Tetrahydroquinoline derivatives for inhibiting cav3.2-usp5 interactions

Abstract

The present application relates to various uses of 5-membered cyclo-fused tetrahydroquinoline derivatives of Formula (I) in the treatment of diseases, disorders or conditions that are treatable by inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5). For example, the compounds of Formula (I) are useful as an analgesic in the treatment of pain. The present application also relates to compounds of Formula (I) or pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

Description

TITLE: TETRAHYDROQUINOLINE DERIVATIVES FOR INHIBITING CAV3.2-USP5 INTERACTIONSRELATED APPLICATIONS

[0001] The present application claims the benefit of priority of co-pending United States provisional patent application no. 63 / 448,421 filed on February 27, 2023, the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] The present application relates to tetrahydroquinoline derivatives to compositions comprising them, and to their use in therapy. More particularly, it relates to 5-membered cyclo-fused tetrahydroquinoline derivatives useful in the treatment of diseases, disorders or conditions treatable by inhibiting interactions between Cav3.2 voltage gated T-type calcium channel and ubiquitin specific peptidase 5 (USP5).BACKGROUND

[0003] In the primary afferent pain pathway, voltage gated T-type calcium channels sustain neuronal firing and appear to contribute to neurotransmitter release at afferent terminals in the spinal dorsal horn. The prominent T-type channel subtype expressed in peripheral afferents is Cav3.2. Cav3.2 T-type calcium channels are important mediators of pain signaling and their activity is upregulated in states of chronic pain (Figure 1)1. Conversely inhibiting these ion channels mediates analgesia in preclinical models. It has been discovered that the aberrant upregulation of Cav3.2 is due to an injury-induced increase in expression of the enzyme USP5, which associates with these channels and increases their stability2-9. This leads to more Cav3.2 channels in pain sensing neurons and thus more pain. It has been shown that depleting sensory neurons of Cav3.2, or preventing the interaction between USP5 and the channels by using cell permeant decoy peptides protects from inflammatory, neuropathic, diabetic and post-surgical pain in mice (Figure 2)9. A high throughput ELISA screen has been used to identify small organic molecules that could prevent USP5 interactions with the channels7(see Figure 3). An initial screen of an active compound library at the Centre for Drug research and Development (CDRD at the University of British Columbia) yielded two hits (suramin and gossypetin) that were found to protect from 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] United States Patent no. 9,993,522 discloses the use of peptide inhibitors of the interaction between Cav3.2 and USP5 for inhibiting a Cav3.2 channel function.

[0005] International application publication no. WO2004 / 098600 discloses tetrahydroquinoline derivatives as positive modulators of nicotinic acetylcholine receptors. International application publication no. WO2004 / 072046 discloses tetrahydroquinoline derivatives for modulating liver-X receptors. International application publication no. WO2016 / 014847 discloses tetrahydroquinoline derivatives ligands for alpha-7 nicotinic acetylcholine receptors. International application publication no. WO2016 / 014847 discloses tetrahydroquinoline derivatives for treating disorders associated with MDM2 activity.

[0006] International application publication no. WO2011 / 009523 discloses methods for predicting the likelihood that a patient suffering from thoracic tumors will respond to treatment with an Eg5 inhibitory compound. SUMMARY

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

[0008] Accordingly, the present application includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:(I) wherein X is selected from C, O, N, NH, S, S(O), and SO2; is a single bond or a double bond, provided is a double bond when X is C or N; A is selected from phenyl and C5-6heteroaryl, R1is selected from R5, OR5and NR5R6; R2is selected from H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter ten groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl);R3is selected from H, halo, C1-6alkyl and C1-6haloalkyl; or R2and R3are joined to form, together with the atom therebetween, a 3- to 7- membered saturated or unsaturated ring, optionally containing one or two heteromoieties selected from N, NH, N(C1-6alkyl), O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl and C1-6haloalkyl; each R4is independently selected from halo, C1-6alkyl, C1-6haloalkyl, OH, NH2, SH, SC1-6alkyl, SC1-6haloalkyl, OC1-6alkyl, OC1-6haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)H, C(O)C1-6alkyl, C(O)C1-6haloalkyl, CO2H, C(O)2C1-6alkyl, C(O)2C1-6haloalkyl, CONH2, CONHC1-6alkyl and CON(C1-6alkyl)(C1-6alkyl); R5is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR7and C1-6haloalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1- 6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)NH2, C(O)NH(C1-6alkyl), C(O)N(C1-6alkyl)(C1-6alkyl), SO2NH2, SO2NH(C1-6alkyl), and SO2N(C1-6alkyl)(C1-6alkyl); R6is selected from H, C1-6alkyl and C1-6haloalkyl; or R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 12- membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8', O, S, S(O), and SO2 and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-6alkyleneNR8R9, C1-6alkyleneOR8, C1- 6alkyleneCO2R8, and C1-6alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3- 10heterocycloalkyl, C1-6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R7is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6-10aryl, C5-10heteroaryl, OC1-10alkyl, OC1-10haloalkyl, SC1-10alkyl, SC1-10haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl),SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-10alkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl); R8is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR10and C1-6haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R8'is selected from H, SO2NH2, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), C(O)NH2, C(O)NH(C1-6alkyl), C(O)N(C1-6alkyl)(C1-6alkyl), C1-6haloalkyl, C1-6alkyleneR10and C1- 6haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5- 10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1- 6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1- 6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R9is selected from H, C1-6alkyl and C1-6haloalkyl; R10is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6-10aryl, C5-10heteroaryl, OC1-10alkyl, OC1- 10haloalkyl, SC1-10alkyl, SC1-10haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl), SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-10alkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl); and n is selected from 0, 1, 2, 3, or 4.

[0009] The present application includes a method for inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to the cell,

[0010] The present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting interactions between Cav3.2 and USP5 comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0011] The present application also includes a method for inhibiting Cav3.2 deubiquitination in a cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to the cell.

[0012] The present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 deubiquitination comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0013] In an embodiment, the disease, disorder or condition treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination is pain.

[0014] The present application also includes a composition comprising a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof and a carrier.

[0015] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole. BRIEF DESCRIPTION OF DRAWINGS

[0016] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0017] Figure 1 are graphs showing the dose dependence of (A) exemplary compound (4R / S trans) I-1 and exemplary compound (4R / S trans) I-2 on biochemical interactions between USP5 and Cav3.2 as assayed by ELISA, and (B) exemplary compounds (S, 4R / S trans) I-51 (first four bars from the left), (R, 4R / S trans) I-51 (bars five to eight from the left), (R, 4R / S trans) I-52 (bars nine to twelve from the left) and (S, 4R / S trans) I-52 (bars thirteen to sixteen from the left) on biochemical interactions between USP5 and Cav3.2 as assayed by ELISA.

[0018] Figure 2 is a molecular docking simulation showing the docking of exemplary compound (4R / S trans) I-1 to the Cav3.2-III-IV linker-USP5 complex. The docking of exemplary compound (4R / S trans) I-1 at three potential sites at USP5 and the Cav3.2-III-IV linker sequence is shown (arrows).

[0019] Figure 3 is a molecular docking simulation showing the docking of exemplary compound (4R / S trans) I-2 to the Cav3.2-III-IV linker-USP5 complex. The docking of exemplary compound (4R / S trans) I-2 at two sites on USP5 and the Cav3.2-III- IV linker sequence is shown (arrows).

[0020] Figure 4 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 currents in tsA-201 cells. (B) shows the lack of effect of exemplary compounds (4R / S trans) I-1 and (4R / S trans) 1-2 on human Nav1.5 channels expressed in tsa-201 cells.

[0021] Figure 5 are graphs showing the effect of exemplary compound (4R / S trans) I-1 on formalin induced nocifensive responses in mice by either intrathecal delivery (top graphs), or systemic (intraperitoneal) delivery (bottom graphs).

[0022] Figure 6 are graphs showing the effect of exemplary compound (4R / S trans) I-2 on formalin-induced nocifensive responses in mice by intrathecal delivery.

[0023] Figure 7 is a graph showing the effect of exemplary compound (4R / S trans) I-40 (10 µg) on formalin-induced nocifensive responses in mice by intrathecal delivery. Left bar: Vehicle. Right bar: (4R / S trans) I-40.

[0024] Figure 8 are graphs showing the effect of exemplary compound (4R / S trans) I-1 on Complete Freund’s Adjuvant (CFA) induced thermal hypersensitivity. Top graph shows the course of analgesic effect of exemplary compound (4R / S trans) I-1 following 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. Top line of the four lines: phosphate buffered saline (PBS) (20 µg / i.pl.) n=7, second line: 10mg / kg, i.p. (4R / S trans) I-1, n=7, third line: 3 mg / kg, i.p. (4R / S trans) I-1, n =7, and bottom line: control (PBS, 10 mL / kg i.p.), n=7. Bottom graph shows a comparison of the effect of 10 mg / kg intraperitoneal exemplary compound (4R / S trans) I-1 on thermal withdrawal latencies in wild type and in Cav3.2 null mice. Left bar of each set of bars: pretreatment (T0), Right bar of each set of bar: post treatment (45 min).

[0025] Figure 9 are graphs showing the comparison of the effect of 10 mg / kg intraperitoneal exemplary compounds (4R / S trans) I-35 (top graph) and (4R / S trans) I-40 (bottom graph) on thermal withdrawal latencies in wild type and in Cav3.2 null mice. Left bar of each set of bars: baseline (B), second bar in each set of bars: pretreatment (T0), Right bar of each set of bar: post treatment (10 mg / kg, i.p., 30 min).

[0026] Figure 10 are graphs showing the effect of exemplary compounds (S, 4R / S trans) I-52 (top graph), (4R / S trans) I-49 (middle graph), and (R, 4R / S trans) I-52 (bottom graph) on CFA induced thermal hypersensitivity. First bar in each graph: Baseline (B), second bar in each graph: pre-treatment (T0) and third bar in each graph: post treatment of exemplary compound, 3 mg / kg, i.p., 30 min.

[0027] Figure 11 are graphs showing the effect of exemplary compounds (4R / S trans) I-2 (top left graph), (4R / S trans) I-40 (top right graph), (4R / S trans) I-1 (bottom left graph), and (4R / S trans) I-31 (bottom right graph) on CFA induced thermal hypersensitivity. For each graph, left bar: baseline (B), second bar: pretreatment (T0) and right bar: post- treatment.

[0028] Figure 12 are graphs showing the effect of exemplary compound (4R / S trans) I-31 delivered orally on CFA induced thermal hypersensitivity (top graph) and showing exemplary compound (4R / S trans) I-31 was ineffective in Cav3.2 null mice upon oral administration (bottom graph). The top graph includes naproxen as a positive control.

[0029] Figure 13 is a graph showing the effect of exemplary compound (4R / S trans) I-40 on nerve injury induced neuropathic pain in a repeat dosing regimen.

[0030] Figure 14 are graphs showing the comparison of the effect of 10 mg / kg intraperitoneal exemplary compound (4R / S trans) I-40 on mechanical hypersensitivity in mice with oxaliplatin induced mechanical hypersensitivity. The bottom graph represents baseline time point, as well as time points T0 and T60 from the top graph, but shows all the individual data points rather than just mean and S.E.M. DETAILED DESCRIPTION I. Definitions

[0031] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0032] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0033] The term “compound(s) of the application” or “compound(s) of the present application” and the like as used herein refers to a compound of Formula I or pharmaceutically acceptable salts and / or solvates thereof.

[0034] The term “composition(s) of the application” or “composition(s) of the present application” and the like as used herein refers to a composition, such a pharmaceutical composition, comprising a compound of the application.

[0035] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present. The term “and / or” with respect to pharmaceutically acceptable salts and / or solvates thereof means that the compounds of the application exist as individual salts and hydrates, as well as a combination of, for example, a solvate of a salt of a compound of the application.

[0036] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.

[0037] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0038] As used in this application and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0039] The term “consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0040] The term “consisting essentially of’, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or stepsas well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and / or steps.

[0041] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0042] The present description refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0043] The terms "about", “substantially” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.

[0044] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”. For example, the term C1-10alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0045] The term “alkylene”, whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cn1-n2”. For example, the term C1-6alkylene means an alkylene group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0046] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing from 3 to 20 atoms and at least one carbocyclic non aromatic ring. Cycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds. The number of carbon atoms that are possible in thereferenced cycloalkyl group are indicated by the numerical prefix “Cn1-n2”. For example, the term C3-10cycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0047] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 20 atoms in which one or more of the atoms are a heteroatom selected from O, S, SO, SO2,N, NH and substituted N and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e., contain one or more double bonds). When a heterocycloalkyl group contains the prefix Cn1-n2this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as selected from O, S, SO, SO2, N, NH and substituted N and the remaining atoms are C. Heterocycloalkyl groups are optionally benzofused. When part of another group, “heterocycloalkyl” also refers to cyclic groups containing at least one heterocycloalkyl group fused to one or more cyclic groups (e.g. heterocycloalkyl groups are optionally fused to aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups as defined herein).

[0048] The term “aryl” as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring and contains either 6, 9 or 10 carbon atoms, such as phenyl, indanyl or naphthyl.

[0049] The term “heteroaryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring containing 5-20 atoms in which one or more of the atoms are a heteroatom selected from O, S, N, NH and substituted N and the remaining atoms are C. When a heteroaryl group contains the prefix Cn1-n2 this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Heteroaryl groups are optionally benzofused.

[0050] All cyclic groups, including aryl, heteroaryl, heterocycloalkyl and cycloalkyl groups, contain one or more than one ring (i.e., are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond.

[0051] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0052] A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.

[0053] A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.

[0054] The term “fluorosubstituted” refers to the substitution of one or more, including all, available hydrogens in a referenced group with fluoro.

[0055] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0056] The term “haloalkyl” as used herein refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen atom. Thus, for example, “C1-6haloalkyl” (or “C1-C6haloalkyl”) refers to a C1to C6linear or branched alkyl group as defined above with one or more halogen substituents.

[0057] The term “chloroalkyl” as used herein refers to an haloalkyl group as defined above wherein the halogen atom is chloro.

[0058] The term “fluoroalkyl” as used herein refers to an haloalkyl group as defined above wherein the halogen atom is fluoro.

[0059] The term “haloalkylene” as used herein refers to an alkylene group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen atom. Thus, for example, “C1-6haloalkylene” refers to a C1 to C6 linear or branched alkylene group as defined above with one or more halogen substituents.

[0060] The term “chloroalkylene” as used herein refers to an haloalkylene group as defined above wherein the halogen atom is chloro.

[0061] The term “fluoroalkylene” as used herein refers to an haloalkylene group as defined above wherein the halogen atom is fluoro.

[0062] The term “substituted” as used herein means that the referenced atom contains at least one substituent group other that a hydrogen atom.

[0063] The term “substituent” as used herein refers to any chemical grouping, including groups comprising carbon atoms and / or heteroatoms that is compatible with the reaction conditions of the processes of the application.

[0064] When a group is substituted with one or more substituents, it understood that the selection of those substituents is independent of each other. That is, the one or more substituents may be the same or different.

[0065] The term “tetrahydroquinoline” as used herein refers to a compound having the chemical formula and atom numbering:.

[0066] As used herein, the tricyclic core structure of the compound of Formula I has the following atom numbering:For example, when X is O, the tricyclic core structure of the compound of Formula I is “hexahydrofuro[3,2-c]quinoline” and has the following chemical formula and atom numbering:.

[0067] As used herein, the term “4R / S cis” in relation to a compound of Formula I of the application means that the compound of Formula I is a mixture of cis isomer forms of the compound of Formula I, (i.e., (3aR,4R,9bR) and (3aS,4S,9bS)) having the following structures(3aR,4R,9bR)-(I) (3aS,4S,9bS)-(I).

[0068] As used herein, “*” drawn at the 3a, 4 and 9b position of one cis isomer form of a compound of Formula I of the application means that the compound of Formula I is a mixture of both cis isomer forms as described above. For example, the following structuremeans the compound of Formula (I) is a mixture of (3aR,4R,9bR)-(I) and (3aS,4S,9bS) – (I) (e.g., (4R / S cis)-(I)):(4R / S cis)-(I): (3aR,4R,9bR)-(I) and (3aS,4S,9bS –(I)

[0069] As used herein, the term “4R / S trans” in relation to a compound of Formula I of the application means that the compound of Formula I is a mixture of trans isomer forms of the compound of Formula I, i.e., (3aR,4S,9bR) and (3aS,4R,9bS), having the following structures(3aR,4S,9bR)-(I) (3aS,4R,9bS)-(I).

[0070] As used herein, “*” drawn at the 3a,4 and 9b position of one trans isomer form of a compound of Formula I of the application means that the compound of Formula I is a mixture of both trans isomer forms as described above. For example, the following structure means the compound of Formula (I) is a mixture of (3aR,4S,9bR)-(I) and (3aS,4R,9bS) –(I) (e.g, (4R / S trans)-(I)):(4R / S trans)-(I): (3aR,4S,9bR)-(I) and (3aS,4R,9bS) –(I)

[0071] In the processes of the application, it is typical for the compounds, including starting materials and products to be present as a mixture of isomers. For example, when it is shown that the R- or S-isomer is a product or starting material of a reaction, this means that that 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.

[0072] The term "solvent" includes both a single solvent and a mixture “comprising two or more solvents.

[0073] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.

[0074] The term “optionally substituted” refers to groups, structures, or molecules that are either unsubstituted or are substituted with one or more substituents.

[0075] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion 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 a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rdEdition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0076] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.

[0077] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0078] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0079] The term “subject” as used herein 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.

[0080] The term “pharmaceutically acceptable” means compatible with the treatment of subjects.

[0081] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0082] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with, the treatment of subjects.

[0083] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0084] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0085] The term “solvates” as used herein refers to complexes formed between a compound and a solvent from which the compound is precipitated or in which the compound is made. The term “solvate” as used herein means a compound, or a salt of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.

[0086] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0087] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations.

[0088] “Palliating” a disease, disorder or condition means that the extent and / or undesirable clinical manifestations of a disease, disorder or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0089] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition treatable by inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5) in a cell, or manifesting asymptom associated with a disease, disorder or condition treatable by inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5) in a cell.

[0090] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or a compound, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result. For example, in the context of treating a disease, disorder or condition treatable by inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5), an effective amount is an amount that, for example, inhibits interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5) compared to the inhibition without administration of the compound. Effective amounts may vary according to factors such as the disease state, age, sex and / or weight of the subject. The amount of a given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. The effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom. When the disease is pain, amounts that are effective can cause a reduction, for example, in the sensation and / or duration of pain.

[0091] The expression “inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5)” or “ inhibiting interactions between Cav3.2 and USP5” as used herein refers to inhibiting, blocking and / or disrupting an interaction between a therapeutically relevant binding partner, such as USP5, with the Cav3.2 binding domain in a cell. The inhibiting, blocking and / or disrupting causes a therapeutic effect in the cell.

[0092] The expression “inhibiting Cav3.2 deubiquitination” as used herein refers to inhibiting, blocking and / or disrupting the removal of ubiquitin from ubiquitin-conjugated Cav3.2. The inhibiting, blocking and / or disrupting the removal of ubiquitin causes a therapeutic effect in the cell.

[0093] By “inhibiting, blocking and / or disrupting” it is meant any detectable inhibition, block and / or disruption in a given activity or function in the presence of a compound compared to otherwise the same conditions, except for in the absence in the compound.

[0094] The term “Cav3.2” as used herein is an isoform of T-type calcium channels which contributes to propagation and transmission of nociceptive information in the afferent pain pathway.

[0095] The term “USP5” or “ubiquitin specific peptidase 5”, as used herein refers to a deubiquitinating enzyme responsible for removing ubiquitin groups from ubiquitin- conjugated proteins.

[0096] The term “administered” as used herein means administration of a therapeutically effective amount of a compound or compositions of the application to a cell, tissue, organ or subject.

[0097] The term “drug” as used herein, is intended to refer to any compound or mixture of compounds which is capable of exerting an effective pharmacological effect.

[0098] The symbol when drawn perpendicularly across a bond indicates a point of covalent attachment of a chemical group. II. Compounds of the Application

[0099] The Applicants have identified a family of compounds that inhibit and / or bloc Cav3.2 T-type calcium channel (Cav3.2) function and / or expression levels by inhibiting, blocking and / or disrupting interactions between Cav3.2 and ubiquitin specific peptidase 5 (USP5).

[0100] Accordingly, the present application includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:(I) wherein X is selected from C, O, N, NH, S, S(O), and SO2; is a single bond or a double bond, provided is a double bond when X is C or N; A is selected from phenyl and C5-6heteroaryl, R1is selected from R5, OR5and NR5R6;R2is selected from H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter ten groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R3is selected from H, halo, C1-6alkyl and C1-6haloalkyl; or R2and R3are joined to form, together with the atom therebetween, a 3- to 7- membered saturated or unsaturated ring, optionally containing one or two heteromoieties selected from N, NH, N(C1-6alkyl), O, S, S(O), and SO2 and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl and C1-6haloalkyl; each R4is independently selected from halo, C1-6alkyl, C1-6haloalkyl, OH, NH2, SH, SC1- 6alkyl, SC1-6haloalkyl, OC1-6alkyl, OC1-6haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)H, C(O)C1-6alkyl, C(O)C1-6haloalkyl, CO2H, C(O)2C1-6alkyl, C(O)2C1-6haloalkyl, CONH2, CONHC1-6alkyl and CON(C1-6alkyl)(C1-6alkyl); R5is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR7and C1-6haloalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1- 6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)NH2, C(O)NH(C1-6alkyl), C(O)N(C1-6alkyl)(C1-6alkyl), SO2NH2, SO2NH(C1-6alkyl) and SO2N(C1-6alkyl)(C1-6alkyl); R6is selected from H, C1-6alkyl and C1-6haloalkyl; or R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 12- membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8', O, S, S(O), and SO2 and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-6alkyleneNR8R9, C1-6alkyleneOR8, C1- 6alkyleneCO2R8, and C1-6alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl);R7is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6-10aryl, C5-10heteroaryl, OC1-10alkyl, OC1-10haloalkyl, SC1-10alkyl, SC1-10haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl), SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-10alkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl); R8is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR10and C1-6haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1- 6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R8'is selected from H, SO2NH2, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), C(O)NH2, C(O)NH(C1-6alkyl), C(O)N(C1-6alkyl)(C1-6alkyl), C1-6haloalkyl, C1-6alkyleneR10and C1- 6haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5- 10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1- 6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1- 6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R9is selected from H, C1-6alkyl and C1-6haloalkyl; R10is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6-10aryl, C5-10heteroaryl, OC1-10alkyl, OC1- 10haloalkyl, SC1-10alkyl, SC1-10haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl), SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-10alkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl); and n is selected from 0, 1, 2, 3, or 4.

[0101] The present application also includes a compound of Formula (I), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:I)wherein X is selected from C, O, N, NH, S, S(O), and SO2; is a single bond or a double bond, provided is a double bond when X is C or N; A is selected from phenyl and C5-6heteroaryl, R1is selected from R5, OR5and NR5R6; R2is selected from H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter ten groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R3is selected from H, halo, C1-6alkyl and C1-6haloalkyl; or R2and R3are joined to form, together with the atom therebetween, a 3- to 7- membered saturated or unsaturated ring, optionally containing one or two additional heteromoieties selected from optionally N, NH, N(C1-6alkyl), O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl and C1-6haloalkyl; each R4is independently selected from halo, C1-6alkyl, C1-6haloalkyl, OH, NH2, SH, SC1-6alkyl, SC1-6haloalkyl, OC1-6alkyl, OC1-6haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)H, C(O)C1-6alkyl, C(O)C1-6haloalkyl, CO2H, C(O)2C1-6alkyl, C(O)2C1-6haloalkyl, CONH2, CONHC1-6alkyl and CON(C1-6alkyl)(C1-6alkyl); R5is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR7and C1-6haloalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1- 6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl), and N(C1-6alkyl)(C1-6alkyl);R6is selected from H, C1-6alkyl and C1-6haloalkyl; or R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 12- membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8, O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-6alkyleneNR8R9, C1-6alkyleneOR8, C1-6alkyleneCO2R8, and C1-6alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1- 6alkylenephenyl, and C1-6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1- 6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R7is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6-10aryl, C5-10heteroaryl, OC1-10alkyl, OC1- 10haloalkyl, SC1-10alkyl, SC1-10haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl), SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-10alkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl); R8is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR10and C1-6haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-6alkylenephenyl, and C1- 6alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl); R9is selected from H, C1-6alkyl and C1-6haloalkyl; R10is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6-10aryl, C5-10heteroaryl, OC1-10alkyl, OC1- 10haloalkyl, SC1-10alkyl, SC1-10haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl), SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-10alkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl); and n is selected from 0, 1, 2, 3, or 4.

[0102] In some embodiments, the substituent groupin the compound of Formula I, is attached at the C5 or C6 position of the tetrahydroquinoline core. In some embodiments, the substituent groupO jn the compound of Formula I, is attached at the C6 or C7 position of the tetrahydroquinoline core. In some embodiments, the 2 R3substituent group O jn the compound of Formula I, is attached at the C7 or C8 position of the tetrahydroquinoline core. In some embodiments, the substituent groupO in the compound of Formula I, is attached at the C6 position of the tetrahydroquinoline core. R3

[0103] In some embodiments, the substituent groupin the compound of Formula I, is attached at the C5 or C6 position of the tetrahydroquinoline core structure, optionally the C8 or C9 position of the tricyclic core structure of the compound of FormulaI. In some embodiments, the substituent group O jn the compound of Formula I, is attached at the C7 or C8 position of the tetrahydroquinoline core structure optionally the C6 or C7 position of the tricyclic core structure of the compound of Formula I. In some embodiments, the substituent groupjn the compound of Formula I, is attached at the C6 position of the tetrahydroquinoline core optionally the C8 position of tricyclic core structure of the compound of Formula I.R2R3

[0104] In some embodiments, the substituent group O in the compound of Formula I, 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 l-A or a pharmaceutically acceptable salt and / or solvate thereof:wherein A, X, R1, R2, R3, R4and n are as defined in Formula I.

[0105] In some embodiments, is a single bond and X is selected from O, NH, S, S(O), and SO2. In some embodiments, is a single bond and X is selected from S, S(O) and SO2. In some embodiments, is a single bond and X is selected from O and NH. In some embodiments, is a single bond and X is O.

[0106] Accordingly, in some embodiments, is a single bond and X is O, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof is a compound of Formula l-B or a pharmaceutically acceptable salt and / or solvate thereof:wherein A, R1, R2, R3, R4and n are as defined in Formula I.

[0107] In some embodiments, A is phenyl. Accordingly, in some embodiments, the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof is a compound of Formula l-C or a pharmaceutically acceptable salt and / or solvate thereof:wherein X, R1, R2, R3, R4and n are as defined in Formula I.

[0108] In some embodiments, is a double bond and X is N or C. In some embodiments, is a double bond and X is N. In some embodiments, is a double bond and X is C.

[0109] In some embodiments, is a single bond and X is O, and A is phenyl, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof is a compound of Formula I-D or a pharmaceutically acceptable salt and / or solvate thereof: )wherein R1, R2, R3, R4and n are as defined in Formula I.

[0110] In some embodiments, A is C5-6heteroaryl. In some embodiment, the C5-6heteroaryl in A is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazoyl, pyrazolyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl and triazinyl. In some embodiment, the C5-6heteroaryl in A is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazoyl, pyrazolyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl and triazinyl. In some embodiments, the C5-6heteroaryl in A is selected from pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, thiophenyl, pyridinyl, pyrimidinyl and pyrazinyl. In some embodiments, the C5- 6heteroaryl in A is selected from pyrrolyl, imidazolyl, pyrazolyl, pyridinyl and pyrimidinyl.

[0111] In some embodiments, R4is selected from halo, C1-4alkyl, C1-4haloalkyl, OH, NH2, OH, SH, SC1-4alkyl, SC1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, NH(C1-4alkyl), N(C1- 4alkyl)(C1-4alkyl), C(O)H, C(O)C1-4alkyl, C(O)C1-4haloalkyl, CO2H, CO2C1-4alkyl, CO2C1- 4haloalkyl, CONH2, CONHC1-4alkyl and CON(C1-4alkyl)(C1-4alkyl). In some embodiments, R4is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, NH2, OH, SH, SC1-4alkyl, SC1- 4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)H, C(O)C1- 4alkyl, C(O)C1-4haloalkyl, CO2H, CO2C1-4alkyl, CO2C1-4haloalkyl, CONH2, CONHC1-4alkyl and CON(C1-4alkyl)(C1-4alkyl).

[0112] In some embodiments, R4is selected from F, Cl, C1-4alkyl, C1-4haloalkyl, OH, NH2, SH, SC1-4alkyl, SC1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, NH(C1-4alkyl), N(C1- 4alkyl)(C1-4alkyl), C(O)H, C(O)C1-4alkyl, C(O)C1-4haloalkyl, CO2H, CO2C1-4alkyl, CO2C1- 4haloalkyl, CONH2, CONHC1-4alkyl and CON(C1-4alkyl)(C1-4alkyl). In some embodiments,R4is selected from F, Cl, C1-4alkyl, C1-2haloalkyl, OH, NH2, SH, SC1-2alkyl, SC1-2haloalkyl, OC1-2alkyl, OC1-2haloalkyl, NH(C1-2alkyl), N(C1-2alkyl)(C1-2alkyl), C(O)H, C(O)C1-2alkyl, C(O)C1-2haloalkyl, CO2H, CO2C1-2alkyl, CO2C1-2haloalkyl, CONH2, CONHC1-2alkyl and CON(C1-2alkyl)(C1-2alkyl). In some embodiments, R4is selected from F, Cl, C1-2alkyl, C1-2fluoroalkyl, C1-2chloroalkyl, OH, NH2, SH, SC1-2alkyl, SC1-2fluoroalkyl, SC1-2chloroalky, OC1-2alkyl, OC1-2fluoroalkyl, OC1-2chloroalkyl, NH(C1-2alkyl), N(C1-2alkyl)(C1-2alkyl), C(O)H, C(O)C1-2alkyl, C(O)C1-2haloalkyl, CO2H, CO2C1-2alkyl, CO2C1-2haloalkyl, CONH2, CONHC1-2alkyl and CON(C1-2alkyl)(C1-2alkyl). In some embodiments, R4is selected from F, Cl, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, OC1-2alkyl, OC1-2fluoroalkyl and OC1-2chloroalkyl. In some embodiments, R4is 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, R4is selected from F, Cl, CH3, CF3, CFH2, CHF2, CCl3, CH3,OCF3, OCFH2, OCHF2 and OCCl3. In some embodiments, R4is selected from F, Cl, CH3 and OCH3. In some embodiments, R4is selected from F, Cl, C1-4alkyl, C1-4fluoroalkyl, C1- 4chloroalkyl. In some embodiments, R4is 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, R4is selected from F, Cl, CH3, CF3, CFH2, CHF2 and CCl3. In some embodiments, R4is selected from F, Cl and CH3.

[0113] In some embodiment, n is selected from 0, 1 and 2. In some embodiment, 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 R4is in a position meta to the attachment point of A in the structure of the compound of Formula I. In some embodiments, n is 1 and is R4is in a position meta or para to the attachment point of A in the structure of the compound of Formula I. In some embodiments, n is 1 and is R4is in a position meta to attachment point of A in the structure of the compound of Formula I.

[0114] In some embodiments, the group in the compound of Formula I is selected from.

[0115] In some embodiments, R2is selected from H, halo, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-7heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R2is selected from H, F, Cl, Br, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, F, Cl, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R2is selected from H, F, Cl, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, F, Cl, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0116] In some embodiments, C3-6cycloalkyl in R2is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, C3-6cycloalkyl in R2is selected from cyclopropyl and cyclobutyl.

[0117] In some embodiments, C3-10heterocycloalkyl in R2is selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, 1,3-dioxolanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, isoxthiolidinyl, thiazolidinyl, 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. In some embodiments, C3-7heterocycloalkyl in R2is selected from aziridinyl, oxiranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, morpholinyl tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0118] In some embodiments, the C5-10heteroaryl in R2is 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.

[0119] In some embodiments, R2is selected from H, halo, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl, C3-7heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, F, Cl, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0120] In some embodiments, R2is selected from H, halo, C1-4alkyl and C1- 4fluoroalkyl. In some embodiments, R2is selected from H, F, Cl, Br, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl. In some embodiments, R2is 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, R2is selected from H, F, Cl, CH3, CF3, CFH2, CHF2, CCl3, CCl2H and CClH2. In some embodiments, R2is selected from H, F, CH3and CF3. In some embodiments, R2is H.

[0121] In some embodiments, R3is selected from H, halo, C1-4alkyl and C1-4haloalkyl. In some embodiments, R3is selected from H, F, Cl, Br, C1-4alkyl, C1-4fluoroalkyland C1-4chloroalkyl. In some embodiments, R3is 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, R3is selected from H, F, Cl, CH3, CF3, CFH2, CHF2, CCl3, CCl2H and CClH2. In some embodiments, R3is selected from H, F, CH3and CF3. In some embodiments, R3is H.

[0122] In some embodiments, R2and R3are both H. In some embodiments, R2and R3are both H, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof is a compound of Formula I- E, I-E(i), I-E(ii) or I-E(iii) a pharmaceutically acceptable salt and / or solvate thereof: E(i)ii)

[0123] wherein R1, and R4and n are as defined in Formula I.In some embodiments, R2and R3are joined to form, together with the atom therebetween, a 3- to 7 membered saturated or unsaturated ring, optionally containing one or two heteromoieties selected from N, NH, N(C1-4alkyl), O, S, S(O), and SO2 and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl.

[0124] In some embodiments, R2and R3are joined to form, together with the atom therebetween, a 3- to 6- membered saturated or unsaturated ring optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl. 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. Accordingly, in some embodiments, R2and R3are joined to form, together with the atom therebetween, a cyclopropyl, cyclobutyl or cyclopentyl ringoptionally substituted with one to two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl.

[0125] In some embodiments, R2and R3are joined to form, together with the atom therebetween, a 3- to 7 membered saturated or unsaturated ring, containing one or two heteromoieties selected from N, NH, N(C1-4alkyl), O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl C1-4fluoroalkyl and C1-4chloroalkyl. In some embodiments, the 3- to 7 membered saturated or unsaturated ring, containing one or two heteromoieties is selected from aziridinyl, oxiranyl, thiiranyl, oxaxiridinyl, 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 heteromoieties selected from aziridinyl, oxiranyl, azetidinyl and oxetanyl.

[0126] In some embodiments, R1is R5. In some embodiments, R1is OR5. In some embodiments, R1is NR5R6.

[0127] In some embodiments, R5is selected from H, C1-4alkyl, C1-4haloalkyl, C1- 4alkyleneR7and C1-4haloalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), SO2NH2, SO2NH(C1-4alkyl) and SO2N(C1- 4alkyl)(C1-4alkyl). In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1- 4chloroalkyl, C1-4alkyleneR7, C1-4flouroalkyleneR7and C1-4chloroalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl)2, C(O)NH2, C(O)NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), SO2NH2, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneR7, and C1-4flouroalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), SO2NH2, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneR7, and C1-4flouroalkyleneR7.

[0128] In some embodiments, R5is selected from H, C1-4alkyl, C1-4haloalkyl, C1-4alkyleneR7and C1-4haloalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1- 4alkyleneR7, C1-4flouroalkyleneR7and C1-4chloroalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1- 4alkyl)(C1-4alkyl)2. In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneR7and C1-4flouroalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl) (C1-4alkyl).

[0129] In some embodiments, R7is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6- 10aryl, C5-10heteroaryl, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl, CO2C1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1-4alkyl), PO(OC1-4alkyl)(OC1-4alkyl), SO2C1-4alkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), NC1-4alkylSO2(C1-4alkyl), and NHSO2(C1-4alkyl). In some embodiments, R7selected from OH, CHO, SH, NH2, CO2H, PO3H, SO2H, SO2NH2,NHSO2H, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl, CO2C1-4alkyl, C(O)NHC1-4alkyl and C(O)N(C1-4alkyl)(C1-4alkyl). In some embodiments, R7selected from OH, CHO, SH, NH2, CO2H, PO3H, SO2H, NHSO2H, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl, CO2C1-4alkyl, C(O)NHC1-4alkyl and C(O)N(C1-4alkyl)(C1-4alkyl). In some embodiments, R7selected from OH, CO2H, PO3H, SO2H, OC1-4alkyl, OC1-4haloalkyl, CO2C1-4alkyl, SO2NH2, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R7selected from OH, CO2H, PO3H, SO2H, OC1-4alkyl, OC1-4haloalkyl and CO2C1-4alkyl. In some embodiments, R7selected from OH, CO2H, OC1-4alkyl, OC1-4haloalkyl and CO2C1-4alkyl. In some embodiments, R7is selected from OH, CO2H, PO3H, SO2H, OC1-4alkyl, OC1-4fluoroalkyl, OC1-4chloroalkyl and CO2C1-4alkyl. In some embodiments, R7is selected from OH, CO2H, OC1-4alkyl, OC1-4fluoroalkyl, OC1-4chloroalkyl and CO2C1-4alkyl. In some embodiments, R7is selected from OH, CO2H, OC1-4alkyl, OC1- 4fluoroalkyl, CO2C1-4alkyl, SO2NH2, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R7is selected from OH, CO2H, OC1-4alkyl, OC1-4fluoroalkyl, and CO2C1-4alkyl.

[0130] In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1- 4chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1- 4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1- 4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneCO2C1-4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), SO2NH2, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R5is selected from H, C1-4alkyl, C1- 4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1- 4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl, C1- 4flouroalkyleneCO2C1-4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0131] In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl, wherein each alkyl is optionally substituted with one or two substituentsselected from OH, C3-6cycloalkyl, C4-6heterocycloalkyl, phenyl, C5-6heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC4-6heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-6heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl wherein each alkyl is optionally substituted with one to two substituents selected from OH, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC4-6heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-6heteroaryl, the four groups being optionally substituted with one to four substituents selected from OH, F, CN, C1-4alkyl, C1- 4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0132] In some embodiments, R5is selected from H, C1-4alkyl and C1-4fluoroalkyl wherein each alkyl is optionally substituted with one or two substituents selected from OH and C1-4alkylenephenyl optionally substituted with one to four substituents selected from OH, F, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1- 4alkyl). In some embodiments, R5is selected from C1-4alkyl and C1-4fluoroalkyl wherein each alkyl is substituted with OH and C1-4alkylenephenyl. In some embodiments, R5is selected from C1-4alkyl and C1-4fluoroalkyl.

[0133] In some embodiments, R5is H.

[0134] In some embodiments, R5is selected from C1-4alkyleneOH, C1- 4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1- 4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneCO2C1-4alkyl, C1- 4alkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl) and C1-4alkyleneSO2N(C1-4alkyl)(C1- 4alkyl), wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R5is selected from C1- 4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneCO2C1-4alkyl, C1- 4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneCO2C1-4alkyl, C1-4alkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl) and C1-4alkyleneSO2N(C1-4alkyl)(C1-4alkyl), wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl. In someembodiments R5is selected from C1-3alkyleneOH, C1-3alkyleneCO2H, C1-3alkyleneOC1-3alkyl, C1-3alkyleneCO2C1-3alkyl, C1-3flouroalkyleneOH, C1-3flouroalkyleneCO2H, C1-3flouroalkyleneOC1-3alkyl, C1-3flouroalkyleneCO2C1-3alkyl, C1-4alkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl) and C1-4alkyleneSO2N(C1-4alkyl)(C1-4alkyl). In some embodiments R5is selected from C1-3alkyleneOH, C1-3alkyleneCO2H, C1-3alkyleneOC1-3alkyl, C1-3alkyleneCO2C1-3alkyl, C1-3flouroalkyleneOH, C1-3flouroalkyleneCO2H, C1-3flouroalkyleneOC1-3alkyl, and C1-3flouroalkyleneCO2C1-3alkyl. In some embodiments R5is selected from C1-3alkyleneOH, C1-3alkyleneCO2H, C1-3alkyleneOC1-3alkyl and C1-3alkyleneCO2C1-3alkyl.

[0135] In some embodiments, R5is selected from C1-4alkyleneOH, C1- 4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1- 4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1- 4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1-4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1- 4alkyl)(C1-4alkyl). In some embodiments, R5is selected from C1-4alkyleneOH, C1- 4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1- 4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1- 4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1-4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl.

[0136] In some embodiments R5is selected from C2-3alkyleneOH, C2- 3alkyleneCO2H, C2-3alkyleneOC1-3alkyl, C2-3alkyleneOC1-3fluoroalkyl, C2-3alkyleneCO2C1- 3alkyl, C2-3flouroalkyleneOH, C2-3flouroalkyleneCO2H, C2-3flouroalkyleneOC1-3alkyl, C2- 3flouroalkyleneOC1-3fluoroalkyl and C2-3flouroalkyleneCO2C1-3alkyl. In some embodiments R5is selected from C1-3alkyleneOH, C1-3alkyleneCO2H, C1-3alkyleneOC1-3alkyl, C1-3alkyleneCO2C1-3alkyl, C1-3flouroalkyleneOH, C1-3flouroalkyleneCO2H, C1-3flouroalkyleneOC1-3alkyl and C1-3flouroalkyleneCO2C1-3alkyl. In some embodiments R5is selected from C1-3alkyleneOH, C1-3alkyleneCO2H, C1-3alkyleneOC1-3alkyl, C1-3alkyleneCO2C1-3alkyl.

[0137] In some embodiments, when R1is OR5, R5is H and R1is OH.

[0138] In some embodiments, when R1is OR5, R5is selected from H, C1-4alkyl and C1-4fluoroalkyl wherein each alkyl is optionally substituted with one or two substituents selected from OH and C1-4alkylenephenyl optionally substituted with one to four substituents selected from OH, F, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, when R1is OR5, R5is selected from C1-4alkyl and C1-4fluoroalkyl wherein each alkyl is substituted with OH and C1-4alkylenephenyl. In some embodiments, when R1is OR5, R5is selected from C1-4alkyl and C1-4fluoroalkyl.

[0139] In some embodiments, when R1is NR5R6, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1- 4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1- 4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl, C1- 4flouroalkyleneCO2C1-4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5- 10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1- 4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1- 4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, when R1is NR5R6, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1- 4chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1- 4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1- 4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneCO2C1-4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0140] In some embodiments, when R1is NR5R6, R5is selected from H, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl, wherein each alkyl is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C4-6heterocycloalkyl, phenyl, C5-6heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC4-6heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-6heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R1is selected from NHR6, NR6C1-4alkyl and N(R6)C1-4fluoroalkyl and each alkyl is optionally substituted with one to two substituents selected from OH, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC4-6heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-6heteroaryl, the latter four groups being optionally substituted with one to four substituents selected from OH, F, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0141] In some embodiments, R1is NHR6.

[0142] In some embodiments, R1is selected from N(R6)C1-4alkyl and N(R6)C1-4fluoroalkyl wherein each alkyl is optionally substituted with one to two substituents selected from OH and C1-4alkylenephenyl optionally substituted with one to four substituents selected from OH, F, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R1is selected from NR6C1-4alkyl and N(R6)C1-4fluoroalkyl wherein each alkyl is substituted with OH and C1-4alkylenephenyl. In some embodiments, R1is selected from N(R6)C1-4alkyl and N(R6)C1-4fluoroalkyl.

[0143] In some embodiments, when R1is NR5R6, R5selected from C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1- 4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1- 4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1- 4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-6alkyl). In some embodiments, R1is selected from N(R6)C1-4alkyleneOH, N(R6)C1-4alkyleneCO2H, N(R6)C1-4alkyleneOC1-4alkyl, N(R6)C1- 4alkyleneOC1-4fluoroalkyl, N(R6)C1-4alkyleneCO2C1-4alkyl, N(R6)C1-4flouroalkyleneOH, N(R6)C1-4flouroalkyleneCO2H, N(R6)C1-4flouroalkyleneOC1-4alkyl, N(R6)C1- 4flouroalkyleneOC1-4fluoroalkyl and N(R6)C1-4flouroalkyleneCO2C1-4alkyl. In some embodiments, R1is selected from N(R6)C1-4alkyleneOH, N(R6)C1-4alkyleneCO2H, N(R6)C1- 4alkyleneOC1-4alkyl, N(R6)C1-4alkyleneCO2C1-4alkyl, N(R6)C1-4flouroalkyleneOH, N(R6)C1- 4flouroalkyleneCO2H, N(R6)C1-4flouroalkyleneOC1-4alkyl, and N(R6)C1- 4flouroalkyleneCO2C1-4alkyl. In some embodiments, R1is selected from N(R6)C2-4alkyleneOH, N(R6)C2-4alkyleneCO2H, N(R6)C2-4alkyleneOC1-4alkyl, N(R6)C2-4alkyleneCO2C1-4alkyl, N(R6)C2-4flouroalkyleneOH, N(R6)C2-4flouroalkyleneCO2H, N(R6)C2-4flouroalkyleneOC1-4alkyl and N(R6)C2-4flouroalkyleneCO2C1-4alkyl, In some embodiments, R1is selected from N(R6)C3alkyleneOH, N(R6)C3alkyleneCO2H and N(R6)C3alkyleneCO2C1-3alkyl. In some embodiments, R1is selected from N(R6)C1-4alkyleneOH, N(R6)C1-4alkyleneCO2H, N(R6)C1-4alkyleneOC1-4alkyl, N(R6)C2-4alkyleneCO2C1-4alkyl.

[0144] In some embodiments, R6is selected from H, C1-4alkyl and C1-4haloalkyl. In some embodiments, R6is selected from H, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl. In some embodiments, R6is 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, R6is selected from H, CH3, CF3, CFH2, CHF2, CCl3, CCl2H and CClH2. In some embodiments, R6is selected from H, CH3 and CF3. In some embodiments, R6is H.

[0145] In some embodiment, R1is selected from N(R6)C1-4alkyleneOH, N(R6)C1- 4alkyleneCO2H, N(R6)C1-4alkyleneOC1-4alkyl, N(R6)C2-4alkyleneCO2C1-4alkyl, N(R6)C2- 4flouroalkyleneOH, N(R6)C2-4flouroalkyleneCO2H, N(R6)C2-4flouroalkyleneOC1-4alkyl and N(R6)C2-4flouroalkyleneCO2C1-4alkyl, X is O, A is phenyl and R4is selected from F, Cl, CH3 and OCH3. In some embodiments, R1is selected from N(R6)C1-4alkyleneOH and N(R6)C1- 4alkyleneCO2C1-4alkyl, X is O, A is phenyl and R4is selected from F, Cl, CH3 and OCH3.In some embodiment, R1is selected from N(R6)C2-4alkyleneOH, N(R6)C2-4alkyleneCO2H, N(R6)C2-4alkyleneOC1-4alkyl, N(R6)C1-4alkyleneOC2-4fluoroalkyl, N(R6)C2-4alkyleneCO2C1- 4alkyl, N(R6)C2-4flouroalkyleneOH, N(R6)C2-4flouroalkyleneCO2H, N(R6)C2- 4flouroalkyleneOC1-4alkyl, N(R6)C2-4flouroalkyleneOC1-4fluoroalkyl and N(R6)C2- 4flouroalkyleneCO2C1-4alkyl, X is O, A is phenyl and R4is selected from F, Cl and CH3. In some embodiments, R1is selected from N(R6)C2-4alkyleneOH and N(R6)C2- 4alkyleneCO2C1-4alkyl, X is O, A is phenyl and R4is selected from F, Cl and CH3.

[0146] In some embodiments, R1is OH, A is phenyl and R4is selected from F, Cl and CH3. In some embodiments, R1is OH, A is phenyl and R4is selected from F, Cl and CH3 and OCH3.

[0147] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8, O, S, S(O), and SO2 and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneNCO2R8, and C1-4alkyleneC(O)R8R9wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one ormore substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0148] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8', O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneNCO2R8, and C1-4alkyleneC(O)R8R9wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0149] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1- 4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0150] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8'and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, thelatter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0151] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 10-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0152] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 10-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8'and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1- 4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0153] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 8- to 10-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1- 4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0154] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 8- to 10-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8'and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0155] In some embodiments, the 8- to 10-membered heterocycloalkyl ring is selected from indolinyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0156] In some embodiments, the 8- to 10-membered heterocycloalkyl is optionally substituted with one substituent selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1- 4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1- 4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, the 8- to 10-membered heterocycloalkyl is optionally substituted with one substituent selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

[0157] In some embodiments, the 8- to 10-membered heterocycloalkyl is unsubstituted.

[0158] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eightgroups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0159] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8'and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0160] 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.

[0161] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring containing one additional NR8heteromoiety and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

[0162] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring containing one additional NR8'heteromoiety and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

[0163] In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing one additional NR8heteromoiety is selected from pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl and piperazinyl.

[0164] In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing one additional NR8'heteromoiety is selected from pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl and piperazinyl. Accordingly, in some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring containing one additional NR8'heteromoiety selected from pyrazolidinyl and piperazinyl, each optionally substituted with one or two substituentsselected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl. In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing one additional NR8heteromoiety is piperazinyl. In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing one additional NR8'heteromoiety is piperazinyl.

[0165] In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing one additional NR8heteromoiety is further optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

[0166] In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing one additional NR8'heteromoiety is further optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

[0167] Accordingly, in some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, piperidinyl, piperazinyl, each independently optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5- 10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1- 4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1- 4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, piperidinyl, piperazinyl, each independently optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1- 4haloalkyl. )In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, piperidinyl and piperazinyl, each independently optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

[0168] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5 to 10-membered heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8and O and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-6alkyl).

[0169] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5 to 10-membered heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8'and O and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1- 6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1- 4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-6alkyl).

[0170] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5 to 10-membered heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8and O and optionally substituted with one or two substituents selected from OH, F, Cl, C1-4alkyl and C1-4haloalkyl. In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5 to 10-membered heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8and O and optionally substituted with one or two substituents selected from C1-4alkyl and C1-4haloalkyl.

[0171] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5 to 10-membered heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8'and O and optionally substituted with one or two substituents selected from OH, F, Cl, C1-4alkyl and C1-4haloalkyl. In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5 to 10-membered heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8'and O and optionally substituted with one or two substituents selected from C1-4alkyl and C1-4haloalkyl.

[0172] In some embodiments, the 5- to 10-membered heteroaryl ring is selected from pyrrole, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, azaindolyl, quinoline, and isoquinoline.

[0173] In some embodiments, R8'is selected from H, SO2NH2, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)(C1-4alkyl), C1-4alkyl, C1-4haloalkyl, C1-4alkyleneR10and C1-4haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl). In some embodiments, R8'is selected from H, SO2NH2, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1- 4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)(C1-4alkyl), C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, R10, C1-4alkyleneR10, C1-4flouroalkyleneR10and C1-4chloroalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0174] In some embodiments, R8'is selected from H, SO2NH2, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)(C1-4alkyl), C1- 4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneR10and C1-4flouroalkyleneR10wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-6heterocycloalkyl, phenyl, C5-6heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-6heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-6heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1- 4alkyl)(C1-4alkyl).

[0175] In some embodiments, R8is selected from H, C1-4alkyl, C1-4haloalkyl, C1-4alkyleneR10and C1-4haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo,CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl). In some embodiments, R8is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneR10, C1-4flouroalkyleneR10and C1-4chloroalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R8is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneR10, and C1-4flouroalkyleneR10wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- 6heterocycloalkyl, phenyl, C5-6heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- 6heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-6heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0176] In some embodiments, R10is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6- 10aryl, C5-10heteroaryl, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl, CO2C1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1- 4alkyl), PO(OC1-4alkyl)(OC1-4alkyl), SO2C1-4alkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1- 4alkyl), NC1-4alkylSO2(C1-4alkyl), and NHSO2(C1-4alkyl). In some embodiments, R10is selected from OH, CHO, SH, NH2, CO2H, PO3H, SO2H, SO2NH2, NHSO2H, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl, CO2C1-4alkyl, C(O)NHC1-4alkyl and C(O)N(C1-4alkyl)(C1-4alkyl). In some embodiments, R10is selected from OH, CO2H, PO3H, SO2H, SO2NH2, OC1-4alkyl, OC1-4haloalkyl, CO2C1-4alkyl, SO2NH(C1-4alkyl), SO2N(C1- 4alkyl)(C1-4alkyl). In some embodiments, haloalkyl in R10is selected from fluoroalkyl and chloroalkyl. In some embodiments, haloalkyl in R10is selected from fluoroalkyl and chloroalkyl and R10is selected from OH, CO2H, PO3H, SO2H, SO2NH2, OC1-4alkyl, OC1- 4fluoroalkyl, OC1-4chloroalkyl, CO2C1-4alkyl, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R10is selected from OH, CO2H, SO2NH2,OC1-4alkyl, OC1-4fluoroalkyl, OC1-4chloroalkyl, CO2C1-4alkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R10is selected from OH, CO2H, SO2NH2, OC1-4alkyl, OC1-4fluoroalkyl, CO2C1-4alkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl). In some embodiments, R10is selected from OH, CHO, SH, NH2, CO2H, PO3H, SO2H, NHSO2H, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl,CO2C1-4alkyl, C(O)NHC1-4alkyl and C(O)N(C1-4alkyl)(C1-4alkyl). In some embodiments, R10is selected from OH, CO2H, PO3H, SO2H, OC1-4alkyl, OC1-4haloalkyl and CO2C1-4alkyl. In some embodiments, R10is selected from OH, CO2H, OC1-4alkyl, OC1-4haloalkyl and CO2C1-4alkyl. In some embodiments, haloalkyl in R10is selected from fluoroalkyl and chloroalkyl. In some embodiments, haloalkyl in R10is selected from fluoroalkyl and chloroalkyl and R10is selected from OH, CO2H, PO3H, SO2H, OC1-4alkyl, OC1-4fluoroalkyl, OC1-4chloroalkyl and CO2C1-4alkyl. In some embodiments, R10is selected from OH, CO2H, OC1-4alkyl, OC1-4fluoroalkyl, OC1-4chloroalkyl and CO2C1-4alkyl. In some embodiments, R10is selected from OH, CO2H, OC1-4alkyl, OC1-4fluoroalkyl, and CO2C1-4alkyl.

[0177] In some embodiments, R8is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1- 4chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1- 4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1- 4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1- 4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0178] In some embodiments, R8is selected from H, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl, wherein each alkyl is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-6heterocycloalkyl, phenyl, C5-6heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-6heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-6heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0179] In some embodiments, R8is selected from H, C1-4alkyl and C1-4fluoroalkyl wherein each alkyl is optionally substituted with one or two substituents selected from OH and C1-4alkylenephenyl optionally substituted with one to four substituents selected from OH, F, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R8is selected from C1-4alkyl and C1-4fluoroalkyl wherein each alkyl is substituted with OH and C1-4alkylenephenyl. In some embodiments, R8is selected from C1-4alkyl and C1-4fluoroalkyl.

[0180] In some embodiments, R8is H.

[0181] In some embodiments, R8is selected from C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl wherein each alkyl is optionally substituted with one or two substituents selected from OH, C1-4alkylenephenyl, and C1-4alkyleneC5-6heteroaryl, the latter two groups being optionally substituted with one to three substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiments, R8is selected from C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl wherein each alkyl is substituted with OH and C1-4alkylenephenyl.

[0182] In some embodiments, R8is selected from C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl.

[0183] In some embodiments, R8'is selected from SO2NH2, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), C1-4alkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl), C1- 4alkyleneSO2N(C1-4alkyl)(C1-4alkyl), C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1- 4alkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1- 4flouroalkyleneOC1-4alkyl, and C1-4flouroalkyleneCO2C1-4alkyl wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3- 6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1- 4alkyl)(C1-4alkyl).

[0184] In some embodiment, R8'is selected from SO2NH2, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), C1-4alkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl), C1- 4alkyleneSO2N(C1-4alkyl)(C1-4alkyl), C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1- 4alkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1- 4flouroalkyleneOC1-4alkyl and C1-4flouroalkyleneCO2C1-4alkyl. In some embodiments, R8'is selected from SO2NH2, SO2NH(CH3), SO2N(CH3)2, C1-4alkyleneSO2NH2, C1- 4alkyleneSO2NH(CH3), C1-4alkyleneSO2N(CH3)2, C1-4alkyleneOH, C1-4alkyleneCO2H, C1- 4alkyleneOC1-3alkyl, C1-4alkyleneCO2C1-3alkyl, C1-4flouroalkyleneOH, C1- 4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-3alkyl, and C1-4flouroalkyleneCO2C1-4alkyl. In some embodiments, R8'is selected from SO2NH2, SO2NH(CH3), SO2N(CH3)2, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-3alkyl, C1-4alkyleneCO2C1-3alkyl.

[0185] In some embodiments, R8is selected from C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1-4alkyl wherein each alkyleneis optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl). In some embodiment, R8is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1- 4alkyl. In some embodiment, R8is selected from C2-4alkyleneOH, C2-4alkyleneCO2H, C2- 4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1- 4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1- 4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1-4alkyl. In some embodiments, R8is selected from C3alkyleneOH, C3alkyleneCO2H, and C3alkyleneCO2C1-3alkyl.

[0186] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 8 to 10-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from N, NR8and O selected from 3H-indolyl, 2H-isoindolyl, tetrahydroquinolinyl and tetrahydroisoquinolinyl, and optionally substituted with one or two substituents selected from C1-4alkyl and C1-4haloalkyl.

[0187] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8and O, optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl and substituted with at least one substituent selected from NR8R9, OR8, CO2R8, C(O)NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, C1-4alkyleneCO2R8and C1- 4alkyleneC(O)NR8R9, and R8is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1- 4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1- 4alkyl, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

[0188] In some embodiments, R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring containing one additional NR8heteromoiety and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl; and R8is selected from C2-4alkyleneOH, C2-4alkyleneCO2H, C2-4alkyleneOC1-4alkyl, C1-4alkyleneOC1-4fluoroalkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneCO2H, C1-4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneOC1-4fluoroalkyl and C1-4flouroalkyleneCO2C1-4alkyl. In some embodiments, the 5- to 6-membered heterocycloalkyl ring containing one additional NR8heteromoiety is piperazinyl. In some embodiments, A is phenyl and R4is selected from F, Cl and CH3.

[0189] In some embodiments, R9is selected from H, C1-4alkyl and C1-4haloalkyl. In some embodiments, R9is selected from H, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl. In some embodiments, R9is 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, R9is selected from H, CH3, CF3, CFH2, CHF2, CCl3, CCl2H and CClH2. In some embodiments, R9is selected from H, CH3 and CF3. In some embodiments, R9is H.

[0190] In some embodiments, R1is selected from.

[0191] In some embodiments, the stereochemistry at carbon 9b, 3a and 4 of the tricyclic core structure of the compound of Formula I is either R or S. Accordingly, 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.

[0192] In some embodiments, the compound of Formula (I) is in a cis isomer form. In some embodiments, the cis isomer form is selected from (3aR, 4R, 9bR) and (3aS, 4S, 9bS), and mixtures thereof having the following structures:(3aR, 4R, 9bR)-(I) (3aS, 4S, 9bS)-(I) or a pharmaceutically acceptable salt and / or solvate thereof wherein: X, , A, R1, R2, R3, R4and n are as defined for Formula (I).

[0193] In some embodiments, the compound of Formula (I) is in a trans isomer form. In some embodiments, the trans isomer form is selected from (3aR, 4S, 9bR)-(I) and (3aS, 4R, 9bS)-(I), and mixtures thereof having the following structures:(3aR, 4S, 9bR)-(I) (3aS, 4R, 9bS)-(I)or a pharmaceutically acceptable salt and / or solvate thereof wherein: X, , A, R1, R2, R3, R4and n are as defined for Formula (I). In some embodiments,

[0194] In some embodiments, the compounds of Formula I are mixtures of enantiomers. In some embodiments, the compound of Formula (I) is a mixture of the two cis isomer forms having the configuration (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 the two trans isomer forms having the configuration (3aR, 4S, 9bR) and (3aS, 4R, 9bS) as defined above (e.g (4R / S trans)-(I)).

[0195] In some embodiments, the compound of Formula (I) has one of the following structures:or a pharmaceutically acceptable salt and / or solvate thereof wherein: X, , A, R1, R2, R3, R4and n are as defined for Formula (I).

[0196] In an embodiment, the compound of Formula I is selected from the compounds listed below:or a pharmaceutically acceptable salt and / or solvate thereof.

[0197] In an embodiment the pharmaceutically acceptable salt of compounds of Formula I and Formula II is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0198] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic,lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2- phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0199] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which 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 the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0200] Solvates of compounds of Formula I and Formula II include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0201] In embodiments of the present application, the compounds of Formula I and Formula II described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to beunderstood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0202] The compounds of Formula I and Formula II may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0203] The compounds of Formula I and Formula II may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.III. Methods and Uses of the Application

[0204] The Applicants have identified a family of compounds which are capable of inhibiting and / or blocking Cav3.2 T-type calcium channel (Cav3.2) function and / or expression levels by inhibiting, blocking and / or disrupting interactions between Cav3.2 and ubiquitin specific peptidase 5 (USP5). In an embodiment, the compounds have been shown to inhibit, block and / or disrupt interactions between Cav3.2 and ubiquitin specific peptidase 5 (USP5). Therefore, the compounds may be useful for inhibiting, blocking and / or disrupting Cav3.2 deubiquitination.

[0205] Accordingly, the present application includes a method for inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of the application a pharmaceutically acceptable salt and / or solvate thereof to the cell.

[0206] The application also includes a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for inhibiting interactions between Cav3.2 and USP5 in a cell as well as a use of a compound or compositions of the application for the preparation of a medicament for inhibiting interactions between Cav3.2 and USP5 in a cell. The application further includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in inhibiting interactions between Cav3.2 and USP5.

[0207] As the compounds of the application have been shown to be capable of inhibiting interactions between Cav3.2 and USP5, a compound of the application are useful for treating diseases, disorders or conditions by inhibiting interactions between Cav3.2 and USP5. Therefore, the compounds of the application are useful as medicaments. Accordingly, the present application includes compounds of the application for use as a medicament.

[0208] The present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting interactions between Cav3.2 and USP5 comprising administering a therapeutically effective amount of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0209] The application also includes a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that is treatable by inhibiting interactions between Cav3.2 and USP5 in a cell as well as a use of a compound of the application ora pharmaceutically acceptable salt and / or solvate thereof for preparing a medicament for treating a disease, disorder or condition that is treatable by inhibiting interactions between Cav3.2 and USP5 in a cell. The application further includes a compound of the application ora pharmaceutically acceptable salt and / or solvate thereof for use in treating a disease, disorder or condition that is treatable by inhibiting interactions between Cav3.2 and USP5.

[0210] The present application also includes a method for inhibiting Cav3.2 T-type calcium channel (Cav3.2) function and / or expression by inhibiting interactions between Cav3.2 and ubiquitin specific peptidase 5 (USP5) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof to the cell.

[0211] The application also includes a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5 in a cell as well as a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5 in a cell. The application further includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5 in a cell.

[0212] The application further includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5.The application also includes a method of treating a disease, disorder or condition mediated or treatable by inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5 in a cell comprising administering a therapeutically effective amount of a compound of the application or a pharmaceutically acceptable salt and / or solvate to a subject in need thereof.

[0213] The application also includes a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5 in a cell as well as a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5 in a cell. The application further includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 function and / or expression by inhibiting interactions between Cav3.2 and USP5.

[0214] As USP5 is a deubiquitinizing enzyme, and the compounds of the application have been shown to inhibit interactions between Cav3.2 and USP5, the compounds of the application may be useful for inhibiting Cav3.2 deubiquitination. Accordingly, the present application also includes a method for inhibiting Cav3.2 deubiquitination in a cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof to the cell.

[0215] The application also includes a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for inhibiting Cav3.2 deubiquitination in a cell as well as a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for inhibiting Cav3.2 deubiquitination in a cell. The application further includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in inhibiting Cav3.2 deubiquitination.

[0216] As the compounds of the application have been shown to be capable of inhibiting interactions between Cav3.2 and the deubiquitinase USP5, therefore thecompounds of the application are useful for treating diseases, disorders or conditions by inhibiting Cav3.2 deubiquitination. Therefore, the present application also includes a method of treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 deubiquitination comprising administering a therapeutically effective amount of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0217] The application also includes a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 deubiquitination in a cell as well as a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 deubiquitination in a cell. The application further includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a disease, disorder or condition that is treatable by inhibiting Cav3.2 deubiquitination.

[0218] In an embodiment, the disease, disorder or condition treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination is pain. Accordingly, the present application also includes a method of treating pain comprising administering a therapeutically effective amount of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof. The present application also includes a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for treatment of pain as well as a use of a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for the preparation of a medicament to treat pain. The application further includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in pain. In an embodiment, the treatment is in an amount effective to ameliorate at least one symptom of pain, for example, reduced sensation and duration, among others, in a subject in need of such treatment.

[0219] In an embodiment, the compound of the application are useful as an analgesic in the treatment of pain.

[0220] In an embodiment, the pain is acute or chronic pain.

[0221] In an embodiment, the chronic pain is any persistent or recurrent pain lasting longer than about 3 months. In an embodiment, the chronic pain is any persistent or recurrent pain lasting longer than about 6 months. In an embodiment, the chronic pain is selected from chronic primary pain, chronic cancer pain, chronic postsurgical andposttraumatic pain, chronic neuropathic pain, orofacial pain, chronic visceral pain, chronic musculoskeletal pain. In an embodiment, the chronic pain is selected from chronic primary pain, chronic neuropathic pain, chronic headache and orofacial pain, chronic visceral pain, and chronic musculoskeletal pain. In an embodiment, the chronic pain is selected from chronic primary pain, chronic neuropathic pain and chronic visceral pain. In an embodiment, the chronic pain is selected from chronic neuropathic pain and chronic visceral pain.

[0222] In an embodiment, the pain is nociceptive pain, inflammatory pain, or neuropathic pain. In an embodiment, the pain is inflammatory pain or neuropathic pain. In an embodiment, the pain is inflammatory pain. In an embodiment, the pain is neuropathic pain.

[0223] In an embodiment, the neuropathic pain is chronic neuropathic pain. In an embodiment, 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 an embodiment, the chronic neuropathic pain is central pain syndrome, complex regional pain syndrome, diabetic peripheral neuropathic pain, shingles, postherpetic neuralgia, , or trigeminal neuralgia. In an embodiment, the chronic neuropathic pain is chemotherapy-induced neuropathic pain.

[0224] In an embodiment, the central pain syndrome is pain that is associated with diseases, disorders or conditions associated with damage to the central nervous system. In an embodiment, the diseases, disorders or conditions associated with damage to the central nervous system are selected from one or more of multiple sclerosis, and tumors.

[0225] In an embodiment, the diabetic peripheral neuropathic pain is associated with diabetes. In an embodiment, the diabetic peripheral neuropathic pain is associated with nerve damage in the feet, legs, hands, or arms associated with diabetes. Therefore, in an embodiment, the pain is pain is associated with diabetes.

[0226] In an embodiment, the inflammatory pain is pain associated with diseases, disorders or conditions associated with inflammation. In an embodiment, the diseases, disorders or conditions associated with inflammation are selected from one or more of diabetes, cardiovascular disease (CVD), arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, menstrual cramps, tendinitis, bursitis, skin-related conditions (such as psoriasis, eczema, burns and dermatitis), and post-operative inflammation. In an embodiment, the diseases, disorders or conditions associated with inflammation is diabetes.

[0227] In an embodiment, the arthritis is, but is not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus or juvenile arthritis.

[0228] In an embodiment, the diseases, disorders or conditions associated with inflammation are selected from one or more of inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis.

[0229] In an embodiment, the diseases, disorders or conditions associated with inflammation are selected from one or more of vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like.

[0230] In an embodiment, the diseases, disorders or conditions associated with inflammation are ophthalmic diseases, including but not limited to retinitis, retinopathies, uveitis, ocular photophobia, and acute injury to the eye tissue.

[0231] In an embodiment, the disease, disorder or condition associated with inflammation is pulmonary inflammation, including but not limited to, that associated with viral infections and cystic fibrosis.

[0232] In an embodiment, the disease, disorder or condition associated with inflammation is a central nervous system disorder such as cortical dementias including Alzheimer's disease.

[0233] In an embodiment, the disease, disorder or condition associated with inflammation is selected from allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and central nervous system damage resulting from stroke, ischemia and trauma.

[0234] In further embodiments, the present application also includes a method of treating a disease, disorder or condition mediated or treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination comprising administering a therapeutically effective amount of a compound of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated or treatable by condition treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination to a subject in need thereof. The present application also includes a use of a compound of the application in combination with a known agent usefulfor treatment of a disease, disorder or condition mediated or treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination protein, and a compound of the application for treatment of a disease, disorder or condition mediated or treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination.

[0235] In a further embodiment, the disease, disorder or condition mediated or treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination protein is pain and the compound of the application is administered in combination with one or more additional pain treatments.

[0236] In an embodiment, effective amounts vary according to factors such as the disease state, age, sex and / or weight of the subject. In a further embodiment, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.

[0237] In an embodiment, the compounds of the application are administered at least once a week. However, in another embodiment, the compounds of the application are administered to the subject from about one time per two weeks, three weeks or one month. In another embodiment, the compounds are administered about one time per week to about once daily. In another embodiment, the compounds of the application are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of the compounds of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds of the application are administered to the subject in an amount and for duration sufficient to treat the subject.

[0238] In an embodiment, the subject is a mammal. In another embodiment, the subject is human.

[0239] Compounds of the application are either used alone or in combination with other known agents useful for treating diseases, disorders or conditions that are mediated or treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2deubiquitination. When used in combination with other agents useful in treating diseases, disorders or conditions mediated or treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination, it is an embodiment that a compound of Formula II is administered contemporaneously with those agents. As used herein, “contemporaneous 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 will 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 administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a noncontemporaneous fashion. In an embodiment, the compounds of the application are administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising a compound of the application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0240] The dosage of a compound of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In some embodiments, a compound of the application is administered initially in a suitable dosage that is adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of the compound of the application from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of a compound of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from 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 will be administered. For oral administration, a representative amount is from 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 about1 mg / kg or about 0.1 mg / kg to about 1 mg / kg. For administration in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg.IV. Compositions of the Application

[0241] The present application includes a composition comprising a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof and carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising a compound of the application and a pharmaceutically acceptable carrier.

[0242] In an embodiment, the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.

[0243] The compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the application is administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0244] Parenteral administration includes systemic delivery routes other than the gastrointestinal (Gl) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0245] In some embodiments, a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient 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. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); 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 sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-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), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0246] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); andpreservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0247] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0248] In some embodiments, a compound of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiment, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0249] In some embodiments, a compound of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in 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 formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0250] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension froma pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. 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 (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0251] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0252] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0253] In some embodiments a compound of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example,polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0254] A compound of the application including pharmaceutically acceptable salts and / or solvates thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the compound of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.IV. Methods of Preparing the Compounds of the Application

[0255] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art.

[0256] The compounds of Formula I generally can be prepared according to the processes illustrated in the Schemes below. In the structural formulae shown below the variables are as defined in Formula I unless otherwise stated. A person skilled in the art would appreciate that many of the reactions depicted in the Schemes below would be sensitive to oxygen and water and would know to perform the reaction under an anhydrous, inert atmosphere if needed. Reaction temperatures and times are presented for illustrative purposes only and may be varied to optimize yield as would be understood by a person skilled in the art.

[0257] Accordingly, in some embodiments, the compounds of Formula I, are prepared as shown in Schemes 1 and 2.

[0258] In some embodiments, the compounds of Formula I wherein X is O, are prepared as shown in Scheme 1 by dissolving an amine compound of Formula A with a compound of Formula B in, for example, a 1 :1 molar equivalent, in a suitable solvent, such as acetonitrile, under an inert atmosphere, such as under N2, adding a suitable acid, such as trifluoroacetic acid, and stirring the reaction mixture at a suitable temperature and time, for example room temperature, and about 1 to about 4 hours, or about 2 hours. Then, cooling the reaction mixture to a suitable temperature, such as 0 °C, and further adding a suitable acid, such as trifluoroacetic acid, in a molar equivalent of about 0.9, followed after a suitable time, such as about 5 to 10 minutes, by 2,3-dyhydrofuran (e.g., 1.2 equiv) and vigorously stirring the reaction mixture at a suitable temperature and time, such as at about 0 °C for about 30 minutes, followed by stirring at room temperature for about16 hours to afford the compound of Formula I in both cis and trans isomer. The cis and trans mixture of compound of Formula I is purified by methods known in the art, such as by silica gel flash chromatography, using suitable elution conditions, such as 0-30% ethyl acetate in hexane gradient to get desired isomer.

[0259] A compound of Formula I may be further converted to another compound of Formula I by methods known in the art. In some embodiments, a compound of Formula I wherein R1is a OCi.6alkyl is converted to a compound of Formula I wherein R1is a OH by methods known in the art. In some embodiments, a compound of Formula I wherein R1is a OCi.6alkyl (e.g. as produced by Scheme 1) is dissolved in a suitable solvent, such as MeOH:THF:H2O (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 provide a compound of Formula I wherein R1is a OH.

[0260] In some embodiments, a compound of Formula I wherein R1is NR5R6is prepared from a compound of Formula I wherein R1is OH according to Scheme 2. Therefore, a compound of Formula I wherein R1is OH is reacted with an amino compound of Formula C in a suitable solvent, such as dimethylformamide, under suitable amide bondforming conditions, such as in the presence of a suitable base such as diisopropylethylamine and hexafluorophosphate azabenzotriazole tetramethyl uronium(HATU), to provide the compound of Formula I wherein R1is NR5R6. The crude mixture of a compound of Formula I wherein R1is NR5R6is purified by methods known in the art, such silica gel flash chromatography using suitable elution conditions such as 0-10% MeOH in DCM gradient.

[0261] The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.

[0262] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”. The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0263] Amide bond forming conditions comprise any known method forthe coupling of carboxylic acids and amines that is compatible with the intermediates and products shown in the above Schemes or that may be used to prepare a compound of the application. Known methods to prepare amides by the coupling of carboxylic acids and amines comprise use of either a coupling reagent or by prior conversion of the carboxylic acid into an activated derivative. Coupling reagents include, but are not limited to, any of the known peptide coupling reagents, such as 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC) diisopropylcarbodiimide (DIC), hexafluorophosphate benzotriazole tetramethyl uranium (HBTU), 2-(1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethylaminium tetrafluoroborate (TBTU), O-(1 / - / -6-chlorobenzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HCTU), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) and propanephosphonic acid anhydride.

[0264] In some embodiments, racemization of an enantiomer of a carboxylic acid occurs during amide bond formation using coupling reagents. In some embodiments, racemization is circumvented with 'racemization suppressing' additives such as the triazoles 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt) and ethyl cyanohydroxyiminoacetate (Oxyma).

[0265] Nucleophilic displacement reaction conditions comprise any known method for the reaction of a nucleophile to displace a leaving group to form a bond that is compatible with the intermediates and products shown in the above Schemes or that may be used to prepare a compound of the application. In some embodiments, such conditions comprise combining reactants in the presence of a base in a suitable solvent.

[0266] It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry", March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis", Smith, McGraw Hill, (1994).

[0267] Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate,recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0268] Generally, the reactions described above are performed in a suitable inert organic solvent and at temperatures and for times that will optimize the yield of the desired compounds. 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.

[0269] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.

[0270] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as 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).

[0271] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0272] Specific enantiomers or diastereomers of the compounds of the application are available by using corresponding single enantiomers or diastereomers of the corresponding starting materials. EXAMPLES:

[0273] The following non-limiting examples are illustrative of the present application. A. Preparation of Exemplary Compounds of the Application Example 1: Synthesis of (4R / S trans) I-1, (4R / S trans) I-8 and (4R / S trans) I-58Step 1: Ethyl 2-(4R / S trans)-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8- yl)acetate ((4R / S trans) I-58)

[0274] Procedure: Ethyl 2-(4-aminophenyl)acetate (1 g; 5.58 mmol) and m- tolualdehyde (670.4 mg; 1 equiv) were dissolved in acetonitrile (20 mL) in a 100 mL round bottom flask under N2.Trifluoroacetic acid (0.1 equiv) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled down to 0 ºC. Trifluoroacetic acid (0.9 equiv) was added and the reaction mixture was stirred at 0 ºC for 5 minutes.2,3-dyhydrofuran (1.2 equiv) was added and the resulting mixture was stirred vigorously at 0 ºC for 30 minutes followed by stirring at room temperature for 16 hours. The reaction mixture was quenched with NaHCO3solution. 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 Hexane gradient) to get desired isomer. Compound was isolated as off white solid (0.65 g; 33% yield);1H NMR (400 MHz, CDCl3): δ 7.33 (d, J = 2.1 Hz, 1H), 7.30-7.22 (m, 4H), 7.20-7.16 (m, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 4.61 (d, J = 5.1 Hz, 1H), 4.16 (q, J = 7.1 Hz, 3H), 4.05 (td, J = 8.4, 6.1 Hz, 1H), 3.88-3.82 (m, 1H), 3.77 (d, J = 11.2 Hz, 1H), 3.54 (d, J = 1.9 Hz, 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 = 7.1 Hz, 3H);13C{1H} NMR (101 MHz, 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]+calcd for C22H26NO3352.1913, found 352.1907.Step 2: 2-(4R / S trans))-4-(m-tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinolin-8-yl)acetic acid ((4R / S trans) I-8).

[0275] 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) in MeOH:THF:H2O (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 1 N HCl solution (~3 pH). The precipitates were filtered off and washed with H2O. The white precipitates were dried to give free acid (165 mg; 90% Yield);1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 2.1 Hz, 1H), 7.28-7.19 (m, 3H), 7.17 (d, J = 7.4 Hz, 1H), 7.05 (dd, J = 8.2, 2.1 Hz, 1H), 6.59 (d, J = 8.2 Hz, 1H), 4.60 (d, J = 5.0 Hz, 1H), 4.03 (td, J = 8.3, 6.2 Hz, 1H), 3.84 (td, J = 9.0, 5.9 Hz, 1H), 3.72 (d, J = 11.1 Hz, 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);13C{1H} NMR (101 MHz, 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]+calcd for C20H22NO3324.1600, found 324.1592. 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)

[0276] 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 minutes, HATU (252 mg; 1.3 equiv) was added. The reaction mixture was allowed to stir at room temperature for overnight. After completion of the reaction, cold water was added into it. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give crude residue. The crude mixture was purified by silica gel flash chromatography (0-10% MeOH in DCM gradient). (4R / S trans) I-1 was isolated as a white solid (120 mg; 58% Yield);1H NMR (600 MHz, CDCl3): δ 7.29-7.19 (m, 4H), 7.15 (d, J = 7.5 Hz, 1H), 6.98 (dd, J = 8.2, 2.1 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.99 (d, J = 6.4 Hz, 1H), 4.56 (d, J = 5.1 Hz, 1H), 4.01 (td, J = 8.4, 6.1 Hz, 1H), 3.82 (td, J = 9.0, 6.0 Hz, 1H), 3.72 (d, J = 11.1 Hz, 1H), 3.65 (s, 3H), 3.49-3.40 (m, 4H), 2.50 (td, J = 6.3, 2.6 Hz, 2H), 2.46-2.42 (m, 1H), 2.38 (s, 3H), 2.01 (dtd, J = 14.1, 8.5, 6.2 Hz, 1H), 1.76-1.67 (m, 1H);13C{1H} NMR (151 MHz, 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]+calcd for C24H29N2O4409.2127, found 409.2104.Example 2: Procedure for the Synthesis of (4R / S trans) I-2

[0277] 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 (1:15 mL) was added sodium borohydride (55.5 mg; 10 equiv) in portion wise 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 solution. The organic layer was concentrated and purified by silica gel flash chromatography (0-10% MeOH in DCM gradient). (4R / S trans) I-2 was isolated as a white solid (33 mg; 59% Yield);1H NMR (600 MHz, MeOD): δ 7.84 (t, J = 5.8 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 7.25-7.20 (m, 3H), 7.15- 7.11 (m, 1H), 7.01 (dd, J = 8.3, 2.1 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 4.55 (d, J = 5.0 Hz, 1H), 3.96 (td, J = 8.4, 6.2 Hz, 1H), 3.79 (ddd, J = 9.4, 8.4, 5.9 Hz, 1H), 3.63 (d, J = 11.1 Hz, 1H), 3.54 (t, J = 6.3 Hz, 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);13C NMR (151 MHz, 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]+calcd for C23H29N2O3381.2178, found 381.2155.

[0278] In a like manner the following additional compounds were also 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. B: Biology Example 3Biological Assays a) Intrathecal drug treatment

[0279] Injections via intrathecal (i.t.) route were performed in fully conscious mice according to procedures previously described (Gadotti et al 2013, Gadotti et al 2015). The dorsal fur of each mouse was shaved 24h prior to injection. Animals were manually restrained, the spinal column was arched, and a 30-gauge needle attached in a PE20 Polyethylene tube to a 25-μl Hamilton® microsyringe (Hamilton, Birmingham, UK) was inserted into the subarachnoid space between the L4 and L5 vertebrae. Positioning of the needle tip was confirmed by a characteristic tail-flick response of animal when the needle if correctly positioned. Intrathecal injections of 10 μl were delivered over a period of a minimum of 5 seconds. b) Formalin-induced pain assay

[0280] Formalin-induced pain assay was performed as originally described (Huskaar et al 1985) and as previously described by the Applicant (Gadotti et al 2013, Gadotti et al 2015). Mice were always allowed to acclimatize in the laboratory for at least 60 min before experiments. Mice received a volume of 20 μl of a formalin solution (2.5 %) prepared in phosphate-buffered saline (PBS) injected intraplantarily (i.pl.) in the ventral surface of the right hindpaw. After formalin injection, mice were immediately kept individually into observation chambers and the time spent licking or biting the injected paw was recorded and considered as nocifensive response. The nociceptive responses of each animal were scored individually from 0 to 5 min (neurogenic phase) and 15 to 30 min (inflammatory phase). Exemplary and test compounds were administrated spinally (i.t.) 20 min prior to when the mice received formalin, and its effect on both nociceptive and inflammatory phases of the formalin test was analysed. Screening of active compounds in a 384 well plate format c) Screening and Cav3.2-USP5 ELISA

[0281] A NeutrAvidin® coated black 384-well plate (Thermoscientific) was pre- incubated with 60 μl blocking buffer (Tris-BSA 1%) (1 hr, RT). The plates were washed 3 times for 7 minutes each with Tris pH 7.5 buffer 60 μl before addition of 25 μl Tris pH 7.5 buffer to wells. 0.0039 μg / μl biotinylated Cav3.2-III-IV linker peptide in 15 μl Tris buffer was then added to the wells (1 hr, RT), followed by addition of 0.00078 μg / μl USP5 human long isoform recombinant protein (Enzo Life Sciences) in 15 μl Tris pH 7.5 buffer to all wells except for the negative control wells (1 hr, RT). The wells were washed 3 times 7 minutes each with Tris pH 7.5 buffer 60 μl before addition of 40 μl anti-USP5 polyclonal antibody inblocking buffer (Tris-BSA 1%, 1:5000 dilution,1 hr RT). The wells were then washed 3 times for 7 minutes each with wash buffer Tris-tween-0.05% 60μl and 40 μl anti-rabbit HRP- conjugated secondary antibody in blocking buffer, 1:10,000 dilution (1 hr, RT) was added. Wells were washed 3 times for 7 min each with wash buffer Tris-tween-0.05% and before addition of 27 μl QuantaBlu® (ThermoScientific) substrate + 3 ul stabilizer (9:1) for 10 minutes.30 μl QuantaBlu® stop solution was added and a relative fluorescence unit (RFU) reading taken (Ex / Em: 325 / 420 nm) at 10 readings per well using the Automatic setting on a SpectraMax® Gemini XS microplate reader. The raw data obtained were converted to percentage inhibition and signal to noise (S / N) values were calculated. Net negative control values for each drug (drug + Cav3.2 III-IV linker) were subtracted from Net values (drug + Cav3.2 III-IV linker + USP5). Dose response curves were performed by adding increasing amounts of compounds. d) USP5 / Cav3.2 interaction docking simulations

[0282] Molecular docking simulations were performed as described by Garcia- Caballero et al (2022). Results and Discussion

[0283] A series of tetrahydroquinolines were synthesized and tested for their abilities to disrupt the interactions between the deubiquitinase USP5 and the Cav3.2 calcium channel domain III-IV linker region. At a screening concentration of 10 μM, among the exemplary compounds, a clear structure activity relationship was observed with some compounds completely inhibiting the interactions, and others having a lesser effect. Table 1 shows the percent inhibition of the exemplary compounds of Formula I in the Cav3.2- USP5 ELISA assay described above. Table 1 040% at ( ( ( (*under noted conditions no activity detected

[0284] Two potent exemplary compounds (4R / S trans) I-1 and (4R / S trans) I-2 were subjected to further analysis. A dose response curve was compiled revealing blocking affinities in the 100 nM range. Table 2 shows the affinity (logIC50-7.48 and -7.02, respectively) and lipophilic ligand activity) of exemplary compounds (4R / S trans) I-1 and (4R / S trans) I-2 for the Cav3.2-USP5 in vitro interaction. Figure 1 shows the dose dependence of exemplary compound (4R / S trans) I-1 and exemplary compound (4R / S trans) I-2 action on biochemical interactions between USP5 and Cav3.2 as assayed by ELISA. Tabl 2(4R / S trans) I-1 2.68 -7.49 4.81

[0285] Figure 3 shows the dose dependence of exemplary compound (4R / S trans) I-1 action on biochemical interactions between USP5 and Cav3.2 as assayed by ELISA.

[0286] Molecular docking simulations of exemplary compounds to the Cav3.2-III-IV linker-USP5 complex was also performed. Docking of exemplary compound (4R / S trans) I- 1 to the Cav3.2-III-IV linker-USP5 complex in shown in Figure 2. Figure 2 shows the docking of exemplary compound (4R / S trans) I-1 at three potential sites at USP5 and the Cav3.2-III-IV linker sequence. Docking of exemplary compound (4R / S trans) I-2 to the Cav3.2-III-IV linker-USP5 complex is shown in Figure 3. Figure 3 shows the docking of exemplary compound (4R / S trans) I-2 at two sites on USP5 and the Cav3.2-III-IV linker sequence. Therefore, molecular docking simulations revealed three potential high affinity interaction sites for exemplary compounds of the application on the Cav3.2-USP5 protein complex.

[0287] Both exemplary compounds (4R / S trans) I-1 and (4R / S trans) I-2 were tested for potential off-target effects on hERG and human Nav1.5 sodium channels. At a concentration of 5 μM, neither compounds showed any inhibitory effect, thus eliminating common concerns about cardiovascular safety. Figure 4 A shows the lack of effect of exemplary compounds (4R / S trans) I-1 and (4R / S trans) 1-2 on hERG1 tail currents in tsA- 201 cells. Figure 4 B shows the lack of effect of exemplary compounds (4R / S trans) I-1 and (4R / S trans) 1-2 on human Nav1.5 channels expressed in tsa-201 cells.

[0288] 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 durations of formalin induced nocifensive responses in both phases I and II, indicating potent analgesic effects. Exemplary compound (4R / S trans) I-1 was also administered intraperitoneally and showed dose dependence inhibition in both phases of formalin induced nocifensive responses.

[0289] Figure 5 shows the effect of exemplary compound (4R / S trans) I-1 on formalin induced nocifensive responses in mice by either intrathecal delivery, or systemic delivery. The compound was delivered intrathecally or intraperitoneally and resulted in the shortening of the duration of both phases of the formalin-induced nocifensive responses in wild type mice. In particular, Figure 5 shows the effect of exemplary compound (4R / S trans)I-1 on formalin induced nocifensive responses in phase I (left graph) and II (right graph) in mice. Formalin injection into the hindpaw mediates nocifensive responses (paw licking, biting). There is an initial phase that reflects an acute responses to formalin injection, followed by a quiescent period and a second phase of nocifensive behaviors that reflects inflammatory pain. The duration of the responses is reflective of the amount of pain. In both phases, the response time is shortened in a dose dependent manner by intrathecal delivery of exemplary compound (4R / S trans) I-1 in a dose-dependent manner. Hence, 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).

[0290] Figure 6 shows the effect of exemplary compound (4R / S trans) I-2 on formalin-induced nocifensive responses in mice by intrathecal delivery. Administration of exemplary compound (4R / S trans) I-2 resulted in the shortening of the duration of both phases of the formalin-induced nocifensive responses in wild type mice.

[0291] Additional testing was conducted with further exemplary compounds of the application. Figure 1 B shows exemplary compounds (S, 4R / S trans) I-51 (first four bars from the left), (R, 4R / S trans) I-51 (bars five to eight from the left), (R, 4R / S trans) I-52 (bars nine to twelve from the left) and (S, 4R / S trans) I-52 (bars thirteen to sixteen from the left) on biochemical interactions between USP5 and Cav3.2 as assayed by ELISA.

[0292] Figure 7 shows the effect of exemplary (4R / S trans) I-40 on formalin induced acute inflammatory pain. The compound was delivered intrathecally and resulted in the shortening of the duration of both phases of the formalin-induced nocifensive responses in wild type mice. Example 4: Paw withdrawal latencies

[0293] The paw withdrawal latency (in seconds) was used to evaluate thermal hyperalgesia in the Complete Freund’s Adjuvant (CFA) model using a Hargreaves apparatus. Animals were placed individually in clear acrylic boxes on a glass platform for acclimation for at least on hour, and then a focused beam of radiant heat source (IR = 30) was positioned beneath the right hind paw, and the latency to paw withdrawal was measured and averaged.

[0294] For mechanical paw withdrawal threshold, a digital plantar aesthesiometer (DPA, Ugo Basile) was used. Animals were placed individually in clear boxes on top of a grid platform. The device was placed underneath the platform and the filament positioned at the plantar surface of the right hind paw of each animal. The force (in grams) needed to elicit a paw withdrawal response was measured. Mechanical hypersensitivity can also betested by examining the frequency of paw withdrawals in response to stimulation with a von Frey filament. Results and Discussion

[0295] Figure 8 shows the effect of exemplary compound (4R / S trans) I-1 on CFA induced thermal hypersensitivity. Top graph shows the course of analgesic effect of exemplary compound (4R / S trans) I-1 following 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. Bottom graph shows a comparison of the effect of 10 mg / kg intraperitoneal exemplary compound (4R / S trans) I-1 on thermal withdrawal latencies in wild type and in Cav3.2 null mice. Note that Cav3.2 null mice do not respond to the compound, suggesting that Cav3.2 is the drug target.

[0296] Figure 9 shows a comparison of the effect of 10 mg / kg intraperitoneal exemplary compounds (4R / S trans) I-35 (top graph) and (4R / S trans) I-40 (bottom graph) on thermal withdrawal latencies in wild type and in Cav3.2 null mice. Note that Cav3.2 null mice do not respond to the compounds, suggesting that Cav3.2 is the drug target.

[0297] Figure 10 shows the effect of exemplary compounds (S,4R / S trans) I-52 (top graph), (4R / S trans) I-49 (middle graph), and (R, 4R / S trans) I-52 (bottom graph) on CFA induced thermal hypersensitivity. CFA injection leads to reduced thermal paw withdrawal latencies, and this is reversed upon intraperitoneal injection of the compounds.

[0298] Figure 11 shows the effect of exemplary compounds (4R / S trans) I-2 (top left graph), (4R / S trans) I-40 (top right graph), (4R / S trans) I-1 (bottom left graph), and (4R / S trans) I-31 (bottom right graph) on CFA induced thermal hypersensitivity. CFA injection leads to reduced thermal paw withdrawal latencies, and this is reversed upon intraperitoneal injection of the compounds.

[0299] Figure 12 (top graph) shows the effect of exemplary compound (4R / S trans) I-31 delivered orally on CFA induced thermal hypersensitivity. CFA injection leads to reduced thermal paw withdrawal latencies, and this is reversed upon 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 is more pronounced than that of the control analgesic naproxen (at the same oral dose). Figure 12 (bottom graph) shows that exemplary compound (4R / S trans) I-31 was ineffective in Cav3.2 null mice upon oral administration (bottom graph) supporting that the Cav3.2 channel is the drug target.

[0300] Figure 13 shows the effect of exemplary compound (4R / S trans) I-40 on nerve injury induced neuropathic pain in a repeat dosing regimen. Mice were subjected toinjury of the sciatic nerve, resulting in neuropathic pain. This was assessed by measuring the threshold for paw withdrawal in response to a mechanical stimulus of increasing force (in grams). Nerve injury reduced withdrawal thresholds and this was partially reversed upon intraperitoneal administration of (4R / S trans) I-40. This effect persisted over repeated daily doses, ceased upon termination of drug administration on day 11, and could be again observed upon reinstatement on day 14. These data show that there is no development of analgesic tolerance.

[0301] Figure 14 shows the comparison of the effect of 10 mg / kg intraperitoneal exemplary compound (4R / S trans) I-40 on mechanical hypersensitivity in mice with oxaliplatin induced mechanical hypersensitivity. Repeated oxaliplatin treatment causes neuropathic pain that was assessed by examining the frequency of paw withdrawal to a mechanical stimulus to the hind paw with a von Frey filament. Oxaliplatin treated mice exhibited an increase in paw withdrawal frequency that is potently reversed by systemic exemplary compound (4R / S trans) I-40. These data show that exemplary compound (4R / S trans) I-40 works in chemotherapy induced neuropathic pain. The data in the bottom graph correspond to data points at baseline T0 and T60 in the top graph, but show individual data points rather than only means.

[0302] While the present application has been described with reference to examples, it is to be understood that the scope of the claims 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.

[0303] 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. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE SPECIFICATION

[0304] A number of publications are cited herein. Full citations for these references are provided below. Each of these references is incorporated herein 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.

[0305] 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

[0306] 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- 0011-822.

[0307] 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

[0308] 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

AMENDED CLAIMS received by the International Bureau on 04 July 2024 (04.07.2024)1 . A compound of Formula (I), or a pharmaceutically acceptable salt, solvate and / or prodrug thereof:whereinX is selected from C, O, N, NH, S, S(O), and SO2; is a single bond or a double bond, provided - is a double bond when X is C orN;A is selected from phenyl and C5-6heteroaryl,R1is selected from R5, OR5and NR5R6;R2is selected from H, halo, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 wheteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1- ealkylenephenyl, and C1-6alkylene C5-10 heteroaryl, the latter ten groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1- ehaloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl);R3is selected from H, halo, C1-6alkyl and C1-6haloalkyl; orR2and R3are joined to form, together with the atom therebetween, a 3- to 7- membered saturated or unsaturated ring, optionally containing one or two heteromoieties selected from N, NH, N(C1-6alkyl), O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl and C1-6haloalkyl; each R4is independently selected from halo, C1-6alkyl, C1-6haloalkyl, OH, NH2, SH, SC1- ealkyl, SC1-6haloalkyl, OC1-6alkyl, OC1-6haloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)H, C(O)C1-6alkyl, C(0)C1-6haloalkyl, CO2H, C(O)2C1-6alkyl, C(0)2C1-6haloalkyl, CONH2, CONHC1-6alkyl and CON(C1-6alkyl)(C1-6alkyl);R5is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR7and C1-6haloalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 heteroaryl, C1- ealkylene C3-6cycloalkyl, C1-6alkylene C3-10heterocycloalkyl, C1-6 aIkylenephenyl, and C1- 6alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one orAMENDED SHEET (ARTICLE 19)more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)NH2, C(O)NH(C1-6alkyl), C(O)N(C1-6alkyl)(C1-6alkyl), SO2NH2, SO2NH(C1-6alkyl) and SO2N(C1-6alkyl)(C1-6alkyl);R6is selected from H, C1-6alkyl and C1-6haloalkyl; orR5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 12- membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8', O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-6alkyleneNR8R9, C1-6alkyleneOR8, C1- 6alkyleneCO2R8, and C1-6alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- wheterocycloalkyl, phenyl, C5-10 heteroaryl, C1-6alkyleneC3-6cycloalkyl, Ciwalkylene C3- wheterocycloalkyl, Ciwalkylenephenyl, and C1-6alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl);R7is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, Cs wheterocycloalkyl, C6-10aryl, C5-10 heteroaryl, OC1-10alkyl, OC1- whaloalkyl, SC1-10alkyl, SC1-whaloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl), SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-10alkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl);R8is selected from H, C1-6alkyl, C1-6haloalkyl, C1-6alkyleneR10and C1-6haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, Cs wheterocycloalkyl, phenyl, C5-10 heteroaryl, C1- ealkyleneC3-6cycloalkyl, CiwalkyleneC3-10heterocycloalkyl, Ciwalkylenephenyl, and C1- 6alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1-6haloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl);R8' is selected from H, SO2NH2, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), C(O)NH2, C(O)NH(C1-6alkyl), C(O)N(C1-6alkyl)(C1-6alkyl), C1-6haloalkyl, C1-6alkyleneR10and C1- ehaloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5- wheteroaryl, C1-6alkyleneC3-6cycloalkyl, C1-6alkylene C3 wheterocycloalkyl, C1- ealkylenephenyl, and C1-6alkylene C5-10 heteroaryl, the latter eight groups being optionallyAMENDED SHEET (ARTICLE 19)substituted with one or more substituents selected from OH, halo, CN, C1-6alkyl, C1- ehaloalkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl) ;R9is selected from H, C1-6alkyl and C1-6haloalkyl;R10is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, Ce-waryl, C5-10 heteroaryl, OC1-walkyl, OC1- whaloalkyl, SC1-walkyl, SC1-whaloalkyl, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, CO2C1-6alkyl, C(O)NHC1-6alkyl, C(O)N(C1-6alkyl)(C1-6alkyl), PO(OC1-6alkyl)(OC1-6alkyl), SO2C1-6alkyl, SO2NH(C1-6alkyl), SO2N(C1-6alkyl)(C1-6alkyl), NC1-ioalkylSO2(C1-6alkyl), and NHSO2(C1-6alkyl); and n is selected from 0, 1 , 2, 3, or 4, provided the compound is not (3aS,4F?,9bF?)- / 'e / -2-(4-phenyl-3a,4,5,9b-tetrahydro-3 / - / - cyclopenta[c]quinolin-8-yl)acetic acid.

2. The compound of claim 1 , wherein the substituent groupthe compound of Formula I, is attached at the C6 position of the tetrahydroquinoline core.

3. The compound of claim 1 or claim 2, wherein is a single bond and X is selected from O, NH, S, S(O), and SO2.

4. The compound of claim 3, wherein is a single bond and X is O.

5. The compound of claim 1 or claim 2, wherein is a double bond and X is N or C.

6. 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 the A is phenyl.

8. The compound of any one of claims 1 to 6, wherein the A is C5-6heteroaryl.

9. The compound of claim 8, wherein the C5-6heteroaryl is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazoyl, pyrazolyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl and triazinyl.

10. The compound of any one of claims 1 to 9, wherein R4is selected from halo, C1-4alkyl, C1-4haloalkyl, OH, NH2, SH, SC1-4alkyl, SC1-4haloalkyl, OC1-4alkyl, OC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)H, C(O)C1-4alkyl, C(0)C1-4haloalkyl, CO2H, CO2C1-4alkyl, C02C1-4haloalkyl, CONH2, CONHC1-4alkyl and CON(C1-4alkyl)(C1-4alkyl).AMENDED SHEET (ARTICLE 19)11 . The compound of claim 10, wherein R4is selected from F, Cl, C1-4alkyl, C1-4fluoroalkyl, C1-4Chloroalkyl, OC1-2alkyl, OC1-2fluoroalkyl and OC1-2Chloroalkyl.

12. The compound of claim 1 1 , wherein R4is selected from F, Cl, CH3, CF3, CFH2, CHF2, CCI3, OCH3,OCF3, OCFH2, OCHF2 and OCCI3.

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

14. The compound of any one of claims 1 to 13, wherein R2is selected from H, halo, C1- 4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-7heterocycloalkyl, phenyl, C5-10 heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-6alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

15. The compound of claim 14, wherein R2is selected from H, halo, Ci^alkyl and C1- 4fluoroalkyl.

16. The compound of claim 15, wherein R2is H.

17. The compound of any one of claims 1 to 16, wherein R3is selected from H, halo, C1- 4alkyl and C1-4haloalkyl.

18. The compound of claim 17, wherein R3is H.

19. The compound of any one of claims 1 to 13, wherein R2and R3are joined to form, together with the atom therebetween, a 3- to 7 membered saturated or unsaturated ring, optionally containing one or two heteromoieties selected from N, NH, N(C1-4alkyl), O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl, C1-4fluoroalkyl and C1-4Chloroalkyl.

20. The compound of claim 19, wherein R2and R3are joined to form, together with the atom therebetween, a cyclopropyl, a cyclobutyl or a cyclopentyl ring optionally substituted with one to two substituents selected from OH, F, Cl, CN, NO2, CHO, Ci^alkyl, C1-4fluoroalkyl and C1-4Chloroalkyl.21 . The compound of claim 19, wherein R2and R3are joined to form, together with the atom therebetween, a 3- to 7- membered saturated or unsaturated ring, containing one or two heteromoieties selected from N, NH, N(C1-4alkyl), O, S, S(O), and SO2 and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl C1-4fluoroalkyl and C1-4Chloroalkyl.

22. The compound of any one of claims 1 to 21 , wherein R1is R5.AMENDED SHEET (ARTICLE 19)23. The compound of any one of claims 1 to 21 , wherein R1is OR5.

24. The compound of any one of claims 1 to 21 , wherein is NR5R6.

25. The compound of any one of claims 1 to 24, wherein R5is selected from H, C1-4alkyl, C1-4haloalkyl, C1-4alkyleneR7and C1-4haloalkyleneR7, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- wheterocycloalkyl, phenyl, C5-10 heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- wheterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl), N( C1-4alkyl)(C1-4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), SO2NH2, SO2NH(C1-4alkyl) and SO2N(CI- 4alkyl)(C1-4alkyl).

26. The compound of claim 25, wherein R7is selected from OH, CN, NO2, CHO, SH, NH2, CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-10heterocycloalkyl, C6- 10aryl, C5-10 heteroaryl, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl, CO2C1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1-4alkyl), PO(OC1-4alkyl)(O C1-4alkyl), SO2C1-4alkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), NC1-4alkylSO2(C1-4alkyl) and NHSO2(C1-4alkyl).

27. The compound of claim 26, wherein R7is selected from OH, CO2H, OC1-4alkyl, OC1- 4fluoroalkyl and CO2C1-4alkyl.

28. The compound of any one of claims 25 to 27, wherein R5is selected from H, C1-4alkyl, C1-4fluoroalkyl, C1-4Chloroalkyl, C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1- 4alkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneC02H, C1- 4flouroalkyleneOC1-4alkyl, C1-4flouroalkyleneCO2C1-4alkyl, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3- wheterocycloalkyl, phenyl, C5-10 heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3- wheterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4Chloroalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)NH2, C(O)NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), SO2NH2, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl).

29. The compound of claim 28, wherein R5is selected from C1-3alkyleneOH, C1- 3alkyleneCO2H, C1-3alkyleneOC1-3alkyl, C1-3alkyleneCO2C1-3alkyl, C1-3flouroalkyleneOH, C1- 3flouroalkyleneC02H, C1-3flouroalkyleneOC1-3alkyl, C1-3flouroalkyleneC02C1-3alkyl, C1-AMENDED SHEET (ARTICLE 19)4alkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl) and C1-4alkyleneSO2N(C1-4alkyl)(C1- 4alkyl).

30. The compound of any one of claims 1 to 29, wherein R6is selected from H, Ci^alkyl and C1-4haloalkyl.31 . The compound of claim 30, wherein R6is H.

32. The compound of claim 24, wherein R5and R6are joined to form, together with the nitrogen atom therebetween, a 3- to 10-membered heterocycloalkyl or heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8', O, S, S(O), and SO2and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1-6haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1-4alkyleneOR8, Ci.4alkyleneCO2R8, and C1-4alkyleneC(O)NR8R9wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 heteroaryl, C1- 4alkyleneC3-6cycloalkyl, C1-4alkylene C3-10heterocycloalkyl, C1-4alkylenephenyl, and C1- 4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, Ci^alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

33. The compound of claim 32, wherein R5and R6are joined to form, together with the nitrogen atom therebetween, a 8- to 10-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8' and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, Ci^alkyl, C1-4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1- 4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3- ecycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

34. The compound of claim 32, wherein R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring optionally containing one or two additional heteromoieties selected from NR8' and O and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, Ci^alkyl, C1-4haloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1- 4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3-AMENDED SHEET (ARTICLE 19)ecycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

35. The compound of claim 32, wherein R5and R6are joined to form, together with the nitrogen atom therebetween, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrrolidinyl, piperidinyl and piperazinyl, each independently optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

36. The compound of claim 32, wherein R5and R6are joined to form, together with the nitrogen atom therebetween, a 5- to 6-membered heterocycloalkyl ring containing one additional NR8' heteromoiety selected from pyrazolidinyl and piperazinyl, and optionally substituted with one or two substituents selected from OH, F, Cl, CN, NO2, CHO, C1-4alkyl and C1-4haloalkyl.

37. The compound of claim 32, wherein R5and R6are joined to form, together with the nitrogen atom therebetween, a 5 to 10-membered heteroaryl ring optionally containing one or two additional heteromoieties selected from N, NR8' and O and optionally substituted with one to four substituents selected from OH, F, Cl, CN, NO2, CHO, C1-6alkyl, C1- ehaloalkyl, NR8R9, OR8, CO2R8, C(O)NR8R9, SO2NR8R9, C1-4alkyleneNR8R9, C1- 4alkyleneOR8, C1-4alkyleneCO2R8and C1-4alkyleneC(O)NR8R9, wherein each alkyl and alkylene are optionally substituted with one or two substituents selected from OH, C3- ecycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-6alkyl).

38. The compound of any one of claims 32 to 34 and 37, wherein R8is selected from H, C1-4alkyl, C1-4haloalkyl, C1-4alkyleneR10and C1-4haloalkyleneR10, wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3- ecycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1- 4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one or more substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl).

39. The compound of claim 38, wherein R10is selected from OH, CN, NO2, CHO, SH, NH2,CO2H, C(O)NH2, PO3H, SO2H, SO2NH2, NHSO2H, C3-6cycloalkyl, C3-i0heterocycloalkyl, C6- waryl, C5-10 heteroaryl, OC1-4alkyl, OC1-4haloalkyl, SC1-4alkyl, SC1-4haloalkyl, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), C(O)C1-4alkyl, CO2C1-4alkyl, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)(C1-AMENDED SHEET (ARTICLE 19)4alkyl), PO(OC1-4alkyl)(OC1-4alkyl), SO2C1-4alkyl, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), NC1-4alkylSO2(C1-4alkyl), and NHSO2(C1-4alkyl).

40. The compound of claim 39, wherein R10is selected from OH, CO2H, PO3H, SO2H, SO2NH2, OC1-4alkyl, OC1-4haloalkyl, CO2C1-4alkyl, SO2NH(C1-4alkyl) and SO2N(C1-4alkyl)(C1-4alkyl).41 . The compound of any one of claims 38 to 40, wherein R8is selected from H, C1-4alkyl, C1-4haloalkyl, C1-4alkyleneSO2NH2, C1-4haloalkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl), C1-4haloalkyleneSO2NH(C1-4alkyl), C1-4alkyleneSO2N(C1-4alkyl)(C1-4alkyl), C1-4haloalkyleneSO2N(C1-4alkyl)(C1-4alkyl), C1-4alkyleneOH, C1-4haloalkyleneOH, C1-4alkyleneCO2H, C1-4haloalkyleneC02H, C1-4alkyleneOC1-4alkyl, C1-4haloalkyleneOC1-4alkyl and C1-4alkyleneCO2C1-4alkyl, wherein each alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5- wheteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4haloalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

42. The compound of claim 41 , wherein R8is H.

43. The compound of claim 41 , wherein R8is selected from C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl.

44. The compound of any one of claims 32 to 34 and 37 to 43, wherein R8' is selected from SO2NH2, SO2NH(C1-4alkyl), SO2N(C1-4alkyl)(C1-4alkyl), C1-4alkyleneSO2NH2, C1-4alkyleneSO2NH(C1-4alkyl), C1-4alkyleneSO2N(C1-4alkyl)(C1-4alkyl), C1-4alkyleneOH, C1-4alkyleneCO2H, C1-4alkyleneOC1-4alkyl, C1-4alkyleneCO2C1-4alkyl, C1-4flouroalkyleneOH, C1-4flouroalkyleneC02H, C1-4flouroalkyleneOC1-4alkyl, and C1-4flouroalkyleneC02C1-4alkyl wherein each alkyl and alkylene is optionally substituted with one or two substituents selected from OH, C3-6cycloalkyl, C3-10heterocycloalkyl, phenyl, C5-10 heteroaryl, C1-4alkyleneC3-6cycloalkyl, C1-4alkyleneC3-10heterocycloalkyl, C1-4alkylenephenyl, and C1-4alkyleneC5-10 heteroaryl, the latter eight groups being optionally substituted with one to four substituents selected from OH, halo, CN, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)(C1-4alkyl).

45. The compound any one of claims 1 to 44, wherein R9is selected from H, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl.

46. The compound of claim 45, wherein R9is H.

47. The compound of any one of claims 1 to 21 , wherein R1is selected fromAMENDED SHEET (ARTICLE 19)48. The compound of any one of claims 1 to 47, wherein the compound of Formula I is a mixture of cis isomer forms having the configuration (3aR, 4R, 9bR) and (3aS, 4S, 9bS) or the compound of Formula I is a mixture of trans isomer forms having the configuration (3aR, 4S, 9bR) and (3aS, 4R, 9bS).

49. The compound of claim 1 , wherein the compound of Formula I is selected from the compounds listed below:AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)or a pharmaceutically acceptable salt and / or solvate thereof.

50. A method for inhibiting interactions between Cav3.2 T-type calcium channels (Cav3.2) and ubiquitin specific peptidase 5 (USP5) in a cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt and / or solvate thereof to the cell.51 . A method of treating a disease, disorder or condition that is treatable by inhibiting interactions between Cav3.2 and USP5 comprising administering a therapeutically effectiveAMENDED SHEET (ARTICLE 19)amount of a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt and / or solvate thereof to a subject in need thereof.

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

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

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

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

56. The method of claim 55, wherein the disease, disorder or condition treatable by inhibiting interactions between Cav3.2 and USP5 or inhibiting Cav3.2 deubiquitination is pain.

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

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

59. A pharmaceutical composition comprising a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt and / or solvate thereof and pharmaceutically acceptable carrier.AMENDED SHEET (ARTICLE 19)

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