clear acrylic box on a glass platform for at least 1 hour of acclimation, and then a focused beam of radiant heat (IR=30) was placed under the right hind paw, and paw withdrawal latency was measured and averaged.

[0413] A digital plantar aesthesiometer (DPA, Ugo Basile) was used to measure mechanical paw withdrawal thresholds. Animals were individually placed in a transparent box on top of a grid platform. A device was placed under the platform, and a filament was placed on the plantar surface of each animal's right hind paw. The force (in grams) required to elicit a paw withdrawal response was measured. Mechanical hypersensitivity can also be tested by examining the frequency of paw withdrawal in response to simulation with von Frey filaments.

[0414] Results and Discussion Figure 8 shows the effect of exemplary compound (4R / S trans) I-1 on CFA-induced thermal hypersensitivity. The upper panel shows the time course of the analgesic effect of exemplary compound (4R / S trans) I-1 after intraperitoneal administration of different doses (3 mg / kg and 10 mg / kg) of exemplary compound (4R / S trans) I-1 in CFA-treated wild-type mice. The lower panel shows a comparison of the effect of 10 mg / kg intraperitoneal administration of exemplary compound (4R / S trans) I-1 on thermal withdrawal latencies in wild-type and Cav3.2 null mice. Note that Cav3.2 null mice did not respond to the compound, suggesting that Cav3.2 is a drug target.

[0415] Figure 9 shows a comparison of the effects of 10 mg / kg i.p. exemplary compounds (4R / S trans)I-35 (top panel) and (4R / S trans)I-40 (bottom panel) on thermal escape latency in wild-type and Cav3.2 null mice, which did not respond to the compounds, suggesting that Cav3.2 is a drug target.

[0416] Figure 10 shows the effects of exemplary compounds (4R / S trans)I-52 (top panel), (4R / S trans)I-49 (middle panel), and (4R / S trans)I-52 (bottom panel) on CFA-induced thermal hypersensitivity. CFA injection resulted in a shortening of the thermal paw withdrawal latency, which was reversed by intraperitoneal injection of the compounds.

[0417] Figure 11 shows the effects of exemplary compounds (4R / S trans)I-2 (top left), (4R / S trans)I-40 (top right), (4R / S trans)I-1 (bottom left), and (4R / S trans)I-31 (bottom right) on CFA-induced thermal hypersensitivity. CFA injection resulted in a shortening of the thermal paw withdrawal latency, which was reversed by intraperitoneal injection of the compounds.

[0418] Figure 12 (top panel) shows the effect of orally delivered exemplary compound (4R / S trans)I-31 on CFA-induced thermal hypersensitivity. CFA infusion resulted in a shortening of the thermal paw withdrawal latency, which was reversed by oral delivery of 30 mg / kg of exemplary compound (4R / S trans)I-31. The analgesic effect of exemplary compound (4R / S trans)I-31 was more pronounced than that of the control analgesic, naproxen, at the same oral dose. Figure 12 (bottom panel) shows that the exemplary compound (4R / S trans)I-31 was ineffective in Cav3.2 null mice upon oral administration (bottom panel), supporting the idea that Cav3.2 channels are a drug target.

[0419] Figure 13 shows the effect of the exemplary compound (4R / S trans)I-40 on nerve injury-induced neuropathic pain in a repeated administration regimen. Mice were subjected to sciatic nerve injury, resulting in neuropathic pain. This was assessed by measuring the paw withdrawal threshold in response to mechanical stimulation with increasing force (unit: grams). Nerve injury reduced the withdrawal threshold, which was partially reversed by intraperitoneal administration of (4R / S trans)I-40. This effect persisted over repeated daily administration, disappeared when drug administration was stopped on day 11, and could be observed again when it was resumed on day 14. These data indicate that there was no development of analgesic tolerance.

[0420] Figure 14 shows a comparison of the effects of 10 mg / kg intraperitoneally of the exemplary compound (4R / S trans) I-40 on mechanical hypersensitivity in mice with oxaliplatin-induced mechanical hypersensitivity. Repeated oxaliplatin treatment caused neuropathic pain, assessed by examining paw withdrawal frequency in response to mechanical stimulation of the hind paw using von Frey filaments. Oxaliplatin-treated mice showed an increase in paw withdrawal frequency that was potently reversed by systemic administration of the exemplary compound (4R / S trans) I-40. These data demonstrate that the exemplary compound (4R / S trans) I-40 acts in chemotherapy-induced neuropathic pain. The data in the lower panel correspond to the baseline T0 and T60 data points in the upper panel, but show individual data points rather than simply average values.

[0421] Although the present application has been described with reference to examples, it should be understood that the scope of the patentable class should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

[0422] All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that terms in this application are found to have different definitions in the documents incorporated herein by reference, the definitions provided herein shall serve as the definitions of such terms.

[0423] Full citations for documents referenced herein Several publications are cited herein. Full citations for these references are provided below. Each of these references is herein incorporated by reference in its entirety into the present disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0424] Hunskaar S, Fasmer OB, Hole K (1985) Formalin test in mice, a useful technique for evaluating mild analgesics. J Neurosci Methods 14(1):69-76.

[0425] Gadotti VM, Caballero AG, Berger ND, Gladding CM, Chen L, Pfeifer TA, Zamponi GW (2015) Small organic molecule disruptors of Cav3.2-USP5 interactions reverse inflammatory and neuropathic pain. Mol Pain 11:12.doi:10.1186 / s12990-015-0011-8 22.

[0426] Gadotti VM,You H,Petrov RR,Berger ND,Diaz P,Zamponi GW(2013)Analgesic effect of a mixed T-type channel inhibitor / CB2 receptor agonist.Mol Pain 9:32. doi:10.1186 / 1744-8069-9-32。

[0427] Garcia-Caballero A,Gadotti VM,Ali MY,Bladen C,Gambeta E, Van Humbeck JF, MacCallum JL,Zamponi GW.(2022)A Synthetically Accessible Small-Molecule Inhibitor of USP5-Cav3.2 Calcium Channel Interactions with Analgesic Properties. ACS Chem Neurosci.13(4):524-536。

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or prodrug thereof: 【Chemistry 1】 In formula (I), X is C, O, N, NH, S, S(O), and SO ２ Selected from: 【Chemistry 2】 is a single or double bond, provided that when X is C or N, 【Transformation 3】 is a double bond; A is phenyl and C ５～６ heteroaryl; R １ is R ５ , OR ５ and NR ５ R ６ Selected from: R ２ is H, halo, C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～６ Alkylene C ３～６ Cycloalkyl, C １～６ Alkylene C ３～１０ Heterocycloalkyl, C １～６ alkylenephenyl, and C １～６ Alkylene C ５～１０ heteroaryl, the latter ten groups being selected from OH, halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, NH ２ , NH(C １～６ alkyl) and N(C １～６ alkyl) (C １～６ alkyl); R ３ is H, halo, C １～６ Alkyl and C １～６ haloalkyl; or R ２ and R ３ together with the atoms between them, N, NH, N(C １－６ alkyl), O, S, S(O), and SO ２ and may contain one or two hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １－６ Alkyl and C １－６ forming a 3- to 7-membered saturated or unsaturated ring optionally substituted by 1 to 4 substituents selected from haloalkyl; Each R ４ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OH, NH ２ , S.H., S.C. １～６ Alkyl, SC １～６ Haloalkyl, OC １～６ Alkyl, OC １～６ Haloalkyl, NH(C １～６ alkyl), N(C １～６ alkyl) (C １～６ alkyl), C(O)H, C(O)C １～６ Alkyl, C(O)C １～６ Haloalkyl, CO ２ H, C(O) ２ C １～６ Alkyl, C(O) ２ C １～６ Haloalkyl, CONH ２ , CONHC １～６ Alkyl and CON(C １～６ alkyl) (C １～６ alkyl); R ５ is H, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylene R ７ and C １～６ Haloalkylene R ７ wherein each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～６ Alkylene C ３～６ Cycloalkyl, C １～６ Alkylene C ３～１０ Heterocycloalkyl, C １～６ alkylenephenyl, and C １～６ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, NH ２ , NH(C １～６ alkyl), N(C １～６ alkyl) (C １～６ alkyl), C(O)NH ２ , C(O)NH(C １～６ alkyl), C(O)N(C １～６ alkyl) (C １～６ alkyl), SO ２ NH ２ , S.O. ２ NH (C １～６ alkyl) and SO ２ N (C １～６ alkyl) (C １～６ alkyl); R ６ is H, C １～６ Alkyl and C １～６ haloalkyl; or R ５ and R ６ together with the nitrogen atom therebetween, form N, NR ８’ , O, S, S(O), and SO ２ and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １～６ Alkyl, C １～６ Haloalkyl, NR ８ R ９ , OR ８ , CO ２ R ８ , C(O)NR ８ R ９ , S.O. ２ NR ８ R ９ , C １～６ Alkylene NR ８ R ９ , C １～６ Alkylene OR ８ , C １～６ Alkylene CO ２ R ８ , and C １～６ AlkyleneC(O)NR ８ R ９ and each alkyl and alkylene forms a 3- to 12-membered heterocycloalkyl or heteroaryl ring optionally substituted with 1 to 4 substituents selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～６ Alkylene C ３～６ Cycloalkyl, C １～６ Alkylene C ３～１０ Heterocycloalkyl, C １～６ alkylenephenyl, and C １～６ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, NH ２ , NH(C １～６ alkyl) and N(C １～６ alkyl) (C １～６ alkyl); R ７ OH, CN, NO ２ , CHO, SH, NH ２ , CO ２ H, C(O)NH ２ , P.O. ３ H, SO ２ H, SO ２ NH ２ , NHSO ２ H, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１０ Aryl, C ５～１０ Heteroaryl, OC １～１０ Alkyl, OC １～１０ Haloalkyl, SC １～１０ Alkyl, SC １～１０ Haloalkyl, NH(C １～６ alkyl), N(C １～６ alkyl) (C １～６ alkyl), C(O)C １～６ Alkyl, CO ２ C １～６ Alkyl, C(O)NHC １～６ Alkyl, C(O)N(C １～６ alkyl) (C １～６ alkyl), PO(OC １～６ alkyl) (OC １～６ alkyl), SO ２ C １～６ Alkyl, SO ２ NH (C １～６ alkyl), SO ２ N (C １～６ alkyl) (C １～６ alkyl), NC １～１０ Alkyl SO ２ (C １～６ alkyl), and NHSO ２ (C １～６ alkyl); R ８ is H, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylene R １０ and C １～６ Haloalkylene R １０ wherein each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～６ Alkylene C ３～６ Cycloalkyl, C １～６ Alkylene C ３～１０ Heterocycloalkyl, C １～６ alkylenephenyl, and C １～６ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, NH ２ , NH(C １～６ alkyl) and N(C １～６ alkyl) (C １～６ alkyl); R ８’ H, SO ２ NH ２ , S.O. ２ NH (C １～６ alkyl), SO ２ N (C １～６ alkyl) (C １～６ alkyl), C(O)NH ２ , C(O)NH(C １～６ alkyl), C(O)N(C １～６ alkyl) (C １～６ alkyl), C １～６ Haloalkyl, C １～６ Alkylene R １０ and C １～６ Haloalkylene R １０ wherein each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～６ Alkylene C ３～６ Cycloalkyl, C １～６ Alkylene C ３～１０ Heterocycloalkyl, C １～６ alkylenephenyl, and C １～６ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～６ Alkyl, C １～６ Haloalkyl, NH ２ , NH(C １～６ alkyl) and N(C １～６ alkyl) (C １～６ alkyl); R ９ is H, C １～６ Alkyl and C １～６ haloalkyl; R １０ OH, CN, NO ２ , CHO, SH, NH ２ , CO ２ H, C(O)NH ２ , P.O. ３ H, SO ２ H, SO ２ NH ２ , NHSO ２ H, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１０ Aryl, C ５～１０ Heteroaryl, OC １～１０ Alkyl, OC １～１０ Haloalkyl, SC １～１０ Alkyl, SC １～１０ Haloalkyl, NH(C １～６ alkyl), N(C １～６ alkyl) (C １～６ alkyl), C(O)C １～６ Alkyl, CO ２ C １～６ Alkyl, C(O)NHC １～６ Alkyl, C(O)N(C １～６ alkyl) (C １～６ alkyl), PO(OC １～６ alkyl) (OC １～６ alkyl), SO ２ C １～６ Alkyl, SO ２ NH (C １～６ alkyl), SO ２ N (C １～６ alkyl) (C １～６ alkyl), NC １～１０ Alkyl SO ２ (C １～６ alkyl), and NHSO ２ (C １～６ alkyl); and n is selected from 0, 1, 2, 3, and 4.

2. The substituents in the compounds of formula I 【Chemistry 4】 is attached at the C6 position of the tetrahydroquinoline core. 【Request Item 3】 【Chemistry 5】 is a single bond, and X is O, NH, S, S(O), and SO ２ 3. The compound of claim 1 or claim 2, selected from: 【Request Item 4】 【Chemistry 6】 The compound of claim 3 , wherein is a single bond and X is O. 【Request Item 5】 【Chemistry 7】 3. The compound of claim 1 or claim 2, wherein: is a double bond; and X is N or C. 【Request Item 6】 【Chemistry 8】 The compound of claim 5 , wherein is a double bond and X is C.

7. The compound of any one of claims 1 to 6, wherein A is phenyl.

8. A is C ５～６ The compound according to any one of claims 1 to 6, which is heteroaryl.

9. Said C ５～６ 9. The compound of claim 8, wherein heteroaryl is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and triazinyl.

10. R ４ Ha, Halo, C １～４ Alkyl, C １～４ Haloalkyl, OH, NH ２ , OH, SH, SC １～４ Alkyl, SC １～４ Haloalkyl, OC １～４ Alkyl, OC １～４ Haloalkyl, NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ alkyl), C(O)H, C(O)C １～４ Alkyl, C(O)C １～４ Haloalkyl, CO ２ H, CO ２ C １～４ Alkyl, CO ２ C １～４ Haloalkyl, CONH ２ , CONHC １～４ Alkyl and CON(C １～４ alkyl) (C １～４ The compound according to any one of claims 1 to 9, wherein the compound is selected from the group consisting of alkyl.

11. R ４ are F, Cl, C １～４ Alkyl, C １～４ Fluoroalkyl, C １～４ Chloroalkyl, OC １～２ Alkyl, OC １～２ Fluoroalkyl and OC １～２ 11. The compound of claim 10, wherein the compound is selected from chloroalkyl.

12. R ４ are F, Cl, CH ３ , C.F. ３ , C.F.H. ２ , CHF ２ , CCl ３ , C.H. ３ , OCF ３ , OCFH ２ , OCHF ２ and OCCl ３ 12. The compound of claim 11 selected from:

13. The compound according to any one of claims 1 to 12, wherein n is selected from 0, 1 and 2.

14. R ２ is H, halo, C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C ３～７ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～６ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ heteroaryl, the latter eight groups being selected from OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl) and N(C １～４ alkyl) (C １～４ The compound according to any one of claims 1 to 13, optionally substituted with one or more substituents selected from the group consisting of alkyl,

15. R ２ is H, halo, C １～４ Alkyl and C １～４ 15. The compound of claim 14, wherein the alkyl is selected from fluoroalkyl.

16. R ２ is H.

17. R ３ is H, halo, C １～４ Alkyl and C １～４ The compound of any one of claims 1 to 16, selected from haloalkyl.

18. R ３ is H.

19. R ２ and R ３ together with the atoms between them, N, NH, N(C １－４ alkyl), O, S, S(O), and SO ２ and may contain one or two hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １－４ Alkyl, C １－４ Fluoroalkyl and C １－４ The compound according to any one of claims 1 to 18, which forms a 3- to 7-membered saturated or unsaturated ring, optionally substituted by 1 to 4 substituents selected from chloroalkyl.

20. R ２ and R ３ together with the atoms between them, form OH, F, Cl, CN, NO ２ , CHO, C １－４ Alkyl, C １－４ Fluoroalkyl and C １－４ 20. The compound according to claim 19, which forms a cyclopropyl, cyclobutyl or cyclopentyl ring optionally substituted with one to two substituents selected from chloroalkyl.

21. R ２ and R ３ together with the atoms between them, N, NH, N(C １－４ alkyl), O, S, S(O), and SO ２ and containing one or two hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １－４ Alkyl, C １－４ Fluoroalkyl and C １－４ 20. The compound according to claim 19, which forms a 3- to 7-membered saturated or unsaturated ring, optionally substituted by 1 to 4 substituents selected from chloroalkyl.

22. R １ is R ５ The compound according to any one of claims 1 to 21,

23. R １ is OR ５ The compound according to any one of claims 1 to 21,

24. NR ５ R ６ The compound according to any one of claims 1 to 21,

25. R ５ is H, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkylene R ７ and C １～４ Haloalkylene R ７ wherein each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ alkyl), C(O)NH ２ , C(O)NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ alkyl), SO ２ NH ２ , S.O. ２ NH (C １～４ alkyl) and SO ２ N (C １～４ alkyl) (C １～４ The compound according to any one of claims 1 to 24, optionally substituted with one or more substituents selected from the group consisting of alkyl,

26. R ７ OH, CN, NO ２ , CHO, SH, NH ２ , CO ２ H, C(O)NH ２ , P.O. ３ H, SO ２ H, SO ２ NH ２ , NHSO ２ H, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１０ Aryl, C ５～１０ Heteroaryl, OC １～４ Alkyl, OC １～４ Haloalkyl, SC １～４ Alkyl, SC １～４ Haloalkyl, NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ alkyl), C(O)C １～４ Alkyl, CO ２ C １～４ Alkyl, C(O)NHC １～４ Alkyl, C(O)N(C １～４ alkyl) (C １～４ alkyl), PO(OC １～４ alkyl) (OC １～４ alkyl), SO ２ C １～４ Alkyl, SO ２ NH (C １～４ alkyl), SO ２ N (C １～４ alkyl) (C １～４ alkyl), NC １～４ Alkyl SO ２ (C １～４ alkyl) and NHSO ２ (C １～４ 26. The compound of claim 25, wherein the aryl group is selected from the group consisting of aryl, ...

27. R ７ OH, CO ２ H, O.C. １～４ Alkyl, OC １～４ Fluoroalkyl and CO ２ C １～４ 27. The compound of claim 26, wherein the alkyl is selected from the group consisting of aryl, aryl, arylsulfonyl ...

28. R ５ is H, C １～４ Alkyl, C １～４ Fluoroalkyl, C １～４ Chloroalkyl, C １～４ Alkylene OH, C １～４ Alkylene CO ２ H, C １～４ Alkylene OC １～４ Alkyl, C １～４ Alkylene CO ２ C １～４ Alkyl, C １～４ Fluoroalkylene OH,C １～４ Fluoroalkylene CO ２ H, C １～４ Fluoroalkylene OC １～４ Alkyl, C １～４ Fluoroalkylene CO ２ C １～４ alkyl, where each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Fluoroalkyl, C １～４ Chloroalkyl, NH ２ , NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ alkyl), C(O)NH ２ , C(O)NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ alkyl), SO ２ NH ２ , S.O. ２ NH (C １～４ alkyl) and SO ２ N (C １～４ alkyl) (C １～４ The compound according to any one of claims 25 to 27, optionally substituted with 1 to 4 substituents selected from alkyl.

29. R ５ is C １～３ Alkylene OH, C １～３ Alkylene CO ２ H, C １～３ Alkylene OC １～３ Alkyl, C １～３ Alkylene CO ２ C １～３ Alkyl, C １～３ Fluoroalkylene OH,C １～３ Fluoroalkylene CO ２ H, C １～３ Fluoroalkylene OC １～３ Alkyl, C １～３ Fluoroalkylene CO ２ C １～３ Alkyl, C １～４ Alkylene SO ２ NH ２ , C １～４ Alkylene SO ２ NH (C １～４ alkyl) and C １～４ Alkylene SO ２ N (C １～４ alkyl) (C １～４ 29. The compound of claim 28, wherein the aryl group is selected from the group consisting of aryl, ...

30. R ６ is H, C １～４ Alkyl and C １～４ The compound of any one of claims 1 to 29, selected from haloalkyl.

31. R ６ is H.

32. R ５ and R ６ together with the nitrogen atom therebetween, form N, NR ８’ , O, S, S(O), and SO ２ and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １～６ Alkyl, C １～６ Haloalkyl, NR ８ R ９ , OR ８ , CO ２ R ８ , C(O)NR ８ R ９ , S.O. ２ NR ８ R ９ , C １～４ Alkylene NR ８ R ９ , C １～４ Alkylene OR ８ , C １～４ Alkylene NCO ２ R ８ , and C １～４ Alkylene C(O)R ８ R ９ and forming a 3- to 10-membered heterocycloalkyl or heteroaryl ring, optionally substituted by 1 to 4 substituents selected from: ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl) and N(C １～４ alkyl) (C １～４ 25. The compound of claim 24, optionally substituted with one or more substituents selected from: alkyl;

33. R ５ and R ６ together with the nitrogen atom therebetween, form NR ８’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １～４ Alkyl, C １～４ Haloalkyl, NR ８ R ９ , OR ８ , CO ２ R ８ , C(O)NR ８ R ９ , S.O. ２ NR ８ R ９ , C １～４ Alkylene NR ８ R ９ , C １～４ Alkylene OR ８ , C １～４ Alkylene CO ２ R ８ and C １～４ AlkyleneC(O)NR ８ R ９ and each alkyl and alkylene forms an 8- to 10-membered heterocycloalkyl ring, optionally substituted by one or two substituents selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl) and N(C １～４ alkyl) (C １～４ 33. The compound of claim 32, optionally substituted with 1 to 4 substituents selected from: alkyl;

34. R ５ and R ６ together with the nitrogen atom therebetween, form NR ８’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １～４ Alkyl, C １～４ Haloalkyl, NR ８ R ９ , OR ８ , CO ２ R ８ , C(O)NR ８ R ９ , S.O. ２ NR ８ R ９ , C １～４ Alkylene NR ８ R ９ , C １～４ Alkylene OR ８ , C １～４ Alkylene CO ２ R ８ and C １～４ AlkyleneC(O)NR ８ R ９ and each alkyl and alkylene forms a 5- to 6-membered heterocycloalkyl ring, optionally substituted by one or two substituents selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl) and N(C １～４ alkyl) (C １～４ 33. The compound of claim 32, optionally substituted with 1 to 4 substituents selected from: alkyl;

35. R ５ and R ６ together with the nitrogen atom therebetween to form tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, piperidinyl and piperazinyl, each of which independently represents OH, F, Cl, CN, NO ２ , CHO, C １～４ Alkyl and C １～４ 33. The compound of claim 32, optionally substituted with one or two substituents selected from haloalkyl.

36. R ５ and R ６ together with the nitrogen atom therebetween to form one additional NR selected from pyrazolidinyl and piperazinyl ８’ Contains hetero moieties, OH, F, Cl, CN, NO ２ , CHO, C １～４ Alkyl and C １～４ 33. The compound of claim 32, which forms a 5- to 6-membered heterocycloalkyl ring, optionally substituted with one or two substituents selected from haloalkoxy.

37. R ５ and R ６ together with the nitrogen atom therebetween, form N, NR ８’ and O, and may contain one or two additional hetero moieties selected from OH, F, Cl, CN, NO ２ , CHO, C １～６ Alkyl, C １～６ Haloalkyl, NR ８ R ９ , OR ８ , CO ２ R ８ , C(O)NR ８ R ９ , S.O. ２ NR ８ R ９ , C １～４ Alkylene NR ８ R ９ , C １～４ Alkylene OR ８ , C １～４ Alkylene CO ２ R ８ and C １～４ AlkyleneC(O)NR ８ R ９ and wherein each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl) and N(C １～４ alkyl) (C １～６ 33. The compound of claim 32, optionally substituted with 1 to 4 substituents selected from: alkyl;

38. R ８ is H, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkylene R １０ and C １～４ Haloalkylene R １０ wherein each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ The compound according to any one of claims 32 to 37, optionally substituted with one or more substituents selected from: alkyl.

39. R １０ OH, CN, NO ２ , CHO, SH, NH ２ , CO ２ H, C(O)NH ２ , P.O. ３ H, SO ２ H, SO ２ NH ２ , NHSO ２ H, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１０ Aryl, C ５～１０ Heteroaryl, OC １～４ Alkyl, OC １～４ Haloalkyl, SC １～４ Alkyl, SC １～４ Haloalkyl, NH(C １～４ alkyl), N(C １～４ alkyl) (C １～４ alkyl), C(O)C １～４ Alkyl, CO ２ C １～４ Alkyl, C(O)NHC １～４ Alkyl, C(O)N(C １～４ alkyl) (C １～４ alkyl), PO(OC １～４ alkyl) (OC １～４ alkyl), SO ２ C １～４ Alkyl, SO ２ NH (C １～４ alkyl), SO ２ N (C １～４ alkyl) (C １～４ alkyl), NC １～４ Alkyl SO ２ (C １～４ alkyl) and NHSO ２ (C １～４ 39. The compound of claim 38, wherein the aryl group is selected from the group consisting of aryl, ...

40. R １０ OH, CO ２ H, P.O. ３ H, SO ２ H, SO ２ NH ２ , O.C. １～４ Alkyl, OC １～４ Haloalkyl, CO ２ C １～４ Alkyl, SO ２ NH (C １～４ alkyl), SO ２ N (C １～４ alkyl) (C １～４ 40. The compound of claim 39, wherein the alkyl is selected from alkyl.

41. R ８ is H, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkylene SO ２ NH ２ , C １～４ Haloalkylene SO ２ NH ２ , C １～４ Alkylene SO ２ NH (C １～４ alkyl), C １～４ Haloalkylene SO ２ NH (C １～４ alkyl), C １～４ Alkylene SO ２ N (C １～４ alkyl) (C １～４ alkyl), C １～４ Haloalkylene SO ２ N (C １～４ alkyl) (C １～４ alkyl), C １～４ Alkylene OH, C １～４ Haloalkylene OH, C １～４ Alkylene CO ２ H, C １～４ Haloalkylene CO ２ H, C １～４ Alkylene OC １～４ Alkyl, C １～４ Haloalkylene OC １～４ Alkyl, C １～４ Alkylene CO ２ C １～４ Alkyl, and C １～４ Alkylene CO ２ C １～４ alkyl, where each alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Haloalkyl, NH ２ , NH(C １～４ alkyl) and N(C １～４ alkyl) (C １～４ The compound according to any one of claims 38 to 40, optionally substituted by 1 to 4 substituents selected from alkyl.

42. R ８ is H.

43. R ８ is C １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ 42. The compound of claim 41, wherein the compound is selected from chloroalkyl.

44. R ８’ is SO ２ NH ２ , S.O. ２ NH (C １～４ alkyl), SO ２ N (C １～４ alkyl) (C １～４ alkyl), C １～４ Alkylene SO ２ NH ２ , C １～４ Alkylene SO ２ NH (C １～４ alkyl), C １～４ Alkylene SO ２ N (C １～４ alkyl) (C １～４ alkyl), C １～４ Alkylene OH, C １～４ Alkylene CO ２ H, C １～４ Alkylene OC １～４ Alkyl, C １～４ Alkylene CO ２ C １～４ Alkyl, C １～４ Fluoroalkylene OH,C １～４ Fluoroalkylene CO ２ H, C １～４ Fluoroalkylene OC １～４ Alkyl, and C １～４ Fluoroalkylene CO ２ C １～４ alkyl, where each alkyl and alkylene is selected from OH, C ３～６ Cycloalkyl, C ３～１０ Heterocycloalkyl, phenyl, C ５～１０ Heteroaryl, C １～４ Alkylene C ３～６ Cycloalkyl, C １～４ Alkylene C ３～１０ Heterocycloalkyl, C １～４ alkylenephenyl, and C １～４ Alkylene C ５～１０ and optionally substituted by one or two substituents selected from heteroaryl, the latter eight groups being OH, halo, CN, C １～４ Alkyl, C １～４ Fluoroalkyl, C １～４ Chloroalkyl, NH ２ , NH(C １～４ alkyl) and N(C １～４ alkyl) (C １～４ 42. The compound of claim 41, optionally substituted with one or two substituents selected from alkyl.

45. R ９ is H, C １～４ Alkyl, C １～４ Fluoroalkyl and C １～４ 45. The compound of any one of claims 1 to 44, selected from chloroalkyl.

46. R ９ is H.

47. R １ but 【Chemistry 9】 【Chemistry 10】 The compound according to any one of claims 1 to 21, selected from:

48. 48. The compound of any one of claims 1 to 47, wherein the compound of formula I is a mixture of cis isomers having the structures (3aR,4R,9bR) and (3aS,4S,9bS), or wherein the compound of formula I is a mixture of trans isomers having the structures (3aR,4S,9bR) and (3aS,4R,9bS).

49. 2. The compound of claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, wherein said compound of formula I is selected from the compounds listed below: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14

50. 50. A method for inhibiting the interaction between CaV3.2 T-type calcium channel (Cav3.2) and ubiquitin-specific peptidase 5 (USP5) in a cell, either in a biological sample or in a patient, comprising administering to the cell an effective amount of a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt and / or solvate thereof.

51. 50. A method for treating a disease, disorder or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt and / or solvate thereof.

52. 50. A method for inhibiting CaV3.2 T-type calcium channel (Cav3.2) function and / or expression in cells, either in a biological sample or in a patient, by inhibiting the interaction between CaV3.2 and ubiquitin-specific peptidase 5 (USP5), comprising administering to said cells an effective amount of a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt and / or solvate thereof.

53. 50. A method for treating a disease, disorder or condition treatable by inhibiting the interaction between Cav3.2 and USP5 in a cell, thereby inhibiting Cav3.2 function and / or expression, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt and / or solvate thereof.

54. 50. A method for inhibiting Cav3.2 deubiquitination in a cell, either in a biological sample or in a patient, comprising administering to said cell an effective amount of a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt and / or solvate thereof.

55. 50. A method for treating a disease, disorder or condition treatable by inhibiting Cav3.2 deubiquitination, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt and / or solvate thereof.

56. 56. The method of claim 55, wherein the disease, disorder or condition that can be treated by inhibiting the interaction between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination is pain.

57. 57. The method of claim 56, wherein the pain is acute or chronic pain.

58. 57. The method of claim 56, wherein the pain is nociceptive pain, inflammatory pain, or neuropathic pain.

59. 50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier.

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