Bicyclic heterocyclic amide inhibitors of NAV1.8 for the treatment of pain

Abstract

Provided herein are compounds of formula (I), pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions in the treatment of conditions associated with voltage-gated sodium channel function, wherein the compound is 1-206. (Formula (I)) JPEG2025516005000954.jpg36143

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Indian Patent Application No. 202311013223 filed on February 27, 2023, which claims the benefit of Indian Patent Application No. 202211024240 filed on April 25, 2022, each of which is incorporated by reference in its entirety herein. Field

[0002]

[0002] Compounds, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods for evaluating voltage-gated sodium channel function, particularly Na V Methods of using the compounds and compositions in treating conditions associated with 1.8, such as pain and conditions associated with pain, are provided herein. Also provided herein are methods of treating pain in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of a compound or composition. [Background technology]

[0003] background Voltage-gated sodium channels are large integral membrane protein complexes present in neurons and excitable tissues, where they contribute to processes such as membrane excitability and muscle contraction (Ogata et al., Jpn. J. Pharmacol. (2002) 88(4) 365-77). They have been identified as a major target for the treatment of pain. Na V There are nine distinct mammalian isoforms of the channel (Na V The genes encoding the isoforms 1.1-1.9 have been sequenced. V Variations in the gating properties, cellular distribution and expression levels of the isoforms affect the physiology of neuronal conduction. A growing body of evidence supports the role of individual Na V The isoform Na V1.3, 1.7, 1.8 and 1.9 are disproportionately involved in pain signaling and nociception, and nonspecific Na V Without the undesirable effects of antagonist or opioid drugs, V It has been suggested that isoform-specific inhibitors of NF-α may provide pain relief (Momin et al., Curr Opin Neurobiol. 18(4): 383-8, 2008;Rush et al., J. Physiol. 579(Pt 1): 1-14, 2007).

[0004]

[0004] Na V 1.8 is selectively expressed in dorsal root ganglion (DRG) neurons, a type of pseudounipolar neuron that projects both centrally and peripherally, and which is involved in pain sensation. As a consequence of its sensory neuron specificity, Na V 1.8 is particularly important in the pathophysiology of pain. V Na rather than channels V It is desirable to design drugs that selectively inhibit mammalian Na V Given the high structural homology (75-96%) between isoforms, such drug design is challenging.

[0005]

[0005] Isoform-selective inhibitors have been explored by many research groups, and several compounds have progressed to clinical development. VIsoform-selective small molecule inhibitors of 1.8 have been disclosed in the following patent applications and publications: WO 2021 / 257490; WO 2021 / 257418; WO 2021 / 257420; WO 2021 / 113627; WO 2021 / 032074; WO 2020 / 261114; WO 2020 / 219867; WO 2020 / 146682; WO 2020 / 092187; WO 2020 / 092667; WO 2020 / 014246; WO 2020 / 014243; WO 2019 / 157505; WO 2019 / 014352; WO 2018 / 213426; WO 2015 / 089361; WO 2015 / 010065; WO 2014 / 120820; WO 2014 / 120815; WO 2014 / 120808; WO 2013 / 114250; WO 2013 / 061205; WO 2008 / 135830; Brown et al., Bioorg Med Chem. 27(1):230-239, 2019; Bagal et al., Med Chem Comm. 7(10), 2016; Bagal et al., ACS Med Chem Lett. 6(6):650-654, 2015; Jarvis et al., PNAS 104(20):8520-8525, 2007. Summary of the Invention [Problem to be solved by the invention]

[0006]

[0006] Na as a human therapy V Previous attempts to develop isoform-selective inhibitors of 1.8 have encountered many challenges. These include off-target human Na V Poor selectivity for 1.x isoforms, limited target engagement in vivo (human Na V Insufficient potency for 1.8, high protein or tissue binding, Na VThese include compound-specific issues such as poor physicochemical properties that preclude oral administration (due to state-dependent inhibition of Na+, safety concerns that preclude dose escalation, or a combination thereof), toxicological findings or the formation of metabolites that may pose safety risks in humans. Certain compounds also have V It exhibits species variability in potency of 1.8 (see, e.g., Bagal et al., Med Chem Comm. 7(10), 2016), and as a result, it is difficult to assess its on-target pharmacodynamic effects in standard preclinical species, i.e., mice and rats.

[0007]

[0007] The present invention relates to a method for treating pain and conditions associated with voltage-gated sodium channel function, particularly other Na V Na isoforms V There is a need for compounds that selectively inhibit 1.8. [Means for solving the problem]

[0008] overview

[0008] Compounds, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods for detecting voltage-gated sodium channels, particularly Na V Methods of using the compounds and compositions are provided herein for the treatment of conditions modulated by 1.8, and in some or any of the embodiments, in the treatment of pain. Also provided herein are methods of treating pain and / or conditions modulated by voltage-gated sodium channels in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of the compound or composition. In some or any of the embodiments, the subject is a human.

[0009] In one embodiment, a compound of formula (I): [ka] [In the formula, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or The Two R's 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R3a ) q 5- to 10-membered heteroaryl, optionally substituted by (R 3a ) q1 may be substituted with [ka] ;(R 3a ) q1 may be substituted with [ka] ; or (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, -C(cyclopropyl)=, or -C(C 1 -C 6 Alkoxy) =; W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C; R 2 is, independently in each occurrence, hydrogen, halogen, C 1 -C 6 Alkyl or halo-C 1 -C 6 is alkyl; or The Two R's 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 3- to 7-membered carbocyclic ring, said ring containing no halogen and C 1 -C 6 alkyl; and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached to the same carbon and together with the carbon to which they are attached form a 3- to 7-membered carbocyclic ring, which ring is free of halogen and C 1 -C 6 alkyl; and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(O)NH 2 , -NHS(O) 2 NH 2 , -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6-Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 Cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from the group consisting of one -NH 2 and said amino-C 1 -C 6 The alkyl in the alkyl may be further substituted with 1, 2, 3, or 4 halo; R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3. or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, provided herein; However, the compound is 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or a pharma- ceutically acceptable salt and / or an isomer thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; or 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof. isn't it.

[0010] In another embodiment, a compound of formula (I-P2): [ka] [In the formula, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q 5- to 10-membered heteroaryl optionally substituted with (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6is -C(alkyl)= or -C(cyclopropyl)=; W 2 and W 3 are each -C-, and W 2 and W 3 the dashed bond between them is a double bond, and

Chemical formula

Chemical formula

[0011] In another embodiment, a compound of formula (I-P1): [ka] [In the formula, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q 5- to 10-membered heteroaryl optionally substituted with (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, or -C(cyclopropyl)=; W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 7-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C; R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached to the same carbon and together with the carbon to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; R 3 is hydrogen, -C(O)NH 2 , -NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -alkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 is cycloalkyl; R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3. or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, are provided herein.

[0012] In a further embodiment, the compound of the formula: [ka] Provided herein is a compound according to any one of During the ceremony, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q 5- to 10-membered heteroaryl, optionally substituted by (R 3a ) q1 may be substituted with [ka] ;(R 3a ) q1 may be substituted with [ka] ; or (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, -C(cyclopropyl)=, or -C(C 1 -C 6 Alkoxy) =; W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 7-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C; R 2 is, independently in each occurrence, hydrogen, halogen, C 1 -C 6 Alkyl or halo-C 1 -C 6 is alkyl; or The Two R's 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 3- to 7-membered carbocyclic ring, said ring containing no halogen and C 1 -C 6 alkyl; and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached to the same carbon and together with the carbon to which they are attached form a 3- to 7-membered carbocyclic ring, which ring is free of halogen and C 1 -C 6alkyl; and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(O)NH 2 , -NHS(O) 2 NH 2 , -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 -cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from one -NH 2 and said amino-C 1 -C 6 The alkyl in the alkyl may be further substituted with 1, 2, 3, or 4 halo; R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C 3Alkyl or C 3 -C 6 is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6 q1 is 0, 1, or 2; and q is 0, 1, 2, or 3.

[0013] In a further embodiment, the compound of the formula: [ka] Provided herein is a compound according to any one of the following, or a salt thereof: During the ceremony, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q 5- to 10-membered heteroaryl optionally substituted with (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, or -C(cyclopropyl)=; W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C; R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached to the same carbon and together with the carbon to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3.

[0014]

[0014] Additional embodiments include R 1is as provided in embodiment 1-1c or 17-17a; A is as provided in embodiment 2-2k; W 1 is as provided in embodiment 3, 3a, or 3b; W 2 and W 3 is as provided in embodiment 4, 4a, 5, 5a, or 6; R 2 is, in each occurrence independently, as provided in embodiments 7-7c; R 3 is as provided in embodiment 8-8c; R 3a is as provided in embodiment 9 or 9a; m, n, p, q, and q1 are as provided in embodiments 10, 11, 12, 13, and 14, respectively; and [ka] as provided in embodiments 15, 15a, 15b, 15c, 15d, 15e, 16, 16a, 16b, and 16c; and any combination thereof.

[0015] In an additional embodiment, the method according to the following scheme: [ka] [ka] to obtain a compound disclosed herein, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; and, optionally, to isolate a compound disclosed herein, During the ceremony, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q 5- to 10-membered heteroaryl optionally substituted with (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 7-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C; R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 3- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2are attached to the same carbon and together with the carbon to which they are attached form a 3- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(O)NH 2 , -NHS(O) 2 NH 2 , -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 -cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from one -NH 2 and said amino-C 1 -C 6 The alkyl in the alkyl may be further substituted with 1, 2, 3, or 4 halo; R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C3 alkyl, or C 3 -C 6 is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3.

[0016]

[0016] In an additional aspect, the following scheme:

Chemical formula

Chemical formula

Chemical formula

[0017]

[0017] Additional embodiments include R 1is as provided in embodiment 1-1c or 17-17a; A is as provided in embodiment 2-2k; W 1 is as provided in embodiment 3, 3a, or 3b; W 2 and W 3 is as provided in embodiment 4, 4a, 5, 5a, or 6; R 2 is, in each occurrence independently, as provided in embodiments 7-7c; R 3 is as provided in embodiment 8-8c; R 3a is as provided in embodiment 9 or 9a; m, n, p, q, and q1 are as provided in embodiments 10, 11, 12, 13, and 14, respectively; and [ka] as provided in embodiments 15, 15a, 15b, 15c, 15d, 15e, 16, 16a, 16b, and 16c; and any combination thereof.

[0018]

[0018] In another aspect, provided herein are pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating pain and / or conditions modulated by voltage-gated sodium channels comprising a therapeutically or prophylactically effective amount of a compound provided herein, e.g., any or all of the embodiments of formulas (I), (I-P1), (I-P2), and compounds 151, 56, 59, 60, 82, 116, 119, and 169-206.

[0019]

[0019] In another aspect, provided herein are pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating pain and / or conditions modulated by voltage-gated sodium channels comprising a therapeutically or prophylactically effective amount of a compound provided herein, e.g., some or any of the embodiments of formulas (I), (I-P2), and compounds 1-127 and 169-206.

[0020]

[0020] In another aspect, provided herein are pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating pain and / or conditions modulated by voltage-gated sodium channels comprising a therapeutically or prophylactically effective amount of a compound provided herein, e.g., some or any of the embodiments of formula (I), and compounds 1-206.

[0021] In one embodiment, the Na ν Methods of treating conditions associated with voltage-gated sodium channel function, including 1.8, are provided, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound provided herein, e.g., any or all of the embodiments of formulas (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206.

[0022] In one embodiment, the present invention relates to a method for the treatment of Na ν Methods of treating conditions associated with voltage-gated sodium channel function, including 1.8, are provided, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound provided herein, e.g., any or all of the embodiments of formulas (I), (I-P2), and compounds 1-127 and 169-206.

[0023] In one embodiment, the Na ν Methods of treating conditions associated with voltage-gated sodium channel function, including 1.8, are provided, comprising administering to an individual in need thereof a therapeutically or prophylactically effective amount of a compound provided herein, e.g., any or all of the embodiments of formula (I), and compounds 1-206.

[0024] In another embodiment, the present invention provides a method for treating Na νProvided are therapeutically or prophylactically effective amounts of compounds provided herein, e.g., any or all of the embodiments of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or therapeutically or prophylactically effective amounts of pharmaceutical compositions, for use in treating conditions associated with voltage-gated sodium channel function, including 1.8.

[0025] In another embodiment, the present invention provides a method for treating Na ν Provided is a therapeutically or prophylactically effective amount of a compound provided herein, e.g., some or any of the embodiments of formula (I), (I-P2), and compounds 1-127 and 169-206, or a therapeutically or prophylactically effective amount of a pharmaceutical composition, for use in treating conditions associated with voltage-gated sodium channel function, including 1.8.

[0026] In another embodiment, the present invention provides a method for treating Na ν Provided are a therapeutically or prophylactically effective amount of a compound provided herein, e.g., any or all of the embodiments of Formula (I) and compounds 1-206, or a therapeutically or prophylactically effective amount of a pharmaceutical composition, for use in treating conditions associated with voltage-gated sodium channel function, including 1.8. [Brief description of the drawings]

[0027]

Figure 1

[0028]

Figure 2

[0029] Detailed Description

[0029] Compounds, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods for treating pain and / or voltage-gated sodium channels, particularly Na V Methods of using the compounds and compositions in treating conditions regulated by 1.8 are provided herein. Also provided herein are methods of treating pain in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of the compound or composition. In one embodiment, the subject is a human.

[0030] definition

[0030] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. If there are multiple definitions for a term in this specification, the one in this section prevails unless otherwise specified. Unless otherwise specified, when a term is defined as substituted, the groups in the list of substituents are themselves unsubstituted. For example, substituted alkyl groups can be substituted with, for example, cycloalkyl groups, and cycloalkyl groups are not further substituted unless otherwise specified.

[0031]

[0031] In this specification, reference to a value or parameter of "about" includes (and describes) a variation that is directed to the value or parameter itself. For example, a description of "about X" includes a description of "X". As used herein and unless otherwise specified, the terms "about" and "approximately", when used in relation to a temperature, dose, amount, or weight percentage of a component of a composition or dosage form, refer to a dose, amount, or weight percentage that is recognized by those skilled in the art to achieve a pharmacological effect equivalent to that obtained from the specific dose, amount, or weight percentage. Specifically, the terms "about" and "approximately", when used in this context, contemplate a dose, amount, or weight percentage that is within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specific dose, amount, or weight percentage.

[0032]

[0032] The terms "a" or "an" as used herein mean one or more, unless the context clearly dictates otherwise.

[0033] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated straight-chain or branched hydrocarbon. In some or any of the embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In some or any of the embodiments, the alkyl group is a group having from 1 to 10 carbon atoms, i.e., C 1 Or C 10 In some or any of the embodiments, alkyl is C 1-6 In some or any embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0034] The term "hydroxyalkyl," as used herein, unless otherwise specified, refers to alkyl, as defined herein, including alcohol (hydroxy). In one or more embodiments, the alcohol group is a primary, secondary, or tertiary alcohol. In one or more embodiments, the hydroxyalkyl group is one to ten carbons, i.e., C 1 Or C 10 In one or more embodiments, the hydroxyalkyl group contains one or two alcohol (hydroxy) groups, provided they are not on the same carbon. In one or more embodiments, the hydroxyalkyl group contains a hydroxy C 1-3 In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, and hydroxyhexyl. In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of C 1-6In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropan-2-yl, and 2-hydroxypropan-2-yl.

[0035] The terms "alkoxy" and "alkyloxy", as used herein and unless otherwise specified, refer to the group -OR', where R' is alkyl. Alkoxy and alkyloxy groups, in some or any embodiments, include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like. In some embodiments, alkoxy is selected from the group consisting of C 1-6 It is an alkoxy.

[0036] The term "amino" refers to -NH 2 means...

[0037]

[0037] The term "aryl," as used herein, and unless otherwise specified, refers to a monovalent C 6 -C 15 It refers to a carbocyclic ring system, and the aryl ring system is monocyclic, bicyclic or tricyclic. The aryl can be attached to the main structure through any of its rings, i.e., any aromatic or non-aromatic ring. In some or any embodiment, the aryl group can be bridged (if chemically possible) or non-bridged, spirocyclic (if chemically possible) or non-spirocyclic and / or fused or non-fused polycyclic groups. In some or any embodiment, the aryl is phenyl, naphthyl, indanyl, fluorenyl, 6,7,8,9-tetrahydro-5H-benzo[7]annulenyl, or tetrahydronaphthyl. When the aryl is substituted, it can be substituted on any ring, i.e., on any aromatic or non-aromatic ring composed of the aryl.

[0038]

[0038] The term “C 3 -C 10"-cycloalkyl" as used herein refers to a monovalent saturated monocyclic hydrocarbon or bicyclic (fused, bridged, or spirocyclic) ring. In some or any of the embodiments, the terms "fused cycloalkyl" and "spirocycloalkyl" are embodiments of cycloalkyl groups. In some or any of the embodiments, the cycloalkyl group contains from 3 to 6 carbon atoms, i.e., C 3 Or C 6 In some or any of the embodiments, the cycloalkyl may include 3, 4, or 5 aryl groups (C 3-5 ); 3 or 4 (C 3-4 );3 pieces(C 3 );4 pieces(C 4 ); or 5 (C 5 ) carbon atoms. In some or any of the embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some or any of the embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In some or any of the embodiments, the cycloalkyl group is cyclopropyl. In some or any of the embodiments, the cycloalkyl group is cyclobutyl. In some or any of the embodiments, the cycloalkyl group is cyclopentyl. In some or any of the embodiments, the cycloalkyl group is bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, or adamantyl.

[0039] The term "cycloalkylalkyl" refers to an alkyl, as defined herein, substituted with one or more cycloalkyl groups, as defined herein, which are independently selected. In some embodiments, "cycloalkylalkyl" refers to a cycloalkyl group, as defined herein, 3-8 Cycloalkyl C 1-6 In some embodiments, "cycloalkylalkyl" is an alkyl substituted with one cycloalkyl. In some embodiments, the cycloalkylalkyl is cyclopropylmethyl.

[0040]

[0040] The term "haloalkyl," as used herein and unless otherwise specified, refers to an alkyl group substituted with one, two, three, four, or five halo groups. In some or any embodiment, haloalkyl is halo-C 1-6 In some or any embodiments, haloalkyl is -CF 3 , -CH 2 F, -CHF 2 or -CH 2 CF 3 It is.

[0041]

[0041] The term "haloalkoxy," as used herein, and unless otherwise specified, refers to a -OR group, where R is halo-C, as defined herein. 1-10 In some or any embodiments, haloalkoxy is halo-C 1-6 It is an alkoxy.

[0042]

[0042] The terms "halogen" and "halo", as used herein, and unless otherwise specified, are synonymous and refer to chloro, bromo, fluoro, or iodo.

[0043]

[0043] The term "heteroaryl," as used herein, and unless otherwise specified, refers to a monocyclic or polycyclic aromatic ring system in which one or more (in some or any embodiment, one, two, three or four) of the ring atoms are O, S(O), 0-2, NH and N, the remaining ring atoms are carbon atoms, and the rings may be optionally substituted as described herein. Heteroaryl groups are attached to the remainder of the molecule through any atom in the ring system, if valence rules permit. In some or any of the embodiments, each ring of the heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms and / or 1 to 4 N atoms, or a combination thereof, provided that the total number of heteroatoms in each ring is 4 or less, and each ring contains at least 1 carbon atom. In some or any of the embodiments, the heteroaryl has 5 to 20, 5 to 15, 5 to 6, or 5 to 10 ring atoms. When the heteroaryl is substituted, it may be substituted on any of the rings. In one or more of the embodiments, the heteroaryl is [ka] where: [ka] indicates the point of attachment of the heteroaryl to the rest of the molecule. In some embodiments, the heteroaryl is [ka] where: [ka] indicates the point of attachment of the heteroaryl to the rest of the molecule.

[0044]

[0044] In some or any embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. In some or any embodiments, bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzotriazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, or quinazolinyl. In some or any of the embodiments, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzoindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, and phenazinyl. In some or any of the embodiments, heteroaryl is indolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl; each of which, in some embodiments, is C 1-6 Alkyl, Hydroxy, Halo, Halo-C 1-6 Alkyl, C 1-6 It may be substituted with one, two, three or four groups as defined throughout the specification, including groups independently selected from alkoxy, cyano or phenyl.

[0045]

[0045] The term "heterocycle", as used herein, and unless otherwise specified, refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring; one or more (in some or any embodiment, one, two, three or four) of the monocyclic non-aromatic ring atoms are O, S(O),0-2 and N, and the remaining ring atoms are carbon atoms; any one or more (in some or any embodiment 1, 2, 3 or 4) of the ring atoms in a polycyclic ring system are O, S(O), 0-2 and N, with the remaining ring atoms being carbon. The term "heterocycle" does not include fully aromatic rings, i.e., does not include imidazole, pyrimidine, pyridine, etc. In some or any embodiment, the heterocyclic ring contains one or two heteroatoms independently selected from nitrogen and oxygen. In some or any embodiment, the heterocyclic ring contains one or two heteroatoms that are oxygen. In some or any embodiment, the heterocyclic ring contains one or two heteroatoms that are nitrogen (wherein the nitrogen is substituted as described in any aspect or embodiment described herein). In some or any embodiment, the heterocycle is polycyclic and contains one heteroatom in a non-aromatic ring, or contains one heteroatom in an aromatic ring, or contains two heteroatoms in an aromatic ring, or contains two heteroatoms, one in the aromatic ring and the other in the non-aromatic ring. In some or any of the embodiments, the heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some or any of the embodiments, the heterocycle is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some or any of the embodiments, the heterocyclic group can be a bridged or unbridged, spirocyclic or non-spirocyclic, and / or fused or non-fused polycyclic group. One or more of the nitrogen and sulfur atoms can be optionally oxidized, one or more of the nitrogen atoms can be optionally quaternized, and one or more of the carbon atoms can be optionally substituted or unsubstituted. [ka] Some rings may be partially or fully saturated or aromatic, but the heterocycles are not fully aromatic. Monocyclic and polycyclic heterocyclic rings may be attached to the main structure at any heteroatom or carbon atom, which results in a stable compound. Polycyclic heterocycles may be attached to the main structure through any of their rings, including any aromatic or non-aromatic ring, regardless of whether the ring contains a heteroatom. In some or any embodiment, the heterocycle is 1) a saturated monovalent monocyclic group containing at least one ring heteroatom as described herein, or 2) a "heterocycloalkyl" in which at least one ring is a saturated monovalent bicyclic or tricyclic group containing at least one heteroatom as described herein. When heterocycles and heterocycloalkyls are substituted, they can be substituted on any ring, i.e., on any aromatic or non-aromatic ring that is composed of the heterocycle and heterocycloalkyl. In some or any embodiments, such heterocycles include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 1,3-dihydroisobenzofuranyl, benzofuranonyl, benzopyranonyl, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothienyl, 2,2-dioxo-1,3-dihydrobenzo[c]thienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroxybenzoyl, benzodihydrobenzo[b]thien ... nolinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl, imidazolinyl, indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, 1-oxo-isoindolinyl, 1,3-Dioxo-isoindolinyl, isothiazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidonyl These include tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiomorpholinyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthenyl and 1,3,5-trithianyl. In some or any of the embodiments, the heterocycle is benzo-1,4-dioxanyl, benzodioxolyl, indolinyl, 2-oxo-indolinyl, pyrrolidinyl, piperidinyl, 2,3-dihydrobenzofuranyl, or decahydroquinolinyl; each of which, in some or any of the embodiments, may be substituted with one, two, three, or four groups as defined throughout the specification, including groups independently selected from halo, alkyl, and phenyl. In some embodiments, the heterocycloalkyl is pyrrolidinyl. In some embodiments, the heterocycloalkyl is an N-linked heterocycloalkyl.

[0046] The term "oxo," as used herein, unless otherwise specified, refers to a keto group (C=O). An oxo group that is a substituent of a non-aromatic carbon is -CH 2- to -C=O. An oxo group that is a substituent of an aromatic carbon results in the conversion of -CH- to -C=O. When the substituent is oxo, two hydrogens on the atom are replaced. When an oxo group replaces an aromatic moiety, the corresponding partially unsaturated ring replaces the aromatic ring. For example, pyridyl groups substituted with oxo groups are pyridone and pyrimidinone. In some embodiments, those skilled in the art will recognize that such groups, such as pyridone, 2,4(1H,3H)-dioxo-pyrimidinyl, 3(2H)-oxo-pyridazinyl, and 3-oxo-1,2-dihydro-3H-indazolyl, can exist in tautomeric forms, such as hydroxypyridine, 2,4-dihydroxypyrimidinyl, hydroxy-pyridazinyl, and -hydroxy-1H-indazolyl, respectively.

[0047]

[0047] The term "protecting group", as used herein and unless otherwise specified, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis (see, for example, those described in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Fourth Edition, 2006, which is incorporated herein by reference).

[0048]

[0048] The term "pharmaceutically acceptable salts", as used herein and unless otherwise specified, refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise desirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art.Such salts include, but are not limited to, (1) organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, , ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfa and (2) base addition salts formed when an acidic proton present in the parent compound is replaced by (a) a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide, and barium hydroxide, ammonia, or (b) an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0049]

[0049] Pharmaceutically acceptable salts, in some or any embodiment, further include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, etc. When the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates, laurates, methanesulfonates (mesylates), and the like, may be used. salts), ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like.

[0050] The terms "substantially free" or "substantially free" of stereoisomers, with respect to a composition, refer to a composition that comprises at least 85% or 90% by weight, and in some or any embodiments 95%, 98%, 99% or 100% by weight of a specified stereoisomer of a compound in the composition. In some or any embodiments, in the methods and compounds provided herein, the compound is substantially free of a stereoisomer.

[0051]

[0051] Similarly, the term "isolated" refers to a composition that contains at least 85%, 90%, 95%, 98%, 99% or 100% by weight of a particular compound, with the remainder containing other chemical species or stereoisomers.

[0052]

[0052] The term "isotopic composition" as used herein and unless otherwise specified, refers to the amount of each isotope present for a given atom, and "natural isotopic composition" refers to the naturally occurring isotopic composition or isotopic abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as "non-enriched" atoms. Unless otherwise specified, the atoms of compounds listed herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen at its natural isotopic composition.

[0053]

[0053] The term "isotopic enrichment", as used herein and unless otherwise specified, refers to the percentage of incorporation of a given amount of a particular isotope at a given atom in a molecule, instead of the natural isotopic abundance of that atom. In some or any embodiment, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that particular position. Since the naturally occurring distribution of deuterium is about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using routine analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0054]

[0054] The term "isotopically enriched," as used herein and unless otherwise specified, refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0055]

[0055] As used herein, the term "local anesthetic" means a drug that provides localized numbness or pain relief. In some or any embodiments, local anesthetic agents include aminoacylanilide compounds (in some or any embodiments, lidocaine, prilocaine, bupivacaine, ropivacaine, and mepivacaine) and related local anesthetic compounds having various substituents on the ring system or amine nitrogen; aminobenzoic acid alkyl compounds (in some or any embodiments, procaine, chloroprocaine, propoxycaine, hexylcaine, tetracaine, cyclomethycaine, benoxinate, butacaine, and proparacaine) and related local anesthetic compounds; cocaine; aminocarbonate compounds (in some or any embodiments, diperodone); N-phenylamidine compounds (in some or any embodiments, phenacaine); N-aminoalkylamide compounds (in some or any embodiments, dibucaine); aminoketone compounds (in some or any embodiments, faricaine and dyclonine); and aminoether compounds (in some or any embodiments, pramoxine and dimethisoquine).

[0056]

[0056] As used herein, "alkyl", "hydroxyalkyl", "carbocycle", "cycloalkyl", "aryl", "alkoxy", "heterocycloalkyl" and "heterocycle" groups may contain deuterium at one or more positions where a hydrogen atom is present, and the deuterium composition of that atom is other than the natural isotopic composition.

[0057]

[0057] Additionally, as used herein, "alkyl," "hydroxyalkyl," "carbocycle," "cycloalkyl," "aryl," "alkoxy," "heterocycloalkyl," and "heterocycle" groups may contain carbon-13 in an amount other than its natural isotopic composition.

[0058]

[0058] As used herein and unless otherwise specified, the term "IC 50 " refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0059]

[0059] As used herein, the terms "subject" and "patient" are used interchangeably. The term "subject" refers to animals, e.g., mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats and mice) and primates (e.g., monkeys, e.g., cynomolgus monkeys, chimpanzees and humans), and in some or any embodiment, humans. In some or any embodiment, the subject is a farm animal (e.g., horse, cow, pig, etc.) or a pet (e.g., dog or cat). In some or any embodiment, the subject is a human.

[0060]

[0060] As used herein, the term "therapeutic agent" refers to any agent that can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In some or any embodiment, the term "therapeutic agent" includes the compounds provided herein. In some or any embodiment, a therapeutic agent is an agent that is known to be useful or has been used or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.

[0061]

[0061] A "therapeutically effective amount" refers to the amount of a compound or composition that, when administered to a subject for treating a condition, is sufficient to effect such treatment for the condition. A "therapeutically effective amount" of, inter alia, a compound may vary depending on the condition and its severity and the age, weight, etc., of the subject being treated.

[0062]

[0062] "Treating" or "treatment" of any condition or disorder refers to reversing a condition or disorder present in a subject, including prophylactically, in some or any embodiment. In another embodiment, "treating" or "treatment" includes reversing at least one physical parameter that may not be clearly detectable by the subject. In yet another embodiment, "treating" or "treatment" includes modulating the condition or disorder physically (e.g., stabilization of a clearly detectable symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, "treating" or "treatment" includes delaying the onset of the condition or disorder. In yet another embodiment, "treating" or "treatment" includes reducing or eliminating the condition (e.g., pain) or one or more symptoms (e.g., pain) of the condition (e.g., sciatica), or slowing the progression of the condition (e.g., pain) or one or more symptoms (e.g., pain) of the condition (e.g., sciatica), or reducing the severity of the condition (e.g., pain) or one or more symptoms (e.g., pain) of the condition (e.g., sciatica). In yet another embodiment, "treating" or "treatment" includes administering a compound described herein prophylactically.

[0063]

[0063] As used herein, the term "prophylactic agent" refers to any agent that can be used in the prevention of a condition or one or more symptoms thereof and / or prevents or hinders the onset, occurrence, progression and / or severity of a condition. In some or any embodiments, the term "prophylactic agent" includes a compound provided herein. In some or any other embodiments, the term "prophylactic agent" does not refer to a compound provided herein. In some or any embodiments, the agent is administered prophylactically, e.g., before surgery, to prevent or hinder the onset, duration, progression and / or severity of pain (e.g., post-surgical pain).

[0064]

[0064] As used herein, the phrase "prophylactically effective amount" refers to an amount of a therapy (e.g., a prophylactic agent) that is sufficient to prevent or reduce the occurrence, recurrence or onset of one or more symptoms associated with a condition, or to enhance or improve the prophylactic effect of another therapy (e.g., another prophylactic agent).

[0065] compound

[0065] Provided herein are compounds capable of modulating the activity of voltage-gated ion channels (e.g., voltage-gated sodium channels). The compounds can be formed as described herein and used for the treatment of conditions associated with voltage-gated sodium channel function. In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is pain or a condition associated with pain. In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is a condition associated with pain. In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is pain, itch, cough, epilepsy, Parkinson's disease, mood disorders, psychosis, amyotrophic lateral sclerosis, glaucoma, ischemia, spasticity disorders, and obsessive-compulsive disorders. In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is pain (in some embodiments, subacute or chronic pain). In some embodiments, pain associated with voltage-gated sodium channel function includes pain and / or discomfort associated with dry eye syndrome, pain associated with (acute) corneal injury or abrasion, acute ocular pain, chronic ocular pain, pain associated with corneal infection, pain associated with Parkinson's disease, pain associated with ALS, and pain associated with surgery (in some embodiments, ophthalmic surgery).

[0066]

[0066] The aspects and embodiments described herein include the recited compounds, and their pharma ceutically acceptable salts and / or isomers thereof.

[0067]

[0067] When chemically possible, all stereoisomers of the compound, including diastereomers and enantiomers, are included herein. Also included are mixtures of possible stereoisomers in any ratio, including but not limited to racemic mixtures. Unless the stereochemical configuration is explicitly shown in the structure at a particular atom, the structure is intended to include all possible stereoisomers of the compound shown. If the stereochemical configuration is explicitly shown for one part of the molecule but not for another part of the molecule, the structure is intended to include all possible stereoisomers for the part where the stereochemical configuration is not explicitly shown.

[0068]

[0068] A particular structure clearly recites a particular stereochemical configuration at particular atoms.

[0069]

[0069] Certain polycyclic structures provided herein are depicted with one or more floating substituents, which, unless otherwise provided or otherwise clear from the context, may be present on any atom of the polycyclic ring, where chemically possible and valence rules permit.

[0070] In some or any of the embodiments, provided herein is a compound of formula (I), (I-P2), or a pharma ceutically acceptable salt thereof and / or an isomer thereof, Wherein: A is R 3 and (R 3a ) q phenyl optionally substituted with R 3 pyridinyl substituted with R 3 Thienyl substituted with R 3 furanyl substituted with R 3 pyrazolyl substituted with R 3 Indazolyl substituted with R 3 Benzisothiazolyl substituted with R 3 Benzisoxazolyl substituted with R, unsubstituted pyrazolyl, 3 or [ka] and; W 1 is -N= or -C(H)=; [ka] and; Each R 1 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 alkoxy, or halogen; Each R 2 are independently hydrogen, C 1 -C 6 alkyl, or halo; R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxy-C 1-3 Alkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH 2 , -S(O) 2 NH 2 , -S(O) 2 CH 3 , Amino-C 1 -C 3 Alkyl, halo-C 1 -C 3 alkyl, cyclopropyl, 4-membered heterocycloalkyl, or [ka] wherein said cyclopropyl and 4-membered heterocycloalkyl are each independently selected from the group consisting of one -NH 2 and said amino-C 1 -C6 The alkyl in alkyl may be further substituted with 1, 2, 3, or 4 halo; R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; m is 1 or 2; n is 0, 1, 2, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.

[0071] In some or any of the embodiments, provided herein is a compound of formula (I), (I-P2), or a pharma ceutically acceptable salt thereof and / or an isomer thereof, Wherein: A is R 3 phenyl substituted with R 3 pyridinyl substituted with R 3 Thienyl substituted with R 3 furanyl substituted with R 3 pyrazolyl substituted with R 3 Indazolyl substituted with R 3 Benzisothiazolyl substituted with R 3 Benzisoxazolyl substituted with R, unsubstituted pyrazolyl, 3 or [ka] and; W 1 is -N= or -C(H)=; [ka] and; Each R 1 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1-C 6 Haloalkyl, Halo-C 1 -C 6 alkoxy, or halogen; Each R 2 are independently hydrogen, C 1 -C 6 alkyl, or halo; R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 -cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from one -NH 2 and said amino-C 1 -C 6 The alkyl in the alkyl may be further substituted with 1, 2, 3, or 4 halo; m is 1 or 2; n is 0, 1, 2, or 4; p is 0, 1, 2, or 3.

[0072]

[0072] In some or any embodiments, provided herein is a compound of formula (I), (I-P1), (I-P2), or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, wherein: A is R 3 phenyl substituted with R 3 pyridinyl substituted with R 3 Benzisoxazolyl substituted with R, unsubstituted pyrazolyl, 3 or [ka] and; W 1 is -N= or -C(H)=; [ka] and; Each R 1 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 alkoxy, or halogen; Each R 2 are independently hydrogen, C 1 -C 6 alkyl, or halo; R 3 is -C(O)NH 2 , -NH 2 , -S(O) 2 NH 2 , -S(O) 2 CH 3 or [ka] and; m is 1 or 2; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0073]

[0073] Embodiment 1: In some or any of the embodiments, provided herein are compounds of formula (I), (I-P1), and (I-P2), wherein R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, halogen, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 In some or any embodiments, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 In some or any embodiments, each R 1 is hydrogen. In some or any embodiments, each R 1 is C 1 -C 6 In some or any embodiments, each R 1 is C 1 -C 6 In some or any embodiments, each R 1 is C 1 -C 6 In some or any embodiments, each R 1 is halogen. In some or any embodiments, each R 1 is C 3 -C 6-cycloalkyl. In some or any embodiments, each R 1 is C 3 -C 6 -Cycloalkyl, C 1 -C 3 -alkyl.

[0074]

[0074] Embodiment 1a: In some or any of the embodiments, one R 1 is present and is other than hydrogen. 1 are present and each is independently other than hydrogen. 1 are present and each is independently other than hydrogen. 1 is C 1 -C 6 In some or any embodiments, at least one R 1 -CH 3 In some or any embodiments, at least one R 1 is C 1 -C 6 In some or any embodiments, at least one R 1 -OCH 3 In some or any embodiments, at least one R 1 is C 1 -C 6 In some or any embodiments, at least one R 1 -CF 3 In some or any embodiments, at least one R 1 is Halo-C 1 -C 6 In some or any embodiments, at least one R 1 -OCF 3 In some or any embodiments, at least one R 1 is halogen. In some or any embodiment, at least one R 1 In some or any embodiments, at least one R 1is -F. In some or any embodiments, R 1 is C 3 -C 6 -cycloalkyl. In some or any embodiments, R 1 is C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl.

[0075]

[0075] Embodiment 1b: In some or any of the embodiments, each R 1 is C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, Halo-C 1 -C 6 In some or any embodiments, each R 1 is hydrogen.

[0076]

[0076] Embodiment 1c: In some or any of the embodiments, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 In some or any embodiment, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and at least one remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 In some or any of the embodiments, [ka] isn't it.

[0077]

[0077] Embodiment 2: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiment 1-1c, A is R 3is replaced with, and (R 3a ) q optionally replaced with C 6 -C 10 aryl; R 3 is replaced with, and (R 3a ) q optionally replaced with a 5- to 10-membered heteroaryl; or (R 3a ) q1 optionally replaced with

Chemical Formula

Chemical Formula

[0078]

[0078] Embodiment 2a: In some or any embodiments of formulas (I), (I-P1), and (I-P2) including Embodiment 1-1c, A is C 3 substituted with, and (R 3a ) q optionally substituted with C 6 -C 10 aryl. In some or any embodiments of formulas (I), (I-P1), and (I-P2) including Embodiment 1-1c, A is C 3 substituted with R 6 -C 10 aryl. In some or any embodiments of formulas (I), (I-P1), and (I-P2) including Embodiment 1-1c, A is phenyl substituted with R 3 . In some or any embodiments of formulas (I), (I-P1), and (I-P2) including Embodiment 1-1c, A is [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments, including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 The bond to is shown.

[0079]

[0079] Embodiment 2b: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-1c, A is R3 and (R 3a ) q In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiment 1-1c, A is R 3 and (R 3a ) q In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiment 1-1c, A is R 3 and (R 3a ) q In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiment 1-1c, A is [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments, including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to R 3 and (R 3a ) q is a 10-membered heteroaryl optionally substituted with

[0080]

[0080] Embodiment 2c: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is a 5- or 6-membered heteroaryl. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is a 5-membered heteroaryl. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is a 6-membered heteroaryl. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is: [ka] wherein: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is: [ka] wherein: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiment 1-1c, A is: In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiment 1-1c, A is: [ka] where: [ka] is R 3In some or any of the embodiments of (I), (I-P1), (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 The bond to is shown.

[0081]

[0081] Embodiment 2d: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-1c, A is (R 3a ) q1 may be substituted with [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to [ka] where: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A represents a bond to (R 3a ) q1 may be substituted with [ka] In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is [ka] It is.

[0082]

[0082] Embodiment 2e: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-1c, A is: [ka] wherein: [ka] is R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is: [ka] wherein: [ka] is R 3 The bond to is shown.

[0083]

[0083] Embodiment 2f: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, A is R 3 and (R 3a ) q phenyl optionally substituted with R 3 and (R 3a ) q pyridinyl, optionally substituted by R 3 and (R 3a ) qthienyl, optionally substituted with R 3 and (R 3a ) q furanyl, optionally substituted by R 3 and (R 3a ) q pyrazolyl, optionally substituted by R 3 and (R 3a ) q indazolyl, optionally substituted by R 3 and (R 3a ) q benzoisothiazolyl, optionally substituted by R 3 and (R 3a ) q benzisoxazolyl, unsubstituted pyrazolyl, 3 and (R 3a ) q or (R 3a ) q may be substituted with [ka] In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiment 1-1c, the A ring is R 3a is not further substituted with

[0084]

[0084] Embodiment 2g: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiment 1-1c, A is R 3 phenyl substituted with R 3 pyridinyl substituted with R 3 Thienyl substituted with R 3 furanyl substituted with R 3 pyrazolyl substituted with R 3 Indazolyl substituted with R 3 Benzisothiazolyl substituted with R 3 Benzisoxazolyl substituted with R, unsubstituted pyrazolyl, 3or [ka] It is.

[0085]

[0085] Embodiment 2h: In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] It is.

[0086]

[0086] Embodiment 2j: In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is [ka] It is.

[0087]

[0087] Embodiment 2k: In some or any of the embodiments of Formula (I), including embodiments 1-1c, A is: [ka] is selected from the group consisting of:

[0088]

[0088] Embodiment 3: In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-2d, W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 In some or any embodiments, W is -C(cyclopropyl)=, or -C(alkyl)=. 1 is -N= or -C(H)=. In some or any of the embodiments, including embodiments 1-2d, W 1 In some or any of the embodiments, including embodiment 1-2a, W 1 In some or any of the embodiments, including embodiments 1-2d, W 1 is -C(halogen)=. In some or any of the embodiments, including embodiments 1-2d, W 1 is -C(C 1 -C 6 In some or any of the embodiments, including embodiments 1-2d, W 1 In some or any of the embodiments, including embodiments 1-2d, W 1 In some or any of the embodiments, including embodiments 1-2d, W 1 In some or any of the embodiments, including embodiments 1-2d, W1 is -C(halogen)=. In some or any of the embodiments, including embodiments 1-2d, W 1 is -C(C 1 -C 6 In some or any of the embodiments, including embodiments 1-2d, W 1 is -C(cyclopropyl)=.

[0089]

[0089] Embodiment 3a: In some or any of the embodiments of Formulae (I) and (I-P2), including embodiments 1-2g, W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 In some or any embodiments, W is -C(cyclopropyl)=, or -C(alkyl)=. 1 is -N= or -C(H)=. In some or any of the embodiments, including embodiments 1-2g, W 1 In some or any of the embodiments, including embodiments 1-2g, W 1 In some or any of the embodiments, including embodiments 1-2g, W 1 In some or any of the embodiments, including embodiments 1-2g, W 1 is -C(C 1 -C 6 In some or any of the embodiments, including embodiments 1-2g, W 1 In some or any of the embodiments, including embodiments 1-2g, W 1 In some or any of the embodiments, including embodiments 1-2g, W 1 In some or any of the embodiments, including embodiments 1-2g, W 1 In some or any of the embodiments, including embodiments 1-2g, W 1 is -C(C 1 -C 6 In some or any of the embodiments, including embodiments 1-2g, W 1In some or any of the embodiments, including embodiments 1-2g, W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring.

[0090]

[0090] Embodiment 3b: In some or any of the embodiments of Formula (I), including embodiments 1-2k, W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, -C(cyclopropyl)=, or -C(C 1 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-2k, W 1 In some or any of the embodiments of Formula (I), including embodiments 1-2k, W 1 In some or any of the embodiments of Formula (I), including embodiments 1-2k, W 1 In some or any of the embodiments of Formula (I), including embodiments 1-2k, W 1 is -C(C 1 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-2k, W 1 In some or any of the embodiments of Formula (I), including embodiments 1-2k, W 1 is -C(C 1 -C 6 Alkoxy)=.

[0091]

[0091] Embodiment 4: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C. In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 8-membered carbocyclic ring or a partially unsaturated 5- to 7-membered heterocyclic ring. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 8-membered carbocyclic ring. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 7-membered heterocyclic ring.

[0092]

[0092] Embodiment 4a: In some or any of the embodiments of Formulae (I) and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 7-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C. In some or any of the embodiments of Formulas (I) and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 7-membered carbocyclic ring or a partially unsaturated 5- to 7-membered heterocyclic ring. In some or any of the embodiments of Formulae (I) and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 7-membered carbocyclic ring. In some or any of the embodiments of formulas (I) and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 7-membered heterocyclic ring.

[0093]

[0093] Embodiment 5: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 are -C- and W 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-4, W2 and W 3 are -C- and W 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 8-membered carbocyclic ring. In some or any of the embodiments, including embodiments 1-4, W 2 and W 3 are -C- and W 2 and W 3 The dashed bond between is a double bond, and [ka] In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 are -C- and W 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 7-membered heterocyclic ring. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 are -C- and W 2 and W 3 The dashed bond between is a double bond, and [ka] is a 5- or 6-membered heteroaromatic ring. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 8-membered carbocyclic ring or a partially unsaturated 5- to 7-membered heterocyclic ring. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 8-membered carbocyclic ring. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiments 1-3, W 2 and W 3 are -C- and W 2 and W 3 When the dashed bond between is a double bond, [ka] is not a partially unsaturated 5- to 7-membered heterocyclic ring.

[0094]

[0094] Embodiment 5a: In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a benzo ring or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between and is a single bond, and

Chemical formula

[0095]

[0095] Embodiment 5b: In some or any embodiments of formula (I), (I-P1), and (I-P2) including Embodiments 1-4, W 2 and W 3 are each -C-; the dashed bond between W 2 and W 3 is a double bond, and

Chemical formula

Chemical formula

Chemical formula

[0096]

[0096] Embodiment 6: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 one of which is -C- and the other is -N-; W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C. In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 HA-C- and W 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 HA-N- and W 3 is -C-. In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-4, [ka] is a 5-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C. In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-4, [ka] is a 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C.

[0097]

[0097] Embodiment 7: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-6, R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 alkyl; or two R 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 alkyl; or two R 2 are attached to the same carbon and together with the carbon to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-6, R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 In some or any of the embodiments, including embodiments 1-6, R 2 is hydrogen. In some or any of the embodiments, including embodiments 1-6, R 2 is halogen. In some or any of the embodiments, including embodiments 1-6, R 2 is C 1 -C 6 In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-6, two R 2are attached on adjacent carbons and together with the carbons to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-6, two R 2 are attached to the same carbon and together with the carbon to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 It is an alkyl.

[0098]

[0098] Embodiment 7a: In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-6, one R 2 is present and is other than hydrogen. In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-6, two R 2 and each is independently other than hydrogen. In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-6, three R 2 and each is independently other than hydrogen. In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 is C 1 -C 6 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 -CH 3 It is.

[0099]

[0099] Embodiment 7b: In some or any embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-6, each R 2 is C 1 -C 6 alkyl and halogen, where in some embodiments, 1, 2, or 3 R 2 is present, and in some embodiments, two or three R 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-6, each R 2 is hydrogen.

[0100]

[0100] Embodiment 7c: In some or any of the embodiments of Formula (I), including embodiments 1-6, R 2 is, independently in each occurrence, hydrogen, halogen, C 1 -C 6 Alkyl or halo-C 1 -C 6 alkyl; or two R 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 3- to 7-membered carbocyclic ring, said ring containing no halogen and C 1 -C 6 alkyl, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 alkyl; or two R 2 are attached to the same carbon and together with the carbon to which they are attached form a 3- to 7-membered carbocyclic ring, which ring is free of halogen and C 1 -C 6 alkyl, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6In some or any of the embodiments of Formula (I), including embodiments 1-6, R 2 is, independently in each occurrence, hydrogen, halogen, C 1 -C 6 Alkyl or halo-C 1 -C 6 In some or any of the embodiments, including embodiments 1-6, R 2 is hydrogen. In some or any of the embodiments, including embodiments 1-6, R 2 is halogen. In some or any of the embodiments, including embodiments 1-6, R 2 is C 1 -C 6 In some or any of the embodiments, including embodiments 1-6, R 2 is Halo-C 1 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-6, two R 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 3- to 7-membered carbocyclic ring, said ring containing no halogen and C 1 -C 6 alkyl, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-6, two R 2 are attached to the same carbon and together with the carbon to which they are attached form a 3- to 7-membered carbocyclic ring, which ring is free of halogen and C 1 -C 6 alkyl, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 It is an alkyl.

[0101]

[0101] Embodiment 8: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -C(O)NH 2 , -NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -alkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 In some or any of the embodiments, including embodiments 1-7b, R 3 is -C(O)NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 -S(O) 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 -S(O) 2 C 1 -C 6 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 teeth, [ka] In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiment 1-7b, R is hydrogen. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiment 1-7b, R is C 1 -C 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R is C 3 -C 5 It is cycloalkyl.

[0102]

[0102] Embodiment 8a: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -C(O)NH 2 , -NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -alkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -C(O)NH 2 In some or any of the embodiments, including embodiments 1-7b, R 3 is -NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -S(O) 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -S(O) 2 C 1 -C 6In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 teeth, [ka] In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiment 1-7b, R is hydrogen. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiment 1-7b, R is C 1 -C 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R is C 3 -C 5 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 -S(O) 2 NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 -S(O) 2 CH 3 In some or any of the embodiments, including embodiments 1-7b, R 3 teeth, [ka] It is.

[0103]

[0103] Embodiment 8b: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 are hydrogen, -OH, -B(OH) 2, -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 Cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from the group consisting of one -NH 2 and said amino-C 1 -C 6 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -B(OH) 2In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -C(=NH)NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -C(O)NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -NHC(O)C 1-3 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -NHC(=NH)NH 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -S(O) 2 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is -S(O) 2 C 1 -C 6 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is amino-C 1 -C 6 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is Halo-C 1 -C 3In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is one -NH 2 C replaced with 3 -C 6 In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 is one -NH 2 In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 teeth, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b and 8b, R 3 is other than hydrogen.

[0104]

[0104] Embodiment 8c: In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(O)NH 2 , -NHS(O) 2 NH 2 , -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 Cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from the group consisting of one -NH 2 and said amino-C 1 -C 6 The alkyl in alkyl may be further substituted with 1, 2, 3, or 4 halo. In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is -B(OH) 2 In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is -C(=NH)NH 2 In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 is -C(O)NH 2 In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 is -NH 2 In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 is -NHC(O)C 1-3 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is -NHC(O)NH 2In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 -NHS(O) 2 NH 2 In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 is -NHC(=NH)NH 2 In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 is -S(O) 2 NHR, where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is -S(O) 2 C 1 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is amino-C 1 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is Halo-C 1 -C 3 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is C 3 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 teeth, [ka] In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 is one -NH 2In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is one -NH 2 In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is amino-C 1 -C 6 alkyl, wherein the amino-C 1 -C 6 The alkyl in alkyl may be further substituted with 1, 2, 3, or 4 halo. In some or any of the embodiments of Formula (I), including embodiments 1-7c, R 3 is amino-C 1 -C 6 alkyl, wherein the amino-C 1 -C 6 In one or more embodiments, including embodiments 1-7c, R 3 is amino-C 1 -C 3 In one or more embodiments, including embodiments 1-7c, R 3 is amino-C 1 -C 3 alkyl, wherein the amino-C 1 -C 3 The alkyl in the alkyl is further substituted with 1, 2, 3, or 4 halo.

[0105]

[0105] Embodiment 9: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-8b, R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C 3 Alkyl or C 3 -C 6 In some or any of the embodiments, including embodiments 1-8b, R 3ais hydrogen. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, each R 3a is hydrogen. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, one R 3a is hydrogen and the other R 3a is other than hydrogen. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, at least one R 3a is hydrogen. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, R 3a is halogen. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, R 3a is C 1 -C 3 alkyl. In some or any embodiments, including Embodiments 1-8b, R 3a is C 3 -C 6 cycloalkyl. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, one R 3a is halogen. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, one R 3a is C 1 -C 3 alkyl. In some or any embodiments of Formulas (I), (I-P1), and (I-P2), including Embodiments 1-8b, one R 3a is C 3 -C 6 cycloalkyl.

[0106]

[0106] Embodiment 9a: In some or any embodiments of Formula (I), including Embodiments 1-8c, R 3a is, in each case independently, hydrogen, halogen, C 1 -C 3 alkyl, or C 3 -C 6In some or any of the embodiments, including embodiments 1-8c, R 3a In some or any of the embodiments of Formula (I), including embodiments 1-8c, each R 3a In some or any of the embodiments of Formula (I), including embodiments 1-8c, one R 3a is hydrogen and other R 3a In some or any of the embodiments of Formula (I), including embodiments 1-8c, at least one R 3a In some or any of the embodiments of Formula (I), including embodiments 1-8c, R 3a is halogen. In some or any of the embodiments of Formula (I), including embodiments 1-8c, R 3a is C 1 -C 3 In some or any of the embodiments, including embodiments 1-8c, R 3a is C 3 -C 6 In some or any of the embodiments of Formula (I), including embodiments 1-8c, one R 3a is halogen. In some or any of the embodiments of Formula (I), including embodiments 1-8c, one R 3a is C 1 -C 3 In some or any of the embodiments of Formula (I), including embodiments 1-8c, one R 3a is C 3 -C 6 It is cycloalkyl.

[0107]

[0107] Embodiment 10: In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiment 1-9a, m is 0, 1, 2, or 3. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiment 1-9a, m is 1 or 2. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiment 1-9a, m is 0. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiment 1-9a, m is 1. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiment 1-9a, m is 2. In some or any of the embodiments, m is 3.

[0108]

[0108] Embodiment 11: In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiments 1-10, n is 0, 1, 2, 3, or 4. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiments 1-10, n is 0, 1, or 2. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiments 1-10, n is 0. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiments 1-10, n is 1. In some or any of the embodiments of formulae (I), (I-P1), and (I-P2), including embodiments 1-10, n is 2. In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-10, n is 3. In some or any of the embodiments, including embodiments 1-10, n is 4.

[0109]

[0109] Embodiment 12: In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 0, 1, 2, 3, 4, 5, or 6. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 0, 1, 2, or 3. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 0. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 1. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 2. In some or any embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 3. In some or any embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 4. In some or any embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 5. In some or any embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-11, p is 6.

[0110]

[0110] Embodiment 13: In some or any embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-12, q is 0, 1, 2, or 3. In some or any embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-12, q is 0. In some or any embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-12, q is 1. In some or any embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-12, q is 2. In some or any embodiments, including embodiments 1-12, q is 3.

[0111]

[0111] Embodiment 14: In some or any embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-12, q1 is 0, 1, or 2. In some or any embodiments, including embodiments 1-12, q1 is 0. In some or any embodiments, including embodiments 1-12, q1 is 1. In some or any embodiments, including embodiments 1-12, q1 is 2.

[0112]

[0112] Embodiment 15: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] And W 4 is O; and in some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] And W 4 is S. In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] And W 4 is O; and in some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] and W 4 is S. In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] It is.

[0113]

[0113] Embodiment 15a: In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] It is.

[0114]

[0114] Embodiment 15b: In some or any of the embodiments of Formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] It is.

[0115]

[0115] Embodiment 15c: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] is not one of the ring systems listed in this paragraph.

[0116]

[0116] Embodiment 15d: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] is not one of the ring systems listed in this paragraph.

[0117]

[0117] Embodiment 15e: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] isn't it.

[0118]

[0118] Embodiment 16: In some or any of the embodiments of Formula (I), (I-P1), and (I-P2), including embodiments 1-14, [ka] It is.

[0119]

[0119] Embodiment 16a: In some or any of the embodiments of Formula (I), including embodiments 1-14, [ka] It is.

[0120]

[0120] Embodiment 16b: In some or any of the embodiments of Formula (I), including embodiments 1-14, [ka] It is.

[0121]

[0121] Embodiment 16c: In some or any of the embodiments of Formulae (I) and (I-P1), including embodiments 1-14, [ka] It is.

[0122]

[0122] Embodiment 17: In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-16a, R 1a In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-16a, R 1a is C 1 -C 6In some or any of the embodiments of Formulae (I), (I-P1), and (I-P2), including embodiments 1-16a, R 1a is C 3 -C 6 -cycloalkyl. In some or any embodiments, R 1a is C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl.

[0123]

[0123] Embodiment 17a: In some or any of the embodiments of Formula (I), including embodiments 1-16a, R 1a is hydrogen, halogen, C 1 -C 6 -Alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -CycloalkylC 1 -C 3 In some or any of the embodiments of Formula (I), including embodiments 1-16a, R 1a is a halogen.

[0124]

[0124] Embodiment 18: In some or any embodiments of formulae (I), (I-P1), and (I-P2), the compound is selected from any of compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206 in Table A, or a pharma- ceutically acceptable salt and / or isomer thereof.

[0125]

[0125] Embodiment 18a: In some or any embodiments of formula (I) and (I-P2), the compound is selected from any of compounds 1-127 and 169-206 in Table A, or a pharma- ceutically acceptable salt and / or isomer thereof.

[0126]

[0126] Embodiment 18c: In some or any of the embodiments of Formula (I), the compound is selected from any of compounds 1-206 of Table A, or a pharma- ceutically acceptable salt and / or isomer thereof.

Table A-1

Table A-2

Table A-3

Table A-4

Table A-5

Table A-6

Table A-7

Table A-8

Table A-9

Table A-10

Table A-11

Table A-12

Table A-13

Table A-14

Table A-15

Table A-16

Table A-17

[0127]

[0127] Embodiment 19: There is provided a compound according to any aspect or embodiment disclosed herein, including any of embodiments 1-18, wherein the compound is: [ka] , 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; [ka] , 2-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; [ka] , 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof;

[0128]

[0128] [ka] , 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; or [ka] , 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof isn't it.

[0129] In some or any embodiments, the compound of the formula: [ka] Provided herein is a compound according to any one of the following, or a salt thereof: During the ceremony, A is R 3 phenyl substituted with R 3 pyridinyl substituted with R 3 Benzisoxazolyl substituted with R, unsubstituted pyrazolyl, 3 or [ka] and; W 1 is -N= or -C(H)=; [ka] and; Each R 1 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 alkoxy, or halogen; Each R 2 are independently hydrogen, C 1 -C 6 alkyl, or halo; R 3 is -C(O)NH 2 , -NH 2 , -S(O) 2NH 2 , -S(O) 2 CH 3 or [ka] and; m is 1 or 2; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0130]

[0130] In one or more embodiments, the compound of the formula: [ka] Provided herein is a compound according to any one of During the ceremony, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] represents the shared carbon, and any remaining R 1 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, C 1 -C 6 haloalkyl, halo-C 1 -C 6 alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -cycloalkylC 1 -C 3 -alkyl, independently selected from; A is R 3 substituted, and (R 3a ) q optionally substituted C 6 -C 10 aryl; R 3 substituted, and (R 3a ) q optionally substituted 5- to 10-membered heteroaryl; or (R 3a ) q1 optionally substituted

Chemical formula

Chemical formula

[0131] Additional Embodiments

[0131] Embodiment 21: A compound as described herein, for example, a compound of formula (I): [ka] [In the formula, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q 5- to 10-membered heteroaryl optionally substituted with (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, or -C(cyclopropyl)=; W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C; R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2are attached on adjacent carbons and together with the carbons to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached to the same carbon and together with the carbon to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 -cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from one -NH 2 and said amino-C 1 -C6 The alkyl in the alkyl may be further substituted with 1, 2, 3, or 4 halo; R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3. or a pharma- ceutically acceptable salt and / or isomer thereof is provided; However, the compound is 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharma-ceutically acceptable salt and / or isomer thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or a pharma-ceutically acceptable salt and / or isomer thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or a pharma-ceutically acceptable salt and / or isomer thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxamide, or a pharma- ceutically acceptable salt and / or isomer thereof; or 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharma- ceutically acceptable salt and / or isomer thereof. isn't it.

[0132]

[0132] Embodiment 21a. R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or where two R 1 but, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] indicates the shared carbon in; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q 5- to 10-membered heteroaryl optionally substituted with (R 3a ) q1 may be substituted with [ka] and; W 1is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 alkyl), or -C(cyclopropyl)=; W 2 and W 3 are each -C-, W 2 and W 3 the dashed bond between is a double bond, and

Chemical formula

Chemical formula

[0133]

[0133] Embodiment 22. A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 aryl, optionally A is R 3 and (R 3a ) q is phenyl optionally substituted with Provided is a compound of embodiment 21 or 21a, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0134]

[0134] Embodiment 23. A is R3 phenyl substituted with Provided is a compound of embodiment 21, 21a, or 22, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0135]

[0135] Embodiment 24. A is [ka] where: [ka] But R 3 or a pharma- ceutically acceptable salt and / or an isomer thereof.

[0136]

[0136] Embodiment 24a. A is [ka] where: [ka] But R 3 or a pharma- ceutically acceptable salt and / or an isomer thereof.

[0137]

[0137] Embodiment 25. A is R 3 and (R 3a ) q 5- to 10-membered heteroaryl optionally substituted with 3 and (R 3a ) q 9-membered heteroaryl optionally substituted with 3 and (R 3a ) qor a pharma- ceutically acceptable salt and / or an isomer thereof.

[0138]

[0138] Embodiment 25a. A is [ka] or a pharma- ceutically acceptable salt and / or an isomer thereof.

[0139]

[0139] Embodiment 26. A is R 3 and (R 3a ) q A is a 5- or 6-membered heteroaryl optionally substituted with R 3 and (R 3a ) q or A is 5-membered heteroaryl optionally substituted by R 3 and (R 3a ) q 21 or 25; or a pharma- ceutically acceptable salt and / or isomer thereof;

[0140]

[0140] Embodiment 26a. A is [ka] or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0141]

[0141] Embodiment 26b. A is: [ka] or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0142]

[0142] Embodiment 27. A is: [ka] wherein: [ka] But R 3 or a pharma- ceutically acceptable salt and / or an isomer thereof.

[0143]

[0143] Embodiment 28. R 3 is hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1 -C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 -cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from one -NH 2and said amino-C 1 -C 6 Compounds according to any one of embodiments 21-27, wherein the alkyl in alkyl is optionally further substituted with 1, 2, 3, or 4 halo; or a pharma- ceutically acceptable salt and / or isomer thereof are provided.

[0144]

[0144] Embodiment 28a. R 3 But -C(O)NH 2 , -NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -alkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 Provided are compounds of any one of embodiments 21-27, or a pharma- ceutically acceptable salt and / or an isomer thereof, wherein is cycloalkyl.

[0145] Embodiment 29. A is pyrazolyl and R 3 Compounds according to any one of embodiments 21-27, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein is hydrogen.

[0146]

[0146] Embodiment 30. R 3 But -C(O)NH 2 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0147]

[0147] Embodiment 31. R 3 But -NH 2 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0148]

[0148] Embodiment 32. R 3 But -S(O) 2 Provided is a compound of any one of embodiments 21-28, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, wherein NHR.

[0149]

[0149] Embodiment 33. R is C 1 -C 3 Provided are compounds of any one of embodiments 21-29, or a pharma- ceutically acceptable salt and / or isomer thereof, wherein R is alkyl.

[0150]

[0150] Embodiment 34. R is C 3 -C 5 Provided are compounds of any one of embodiments 21-29, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, wherein is cycloalkyl.

[0151]

[0151] Embodiment 35. R 3 But -S(O) 2 NH 2 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0152]

[0152] Embodiment 36. R 3 But -S(O) 2 C 1 -C 6

[0043] Provided herein is a compound of any one of embodiments 21-28, or a pharma- ceutically acceptable salt and / or an isomer thereof, wherein -alkyl.

[0153]

[0153] Embodiment 37. R 3 But -S(O) 2 CH 3 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0154]

[0154] Embodiment 38. R 3 but, [ka] or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0155]

[0155] Embodiment 39. R 3 but, [ka] or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0156]

[0156] Embodiment 40. [ka] where W 4 is O or S; One R 1 is expressed as R 1a and R 1a But hydrogen, C 1 -C 6 -Alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl, Provided is a compound according to any one of embodiments 21-39; or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0157]

[0157] Embodiment 40a. [ka] and; Here, W 4 is O or S; One R 1 is expressed as R 1a and R 1a But hydrogen, C 1 -C 6 -Alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl, Provided is a compound according to any one of embodiments 21-40; or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0158]

[0158] Embodiment 41. [ka] or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0159]

[0159] Embodiment 41a. [ka] or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0160]

[0160] Embodiment 42. R 1a Compounds according to any one of embodiments 40 and 41, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein is hydrogen.

[0161]

[0161] Embodiment 43. R 1a But, C 1 -C 642. The compound of any one of embodiments 40 and 41, or a pharma- ceutically acceptable salt and / or an isomer thereof, is provided, wherein R is -alkyl.

[0162]

[0162] Embodiment 44. R 1a But, C 3 -C 6 42. The compound of any one of embodiments 40 and 41, or a pharma- ceutically acceptable salt and / or an isomer thereof, is provided, wherein R is -cycloalkyl.

[0163]

[0163] Embodiment 45. R 1a But, C 3 -C 6 -CycloalkylC 1 -C 3 42. The compound of any one of embodiments 40 and 41, or a pharma- ceutically acceptable salt and / or an isomer thereof, is provided, wherein R is -alkyl.

[0164]

[0164] Embodiment 46. One R 1 Compounds according to any one of embodiments 21-45, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0165]

[0165] Embodiment 47. Two R 1 Compounds according to any one of embodiments 21-45, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0166]

[0166] Embodiment 48: Three R 1 Compounds according to any one of embodiments 21-45, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0167]

[0167] Embodiment 49. At least one R 1 But, C 1 -C 6Provided are compounds of any one of embodiments 21-48, or a pharma- ceutically acceptable salt and / or isomer thereof, wherein R is alkyl.

[0168]

[0168] Embodiment 50. At least one R 1 But -CH 3 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0169]

[0169] Embodiment 51. At least one R 1 But, C 1 -C 6 Provided are compounds of any one of embodiments 21-48, or a pharma- ceutically acceptable salt and / or isomer thereof, wherein is alkoxy.

[0170]

[0170] Embodiment 52. At least one R 1 But, -OCH 3 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0171]

[0171] Embodiment 53. At least one R 1 But, C 1 -C 6 Provided are compounds of any one of embodiments 21-48, or a pharma- ceutically acceptable salt and / or an isomer thereof, wherein is haloalkyl.

[0172]

[0172] Embodiment 54. At least one R 1 But -CF 3 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0173]

[0173] Embodiment 55. At least one R 1Compounds according to any one of embodiments 21-48, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein is halogen.

[0174]

[0174] Embodiment 56. At least one R 1 Compounds according to any one of embodiments 21-48 and 55, or a pharma- ceutically acceptable salt and / or an isomer thereof, are provided, wherein:

[0175]

[0175] Embodiment 57. At least one R 1 Compounds according to any one of embodiments 21-48 and 55, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0176]

[0176] Embodiment 58. At least one R 1 But, Halo-C 1 -C 6 Provided are compounds of any one of embodiments 21-48, or a pharma- ceutically acceptable salt and / or isomer thereof, wherein is alkoxy.

[0177]

[0177] Embodiment 59. At least one R 1 But, -OCF 3 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0178]

[0178] Embodiment 60. Each R 1 But, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, Halo-C 1 -C 6 Compounds according to any one of embodiments 21-48, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein R is independently selected from alkoxy, and halogen.

[0179]

[0179] Embodiment 61. Each R1 Compounds according to any one of embodiments 21-45, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein is hydrogen.

[0180]

[0180] Embodiment 61a. Two R 1 but, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 But hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 Compounds of any one of embodiments 21-48 are provided, wherein:

[0181]

[0181] Embodiment 62. One R 2 Compounds according to any one of embodiments 21-61, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0182]

[0182] Embodiment 63. Two R 2Compounds according to any one of embodiments 21-61, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0183]

[0183] Embodiment 64. Three R 2 Compounds according to any one of embodiments 21-61, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0184]

[0184] Embodiment 65. At least one R 2 Compounds according to any one of embodiments 21-64, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein is halogen.

[0185]

[0185] Embodiment 66. At least one R 2 Compounds according to any one of embodiments 21-65, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein:

[0186]

[0186] Embodiment 67. At least one R 2 But, C 1 -C 6 Provided are compounds of any one of embodiments 21-64, or a pharma- ceutically acceptable salt and / or an isomer thereof, wherein R is alkyl.

[0187]

[0187] Embodiment 68. At least one R 2 But -CH 3 or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0188]

[0188] Embodiment 69. Two R 2 are attached to adjacent carbons and together with the carbons to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 Provided are compounds of any one of embodiments 21-61, 63, and 64, or a pharma- ceutically acceptable salt and / or isomer thereof, wherein R is alkyl.

[0189]

[0189] Embodiment 70. Two R 2 are attached to the same carbon and together with the carbons to which they are attached form a 4- to 7-membered carbocyclic ring, and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 Provided are compounds of any one of embodiments 21-61, 63, and 64, or a pharma- ceutically acceptable salt and / or isomer thereof, wherein R is alkyl.

[0190]

[0190] Embodiment 71. Each R 2 But, C 1 -C 6 Compounds according to any one of embodiments 21-64, or a pharma- ceutically acceptable salt and / or an isomer thereof, are provided, wherein is independently selected from alkyl and halogen.

[0191]

[0191] Embodiment 72. Each R 2 Compounds of any one of embodiments 21-71, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, are provided, wherein is hydrogen.

[0192]

[0192] Embodiment 73. Provided is a compound of any one of embodiments 21-72, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, wherein m is 1 or 2.

[0193]

[0193] Embodiment 74. Provided is a compound of any one of embodiments 21-73, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, wherein m is 1.

[0194]

[0194] Embodiment 75. Provided is a compound of any one of embodiments 21-73, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, wherein m is 2.

[0195]

[0195] Embodiment 76. W 1 Compounds according to any one of embodiments 21-75, or a pharma- ceutically acceptable salt and / or an isomer thereof, are provided, wherein N= is -N=.

[0196]

[0196] Embodiment 77. W 1 Compounds according to any one of embodiments 21-75, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein: is -C(H)=.

[0197]

[0197] Embodiment 78. W 1 Compounds according to any one of embodiments 21-75, or a pharma- ceutically acceptable salt and / or isomer thereof, are provided, wherein: is -C(halogen)=.

[0198]

[0198] Embodiment 79. W 1 But -C(C 1 -C 6 Compounds according to embodiments 21-75, or a pharma- ceutically acceptable salt and / or an isomer thereof, are provided, wherein R is 0, R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11, R is 12, R is 13, R is 14, R is 15, R is 16

[0199]

[0199] Embodiment 80. W 1 Compounds according to embodiments 21-75, or a pharma- ceutically acceptable salt and / or an isomer thereof, are provided, wherein is -C(cyclopropyl)=.

[0200]

[0200] Embodiment 81. Provided is a compound selected from the group consisting of the compounds provided in Table A, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof.

[0201]

[0201] Embodiment 82. Provided is a pharmaceutical composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof, and a pharma- ceutically acceptable carrier.

[0202]

[0202] Embodiment 83. The pharmaceutical composition of embodiment 82 is provided, wherein the composition is an oral or injectable composition.

[0203]

[0203] Embodiment 84. The pharmaceutical composition of embodiment 83 is provided, wherein the injectable composition is a subcutaneous injectable composition.

[0204]

[0204] Embodiment 85. A method for treating Na+ in a subject comprising administering a therapeutically or prophylactically effective amount of a compound disclosed herein, or a pharmaceutical composition disclosed herein. ν Methods of treating conditions associated with voltage-gated sodium channel function, including 1.8, are provided.

[0205]

[0205] Embodiment 86. The method of embodiment 85 is provided, wherein the subject is a human.

[0206]

[0206] Embodiment 87. The method of embodiment 85 or 86 is provided, wherein the condition is pain or the condition is associated with pain.

[0207]

[0207] Embodiment 88. The method of embodiment 85 or 86 is provided, wherein the condition is pain.

[0208]

[0208] Embodiment 89. The method of embodiment 85 or 86 is provided, wherein the condition is associated with pain.

[0209]

[0209] Embodiment 90. The condition is selected from the group consisting of pain associated with erythromelalgia, pain associated with diabetic peripheral neuropathy, paroxysmal excruciating pain, complex regional pain syndrome, pain associated with trigeminal neuralgia, pain associated with multiple sclerosis, pain associated with arthritis (including osteoarthritis), pain associated with postherpetic neuralgia, cancer pain, pain associated with cluster headache, pain associated with migraine, pain associated with sciatica, pain associated with endometriosis, pain associated with fibromyalgia, post-operative pain, subacute pain, chronic pain, dry eye syndrome and the like. The method of any one of embodiments 85 or 85-89 is provided, wherein the pain and / or discomfort associated with is selected from the group consisting of pain associated with (acute) corneal injury or abrasion, acute eye pain, chronic eye pain, pain associated with corneal infection, pain associated with Parkinson's disease, pain associated with ALS, pain associated with ophthalmic surgery, pain associated with epilepsy, pain associated with Parkinson's disease, mood disorders, psychosis, pain associated with amyotrophic lateral sclerosis, glaucoma, ischemia, spasticity disorders, and obsessive-compulsive disorder.

[0210]

[0210] Embodiment 91. The method of embodiment 85 or 86 is provided, wherein the condition is selected from the group consisting of acute pain, subacute pain, post-surgical pain, and ocular pain.

[0211]

[0211] Embodiment 92 NA ν 1.8 with a compound disclosed herein. ν Methods for inhibiting 1.8 are provided.

[0212]

[0212] In some or any of the embodiments, the following is provided: (a) the compounds described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, and pharma- ceutically acceptable salts and compositions thereof; (b) compounds as described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, and pharma- ceutically acceptable salts and compositions thereof, for use in the treatment of pain and / or conditions modulated by voltage-gated sodium channels; (c) processes for the preparation of the compounds described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, as described in more detail elsewhere herein; (d) a pharmaceutical formulation comprising a compound as described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent; (e) a method of treating a condition associated with voltage-gated sodium channel function in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharma- ceutically acceptable salt or composition thereof; (f) a method of treating pain in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharma- ceutically acceptable salt or composition thereof; (g) a pharmaceutical formulation comprising a compound as described herein, e.g., a compound of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharma- ceutically acceptable salt thereof, together with one or more other active agents for treating pain and / or conditions modulated by voltage-gated sodium channels, optionally in a pharma- ceutically acceptable carrier or diluent; (h) a method of treating pain in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., compounds of Formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharma- ceutically acceptable salt or composition thereof, in combination and / or alternation with one or more agents for the treatment of pain and / or a condition modulated by voltage-gated sodium channels; (i) a method of treating a condition associated with voltage-gated sodium channel function in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharma- ceutically acceptable salt or composition thereof, in combination and / or alternation with one or more agents for the treatment of pain; and (j) Use of any compound described herein, e.g., compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a composition comprising any compound described herein, e.g., compounds of formula (I) and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharma- ceutically acceptable salt, or a composition, for the treatment of a condition associated with voltage-gated sodium channel function (e.g., pain) as described herein, optionally in combination and / or alternation with one or more agents for the treatment of pain.

[0213]

[0213] In some or any embodiments, the following is provided: (a) the compounds described herein, e.g., compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, and pharma- ceutically acceptable salts and compositions thereof; (b) compounds as described herein, e.g., compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, and pharma- ceutically acceptable salts and compositions thereof, for use in the treatment of pain and / or conditions modulated by voltage-gated sodium channels; (c) processes for the preparation of the compounds described herein, e.g., compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, as described in more detail elsewhere herein; (d) a pharmaceutical formulation comprising a compound described herein, e.g., a compound of Formula (I), (I-P2), and compounds 1-127 and 169-206, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent; (e) a method of treating a condition associated with voltage-gated sodium channel function in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., a compound of Formula (I), (I-P2), and compounds 1-127 and 169-206, or a pharma- ceutically acceptable salt or composition thereof; (f) a method of treating pain in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., a compound of Formula (I), (I-P2), and compounds 1-127 and 169-206, or a pharma- ceutically acceptable salt or composition thereof; (g) a pharmaceutical formulation comprising a compound as described herein, e.g., a compound of formula (I), (I-P2), and compounds 1-127 and 169-206, or a pharma- ceutically acceptable salt thereof, together with one or more other active agents for treating pain and / or conditions modulated by voltage-gated sodium channels, optionally in a pharma- ceutically acceptable carrier or diluent; (h) a method of treating pain in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., a compound of Formula (I), (I-P2), and compounds 1-127 and 169-206, or a pharma- ceutically acceptable salt or composition thereof, in combination and / or alternation with one or more agents for the treatment of pain and / or a condition modulated by voltage-gated sodium channels; (i) a method of treating a condition associated with voltage-gated sodium channel function in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., a compound of Formula (I), (I-P2), and compounds 1-127 and 169-206, or a pharma- ceutically acceptable salt or composition thereof, in combination and / or alternation with one or more agents for the treatment of pain; and (j) Use of any compound described herein, e.g., the compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, or a composition comprising any compound described herein, e.g., the compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, or a pharma- ceutically acceptable salt, or a composition for the treatment of a condition associated with voltage-gated sodium channel function (e.g., pain) as described herein, optionally in combination and / or alternation with one or more agents for the treatment of pain.

[0214]

[0214] In some or any embodiments, the following is provided: (a) the compounds described herein, e.g., compounds of formula (I) and compounds 1-206, and pharma- ceutically acceptable salts and compositions thereof; (b) the compounds described herein, e.g., compounds of formula (I), and compounds 1-206, and pharma- ceutically acceptable salts and compositions thereof, for use in the treatment of pain and / or conditions modulated by voltage-gated sodium channels; (c) processes for the preparation of the compounds described herein, e.g., compounds of formula (I), and compounds 1-206, as described in more detail elsewhere herein; (d) a pharmaceutical formulation comprising a compound described herein, e.g., a compound of Formula (I) and Compound 1-206, or a pharma- ceutically acceptable salt thereof, together with a pharma- ceutically acceptable carrier or diluent; (e) a method of treating a condition associated with voltage-gated sodium channel function in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound described herein, e.g., compounds of Formula (I) and Compounds 1-206, or a pharma- ceutically acceptable salt or composition thereof; (f) a method of treating pain in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., compounds of Formula (I) and Compounds 1-206, or a pharma- ceutically acceptable salt or composition thereof; (g) a pharmaceutical formulation comprising a compound as described herein, e.g., the compounds of formula (I) and compounds 1-206, or a pharma- ceutically acceptable salt thereof, together with one or more other active agents for treating pain and / or conditions modulated by voltage-gated sodium channels, optionally in a pharma- ceutically acceptable carrier or diluent; (h) a method of treating pain in a subject, comprising administration of a therapeutically or prophylactically effective amount of a compound described herein, e.g., the compounds of Formula (I) and Compounds 1-206, or a pharma- ceutically acceptable salt or composition thereof, in combination and / or alternation with one or more agents for the treatment of pain and / or conditions modulated by voltage-gated sodium channels; (i) a method of treating a condition associated with voltage-gated sodium channel function in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound described herein, e.g., the compounds of Formula (I) and Compounds 1-206, or a pharma- ceutically acceptable salt or composition thereof, in combination and / or alternation with one or more agents for the treatment of pain; and (j) Use of any compound described herein, e.g., compounds of Formula (I) and compounds 1-206, or compositions comprising any compound described herein, e.g., compounds of Formula (I) and compounds 1-206, or a pharma- ceutically acceptable salt, or composition for the treatment of a condition associated with voltage-gated sodium channel function (e.g., pain) as described herein, optionally in combination and / or alternation with one or more agents for the treatment of pain.

[0215] optically active compound It is recognized that the compounds provided herein have some chiral centers and can exist and be isolated in optically active racemates. It should be understood that any racemic, optically active, diastereomeric, tautomeric or stereoisomeric form, mixture or combination thereof of the compounds provided herein that have the useful properties described herein are within the scope of the present invention. How to prepare optically active forms (in some or any embodiment, by resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis or chromatographic separation using chiral stationary phases) is well known in the art.

[0216]

[0216] In some or any of the embodiments, methods for obtaining optically active materials are known in the art and include at least the following. i) Physical separation of crystals - a technique whereby visible crystals of individual stereoisomers are manually separated. This technique can be used when crystals of separate stereoisomers are present, i.e. the material is a conglomerate and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby individual stereoisomers are crystallized separately from a solution of a racemate (possible only if the latter are solid-state conglomerates); iii) enzymatic resolution - a technique whereby racemates are partially or completely separated by virtue of the different rates of reaction of the stereoisomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to yield a stereomerically pure or enriched synthetic precursor of a desired stereoisomer; v) chemical asymmetric synthesis - a synthetic technique whereby a desired stereoisomer is synthesized from an achiral precursor under conditions that give rise to asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomeric separation - a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) which converts the individual enantiomers into diastereomers. The diastereomers thus obtained are then separated by chromatography or crystallization by virtue of their now more distinct structural differences, and the chiral auxiliary is subsequently removed to give the desired enantiomer; vii) primary and secondary asymmetric transformation - techniques whereby the diastereomers from the racemate equilibrate, resulting in a predominance in solution of the diastereomer from the desired enantiomer, or preferential crystallization of the diastereomer from the desired enantiomer disrupts the equilibrium, such that ultimately in principle all of the material is converted to the crystalline diastereomer from the desired enantiomer, which is then released from the diastereomer; viii) Kinetic Resolution - this technique refers to achieving partial or complete resolution of a racemic compound (or further resolution of a partially resolved compound) by the unequal reaction rates of stereoisomers with a chiral non-racemic reagent or catalyst under kinetic conditions; ix) stereospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired stereoisomer is obtained from non-chiral starting materials and the stereochemical integrity is not or only minimally compromised throughout the synthesis; x) Chiral Liquid Chromatography - a technique whereby stereoisomers of a racemate are separated in a liquid mobile phase by their different interactions with a stationary phase. The stationary phase may be made of a chiral material or the mobile phase may contain additional chiral materials that induce different interactions; xi) Chiral gas chromatography - a technique whereby the racemic compound is volatilized and stereoisomers are separated by their different interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) Extraction with chiral solvent- a technique whereby stereoisomers are separated by preferential dissolution of one stereoisomer in a particular chiral solvent; xiii) Transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin film barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force, e.g., concentration or pressure difference, results in preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one stereoisomer of the racemate to pass.

[0217]

[0217] In some or any of the embodiments, the composition of the compound is provided that comprises a substantially pure designated stereoisomer of the compound. In some or any of the embodiments, the method and the compound, the compound is substantially free of other stereoisomers. In some or any of the embodiments, the composition comprises at least 85%, 90%, 95%, 98%, 99% or 100% by weight of the compound that is the designated stereoisomer, with the remainder comprising other species or stereoisomers.

[0218] Isotopically enriched compounds

[0218] Also provided herein are isotopically enriched compounds.

[0219]

[0219] Isotopic enrichment (in some or any embodiment, deuteration) of pharmaceuticals to improve pharmacokinetics ("PK"), pharmacodynamics ("PD") and toxicity profiles has previously been shown for several classes of drugs. See, e.g., Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).

[0220]

[0220] Isotopic enrichment of a drug can be used, in some or any embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses required to achieve a desired effect, (4) decrease the dose required to achieve a desired effect, (5) increase the formation of active metabolites, if formed, and / or (6) decrease the production of harmful metabolites in certain tissues, and / or produce more effective drugs and / or safer drugs for combination therapy, whether the combination therapy is intended or unintended.

[0221]

[0221] The substitution of an atom with one of its isotopes often results in a change in the reaction rate of a chemical reaction. This phenomenon is known as kinetic isotope effect ("KIE"). For example, if a C-H bond is broken during the rate-determining step of a chemical reaction (i.e., the step with the highest transition state energy), the substitution of deuterium for that hydrogen results in a decrease in the reaction rate, and the profile slows down. This phenomenon is known as deuterium kinetic isotope effect ("DKIE"). See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999).

[0222] The magnitude of the DKIE can be expressed as the ratio between the rate of a given reaction in which a C-H bond is broken and the same reaction in which deuterium is used instead of hydrogen. The DKIE can range from about 1 (no isotope effect) to a very large number, for example, 50 or more, which means that when deuterium is used instead of hydrogen, the reaction can be slowed down by a factor of 50 or more. High DKIE values ​​can be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling occurs because of the small mass of the hydrogen atom, and transition states involving protons can sometimes be formed in the absence of the required activation energy. Deuterium has a higher mass than hydrogen, and therefore has a much lower statistical chance of undergoing this phenomenon.

[0223] Tritium ("T") is a radioactive isotope of hydrogen that is used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with two neutrons in its nucleus and an atomic mass close to 3. It occurs naturally in the environment in very low concentrations and is most commonly found in the form of T 2It is found as O. Tritium decays slowly (half-life = 12.3 years) and emits low energy beta particles that are unable to penetrate the outer layer of human skin. Internal exposure is the primary hazard associated with this isotope, which must be ingested in large quantities to pose a significant health risk. Compared to deuterium, a smaller amount of tritium must be consumed before it reaches harmful levels. Substitution of tritium ("T") for hydrogen results in stronger binding than deuterium, giving a numerically larger isotope effect. Similarly, but not limited to, for carbon 13 C or 14 C. Sulfur 33 S, 34 S or 36 S, Nitrogen 15 N and oxygen 17 O or 18 Isotopic substitutions for other elements, including O, may result in similar kinetic isotope effects.

[0224] For example, DKIE was used to reduce the hepatotoxicity of halothane, possibly by limiting the generation of reactive species, such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation may result in metabolic switching. The concept of metabolic switching assumes that when a foreign entity is sequestered by a phase I enzyme, it may bind temporarily and rebind in various conformations before chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large size of the binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially result in different ratios of known and entirely novel metabolites. This novel metabolic profile may confer more or less toxicity.

[0225]

[0225] In some embodiments, the compounds described herein may be used as radiopharmaceuticals, e.g., imaging agents. In some cases, the radiopharmaceutical is a positron emission tomography (PET) imaging agent. In such embodiments, the substitution of an atom in the compound with a radionuclide (e.g., a positron-emitting isotope) allows for the synthesis of a radiopharmaceutical that can function as an imaging agent. In some embodiments, radionuclides that can be substituted in the compounds described herein include, but are not limited to: 18 F, 11 C. 13 N, 15 O. 76 Br and 124 I. In some embodiments, the compound is isotopically enriched at one or more atoms, one atom, two atoms, or three atoms. In some embodiments, the compound is administered as an isotopic composition.

[0226]

[0226] Animal bodies express various enzymes for the purpose of eliminating foreign substances, e.g., therapeutic agents, from their circulatory system. In some or any embodiment, such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases that react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) pi bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles compared to the parent compound. For many drugs, such oxidation is rapid. Thus, these drugs often require the administration of multiple or high daily doses.

[0227]

[0227] Thus, isotopic enrichment at specific positions in the compounds provided herein results in a detectable KIE that affects the pharmacokinetic, pharmacological and / or toxicological profiles of the compounds provided herein compared to similar compounds having natural isotopic composition.

[0228] Preparation of compounds

[0228] The compounds provided herein can be prepared, isolated or obtained by any method apparent to those skilled in the art. The compounds provided herein can be prepared by the exemplary preparation schemes provided below. Reaction conditions, steps and reactants not provided in the exemplary preparation schemes are apparent and known to those skilled in the art.

[0229]

[0229] The additional steps and reagents not provided in the exemplary preparation scheme are known to those skilled in the art.For example, intermediates and compounds can be prepared using procedures known to those skilled in the art or procedures disclosed in International Patent Application Nos. PCT / US2019 / 058251 and PCT / US2019 / 058999 (the synthetic methods disclosed herein are incorporated herein by reference in their entirety).Exemplary preparation methods are described in detail in the examples herein.

[0230]

[0230] In one or more embodiments, the following scheme: [ka] [ka] to obtain a compound disclosed herein, or a pharma- ceutically acceptable salt thereof and / or an isomer thereof; and, optionally, to isolate a compound disclosed herein, During the ceremony, R 1 is, independently in each occurrence, hydrogen, C 1 -C 6 Alkyl, C 1 -C6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 -alkyl; or Here, two R 1 teeth, [ka] and together with the adjacent carbons to which they are attached, [ka] where * is [ka] and any remaining R 1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 Alkoxy, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -CycloalkylC 1 -C 3 - independently selected from alkyl; A is R 3 and (R 3a ) q C which may be substituted with 6 -C 10 Aryl; R 3 and (R 3a ) q5- to 10-membered heteroaryl, optionally substituted by (R 3a ) q1 may be substituted with [ka] ;(R 3a ) q1 may be substituted with [ka] ; or (R 3a ) q1 may be substituted with [ka] and; W 1 is -N=, -C(H)=, -C(halogen)=, -C(C 1 -C 6 -C(alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 are -C- and W, respectively. 2 and W 3 The dashed bond between is a double bond, and [ka] is a partially unsaturated 5- to 7-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W 2 and W 3 One of them is -C- and the other is -N-, and W 2 and W 3 The dashed bond between is a single bond, and [ka] is a 5- or 6-membered heterocyclic ring optionally containing an additional N, where the remaining ring atoms are C; R 2 is, independently in each occurrence, hydrogen, halogen, C 1 -C 6 Alkyl or halo-C 1 -C 6 is alkyl; or The Two R's 2 are attached on adjacent carbons and together with the carbons to which they are attached form a 3- to 7-membered carbocyclic ring, said ring containing no halogen and C 1 -C 6 alkyl; and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; or The Two R's 2 are attached to the same carbon and together with the carbon to which they are attached form a 3- to 7-membered carbocyclic ring, which ring is free of halogen and C 1 -C 6 alkyl; and the remaining R 2 is, independently in each occurrence, hydrogen, halogen, or C 1 -C 6 is alkyl; R 3 are hydrogen, -OH, -B(OH) 2 , -COOH, hydroxyalkyl, -C(=NH)NH 2 , -C(O)NH 2 , -NH 2 , -NHC(O)C 1-3 Alkyl, -NHC(O)NH 2 , -NHS(O) 2 NH 2 , -NHC(=NH)NH 2 , -S(O) 2 NHR, -S(O) 2 C 1 -C 6 -Alkyl, Amino-C 1-C 6 Alkyl, halo-C 1 -C 3 Alkyl, C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, or [ka] where R is hydrogen, C 1 -C 3 Alkyl or C 3 -C 5 cycloalkyl; 3 -C 6 -cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently selected from one -NH 2 and said amino-C 1 -C 6 The alkyl in the alkyl may be further substituted with 1, 2, 3, or 4 halo; R 3a is, independently in each occurrence, hydrogen, halogen, C 1 -C 3 Alkyl or C 3 -C 6 is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3.

[0231]

[0231] In one or more embodiments, the following scheme: [ka] [ka] to prepare a compound disclosed herein according to any of the methods described above to obtain a compound disclosed herein; and b) optionally isolating the compounds disclosed herein; A method is provided herein, comprising: During the ceremony, A is R 3 phenyl substituted with R 3 pyridinyl substituted with R 3 Benzisoxazolyl substituted with R, unsubstituted pyrazolyl, 3 or [ka] and; W 1 is -N= or -C(H)=; [ka] and; Each R 1 are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkyl, Halo-C 1 -C 6 alkoxy, or halogen; Each R 2 are independently hydrogen, C 1 -C 6 alkyl, or halo; R 3 is -C(O)NH 2 , -NH 2 , -S(O) 2 NH 2 , -S(O) 2 CH 3 or [ka] and; m is 1 or 2; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0232]

[0232] Those skilled in the art will understand that the order of steps of any process described herein may be varied. Other variations will be apparent to those skilled in the art, and all such variations are contemplated within the scope of the embodiments described herein.

[0233] Pharmaceutical Compositions and Methods of Administration

[0233] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and disclosed herein. Any of the compounds disclosed herein can be provided in a suitable pharmaceutical composition and administered by a suitable route of administration. Provided herein is a pharmaceutical composition comprising a compound of formula (I), (I-P1), or (I-P2) as described herein in some and any embodiments, and a pharma- ceutically acceptable carrier. In some embodiments, the composition is an oral or injectable composition. In some such embodiments, the injectable composition is a subcutaneous injectable composition.

[0234]

[0234] The methods provided herein include administering a pharmaceutical composition containing at least one compound as described herein, including a compound of formula (I), (I-P1), or (I-P2), in salt form, as appropriate, used alone or in combination with one or more compatible pharma- ceutically acceptable carriers, such as excipients or adjuvants, or in combination with another agent for the treatment of pain and / or a condition modulated by voltage-gated sodium channels.

[0235] In some or any embodiment, the second agent can be formulated or packaged together with the compound provided herein. Of course, the second agent is formulated together with the compound provided herein when such co-formulation should not interfere with the activity or administration method of either agent, as determined by one skilled in the art. In some or any embodiment, the compound provided herein and the second agent are formulated separately. They can be packaged together or packaged separately, for the convenience of one skilled in the art.

[0236] In clinical practice, the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g., in the form of an aerosol). In some or any of the embodiments, the compounds provided herein are administered orally.

[0237]

[0237] As solid compositions for oral administration, tablets, pills, hard gelatin capsules, powders or granules can be used. In these compositions, the active product is mixed with one or more inert excipients or adjuvants, such as sucrose, lactose or starch.

[0238]

[0238] These compositions may contain substances other than excipients, for example, lubricants such as magnesium stearate or coatings for controlled release.

[0239]

[0239] As liquid compositions for oral administration, pharma- ceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert excipients, such as water or liquid paraffin, may be used. These compositions may also contain substances other than excipients, such as moistening, sweetening or flavoring products in some or any embodiment.

[0240]

[0240] The composition for parenteral administration may be an emulsion or a sterile solution. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oil, especially olive oil or injectable organic ester, in some or any embodiment, ethyl oleate may be used. These compositions may also contain adjuvants, especially wetting agents, isotonicity agents, emulsifiers, dispersants and stabilizers. In some or any embodiment, sterilization may be carried out in several ways, by using a bacteriofilter, by irradiation or by heating. They may also be prepared in the form of a sterile solid composition that can be dissolved at the time of use in sterile water or any other injectable sterile medium.

[0241]

[0241] Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, additives such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

[0242]

[0242] The composition can also be an aerosol.For use in the form of liquid aerosol, the composition can be a stable sterile solution or a solid composition that is dissolved at the time of use in non-pyrogenic sterile water, saline solution or any other pharma- ceutically acceptable vehicle.For use in the form of dry aerosol that is intended to be directly inhaled, the active ingredient is finely divided and combined with a water-soluble solid excipient or vehicle, in some or any embodiment, dextran, mannitol or lactose.

[0243] In some or any embodiment, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein contain a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein or other prophylactic or therapeutic agents) and typically one or more pharma- ceutically acceptable carriers or excipients. In certain embodiments, the term "pharma-ceutically acceptable" in this context means approved by a federal or state regulatory agency for use in animals, more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias. The term "carrier" includes an excipient, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), additive, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water can be used as a carrier.Saline and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions.Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[0244]

[0244] Typical pharmaceutical compositions and dosage forms include one or more additives. Suitable additives are well known to those skilled in the art of pharmacy, and in some or any embodiment, suitable additives include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. Whether a particular additive is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, the way the dosage form is administered to a subject and the particular active ingredients in the dosage form. The composition or single unit dosage form can also contain small amounts of wetting agents or emulsifying agents or pH buffering agents, if necessary.

[0245]

[0245] The lactose-free compositions provided herein may contain additives known in the art, and in some or any embodiment, are listed in the United States Pharmacopoeia (USP36-NF31S2).In general, lactose-free compositions contain active ingredients, binders / fillers and lubricants in pharmaceutically compatible and pharmaceutically acceptable amounts.An exemplary lactose-free dosage form contains active ingredients, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

[0246]

[0246] Anhydrous pharmaceutical compositions and dosage forms containing active ingredients are further included herein. This is because water can accelerate the decomposition of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in pharmaceutical technology as a means of simulating long-term storage to determine characteristics such as the shelf life or stability of a formulation over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379 80. In reality, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be very important, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipping and use of the formulation.

[0247] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that contain at least one active ingredient that contains lactose and a primary or secondary amine can be anhydrous if significant contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0248]

[0248] Anhydrous pharmaceutical compositions should be prepared and stored so that their anhydrous nature is maintained.Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in suitable formulary kits.In some or any embodiment, suitable packaging includes, but is not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0249] Further provided are pharmaceutical compositions and dosage forms that contain one or more compounds that reduce the rate at which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants, such as ascorbic acid, pH buffers, or salt buffers.

[0250]

[0250] The pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, etc. Oral formulations can include standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions and dosage forms, in some or any embodiment, contain a prophylactically or therapeutically effective amount of the prophylactic or therapeutic agent in purified form together with a suitable amount of carrier to provide a form for proper administration to a subject. The formulation should be suitable for the mode of administration. In some or any embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in a suitable form for administration to a subject, in some or any embodiment, an animal subject, such as a mammalian subject, in some or any embodiment, a human subject.

[0251]

[0251] The pharmaceutical composition is formulated to be compatible with its intended route of administration. In some or any embodiment, the route of administration includes, but is not limited to, parenteral, e.g., intrathecal, epidural, local or regional for peripheral nerve block, intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, local (including administration to the eye, in some embodiments to the cornea), transmucosal, intratumoral, intrasynovial and rectal administration. In certain embodiments, the composition is formulated by conventional procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or local (including administration to the eye, in some embodiments to the cornea) administration to humans. In certain embodiments, the pharmaceutical composition is formulated by conventional procedures for subcutaneous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.

[0252]

[0252] In some or any embodiments, dosage forms include, but are not limited to, tablets; caplets; capsules, e.g., soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; poultices (cowplasters); pastes; powders; dressings; creams; patches; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0253]

[0253] The composition, shape and type of the dosage forms provided herein typically vary with their use. In some or any embodiment, a dosage form used in the initial treatment of pain may contain a greater amount of one or more of the active ingredients it contains than a dosage form used in the maintenance treatment of the same infection. Similarly, a parenteral dosage form may contain a lesser amount of one or more of the active ingredients it contains than an oral dosage form used to treat the same disease or disorder. These and other ways in which the specific dosage forms encompassed herein vary from one another are readily apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[0254]

[0254] In general, the components of the composition are supplied separately or mixed together in unit dosage form, in some or any embodiment as lyophilized powder or water-free concentrate in a sealed container, for example, an ampoule or sachet, indicating the amount of active agent.When the composition is administered by injection, it can be dispensed in an injection bottle containing sterile pharmaceutical grade water or saline.When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed before administration.

[0255]

[0255] Typical dosage forms include a compound provided herein or a pharma- ceutically acceptable salt, solvate or hydrate thereof in the range of about 0.1 mg to about 1000 mg / day given as a single once-daily dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms can have about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1.0 mg, 2.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 100 mg, 200 mg, 250 mg, 500 mg or 1000 mg of active compound.

[0256] Oral dosage form

[0256] Pharmaceutical compositions suitable for oral administration can be presented as separate dosage forms, such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active ingredient and can be prepared by methods of pharmacy well known to those skilled in the art. See generally Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[0257]

[0257] In some or any embodiment, the oral dosage form is solid and prepared with anhydrous ingredients under anhydrous conditions as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous solid oral dosage forms. Thus, additional forms are described herein.

[0258]

[0258] A typical oral dosage form is prepared by combining the active ingredient in an intimate mixture with at least one additive by conventional pharmaceutical compounding techniques. The additive can take a wide variety of forms depending on the form of preparation desired for administration. In some or any of the embodiments, the additives suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. In some or any of the embodiments, the additives suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, excipients, granulating agents, lubricants, binders, and disintegrants.

[0259]

[0259] Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid additives are used.If necessary, tablets can be coated by standard aqueous or non-aqueous techniques.Such dosage forms can be prepared by any of the methods of pharmacy.In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into desired appearance as necessary.

[0260]

[0260] In some or any embodiment, the tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, for example, powder or granules, optionally mixed with an excipient, in a suitable machine. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid excipient in a suitable machine.

[0261]

[0261] In some or any embodiment, additives that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants and lubricants.Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums, such as acacia, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (e.g., No. 2208, No. 2906, No. 2910), microcrystalline cellulose and mixtures thereof.

[0262]

[0262] In some or any embodiments, fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in a pharmaceutical composition is typically present in about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0263] In some or any embodiment, suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH 101, AVICEL PH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture additives or additives include AVICEL PH 103™ and Starch 1500 LM.

[0264]

[0264] Disintegrants are used in the composition to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate during storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant, neither too much nor too little, that does not adversely alter the release of the active ingredient, should be used to form a solid oral dosage form. The amount of disintegrant used varies based on the type of formulation and is readily discernible to those skilled in the art. A typical pharmaceutical composition contains about 0.5 to about 15 weight percent of disintegrant, particularly about 1 to about 5 weight percent of disintegrant.

[0265]

[0265] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums and mixtures thereof.

[0266]

[0266] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Further lubricants include, in some or any embodiments, colloidal silica gel (AEROSIL 200, manufactured by W.R. Grace Co., Baltimore, MD), coagulated aerosols of synthetic silica (commercially available from Degussa Co., Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, MA), and mixtures thereof. When used, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical composition or dosage form in which they are incorporated.

[0267] Extended-release dosage form

[0267] The active ingredient, e.g., the compounds provided herein, can be administered by controlled release means or delivery devices known to those skilled in the art. In some or any embodiment, the compositions and methods described herein, including but not limited to, those disclosed in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; and 5,822,572, each of which is incorporated herein by reference in its entirety. Nos. 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500. Such dosage forms can be used in some or any embodiment to achieve sustained or controlled release of one or more active ingredients, using hydropropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres or combinations thereof, to provide desired release profiles with varying rates.Suitable controlled release formulations known to those skilled in the art, including those described herein, can be easily selected for use with the active ingredients provided herein.Thus, unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps and caplets adapted for controlled release, are included herein.

[0268] All controlled release pharmaceutical products have a common goal of improving drug therapy beyond that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by the minimum amount of drug substance used to cure or control the condition in the minimum time. The advantages of controlled release formulations include extended activity of the drug, reduced administration frequency and improved subject compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as the blood concentration of the drug, and thus affect the occurrence of side effects (e.g., adverse effects).

[0269]

[0269] Most controlled release formulations are designed to initially release a certain amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and then gradually release another amount of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0270] In some or any of the embodiments, the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other administration methods. In some or any of the embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, a polymeric material may be used. In yet another embodiment, the controlled release system may be placed at an appropriate site in the subject, as determined by one skilled in the art, thus requiring only a small systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in a review by Langer (Science 249:1527-1533 (1990)).The active ingredient is coated with an outer polymeric membrane that is insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers, polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanoic acid terpolymers. The active ingredient can be dispersed in a solid inner matrix, such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, surrounded by a terpenic acid copolymer. The active ingredient then diffuses through the outer polymer membrane in a release rate controlling step. The percentage of active ingredient in such parenteral compositions is highly dependent on its specific nature and the needs of the subject.

[0271] Parenteral Dosage Forms

[0271] In some or any embodiment, a parenteral dosage form is provided. Parenteral dosage forms can be administered to a subject by various routes, including but not limited to subcutaneous, intravenous (including bolus injection), intramuscular and intraarterial. Because their administration typically bypasses the subject's natural defense against contaminants, parenteral dosage forms are typically sterile or can be sterilized before administration to a subject. In some or any embodiment, parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharma- ceutically acceptable vehicle for injection, suspensions and emulsions ready for injection.

[0272]

[0272] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. In some or any embodiment, suitable vehicles include, but are not limited to, water for injection (USP); aqueous vehicles such as, but are not limited to, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection and lactated Ringer's injection; water-miscible vehicles such as, but are not limited to, ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but are not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and benzyl benzoate.

[0273] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms.

[0274] Transdermal, topical and mucosal dosage forms

[0274] Transdermal, topical and mucosal dosage forms are also provided. Transdermal, topical and mucosal dosage forms include, but are not limited to, eye drops, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions or other forms known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues in the oral cavity can be formulated as mouthwashes or oral gels. In addition, transdermal dosage forms include "reservoir type" or "matrix type" patches that can be applied to the skin and worn for a certain period of time to allow the penetration of a desired amount of active ingredient.

[0275]

[0275] Suitable additives (e.g., carriers and excipients) and other materials that can be used to provide transdermal, topical and mucosal dosage forms encompassed herein are well known to those skilled in the art of pharmaceutical technology and depend on the specific tissue to which a given pharmaceutical composition or dosage form is applied. With that in mind, typical additives include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil and mixtures thereof to form non-toxic and pharma-ceutically acceptable lotions, tinctures, creams, emulsions, gels or ointments. If necessary, moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms. Examples of such additional components are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[0276]

[0276] Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or following treatment with the active ingredient provided. In some or any embodiment, a penetration enhancer may be used to help deliver the active ingredient to the tissue. Suitable penetration enhancers include, but are not limited to, acetone; various alcohols, such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides, such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidone, such as polyvinylpyrrolidone; Kollidon grades (povidone, polyvidone); urea; and various water-soluble or insoluble sugar esters, such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[0277]

[0277] The pH of the pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, can also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of the solvent carrier, its ionic strength, or osmolality can be adjusted to improve delivery. Compounds, such as stearates, can also be added to the pharmaceutical composition or dosage form to advantageously change the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery. In this regard, stearates can serve as lipid vehicles for the formulation, emulsifiers or surfactants, and delivery enhancers or penetration enhancers. Different salts, hydrates, or solvates of the active ingredients can be used to further adjust the properties of the composition thus obtained.

[0278] Dosage and unit dosage form

[0278] In human treatment, the physician will determine the dosage that he or she considers most appropriate depending on whether prophylactic or curative treatment is required, as well as the age, weight, stage of infection, and other factors specific to the subject being treated. In some or any of the embodiments, the dosage is about 1 to about 1000 mg / day for an adult, or about 5 to about 250 mg / day for an adult, or about 10 to 50 mg / day. In some or any of the embodiments, the dosage is about 5 to about 400 mg / day, or 25 to 200 mg / day for an adult. In some or any of the embodiments, dosage rates of about 50 to about 500 mg / day are also contemplated. In some or any embodiment, the dose for subcutaneous administration is about 1 to about 50 mg / day, or about 1 to about 25 mg / day, or about 1 to about 10 mg / day, or about 1 to about 20 mg / day, or about 5 to about 25 mg / day, or about 5 mg to about 20 mg / day, or about 10 to about 20 mg / day. In some or any embodiment, the dose for oral administration is about 5 to about 250 mg / day, about 5 to about 200 mg / day, or about 50 mg to about 100 mg / day, or about 75 mg to about 1125 mg / day, or about 10 mg to about 200 mg / day. In some embodiments, the mg / day amount is for an adult. In a further aspect, there is provided a method of treating a condition associated with voltage-gated sodium channel function and / or pain in a subject by administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound provided herein or a pharma- ceutically acceptable salt thereof. The amount of a compound or composition that is therapeutically or prophylactically effective in treating a disorder or one or more of its symptoms varies depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The frequency and dosage also vary according to factors specific to each subject, such as the specific treatment (e.g., therapeutic or prophylactic agent) administered, the severity of the disorder, disease or condition, the route of administration, and the age, body weight, response, and past medical history of the subject. Effective doses can be extrapolated from dose-response curves calculated from in vitro or animal model test systems.

[0279] In some or any of the embodiments, an exemplary dose of the composition includes milligram or microgram amounts of active compound per kilogram of subject or sample weight (e.g., about 10 micrograms / kilogram to about 50 milligrams / kilogram, about 100 micrograms / kilogram to about 25 milligrams / kilogram, or about 100 micrograms / kilogram to about 10 milligrams / kilogram). For the compositions provided herein, in some or any of the embodiments, the dosage administered to the subject is 0.01 mg / kg to 3 mg / kg (body weight of the subject) or 0.10 mg / kg to 3 mg / kg (body weight of the subject) based on the weight of the active compound. In some or any of the embodiments, the dosage administered to the subject is 0.20 mg / kg to 2.00 mg / kg or 0.30 mg / kg to 1.50 mg / kg (body weight of the subject). In some embodiments, the dosage is administered subcutaneously to a subject and is about 0.01 mg / kg to 1 mg / kg, inclusive, or about 0.03 mg / kg to 0.5 mg / kg, inclusive, of the subject's body weight based on the weight of the active compound. In some embodiments, the dosage is administered orally to a subject and is about 0.10 mg / kg to 5 mg / kg, inclusive, or about 0.10 mg / kg to 2 mg / kg, inclusive, of the subject's body weight based on the weight of the active compound.

[0280] In some or any embodiment, the recommended daily dose range of the compositions provided herein for the conditions described herein is within the range of about 0.1 mg to about 1000 mg / day given as a single once-daily dose or as divided doses throughout the day. In some or any embodiment, the daily dose is administered twice daily in equally divided doses. In some or any embodiment, the daily dose is administered three times daily in equally divided doses. In some or any embodiment, the daily dose range should be about 0.01 mg to about 400 mg / day, about 0.1 mg to about 250 mg / day, about 10 mg to about 200 mg / day, or in other embodiments, about 10 mg to about 150 mg / day, and in further embodiments, about 25 to about 100 mg / day. In some cases, it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein, as will be apparent to one of skill in the art. Furthermore, it should be noted that the clinician or attending physician will know when and how to interrupt, adjust or terminate treatment in conjunction with the subject's response.

[0281]

[0281] Different therapeutically effective amounts may be applicable for different diseases and conditions, as those skilled in the art will readily know. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause or reduce adverse effects associated with the compositions provided herein, are also encompassed by the dosage and frequency of administration schedules described herein. Furthermore, when a subject is administered multiple doses of the compositions provided herein, not all of the doses need to be the same. In some or any embodiment, the dosage administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or the dosage may be decreased to reduce one or more side effects experienced by a particular subject.

[0282] In some or any embodiments, the dosage of the compositions provided herein based on the weight of the active compound administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg (of the subject's body weight) or more. In another embodiment, the dosage of the compositions or compositions provided herein administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, The unit doses are 0.1mg to 5mg, 0.1 to 2.5mg, 0.25mg to 20mg, 0.25 to 15mg, 0.25 to 12mg, 0.25 to 10mg, 0.25mg to 7.5mg, 0.25mg to 5mg, 0.5mg to 2.5mg, 1mg to 20mg, 1mg to 15mg, 1mg to 12mg, 1mg to 10mg, 1mg to 7.5mg, 1mg to 5mg or 1mg to 2.5mg.

[0283] In some or any of the embodiments, the treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein, followed by one or more maintenance doses. In such embodiments, the loading dose can be, for example, about 6 to about 40 mg / day or about 10 to about 20 mg / day for 1 day to 5 weeks. The loading dose can be followed by one or more maintenance doses. In some or any of the embodiments, each maintenance dose is independently about 1 mg to about 20 mg / day, about 2.5 mg to about 15 mg / day, or about 2.5 to about 8 mg / day. The maintenance dose can be administered daily and can be administered as a single dose or divided doses.

[0284] In some or any of the embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady state concentration of the active ingredient in the blood or serum of the subject. The steady state concentration can be determined by measurements by techniques available to one of skill in the art, or can be based on the subject's physical characteristics, such as height, weight, and age. In some or any of the embodiments, a sufficient amount of a compound or composition provided herein can be administered to achieve a steady state concentration of about 100 to about 1000 ng / mL, about 150 to about 800 ng / mL, or about 300 to about 600 ng / mL in the subject's blood or serum. In some or any of the embodiments, a loading dose can be administered to achieve a steady state blood or serum concentration of about 300 to about 2000 ng / mL, or about 400 to about 800 ng / mL for 1 to 5 days. In some or any embodiments, the maintenance dose can be administered to achieve a steady state concentration in the subject's blood or serum of about 100 to about 1000 ng / mL, about 150 to about 800 ng / mL, or about 300 to about 600 ng / mL. In some or any embodiments, the administration of the same composition can be repeated, and the administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, the administration of the same prophylactic or therapeutic agent can be repeated, and the administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0285] In some or any of the embodiments, a unit dose is provided herein that contains the compound or a pharma- ceutically acceptable salt thereof in a form suitable for administration. Such forms are described in detail herein. In some or any of the embodiments, the unit dose contains 1-1000 mg, 1-100 mg, or 10-50 mg of active ingredient. In certain embodiments, the unit dose contains about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 125 mg, 250 mg, 500 mg, or 1000 mg of active ingredient. Such unit doses can be prepared by techniques familiar to those skilled in the art.

[0286]

[0286] In some or any of the embodiments, the dosage of the second agent used in the combination therapy is provided herein. In some or any of the embodiments, a lower dosage than has been or is currently used to treat pain is used in the combination therapy provided herein. The recommended dosage of the second agent can be obtained from the knowledge of one of ordinary skill in the art. For those second agents that have been approved for clinical use, the recommended dosages can be found, for example, in Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Therapeutics 9, the entire contents of which are incorporated herein by reference. th Ed, Mc-Graw-Hill, New York;Physician's Desk Reference (PDR) 57 th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ.

[0287] In various embodiments, the treatments (e.g., a compound provided herein and a second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 hours apart, or about 10 hours apart. The treatments are administered up to about 10 hours apart, about 10 hours to about 11 hours apart, about 11 hours to about 12 hours apart, about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart. In various embodiments, the treatments are administered 24 hours or less apart or 48 hours or less apart. In some or any of the embodiments, the two or more treatments are administered in the same visit of the patient. In other embodiments, the compound provided herein and the second agent are administered concurrently.

[0288]

[0288] In other embodiments, the compound provided herein and the second agent are administered about 2-4 days apart, about 4-6 days apart, about 1 week apart, about 1-2 weeks apart, or more than 2 weeks apart.

[0289] In some or any embodiments, administration of the same agent may be repeated and administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same agent may be repeated and administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0290] In some or any embodiment, the compound provided herein and the second agent are administered to a patient, in some or any embodiment, a subject, e.g., a human, sequentially and within a time interval such that the compound provided herein can act together with the other agent to provide increased benefits than if they were administered otherwise. In some or any embodiment, the second active agent can be administered simultaneously or sequentially in any order at different times, but if not administered simultaneously, they should be administered sufficiently close in time to achieve the desired therapeutic or prophylactic effect. In some or any embodiment, the compound provided herein and the second active agent exert their effects at overlapping times. Each second active agent can be administered separately in any suitable form and by any suitable route. In other embodiments, the compound provided herein is administered before, concurrently, or after administration of the second active agent.

[0291] In some or any of the embodiments, the compound provided herein and the second agent are administered to the patient in a cyclical manner. Cycling therapy involves administering a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by administration of a second agent and / or a third agent (e.g., a second and / or a third prophylactic or therapeutic agent) for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the efficacy of the treatment.

[0292] In some or any of the embodiments, the compound provided herein and the second active agent are administered in cycles of less than about 3 weeks, about once every 2 weeks, about once every 10 days, or about once every week. A cycle can include administration of the compound provided herein and the second agent by infusion over about 90 minutes per cycle, about 1 hour per cycle, or about 45 minutes per cycle. Each cycle can include at least a 1 week rest, at least a 2 week rest, or at least a 3 week rest. The number of cycles administered is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, and more typically about 2 to about 8 cycles.

[0293] In other embodiments, the series of treatments are administered to the patient in a concurrent manner, i.e., individual doses of the second agent are administered separately within a time interval so that the compound provided herein can act together with the second active agent. In some or any embodiment, one component can be administered once a week, with the other component being administered once every two weeks or once every three weeks. In other words, the dosing regimen is administered in a concurrent manner, even if the treatments are not administered at the same time or during the same day.

[0294] The second agent can act additively or synergistically with the compound provided herein. In some or any of the embodiments, the compound provided herein is administered in the same pharmaceutical composition in parallel with one or more second agents. In another embodiment, the compound provided herein is administered in separate pharmaceutical compositions in parallel with one or more second agents. In yet another embodiment, the compound provided herein is administered prior to or following administration of the second agent. Administration of the compound provided herein and the second agent by the same or different routes of administration, for example, oral and parenteral, is also contemplated. In some or any of the embodiments, when the compound provided herein is administered in parallel with a second agent that potentially produces adverse side effects, including but not limited to toxicity, the second active agent can be advantageously administered at a dose below the threshold at which adverse side effects are induced.

[0295] kit

[0295] Kits for use in methods of treating pain and / or conditions associated with voltage-gated sodium channel function or pain-related disorders are also provided. The kits can include a compound or composition provided herein, a second agent or composition, and instructions that provide information to a health care provider regarding use to treat pain or pain-related disorders. The instructions can be provided in printed form or in electronic form, such as a floppy disk, CD, or DVD, or in the form of a website address where such instructions can be obtained. A unit dose of a compound or composition provided herein or a second agent or composition can include a dosage amount that, when administered to a subject, can maintain a therapeutically or prophylactically effective plasma level of the compound or composition in the subject for at least one day. In some or any embodiment, the compound or composition can be included as a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0296] In some or any embodiment, suitable packaging is provided. As used herein, "packaging" includes solid matrices or materials that are conventionally used in systems and can hold the compounds provided herein and / or second agents suitable for administration to a subject within defined limits. Such materials include glass and plastic (e.g., polyethylene, polypropylene and polycarbonate) bottles, vials, paper, plastic and plastic foil laminate envelopes, etc. If e-beam sterilization techniques are used, the packaging should have a sufficiently low density to allow sterilization of the contents.

[0297] How to use Provided herein is a method for treating a condition associated with voltage-gated sodium channel function and / or pain in a subject, comprising contacting the subject with a therapeutically or prophylactically effective amount of a compound of Formula (I), (I-P1), or (I-P2) disclosed herein, including a single enantiomer, a mixture of enantiomeric pairs, individual diastereomers, a mixture of diastereomers, individual stereoisomers, a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.

[0298]

[0298] Provided herein is a method for treating a condition associated with voltage-gated sodium channel function in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of formula (I), (I-P1), or (I-P2) described herein or a pharmaceutical composition described herein.

[0299] In some embodiments, the subject is a human. In a group of embodiments, the condition is pain or the condition is associated with pain. In some embodiments, the condition is pain. In some embodiments, the condition is associated with pain. In some embodiments, the pain is nociceptive pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the pain is refractory to other forms of pain medication.

[0300] In one group of embodiments, the condition is selected from the group consisting of erythromelalgia, diabetic peripheral neuropathy, paroxysmal severe pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, postherpetic neuralgia, cancer pain, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, and post-operative pain. In one group of embodiments, the condition is selected from the group consisting of epilepsy, Parkinson's disease, mood disorders, psychoses, amyotrophic lateral sclerosis, glaucoma, ischemia, spasticity disorders, and obsessive-compulsive disorder.

[0301] In some or any of the embodiments, provided herein is a method of treating a condition associated with pain and / or voltage-gated sodium channel function in a subject. In some or any of the embodiments, the method comprises administering to a subject in need thereof an amount of a compound effective for treating pain and / or a condition associated with voltage-gated sodium channel function in combination with a second agent effective for treating or preventing pain and / or a condition associated with voltage-gated sodium channel function. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In some or any of the embodiments, the compound is in the form of a pharmaceutical composition or dosage form as described elsewhere herein.

[0302] In some or any of the embodiments, provided herein is a method of treating a condition associated with voltage-gated sodium channel function in a subject. In some or any of the embodiments, the method comprises administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound effective for treating a condition associated with voltage-gated sodium channel function in combination with a second agent effective for treating a condition associated with voltage-gated sodium channel function. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In some or any of the embodiments, the compound is in the form of a pharmaceutical composition or dosage form as described elsewhere herein.

[0303] In some or any embodiments, NA ν NA 1.8 with a compound of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206. ν 1.8 is provided herein.

[0304] In some or any embodiments, NA ν 1.8 with a compound of formula (I), (I-P2), and compounds 1-127 and 169-206. ν 1.8 is provided herein.

[0305] In some or any embodiments, NA ν 1.8 with a compound of formula (I) and compound 1-206, ν 1.8 is provided herein.

[0306]

[0306] In some or any of the embodiments, the pain that is reduced, ameliorated, treated or prevented is acute pain, anal fissure, back pain, chronic pain, toothache, joint pain, neck pain, neuropathic pain, labor pain, post-herpetic neuralgia, shingles, tension headache, trigeminal blepharospasm, pain associated with cardiac arrhythmias, focal dystonia, hyperhidrosis, muscle spasms, bladder atonicity, visceral pain, sympathetically maintained pain, myositis pain, musculoskeletal pain, lower back pain, pain from sprains and strains, pain associated with functional bowel disorders, non-cardiac chest pain, pain associated with irritable bowel syndrome, pain associated with myocardial ischemia. The pain is associated with or is a condition selected from pain from chronic pain, dental pain, pain from dysmenorrhea, erythromelalgia, diabetic peripheral neuropathy, paroxysmal acute pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, post-herpetic neuralgia, cancer, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, dry eye syndrome, (acute) corneal injury or abrasion, corneal infection, pain associated with Parkinson's disease, pain associated with ALS, and surgery (in some embodiments, post-operative; in some embodiments, ophthalmic surgery). In some or any embodiment, the pain to be reduced, ameliorated, treated or prevented is acute hospital pain, including post-operative pain. In some or any embodiment, the pain to be reduced, ameliorated, treated or prevented is acute hospital pain, including post-operative pain, and the compound is administered intravenously. In some or any embodiment, the pain to be reduced, ameliorated, treated or prevented is ocular pain. In some or any of the embodiments, the pain to be reduced, ameliorated, treated or prevented is ocular pain and the compound is administered topically. In some or any of the embodiments, the pain to be reduced, ameliorated, treated or prevented is subacute or chronic pain. In some or any of the embodiments, the pain to be reduced, ameliorated, treated or prevented is subacute or chronic pain and the compound is administered subcutaneously. In some or any of the embodiments, the pain to be reduced, ameliorated, treated or prevented is subacute or chronic pain and the compound is administered orally.

[0307] In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is selected from itch, cough, epilepsy, Parkinson's disease, mood disorder, psychosis, amyotrophic lateral sclerosis (ALS), cardiac arrhythmia, glaucoma, ischemia, spasticity disorder, and obsessive-compulsive disorder. In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is selected from pain, itch, cough, glaucoma, and ischemia. In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is selected from pain, itch, and cough. In some or any of the embodiments, the condition associated with voltage-gated sodium channel function is pain.

[0308] In some or any of the embodiments, the compounds described herein are used to delay the onset of pain or reduce the severity or duration of pain. In some or any of the embodiments, the compounds described herein are used to reduce the severity or duration of pain associated with voltage-gated sodium channel function. In some of the embodiments, the compounds described herein are used to delay or prevent the onset of pain.

[0309]

[0309] In some or any of the embodiments, the compounds described herein are used for the prevention of pain or conditions associated with voltage-gated sodium channel function.

[0310]

[0310] In some or any of the embodiments, the compounds described herein are used for the treatment of pain or conditions associated with voltage-gated sodium channel function.

[0311] Assay Method

[0311] Compounds can be assayed for effectiveness in treating pain and / or conditions associated with voltage-gated sodium channel function by any assay known to one of skill in the art. Exemplary assay methods are provided elsewhere herein.

[0312] Second Therapeutic Agent In some or any of the embodiments, the compounds and compositions provided herein are useful in a method of treating pain and / or conditions associated with voltage-gated sodium channel function, comprising the further administration of a second agent that is effective in treating pain and / or pain-related disorders and / or conditions associated with voltage-gated sodium channel function. The second agent can be any agent known to those skilled in the art to be effective in treating pain and / or pain-related disorders and / or conditions associated with voltage-gated sodium channel function, including those currently approved by the U.S. Food and Drug Administration or other similar organizations of countries that are foreign to the United States. In some or any of the embodiments, the second agent is a local anesthetic (in some or any of the embodiments, a steroid), an opioid, a vasoconstrictor, a glucocorticoid, an adrenergic agent (in some or any of the embodiments, an alpha agonist or a mixed central-peripheral alpha-2-agonist), a vanilloid, an anti-inflammatory agent (e.g., an NSAID or an anti-inflammatory agent associated with an ocular condition, including cyclosporine and lifitegrast), or a chemical penetration enhancer. In some embodiments, the second agent is Na V In some or any of the embodiments, the chemical penetration enhancer comprises an anionic surfactant, a cationic surfactant, a non-ionic surfactant. In some or any of the embodiments, the second agent is bupivacaine, levobupivacaine, tetracaine, ropivacaine, epinephrine, phenylephrine, clonidine, sodium lauryl sulfate, sodium octyl sulfate, dodecyltrimethylammonium bromide, octyltrimethylammonium bromide, polyoxyethylene(20)sorbitan monolaurate, and / or polyoxyethylene(20)sorbitan monooleate.

[0313] In some or any of the embodiments, the compounds provided herein are administered in combination with one second agent. In further embodiments, the compounds provided herein are administered in combination with two second agents. In yet further embodiments, the compounds provided herein are administered in combination with two or more second agents.

[0314] As used herein, the term "in combination" includes the use of more than one therapies (e.g., one or more prophylactic and / or therapeutic agents). The use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disorder. A first treatment (e.g., a prophylactic or therapeutic agent, e.g., a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second treatment (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.

[0315]

[0315] As used herein, the term "synergistic" includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently being used to prevent, manage, or treat a disorder, which is more effective than the additive effect of the therapies. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) allows for the use of lower dosages of one or more of the therapies and / or less frequent administration of said therapies to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or administer said therapy less frequently reduces the toxicity associated with administration of said therapy to a subject without reducing the effectiveness of said therapy in preventing or treating a disorder). Furthermore, synergistic effects can result in improved efficacy of agents in preventing or treating a disorder. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[0316]

[0316] The active compounds provided herein can be administered in combination or alternation with another therapeutic agent, particularly an agent effective in treating pain and / or pain-related disorders and / or conditions associated with voltage-gated sodium channel function. In combination therapy, effective dosages of two or more agents are administered together, while in alternation therapy or sequential step therapy, effective dosages of each agent are administered sequentially or sequentially. A given dosage amount will depend on the absorption, inactivation and excretion rates of the drug and other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary with the severity of the pain or pain-related disorder being alleviated. It is further understood that for any particular subject, the specific dosage regimen and schedule should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition. EXAMPLES

[0317]

[0317] As used herein, the symbols and conventions used in these processes, schemes and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimoles); μM (micromoles); Hz (Hertz); MHz (Megahertz); mmol (millimoles); hr or hrs (hours); min (minutes); MS (Mass Spectrometry); ESI (Electrospray Ionization); Ph (Phenyl); TLC (Thin Layer Chromatography); HPLC (High Pressure Liquid Chromatography); THF (Tetrahydrofuran); CDCl 3 (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethyl sulfoxide); DMSO-d 6(deuterated dimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol); Tces (2,2,2-trichloroethoxysulfonyl); -Si(tert-Bu)(Ph) 2 and -Si t BuPh 2 (tert-butyl-diphenylsilyl); and BOC (t-butyloxycarbonyl). AZADO is [ka] CDI refers to [ka] Refers to...

[0318]

[0318] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ° C (degrees Celsius). All reactions are carried out at room temperature unless otherwise indicated. The synthetic methodology illustrated herein is intended to illustrate applicable chemical reactions by the use of specific examples and does not represent the scope of this disclosure. Synthesis Examples compound 1 Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)quinoline-3-carboxamide [ka] Synthesis of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid [ka]

[0319] To a mixture of 2-chloroquinoline-3-carboxylic acid (104 mg, 0.5 mmol) and 4,4-difluoroazepane hydrogen chloride (85.5 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (345 mg, 2.5 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 16 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography with a gradient of 0-100% ethyl acetate in hexane to give 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid as a yellow oil. Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-(methylthio)phenyl)quinoline-3-carboxamide [ka] Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)quinoline-3-carboxamide

[0320] To a stirred solution of 2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (18.5 mg, 0.06 mmol) in dichloromethane (2 mL) were added (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.344 mg, 0.09 mmol) and 4-dimethylaminopyridine (DMAP) (22.1 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 15 minutes. Then, 3-(methylthio)aniline (7.4 μL, 0.06 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. The progress of the reaction was monitored by LCMS. After completion of the reaction, dichloromethane was removed under vacuum, and the resulting mixture was diluted with water and acetonitrile and purified using a reverse-phase HPLC with a gradient of 5-95% acetonitrile in water to obtain 2-(4,4-difluoroazepan-1-yl)-N-(3-(methylthio)phenyl)quinoline-3-carboxamide as a white powder. Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)quinoline-3-carboxamide

[0321]

[0321] To a stirred solution of 2-(4,4-difluoroazepan-1-yl)-N-(3-(methylthio)phenyl)quinoline-3-carboxamide (25.8 mg, 0.056 mmol) in MeOH (3 mL) were added ammonium carbonate (10.7 mg, 0.11 mmol), then (diacetoxyiodo)benzene (44.8 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 90 minutes. The progress of the reaction was monitored by LCMS. Methanol was removed under vacuum, and the resulting crude mass was diluted with water and acetonitrile and purified using a reverse-phase HPLC with a gradient of 5-95% acetonitrile in water to obtain 2-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)quinoline-3-carboxamide as a white powder. LRMS (ESI): Calcd [M+H] +: 459.17, found: 458.8

[0322]

[0322] 1 H NMR (400 MHz, CD 3 CN) δ 8.52 (s, 1H), 8.43 (s, 1H), 7.96 (dd, J = 8.0, 1.8 Hz, 1H), 7.93 - 7.85 (m, 2H), 7.82 - 7.75 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 1H), 3.91 - 3.83 (m, 2H), 3.73 (t, J = 5.8 Hz, 2H), 3.23 (s, 3H), 2.17 - 2.07 (m, 2H), 2.03 - 1.97 (m, 4H). compound 2 Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2-chloro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka]

[0323]

[0323] A mixture of 2-chloroquinoline-3-carboxylic acid (52 mg, 0.25 mmol) and oxalyl chloride (39.4 μL, 0.45 mmol) in dichloromethane (2 mL) was added a drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 15 minutes. Then, a solution of 3-aminobenzenesulfonamide (43 mg, 0.25 mmol) and diisopropylethylamine (131 μL, 0.75 mmol) in dichloromethane (2 mL) and N,N-dimethylformamide (0.5 mL) was added to the stirred solution. The reaction mixture was stirred at room temperature for 1 hour. Dichloromethane was removed under vacuum, and the crude mixture was purified by silica gel column chromatography with a gradient of ethyl acetate and hexane to give 2-chloro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a yellow oil. Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0324]

[0324] To a solution of 2-chloro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (14 mg, 0.04 mmol) and 4,4-difluoroazepane hydrochloride (7 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (22 mg, 0.16 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 16 hours and then at 80 °C for 18 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and 1N hydrochloric acid, and then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude residue was purified by reverse-phase HPLC to give 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a white solid. LRMS (ESI): Calcd [M+H] + : 461.15, found: 460.9.

[0325]

[0325] 1H NMR (400 MHz, CD 3 CN) δ 8.44 (s, 1H), 8.38 - 8.32 (m, 1H), 7.92 - 7.87 (m, 1H), 7.83 - 7.80 (m, 2H), 7.69 - 7.63 (m, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.00 - 6.93 (m, 1H), 3.87 - 3.79 (m, 2H), 3.72 - 3.65 (m, 2H), 2.49 - 2.40 (m, 4H), 2.15 - 2.06 (m, 2H). compound 3 Synthesis of N-(3-aminobenzo[d]isoxazol-5-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide [ka] Synthesis of tert-butyl (5-(2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamido)benzo[d]isoxazol-3-yl)carbamate [ka]

[0326] To a mixture of 2-chloroquinoline-3-carboxylic acid (15 mg, 0.05 mmol) and oxalyl chloride (8 μL, 0.09 mmol) in dichloromethane (1 mL) was added a drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 15 minutes. Then, a solution of tert-butyl (5-aminobenzo[d]isoxazol-3-yl)carbamate (14 mg, 0.05 mmol) and diisopropylethylamine (26 μL, 0.15 mmol) in dichloromethane (1 mL) was added to the stirred solution. The reaction mixture was stirred at room temperature for 18 hours. The dichloromethane was removed under vacuum and the crude mixture was purified by reverse phase HPLC to give tert-butyl (5-aminobenzo[d]isoxazol-3-yl)carbamate as a white solid. Synthesis of N-(3-aminobenzo[d]isoxazol-5-yl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide

[0327] To a solution of tert-butyl (5-(2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide)benzo[d]isoxazol-3-yl)carbamate (26 mg, 0.05 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (300 μL). The reaction mixture was stirred for 2 h and then the volatiles were removed in vacuo. The crude mixture was purified by Combiflash with a gradient of 0 to 100% ethyl acetate in hexanes to give tert-butyl (5-(2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide)benzo[d]isoxazol-3-yl)carbamate as a pale yellow oil. LRMS (ESI): Calcd [M+H] + : 438.17, found: 437.9

[0328]

[0328] 1 H NMR (400 MHz, CD 3CN) δ 8.31 (s, 1H), 8.29 - 8.26 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.72 - 7.57 (m, 3H), 7.41 (d, J = 9.0 Hz, 1H), 7.37 - 7.28 (m, 1H), 3.84 - 3.76 (m, 2H), 3.65 (t, J = 6.0 Hz, 2H), 2.51 - 2.37 (m, 2H), 2.34 - 2.31 (m, 2H), 2.13 - 2.02 (m, 2H). compound 4 Synthesis of N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide [ka] Synthesis of methyl 3-(2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamido)benzoate [ka]

[0329] To a mixture of 2-chloroquinoline-3-carboxylic acid (15 mg, 0.05 mmol) and oxalyl chloride (8 μL, 0.09 mmol) in dichloromethane (1 mL) was added a drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 15 minutes. Then, a solution of 3-aminobenzamide (8 mg, 0.05 mmol) and diisopropylethylamine (26 μL, 0.15 mmol) in dichloromethane (1 mL) was added to the stirred solution. The reaction mixture was stirred at room temperature for 18 hours. The dichloromethane was removed under vacuum and the crude mixture was purified by reverse phase HPLC to give methyl 3-(2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide)benzoate as a white solid. Synthesis of N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide

[0330] Methyl 3-(2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide)benzoate (19 mg, 4.3 mmol) was mixed with 7N ammonia in methanol (5 mL) in a sealed vial at 50° C. for 18 hours. The volatiles were removed under vacuum and the crude mixture was purified by reverse phase HPLC to give N-(3-carbamoylphenyl)-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxamide as a white solid. LRMS (ESI): Calcd [M+H] + : 425.18, found: 424.9.

[0331]

[0331] 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1H), 7.88 - 7.78 (m, 2H), 7.65 - 7.57 (m, 2H), 7.54 - 7.46 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 3.73 - 3.64 (m, 2H), 3.56 - 3.47 (m, 2H), 2.39 - 2.26 (m, 2H), 2.00 - 1.86 (m, 2H), 1.86 - 1.77 (m, 2H). compound 5 [ka] Synthesis of 2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0332] To a solution of 2-chloro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (14 mg, 0.04 mmol) and 4,4-difluoro-3-methylpiperidine hydrogen chloride (7 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (22 mg, 0.16 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 16 hours and then at 80° C. for 18 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was diluted with water and hydrochloric acid 1N, then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by reverse phase HPLC to give 2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a white solid. LRMS (ESI): Calcd [M+H] + : 461.15, found: 460.9.

[0333]

[0333] 1 H NMR (400 MHz, CDCl 3 ) δ 10.70 (s, 1H), 8.85 (s, 1H), 8.49 - 8.40 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.81 - 7.70 (m, 3H), 7.58 - 7.48 (m, 2H), 3.78 - 3.61 (m, 2H), 3.46 - 3.33 (m, 1H), 3.19 - 3.09 (m, 1H), 2.40 - 2.33 (m, 1H), 2.29 - 2.17 (m, 2H), 1.09 (d, J = 6.8 Hz, 3H). compound 6 Synthesis of 2-(4,4-difluoroazepan-1-yl)-7-fluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2-chloro-7-fluoroquinoline-3-carboxylic acid [ka]

[0334] To a stirred solution of 2-chloro-7-fluoroquinoline-3-carbaldehyde (1.0 g, 4.77 mmol) in ethanol (30 mL) was added silver nitrate (1.3 g, 7.63 mmol). The reaction mixture was stirred at room temperature for 1 hour. Sodium hydroxide (0.95 g, 23.9 mmol) in 80% ethanol was then added dropwise. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed, the solvent was removed by rotary evaporation, diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-chloro-7-fluoroquinoline-3-carboxylic acid as an off-white solid. Synthesis of methyl 2-chloro-7-fluoroquinoline-3-carboxylate [ka]

[0335]

[0335] To a solution of 2-chloro-7-fluoroquinoline-3-carboxylic acid (0.9 g, 3.99 mmol) in N,N-dimethylformamide (10 mL), potassium carbonate (2.21 g, 12 mmol) and (0.60 ml, 9.97 mmol) were added at room temperature and stirred at 50°C for 12 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give methyl 2-chloro-7-fluoroquinoline-3-carboxylate as a pale yellow solid. Synthesis of methyl 2-(4,4-difluoroazepan-1-yl)-7-fluoroquinoline-3-carboxylate [ka]

[0336] To a mixture of methyl 2-chloro-7-fluoroquinoline-3-carboxylate (550 mg, 2.3 mmol) and 4,4-difluoroazepane hydrochloride (0.59 g, 3.44 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.27 g, 12 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography with a gradient of 40-50% ethyl acetate in hexane to give methyl 2-(4,4-difluoroazepan-1-yl)-7-fluoroquinoline-3-carboxylate as a yellow solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-7-fluoroquinoline-3-carboxylic acid [ka]

[0337] To a stirred solution of methyl 2-(4,4-difluoroazepan-1-yl)-7-fluoroquinoline-3-carboxylate (0.65 g, 1.92 mmol) in methanol (8 mL), tetrahydrofuran (8 mL) and water (8 mL) was added lithium hydroxide (0.162 g, 3.84 mmol). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was removed on a rotary evaporator, diluted with water, and then acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 2-(4,4-difluoroazepan-1-yl)-7-fluoroquinoline-3-carboxylic acid as a yellow solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-7-fluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0338] To a solution of 2-(4,4-difluoroazepan-1-yl)-7-fluoroquinoline-3-carboxylic acid (0.2 g, 0.62 mmol) in anhydrous dichloromethane (2 mL) was added oxalyl chloride (0.16 g, 1.2 mmol) and a drop of anhydrous N,N-dimethylformamide at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was evaporated in vacuo under nitrogen atmosphere. The crude residue was dissolved in dry dichloromethane (6 mL) and added to a solution of 3-aminobenzene-1-sulfonamide (0.13 g, 0.74 mmol) and N,N-diisopropylethylamine (0.32 g, 2.5 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. Upon completion, the reaction mixture was diluted with dichloromethane and washed with water and brine solution. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product. The crude residue was purified by silica gel column chromatography with a gradient of 20-50% ethyl acetate in hexanes to give 2-(4,4-difluoroazepan-1-yl)-7-fluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a white solid. MS (ESI): Calcd [M+H] + : 479.14, found: 479.21.

[0339]

[0339] 1 H NMR (400 MHz, DMSO-d 6 ): δ10.95 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.94 (t, J = 8 Hz, 1H), 7.86-7.84 (m, 1H), 7.58-7.56 (m, 2H), 7.42 (s, 2H), 7.34-7.31 (m, 1H), 7.23-7.18 (m, 1H), 4.04 (d, J = 3.2 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 2.40-2.35 (m, 2H), 2.06-1.98 (m, 2H), 1.90-1.88 (m, 2H). compound 7 Synthesis of 3-(4,4-difluoroazepan-1-yl)-N-(3-methanesulfonylphenyl)quinoxaline-2-carboxamide [ka]

[0340]

[0340] To a solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (0.2 g, 0.65 mmol) in N,N-dimethylformamide (5 mL), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.37 g, 0.98 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.25 mmol) were added at 0°C, and the resulting mixture was stirred at the same temperature for 15 minutes. Then, 3-methanesulfonylaniline (0.13 g, 0.78 mmol) was added to the solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (0.2 g, 0.65 mmol) in N,N-dimethylformamide (5 mL). (mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to give the crude product. The crude product was purified by flash column chromatography with a gradient of 40-50% ethyl acetate in hexane to give 3-(4,4-difluoroazepan-1-yl)-N-(3-methanesulfonylphenyl)quinoxaline-2-carboxamide as a yellow solid. MS (ESI): Calcd [M+H] + : 461.15, found: 461.20.

[0341]

[0341] 1 H NMR (400 MHz, DMSO-d 6): δ11.40 (s, 1H), 8.39 (s, 1H), 8.08-8.06 (m, 1H), 7.95-7.93 (d, J = 8 Hz, 1H), 7.72-7.67 (m, 4H), 7.52-7.48 (m, 1H), 3.80-3.78 (m, 2H), 3.67-3.64 (m, 2H), 3.24 (s, 3H), 2.55-2.32 (m, 2H), 2.04-2.02 (m, 2H), 1.93-1.92 (m, 2H). compound 8 3-(4,4-Difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)quinoxaline-2-carboxamide [ka]

[0342]

[0342] To a solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (0.35 g, 1.15 mmol) in N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (0.77 g, 5.7 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.65 g, 1.7 mmol) were added at 0°C and stirred at room temperature for 15 minutes. Then, (3-aminophenyl)(imino)methyl-λ 6 -sulfanone (0.23 g, 1.4 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the crude. The crude mass was purified by reverse phase HPLC to give 3-(4,4-difluoroazepan-1-yl)-N-(3-(S-methylsulfonimidoyl)phenyl)quinoxaline-2-carboxamide as a white solid. MS (ESI): Calcd [M+H] + : 460.16, found: 460.25.

[0343]

[0343] 1 H NMR (400 MHz, DMSO-d 6 ) δ11.31 (s, 1H), 8.38 (s, 1H), 8.031 (d, J = 8 Hz, 1H), 7.95 (d, J = 8 Hz, 1H), 7.71 (d, J = 8 Hz, 3H), 7.65 (t, J = 8 Hz, 1H), 7.52-7.49 (m, 1H), 4.34 (s, 1H), 3.80.-3.78 (m, 2H), 3.67-3.64 (m, 2H), 3.085 (s, 3H), 2.40-2.37 (m, 2H), 2.07-1.99 (m, 2H), 1.89-1.88 (m, 2H). compound 9 Synthesis of 3-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide [ka] Synthesis of methyl 3-hydroxyquinoxaline-2-carboxylate [ka]

[0344] A stirred solution of 2-hydroxyquinoline-3-carboxylic acid (10 g, 52.6 mmol) in methanol (100 mL) was cooled to 0° C. Then sulfuric acid (20 mL) was added dropwise. The reaction mixture was heated at 70° C. for 12 hours. The progress of the reaction was monitored by TLC. After completion, methanol was removed under vacuum. The residue thus obtained was dissolved in ethyl acetate and washed with sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude material. The crude material was triturated with diethyl ether and pentane to obtain the desired product, methyl 3-hydroxyquinoxaline-2-carboxylate, as a pale orange solid. Synthesis of methyl 3-chloroquinoxaline-2-carboxylate [ka]

[0345] A mixture of methyl 3-hydroxyquinoxaline-2-carboxylate (5 g, 24.5 mmol) and phosphorus oxychloride (75 mL) was refluxed at 130° C. for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was then cooled to room temperature and excess phosphorus oxychloride was distilled off. The residue thus obtained was dissolved in ethyl acetate and neutralized with sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude material. The crude material was triturated with diethyl ether and pentane to obtain the desired product, methyl 3-chloroquinoxaline-2-carboxylate, as a light brown solid. Synthesis of methyl 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylate [ka]

[0346] To a solution of methyl 3-chloroquinoxaline-2-carboxylate (5 g, 22.5 mmol) in N,N-dimethylformamide (50 mL) was added 4,4-difluoroazepane hydrochloride (5.8 g, 33.7 mmol) and potassium carbonate (15.5 g, 112 mmol). The mixture was heated at 70° C. for 16 h. 2 The mixture was heated under atmospheric pressure. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography with a gradient of 20-30% ethyl acetate in hexane to give the desired compound, methyl 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylate, as a brown solid. Synthesis of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid [ka]

[0347] To a solution of methyl 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylate (5 g, 15.6 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added lithium hydroxide (1.5 g, 62 mmol) and water (20 mL). The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed under vacuum, and the residue was diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude material, which was purified by trituration with diethyl ether and pentane to obtain 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid as a light brown solid. Synthesis of 3-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide

[0348]

[0348] To a solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (0.3 g, 0.9 mmol) in dichloromethane (6 mL), N,N'-dicyclohexylmethanediimine (0.24 mg, 1.17 mmol) and N,N-dimethylpyridin-4-amine (5.96 mg, 5 mol%) were added at 0°C. Then 3-aminobenzene-1-sulfonamide (0.2 mg, 1.17 mmol) was slowly added, and the resulting mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was passed through a Celite pad, and the filtrate was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude material. The crude residue was purified by flash column chromatography with a gradient of 50-60% ethyl acetate in hexanes to give 3-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide as a yellow solid. MS (ESI): Calcd [M+H] + : 462.14, found: 462.20

[0349]

[0349] 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.27 (s, 1H), 8.33 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.91-7.88 (m, 1H), 7.10 (d, J = 3.6 Hz, 2H), 7.61-7.59 (m, 2H), 7.52-7.48 (m, 1H), 7.43 (brs, 2H), 3.80-3.78 (m, 2H), 3.67 (t, J = 7.5 Hz, 2H), 2.44-2.40 (m, 2H), 2.09-2.04 (m, 2H), 1.99-1.92 (m, 2H). compound 10 Synthesis of 2-(4,4-difluoroazepan-1-yl)-6-fluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2-Chloro-6-fluoroquinoline-3-carboxylic Acid

Chem.

[0350]

[0350] To a stirred solution of 2-chloro-6-fluoroquinoline-3-carbaldehyde (= 1 g, 4.8 mmol) in ethanol (30 mL) was added silver nitrate (1.3 g, 7.6 mmol), and the resulting reaction mixture was stirred at room temperature for 1 hour. Then, a solution of sodium hydroxide (0.96 g, 24 mmol) in 80% aqueous ethanol was added dropwise thereto. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was filtered through celite, the solvent was distilled off under rotary evaporation, diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 2-chloro-6-fluoroquinoline-3-carboxylic acid as an off-white solid. Synthesis of Methyl 2-Chloro-6-fluoroquinoline-3-carboxylate

Chem.

[0351]

[0351] To a solution of 2-chloro-6-fluoroquinoline-3-carboxylic acid (0.75 g, 3.3 mmol) in N,N-dimethylformamide (7.5 mL) was added potassium carbonate (1.4 g, 10 mmol) and methyl iodide (0.5 ml, 8.3 mmol) at room temperature, and the mixture was stirred at 50 °C for 12 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain methyl 2-chloro-6-fluoroquinoline-3-carboxylate as a pale yellow solid. Synthesis of Methyl 2-(4,4-difluoroazepan-1-yl)-6-fluoroquinoline-3-carboxylate

Chem.

[0352] To a stirred solution of methyl 2-chloro-6-fluoroquinoline-3-carboxylate (0.55 g, 2.3 mmol) in N,N-dimethylformamide (5.5 mL) was added 4,4-difluoroazepane hydrochloride (0.59 g, 3.45 mmol) and potassium carbonate. (1.3 g, 9.2 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography with a gradient of 20-30% ethyl acetate in hexane to give methyl 2-(4,4-difluoroazepan-1-yl)-6-fluoroquinoline-3-carboxylate as a yellow solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-6-fluoroquinoline-3-carboxylic acid [ka]

[0353] To a stirred solution of methyl 2-(4,4-difluoroazepan-1-yl)-6-fluoroquinoline-3-carboxylate (0.55 g, 1.6 mmol) in a mixture of methanol (5.5 mL), tetrahydrofuran (5.5 mL) and water (5.5 mL) (1:1:1), lithium hydroxide (0.14 g, 3.2 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was removed on a rotary evaporator, diluted with water, acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-(4,4-difluoroazepan-1-yl)-6-fluoroquinoline-3-carboxylic acid as an off-white solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-6-fluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0354]

[0354] To a stirred solution of 2-(4,4-difluoroazepan-1-yl)-6-methoxyquinoline-3-carboxylic acid (0.4 g, 1.2 mmol) in dichloromethane (4 mL), oxalyl chloride (0.2 mL, 2.5 mmol) and a drop of N,N-dimethylformamide were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed under nitrogen atmosphere, diluted with dry dichloromethane (4 mL), and added to a mixture of 3-aminobenzenesulfonamide (0.25 g, 1.5 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.2 mmol) in dry dichloromethane (4 mL) at 0°C and allowed to stir at room temperature for 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography with a gradient of 40-60% ethyl acetate in hexanes to give 2-(4,4-difluoroazepan-1-yl)-6-fluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as an off-white solid. MS (ESI): Calcd [M+H] + : 479.14, found: 479.25.

[0355]

[0355] 1 H NMR (400 MHz, DMSO-d 6): δ10.99 (brs, 1H), 8.33 (s, 1H), 8.31 (s, 1H), 7.86-7.83 (m, 1H), 7.70-7.67 (m, 1H), 7.67-7.65 (m, 1H), 7.58.751 (m, 3H), 7.43 (brs, 2H), 3.75-3.73 (m, 2H), 3.61-3.58 (t, J = 6.0 Hz, 2H), 2.54-2.38 (m, 2H), 2.07-1.96 (m, 2H), 1.89-1.88 (m, 2H). compound 11 Synthesis of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid [ka]

[0356] To a stirred solution of 2-chloro-6,7-difluoroquinoline-3-carbaldehyde (1 g, 4.4 mmol) in ethanol (50 mL) was added silver nitrate (1.1 g, 6.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. To this was added a solution of sodium hydroxide (0.88 g, 22 mmol) in 80% aqueous ethanol dropwise. The reaction mixture was stirred at room temperature for 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite, the solvent was removed by rotary evaporation, diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give 2-chloro-6,7-difluoroquinoline-3-carboxylic acid as a pale yellow solid. Synthesis of methyl 2-chloro-6,7-difluoroquinoline-3-carboxylate [ka]

[0357] To a stirred solution of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid (1 g, 4.1 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.3 g, 16. mmol) and iodomethane (0.62 mL, 12.3 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give methyl 2-chloro-6,7-difluoroquinoline-3-carboxylate as a white solid. Synthesis of methyl 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylate [ka]

[0358] To a solution of methyl 2-chloro-6,7-difluoroquinoline-3-carboxylate (1 g, 3.9 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.2 g, 15.5 mmol) and 4,4-difluoroazepane hydrochloride (1.0 g, 5.8 mmol). The resulting reaction mixture was heated to 70° C. and stirred for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the crude material. The crude material was purified by CombiFlash with a gradient of 30-50% ethyl acetate in heptane to give methyl 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylate as a white solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid [ka]

[0359] To a solution of methyl 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylate (0.75 g, 2.1 mmol) in 1:1 methanol (5.48 mL) and tetrahydrofuran (5.48 mL) was added lithium hydroxide (0.18 g, 4.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated to remove the solvent. The crude residue was diluted with water, acidified with 1N hydrochloric acid solution, extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid as a yellow solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0360] To a solution of 2-(4,4-difluoroazepan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid (0.5 g, 1.5 mmol) in anhydrous dichloromethane (10 mL) was added oxalyl chloride (0.25 mL, 2.9 mmol) and a drop of anhydrous N,N-dimethylformamide at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. After completion of the reaction, the reaction mixture was evaporated under vacuum. The crude residue was redissolved in dry dichloromethane and added to a solution of 3-aminobenzene-1-sulfonamide (0.3 g, 1.75 mmol) and N,N-diisopropylethylamine (0.76 g, 5.8 mmol) in dichloromethane (70 mL) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and brine solution. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude material was purified using flash chromatography with a gradient of 20-50% ethyl acetate in hexanes to give 2-(4,4-difluoroazepan-1-yl)-6,7-difluoro-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a white solid. MS (ESI): Calcd [M+H] + : 497.13, found: 497.15.

[0361]

[0361] 1 H NMR (400 MHz, DMSO-d 6 ): δ10.99 (s, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.94 (t, J = 9.6 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.58 (d, J = 8 Hz, 2H), 7.42 (s, 2H), 3.74 (s, 2H), 3.60-3.58 (m, 2H), 2.40-2.37 (m, 2H), 2.07-1.99 (m, 2H), 1.89-1.88 (m, 2H). compound 12 Synthesis of 2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2-chloro-6-methoxyquinoline-3-carboxylic acid [ka]

[0362]

[0362] To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (1.4 g, 6.3 mmol) in ethanol (28 mL), silver nitrate (1.7 g, 10 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Then, a solution of sodium hydroxide (1.3 g, 32 mmol) in 80% aqueous ethanol was added dropwise. The reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was filtered through Celite, the solvent was removed by rotary evaporation, diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-chloro-6-methoxyquinoline-3-carboxylic acid as an off-white solid. Synthesis of methyl 2-chloro-6-methoxyquinoline-3-carboxylate [ka]

[0363]

[0363] To a solution of 2-chloro-6-methoxyquinoline-3-carboxylic acid (0.6 g, 2.5 mmol) in N,N-dimethylformamide (6 mL), potassium carbonate was added. (1.0 g, 7.6 mmol) and methyl iodide (0.4 ml, 6.3 mmol) were added at room temperature and stirred at 50° C. for 12 hours. After the reaction was completed, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with anhydrous Na 2 SO 4It was dried and filtered. The filtrate was concentrated under reduced pressure to obtain methyl 2-chloro-6-methoxyquinoline-3-carboxylate as a pale yellow solid. Synthesis of Methyl 2-(4,4-Difluoroazepan-1-yl)-6-methoxyquinoline-3-carboxylate [Chemical formula]

[0364]

[0364] To a stirred solution of methyl 2-chloro-6-methoxyquinoline-3-carboxylate (0.5 g, 2 mmol) in N,N-dimethylformamide (10 mL) was added 4,4-difluoroazepane hydrochloride (0.50 g, 3.0 mmol), and potassium carbonate (1 g, 8 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude residue was purified by flash column chromatography with a gradient of 30 - 50% ethyl acetate in hexane to obtain methyl 2-(4,4-difluoroazepan-1-yl)-6-methoxyquinoline-3-carboxylate as a yellow solid. Synthesis of 2-(4,4-Difluoroazepan-1-yl)-6-methoxyquinoline-3-carboxylic Acid [Chemical formula]

[0365] To a stirred solution of methyl 2-(4,4-difluoroazepan-1-yl)-6-methoxyquinoline-3-carboxylate (0.45 g, 1.3 mmol) in a mixture of methanol (4.5 mL), tetrahydrofuran (4.5 mL) and water (4.5 mL), lithium hydroxide (0.11 g, 2.6 mmol) was added at room temperature and stirred for 16 hours. After completion of the reaction, the solvent was removed by rotary evaporation, diluted with water, acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 2-(4,4-difluoroazepan-1-yl)-6-methoxyquinoline-3-carboxylic acid as a yellow solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0366]

[0366] To a stirred solution of 2-(4,4-difluoroazepan-1-yl)-6-methoxyquinoline-3-carboxylic acid (0.24 g, 0.71 mmol) in dichloromethane (3 mL), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.41 g, 1.1 mmol) and 4-dimethylaminopyridine (DMAP) (0.043 g, 0.36 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction, the solvent was evaporated and diluted with acetonitrile (3 mL) to give 3-aminobenzenesulfonamide (122 mg, 0.71 mmol). (mmol) was added to the above solution and stirred at 70° C. for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude material. The crude residue was purified by flash column chromatography with a gradient of 50-70% ethyl acetate in hexane to give 2-(4,4-difluoroazepan-1-yl)-6-methoxy-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a yellow solid. MS (ESI): Calcd [M+H]+ : 491.16, found: 491.20.

[0367]

[0367] 1 H NMR (400 MHz, DMSO-d 6 ): δ10.91 (s, 1H), 8.34 (brs, 1H), 8.24 (s, 1H), 7.86-7.83 (m, 1H), 7.60-7.54 (m, 3H), 7.42 (s, 2H), 7.32-7.30 (m, 2H), 3.25 (s, 3H), 3.72-3.70 (m, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.43-2.36 (m, 2H), 2.02-1.96 (m, 2H), 1.88-1.86 (m, 2H). compound 13 Synthesis of 6-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2,6-dichloroquinoline-3-carboxylic acid [ka]

[0368]

[0368] To a stirred solution of 2,6-dichloroquinoline-3-carbaldehyde (1.0 g, 4.4 mmol) in ethanol (30 mL), silver nitrate (1.2 g, 7.1 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Then, a solution of sodium hydroxide (0.88 g, 22 mmol) in 80% aqueous ethanol was added dropwise and allowed to stir at room temperature for 5 hours. After completion of the reaction, the reaction mixture was filtered through Celite, the solvent was removed by rotary evaporation, diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2,6-dichloroquinoline-3-carboxylic acid as an off-white solid. Synthesis of methyl 2,6-dichloroquinoline-3-carboxylate [ka]

[0369]

[0369] To a solution of 2,6-dichloroquinoline-3-carboxylic acid (0.9 g, 3.7 mmol) in N,N-dimethylformamide (9 mL), potassium carbonate was added. (1.5 g, 11 mmol) and methyl iodide (0.6 ml, 9.3 mmol) were added at room temperature and stirred at 50° C. for 12 hours. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give methyl 2,6-dichloroquinoline-3-carboxylate as a pale yellow solid. Synthesis of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate [ka]

[0370] To a stirred solution of methyl 2,6-dichloroquinoline-3-carboxylate (0.8 g, 3.1 mmol) in N,N-dimethylformamide (8 mL) was added 4,4-difluoroazepane hydrochloride (0.63 g, 4.7 mmol) and potassium carbonate. (1.7 g, 12.5 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the crude residue obtained was purified by flash column chromatography with a gradient of 50-70% ethyl acetate in hexane to give methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate as a yellow solid. Synthesis of 6-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid [ka]

[0371]

[0371] To a stirred solution of methyl 6-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylate (0.8 g, 2.3 mmol) in a mixture of methanol (8 mL), tetrahydrofuran (8 mL), and water (8 mL), lithium hydroxide (0.19 g, 4.5 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed by rotary evaporation, diluted with water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 6-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid as a yellow solid. Synthesis of 6-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0372] To a stirred solution of 6-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (0.33 g, 0.88 mmol) in dichloromethane (3 mL), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.50 g, 1.3 mmol) and 4-dimethylaminopyridine (DMAP) (0.054 g, 0.44 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was rotary evaporated and diluted with acetonitrile (3 mL), to which was added 3-aminobenzenesulfonamide (0.18 g, 1.1 mmol). (mmol) was added and refluxed for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography with a gradient of 50-70% ethyl acetate in hexane to give 6-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a yellow solid. MS (ESI): Calcd [M+H] + : 495.11, found: 495.20.

[0373]

[0373] 1 H NMR (400 MHz, DMSO-d 6 ): δ10.99 (s, 1H), 8.31 (d, J = 6.0 Hz, 2H), 7.95 (s, 1H), 7.85-7.83 (m, 1H), 7.65-7.62 (m, 2H), 7.60-7.55 (m, 2H), 7.42 (brs, 2H), 3.76-3.74 (m, 2H), 3.61 (t, J = 6.0 Hz, 2H), 2.40-2.38 (m, 2H), 2.06-1.99 (m, 2H), 1.96-1.88 (m, 2H). compound 14 Synthesis of 7-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2,7-dichloroquinoline-3-carboxylic acid [ka]

[0374] To a stirred solution of 2,7-dichloroquinoline-3-carbaldehyde (1.0 g, 4.4 mmol) in ethanol (20 mL) was added silver nitrate (1.2 g, 7.1 mmol). To this mixture was added a solution of sodium hydroxide (0.9 g, 22 mmol) in water (3 mL) dropwise. The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was filtered through a pad of Celite and the solvent was removed under rotary evaporation to obtain a crude mixture. The crude mixture was diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude material. The crude material was triturated with diethyl ether and pentane to obtain 2,7-dichloroquinoline-3-carboxylic acid as an off-white solid. Synthesis of 7-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid [ka]

[0375] To a solution of 2,7-dichloroquinoline-3-carboxylic acid (0.65 g, 2.7 mmol) in N,N-dimethylformamide (20 mL) was added 4,4-difluoroazepane hydrochloride (0.67 g, 34 mmol) and potassium carbonate (1.5 g, 11 mmol). The mixture was heated at 70° C. under nitrogen atmosphere for 12 hours. The progress of the reaction was monitored by TLC. Upon completion, the crude material was diluted with water, followed by treatment with 1N hydrochloric acid solution to pH 6.0 and extraction with ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous sodium sulfate. The crude material was triturated with diethyl ether and pentane to give the product 7-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid as a light brown solid. Synthesis of 7-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide

[0376] To a solution of 7-chloro-2-(4,4-difluoroazepan-1-yl)quinoline-3-carboxylic acid (0.30 g, 0.90 mmol) in dichloromethane (6 mL), oxalyl chloride (0.15 g, 1.0 mmol) was added under nitrogen atmosphere, followed by 1-2 drops of N,N-dimethylformamide at 0° C., and the reaction was continued at room temperature for 1 hour. After completion of the reaction, the solvent was removed under nitrogen atmosphere. The crude mixture was dissolved in dichloromethane (6 mL) and added to a solution of 3-aminobenzene-1-sulfonamide (0.18 g, 1.2 mmol) and N,N-diisopropylethylamine (0.4 mL, 4.5 mmol) in dichloromethane (6 mL) at 0° C., and the mixture was stirred at room temperature for an additional hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water and then extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the crude material. The crude residue was purified by flash column chromatography with a gradient of 40-50% ethyl acetate in hexanes to give 7-chloro-2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide as a light brown solid. MS (ESI): Calcd [M+H] + : 495.11, found: 495.15.

[0377]

[0377] 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.98 (s, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 7.88-7.83 (m, 2H), 7.64 (d, J = 1.6 Hz, 1H), 7.58-7.54 (m, 2H), 7.42 (s, 2H), 7.32 (dd, J = 2.4, 8.8 Hz, 1H), 3.77-3.74 (m, 2H), 3.60 (t, J = 5.6 Hz, 2H), 2.44-2.37 (m, 2H), 2.00-1.99 (m, 2H), 1.95-1.88 (m, 2H). compound 15 Synthesis of N-(3-carbamoylphenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide [ka] Synthesis of 3-chloroquinoxaline-2-carboxylic acid [ka]

[0378] A mixture of 3-hydroxyquinoxaline-2-carboxylic acid (2 g, 9.6 mmol) and phosphorus oxychloride (20 mL) was slowly heated to 120° C. for 5 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude residue obtained was triturated with n-pentane and diethyl ether to give 3-chloroquinoxaline-2-carboxylic acid as a yellow solid. Synthesis of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid [ka]

[0379] To a solution of 3-chloroquinoxaline-2-carboxylic acid (1.0 g, 1.65 mmol) in N,N-dimethylformamide (10 mL) was added 4,4-difluoroazepane hydrochloride (0.43 g, 2.5 mmol) and potassium carbonate (0.9 g, 6.6 mmol) at room temperature. The reaction mixture was heated at 78° C. for 12 hours. After completion of the reaction, the crude material was diluted with cold water, followed by treatment with 1N hydrochloric acid solution and extraction with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography with a gradient of 50-70% ethyl acetate in hexane to give the desired compound 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid as a yellow solid. Synthesis of methyl 3-(3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamido)benzoate [ka]

[0380]

[0380] To a solution of 3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxylic acid (0.4 g, 1.4 mmol) in dichloromethane (10 mL), oxalyl chloride (0.15 g, 2.7 mmol) and a drop of N,N-dimethylformamide were added at 0°C under nitrogen atmosphere and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under nitrogen atmosphere. The crude mixture was dissolved in dichloromethane (10 mL) and added to a solution of 3-aminomethylbenzoate (0.29 g, 1.7 mmol) and N,N-diisopropylethylamine (0.40 mL, 4.5 mmol) in dichloromethane (10 mL) at 0°C, and the mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude residue which was purified by flash column chromatography with a gradient of 40-50% ethyl acetate in hexanes to give methyl 3-(3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamido)benzoate as a yellow solid. Synthesis of N-(3-carbamoylphenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide

[0381] Methyl 3-(3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide)benzoate (0.28 g, 0.75 mmol) was added to a stirred solution of ammonia (7N ammonia in methanol, 10 mL) at room temperature. The reaction mixture was stirred in an autoclave at 100° C. for 28 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the solvent was removed under vacuum. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude residue was purified by flash column chromatography with a gradient of 50-70% ethyl acetate in hexane to give N-(3-carbamoylphenyl)-3-(4,4-difluoroazepan-1-yl)quinoxaline-2-carboxamide as a yellow solid. MS (ESI): Calcd [M+H] + : 426.17, found: 426.20.

[0382]

[0382] 1 H NMR (400 MHz, DMSO-d 6 ): δ11.07 (s, 1H), 8.21 (t, J = 16.0 Hz, 1H), 7.95 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 8 Hz, 1.6 Hz, 1H), 7.70-7.71 (m, 2H), 7.64 (d, J = 8 Hz, 1H), 7.45-7.52 (m, 2H), 7.40 (s, 1H), 3.79-3.81 (m, 2H), 3.68 (t, J = 6Hz, 2H), 2.34-2.43(m, 2H), 2.03-2.08 (m, 2H), 1.91-1.99 (m, 2H) compound 16 Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-1,7-naphthyridine-3-carboxamide [ka] Synthesis of ethyl 2-hydroxy-1,7-naphthyridine-3-carboxylate [ka]

[0383] To a stirred solution of 3-aminoisonicotinaldehyde (2.5 g, 20.4 mmol) in ethanol (25 mL) was added diethyl malonate (9.4 mL, 61.5 mmol) and piperidine (0.65 mL, 6.2 mmol). The reaction mixture was refluxed and stirred for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude material, which was triturated with diethyl ether and pentane to give ethyl 2-hydroxy-1,7-naphthyridine-3-carboxylate as a yellow solid. Synthesis of ethyl 2-chloro-1,7-naphthyridine-3-carboxylate [ka]

[0384] A mixture of ethyl 2-hydroxy-1,7-naphthyridine-3-carboxylate (2.8 g, 12.8 mmol) and phosphorus oxychloride (14 mL) was heated at 130° C. for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with cold water, basified with sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give the crude material. The crude residue was purified by flash column chromatography with a gradient of 20-30% ethyl acetate in hexane to give ethyl 2-chloro-1,7-naphthyridine-3-carboxylate as a yellow solid. Synthesis of ethyl 2-(4,4-difluoroazepan-1-yl)-1,7-naphthyridine-3-carboxylate [ka]

[0385] To a stirred solution of ethyl 2-chloro-1,7-naphthyridine-3-carboxylate (1.0 g, 4.2 mmol) in N,N-dimethylformamide (10 mL) was added 4,4-difluoroazepane hydrochloride (1.0 g, 6.4 mmol) and potassium carbonate. (2.3 g, 17 mmol) was added at room temperature and slowly heated to 70° C. and stirred for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ice-cold water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography with a gradient of 30-40% ethyl acetate in hexane to give ethyl 2-(4,4-difluoroazepan-1-yl)-1,7-naphthyridine-3-carboxylate as a pale yellow solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-1,7-naphthyridine-3-carboxylic acid [ka]

[0386] To a stirred solution of ethyl 2-(4,4-difluoroazepan-1-yl)-1,7-naphthyridine-3-carboxylate (0.8 g, 2.4 mmol) in a mixture of methanol (8 mL), tetrahydrofuran (8 mL), and water (8 mL) was added lithium hydroxide (0.7 g, 4.8 mmol). The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under rotary evaporation, diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude material. The crude material was triturated with diethyl ether and pentane to give 2-(4,4-difluoroazepan-1-yl)-1,7-naphthyridine-3-carboxylic acid as a yellow solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-1,7-naphthyridine-3-carboxamide

[0387]

[0387] To a stirred solution of 2-(4,4-difluoroazepan-1-yl)-1,7-naphthyridine-3-carboxylic acid (0.4 g, 1.3 mmol) in dichloromethane (4 mL), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (0.74 g, 2 mmol) and 4-dimethylaminopyridine (DMAP) (0.08 g, 0.65 mmol) were added at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed under rotary evaporation, and the residue was diluted with acetonitrile (4 mL), and 3-aminobenzenesulfonamide (0.27 g, 1.6 mmol) was added to the solution in one portion. The reaction mixture was stirred at room temperature for 16 hours. Heated to 70° C. for 18 hours. Reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude material. The crude residue was purified by flash column chromatography with a gradient of 30-50% ethyl acetate in hexanes to give 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-1,7-naphthyridine-3-carboxamide as an off-white solid. MS (ESI): Calcd [M+H] + : 462.14, found: 462.20

[0388]

[0388] 1 H NMR (400 MHz, DMSO-d 6): δ11.07 (s, 1H), 9.01 (s, 1H), 8.40 (s, 1H), 8.35 (d, J = 6.5 Hz, 1H), 8.30 (brs, 1H), 7.87-7.84 (m, 1H), 7.73 (d, J = 6.5 Hz, 1H), 7.60-7.56 (m, 2H), 7.43 (brs, 2H), 3.80-3.78 (m, 2H), 3.64 (t, J = 6.0 Hz, 2H), 2.42-2.39 (m, 2H), 2.07-1.98 (m, 2H), 1.92-1.90 (m, 2H) compound 17 Synthesis of 2-(4,4-difluoroazepan-1-yl)-7-methoxy-N-(3-sulfamoylphenyl)quinoline-3-carboxamide [ka] Synthesis of 2-chloro-7-methoxyquinoline-3-carboxylic acid (2) [ka]

[0389] To a stirred solution of 2-chloro-7-methoxyquinoline-3-carbaldehyde (2.0 g, 9.0 mmol) in ethanol (40 mL) was added silver nitrate (2.45 g, 14.4 mmol). To this mixture was added dropwise a solution of sodium hydroxide (1.8 g, 45 mmol) in water (10 mL). The reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated under vacuum to obtain a crude mixture. The crude mixture was diluted with water, acidified with 1N hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude material, which was purified by trituration with diethyl ether and n-pentane to obtain 2-chloro-7-methoxyquinoline-3-carboxylic acid as a brown solid. Synthesis of 2-(4,4-difluoroazepan-1-yl)-7-methoxyquinoline-3-carboxylic acid [ka]

[0390] To a solution of 2-chloro-7-methoxyquinoline-3-carboxylic acid (1.0 g, 4.2 mmol) in N,N-dimethylformamide (20 mL) was added 4,4-difluoroazepane hydrochloride (0.85 g...

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R １ is, in each case independently, hydrogen, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, halogen, C １ -C ６ -haloalkyl, halo-C １ -C ６ -alkoxy, C ３ -C ６ -cycloalkyl, and C ３ -C ６ -cycloalkylC １ -C ３ -alkyl; or or Two R's １ teeth, 【Chemistry 2】 They are bonded to adjacent ring carbons in the ring, and together with the adjacent carbons to which they are bonded, 【Transformation 3】 It forms, where * is 【Chemistry 4】 This shows the shared carbon in and any remaining R １ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, Halo-C １ -C ６ Alkoxy, C ３ -C ６ -Cycloalkyl and C ３ -C ６ -Cycloalkyl C １ -C ３ - Selected independently of alkyl; A is R ３ Replaced by and (R ３ａ ) ｑ C may be replaced with ６ -C １０ Ariel; R ３ Replaced by and (R ３ａ ) ｑ A 5- to 10-membered heteroaryl that may be substituted with (R ３ａ ) ｑ１ It may be replaced with 【Transformation 5】 ; (R ３ａ ) ｑ１ It may be replaced with 【Transformation 6】 ; or (R ３ａ ) ｑ１ It may be replaced with 【Transformation 7】 And; W １ -N=, -C(H)=, -C(halogen)=, -C(C １ -C ６ Alkyl) =, -C (cyclopropyl) =, or -C (C １ -C ６ Alkoxy) = and; W ２ and W ３ These are -C- and W ２ and W ３ The dashed bond between them is a double bond, and 【Transformation 8】 is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W ２ and W ３ One of them is -C- and the other is -N-, W ２ and W ３ The dashed line connection between them is a simple connection, and 【Chemistry 9】 is a 5- or 6-membered heterocyclic ring which may contain an additional N, where the remaining ring atoms are C; R ２ In each case, independently, hydrogen, halogen, and C １ -C ６ Alkyl or halo-C １ -C ６ Is it alkyl? or Two R's ２ These atoms are bonded to adjacent carbon atoms, and together with the carbon atoms to which they are bonded, they form a 3- to 7-membered carbocyclic ring, the ring being composed of halogens and C １ -C ６ It may be substituted with one, two, or three groups independently selected from alkyl; and the remaining R ２ In each case, independently, hydrogen, halogen, or C １ -C ６ Is it alkyl; or Two R's ２ These are bonded to the same carbon, and together with the carbon to which they are bonded, they form a 3- to 7-membered carbocyclic ring, and the ring is composed of halogens and C １ -C ６ It may be substituted with one, two, or three groups independently selected from alkyl; and the remaining R ２ In each case, independently, hydrogen, halogen, or C １ -C ６ It is alkyl; R ３ is hydrogen, -OH, -B(OH) ２ , -COOH, hydroxyalkyl, -C(=NH)NH ２ , -C(O)NH ２ , -NH ２ , -NHC(O)C １－３ alkyl, -NHC(O)NH ２ , -NHSO ２ NH ２ , -NHC(=NH)NH ２ , -SO ２ NHR, -SO ２ C １ -C ６ -alkyl, amino-C １ -C ６ alkyl, halo-C １ -C ３ alkyl, C ３ -C ６ -cycloalkyl, 3- to 6-membered heterocycloalkyl, or 【Chemistry 10】 and wherein R is hydrogen, C １ -C ３ alkyl, or C ３ -C ５ cycloalkyl; wherein the C ３ -C ６ cycloalkyl and 3- to 6-membered heterocycloalkyl may be substituted with one -NH ２ ; and the alkyl in the amino-C １ -C ６ alkyl may be further substituted with 1, 2, 3, or 4 halos; R ３ａ In each case, independently, hydrogen, halogen, and C １ -C ３ Alkyl, or C ３ -C ６ It is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3. Compounds thereof; or pharmaceutically acceptable salts thereof and / or isomers thereof (However, the aforementioned compound is 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or pharmaceutically acceptable salts thereof and / or isomers thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or pharmaceutically acceptable salts and / or isomers thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide, or pharmaceutically acceptable salts and / or isomers thereof; 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxamide, or pharmaceutically acceptable salts and / or isomers thereof; (or not 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or any pharmaceutically acceptable salt thereof and / or its isomers).

2. A is R ３ Replaced by and (R ３ａ ) ｑ C may be replaced with ６ -C １０ It is an arrow, and arbitrarily, A is R ３ Replaced by and (R ３ａ ) ｑ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the phenyl is optionally substituted with phenyl.

3. A is R ３ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is a phenyl substituted with .

4. A, 【Chemistry 11】 And here, 【Chemistry 12】 R ３ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, exhibiting bonding to a compound.

5. A, 【Chemistry 13】 And here, 【Chemistry 14】 R ３ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, exhibiting bonding to a compound.

6. A is R ３ Replaced by and (R ３ａ ) ｑ It is a 5- to 10-membered heteroaryl that may be substituted with R ３ Replaced by and (R ３ａ ) ｑ It is a 9-membered heteroaryl that may be substituted with R ３ Replaced by and (R ３ａ ) ｑ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, which may be a 10-membered heteroaryl substituted with .

7. A, 【Chemistry 15】 The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

8. A is R ３ Replaced by and (R ３ａ ) ｑ It is a 5- or 6-membered heteroaryl that may be substituted with R ３ Replaced by and (R ３ａ ) ｑ It is a 5-membered heteroaryl that may be substituted with R ３ Replaced by and (R ３ａ ) ｑ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, which is a 6-membered heteroaryl that may be substituted with .

9. A, 【Chemistry 16】 The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

10. A, 【Chemistry 17】 A compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of and / or Or its isomer.

11. A, [Chemistry 18] A group consisting of the following is selected, where, 【Chemistry 19】 R ３ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, exhibiting bonding to a compound.

12. R ３ However, hydrogen, -OH, -B(OH) ２ ,-COOH,hydroxy-C １ -C ３ Alkyl, -C(=NH)NH ２ , -C(O)NH ２ NH ２ ,-NHC(O)C １－３ Alkyl, -NHC(O)NH ２ , -NHS(O) ２ NH ２ , -NHC(=NH)NH ２ , -S(O) ２ NHR, -S(O) ２ C １ -C ６ -Alkyl, amino-C １ -C ３ Alkyl, Halo-C １ -C ３ Alkyl, C ３ -C ６ -Cycloalkyl, 3- to 6-membered heterocycloalkyl, or 【Chemistry 20】 Here, R is hydrogen, C １ -C ３ Alkyl, or C ３ -C ５ It is a cycloalkyl; where the C ３ -C ６ -Cycloalkyl and 3- to 6-membered heterocycloalkyl groups have one -NH ２ It may also be substituted with; and the amino-C １ -C ３ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the alkyl in the alkyl group may be further substituted with 1, 2, 3, or 4 halos.

13. R ３ However, -C(O)NH ２ , -NH ２ , -S(O) ２ NHR, -S(O) ２ C １ -C ６ - Alkyl, or 【Chemistry 21】 Here, R is hydrogen, C １ -C ３ Alkyl or C ３ -C ５ A compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt and / or isomer thereof.

14. A is pyrazolyl, and R ３ However, the compound of claim 1, or a pharmaceutically acceptable salt thereof and / or isomer thereof, is hydrogen.

15. A is pyridinyl and R ３ However, -S(O) ２ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein R is NHR, where R is hydrogen.

16. A is pyridinyl and R ３ However, -C(O)NH ２ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

17. R ３ However, -C(O)NH ２ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

18. R ３ However, -NH ２ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

19. R ３ However, -S(O) ２ NHR is, and optionally R is C １ -C ３ It is alkyl, or R is C ３ -C ５ A compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt and / or isomer thereof.

20. R ３ However, -S(O) ２ NH ２ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

21. R ３ However, -S(O) ２ C １ -C ６ - The compound of claim 1, which is alkyl, or a pharmaceutically acceptable salt and / or isomer thereof.

22. R ３ However, -S(O) ２ CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

23. R ３ but, 【Chemistry 22】 The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

24. R ３ but, 【Chemistry 23】 The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof. 【Request Item 25】 【Chemistry 24】 or its pharmaceutically acceptable salts and / or isomers thereof; Here, W ４ is either O or S; One R １ As shown in the above ring, R １ａ It may be; and R １ａ is hydrogen, halogen, C １ -C ６ - Alkyl, C ３ -C ６ -Cycloalkyl, or C ３ -C ６ -Cycloalkyl C １ -C ３ - It is alkyl; The compound according to claim 1, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. 【Request Item 26】 【Chemistry 25】 And; One R １ As shown in the above ring, R １ａ It may be; and R １ａ is hydrogen, halogen, C １ -C ６ - Alkyl, C ３ -C ６ -Cycloalkyl, or C ３ -C ６ -Cycloalkyl C １ -C ３ - It is alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. 【Request Item 27】 【Chemistry 26】 And; Here, W ４ is either O or S; One R １ As shown in the above ring, R １ａ It may be; and R １ａ is hydrogen, halogen, C １ -C ６ - Alkyl, C ３ -C ６ -Cycloalkyl, or C ３ -C ６ -Cycloalkyl C １ -C ３ - It is alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. 【Request Item 28】 【Chemistry 27】 And; One R １ As shown in the above ring, R １ａ It may be; and R １ａ is hydrogen, halogen, C １ -C ６ - Alkyl, C ３ -C ６ -Cycloalkyl, or C ３ -C ６ -Cycloalkyl C １ -C ３ - It is alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. 【Request Item 29】 【Chemistry 28】 And; One R １ As shown in the above ring, R １ａ It may be; and R １ａ is hydrogen, halogen, C １ -C ６ - Alkyl, C ３ -C ６ -Cycloalkyl, or C ３ -C ６ -Cycloalkyl C １ -C ３ - It is alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. 【Request Item 30】 【Chemistry 29】 And here, R １ａ is hydrogen, halogen, C １ -C ６ - Alkyl, C ３ -C ６ -Cycloalkyl, or C ３ -C ６ -Cycloalkyl C １ -C ３ - It is alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

31. R １ａ The compound of claim 27, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is hydrogen.

32. R １ａ The compound of claim 27, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is a halogen.

33. R １ａ However, C １ -C ６ - The compound of claim 27, which is alkyl, or a pharmaceutically acceptable salt and / or isomer thereof.

34. R １ａ However, C ３ -C ６ - The compound of claim 27, which is cycloalkyl, or a pharmaceutically acceptable salt and / or isomer thereof.

35. R １ａ However, C ３ -C ６ -Cycloalkyl C １ -C ３ - The compound of claim 27, which is alkyl, or a pharmaceutically acceptable salt and / or isomer thereof.

36. One R １ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein a isomeric character exists and is not hydrogen.

37. Two R's １ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein each of the above is independently other than hydrogen.

38. The three R's １ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein each of the above is independently other than hydrogen.

39. at least one R １ However, C １ -C ６ It is alkyl, and optionally has at least one R １ However, -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

40. at least one R １ However, C １ -C ６ It is an alkoxy, and optionally contains at least one R １ However, -OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

41. at least one R １ However, C １ -C ６ It is a haloalkyl group, and optionally contains at least one R １ However, -CF ３ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

42. at least one R １ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is a halogen.

43. at least one R １ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is -Cl.

44. at least one R １ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is -F.

45. at least one R １ However, Hello C １ -C ６ It is an alkoxy, and optionally contains at least one R １ However, -OCF ３ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

46. Each R １ However, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, Halo-C １ -C ６ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, independently selected from alkoxys and halogens.

47. Each R １ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is hydrogen.

48. Two R's １ but, 【Transformation 30】 They are bonded to adjacent ring carbons in the ring, and together with the adjacent carbons to which they are bonded, 【Chemistry 31】 It forms, where * is 【Chemistry 32】 This shows the shared carbon in and any remaining R １ However, hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, Halo-C １ -C ６ Alkoxy, C ３ -C ６ -Cycloalkyl and C ３ -C ６ -Cycloalkyl C １ -C ３ - A compound according to claim 1, independently selected from alkyl groups, or a pharmaceutically acceptable salt and / or isomer thereof.

49. One R ２ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein a isomeric character exists and is not hydrogen.

50. Two R's ２ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein each of the above is independently other than hydrogen.

51. The three R's ２ A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein each of the above is independently other than hydrogen.

52. at least one R ２ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is a halogen.

53. at least one R ２ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is -F.

54. at least one R ２ However, C １ -C ６ A compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt and / or isomer thereof.

55. at least one R ２ However, -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof.

56. Two R's ２ However, they are bonded to adjacent carbon atoms, and together with the carbon atoms to which they are bonded, they form a 3- to 7-membered carbocyclic ring, and the ring is composed of halogens and C １ -C ６ It may be substituted with one, two, or three groups independently selected from alkyl; and the remaining R ２ However, in each case independently, hydrogen, halogen, or C １ -C ６ It is alkyl; or it has two R's ２ These are bonded to the same carbon, and together with the carbon to which they are bonded, they form a 3- to 7-membered carbocyclic ring, and the ring is composed of halogens and C １ -C ６ It may be substituted with one, two, or three groups independently selected from alkyl; and the remaining R ２ However, in each case independently, hydrogen, halogen, or C １ -C ６ A compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt and / or isomer thereof.

57. Each R ２ However, C １ -C ６ A compound according to claim 1, independently selected from alkyl and halogen, or a pharmaceutically acceptable salt and / or isomer thereof.

58. Each R ２ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein the compound is hydrogen.

59. A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein m is 1 or 2.

60. The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein m is 2.

61. W １ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein -N =

62. W １ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein -C(H)=.

63. W １ However, -C(C １ -C ６ A compound according to claim 1, wherein alkyl) =, or a pharmaceutically acceptable salt and / or isomer thereof.

64. W １ However, -C(C １ -C ６ The compound of claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, wherein alkoxy =

65. The following compounds: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 A compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, selected from the group consisting of the above.

66. A pharmaceutical composition comprising any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, and a pharmaceutically acceptable carrier.

67. The pharmaceutical composition according to claim 66, wherein the composition is an oral or injectable composition, and optionally the injectable composition is a subcutaneous injection composition.

68. In the subject, Na ν A pharmaceutical composition according to claim 66 for treating a condition associated with voltage-gated sodium channel function, comprising 1.

8.

69. The pharmaceutical composition of claim 68, wherein the subject is a human.

70. The pharmaceutical composition of claim 68, wherein the condition is pain, or the condition is associated with pain.

71. The pharmaceutical composition of claim 68, wherein the aforementioned condition is pain.

72. The pharmaceutical composition of claim 68, wherein the aforementioned condition is related to pain.

73. The aforementioned conditions include pain associated with erythromelalgia, pain associated with diabetic peripheral neuropathy, paroxysmal severe pain, complex regional pain syndrome, pain associated with trigeminal neuralgia, pain associated with multiple sclerosis, pain associated with arthritis (including osteoarthritis), pain associated with postherpetic neuralgia, cancer pain, pain associated with cluster headache, pain associated with migraine, pain associated with sciatica, pain associated with endometriosis, pain associated with fibromyalgia, postoperative pain, subacute pain, and chronic pain. The pharmaceutical composition of claim 68, selected from the group consisting of, pain and / or discomfort associated with dry eye syndrome, pain associated with (acute) corneal injury or abrasion, acute eye pain, chronic eye pain, pain associated with corneal infection, pain associated with Parkinson's disease, pain associated with ALS, pain associated with ophthalmic surgery, pain associated with epilepsy, pain associated with Parkinson's disease, mood disorders, psychosis, pain associated with amyotrophic lateral sclerosis, glaucoma, ischemia, spastic disorder, and obsessive-compulsive disorder.

74. The pharmaceutical composition of claim 68, wherein the aforementioned condition is selected from the group consisting of acute pain, subacute pain, postoperative pain, and eye pain.

75. A compound comprising any one of claims 1-65, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, ν 1.8 Inhibitor.

76. The following formula: 【Transformation 33】 A compound comprising any one of the following, or a salt thereof and / or an isomer thereof. [In the formula, R １ In each case, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, Halo-C １ -C ６ Alkoxy, C ３ -C ６ -Cycloalkyl and C ３ -C ６ -Cycloalkyl C １ -C ３ - Is it selected from alkyl groups? or Two R's １ teeth, 【Transformation 34】 They are bonded to adjacent ring carbons in the ring, and together with the adjacent carbons to which they are bonded, 【Chemistry 35】 It forms, where * is 【Transformation 36】 This shows the shared carbon in and any remaining R １ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, halogen, C １ -C ６ Haloalkyl, Halo-C １ -C ６ Alkoxy, C ３ -C ６ -Cycloalkyl and C ３ -C ６ -Cycloalkyl C １ -C ３ - Selected independently of alkyl; A is R ３ Replaced by and (R ３ａ ) ｑ C may be replaced with ６ -C １０ Ariel; R ３ Replaced by and (R ３ａ ) ｑ A 5- to 10-membered heteroaryl that may be substituted with (R ３ａ ) ｑ１ It may be replaced with 【Chemistry 37】 ; (R ３ａ ) ｑ１ It may be replaced with 【Transformation 38】 ; or (R ３ａ ) ｑ１ It may be replaced with 【Chemistry 39】 And; W １ -N=, -C(H)=, -C(halogen)=, -C(C １ -C ６ Alkyl) =, -C (cyclopropyl) =, or -C (C １ -C ６ Alkoxy) = and; W ２ and W ３ These are -C- and W ２ and W ３ The dashed bond between them is a double bond, and 【Chemistry 40】 is a partially unsaturated 5- to 8-membered carbocyclic ring, a benzo ring, a partially unsaturated 5- to 7-membered heterocyclic ring, or a 5- or 6-membered heteroaromatic ring; or W ２ and W ３ One of them is -C- and the other is -N-, W ２ and W ３ The dashed line connection between them is a simple connection, and 【Chemistry 41】 is a 5- or 6-membered heterocyclic ring which may contain an additional N, where the remaining ring atoms are C; R ２ In each case, independently, hydrogen, halogen, and C １ -C ６ Alkyl or halo-C １ -C ６ Is it alkyl? or Two R's ２ These atoms are bonded to adjacent carbon atoms, and together with the carbon atoms to which they are bonded, they form a 3- to 7-membered carbocyclic ring, the ring being composed of halogens and C １ -C ６ It may be substituted with one, two, or three groups independently selected from alkyl; and the remaining R ２ In each case, independently, hydrogen, halogen, or C １ -C ６ Is it alkyl; or Two R's ２ These are bonded to the same carbon, and together with the carbon to which they are bonded, they form a 3- to 7-membered carbocyclic ring, and the ring is composed of halogens and C １ -C ６ It may be substituted with one, two, or three groups independently selected from alkyl; and the remaining R ２ In each case, independently, hydrogen, halogen, or C １ -C ６ It is alkyl; R ３ This is hydrogen, -OH, -B(OH) ２ -COOH, hydroxyalkyl, -C(=NH)NH ２ , -C(O)NH ２ , -NH ２ ,-NHC(O)C １－３ Alkyl, -NHC(O)NH ２ , -NHS(O) ２ NH ２ , -NHC(=NH)NH ２ , -S(O) ２ NHR, -S(O) ２ C １ -C ６ -Alkyl, amino-C １ -C ６ Alkyl, Halo-C １ -C ３ Alkyl, C ３ -C ６ -Cycloalkyl, 3- to 6-membered heterocycloalkyl, or 【Chemistry 42】 Here, R is hydrogen, C １ -C ３ Alkyl, or C ３ -C ５ It is a cycloalkyl; where the C ３ -C ６ Cycloalkyls and 3- to 6-membered heterocycloalkyls have one -NH ２ It may also be substituted with; and the amino-C １ -C ６ The alkyl group in the alkyl group may be further substituted with 1, 2, 3, or 4 halos; R ３ａ In each case, independently, hydrogen, halogen, and C １ -C ３ Alkyl, or C ３ -C ６ It is cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, 5, or 6; q1 is 0, 1, or 2; and q is 0, 1, 2, or 3.

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