Bicyclic heterocyclic amide inhibitors of NaV1.8 for treatment of pain

Abstract

The present invention provides compounds of Formula (I) wherein the compounds are 1-206, pharmaceutical compositions comprising the compounds, methods of making the compounds, and methods of using the compounds and compositions for treating conditions associated with voltage gated sodium channel function. (Formula (I)) # imgabs0 #

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims and enjoys the benefits of Indian Patent Application No. 202311013223, filed on February 27, 2023, and Indian Patent Application No. 202211024240, filed on April 25, 2022, both of which are incorporated herein by reference in their entirety. Field of the Invention

[0002] This invention provides compounds, methods for preparing said compounds, pharmaceutical compositions comprising said compounds, and methods for using said compounds and compositions to treat voltage-gated sodium ion channel function (especially Na+). V 1.8) Methods for treating related conditions (e.g., pain and pain-related conditions). The present invention also provides a method for treating pain in a subject, comprising administering to the subject a therapeutically or preventively effective amount of a compound or composition. Background of the Invention

[0003] Voltage-gated sodium channels are large integrated 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 pain treatment. Encoding Na V The channel contains nine different mammalian isotypes of the gene (Na) V Isotypes 1.1-1.9 have been sequenced. Different Na+ types... V Variations in isoform gating properties, cellular distribution, and expression levels affect the physiology of neuronal conduction. Increasing evidence suggests that Na+ alone... V Homotype Na V 1.3, Na V 1.7, Na V 1.8 and Na V 1.9 disproportionately participates in pain signal transduction and nociception, and Na V Homotype-specific inhibitors can relieve pain without the corresponding nonspecific sodium. V Adverse effects of antagonists or opioids (Momin et al., Curr Opin Neurobiol. 18(4): 383-8, 2008; Rush et al., J. Physiol. 579(Pt 1): 1-14, 2007).

[0004] Na V1.8 It is selectively expressed in dorsal root ganglion (DRG) neurons, which are pseudounipolar neurons that project both centrally and peripherally and are involved in nociception. Due to Na... V 1.8 Because it possesses sensory neuron specificity, it is particularly important in the pathophysiology of pain. Therefore, a selective inhibitory neuron, Na+, is designed. V 1.8 instead of other Na V Drugs targeting pathways are preferable. Given that mammals have Na+... V The isotypes share a high degree of structural homology (75-96%), making drug design in this context challenging.

[0005] Many research groups have been searching for isotype-selective inhibitors, and some compounds have entered clinical development. Na V The isotype-selective small molecule inhibitors of 1.8 are 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 ChemLett. 6(6): 650-654, 2015; Jarvis et al., PNAS 104(20): 8520-8525, 2007.

[0006] Previously developed Na V 1.8 Efforts to develop isotype-selective inhibitors as human therapeutics have encountered numerous challenges. These challenges include off-target effects on human Na+. V 1.x Insufficient selectivity of homotypes and limited in vivo target binding (due to human Na+). V1.8 Insufficient potency, high protein or tissue binding rate, Na V 1.8 State-dependent inhibition, safety issues hindering dose escalation, or a combination of these factors), physicochemical properties (e.g., poor solubility that hinders oral administration), and compound-specific issues (e.g., toxicological findings or metabolite formation that may pose a safety risk to humans). Some compounds in Na V 1.8 It also exhibits species-specific differences in efficacy (see, for example, Bagal et al., Med Chem Comm. 7(10), 2016), making it difficult to assess its targeted pharmacodynamic effects in standard preclinical species (i.e., mice and rats).

[0007] There is a need for compounds used to treat pain and conditions related to the function of voltage-gated sodium ion channels, particularly those with other Na+ ions. V Compared to the same type, it selectively inhibits Na V Compound 1.8. Invention Abstract

[0008] This invention provides compounds, methods for preparing said compounds, pharmaceutical compositions comprising said compounds, and the use of said compounds and compositions to treat sodium ion channels (especially Na+) affected by voltage-gated sodium ion channels. V 1.8) Methods for regulating conditions, and methods for treating pain in some or any of the embodiments. The present invention also provides methods for treating pain and / or conditions regulated by voltage-gated sodium ion channels in a subject, comprising administering to the subject a therapeutically or preventively effective amount of a compound or composition. In some or any of the embodiments, the subject is a human being.

[0009] On the one hand, the present invention provides the compound shown in formula (I): in R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two R's 1 Connected to On the adjacent carbon atom in the middle ring, and together with the adjacent carbon atom to which it is attached, it forms Where * represents The shared carbon atom described in the text, and any other R 1Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; optionally replaced by (R 3a ) q1 Replacement Optional land cover (R) 3a ) q1 Replacement Or optionally by (R) 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, C1-C6 alkyl, or halo-C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups; and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring of 3 to 7 atoms, the ring optionally being substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups; and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halo-C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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 its pharmaceutically acceptable salts and / or its isomers; The condition is that the compound is not: 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-(methanesulfonyl)phenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)-6,7,8,9-tetrahydro-5H-cycloheptan[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; or 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0010] On the other hand, the present invention provides compounds of formula (I-P2): in R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two R's 1 Connected to It is formed on the adjacent carbon atom of the ring, and together with the adjacent carbon atom to which it is attached. Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally, a heteroaryl group consisting of (R... 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen=, -C(C1-C6 alkyl=, or -C(cyclopropyl=); W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halogenated C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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 its pharmaceutically acceptable salts and / or its isomers.

[0011] On the other hand, the present invention provides compounds represented by formula (I-P1): in R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two R's 1 Connected to On the adjacent carbon atom in the middle ring, and together with the adjacent carbon atom to which it is attached, it forms Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally replaced by (R 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen=, -C(C1-C6 alkyl=, or -C(cyclopropyl=); W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -C(O)NH2, -NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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 Its pharmaceutically acceptable salts and / or its isomers.

[0012] On the other hand, the present invention provides compounds represented by any of the following general formulas: in, R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two of the R 1 Connected to On the adjacent carbon atom in the middle ring, and together with the adjacent carbon atom to which it is attached, it forms Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; optionally replaced by (R 3a ) q1 Replacement Optional land cover (R) 3a ) q1 Replacement Or optionally by (R) 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, C1-C6 alkyl, or halo-C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups; and the remaining R 2In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring of 3 to 7 atoms, the ring optionally being substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups; and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halo-C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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 can be 0, 1, 2, or 3.

[0013] On the other hand, the present invention provides compounds represented by any of the following general formulas: or its salt, in, R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two of the R 1 Connected to It is formed on the adjacent carbon atom of the ring, and together with the adjacent carbon atom to which it is attached. Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally replaced by (R 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen=, -C(C1-C6 alkyl=, or -C(cyclopropyl=); W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 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 can be 0, 1, 2, or 3.

[0014] The additional implementation scheme is as follows, where R 1 As provided in implementation scheme 1-1c or 17-17a; A as provided in implementation scheme 2-2k; W 1 As provided in implementation scheme 3, 3a or 3b; W 2 and W 3 All as provided in implementation schemes 4, 4a, 5, 5a or 6; R 2 In each case, independently as provided in implementation scheme 7-7c; R 3 As provided in implementation scheme 8-8c; R 3a As provided in implementation scheme 9 or 9a; m, n, p, q and q1 as provided in implementation schemes 10, 11, 12, 13 and 14 respectively; and As provided in implementation schemes 15, 15a, 15b, 15c, 15d, 15e, 16, 16a, 16b and 16c; and any combination thereof.

[0015] On the other hand, the present invention provides a method for preparing the compounds disclosed herein according to any of the following schemes: in, R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two of the R 1 Connected to On the adjacent carbon atom in the middle ring, and together with the adjacent carbon atom to which it is attached, it forms Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally, a heteroaryl group consisting of (R... 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring of 3 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 3 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halo-C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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; To obtain the compounds disclosed in this invention, or pharmaceutically acceptable salts thereof and / or isomers thereof; and optionally to isolate the compounds disclosed in this invention.

[0016] On the other hand, the present invention provides a method for preparing the compounds disclosed herein according to any of the following schemes: in, R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two of the R 1 Connected to It is formed on the adjacent carbon atom of the ring, and together with the adjacent carbon atom to which it is attached. Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) qReplacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally replaced by (R 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen=, -C(C1-C6 alkyl=, or -C(cyclopropyl=); W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, 4, 5, or 6; To obtain the compounds disclosed in this invention; and optionally to isolate the compounds disclosed in this invention.

[0017] The additional implementation scheme is as follows, where R 1As provided in implementation scheme 1-1c or 17-17a; A as provided in implementation scheme 2-2k; W 1 As provided in implementation scheme 3, 3a or 3b; W 2 and W 3 All as provided in implementation schemes 4, 4a, 5, 5a or 6; R 2 In each case, independently as provided in implementation scheme 7-7c; R 3 As provided in implementation scheme 8-8c; R 3a As provided in implementation scheme 9 or 9a; m, n, p, q and q1 as provided in implementation schemes 10, 11, 12, 13 and 14 respectively; and As provided in implementation schemes 15, 15a, 15b, 15c, 15d, 15e, 16, 16a, 16b and 16c; and any combination thereof.

[0018] On the other hand, the present invention provides pharmaceutical compositions, single-unit dosage forms, and kits suitable for treating pain and / or conditions regulated by voltage-gated sodium ion channels, comprising therapeutically or preventively effective amounts of compounds provided by the present invention, such as those of formulas (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or any of the embodiments thereof.

[0019] On the other hand, the present invention provides pharmaceutical compositions, single-unit dosage forms and kits suitable for treating pain and / or conditions regulated by voltage-gated sodium ion channels, comprising therapeutically or preventively effective amounts of compounds provided by the present invention, such as those of formula (I), (I-P2) and some or any embodiments of compounds 1-127 and 169-206.

[0020] On the other hand, the present invention provides pharmaceutical compositions, single-unit dosage forms and kits suitable for treating pain and / or conditions regulated by voltage-gated sodium ion channels, comprising therapeutically or preventively effective amounts of compounds provided by the present invention, such as compounds of formula (I) and some or any embodiments of compounds 1-206.

[0021] On the one hand, this invention provides a treatment subject with voltage-gated sodium ion channel function (including Na+). ν 1.8) A method for treating or preventing a disease, comprising administering to an individual in need a therapeutic or preventative amount of a compound provided by the present invention, such as compounds of formula (I), (I-P1), (I-P2), and some or any embodiment of compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206.

[0022] On the one hand, this invention provides a treatment subject with voltage-gated sodium ion channel function (including Na+). ν 1.8) A method for treating or preventing a disease, comprising administering to an individual in need a therapeutic or preventative amount of a compound provided by the present invention, such as compounds of formula (I), (I-P2), and some or any embodiment of compounds 1-127 and 169-206.

[0023] On the one hand, this invention provides a treatment subject with voltage-gated sodium ion channel function (including Na+). ν 1.8) A method for treating or preventing a disease, comprising administering to an individual in need a therapeutic or preventative amount of a compound provided by the present invention, such as a compound of formula (I) and any embodiment of compounds 1-206.

[0024] On the other hand, the present invention provides therapeutic or preventative amounts of compounds provided by the present invention (e.g., compounds of formulas (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or any embodiment thereof), or therapeutic or preventative amounts of pharmaceutical compositions thereof, for treating subjects in need of voltage-gated sodium ion channel function (including Na+). ν 1.8) Related symptoms.

[0025] On the other hand, the present invention provides therapeutic or preventative amounts of compounds provided by the present invention (e.g., compounds of formula (I), (I-P2), and some or any embodiments of compounds 1-127 and 169-206), or therapeutic or preventative amounts of pharmaceutical compositions for treating subjects in need of voltage-gated sodium ion channel function (including Na+). ν 1.8) Related symptoms.

[0026] On the other hand, the present invention provides therapeutic or preventative amounts of compounds provided by the present invention (e.g., compounds of formula (I) and some or any embodiments of compounds 1-206), or therapeutic or preventative amounts of pharmaceutical compositions for treating subjects in need of voltage-gated sodium ion channel function (including Na+). ν 1.8) Related symptoms. Brief description of the attached figures

[0027] Figure 1 depicts the voltage scheme of the new test procedure (Scheme A).

[0028] Figure 2 depicts the voltage scheme of the new test procedure (Scheme B). Invention Details

[0029] This invention provides compounds, methods for preparing said compounds, pharmaceutical compositions comprising said compounds, and the use of said compounds and compositions to treat pain and / or voltage-gated sodium ion channels (especially Na+). V 1.8) Methods for regulating symptoms. The present invention also provides a method for treating pain in a subject, comprising administering to the subject a therapeutically or preventively effective amount of a compound or composition. In an embodiment, the subject is a human being. definition

[0030] When referring to the compounds provided by this invention, unless otherwise stated, the following terms have the following meanings. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. If a term in this invention has multiple definitions, the definition in this section shall prevail unless otherwise stated. Unless otherwise indicated, when a term is defined as substituted, the group in the list of substituents is itself unsubstituted. For example, unless otherwise stated, a substituted alkyl group may be substituted, for example, a cycloalkyl group, and said cycloalkyl group is not further substituted.

[0031] References to “about / approximately” values ​​or parameters in this invention include (and describe) variations for the value or parameter itself. For example, a description of “about / approximately X” includes a description of “X”. Unless otherwise stated, the terms “about / approximately” and “approximately” as used in this invention, when used in conjunction with the temperature, dosage, amount, or weight percentage of an ingredient in a composition or dosage form, refer to a dosage, amount, or weight percentage recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from a specified dosage, amount, or weight percentage. Specifically, when used in this invention, the terms “about / approximately” and “approximately” mean a dosage, amount, or weight percentage within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dosage, amount, or weight percentage.

[0032] Unless the context clearly indicates otherwise, the term "a / type" as used in this invention means one / type or more / types.

[0033] The term "alkyl" as used in this invention, unless otherwise specified, refers to a saturated straight-chain or branched hydrocarbon. In some or any embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In some or any embodiments, the alkyl group comprises 1-10 carbon atoms, i.e., C1-C2. 10 Alkyl group. In some or any embodiment, the alkyl group is C10. 1-6Alkyl group. In some or any embodiment, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0034] The term "hydroxyalkyl" or "hydroxyalkyl" as used in this invention, unless otherwise specified, refers to an alkyl group as defined in this invention that contains an alcohol (hydroxyl group). In one or more embodiments, the alcohol group is a primary, secondary, or tertiary alcohol. In one or more embodiments, the hydroxyalkyl group comprises 1 to 10 carbon atoms, i.e., C1-C1. 10 Hydroxyalkyl group. In one or more embodiments, the hydroxyalkyl group comprises one or two alcohol (hydroxy) groups, provided that they are not located on the same carbon atom. In one or more embodiments, the hydroxyalkyl group is a hydroxyl C. 1-3 Alkyl group. 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 C10. 1-6 Hydroxyalkyl. In one or more embodiments, the hydroxyalkyl group is selected from the group consisting of: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropane-2-yl, and 2-hydroxypropane-2-yl.

[0035] The terms "alkoxy" and "alkyloxy" as used in this invention, unless otherwise specified, refer to the group –OR′, where R′ is an alkyl group. In some or any embodiments, the alkoxy and alkyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, etc. In some embodiments, the alkoxy group is C 1-6 Alkoxy.

[0036] The term "amino" refers to –NH2.

[0037] The term "aryl" as used in this invention, unless otherwise stated, refers to a monovalent C6-C group containing at least one aromatic ring. 15A carbocyclic system, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic. The aryl group can be attached to the main structure via any of its rings, i.e., any aromatic or non-aromatic ring. In some or any embodiment, the aryl group can be a bridged (where chemically feasible) or non-bridged, spirocyclic (where chemically feasible) or non-spirocyclic, and / or fused or non-fused polycyclic group. In some or any embodiment, the aryl group is phenyl, naphthyl, indanyl, fluorenyl, 6,7,8,9-tetrahydro-5H-benzo[7]arunenyl, or tetrahydronaphthyl. When the aryl group is substituted, it can be substituted on any ring, i.e., on any aromatic or non-aromatic ring contained by the aryl group.

[0038] The term "C3-C" used in this invention 10 "Cycloalkyl" refers to a monovalent, saturated monocyclic hydrocarbon or a bicyclic (fused, bridged, or spirocyclic) ring. In some or any embodiments, the terms "fused cycloalkyl" and "spirocycloalkyl" refer to embodiments of the cycloalkyl group. In some or any embodiments, the cycloalkyl group comprises 3 to 6 carbon atoms, i.e., C3-C6 cycloalkyl. In some or any embodiments, the cycloalkyl group has 3, 4, or 5 carbon atoms (C3-C6). 3-5 ); 3 or 4 (C) 3-4 ); 3 (C3); 4 (C4); or 5 (C5) carbon atoms. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In some or any embodiments, the cycloalkyl group is cyclopropyl. In some or any embodiments, the cycloalkyl group is cyclobutyl. In some or any embodiments, the cycloalkyl group is cyclopentyl. In some or any 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 group as defined in this invention, which is substituted with one or more cycloalkyl groups as defined in this invention (the cycloalkyl group is independently selected). In some embodiments, "cycloalkylalkyl" is a C14-C ... 3-8 cycloalkyl C 1-6 Alkyl. In some embodiments, "cycloalkylalkyl" is an alkyl group substituted with a cycloalkyl group. In some embodiments, the cycloalkylalkyl group is cyclopropylmethyl.

[0040] The term "haloalkyl" as used in this invention, unless otherwise stated, refers to an alkyl group substituted with 1, 2, 3, 4, or 5 halogen groups. In some or any embodiment, the haloalkyl group is a halogenated C-hydroxyl group. 1-6Alkyl group. In some or any embodiment, the haloalkyl group is -CF3, -CH2F, -CHF2 or -CH2CF3.

[0041] As used in this invention, the term "haloalkoxy" refers to the -OR group unless otherwise specified, where R is a halogenated C. 1-10 Alkyl group, as defined in this invention. In some or any embodiment, the haloalkoxy group is a halogenated C. 1-6 Alkoxy.

[0042] The terms “halogen” and “halogen group” used in this invention are synonyms and refer to chlorine, bromine, fluorine or iodine unless otherwise stated.

[0043] The term "heteroaryl" as used in this invention, unless otherwise stated, refers to a monocyclic or polycyclic aromatic ring system, wherein one or more of the ring atoms (in some or any embodiment, 1, 2, 3 or 4) are independently selected from O, S(O). 0-2 The heteroaryl group is a heteroatom of NH and N, wherein the remaining ring atoms are all carbon atoms, and wherein the rings may optionally be substituted as described in this invention. The heteroaryl group is attached to the remainder of the molecule by any atom in the ring system, where the valence rules permit. In some or any embodiment, 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 combinations 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 embodiment, the heteroaryl group has 5-20, 5-15, 5-6 ring atoms, or 5-10 ring atoms. When the heteroaryl group is substituted, it may be substituted on any ring. In one or more embodiments, the heteroaryl group is... in This indicates the connection point where the heteroaryl group is attached to the rest of the molecule. In some embodiments, the heteroaryl group is... in This indicates the connection point where the heteroaryl group is attached to the rest of the molecule.

[0044] In some or any of the embodiments, the monocyclic heteroaryl group includes, but is not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroleyl, thiadiazolyl, thiazolyl, thiophenyl, tetrazolyl, triazinyl, and triazolyl. In some or any of the embodiments, the bicyclic heteroaryl group includes, but is not limited to, benzofuranyl, benzoimidazolyl, benzooxazolyl, benzoisooxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiophene, benzotriazolyl, furanopyridyl, imidazopyridyl, imidazothiazolyl, indazinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiaphene, isoindolyl, isoquinolinyl, isothiazolyl, naphridyl, oxazolopyridyl, phthalazinyl, pteridinyl, purine, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, or quinazolinyl. In some or any embodiments, the tricyclic heteroaryl group includes, but is not limited to, acridinel, benzoindolyl, carbazolel, dibenzofuranyl, quinidinel, phenanthrolinel, phenanthidinel, and phenazinyl. In some or any embodiments, the heteroaryl group is indolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl, or pyrazolyl; each optionally substituted by one, two, three, or four groups defined throughout this specification, and in some embodiments, including groups independently selected from C... 1-6 Alkyl, hydroxyl, halogen, halogenated C 1-6 Alkyl, C 1-6 Substitution with alkoxy, cyano, or phenyl groups.

[0045] The term "heterocyclic group" or "heterocycle" as used in this invention, unless otherwise stated, refers to a monovalent monocyclic non-aromatic system or a monovalent polycyclic system comprising at least one non-aromatic ring; wherein one or more of the monocyclic non-aromatic ring atoms (in some or any embodiment, 1, 2, 3 or 4) are independently selected from O, S(O). 0-2 The heteroatoms of N and the remaining ring atoms are all carbon atoms; and one or more atoms on any ring of the polycyclic system (in some or any embodiment, 1, 2, 3 or 4) are independently selected from O, S(O). 0-2The heteroatom of N and the remaining ring atoms are all carbon atoms. The terms "heterocyclic group" or "heterocycle" do not contain a fully aromatic ring, i.e., they do not contain imidazole, pyrimidine, pyridine, etc. In some or any embodiments, the heterocycle contains one or two heteroatoms, which are independently selected from nitrogen and oxygen atoms. In some or any embodiments, the heterocycle contains one or two heteroatoms, both of which are oxygen atoms. In some or any embodiments, the heterocycle contains one or two heteroatoms, both of which are nitrogen atoms (wherein the nitrogen atom is substituted as described in any aspect or embodiment of the invention). In some or any embodiments, the heterocyclic group or 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 an aromatic ring and the other in a non-aromatic ring. In some or any embodiment, the heterocyclic group or heterocyclic group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some or any embodiment, the heterocyclic group or heterocycle is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some or any embodiment, the heterocyclic group or 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 may optionally be oxidized, one or more of the nitrogen atoms may optionally be quaternized, and one or more carbon atoms may optionally be... Replacement. Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic. The monocyclic and polycyclic heterocycles may be attached to the host structure at any heteroatom or carbon atom that produces a stable compound. The polycyclic heterocyclic group or heterocycle may be attached to the host structure via any of its rings, including any aromatic or non-aromatic rings, regardless of whether the ring contains a heteroatom. In some or any embodiment, the heterocyclic group or heterocycle is a "heterocyclic alkyl group", which is 1) a saturated monovalent monocyclic group containing at least one ring heteroatom as described in this invention, or 2) a saturated monovalent bicyclic or tricyclic group, wherein at least one ring contains at least one heteroatom as described in this invention. When the heterocyclic group or heterocyclic and heterocyclic alkyl group is substituted, it may be substituted on any ring, i.e., on any aromatic or non-aromatic ring contained in the heterocyclic group or heterocyclic and heterocyclic alkyl group.In some or any embodiment, such heterocyclic groups or heterocycles include, but are not limited to, aheptagenyl, benzodioxane-hexyl, benzodioxane-pentenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxane-heptenyl, 1,3-dihydroisobenzofuranyl, benzofuranoneyl, benzopyranoneyl, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothiophenyl, 2,2-dioxo-1,3-dihydrobenzo[c]thiophenyl, benzothiophenyl Brønsted, benzoxazinyl, β-carbolinyl, benzodihydropyranyl, cronoyl, cenolinyl, coumarinyl, decahydroquinolinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisothiazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrroleyl, dioxacyclopentyl, 1,4-dithiaranyl, furanoneyl, imidazoalkyl, 2,4-dioxo-imidazoalkyl, imidazolinyl, indololinyl, 2-oxo-indololinyl, isobenzene Tetrahydrofuranyl, isobenzotetrahydrothiophenyl, isobenzodihydropyranyl, isocoumarinyl, isodihydroindolyl (isoindolinyl), 1-oxo-isodihydroindolyl, 1,3-dioxo-isodihydroindolyl, isothiazolyl, isoxazolyl, 3-oxo-isooxazolyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxazolidinone, oxazolyl, ethylene oxide, piperazine, 2,6-dioxo Piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidinoneyl, pyrazolyl, pyrazolinyl, pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiomorpholinyl, thiomorpholinyl, 3,5-dioxo-thiomorpholinyl, thiazolyl, 2,4-dioxo-thiazolyl, tetrahydroquinolinyl, phenothiazinyl, phenotoxazinyl, xanthaneyl, and 1,3,5-trithiacyclohexyl. In some or any embodiments, the heterocyclic group or heterocycle is benzo-1,4-dioxane-hexyl, benzodioxane-pentenyl, indololinyl, 2-oxo-indololinyl, pyrrolyl, piperidinyl, 2,3-dihydrobenzofuranyl, or decahydroquinolinyl; each optionally substituted with one, two, three, or four groups as defined throughout this specification, including, in some or any embodiments, substitution with groups independently selected from halogens, alkyl groups, and phenyl groups. In some embodiments, the heterocyclic alkyl group is pyrrolyl. In some embodiments, the heterocyclic alkyl group is an N-linked heterocyclic alkyl group.

[0046] The term "oxo" as used in this invention, unless otherwise specified, refers to a ketone group (C=O). An oxo group, as a substituent for a non-aromatic carbon, converts -CH₂- to -C=O. An oxo group, as a substituent for an aromatic carbon, converts -CH- to -C=O. When the substituent is oxo, the two hydrogen atoms on the atom are substituted. When an oxo group substitutes for an aromatic molecule portion, the corresponding partially unsaturated ring replaces the aromatic ring. For example, the pyridyl group substituted by the oxo group is a pyridinone or a pyrimidinone. Those skilled in the art will understand that in some embodiments, such groups, for example, pyridinones, 2,4(1H,3H)-dioxo-pyrimidinyl, 3(2H)-oxo-pyridazinyl, and 3-oxo-1,2-dihydro-3H-indazoleyl, may exist in their tautomeric forms, for example, hydroxypyridine, 2,4-dihydroxypyrimidinyl, hydroxy-pyridazinyl, and 3-hydroxy-1H-indazoleyl, respectively.

[0047] As used in this invention, the term "protecting group" means, unless otherwise stated, a group added to an oxygen, nitrogen, or phosphorus atom to prevent further reaction or for other purposes. A wide variety of oxygen-protecting 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 are incorporated herein by reference).

[0048] The term "pharmaceutically acceptable salt" as used in this invention, unless otherwise stated, refers to any salt of the compounds provided by this invention that retains its biological properties and is non-toxic or otherwise desired for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions known in the art. Such salts include, but are not limited to: (1) salts reacting with 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-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid (a) Acid addition salts formed by acids such as hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, and mucoconic acid; and (2) when an acidic proton is present in the parent compound, then (a) a base addition salt is formed by substitution with a metal ion such as an alkali metal ion, an alkaline earth metal ion or an 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, or ammonia hydroxide, or (b) a base addition salt is formed by coordination with an organic base, such as an aliphatic, alicyclic or aromatic organic amine such as ammonia, methylamine, dimethylamine, diethylamine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, N-methylglucosamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc.

[0049] In some or any of the embodiments, pharmaceutically acceptable salts further include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, 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 hydrobromates), sulfates, phosphates, aminosulfonates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbic acid salts, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoates, picrates, cinnamates, mandelates, phthalates. Laurate, methanesulfonate, ethanesulfonate, 1,2-ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, gluconate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthylcarboxylate, salicylate, stearate, cyclohexylaminosulfonate, quinic acid salt, mucoconate, etc.

[0050] With respect to the composition, the terms "substantially free of" or "substantially absent" stereoisomers mean that the composition contains at least 85% or 90% by weight, and in some or any embodiments, 95% by weight, 98% by weight, 99% by weight, or 100% by weight of a specified stereoisomer of the compound in the composition. In some or any embodiments, in the methods and compounds provided by the present invention, the compound is substantially free of stereoisomers.

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

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

[0053] The term "isotope enrichment" as used in this invention, unless otherwise stated, refers to the percentage of a specific isotope that replaces the natural isotopic abundance of a given atom in a molecule. 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 specified position. Since the natural 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 by this invention can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0054] The term "isotopically enriched" as used in this invention, unless otherwise stated, refers to an atom having an isotopic composition other than the natural isotopic composition of the 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 the atom.

[0055] The term "local anesthetic" as used in this invention refers to a drug that provides local numbness or pain relief. In some or any of the embodiments, the local anesthetic includes aminoaniline compounds (in some or any of the embodiments, lidocaine, prilocaine, bupivacaine, ropivacaine, and mepivacaine) and related classes of local anesthetic compounds having various substituents on the ring system or amine nitrogen; aminoalkylbenzoate compounds (in some or any of the embodiments, procaine, chloroprocaine, propyloxycaine, hexacaine, tetracaine, cyclomicaine, benzoxime ester, butacaine, and prilocaine) and related classes of local anesthetic compounds; cocaine; aminocarbonate compounds (in some or any of the embodiments, depiperone); N-phenylamidine compounds (in some or any of the embodiments, phenacaine); N-aminoalkylamide compounds (in some or any of the embodiments, dibutylcaine); aminoketone compounds (in some or any of the embodiments, falicaine and dapoxetine); and amino ether compounds (in some or any of the embodiments, promocaine and dimethisoquien).

[0056] The “alkyl”, “hydroxyalkyl”, “carbocyclic” / “carbocyclic”, “cycloalkyl”, “aryl”, “alkoxy”, “heterocyclic”, and “heterocyclic” / “heterocyclic” groups used in this invention optionally contain deuterium at one or more positions where hydrogen atoms are present, and the deuterium composition of said one or more atoms is not a natural isotopic composition.

[0057] Similarly, the “alkyl,” “hydroxyalkyl,” “carbocyclic,” “carbocyclic,” “cycloalkyl,” “aryl,” “alkoxy,” “heterocyclic,” and “heterocyclic” groups used in this invention optionally contain C-13 in amounts other than those of the natural isotopic composition.

[0058] Unless otherwise stated, the term "IC" as used in this invention is used in general. 50 "" refers to the amount, concentration, or dose of a specific test compound that achieves 50% inhibition of the maximum response in a test that measures this response.

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

[0060] As used in this invention, the terms "therapeutic agent" and "therapeutic medicine / pharmaceutical" refer to any medicine / pharmaceutical that can be used to treat or prevent a disease / condition or one or more symptoms thereof. In some or any embodiments, the term "therapeutic agent" includes compounds provided by this invention. In some or any embodiments, a therapeutic agent is a medicine / pharmaceutical that is known to be used, has been used, or is currently used to treat or prevent a disease / condition or one or more symptoms thereof.

[0061] "Therapeutic effective amount" refers to the amount of a compound or composition sufficient to treat a condition when administered to a subject. The "therapeutic effective amount" can vary depending on, in particular, the compound, the condition and its severity, and the age, weight, etc., of the subject to be treated.

[0062] In some or any embodiment, “treatment” or “management” for any symptom or disease means improving (including preventively improving) the symptom or disease present in the subject. In another embodiment, “treatment” or “management” includes improving at least one physical parameter, which may be imperceptible to the subject. In yet another embodiment, “treatment” or “management” includes modulating the symptom or disease physically (e.g., stabilizing identifiable symptoms) or physiologically (e.g., stabilizing body parameters) or both. In yet another embodiment, “treatment” or “management” includes delaying the onset of the symptom or disease. In yet another embodiment, “treatment” or “management” includes reducing or eliminating the symptom (e.g., pain) or one or more symptoms of the symptom (e.g., sciatica) (e.g., pain), or delaying the progression of the symptom (e.g., pain) or one or more symptoms of the symptom (e.g., sciatica) (e.g., pain), or reducing the severity of the symptom (e.g., pain) or one or more symptoms of the symptom (e.g., pain) (e.g., sciatica). In yet another embodiment, “treatment” or “management” includes the preventive application of the compounds described in this invention.

[0063] As used in this invention, the terms "preventive agent" and "preventive medicine / pharmaceutical" refer to any medicine / pharmaceutical that can be used to prevent a disease / symptom or one or more symptoms thereof, and / or prevent or stop the onset, development, progression, and / or severity of a disease / symptom. In some or any of the embodiments, the term "preventive agent" includes compounds provided by this invention. In some or any other embodiments, the term "preventive agent" does not refer to compounds provided by this invention. In some or any of the embodiments, the medicine or pharmaceutical is administered prophylactically, for example, before surgery, to prevent or stop the onset, duration, progression, and / or severity of pain (e.g., postoperative pain).

[0064] The phrase "preventive effective amount" as used in this invention refers to an amount of treatment / therapy (e.g., a preventive agent) sufficient to prevent or reduce the development, recurrence, or onset of one or more symptoms associated with the disease / condition, or an amount sufficient to enhance or improve the preventive effect of another treatment / therapy (e.g., another preventive agent). compound

[0065] This invention provides compounds that modulate the activity of voltage-gated ion channels (e.g., voltage-gated sodium ion channels). These compounds, as described in this invention, can be formed and used to treat conditions associated with the function of voltage-gated sodium ion channels. In some or any embodiments, the condition associated with the function of voltage-gated sodium ion channels is pain or a pain-related condition. In some or any embodiments, the condition associated with the function of voltage-gated sodium ion channels is a pain-related condition. In some or any embodiments, the condition associated with the function of voltage-gated sodium ion channels is pain, itching, cough, epilepsy, Parkinson's disease, mood disorders, psychosis, amyotrophic lateral sclerosis, glaucoma, ischemia, spasticity, and obsessive-compulsive disorder. In some or any embodiments, the condition associated with the function of voltage-gated sodium ion channels is pain (in some embodiments, subacute or chronic pain). In some embodiments, the pain associated with voltage-gated sodium ion channel function includes 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, and pain associated with surgery (in some embodiments, ophthalmic surgery).

[0066] The aspects and embodiments described in this invention include the listed compounds and their pharmaceutically acceptable salts and / or isomers thereof.

[0067] Where chemically possible, this invention includes all stereoisomers of the compound, including diastereomers and enantiomers. This invention also includes mixtures of possible stereoisomers in any proportion, including but not limited to racemic mixtures. Unless the stereochemistry is explicitly indicated at a specific atom of the structure, the structure is intended to cover all possible stereoisomers of the described compound. If the stereochemistry is explicitly indicated for one or more parts of the molecule, but not for another part or more parts of the molecule, the structure is intended to cover all possible stereoisomers of the one or more parts for which the stereochemistry is not explicitly indicated.

[0068] Clearly, certain structures exhibit specific stereochemistry at specific atoms.

[0069] Some of the polycyclic structures provided by this invention are plotted with one or more floating substituents. Unless otherwise provided or clearly understood from the context, substituents may be present on any atom of the polycyclic ring, where chemically feasible and permitted by the rules of valence.

[0070] In some or any embodiment, the present invention provides compounds of formula (I), (I-P2), or pharmaceutically acceptable salts thereof and / or isomers thereof, wherein, A is R 3Replaced and optionally by (R) 3a ) q Substituted phenyl, by R 3 The substituted pyridyl group is R 3 The substituted thiophene group, by R 3 The substituted furanyl group, by R 3 The substituted pyrazol group is replaced by R 3 The substituted indazole group is R 3 The substituted benzisothiazolyl group was R 3 Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R 3 Substituted pyrazol group, or W 1 It is -N= or -C(H)=; Each R 1 Each of the following can be independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, or halogen; Each R 2 Each can be independently H, C1-C6 alkyl, or halogen; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyl group -C 1-3 Alkyl groups, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH2, -S(O)2NH2, -S(O)2CH3, amino-C1-C3 alkyl, halo-C1-C3 alkyl, cyclopropyl, heterocyclic alkyl composed of 4 atoms, or The cyclopropyl group and the heterocyclic alkyl group consisting of the four atoms are optionally substituted with a -NH2 group; and the alkyl group in the amino-C1-C6 alkyl group is optionally further substituted with one, two, three, or four halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; m is 1 or 2; n is 0, 1, 2, or 4; p is 0, 1, 2, or 3; and q can be 0, 1, 2, or 3.

[0071] In some or any embodiment, the present invention provides compounds of formula (I), (I-P2), or pharmaceutically acceptable salts thereof and / or isomers thereof, wherein, A is R 3 Substituted phenyl, by R 3 The substituted pyridyl group is R3 The substituted thiophene group, by R 3 The substituted furanyl group, by R 3 The substituted pyrazol group is replaced by R 3 The substituted indazole group is R 3 The substituted benzisothiazolyl group was R 3 Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R 3 Substituted pyrazol group, or W 1 It is -N= or -C(H)=; Each R 1 Each of the following can be independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, or halogen; Each R 2 Each can be independently H, C1-C6 alkyl, or halogen; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halogenated C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; m is 1 or 2; n is 0, 1, 2, or 4; and p is 0, 1, 2, or 3.

[0072] In some or any embodiment, the present invention provides compounds of formula (I), (I-P1), (I-P2), or pharmaceutically acceptable salts thereof and / or isomers thereof, wherein, A is R 3 Substituted phenyl, by R 3 The substituted pyridyl group is R 3 Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R 3 Substituted pyrazol group, or W 1 It is -N= or -C(H)=; yes Each R 1 Each of the following can be independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, or halogen; Each R 2 Each can be independently H, C1-C6 alkyl, or halogen; R 3 It is -C(O)NH2, -NH2, -S(O)2NH2, -S(O)2CH3, or m is 1 or 2; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0073] Implementation Scheme 1: In some or any of these embodiments, the present invention provides compounds of formulas (I), (I-P1), and (I-P2), wherein R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, halogen, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl. In some or any of the embodiments, R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, and halogen. In some or any of the embodiments, each R 1 H is represented by each of the following. In some or any implementations, each R... 1 They are C1-C6 alkyl groups, respectively. In some or any embodiment, each R... 1 They are C1-C6 alkoxy groups, respectively. In some or any embodiment, each R... 1 They are C1-C6 haloalkyl groups, respectively. In some or any of the embodiments, each R... 1 Each is a halogen. In some or any embodiment, each R... 1 They are C3-C6-cycloalkyl groups, respectively. In some or any embodiment, each R... 1 They are C3-C6-cycloalkyl or C1-C3-alkyl, respectively.

[0074] Implementation scheme 1a: In some or any of the implementation schemes, there exists an R 1 , and R 1 Not H. In some or any implementation, there exist two Rs. 1 , and each R 1Each is independently not H. In some or any implementation, there are three Rs. 1 , and each R 1 Each is independently not H. In some or any of the embodiments, at least one R 1 It is a C1-C6 alkyl group. In some or any embodiments, at least one R 1 Yes -CH3. In some or any implementation, at least one R 1 It is a C1-C6 alkoxy group. In some or any embodiments, at least one R 1 Yes -OCH3. In some or any implementation, at least one R 1 It is a C1-C6 haloalkyl group. In some or any of the embodiments, at least one R 1 Yes -CF3. In some or any implementation, at least one R 1 It is a halogenated C1-C6 alkoxy group. In some or any embodiments, at least one R 1 Yes -OCF3. In some or any implementation, at least one R 1 It is a halogen. In some or any embodiment, at least one R 1 Yes -Cl. In some or any implementation, at least one R 1 Yes -F. In some or any implementation, R 1 It is a C3-C6-cycloalkyl group. In some or any of the embodiments, R 1 It is a C3-C6-cycloalkyl C1-C3-alkyl.

[0075] Implementation Scheme 1b: In some or any of the implementation schemes, each R 1 Each R is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and halogen. In some or any of the embodiments, each R 1 They are H respectively.

[0076] Implementation scheme 1c: In some or any of the implementation schemes, the two Rs 1 Connected to On the adjacent carbon atom in the middle ring, and together with the adjacent carbon atom to which it is attached, it forms Where * represents The shared carbon atom described in the text, and any other R 1 Each of the two Rs is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl. In some or any of the embodiments, the two Rs 1 Connected to On the adjacent carbon atom in the middle ring, and together with the adjacent carbon atom to which it is attached, it forms Where * represents The shared carbon atom mentioned in the text, and the remaining R 1 At least one of them is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl. In some or any of the embodiments, Not for

[0077] Implementation Scheme 2: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-1c, A is R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally, a heteroaryl group consisting of (R... 3a ) q1 Replacement In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is R 3 Substituted phenyl, by R 3 The substituted pyridyl group is R 3 Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R 3 Substituted pyrazol group, or

[0078] Implementation scheme 2a: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-1c, A is R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is R 3 Replacement C6-C 10 Aryl. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is R 3 A substituted phenyl group. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is... in Indicates connection to R 3In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments, including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 .

[0079] Implementation scheme 2b: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-1c, A is R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is a heteroaryl group composed of R. 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 9 to 10 substituted atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is a heteroaryl group composed of R. 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of nine substituted atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments, including embodiments 1-1c, A is in Indicates connection to R 3In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 10 substituted atoms.

[0080] Implementation Scheme 2c: In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is a heteroaryl group consisting of 5 to 6 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is a heteroaryl group consisting of 5 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is a heteroaryl group consisting of 6 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is selected from the group consisting of: in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is selected from the group consisting of: in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiment 1-1c, A is... in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 .

[0081] Implementation scheme 2d: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-1c, A is optionally (R 3a ) q1 Replacement in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is optionally (R 3a ) q1 Replacement In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is

[0082] Implementation scheme 2e: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-1c, A is selected from the group consisting of: in Indicates connection to R 3 In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, A is selected from the group consisting of: in Indicates connection to R 3 .

[0083] Implementation scheme 2f: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-1c, A is R 3 Replaced and optionally by (R) 3a ) q Substituted phenyl, by R 3 Replaced and optionally by (R) 3a ) q The substituted pyridyl group is R 3 Replaced and optionally by (R) 3a ) q The substituted thiophene group, by R 3 Replaced and optionally by (R) 3a ) q The substituted furanyl group, by R 3 Replaced and optionally by (R) 3a ) q The substituted pyrazol group is replaced by R 3 Replaced and optionally by (R) 3a ) q The substituted indazole group is R 3 Replaced and optionally by (R) 3a ) q The substituted benzisothiazolyl group was R 3 Replaced and optionally by (R) 3a ) q Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R 3 Replaced and optionally by (R) 3a ) q Substituted pyrazol group, or and optionally by (R) 3a ) q Replacement In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-1c, the A ring is no longer further subjected to R. 3a replace.

[0084] Implementation scheme 2g: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-1c, A is R 3 Substituted phenyl, by R 3 The substituted pyridyl group is R 3 The substituted thiophene group, by R 3 The substituted furanyl group, by R 3 The substituted pyrazol group is replaced by R 3 The substituted indazole group is R 3 The substituted benzisothiazolyl group was R 3 Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R3 Substituted pyrazol group, or

[0085] Implementation scheme 2h: In some or any of the implementation schemes of formula (I), including implementation schemes 1-1c, A is In some or any of the embodiments of formula (I), including embodiments 1-1c, A is

[0086] Implementation scheme 2j: In some or any of the implementation schemes of formula (I), including implementation schemes 1-1c, A is In some or any of the embodiments of formula (I), including embodiments 1-1c, A is In some or any of the embodiments of formula (I), including embodiments 1-1c, A is In some or any of the embodiments of formula (I), including embodiments 1-1c, A is In some or any of the embodiments of formula (I), including embodiments 1-1c, A is In some or any of the embodiments of formula (I), including embodiments 1-1c, A is

[0087] Implementation scheme 2k: In some or any of the implementation schemes of formula (I), including implementation schemes 1-1c, A is selected from the group consisting of:

[0088] Implementation Scheme 3: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-2d, W 1 It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, or -C(cyclopropyl)=. In some or any of the embodiments, W 1 It is -N= or -C(H)=. In some or any of the embodiments, including embodiments 1-2d, W 1 It is -N=. In some or any of the implementation schemes, including implementation schemes 1-2a, W 1 It is -C(H) = . In some or any of the implementation schemes, including implementation schemes 1-2d, W 1 Is -C (halogen) = . In some or any of the embodiments, including embodiments 1-2d, W 1 It is -C(C1-C6 alkyl)=. In some or any of the embodiments, including embodiments 1-2d, W 1 It is -C(cyclopropyl)=. In some or any of the embodiments, including embodiments 1-2d, W 1It is -N=. In some or any of the implementation schemes, including implementation schemes 1-2d, W 1 It is -C(H) = . In some or any of the implementation schemes, including implementation schemes 1-2d, W 1 Is -C (halogen) = . In some or any of the embodiments, including embodiments 1-2d, W 1 It is -C(C1-C6 alkyl)=. In some or any of the embodiments, including embodiments 1-2d, W 1 It is -C(cyclopropyl)=.

[0089] Implementation scheme 3a: In some or any of the implementation schemes of formulas (I) and (I-P2), including implementation schemes 1-2g, W 1 It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, or -C(cyclopropyl)=. In some or any of the embodiments, W 1 It is -N= or -C(H)=. In some or any of the embodiments, including embodiments 1-2g, W 1 Yes -N=. In some or any of the implementation schemes, including implementation schemes 1-2g, W 1 It is -C(H) = . In some or any of the embodiments, including embodiments 1-2g, W 1 It is -C (halogen) =. In some or any of the embodiments, including embodiment 1-2g, W 1 It is -C(C1-C6 alkyl)=. In some or any of the embodiments, including embodiment 1-2g, W 1 It is -C(cyclopropyl)=. In some or any of the embodiments, including embodiments 1-2g, W 1 Yes -N=. In some or any of the implementation schemes, including implementation schemes 1-2g, W 1 It is -C(H) = . In some or any of the embodiments, including embodiments 1-2g, W 1 It is -C (halogen) =. In some or any of the embodiments, including embodiment 1-2g, W 1 It is -C(C1-C6 alkyl)=. In some or any of the embodiments, including embodiment 1-2g, W 1 It is -C(cyclopropyl)=. In some or any of the embodiments, including embodiments 1-2g, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle consisting of 5 to 7 atoms, or a heteroaromatic ring consisting of 5 or 6 atoms.

[0090] Implementation scheme 3b: In some or any of the implementation schemes of formula (I), including implementation schemes 1-2k, W 1 It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=. In some or any embodiment of formula (I), including embodiments 1-2k, W 1 It is -N=. In some or any of the embodiments of formula (I), including embodiments 1-2k, W 1 It is -C(H) = . In some or any of the embodiments of formula (I), including embodiments 1-2k, W 1 Is -C(halogen) =. In some or any embodiment of formula (I), including embodiments 1-2k, W 1 It is -C(C1-C6 alkyl)=. In some or any embodiment of formula (I), including embodiments 1-2k, W 1 It is -C(cyclopropyl)=. In some or any embodiment of formula (I), including embodiments 1-2k, W 1 It is -C(C1-C6 alkoxy)=.

[0091] Implementation Scheme 4: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-3, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle optionally contains an additional N atom and wherein the remaining ring atoms are all C. In some or any embodiment of formula (I), (I-P1), and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then Not a partially unsaturated carbon ring consisting of 5 to 8 atoms, or a partially unsaturated heterocycle consisting of 5 to 7 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-3, when W2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then A carbon ring consisting of 5 to 8 atoms that is not partially unsaturated. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then A heterocycle consisting of 5 to 7 atoms that is not partially unsaturated.

[0092] Implementation scheme 4a: In some or any of the implementation schemes of formulas (I) and (I-P2), including implementation schemes 1-3, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle optionally contains an additional N atom and wherein the remaining ring atoms are all C. In some or any embodiment of formula (I) and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then Not a partially unsaturated carbon ring consisting of 5 to 7 atoms, or a partially unsaturated heterocycle consisting of 5 to 7 atoms. In some or any embodiment of formulas (I) and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then A carbon ring consisting of 5 to 7 atoms that is not partially unsaturated. In some or any of the embodiments of formulas (I) and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W2 With W 3 When the virtual bond between them is a double bond, then A heterocycle consisting of 5 to 7 atoms that is not partially unsaturated.

[0093] Implementation Scheme 5: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-4, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms. In some or any embodiment of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring composed of 5 to 8 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a benzo[a]cyclic ring. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated heterocycle composed of 5 to 7 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a heteroaromatic ring composed of 5 or 6 atoms. In some or any embodiment of formula (I), (I-P1), and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then Not a partially unsaturated carbon ring consisting of 5 to 8 atoms, or a partially unsaturated heterocycle consisting of 5 to 7 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then A carbon ring consisting of 5 to 8 atoms that is not partially unsaturated. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then A heterocycle consisting of 5 to 7 atoms that is not partially unsaturated.

[0094] Implementation scheme 5a: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-4, W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a benzo[a] ring, or a heteroaromatic ring composed of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle consisting of 5 or 6 atoms, wherein the heterocycle optionally contains an additional N atom and wherein the remaining ring atoms are all C.

[0095] Implementation scheme 5b: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-4, W 2 and W 3 Each is -C-; W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms. In some or any embodiment of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 Each is -C-; W 2 With W 3The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring composed of 5 to 7 atoms. In some or any of the embodiments, including embodiments 1-4, W 2 and W 3 Each is -C-; W 2 With W 3 The dotted bond between them is a double bond, and It is a benzo[a]cyclic ring. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 Each is -C-; W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated heterocycle composed of 5 to 7 atoms. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 and W 3 Each is -C-; W 2 With W 3 The dotted bond between them is a double bond, and It is a heteroaromatic ring composed of 5 or 6 atoms. In some or any embodiment of formula (I) and (I-P1), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then Not a partially unsaturated carbon ring consisting of 5 to 7 atoms, or a partially unsaturated heterocycle consisting of 5 to 7 atoms. In some or any embodiment of formula (I) and (I-P1), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then A carbon ring consisting of 5 to 7 atoms that is not partially unsaturated. In some or any of the embodiments of formulas (I) and (I-P1), including embodiments 1-3, when W 2 and W 3 Each is -C- and W 2 With W 3 When the virtual bond between them is a double bond, then A heterocycle consisting of 5 to 7 atoms that is not partially unsaturated.

[0096] Implementation Scheme 6: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-4, W 2 and W 3One is -C-, the other is -N-; W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle optionally contains an additional N atom and wherein the remaining ring atoms are all C. In some or any embodiment of formula (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 It is -C- and W 3 Yes -N-. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, W 2 It is -N- and W 3 Yes -C-. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, It is a heterocycle composed of 5 atoms, wherein the heterocycle optionally contains an additional N atom and wherein the remaining ring atoms are all C. In some or any embodiment of formulas (I), (I-P1), and (I-P2), including embodiments 1-4, It is a heterocycle composed of 6 atoms, wherein the heterocycle optionally contains an additional N atom and the remaining ring atoms are all C.

[0097] Implementation Scheme 7: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-6, R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or two R 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or two R 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, a halogen, or a C1-C6 alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-6, R 2 In each case, it is independently H, halogen, or C1-C6 alkyl. In some or any of the embodiments, including embodiments 1-6, R 2 It is H. In some or any of the implementation schemes, including schemes 1-6, R 2 It is halogen. In some or any of the embodiments, including embodiments 1-6, R 2It is a C1-C6 alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-6, two R 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-6, two R 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl.

[0098] Implementation scheme 7a: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-6, there exists an R 2 , and R 2 Not H. In some or any of the embodiments of equations (I), (I-P1), and (I-P2), including embodiments 1-6, there are two R. 2 , and each R 2 Each is independently not H. In some or any of the embodiments of equations (I), (I-P1), and (I-P2), including embodiments 1-6, there are three R. 2 , and each R 2 Each is independently not H. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 It is a halogen. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 Yes -F. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 It is a C1-C6 alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-6, at least one R 2 It is -CH3.

[0099] Implementation scheme 7b: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-6, each R 2 The alkyl groups and halogens are selected independently from C1-C6 alkyl groups, and in some embodiments, one, two, or three R groups are present. 2 In some implementation schemes, there are 2 or 3 Rs. 2In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-6, each R 2 They are H respectively.

[0100] Implementation scheme 7c: In some or any of the implementation schemes of formula (I), including implementation schemes 1-6, R 2 In each case, it is independently H, halogen, C1-C6 alkyl, or halo-C1-C6 alkyl; or two Rs. 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or two R 2 All atoms are attached to the same carbon atom and together with the attached carbon atom form a carbon ring of 3 to 7 atoms, the ring being optionally substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl. In some or any embodiment of formula (I), including embodiments 1-6, R 2 In each case, it is independently H, halogen, C1-C6 alkyl, or halogenated C1-C6 alkyl. In some or any of the embodiments, including embodiments 1-6, R 2 It is H. In some or any of the implementation schemes, including schemes 1-6, R 2 It is halogen. In some or any of the embodiments, including embodiments 1-6, R 2 It is a C1-C6 alkyl group. In some or any of the embodiments, including embodiments 1-6, R 2 It is a halogenated C1-C6 alkyl group. In some or any embodiment of formula (I), including embodiments 1-6, two R 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl. In some or any embodiment of formula (I), including embodiments 1-6, two R 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring of 3 to 7 atoms, the ring optionally being substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups; and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl.

[0101] Implementation Scheme 8: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-7b, R 3 It is -C(O)NH2, -NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, or Wherein R is H, a C1-C3 alkyl group, or a C3-C5 cycloalkyl group. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -C(O)NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -S(O)2NHR. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -S(O)2C1-C6-alkyl. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 yes In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R is H, C1-C3 alkyl, or C3-C5 cycloalkyl.

[0102] Implementation scheme 8a: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-7b, R 3 It is -C(O)NH2, -NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, or Wherein R is H, a C1-C3 alkyl group, or a C3-C5 cycloalkyl group. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -C(O)NH2. In some or any of the embodiments, including embodiments 1-7b, R 3It is -NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -S(O)2NHR. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -S(O)2C1-C6-alkyl. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 yes In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R is H, C1-C3 alkyl, or C3-C5 cycloalkyl. 3 It is -S(O)2NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -S(O)2CH3. In some or any of the embodiments, including embodiments 1-7b, R 3 yes

[0103] Implementation scheme 8b: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-7b, R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halogenated C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2 group; and wherein the alkyl group in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3, or 4 halogens. In some or any embodiment of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is H. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is a halogen. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -OH. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -B(OH)2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -COOH. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is a hydroxyalkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -C(=NH)NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -C(O)NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -NHC(O)C 1-3 Alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -NHC(=NH)NH2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is -S(O)2NHR. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3It is -S(O)2C1-C6-alkyl. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is an amino-C1-C6 alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is a halogenated C1-C3 alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is a C3-C6-cycloalkyl group substituted with a -NH2 group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 It is a heterocyclic alkyl group consisting of 3 to 6 atoms substituted with a -NH2 group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-7b, R 3 yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-7b and 8b, R 3 Not H.

[0104] Implementation scheme 8c: In some or any of the implementation schemes of formula (I), including implementation schemes 1-7c, R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halo-C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2 group; and wherein the alkyl group in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3, or 4 halogens. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is H. In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 It is -OH. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -B(OH)2. In some or any embodiment of formula (I), including embodiments 1-7c, R 3It is -COOH. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is a hydroxyalkyl group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -C(=NH)NH2. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -C(O)NH2. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -NH2. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -NHC(O)C 1-3 Alkyl group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -NHC(O)NH2. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -NHS(O)2NH2. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -NHC(=NH)NH2. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -S(O)2NHR, where R is H, a C1-C3 alkyl group, or a C3-C5 cycloalkyl group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is -S(O)2C1-C6-alkyl. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is an amino-C1-C6 alkyl group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is a halogenated C1-C3 alkyl group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is a C3-C6-cycloalkyl group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is a heterocyclic alkyl group consisting of 3 to 6 atoms. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 yes In some or any of the embodiments of formula (I), including embodiments 1-7c, R 3 It is a heterocyclic alkyl group consisting of 3 to 6 atoms optionally substituted with a -NH2 group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3It is a heterocyclic alkyl group consisting of 3 to 6 atoms substituted with a -NH2 group. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is an amino-C1-C6 alkyl group, wherein the alkyl group in the amino-C1-C6 alkyl group is optionally further substituted with 1, 2, 3 or 4 halogens. In some or any embodiment of formula (I), including embodiments 1-7c, R 3 It is an amino-C1-C6 alkyl group, wherein the alkyl group in the amino-C1-C6 alkyl group is further substituted with 1, 2, 3, or 4 halogens. In one or more embodiments, including embodiments 1-7c, R 3 It is an amino-C1-C3 alkyl group. In one or more embodiments, including embodiments 1-7c, R 3 It is an amino-C1-C3 alkyl group, wherein the alkyl group in the amino-C1-C3 alkyl group is further replaced by 1, 2, 3 or 4 halogens.

[0105] Implementation Scheme 9: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-8b, R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl. In some or any of the embodiments, including embodiments 1-8b, R 3a It is H. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-8b, each R 3a H, respectively. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-8b, an R 3a It's H, and the other is R. 3a Not H. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-8b, at least one R 3a It is H. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-8b, R 3a It is a halogen. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-8b, R 3a It is a C1-C3 alkyl group. In some or any of the embodiments, including embodiments 1-8b, R 3a It is a C3-C6 cycloalkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-8b, an R 3a It is a halogen. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-8b, an R 3aIt is a C1-C3 alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-8b, an R 3a It is a C3-C6 cycloalkyl group.

[0106] Implementation scheme 9a: In some or any of the implementation schemes of formula (I), including implementation schemes 1-8c, R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl. In some or any of the embodiments, including embodiments 1-8c, R 3a It is H. In some or any of the embodiments of formula (I), including embodiments 1-8c, each R 3a H is represented by H. In some or any embodiment of formula (I), including embodiments 1-8c, an R 3a It's H, and the other is R. 3a Not H. In some or any of the embodiments of formula (I), including embodiments 1-8c, at least R 3a It is H. In some or any of the embodiments of formula (I), including embodiments 1-8c, R 3a It is a halogen. In some or any embodiment of formula (I), including embodiments 1-8c, R 3a It is a C1-C3 alkyl group. In some or any of the embodiments, including embodiments 1-8c, R 3a It is a C3-C6 cycloalkyl group. In some or any embodiment of formula (I), including embodiments 1-8c, an R 3a It is a halogen. In some or any embodiment of formula (I), including embodiments 1-8c, an R 3a It is a C1-C3 alkyl group. In some or any embodiment of formula (I), including embodiments 1-8c, an R 3a It is a C3-C6 cycloalkyl group.

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

[0108] Implementation Scheme 11: In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-10 are included, where n is 0, 1, 2, 3, or 4. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-10 are included, where n is 0, 1, or 2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-10 are included, where n is 0. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-10 are included, where n is 1. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-10 are included, where n is 2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-10 are included, where n is 3. In some or any of the embodiments, embodiments 1-10 are included, where n is 4.

[0109] Implementation Scheme 12: In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-11 are included, where p is 0, 1, 2, 3, 4, 5, or 6. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-11 are included, where p is 0, 1, 2, or 3. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-11 are included, where p is 0. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-11 are included, where p is 1. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-11 are included, where p is 2. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), embodiments 1-11 are included, where p is 3. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-11, p is 4. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-11, p is 5. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-11, p is 6.

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

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

[0112] Implementation Scheme 15: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes and W 4 It is O; and in some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes and W 4 It is S. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes and W 4 It is O; and in some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes and W 4 It is S. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes

[0113] Implementation scheme 15a: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes

[0114] Implementation scheme 15b: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes

[0115] Implementation scheme 15c: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, It is not one of the ring systems listed in this paragraph.

[0116] Implementation scheme 15d: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, It is not one of the ring systems listed in this paragraph.

[0117] Implementation scheme 15e: In some or any of the implementation schemes of formulas (I), (I-P1), and (I-P2), including implementation schemes 1-14, yes In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, Not for

[0118] Implementation Scheme 16: In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-14, yes

[0119] Implementation scheme 16a: In some or any of the implementation schemes of formula (I), including implementation schemes 1-14, yes

[0120] Implementation scheme 16b: In some or any of the implementation schemes of formula (I), including implementation schemes 1-14, yes

[0121] Implementation scheme 16c: In some or any of the implementation schemes of formulas (I) and (I-P1), including implementation schemes 1-14, yes

[0122] Implementation Scheme 17: In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-16a, R 1a It is H. In some or any of the embodiments of formulas (I), (I-P1), and (I-P2), including embodiments 1-16a, R 1a It is a C1-C6 alkyl group. In some or any of the embodiments of formula (I), (I-P1), and (I-P2), including embodiments 1-16a, R 1a It is a C3-C6-cycloalkyl group. In some or any of the embodiments, R 1a It is a C3-C6-cycloalkyl C1-C3-alkyl.

[0123] Implementation scheme 17a: In some or any of the implementation schemes of formula (I), including implementation schemes 1-16a, R 1a It is H, halogen, C1-C6 alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl. In some or any embodiment of formula (I), including embodiments 1-16a, R 1a It is halogen.

[0124] Implementation Scheme 18: In some or any of the embodiments of formula (I), (I-P1) and (I-P2), the compound is selected from any one of compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206 shown in Table A, or pharmaceutically acceptable salts and / or isomers thereof.

[0125] Implementation scheme 18a: In some or any of the embodiments of formula (I) and (I-P2), the compound is selected from any one of compounds 1-127 and 169-206 shown in Table A, or pharmaceutically acceptable salts and / or isomers thereof.

[0126] Implementation Scheme 18c: In some or any of the embodiments of formula (I), the compound is selected from any one of compounds 1-206 shown in Table A, or a pharmaceutically acceptable salt and / or isomer thereof. Table A

[0127] Implementation Scheme 19: The present invention provides compounds according to any aspect or embodiment disclosed herein, including compounds shown in any of embodiments 1-18, wherein said compounds are not: 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-(methanesulfonyl)phenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers;

[0128] 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)-6,7,8,9-tetrahydro-5H-cycloheptan[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; or 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0129] In some or any of the embodiments, the present invention provides compounds represented by any of the following general formulas: or its salt, in, A is R 3 Substituted phenyl, by R 3 The substituted pyridyl group is R 3 Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R 3 Substituted pyrazol group, or W 1 It is -N= or -C(H)=; yes Each R 1 Each of the following can be independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, or halogen; Each R 2 Each can be independently H, C1-C6 alkyl, or halogen; R 3 It is -C(O)NH2, -NH2, -S(O)2NH2, -S(O)2CH3, or m is 1 or 2; n is 0, 1, or 2; and p is 0, 1, 2, or 3.

[0130] In some or any of the embodiments, the present invention provides compounds represented by any of the following general formulas: in, R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two of the R 1 Connected to It is formed on the adjacent carbon atom of the ring, and together with the adjacent carbon atom to which it is attached. Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q The 5 to 10 atoms are replaced Composed of heteroaryl groups; or optionally coated with (R 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring of 3 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 3 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halo-C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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 can be 0, 1, 2, or 3. Additional Implementation Plan

[0131] Implementation Scheme 21: The present invention provides compounds as described herein, for example, compounds of formula (I): in, R 1In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two of the R 1 Connected to It is formed on the adjacent carbon atom of the ring, and together with the adjacent carbon atom to which it is attached. Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally, a heteroaryl group consisting of (R... 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen=, -C(C1-C6 alkyl=, or -C(cyclopropyl=); W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl group, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6-alkyl, halo-C1-C3-alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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 its pharmaceutically acceptable salts and / or its isomers; The condition is that the compound is not: 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopentano[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-6,7-dihydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; -5H-cyclopentano[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-6,7,8,9-tetrahydro-5H-cycloheptano[b]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers; or 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0132] Implementation Scheme 21a. The present invention provides the compound of Implementation Scheme 21, wherein: R 1 In each case, R is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or two of R. 1 Connected to It is formed on the adjacent carbon atom of the ring, and together with the adjacent carbon atom to which it is attached. Where * represents The shared carbon atom mentioned in the text; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; or optionally, a heteroaryl group consisting of (R... 3a ) q1 Replacement W 1 It is -N=, -C(H)=, -C(halogen=, -C(C1-C6 alkyl=, or -C(cyclopropyl=); W 2 and W 3 Each is -C-, W 2 With W3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -C(O)NH2, -NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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 its pharmaceutically acceptable salts and / or its isomers.

[0133] Implementation Scheme 22. The present invention provides a compound according to Embodiment 21 or 21a, wherein A is reacted with R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl, optionally, where A is the derivative of R3 Replaced and optionally by (R) 3a ) q Substituted phenyl groups, or pharmaceutically acceptable salts thereof and / or isomers thereof.

[0134] Implementation Scheme 23. The present invention provides a compound according to embodiments 21, 21a or 22, wherein A is reacted with R 3 Substituted phenyl groups, or pharmaceutically acceptable salts thereof and / or isomers thereof.

[0135] Implementation Scheme 24. The present invention provides the compounds described in embodiments 21-23, wherein A is in Indicates connection to R 3 ; or its pharmaceutically acceptable salts and / or its isomers.

[0136] Implementation Scheme 24a. The present invention provides the compounds described in embodiments 21-24, wherein A is in Indicates connection to R 3 ; or its pharmaceutically acceptable salts and / or its isomers.

[0137] Implementation Scheme 25. The present invention provides the compound of Implementation Scheme 21, wherein A is reacted with R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms, optionally, wherein A is replaced by R 3 Replaced and optionally by (R) 3a ) q The heteroaryl group consists of nine substituted atoms, optionally, where A is replaced by R. 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 10 substituted atoms, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0138] Implementation Scheme 25a. The present invention provides a compound according to Embodiment 21 or 25, wherein A is Or its pharmaceutically acceptable salts and / or its isomers.

[0139] Implementation scheme 26.21 or 25, where A is R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 or 6 substituted atoms, where A is replaced by R 3 Replaced and optionally by (R) 3a ) qA heteroaryl group consisting of 5 substituted atoms, or where A is replaced by R. 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 6 substituted atoms; or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0140] Implementation Scheme 26a. The present invention provides the compound described in Implementation Scheme 21, 25, or 26, wherein A is Or its pharmaceutically acceptable salts and / or its isomers.

[0141] Implementation Scheme 26b. The present invention provides the compound of Implementation Scheme 21, wherein A is selected from the group consisting of: Or its pharmaceutically acceptable salts and / or its isomers.

[0142] Implementation Scheme 27. The present invention provides the compound of Implementation Scheme 21, wherein A is selected from the group consisting of: in Indicates connection to R 3 ; or its pharmaceutically acceptable salts and / or its isomers.

[0143] Implementation Scheme 28. The present invention provides a compound according to any one of embodiments 21-27, wherein R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl group, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6-alkyl, halo-C1-C3-alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0144] Implementation Scheme 28a. The present invention provides a compound according to any one of embodiments 21-27, wherein R 3It is -C(O)NH2, -NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, or R is H, a C1-C3 alkyl group, or a C3-C5 cycloalkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0145] Implementation Scheme 29. The present invention provides a compound according to any one of embodiments 21-27, wherein A is a pyrazolyl group, and R 3 It is H, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0146] Implementation Scheme 30. The present invention provides a compound according to any one of embodiments 21-28, wherein R 3 It is -C(O)NH2, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0147] Implementation Scheme 31. The present invention provides a compound according to any one of embodiments 21-28, wherein R 3 It is -NH2, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0148] Implementation Scheme 32. The present invention provides a compound according to any one of embodiments 21-28, wherein R 3 It is -S(O)2NHR, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0149] Implementation Scheme 33. The present invention provides a compound according to any one of embodiments 21-29, wherein R is a C1-C3 alkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0150] Implementation Scheme 34. The present invention provides a compound according to any one of embodiments 21-29, wherein R is a C3-C5 cycloalkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0151] Implementation Scheme 35. The present invention provides a compound according to any one of embodiments 21-28, wherein R 3 It is -S(O)2NH2, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0152] Implementation Scheme 36. The present invention provides a compound according to any one of embodiments 21-28, wherein R 3 It is -S(O)2C1-C6-alkyl, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0153] Implementation Scheme 37. The present invention provides a compound according to any one of embodiments 21-28 and 36, wherein R 3 It is -S(O)2CH3, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0154] Implementation Scheme 38. The present invention provides a compound according to any one of embodiments 21-28, wherein R 3 yes Or its pharmaceutically acceptable salts and / or its isomers.

[0155] Implementation Scheme 39. The present invention provides a compound according to any one of embodiments 21-28 and 38, wherein R 3 yes Or its pharmaceutically acceptable salts and / or its isomers.

[0156] Implementation Scheme 40. The present invention provides a compound according to any one of embodiments 21-39, wherein, yes Where W 4 Is it O or S? An R 1 It can be R as shown in the above ring. 1a ;and R 1a It is H, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl; Or its pharmaceutically acceptable salts and / or its isomers.

[0157] Implementation Scheme 40a. The present invention provides a compound according to any one of embodiments 21-40, wherein, yes Where W 4 Is it O or S? An R 1 It can be R as shown in the above ring. 1a ;and R 1a It is H, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl; Or its pharmaceutically acceptable salts and / or its isomers.

[0158] Implementation Scheme 41. The present invention provides a compound according to any one of embodiments 21-40, wherein, yes Or its pharmaceutically acceptable salts and / or its isomers.

[0159] Implementation Scheme 41a. The present invention provides a compound according to any one of embodiments 21-40, wherein, yes Or its pharmaceutically acceptable salts and / or its isomers.

[0160] Implementation Scheme 42. The present invention provides a compound according to any one of embodiments 40 and 41, wherein R 1 a is H, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0161] Implementation Scheme 43. The present invention provides a compound according to any one of embodiments 40 and 41, wherein R 1 a is a C1-C6-alkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0162] Implementation Scheme 44. The present invention provides a compound according to any one of embodiments 40 and 41, wherein R 1 a is a C3-C6-cycloalkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0163] Implementation Scheme 45. The present invention provides a compound according to any one of embodiments 40 and 41, wherein R 1 a is a C3-C6-cycloalkyl-C1-C3-alkyl, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0164] Implementation Scheme 46. The present invention provides a compound according to any one of embodiments 21-45, wherein an R is present. 1 , and R 1 Not H, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0165] Implementation Scheme 47. The present invention provides a compound according to any one of embodiments 21-45, wherein two R are present. 1 , and each R 1 Each is independently not H, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0166] Implementation Scheme 48. The present invention provides a compound according to any one of embodiments 21-45, wherein three R are present. 1 , and each R 1 Each is independently not H, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0167] Implementation Scheme 49. The present invention provides a compound according to any one of embodiments 21-48, wherein at least one R 1 It is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0168] Implementation Scheme 50. The present invention provides a compound according to any one of embodiments 21-49, wherein at least one R 1It is -CH3, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0169] Implementation Scheme 51. The present invention provides a compound according to any one of embodiments 21-48, wherein at least one R 1 It is a C1-C6 alkoxy group, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0170] Implementation Scheme 52. The present invention provides a compound according to any one of embodiments 21-48 and 51, wherein at least one R 1 It is -OCH3, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0171] Implementation Scheme 53. The present invention provides a compound according to any one of embodiments 21-48, wherein at least one R 1 It is a C1-C6 haloalkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0172] Implementation Scheme 54. The present invention provides a compound according to any one of embodiments 21-48 and 53, wherein at least one R 1 It is -CF3, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0173] Implementation Scheme 55. The present invention provides a compound according to any one of embodiments 21-48, wherein at least one R 1 It is a halogen, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0174] Implementation Scheme 56. The present invention provides a compound according to any one of embodiments 21-48 and 55, wherein at least one R 1 It is –Cl, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0175] Implementation Scheme 57. The present invention provides a compound according to any one of embodiments 21-48 and 55, wherein at least one R 1 It is –F, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0176] Implementation Scheme 58. The present invention provides a compound according to any one of embodiments 21-48, wherein at least one R 1 It is a halogenated C1-C6 alkoxy group, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0177] Implementation Scheme 59. The present invention provides a compound according to any one of embodiments 21-48 and 58, wherein at least one R 1 It is -OCF3, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0178] Implementation Scheme 60. The present invention provides a compound according to any one of embodiments 21-48, wherein each R 1 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, and halogen, or pharmaceutically acceptable salts thereof and / or isomers thereof.

[0179] Implementation Scheme 61. The present invention provides a compound according to any one of embodiments 21-45, wherein each R 1 Each is independently H, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0180] Implementation Scheme 61a. The present invention provides a compound according to any one of embodiments 21-48, wherein the two R 1 Connected to On the adjacent carbon atom in the middle ring, and together with the adjacent carbon atom to which it is attached, it forms Where * represents The shared carbon atom described in the text, and any other R 1 The components are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl.

[0181] Implementation Scheme 62. The present invention provides a compound according to any one of embodiments 21-61, wherein an R is present. 2 , and R 2 Not H, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0182] Implementation Scheme 63. The present invention provides a compound according to any one of embodiments 21-61, wherein two R are present. 2 , and each R 2 Each is independently not H, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0183] Implementation Scheme 64. The present invention provides a compound according to any one of embodiments 21-61, wherein three R are present. 2 , and each R 2 Each is independently not H, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0184] Implementation Scheme 65. The present invention provides a compound according to any one of embodiments 21-64, wherein at least one R 2 It is a halogen, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0185] Implementation Scheme 66. The present invention provides a compound according to any one of embodiments 21-65, wherein at least one R2 It is –F, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0186] Implementation Scheme 67. The present invention provides a compound according to any one of embodiments 21-64, wherein at least one R 2 It is a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0187] Implementation Scheme 68. The present invention provides a compound according to any one of embodiments 21-64 and 67, wherein at least one R 2 It is -CH3, or a pharmaceutically acceptable salt thereof and / or its isomer.

[0188] Implementation Scheme 69. The present invention provides a compound according to any one of embodiments 21-61, 63 and 64, wherein the two R 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring consisting of 4 to 7 atoms, and the remaining R... 2 In each case, it is independently H, a halogen, or a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0189] Implementation Scheme 70. The present invention provides a compound according to any one of embodiments 21-61, 63 and 64, wherein the two R 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring consisting of 4 to 7 atoms, and the remaining R 2 In each case, it is independently H, a halogen, or a C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0190] Implementation Scheme 71. The present invention provides a compound according to any one of embodiments 21-64, wherein each R 2 It is independently selected from C1-C6 alkyl and halogen, or pharmaceutically acceptable salts and / or isomers thereof.

[0191] Implementation Scheme 72. The present invention provides a compound according to any one of embodiments 21-71, wherein each R 2 Each is independently H, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0192] Implementation Scheme 73. The present invention provides a compound according to any one of embodiments 21-72, wherein m is 1 or 2, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0193] Implementation Scheme 74. The present invention provides a compound according to any one of embodiments 21-73, wherein m is 1, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0194] Implementation Scheme 75. The present invention provides a compound according to any one of embodiments 21-73, wherein m is 2, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0195] Implementation Scheme 76. The present invention provides a compound according to any one of embodiments 21-75, wherein W 1 It is -N=, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0196] Implementation Scheme 77. The present invention provides a compound according to any one of embodiments 21-75, wherein W 1 It is -C(H)=, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0197] Implementation Scheme 78. The present invention provides a compound according to any one of embodiments 21-75, wherein W 1 It is -C (halogen), or a pharmaceutically acceptable salt thereof and / or its isomer.

[0198] Implementation Scheme 79. The present invention provides a compound according to any one of embodiments 21-75, wherein W 1 It is -C(C1-C6 alkyl)=, or a pharmaceutically acceptable salt thereof and / or an isomer thereof.

[0199] Implementation Scheme 80. The present invention provides a compound according to any one of embodiments 21-75, wherein W 1 It is -C(cyclopropyl)=, or a pharmaceutically acceptable salt thereof and / or its isomers.

[0200] Implementation Scheme 81. The present invention provides compounds, or pharmaceutically acceptable salts thereof and / or isomers thereof, selected from the group consisting of the compounds provided in Table A.

[0201] Implementation Scheme 82. The present invention provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, and a pharmaceutically acceptable carrier.

[0202] Implementation Scheme 83. The present invention provides the pharmaceutical composition of Implementation Scheme 82, wherein the composition is an oral or injectable composition.

[0203] Implementation Scheme 84. The present invention provides the pharmaceutical composition of Implementation Scheme 83, wherein the injectable composition is a subcutaneously injectable composition.

[0204] Implementation Scheme 85. This invention provides a treatment subject with voltage-gated sodium ion channel function including Na ν1.8 A method for treating or preventing related conditions, the method comprising administering a therapeutic or preventative amount of the compound or pharmaceutical composition disclosed herein.

[0205] Implementation Scheme 86. The present invention provides the method of implementation scheme 85, wherein the subject is a human being.

[0206] Implementation Scheme 87. The present invention provides the method of implementation scheme 85 or 86, wherein the symptom is pain, or wherein the symptom is related to pain.

[0207] Implementation Scheme 88. The present invention provides the method of implementation scheme 85 or 86, wherein the symptom is pain.

[0208] Implementation Scheme 89. The present invention provides the method of implementation scheme 85 or 86, wherein the symptom is related to pain.

[0209] Implementation Scheme 90. The present invention provides a method according to any one of Implementation Scheme 85 or 85-89, wherein the condition is selected from the group consisting of: 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 headaches, pain associated with migraines, pain associated with sciatica, pain associated with endometriosis, pain associated with fibromyalgia, postoperative pain, subacute pain, chronic pain, 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, spasm, and obsessive-compulsive disorder.

[0210] Implementation Scheme 91. The present invention provides the method described in Implementation Scheme 85 or 86, wherein the symptom is selected from the group consisting of acute pain, subacute pain, postoperative pain, and eye pain.

[0211] Implementation Scheme 92. This invention provides a method for suppressing NA. ν Method 1.8, which includes enabling NA ν 1.8 Contact with the compounds disclosed in this invention.

[0212] In some or any of the embodiments, the present invention provides: (a) Compounds as described in this invention, such as those of formula (I), (I-P1), (I-P2) and compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206, and their pharmaceutically acceptable salts and compositions thereof. (b) Compounds as described in this invention, such as those of formula (I), (I-P1), (I-P2) and compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206, and pharmaceutically acceptable salts and compositions thereof, for the treatment of pain and / or conditions regulated by voltage-gated sodium ion channels. (c) Methods for preparing the compounds of the present invention, such as those 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 in other aspects of the present invention. (d) A pharmaceutical preparation comprising the compounds of the present invention, such as those of formula (I), (I-P1), (I-P2) and compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or diluents. (e) A method of treating a subject for a condition related to the function of a voltage-gated sodium ion channel, comprising administering a therapeutic or preventative amount of a compound of the present invention, such as, compounds of formula (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206, or pharmaceutically acceptable salts or compositions thereof. (f) A method for treating pain in a subject, comprising administering a therapeutically or preventively effective amount of the compound of the present invention, such as formula (I), (I-P1), (I-P2) and compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206, or pharmaceutically acceptable salts or combinations thereof; (g) A pharmaceutical preparation comprising the compounds described in this invention, such as those of formula (I), (I-P1), (I-P2) and compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206, or pharmaceutically acceptable salts thereof, and one or more other effective medicaments for treating pain and / or conditions regulated by voltage-gated sodium ion channels, optionally comprising a pharmaceutically acceptable carrier or diluent; (h) A method of treating pain in a subject, comprising administering a therapeutically or preventively effective amount of the compound of the present invention, such as formula (I), (I-P1), (I-P2) and the compounds shown in compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206, or pharmaceutically acceptable salts or combinations thereof, in combination with or in combination with and / or alternately with one or more drugs for the treatment of pain and / or conditions regulated by voltage-gated sodium ion channels. (i) A method of treating a subject for a condition related to the function of a voltage-gated sodium ion channel, comprising administering a therapeutically or preventively effective amount of a compound of the present invention, such as those of formulas (I), (I-P1), (I-P2), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or pharmaceutically acceptable salts or compositions thereof, in combination with / in combination with and / or alternately with one or more drugs for the treatment of pain; and (j) Use of any compound described in this invention, such as those 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 in this invention, such as those of formula (I), and compounds 1-51, 56, 59, 60, 82, 116, 119, and 169-206, or a pharmaceutically acceptable salt or composition thereof, for the treatment of conditions (e.g., pain) related to the function of the voltage-gated sodium ion channel described in this invention, optionally in combination with / in combination with and / or alternating with one or more drugs for the treatment of pain.

[0213] In some or any of the embodiments, the present invention provides: (a) Compounds as described in this invention, such as those of formula (I), (I-P2) and compounds 1-127 and 169-206, and their pharmaceutically acceptable salts and compositions thereof; (b) Compounds as described in this invention, such as those of formula (I), (I-P2) and compounds 1-127 and 169-206, and pharmaceutically acceptable salts and compositions thereof, for the treatment of pain and / or conditions regulated by voltage-gated sodium ion channels. (c) Methods for preparing the compounds of the present invention, such as those of formula (I), (I-P2), and compounds 1-127 and 169-206, as described in more detail in other aspects of the present invention; (d) A pharmaceutical preparation comprising the compounds described in this invention, such as those of formula (I), (I-P2), and compounds 1-127 and 169-206, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or diluents. (e) A method of treating a subject for a condition related to the function of a voltage-gated sodium ion channel, comprising administering a therapeutic or preventative amount of a compound of the present invention, such as compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, or pharmaceutically acceptable salts or compositions thereof. (f) A method of treating pain in a subject, comprising administering a therapeutic or preventative amount of a compound of the present invention, such as compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, or pharmaceutically acceptable salts or compositions thereof. (g) A pharmaceutical preparation comprising the compounds described in this invention, such as those of formula (I), (I-P2), and compounds 1-127 and 169-206, or pharmaceutically acceptable salts thereof, and one or more other effective medicaments for treating pain and / or conditions regulated by voltage-gated sodium ion channels, optionally comprising a pharmaceutically acceptable carrier or diluent. (h) A method of treating pain in a subject, comprising administering a therapeutically or preventively effective amount of a compound of the present invention, such as compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, or pharmaceutically acceptable salts or compositions thereof, in combination with a compound for treating pain and / or... Or, one or more drugs in combination / in combination and / or alternately administered for conditions regulated by voltage-gated sodium ion channels; (i) A method of treating a subject for a condition related to the function of a voltage-gated sodium ion channel, comprising administering a therapeutically or preventively effective amount of a compound of the present invention, such as compounds of formula (I), (I-P2), and compounds 1-127 and 169-206, or pharmaceutically acceptable salts or combinations thereof, in combination with / in conjunction with and / or alternately with one or more drugs for the treatment of pain; and (j) Use of any compound described in this invention, such as compounds of formula (I), (I-P2) and compounds 1-127 and 169-206, or a composition comprising any compound described in this invention, such as compounds of formula (I), (I-P2) and compounds 1-127 and 169-206, or a pharmaceutically acceptable salt or composition thereof, for the treatment of conditions (e.g., pain) related to the function of the voltage-gated sodium ion channel described in this invention, optionally in combination with / in combination with and / or alternating with one or more drugs for the treatment of pain.

[0214] In some or any of the embodiments, the present invention provides: (a) Compounds as described in this invention, such as those of formula (I) and compounds 1-206, and pharmaceutically acceptable salts and compositions thereof; (b) Compounds as described in this invention, such as those of formula (I) and compounds 1-206, and pharmaceutically acceptable salts and compositions thereof, for the treatment of pain and / or conditions regulated by voltage-gated sodium ion channels; (c) Methods for preparing the compounds of the present invention, such as those of formula (I) and compounds 1-206, as described in more detail in other aspects of the present invention; (d) A pharmaceutical preparation comprising the compounds described in this invention, such as compounds of formula (I) and compounds 1-206, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or diluents. (e) A method of treating a subject for a condition related to the function of a voltage-gated sodium ion channel, comprising administering a therapeutic or preventative amount of a compound of the present invention, such as, compounds of formula (I) and compounds 1-206, or pharmaceutically acceptable salts or compositions thereof. (f) A method of treating pain in a subject, comprising administering a therapeutic or preventative amount of a compound of the present invention, such as, the compound of formula (I) and compounds 1-206, or a pharmaceutically acceptable salt or composition thereof. (g) A pharmaceutical preparation comprising the compounds described in this invention, such as those of formula (I) and compounds 1-206, or pharmaceutically acceptable salts thereof, and one or more other effective medicaments for treating pain and / or conditions regulated by voltage-gated sodium ion channels, optionally comprising a pharmaceutically acceptable carrier or diluent. (h) A method of treating pain in a subject, comprising administering a therapeutic or preventative amount of a compound of the present invention, such as, of formula (I) and compounds 1-206, or a pharmaceutically acceptable salt or combination thereof, in combination with or in combination with and / or alternately with one or more drugs for treating pain and / or conditions regulated by voltage-gated sodium ion channels. (i) A method of treating a subject for a condition related to the function of a voltage-gated sodium ion channel, comprising administering a therapeutically or preventively effective amount of a compound of the present invention, such as, compounds of formula (I) and compounds 1-206, or pharmaceutically acceptable salts or combinations thereof, in combination with / in conjunction with and / or alternately with one or more drugs for the treatment of pain; and (j) Use of any compound described in this invention, such as compounds of formula (I) and compounds 1-206, or compositions comprising any compound described in this invention, such as compounds of formula (I) and compounds 1-206, or pharmaceutically acceptable salts or compositions thereof, for the treatment of conditions (e.g., pain) related to the function of the voltage-gated sodium ion channels described in this invention, optionally in combination with / in combination with and / or alternating with one or more drugs for the treatment of pain. Optically active compounds

[0215] It should be understood that the compounds provided by this invention have several chiral centers and can exist and be separated in both optically active and racemic forms. It should be understood that any racemic, optically active, diastereomer, tautomer, or stereoisomer form, mixtures thereof, or combinations thereof of the compounds provided by this invention having the useful properties described herein are included within the scope of this invention. It is well known in the art how the optically active form should be prepared (in some or any embodiment, by recrystallization of the racemate, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase).

[0216] In some or any of the embodiments, the methods for obtaining the optically active material are known in the art and include at least the following. i) Physical separation of crystals – a technique for manually separating macroscopic crystals of individual stereoisomers. This technique can be used if individual stereoisomers of crystals exist, i.e., the substance is an aggregate, and the crystals are visually distinct. ii) Simultaneous crystallization – a technique for crystallizing individual stereoisomers separately from a racemic solution, provided that the latter is a solid aggregate; iii) Enzymatic resolution – a technique that uses the different reaction rates of stereoisomers and enzymes to partially or completely separate racemic mixtures; iv) Enzymatic asymmetric synthesis – a synthetic technique that uses an enzymatic reaction in at least one step of the synthesis to obtain pure or enriched synthetic precursors of the desired stereoisomer. v) Chemical asymmetric synthesis – a synthetic technique that synthesizes the desired stereoisomer from an achiral precursor under conditions of product asymmetry (i.e. chirality), which can be achieved using chiral catalysts or chiral auxiliaries. vi) Diastereomer Separation – A technique that reacts a racemic compound with an enantiomer-pure reagent (chiral auxiliary agent) to convert a single enantiomer into a diastereomer. The resulting diastereomers are then separated by chromatography or crystallization, taking advantage of their more pronounced structural differences, and the chiral auxiliary agent is subsequently removed to obtain the desired enantiomer. vii) Primary and secondary asymmetric transformations—the technique of generating a diastereomer's dominance over the desired enantiomer in solution through diastereomeric equilibrium from the racemic mixture, or by disrupting the equilibrium through preferential crystallization of the diastereomer relative to the desired enantiomer, such that ultimately, in principle, all substances are converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then released from the diastereomer. viii) Kinetic resolution – The technique refers to the partial or complete resolution (or further resolution of partially resolved compounds) of a racemic mixture due to the unequal reaction rates of the stereoisomer with chiral, non-racemic reagents or catalysts under kinetic conditions. ix) Stereo-oriented synthesis from non-racemic precursors—a synthetic technique that obtains the desired stereoisomer from a non-chiral starting material, wherein the stereochemical integrity is not or only minimally impaired during the synthesis process; x) Chiral liquid chromatography—a technique for separating stereoisomers of racemic mixtures in a liquid mobile phase by means of their different interactions with the stationary phase. The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce different interactions; xi) Chiral gas chromatography – a technique for separating stereoisomers by volatilizing racemic mixtures and separating them by their different interactions with a chromatographic column containing a fixed non-racemic chiral adsorbent phase in a gas mobile phase. xii) Chiral solvent extraction – a technique for separating stereoisomers by preferentially dissolving a stereoisomer to form a specific chiral solvent; xiii) Transchiral membrane transport—a technique for bringing a racemic mixture into contact with a membrane barrier. The barrier typically separates two miscible fluids, one of which contains a racemic mixture, and driving forces such as concentration or pressure differential cause preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one stereoisomer of the racemic mixture to pass through.

[0217] In some or any embodiment, the present invention provides compositions of compounds comprising a substantially pure, specified stereoisomer of the compound. In some or any embodiment, in the methods and compounds of the present invention, the compound is substantially free of other stereoisomers. In some or any embodiment, the composition comprises at least 85 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt%, or 100 wt% of the specified stereoisomer of the compound, with the remainder comprising other chemical substances or stereoisomers. Isotope-enriched compounds

[0218] The present invention also provides isotope-enriched compounds.

[0219] Previous studies using certain classes of drugs have demonstrated that isotopic enrichment of drugs (in some or any of the embodiments, deuteration) can improve pharmacokinetic (“PK”), pharmacodynamic (“PD”) and toxicity profiles. See, for example, 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] In some or any of the embodiments, isotopic enrichment of a drug can be used to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) reduce the number of doses required to achieve the desired effect, (4) reduce the amount of dose necessary to achieve the desired effect, (5) increase the formation of active metabolites (if any), and / or (6) reduce the production of harmful metabolites in specific tissues and / or create more effective and / or safer drugs for combination therapy, whether the combination therapy is intentional or unintentional.

[0221] Replacing one of the isotopes of a chemical reaction typically results in a change in the reaction rate. This phenomenon is known as the kinetic isotope effect (“KIE”). For example, if the CH bond breaks during the rate-determining step of a chemical reaction (i.e., the step with the highest transition state energy), then replacing hydrogen with deuterium will result in a decrease in the reaction rate, and the process will slow down. This phenomenon is known as the 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 the CH bond breaks and the rate of the same reaction in which deuterium substitutes for hydrogen. The DKIE can range from about 1 (without isotope effects) to very large values, such as 50 or more, meaning that the reaction can be 50 times or more slower when deuterium substitutes for hydrogen. High DKIE values ​​may be partly attributed to a phenomenon known as the tunneling effect, a consequence of the uncertainty principle. The tunneling effect is attributed to the smaller mass of the hydrogen atom and occurs because transition states involving protons can sometimes form in the absence of the required activation energy. Since the mass of deuterium is greater than that of hydrogen, this phenomenon is statistically much less likely to occur.

[0223] Tritium (“T”) is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with two neutrons in its nucleus and an atomic weight close to three. It exists naturally in the environment at very low concentrations, most commonly as T₂O. Tritium decays slowly (half-life = 12.3 years), releasing low-energy beta particles that cannot penetrate the outer layer of human skin. Internal radiation is the main hazard associated with this isotope, but it requires a large intake to pose a significant health risk. Compared to deuterium, a smaller amount of tritium must be consumed before reaching dangerous levels. Displacing hydrogen with tritium (“T”) creates stronger bonds than deuterium and produces a numerically larger isotopic effect. Similarly, isotopic substitutions of other elements, including but not limited to… 13 C or 14 C replaces carbon, 33 S. 34 S, or 36 S replaces sulfur, 15 N replaces nitrogen, and 17 O or 18 O replacing oxygen can produce similar kinetic isotope effects.

[0224] For example, DKIE can be used to reduce the hepatotoxicity of halothanes by hypothesizing the restriction of the formation of reactive substances such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For instance, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching asserts that a foreign metabolite, isolated by a phase I enzyme, can transiently bind and recombine in various conformations before a chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large number of binding pockets in many phase I enzymes and the heterogeneity of many metabolic reactions. Metabolic switching can result in different proportions of known metabolites as well as entirely new metabolites. This new metabolic signature may transfer more or less toxicity.

[0225] In some embodiments, the compounds of the present invention can be used as radiopharmaceuticals, for example, imaging agents. In one embodiment, the radiopharmaceutical is a positron emission tomography (PET) imaging agent. In such embodiments, a radionuclide (e.g., a positron emission isotope) replaces atoms in the compound to synthesize a radiopharmaceutical that can be used as an imaging agent. In some embodiments, the radionuclides that can be replaced in the compounds of the present invention include, but are not limited to, those mentioned above. 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] Animals express various enzymes to remove foreign substances, such as therapeutic agents, from their circulatory system. In some or any embodiment, these enzymes include cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases to 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) π bonds. The resulting metabolites may be stable or unstable under physiological conditions and may have significantly different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity characteristics relative to the parent compound. For many drugs, this oxidation reaction is rapid. Therefore, these drugs often require multiple or high-dose daily administration.

[0227] Therefore, compared with similar compounds having a natural isotopic composition, the isotopic enrichment at certain locations of the compounds provided by the present invention will produce detectable KIE, which will affect the pharmacokinetic, pharmacological and / or toxicological characteristics of the compounds of the present invention. Preparation of compounds

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

[0229] Additional steps and reagents not provided in the exemplary preparation methods are known to those skilled in the art. For example, intermediates and compounds can be prepared using methods known to those skilled in the art or methods disclosed in International Patent Applications PCT / US2019 / 058251 and PCT / US2019 / 058999 (wherein all disclosed synthetic methods are incorporated herein by reference in their entirety). Exemplary preparation methods are described in detail in the embodiments of the present invention.

[0230] In one or more embodiments, the present invention provides a method for preparing the compounds of the present invention according to any of the following schemes: in, R 1 In each case, it is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two of the R 1 Connected to It is formed on the adjacent carbon atom of the ring, and together with the adjacent carbon atom to which it is attached. Where * represents The shared carbon atom described in the text, and any other R 1 Each of the following is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: being R 3 Replaced and optionally by (R) 3a ) q Replacement C6-C 10 Aryl; R 3 Replaced and optionally by (R) 3a ) q A heteroaryl group consisting of 5 to 10 substituted atoms; optionally replaced by (R 3a ) q1 Replacement Optional land cover (R) 3a ) q1 Replacement Or optionally by (R) 3a ) q1 Replacement W 1It is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 Each is -C-, W 2 With W 3 The dotted bond between them is a double bond, and It is a partially unsaturated carbon ring, benzo[a] ring, a partially unsaturated heterocycle of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One is -C-, the other is -N-, W 2 With W 3 The dotted keys between them are single keys, and It is a heterocycle composed of 5 or 6 atoms, wherein the heterocycle composed of 5 or 6 atoms optionally includes an additional N atom and wherein the remaining ring atoms are all C; R 2 In each case, it is independently H, halogen, C1-C6 alkyl, or halo-C1-C6 alkyl; or Two R's 2 Each atom is attached to an adjacent carbon atom and together with the attached carbon atom forms a carbon ring of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups; and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; or Two R's 2 All are attached to the same carbon atom and together with the attached carbon atom form a carbon ring of 3 to 7 atoms, the ring optionally being substituted by 1, 2 or 3 groups independently selected from halogens and C1-C6 alkyl groups; and the remaining R 2 In each case, it is independently H, halogen, or C1-C6 alkyl; R 3 It is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6 alkyl, halo-C1-C3 alkyl, C3-C6-cycloalkyl, heterocyclic alkyl consisting of 3 to 6 atoms, or Wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the heterocyclic alkyl consisting of 3 to 6 atoms are optionally substituted with a -NH2; and wherein the alkyl in the amino-C1-C6 alkyl is optionally further substituted with 1, 2, 3 or 4 halogens; R 3a In each case, it is independently H, halogen, C1-C3 alkyl, or C3-C6 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; To obtain the compounds disclosed in this invention, or pharmaceutically acceptable salts thereof and / or isomers thereof; and optionally to isolate the compounds disclosed in this invention.

[0231] In one or more embodiments, the present invention provides a method for preparing the compounds disclosed herein according to any of the following schemes: in, A is R 3 Substituted phenyl, by R 3 The substituted pyridyl group is R 3 Substituted benzoxoxazolyl group, unsubstituted pyrazolyl group, by R 3 Substituted pyrazol group, or W 1 It is -N= or -C(H)=; Each R 1 Each of the following can be independently H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, or halogen; Each R 2 Each can be independently H, C1-C6 alkyl, or halogen; R 3 It is -C(O)NH2, -NH2, -S(O)2NH2, -S(O)2CH3, or m is 1 or 2; n is 0, 1, or 2; and p is 0, 1, 2, or 3; To obtain the compounds disclosed in this invention; and b) Optionally isolate the compounds disclosed in this invention.

[0232] Those skilled in the art will understand that the order of steps in any process method described in this invention can be changed. Other variations will be obvious to those skilled in the art, and all such variations are included within the scope of the embodiments described in this invention. Pharmaceutical Compositions and Administration

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

[0234] The method provided by the present invention includes administering alone a pharmaceutical composition containing at least one compound of the present invention (including compounds of formula (I), (I-P1), or (I-P2), which may be in salt form if suitable), or in combination with one or more compatible and pharmaceutically acceptable carriers (e.g., diluents or adjuvants) or in combination with another drug for treating pain and / or conditions regulated by voltage-gated sodium ion channels.

[0235] In some or any of the embodiments, the second drug may be formulated or packaged with the compound provided by the present invention. Of course, when it is in the judgment of someone skilled in the art that such co-formulation should not interfere with the activity or method of administration of any drug, the second drug will be formulated only with the compound provided by the present invention. In some or any of the embodiments, the compound provided by the present invention and the second drug are formulated separately. For the convenience of those skilled in the art, they may be packaged together or separately.

[0236] In clinical practice, the active agents / medications provided by this invention can be administered / taken via any conventional route, particularly oral, parenteral, rectal, or by inhalation (e.g., in aerosol form). In some or any embodiment, the compounds provided by this invention are for oral administration.

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

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

[0239] As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs containing inert diluents such as water or liquid paraffin can be used. These compositions may also contain substances other than diluents, and in some or any of the embodiments, include wetting agents, sweeteners, or flavoring agents.

[0240] Compositions for parenteral administration can be emulsions or sterile solutions. Propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or injectable organic esters can be used as solvents or mediators; in some or any embodiments, ethyl oleate is used as a solvent or mediator. These compositions may also contain adjuvants, particularly wetting agents, isotonic agents, emulsifiers, dispersants, and stabilizers. Sterilization can be performed in several ways, including in some or any embodiments using bacteriological filters, by radiation, or by heat. They can also be prepared as sterile solid compositions that are soluble in sterile water or any other injectable sterile medium upon use.

[0241] Compositions for rectal administration are suppositories or rectal capsules that contain excipients such as cocoa butter, semi-synthetic glycerides, or polyethylene glycol in addition to the active ingredient.

[0242] The composition may also be an aerosol. For use as a liquid aerosol, the composition may be a stable sterile solution or a solid composition dissolved in pyrogen-free sterile water, saline, or any other pharmaceutically acceptable solvent upon use. For use as a dry aerosol intended for direct inhalation, the active ingredient is finely separated and combined with a water-soluble solid diluent or solvent, and in some or any of the embodiments, with dextran, mannitol, or lactose.

[0243] In some or any embodiment, the compositions provided by this invention are pharmaceutical compositions or single-unit dosage forms. The pharmaceutical compositions and single-unit dosage forms provided by this invention comprise a preventative or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., the compounds provided by this invention or other prophylactic or therapeutic agents) and typically one or more pharmaceutically acceptable carriers or excipients. In specific embodiments and in this invention, the term "pharmaceuticalally acceptable" means a drug approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, particularly for humans. The term "carrier" includes diluents, adjuvants (e.g., Freund's adjuvants (complete and incomplete)), excipients, or mediators administered with the therapeutic agent. Such drug 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, etc. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions, glucose solutions, and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Examples of suitable drug carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0244] Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical art, and in some or any of the embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc. Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including but not limited to the manner in which the dosage form is administered to a subject and the specific active ingredient in the dosage form. If desired, the composition or single-unit dosage form may also contain small amounts of wetting agents or emulsifiers, or pH buffers.

[0245] The lactose-free compositions provided by this invention may contain excipients known in the art, as well as those listed in some or any of the embodiments in the United States Pharmacopeia (USP 36-NF 31S2). Typically, lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of an active ingredient, a binder / filler, and a lubricant. Exemplary lactose-free dosage forms contain the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0246] This invention further covers anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can promote the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical industry as a means of simulating long-term storage in order to determine characteristics such as shelf life or the stability of the formulation over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd ed., Marcel Dekker, New York, 1995, pp. 379-80. In fact, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of water on formulations can be significant because moisture and / or humidity are frequently encountered during manufacturing, handling, packaging, storage, transportation, and use of the formulation.

[0247] The anhydrous pharmaceutical compositions and dosage forms provided by this invention can be prepared using anhydrous or low-water-content components and low-humidity or low-humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine can be anhydrous if they are intended to be substantially in contact with moisture and / or humidity during manufacturing, packaging, and / or storage.

[0248] Anhydrous pharmaceutical compositions should be prepared and stored to maintain their anhydrous properties. Therefore, materials known to prevent exposure to water can be used to package the anhydrous compositions so that they can be included in suitable formulation kits. In some or any embodiment, suitable packaging includes, but is not limited to, hermetically sealed foil, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0249] The present invention further provides pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the degradation rate of the active ingredient. Such compounds, referred to as "stabilizers" in this invention, include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0250] The pharmaceutical compositions and single-unit dosage forms may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral formulations may include standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such compositions and dosage forms will contain a preventative or therapeutically effective amount of a prophylactic or therapeutic agent, which, in some or any of the embodiments, is provided in a purified form along with a suitable amount of carrier to provide appropriate administration to the subject. The formulation should be suitable for the route of administration. In some or any of the embodiments, the pharmaceutical composition or single-unit dosage form is sterile and administered to the subject in a suitable form, in some or any of the embodiments to animal subjects such as mammalian subjects, and in some or any of the embodiments to human subjects.

[0251] The pharmaceutical composition is formulated to suit its intended route of administration. In some or any of the embodiments, the route of administration includes, but is not limited to, parenteral administration, such as intrathecal, epidural, local or regional peripheral nerve block, intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, oral, sublingual, inhalation, intranasal, transdermal, topical / external (including application to the eye, and in some embodiments to the cornea), transmucosal, intratumoral, intrasynovial, and rectal administration. In a specific embodiment, the composition is formulated according to conventional procedures for administration to humans via intravenous, subcutaneous, intramuscular, oral, intranasal, or topical / external (including application to the eye, and in some embodiments to the cornea). In a specific embodiment, the pharmaceutical composition is formulated according to conventional procedures for subcutaneous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic buffer solution. If necessary, the composition may also contain a solubilizer and a local anesthetic such as lidocaine to relieve pain at the injection site.

[0252] In some or any of these embodiments, the dosage forms include, but are not limited to: tablets; capsules; capsules, such as soft elastic gelatin capsules; flat capsules; lozenges; dispersants; suppositories; ointments; poultices; pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to subjects, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to subjects; and sterile solids (e.g., crystalline or amorphous solids) that can be reconfigured to provide a liquid dosage form suitable for parenteral administration to subjects.

[0253] The composition, shape, and type of dosage forms provided by this invention will generally vary depending on their intended use. In some or any embodiment, a dosage form for initial treatment of pain may contain one or more active ingredients in a larger amount than that contained in a dosage form for maintenance treatment of the same infection. Similarly, parenteral dosage forms may contain smaller amounts of one or more of their active ingredients compared to oral dosage forms for treating the same disease or condition. These and other forms of specific dosage forms included in this invention will vary from one another, as will be apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0254] Typically, the components of the composition are provided individually or in combination in unit dosage forms, and in some or any embodiment, as lyophilized powders or anhydrous concentrates, sealed in airtight containers such as ampoules or pouches indicating the amount of active agent. When the composition is administered by infusion, it can be dispensed using infusion bottles containing sterile pharmaceutical-grade water or saline. When the composition is administered by injection, ampoules of sterile water or saline for injection can be provided, allowing the components to be mixed prior to administration.

[0255] Typical dosage forms comprise the compounds provided by this invention or their pharmaceutically acceptable salts, solvates, or hydrates, administered daily in doses ranging from about 0.1 mg to about 1000 mg, either once daily in the morning or divided into several doses throughout the day with food. Specific dosage forms may contain about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500, or 1000 mg of the active compound. oral dosage form

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

[0257] In some or any of the embodiments, the oral dosage form is a solid and prepared under anhydrous conditions with anhydrous components, as described in detail in this invention. However, the scope of the compositions provided by this invention extends beyond anhydrous, solid oral dosage forms. Therefore, other forms are also described in this invention.

[0258] Typical oral dosage forms are prepared by thoroughly mixing the active ingredient with at least one excipient according to conventional pharmaceutical formulation techniques. The excipients can take various forms, depending on the desired formulation for administration. In some or any of these embodiments, excipients suitable for 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 these embodiments, excipients suitable for solid oral dosage forms (e.g., powders, tablets, capsules, and granules) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0259] Tablets and capsules represent the most advantageous oral dosage unit form due to their ease of administration, in which case solid excipients are used. If desired, tablets can be coated using standard aqueous or anhydrous techniques. This dosage form can be prepared by any pharmaceutical method. Typically, pharmaceutical compositions and dosage forms are prepared by uniformly and tightly mixing the active ingredient with a liquid carrier, a finely separated solid carrier, or both, and then, if necessary, shaping the product into the desired form.

[0260] In some or any of these embodiments, tablets may be prepared by compression or molding. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with excipients. Molded tablets may be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0261] In some or any of the embodiments, excipients suitable for oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for 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 gum arabic, sodium alginate, alginic acid, other alginates, powdered astragalus gum, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., numbers 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0262] In some or any embodiment, fillers suitable for the pharmaceutical compositions and dosage forms disclosed in this invention include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, glucose binders, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binders or fillers in the pharmaceutical compositions are typically present in an amount of about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

[0263] In some or any of these embodiments, suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH101, AVICEL PH 103, AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, U.S. Adhesives Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A particular adhesive is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581. Suitable anhydrous or low-moisture excipients or additives include AVICEL PH 103. TM Starch 1500LM.

[0264] A disintegrant is used in the composition to cause the tablets to disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant should be used to form a solid oral dosage form, neither too much nor too little, so as not to adversely alter the release of the active ingredient. The amount of disintegrant used may vary depending 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% by weight of disintegrant, specifically about 1% to about 5% by weight.

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

[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 mineral 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. In some or any embodiment, other lubricants include syloid silica gel (AEROSIL 200, manufactured by WRGrace, Baltimore, Maryland), condensed aerosols of synthetic silica (sold by Degussa, Plano, Texas), CAB O SIL (a pyrolytic silica product sold by Cabot, Boston, Massachusetts), and mixtures thereof. When lubricants are used, the amount of lubricant is generally less than about 1% by weight of the pharmaceutical composition or dosage form in which it is incorporated. Delayed-release formulation

[0267] The active ingredients, such as those provided in this invention, can be administered via a controlled-release method or through delivery devices well known to those skilled in the art. In some or any of these embodiments, but not limited to, 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; 5,739,108; 5,891,474; Those described in 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; each of which is incorporated herein by reference in its entirety. Such dosage forms can be used to provide sustained or controlled release of one or more active ingredients, wherein in some or any embodiment, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, percolation systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof are used to provide different proportions of desired release profiles. Suitable controlled-release formulations (including those described herein) known to those skilled in the art can be readily selected for the active ingredients provided by the present invention. Therefore, the present invention covers unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gel capsules, and sac tablets suitable for controlled release.

[0268] All controlled-release pharmaceutical preparations share the common goal of improving drug therapy / treatment, achieving a goal superior to that achieved by their non-controlling counterparts. Ideally, the use of optimally designed controlled-release formulations in drug therapy is characterized by curing or controlling disease / symptoms with the minimum amount of drug in the shortest time. The advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and increased subject compliance. Furthermore, controlled-release formulations can be used to influence the onset time of action or other characteristics, such as drug blood levels, and thus the occurrence of side effects (such as adverse reactions).

[0269] Most controlled-release formulations are designed to initially release a specific amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and then gradually and continuously release additional amounts of drug to maintain this level of therapeutic or preventative effect over a prolonged period. To maintain this constant drug level in the body, the drug must be released from the dosage form at a rate that replaces the amount metabolized and excreted from the body. The 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 via intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other routes of administration. 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); Saudeket 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 configured at an appropriate location on the subject, as determined by a technician, thus requiring only a portion of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled-release systems are discussed in Langer's review (Science 249:1527-1533 (1990)). The active ingredients can be dispersed in a solid matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of acrylic and methacrylate esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, which can be externally dispersed. Polymer films, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene, and propylene, ionomers of polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / ethyleneoxyethanol copolymers, are insoluble in body fluids. The active ingredient then diffuses through the external polymer film in a release rate control step. The percentage of the active ingredient in such parenteral compositions is highly dependent on their specific properties and the needs of the subject. Parenteral dosage form

[0271] In some or any of these embodiments, the present invention provides parenteral dosage forms. Parenteral dosage forms can be administered to subjects via various routes, including but not limited to subcutaneous, intravenous (including bolus), intramuscular, and intra-arterial administration. Because their administration typically bypasses the subject's natural defenses against contaminants, parenteral dosage forms are generally sterile or can be sterilized prior to administration to the subject. In some or any of these embodiments, parenteral dosage forms include, but are not limited to, solutions prepared for injection, dry preparations prepared for dissolution or suspension in pharmaceutically acceptable solvents for injection, suspensions prepared for injection, and emulsions.

[0272] Suitable solvents for providing parenteral dosage forms are well known to those skilled in the art. In some or any of the embodiments, suitable solvents include, but are not limited to: water for injection (USP); aqueous solvents, such as, but not limited to, sodium chloride injection, Ringer's solution, glucose injection, glucose and sodium chloride injection, and lactated Ringer's solution; water-miscible solvents, such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and anhydrous solvents, such as, but 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 active ingredients disclosed in this invention may also be incorporated into parenteral dosage forms. Transdermal, topical and mucosal formulations

[0274] This invention also provides transdermal, topical, and mucosal dosage forms. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, 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; 22nd edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febbiger, Philadelphia (1985). Dosage forms suitable for treating oral mucosal tissues can be formulated as mouthwashes or oral gels. Furthermore, transdermal dosage forms include "reservoir" or "matrix" patches that can be applied to the skin and worn for a specific period of time to allow the desired amount of active ingredient to penetrate.

[0275] Suitable excipients (e.g., carriers and diluents) and other materials that may be used to provide the transdermal, topical, and mucosal dosage forms covered by this invention are well known to those skilled in the pharmaceutical art and depend on the specific tissue to which a given pharmaceutical composition or dosage form will be applied. In light of this fact, typical excipients 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 that can form lotions, tinctures, creams, emulsions, gels, or ointments, all of which are non-toxic and pharmaceutically acceptable. Humectants or moisturizers may also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additives are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0276] Depending on the specific tissue to be treated, additional components may be used before, in combination with, or after treatment with the provided active ingredient. In some or any of the embodiments, a penetration enhancer may be used to assist in the delivery of the active ingredient to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl alcohols, and tetrahydrofuranyl alcohols; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (polyvinylpyrrolidone, povidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitol monostearate).

[0277] The pH of the pharmaceutical composition or dosage form, or the pH of the tissue to which the pharmaceutical composition or dosage form is applied, can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity, ionic strength, or tonicity of the solvent carrier can be adjusted to improve delivery. Compounds such as stearates can also be added to the pharmaceutical composition or dosage form to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients, thereby improving delivery. In this regard, stearates can be used as lipid carriers for formulations, as emulsifiers or surfactants, and as delivery enhancers or penetration enhancers. Different salts, hydrates, or solvates of the active ingredient can be used to further adjust the properties of the resulting composition. Dosage and unit dosage form

[0278] In human treatment, the physician will determine the dosing they deem most appropriate based on prophylactic or curative treatment and considering factors such as age, weight, stage of infection, and other factors specific to the patient being treated. In some or any of these embodiments, the adult daily dose is about 1 mg to about 1000 mg, or about 5 mg to about 250 mg, or about 10 mg to about 50 mg. In some or any of these embodiments, the dose is about 5 mg to about 400 mg per adult daily, or 25 mg to about 200 mg per adult daily. In some or any of these embodiments, a dose rate of about 50 mg to about 500 mg per day may also be considered. In some or any of these embodiments, the subcutaneous dose is about 1 mg to about 50 mg per day, or about 1 mg to about 25 mg per day, or about 1 mg to about 10 mg per day, or about 1 mg to about 20 mg per day, or about 5 mg to about 25 mg per day, or about 5 mg to about 20 mg per day, or about 10 mg to about 20 mg per day. In some or any of the embodiments, the oral dose is about 5 mg to about 250 mg daily, or about 5 mg to about 200 mg daily, or about 50 mg to about 100 mg daily, or about 75 mg to about 1125 mg daily, or about 10 mg to about 200 mg daily. In some embodiments, the mg / day dose is for adults. In a further aspect, the present invention provides a method for treating a subject with a condition and / or pain related to the function of voltage-gated sodium ion channels by administering to a subject in need a therapeutically or preventively effective amount of the compound provided by the present invention or a pharmaceutically acceptable salt thereof. The amount of the compound or composition that is therapeutically or preventively effective in treating the condition or one or more of its symptoms will vary depending on the nature and severity of the disease or condition and the route of administration / prescription of the active ingredient. The frequency and dose of administration will also vary based on factors specific to each subject, specifically depending on the particular therapy administered (e.g., a therapeutic or preventative agent), the severity of the disease, condition, or illness, the route of administration, and the subject's age, body, weight, response, and medical history. The effective dose can be extrapolated from the dose-response curves obtained from in vitro or animal model testing systems.

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

[0280] In some or any embodiments, the recommended daily dose range of the compositions provided by the present invention for the conditions described herein is from about 0.1 mg to about 1000 mg per day, administered as a single once-daily dose or divided into several doses throughout the day. In some or any embodiments, the daily dose is administered as two equal doses per day. In some or any embodiments, the daily dose is administered as three equal doses per day. In some or any embodiments, the daily dose is administered as four equal doses per day. In some or any embodiments, the daily dose range is from about 0.01 mg to about 400 mg per day, from about 0.1 mg to about 250 mg per day, from about 10 mg to about 200 mg per day, in other embodiments from about 10 mg to about 150 mg per day, and in further embodiments between about 25 mg and about 100 mg per day. In some cases, it may be necessary to use doses of active ingredients outside the scope disclosed in this invention, which will be apparent to those skilled in the art. Furthermore, it should be noted that clinicians or treating physicians will know how and when to interrupt, adjust, or terminate treatment based on the subject's response.

[0281] As will be readily apparent to those skilled in the art, different therapeutically effective amounts are applicable to different diseases and conditions. Similarly, amounts sufficient to prevent, control, treat, or improve such diseases / conditions but insufficient to cause or alleviate adverse reactions associated with the compositions provided by this invention are also included in the dosage and dosing frequency schedules described herein. Furthermore, when multiple doses of the compositions provided by this invention are administered to a subject, not all doses need to be identical. In some or any embodiment, the dose administered to the subject may be increased to improve the preventive or therapeutic effect of the composition, or its dose may be decreased to reduce one or more side effects experienced by a particular subject.

[0282] In some or any embodiment, based on the weight of the active compound, the dosage of the composition provided by the present invention administered for the prevention, treatment, control, or improvement of a subject's disease / condition or one or more symptoms thereof 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 composition provided by the present invention or said composition administered for the prevention, treatment, control, or improvement of a subject's disease / condition or one or more symptoms thereof 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, 0.1 mg to 5 mg, 0 Unit doses of 1 mg to 2.5 mg, 0.25 mg to 20 mg, 0.25 mg to 15 mg, 0.25 mg to 12 mg, 0.25 mg to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0283] In some or any of these embodiments, initial treatment or prophylaxis may be initiated with one or more loading doses of the compounds or compositions provided by the present invention, followed by one or more maintenance doses. In this embodiment, the loading dose may be, for example, about 6 mg to about 40 mg daily for one to five weeks, or about 10 mg to about 20 mg daily. The loading dose may be immediately followed by one or more maintenance doses. In some or any of these embodiments, each maintenance dose is independently about 1 mg to about 20 mg daily, between about 2.5 mg and about 15 mg daily, or between about 2.5 mg and about 8 mg daily. The maintenance dose may be administered daily and may be administered as a single dose or in divided doses.

[0284] In some or any of the embodiments, a dose of the compound or composition provided by the present invention may be administered to achieve a steady-state concentration of the active ingredient in the blood or serum of a subject. The steady-state concentration may be determined by measurement using techniques available to a person skilled in the art, or may be determined based on the subject's physical characteristics such as height, weight, and age. In some or any of the embodiments, a sufficient amount of the compound or composition provided by the present invention may be administered to achieve a steady-state concentration in the blood or serum of the subject 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 of the embodiments, a loading dose may be administered to achieve a steady-state concentration in the blood or serum 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 of the embodiments, a maintenance dose may be administered to achieve a steady-state concentration in the blood or serum of the subject 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 of the embodiments, the same composition may be repeatedly applied, and the applications may be spaced at intervals of 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 same preventative or therapeutic agent may be repeatedly applied, and the applications may be spaced at intervals of 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 embodiment, the present invention provides a unit dose comprising a compound or a pharmaceutically acceptable salt thereof suitable for administration. Such forms will be described in detail herein. In some or any embodiment, the unit dose comprises 1 to 1000 mg, 1 to 100 mg, or 10 to 50 mg of the active ingredient. In a particular embodiment, the unit dose comprises about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of the active ingredient. Such unit doses can be prepared according to techniques well known to those skilled in the art.

[0286] In some or any of the embodiments, the present invention provides a dosage of a second drug for combination therapy. In some or any of the embodiments, a dosage lower than that already or currently used to treat pain may be used in the combination therapy provided by the present invention. Recommended dosages of the second drug can be obtained from the knowledge of those skilled in the art. For those second drugs approved for clinical use, recommended dosages are described, for example, in Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Therapeutics. thEd, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57 th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ; each of these publications is incorporated herein by reference in its entirety.

[0287] In different implementations, the intervals are: less than 5 minutes, less than 30 minutes, 1 hour, about 1 hour, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours, about 5 hours to about 6 hours, about 6 hours to about 7 hours, about 7 hours to about 8 hours, about 8 hours to about 9 hours, about 9 hours to about 10 hours, about 10 hours to about 11 hours, and so on. The treatment / therapy (e.g., the compound provided by the present invention and the second drug) is administered approximately 11 to approximately 12 hours, at intervals of approximately 12 to 18 hours, at intervals of 18 to 24 hours, at intervals of 24 to 36 hours, at intervals of 36 to 48 hours, at intervals of 48 to 52 hours, at intervals of 52 to 60 hours, at intervals of 60 to 72 hours, at intervals of 72 to 84 hours, at intervals of 84 to 96 hours, or at intervals of 96 to 120 hours. In various embodiments, the treatment / therapy is administered no more than 24 hours or no more than 48 hours apart. In some or any of the embodiments, two or more treatments / therapyes are administered during the same patient visit. In other embodiments, the compound provided by the present invention and the second drug are administered simultaneously.

[0288] In other embodiments, the compound provided by the present invention and the second drug are administered at intervals of about 2 to 4 days, about 4 to 6 days, about 1 week, about 1 to 2 weeks, or more than 2 weeks.

[0289] In some or any of the embodiments, the same drug may be repeatedly administered, and the administration may be spaced at intervals of 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 same drug may be repeatedly administered, and the administration may be spaced at intervals of 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 of the embodiments, the compounds and second drugs provided by the present invention are administered to a patient in a specific order and at time intervals, or to a subject, such as a human, such that the compounds provided by the present invention can act synergistically with other drugs to provide a greater benefit than that of other administered drugs. In some or any of the embodiments, the second active agent may be administered simultaneously or sequentially at any different time points; however, if not administered simultaneously, it should be administered in a timely and sufficiently close manner to provide the desired therapeutic or preventative effect. In some or any of the embodiments, the compounds provided by the present invention and the second active agent exert their effects at overlapping times. Each second active agent may be administered separately in any suitable form and via any suitable route. In other embodiments, the compounds provided by the present invention are administered before, simultaneously with, or after the administration of the second active agent.

[0291] In some or any of the embodiments, the compounds provided by the present invention and the second drug are periodically administered to a patient. Periodic treatment includes administering a first drug (e.g., a first preventative or therapeutic agent) for a period of time, followed by administering a second and / or a third drug (e.g., a second and / or a third preventative or therapeutic agent) for a period of time, and repeating this sequential administration. Periodic treatment can reduce the development of resistance to one or more treatments, avoid or reduce the side effects of one of the treatments, and / or improve the efficacy of the treatment.

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

[0293] In other embodiments, the treatment is administered to the patient concurrently, i.e., a single dose of the second drug is administered alone at time intervals, allowing the compound provided by the present invention to act synergistically with the second active agent. In some or any embodiments, a component administered weekly may be co-administered with other components administered every two weeks or every three weeks. In other words, the dosing regimen is carried out concurrently even if the drug treatment is not performed simultaneously or on the same day.

[0294] The second drug may act additively or synergistically with the compounds provided by the present invention. In some or any embodiments, the compounds provided by the present invention may be administered simultaneously with one or more second drugs in the same pharmaceutical composition. In another embodiment, the compounds provided by the present invention may be administered simultaneously with one or more second drugs in different pharmaceutical compositions. In yet another embodiment, the compounds provided by the present invention may be administered before or after the administration of the second drug. Administration of the compounds provided by the present invention and the second drug via the same or different routes of administration, such as oral and parenteral administration, is also contemplated. In some or any embodiments, when the compounds provided by the present invention are administered simultaneously with a second drug that may produce adverse side effects (including, but not limited to, toxicity), the second active drug may advantageously be administered at a dose below the adverse side effect initiation threshold. Reagent test kit

[0295] This invention also provides a kit for treating pain and / or conditions related to voltage-gated sodium ion channel function or pain-related disorders. The kit may include the compounds or compositions provided by this invention, a second drug or composition, and instructions for use providing healthcare professionals with information on the treatment of pain or pain-related disorders / conditions. The instructions may be provided in printed form or on electronic media (such as floppy disks, CDs, or DVDs), or as a website address from which such instructions are obtained. The unit dose of the compounds or compositions provided by this invention, or the second drug or composition, may include a dose such that, when administered to a subject, a therapeutic or preventative effective plasma level of the compound or composition is maintained in the subject for at least one day. In some or any embodiment, the compound or composition may be included as a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0296] In some or any of the embodiments, suitable packaging may be provided. The term "packaging" as used in this invention includes a solid matrix or solid matrix or material commonly used in systems, capable of holding the compound provided by this invention and / or a second drug suitable for administration to a subject within a fixed range. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic foil stacks, etc. If electron beam sterilization technology is used, the packaging should have a sufficiently low density to allow for the sterilization of the contents. How to use

[0297] The present invention provides a method for treating a subject for symptoms and / or pain related to the function of a voltage-gated sodium ion channel, the method comprising exposing the subject to a therapeutically or preventively effective amount of a compound of formula (I), (I-P1), or (I-P2), including a single enantiomer, a mixture of enantiomer pairs, a single diastereomer, a mixture of diastereomers, a single stereoisomer, a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.

[0298] The present invention provides a method for treating a subject for a condition related to the function of a voltage-gated sodium ion channel, comprising administering a therapeutic or preventative amount of a compound of formula (I), (I-P1), or (I-P2) of the present invention or a pharmaceutical composition of the present invention.

[0299] In some embodiments, the subject is a human being. In one set of embodiments, the condition is pain or the condition is related to pain. In some embodiments, the condition is pain. In some embodiments, the condition is related to pain. In some embodiments, the pain is anesthetic 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 analgesics.

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

[0301] In some or any embodiment, the present invention provides a method for treating pain and / or conditions related to voltage-gated sodium ion channel function in a subject. In some or any embodiment, the method includes administering to a subject in need an amount of a compound that is effective in treating pain and / or conditions related to voltage-gated sodium ion channel function, in conjunction with a second drug administration that is effective in treating or preventing pain and / or conditions related to voltage-gated sodium ion channel function. The compound may be any compound described in this invention, and the second drug may be any second drug described in the art or in this invention. In some or any embodiment, the compound is in the form of a pharmaceutical composition or dosage form, as described in other aspects of the invention.

[0302] In some or any embodiments, the present invention provides a method for treating a subject for a condition related to the function of voltage-gated sodium ion channels. In some or any embodiments, the method includes administering to a subject in need a therapeutic or preventative amount of a compound that is effective in treating the condition related to the function of voltage-gated sodium ion channels, in combination with a second drug that is effective in treating the condition related to the function of voltage-gated sodium ion channels. The compound may be any compound described in this invention, and the second drug may be any second drug described in the art or in this invention. In some or any embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described in other aspects of the invention.

[0303] In some or any of the embodiments, the present invention provides suppression of NA ν Method 1.8, which includes enabling NA ν 1.8 Contact with compounds of formula (I), (I-P1), (I-P2) and compounds 1-51, 56, 59, 60, 82, 116, 119 and 169-206.

[0304] In some or any of the embodiments, the present invention provides suppression of NA ν Method 1.8, which includes enabling NA ν 1.8 Contact with compounds of formula (I), (I-P2), and compounds 1-127 and 169-206.

[0305] In some or any of the embodiments, the present invention provides suppression of NA ν Method 1.8, which includes enabling NA ν 1.8 Contact with the compounds of formula (I) and compounds 1-206.

[0306] In some or any of these implementations, the pain to be relieved, improved, treated, or prevented is associated with or selected from the following conditions: acute pain, anal fissure, back pain, chronic pain, dental pain, arthralgia, neck pain, neuropathic pain, obstetric pain, postherpetic neuralgia, herpes zoster, tension headache, trigeminal blepharospasm, pain associated with arrhythmia, focal dystonia, hyperhidrosis, muscle spasms, bladder relaxation, visceral pain, sympathetic maintenance pain, myositis pain, musculoskeletal pain, lower back pain, pain from sprains and strains, pain associated with functional bowel disorders, and non-cardiac chest pain. Pain associated with irritable bowel syndrome, pain associated with myocardial ischemia, toothache, dysmenorrhea, erythromelalgia, diabetic peripheral neuropathy, paroxysmal severe pain syndrome, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, postherpetic neuralgia, cancer pain, 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 pain associated with surgery (postoperative in some implementations; ophthalmic surgery in some implementations). In some or any implementations, the pain to be alleviated, improved, treated, or prevented refers to pain in an acute care setting, including postoperative pain. In some or any implementations, the pain to be alleviated, improved, treated, or prevented is pain in an acute care setting, including postoperative pain, and the compound is administered intravenously. In some or any implementations, the pain to be alleviated, improved, treated, or prevented is ocular pain. In some or any of the embodiments, the pain to be relieved, improved, treated, or prevented is ocular pain, and the compound is administered topically. In some or any of the embodiments, the pain to be relieved, improved, treated, or prevented is subacute or chronic pain. In some or any of the embodiments, the pain to be relieved, improved, 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 relieved, improved, 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 ion channel function is selected from pruritus, cough, epilepsy, Parkinson's disease, mood disorders, psychosis, amyotrophic lateral sclerosis (ALS), arrhythmia, glaucoma, ischemia, spasms, and obsessive-compulsive disorder. In some or any of the embodiments, the condition associated with voltage-gated sodium ion channel function is selected from pain, pruritus, cough, glaucoma, and ischemia. In some or any of the embodiments, the condition associated with voltage-gated sodium ion channel function is selected from pain, pruritus, and cough. In some or any of the embodiments, the condition associated with voltage-gated sodium ion channel function is pain.

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

[0309] In some or any of the embodiments, the compounds of the present invention are used to prevent pain or to prevent conditions related to the function of voltage-gated sodium ion channels.

[0310] In some or any of the embodiments, the compounds of the present invention are used to treat pain or to treat conditions related to the function of voltage-gated sodium ion channels. Test methods

[0311] The efficacy of the compound in treating pain and / or conditions related to the function of voltage-gated sodium ion channels can be determined using any testing method known to those skilled in the art. Exemplary assay methods are provided in other aspects of the invention. Second treatment agent

[0312] In some or any embodiment, the compounds and compositions provided by the present invention can be used in a method of treating pain and / or conditions related to voltage-gated sodium ion channel function, the method comprising further administration of a second drug that is effective in treating pain and / or pain-related conditions and / or conditions related to voltage-gated sodium ion channel function. The second drug can be any drug known to those skilled in the art that is effective in treating pain and / or pain-related conditions and / or conditions related to voltage-gated sodium ion channel function, including those currently approved by the U.S. Food and Drug Administration or other similar agencies outside the United States. In some or any embodiment, the second drug is a local anesthetic (in some or any embodiment, a steroid), an opioid, a vasoconstrictor, a glucocorticoid, an adrenergic drug (in some or any embodiment, an alpha agonist or a mixed central-peripheral alpha-2 agonist), a vanillin-like drug, an anti-inflammatory agent (e.g., an NSAID, or an anti-inflammatory agent associated with eye diseases, including cyclosporine and lifitegrast), or a chemopreservation enhancer. In some or any embodiment, the second drug is Na... V1.8 Inhibitor. In some or any embodiment, the chemical penetration enhancer includes anionic surfactants, cationic surfactants, and nonionic surfactants. In some or any embodiment, the second drug is bupivacaine, levobupivacaine, tetracaine, ropivacaine, adrenaline, phenylephrine, clonidine, sodium lauryl sulfate, sodium octyl sulfate, dodecyltrimethylammonium bromide, n-octyltrimethylammonium bromide, polyoxyethylene (20) sorbitol monolaurate, and / or polyoxyethylene (20) sorbitol monooleate.

[0313] In some or any of the embodiments, the compounds provided by the present invention can be administered in combination with / in combination with one second drug. In a further embodiment, the compounds provided by the present invention can be administered in combination with / in combination with two second drugs. In an even further embodiment, the compounds provided by the present invention can be administered in combination with / in combination with two or more second drugs.

[0314] The term "combination / in combination" as used in this invention includes the use of more than one therapy / treatment (e.g., one or more preventative and / or therapeutic agents). The use of the term "combination / in combination" does not limit the order in which the therapy / treatment (e.g., preventative and / or therapeutic agents) are administered to a subject with a disease. A first therapy / treatment (e.g., a preventative or therapeutic agent such as a compound described in this invention) may be administered to a subject with the disease before (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 prior), accompanied by or subsequently (e.g., after 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 prior) to the administration of a second therapy / treatment (e.g., a preventative or therapeutic agent).

[0315] The term "synergy" as used in this invention includes combinations / combinations of the compounds provided by this invention with another therapy / treatment (e.g., a preventative or therapeutic agent) that is already or currently used for the prevention, control, or treatment of a disease / condition, which is more effective than the additive effect of said therapy / treatment. The synergistic effect of a combination / combination of treatments (e.g., a combination / combination of preventative or therapeutic agents) allows for the use of one or more therapies / treatments at lower doses and / or less frequent administration of said therapy / treatment to a subject with the disease. The ability to utilize lower doses of therapies / treatments (e.g., preventative or therapeutic agents) and / or less frequent administration of said therapy / treatment reduces the toxicity associated with administering said therapy / treatment to the subject without reducing the efficacy of said therapy / treatment in preventing or treating the disease. Furthermore, synergy can improve the efficacy of the drug in preventing or treating a condition. Finally, the synergistic effect of combinations / combinations of treatments / therapies (e.g., a combination of preventative or therapeutic agents) can avoid or reduce side effects or adverse reactions associated with the use of any single treatment / therapy alone.

[0316] The active compounds provided by this invention can be combined with, in combination with, or alternately administered with another therapeutic agent, particularly a drug effective in treating pain and / or pain-related diseases / conditions and / or conditions related to the function of voltage-gated sodium ion channels. In combination therapy, effective doses of two or more drugs can be administered together, while in alternating or sequential therapy, effective doses of each drug can be administered continuously or sequentially. The administered dose will depend on the absorption, inactivation, and excretion rates of the drugs, as well as other factors known to those skilled in the art. It is noteworthy that dose values ​​may also vary with the severity of pain or the relief of pain-related diseases. It should be further understood that, for any particular subject, the specific dosing regimen and schedule should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the dosing of the composition. Example

[0317] As used in this invention, the symbols and conventions used in these methods, synthetic schemes and embodiments of this invention, whether or not specific abbreviations are specifically defined, are consistent with those used in contemporary scientific literature such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but not as a limitation, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromolar); Hz (hertz); MHz (megahertz); mmol (millimole); hr or hrs (hour); min (minute); MS (mass spectrometry); ESI (electrospray ionization); Ph (phenyl); TLC (thin-layer chromatography); HPLC (high-performance liquid chromatography); THF (tetrahydrofuran); CDCl3 (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide); EtOAc (ethyl acetate); MeOH (methanol); Tces (2,2,2-trichloroethoxysulfonyl); -Si(t-Bu)(Ph)2 and -Si t BuPh2 (tert-butyldiphenylsilyl); and BOC (tert-butoxycarbonyl). AZADO refers to... CDI refers to

[0318] For all the following examples, standard post-processing and purification methods known to those skilled in the art can be used. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methodologies illustrated in this invention are intended to illustrate applicable chemistry through specific examples, but do not represent the scope of the invention. Synthesis Examples Compound 1 Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-(S-methylsulfinimino)phenyl)quinoline-3-carboxamide Synthesis of 2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxylic acid

[0319] Potassium carbonate (345 mg, 2.5 mmol) was added to a mixture of 2-chloroquinoline-3-carboxylic acid (104 mg, 0.5 mmol) and 4,4-difluoroazacycloheptan hydrochloride (85.5 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred at 60 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and then 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 using a 0-100% ethyl acetate / hexane gradient to give 2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxylic acid as a yellow oil. Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-(methylthio)phenyl)quinoline-3-carboxamide Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-(S-methylsulfinimino)phenyl)quinoline-3-carboxamide

[0320] To a stirred solution of 2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxylic acid (18.5 mg, 0.06 mmol) in dichloromethane (2 mL), (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) were added. The reaction mixture was incubated at room temperature. The mixture was stirred for 15 minutes. Then, 7.4 μL (0.06 mmol) of 3-(methylthio)aniline was added to the reaction mixture and stirred at room temperature for 18 hours. The reaction progress was monitored by LCMS. After the reaction was complete, dichloromethane was removed under vacuum, and the resulting mixture was diluted with water and acetonitrile and purified by reversed-phase HPLC using a 5-95% acetonitrile / water gradient to give 2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-(methylthio)phenyl)quinoline-3-carboxamide as a white powder. Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-(S-methylsulfinimino)phenyl)quinoline-3-carboxamide

[0321] Ammonium carbonate (10.7 mg, 0.11 mmol) was added to a stirred solution of 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-(methylthio)phenyl)quinoline-3-carboxamide (25.8 mg, 0.056 mmol) in MeOH (3 mL), followed by (diacetoxyiodine)benzene (44.8 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 90 min. The reaction progress was monitored by LCMS. Methanol was removed under vacuum, and the crude product was diluted with water and acetonitrile and purified by reversed-phase HPLC using a 5-95% acetonitrile / water gradient to give 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-(S-methylsulfinimino)phenyl)quinoline-3-carboxamide as a white powder. LRMS (ESI): Calculated value [M+H] + :459.17, measured value:458.8.

[0322] 1 H NMR (400MHz, CD3CN) δ8.52(s,1H),8.43(s,1H),7.96(dd,J=8.0,1.8Hz,1H),7.93–7.85(m,2H),7.82–7.75(m,2H),7.66(t,J =8.0Hz,1H),7.52–7.45(m,1H),3.91–3.83(m,2H),3.73(t,J=5.8Hz,2H),3.23(s,3H),2.17–2.07(m,2H),2.03–1.97(m,4H). Compound 2 Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide Synthesis of 2-chloro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide

[0323] One drop of N,N-dimethylformamide was added to 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). 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 using an ethyl acetate / hexane gradient elution to give 2-chloro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide as a yellow oil. Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide

[0324] Potassium carbonate (22 mg, 0.16 mmol) was added to a solution of 2-chloro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide (14 mg, 0.04 mmol) and 4,4-difluoroazacycloheptan hydrochloride (7 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was stirred at 70 °C for 16 h, and then at 80 °C for 18 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, 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 reversed-phase HPLC to give 2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide as a white solid. LRMS(ESI): Calculated value [M+H] + :461.15, measured value:460.9.

[0325] 1 H NMR (400MHz, CD3CN) δ8.44(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. 0Hz,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-difluoroazacycloheptane-1-yl)quinoline-3-carboxamide Synthesis of (5-(2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxamido)benzo[d]isoxazol-3-yl)tert-butyl carbamate

[0326] One drop of N,N-dimethylformamide was added 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). The reaction mixture was stirred at room temperature for 15 min. Then, a solution of (5-aminobenzo[d]isoxazol-3-yl)carbamate tert-butyl ester (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 h. Dichloromethane was removed under vacuum, and the crude mixture was purified by reversed-phase HPLC to give (5-aminobenzo[d]isoxazol-3-yl)carbamate tert-butyl ester as a white solid. Synthesis of N-(3-aminobenzo[d]isoxazol-5-yl)-2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxamide

[0327] Trifluoroacetic acid (300 μL) was added to a solution of (26 mg, 0.05 mmol) of tert-butyl carbamate in dichloromethane (5 mL). The reaction mixture was stirred for 2 hours, and then the volatiles were removed under vacuum. The crude mixture was purified by combiflash chromatography using a 0-100% ethyl acetate / hexane gradient to give tert-butyl carbamate as a pale yellow oil. LRMS (ESI): Calculated value [M+H] + :438.17, measured value:437.9.

[0328] 1H NMR(400MHz,CD3CN)δ8.31(s,1H),8.29–8.26(m,1H),7.78(d,J=8.1Hz,1H),7.72–7.57(m,3H),7.41(d,J=9.0Hz,1H), 7.37–7.28(m,1H),3.84–3.76(m,2H),3.65(t,J=6.0Hz,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-difluoroazacycloheptane-1-yl)quinoline-3-carboxamide Synthesis of methyl 3-(2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carbamate)benzoate

[0329] One drop of N,N-dimethylformamide was added 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). 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. Dichloromethane was removed under vacuum, and the crude mixture was purified by reversed-phase HPLC to give methyl 3-(2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxamido)benzoate as a white solid. Synthesis of N-(3-carbamoylphenyl)-2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxamide

[0330] Methyl 3-(2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxamido)benzoate (19 mg, 4.3 mmol) was mixed with 7N ammonia / methanol (5 mL) in a sealed vial and reacted at 50 °C for 18 hours. Volatile substances were removed under vacuum, and the crude mixture was purified by reversed-phase HPLC to obtain N-(3-carbamoylphenyl)-2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxamide as a white solid. LRMS(ESI): Calculated value [M+H] + :425.18, measured value:424.9.

[0331] 1H NMR(400MHz, CDCl3)δ8.17(s,1H),7.88–7.78(m,2H),7.65–7.57(m,2H),7.54–7.46(m,2H),7.33(t,J=7.9Hz,1H),7 .19(t,J=7.5Hz,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 Synthesis of 2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide

[0332] Potassium carbonate (22 mg, 0.16 mmol) was added to a solution of 2-chloro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide (14 mg, 0.04 mmol) and 4,4-difluoro-3-methylpiperidine hydrochloride (7 mg, 0.04 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was stirred at 70 °C for 16 h, and then at 80 °C for 18 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, 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 reversed-phase HPLC to give 2-(4,4-difluoro-3-methylpiperidin-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide as a white solid. LRMS(ESI): Calculated value [M+H] + :461.15, measured value:460.9.

[0333] 1 H NMR (400MHz, CDCl3) δ10.70(s,1H),8.85(s,1H),8.49–8.40(m,1H),7.93(d,J=8.4Hz,1H),7.87(d,J=8.0Hz,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=6.8Hz,3H). Compound 6 Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-7-fluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide Synthesis of 2-chloro-7-fluoroquinoline-3-carboxylic acid

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

[0335] At room temperature, potassium carbonate (2.21 g, 12 mmol) and potassium dimethylformamide (0.60 mL, 9.97 mmol) were added to a solution of 2-chloro-7-fluoroquinoline-3-carboxylic acid (0.9 g, 3.99 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with ice water and then 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-carboxylic acid, a pale yellow solid. Synthesis of methyl 2-(4,4-difluoroazacycloheptane-1-yl)-7-fluoroquinoline-3-carboxylate

[0336] Potassium carbonate (1.27 g, 12 mmol) was added to a mixture of methyl 2-chloro-7-fluoroquinoline-3-carboxylate (550 mg, 2.3 mmol) and 4,4-difluoroazacycloheptane hydrochloride (0.59 g, 3.44 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice water and then 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 using a 40–50% ethyl acetate / hexane gradient to give methyl 2-(4,4-difluoroazacycloheptan-1-yl)-7-fluoroquinoline-3-carboxylate as a yellow solid. Synthesis of 2-(4,4-difluoroazacycloheptane-1-yl)-7-fluoroquinoline-3-carboxylic acid

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

[0338] At 0 °C, oxaloyl chloride (0.16 g, 1.2 mmol) and one drop of anhydrous N,N-dimethylformamide were added to a solution of 2-(4,4-difluoroazacycloheptane-1-yl)-7-fluoroquinoline-3-carboxylic acid (0.2 g, 0.62 mmol) in anhydrous dichloromethane (2 mL). The reaction mixture was stirred at 0 °C for 30 min. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was evaporated under vacuum under a nitrogen atmosphere. The crude residue was dissolved in anhydrous dichloromethane (6 mL), and 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) was added to the resulting solution at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was diluted with dichloromethane and then washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude residue was purified by silica gel column chromatography, eluting with a 20-50% ethyl acetate / hexane gradient, to give 2-(4,4-difluoroazacycloheptan-1-yl)-7-fluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide as a white solid. MS (ESI): Calculated value [M+H] + :479.14, measured value:479.21.

[0339] 1H NMR (400MHz, DMSO-d6): δ10.95(s,1H),8.37(s,1H),8.31(s,1H),7.94(t,J=8Hz,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=3.2Hz,2H),3.60(t,J=5.6Hz,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-difluoroazacycloheptan-1-yl)-N-(3-methanesulfonylphenyl)quinoxaline-2-carboxamide

[0340] At 0 °C, (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 to a solution of 3-(4,4-difluoroazacycloheptan-1-yl)quinoxalo-2-carboxylic acid (0.2 g, 0.65 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture was stirred at this temperature for 15 minutes. Then, 3-methanesulfonyl aniline (0.1 g, 0.65 mmol) was added. 3 g (0.78 mmol) was used to stir the reaction mixture at room temperature for 12 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under vacuum to give the crude product. The crude product was purified by rapid column chromatography using a 40-50% ethyl acetate / hexane gradient to give 3-(4,4-difluoroazacycloheptan-1-yl)-N-(3-methanesulfonylphenyl)quinoxalin-2-carboxamide as a yellow solid. MS (ESI): Calculated value [M+H] + :461.15, measured value:461.20.

[0341] 1H NMR (400MHz, DMSO-d6): δ11.40(s,1H),8.39(s,1H),8.08-8.06(m,1H),7.95-7.93(d,J=8Hz,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-Difluoroazacycloheptan-1-yl)-N-(3-(S-methylsulfinimino)phenyl)quinoxalin-2-carboxamide

[0342] At 0 °C, 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 to a solution of 3-(4,4-difluoroazacycloheptan-1-yl)quinoxaline-2-carboxylic acid (0.35 g, 1.15 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 15 minutes. Then, (3-aminophenyl)(imino)methyl-λ was added. 6 - Sulfophenone (0.23 g, 1.4 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the crude product. The crude product was purified by reversed-phase HPLC to give 3-(4,4-difluoroazacycloheptan-1-yl)-N-(3-(S-methylsulfinimino)phenyl)quinoxalin-2-carboxamide, as a white solid. MS (ESI): Calculated value [M+H] + :460.16, measured value:460.25.

[0343] 1H NMR (400MHz, DMSO-d6) δ11.31(s,1H),8.38(s,1H),8.031(d,J=8Hz,1H),7.95(d,J=8Hz,1H),7.71(d,J=8Hz,3H),7.65(t,J=8Hz,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-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoxalin-2-carboxamide Synthesis of methyl 3-hydroxyquinoxaline-2-carboxylate

[0344] A stirred solution of 10 g (52.6 mmol) of 2-hydroxyquinoline-3-carboxylic acid in methanol (100 mL) was cooled to 0 °C. Sulfuric acid (20 mL) was then added dropwise. The reaction mixture was heated at 70 °C for 12 hours. The reaction progress was monitored by TLC. After the reaction was complete, methanol was removed under vacuum. The resulting residue 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 a crude product. The crude product was ground with diethyl ether and pentane to obtain the desired product, methyl 3-hydroxyquinoxaloline-2-carboxylic acid, as a light orange solid. Synthesis of methyl 3-chloroquinoxaline-2-carboxylic acid ester

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

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

[0347] Lithium hydroxide (1.5 g, 62 mmol) and water (20 mL) were added to a solution of methyl 3-(4,4-difluoroazacycloheptan-1-yl)quinoxaloline-2-carboxylic acid (5 g, 15.6 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was evaporated under vacuum, the residue was diluted with water, acidified with 1 N hydrochloric acid solution, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by grinding with diethyl ether and pentane to obtain 3-(4,4-difluoroazacycloheptan-1-yl)quinoxaloline-2-carboxylic acid, a light brown solid. Synthesis of 3-(4,4-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoxalin-2-carboxamide

[0348] At 0 °C, N,N'-dicyclohexylcarbodiimide (0.24 mg, 1.17 mmol) and N,N-dimethylpyridin-4-amine (5.96 mg, 5 mol%) were added to a solution of 0.3 g (0.9 mmol) in dichloromethane (6 mL). Then, 3-aminobenzene-1-sulfonamide (0.2 mg, 1.17 mmol) was slowly added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was passed through a diatomaceous earth mat, the filtrate was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude residue was purified by rapid column chromatography using a 50-60% ethyl acetate / hexane gradient to give 3-(4,4-difluorozapylhexylcarbodiimide)-N-(3-aminosulfonylphenyl)quinoxalin-2-carboxamide as a yellow solid. MS(ESI): Calculated value [M+H]+ :462.14, measured value:462.20.

[0349] 1 H NMR (400MHz, DMSO-d6): δ11.27(s,1H),8.33(s,1H),7.94(d,J=8.4Hz,1H),7.91-7.88(m,1H),7.10(d,J=3.6Hz,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=7.5Hz,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-difluoroazacycloheptan-1-yl)-6-fluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide Synthesis of 2-chloro-6-fluoroquinoline-3-carboxylic acid

[0350] Silver nitrate (1.3 g, 7.6 mmol) was added to a stirred solution of 2-chloro-6-fluoroquinoline-3-carboxaldehyde (1 g, 4.8 mmol) in ethanol (30 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. Then, an 80% aqueous solution of sodium hydroxide (0.96 g, 24 mmol) in ethanol was added dropwise. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the solvent was rotary evaporated, diluted with water, acidified with 1N hydrochloric acid solution, and then 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-fluoroquinoline-3-carboxylic acid as a grayish-white solid. Synthesis of methyl 2-chloro-6-fluoroquinoline-3-carboxylic acid

[0351] At room temperature, potassium carbonate (1.4 g, 10 mmol) and iodomethane (0.5 mL, 8.3 mmol) were added to a solution of 2-chloro-6-fluoroquinoline-3-carboxylic acid (0.75 g, 3.3 mmol) in N,N-dimethylformamide (7.5 mL), and the mixture was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with ice water and then 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-6-fluoroquinoline-3-carboxylic acid, a pale yellow solid. Synthesis of methyl 2-(4,4-difluoroazacycloheptan-1-yl)-6-fluoroquinoline-3-carboxylate

[0352] At room temperature, 4,4-difluoroazinesepane hydrochloride (0.59 g, 3.45 mmol) and potassium carbonate (1.3 g, 9.2 mmol) were added 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). The reaction mixture was stirred at 80 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice 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 rapid column chromatography using a 20–30% ethyl acetate / hexane gradient to give methyl 2-(4,4-difluoroazinesepane-1-yl)-6-fluoroquinoline-3-carboxylate as a yellow solid. Synthesis of 2-(4,4-difluoroazacycloheptane-1-yl)-6-fluoroquinoline-3-carboxylic acid

[0353] At room temperature, lithium hydroxide (0.14 g, 3.2 mmol) was added to a stirred solution of methyl 2-(4,4-difluoroazacycloheptan-1-yl)-6-fluoroquinoline-3-carboxylic acid (0.55 g, 1.6 mmol) in methanol (5.5 mL), tetrahydrofuran (5.5 mL), and water (5.5 mL) (1:1:1). The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the solvent was removed by rotary evaporation, diluted with water, acidified with 1 N hydrochloric acid solution, and then 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-difluoroazacycloheptan-1-yl)-6-fluoroquinoline-3-carboxylic acid as a grayish-white solid. Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-6-fluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide

[0354] At 0 °C, oxaloyl chloride (0.2 mL, 2.5 mmol) and one drop of N,N-dimethylformamide were added to a stirred solution of 2-(4,4-difluoroazacycloheptan-1-yl)-6-methoxyquinoline-3-carboxylic acid (0.4 g, 1.2 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated under a nitrogen atmosphere, diluted with anhydrous dichloromethane (4 mL), and a mixture of 3-aminobenzenesulfonamide (0.25 g, 1.5 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.2 mmol) in anhydrous dichloromethane (4 mL) was added at 0 °C. The mixture was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water 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 rapid column chromatography using a 40-60% ethyl acetate / hexane gradient elution to give 2-(4,4-difluoroazacycloheptan-1-yl)-6-fluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide, as a grayish-white solid. MS (ESI): Calculated value [M+H] + :479.14, measured value:479.25.

[0355] 1 H NMR (400MHz, DMSO-d6): 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=6.0Hz,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-difluoroazacycloheptan-1-yl)-6,7-difluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide Synthesis of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid

[0356] Silver nitrate (1.1 g, 6.6 mmol) was added to a stirred solution of 2-chloro-6,7-difluoroquinoline-3-carboxaldehyde (1 g, 4.4 mmol) in ethanol (50 mL). The reaction mixture was stirred at room temperature for 30 minutes. An 80% aqueous solution of sodium hydroxide (0.88 g, 22 mmol) in ethanol was added dropwise. The reaction mixture was stirred at room temperature for 5 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the solvent was rotary evaporated, diluted with water, acidified with 1N hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic layers were 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

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

[0358] Potassium carbonate (2.2 g, 15.5 mmol) and 4,4-difluoroquinoline-3-carboxylic acid methyl ester (1 g, 3.9 mmol) were added to a solution of 2-chloro-6,7-difluoroquinoline-3-carboxylic acid methyl ester (1 g, 3.9 mmol) in N,N-dimethylformamide (10 mL). The resulting reaction mixture was heated to 70 °C and stirred for 16 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by combi-flash chromatography using a 30–50% ethyl acetate / heptane gradient to give 2-(4,4-difluoroquinoline-1-yl)-6,7-difluoroquinoline-3-carboxylic acid methyl ester as a white solid. Synthesis of 2-(4,4-difluoroazacycloheptane-1-yl)-6,7-difluoroquinoline-3-carboxylic acid

[0359] Lithium hydroxide (0.18 g, 4.2 mmol) was added to a 1:1 methanol (5.48 mL) / tetrahydrofuran (5.48 mL) solution of methyl 2-(4,4-difluoroazacycloheptane-1-yl)-6,7-difluoroquinoline-3-carboxylic acid. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was concentrated and the solvent was removed. 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-difluoroazacycloheptane-1-yl)-6,7-difluoroquinoline-3-carboxylic acid as a yellow solid. Synthesis of 2-(4,4-difluoroazacycloheptan-1-yl)-6,7-difluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide

[0360] At 0 °C, oxaloyl chloride (0.25 mL, 2.9 mmol) and one drop of anhydrous N,N-dimethylformamide were added to a solution of 2-(4,4-difluoroazacycloheptan-1-yl)-6,7-difluoroquinoline-3-carboxylic acid (0.5 g, 1.5 mmol) in 10 mL of anhydrous dichloromethane. The reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete, the reaction mixture was evaporated under vacuum. The crude residue was redissolved in anhydrous dichloromethane, and a solution of 3-aminobenzene-1-sulfonamide (0.3 g, 1.75 mmol) and N,N-diisopropylethylamine (0.76 g, 5.8 mmol) in 70 mL of dichloromethane was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was diluted with dichloromethane and then washed with water and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product. The crude material was purified by rapid chromatography with an elution gradient of 20-50% ethyl acetate / hexane to give 2-(4,4-difluoroazacycloheptane-1-yl)-6,7-difluoro-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide, a white solid. MS (ESI): Calculated value [M+H] + :497.13, measured value:497.15.

[0361] 1H NMR (400MHz, DMSO-d6): δ10.99(s,1H),8.33(s,1H),8.30(s,1H),7.94(t,J=9.6Hz,1H),7.85(d,J=8Hz,1H),7.61(s,1H), 7.58(d,J=8Hz,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-difluoroazacycloheptan-1-yl)-6-methoxy-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide Synthesis of 2-chloro-6-methoxyquinoline-3-carboxylic acid

[0362] Silver nitrate (1.7 g, 10 mmol) was added to a stirred solution of 2-chloro-6-methoxyquinoline-3-carboxaldehyde (1.4 g, 6.3 mmol) in ethanol (28 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, an 80% aqueous solution of sodium hydroxide (1.3 g, 32 mmol) in ethanol was added dropwise. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the solvent was rotary evaporated, diluted with water, acidified with 1N hydrochloric acid solution, and then 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 a grayish-white solid. Synthesis of methyl 2-chloro-6-methoxyquinoline-3-carboxylic acid

[0363] At room temperature, potassium carbonate (1.0 g, 7.6 mmol) and iodomethane (0.4 mL, 6.3 mmol) were added to a solution of 2-chloro-6-methoxyquinoline-3-carboxylic acid (0.6 g, 2.5 mmol) in N,N-dimethylformamide (6 mL). The mixture was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with ice water and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give methyl 2-chloro-6-methoxyquinoline-3-carboxylic acid, a pale yellow solid. Synthesis of methyl 2-(4,4-difluoroazacycloheptan-1-yl)-6-methoxyquinoline-3-carboxylate

[0364] At room temperature, 0.5 g (2 mmol) of methyl 2-chloro-6-methoxyquinoline-3-carboxylate in 10 mL of N,N-dimethylformamide was added to a stirred solution of 4,4-difluoroazacycloheptan hydrochloride (0.50 g, 3.0 mmol) and potassium carbonate (1 g, 8 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice 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 rapid column chromatography using a 30–50% ethyl acetate / hexane gradient to give methyl 2-(4,4-difluoroazacycloheptan-1-yl)-6-methoxyquinoline-3-carboxylate as a yellow solid. Synthesis of 2-(4,4-difluoroazacycloheptane-1-yl)-6-methoxyquinoline-3-carboxylic acid

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

[0366] At 0 °C, (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 to a stirred solution of 2-(4,4-difluoroazacycloheptan-1-yl)-6-methoxyquinoline-3-carboxylic acid (0.24 g, 0.71 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 8 hours. After the reaction was complete, the solvent was evaporated, diluted with acetonitrile (3 mL), and the 3-amino... Benzenesulfonamide (122 mg, 0.71 mmol) was added to the above solution, and the mixture was stirred at 70 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude residue was purified by rapid column chromatography using a 50-70% ethyl acetate / hexane gradient to give 2-(4,4-difluoroazacycloheptan-1-yl)-6-methoxy-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide as a yellow solid. MS (ESI): Calculated value [M+H] + :491.16, measured value:491.20.

[0367] 1 H NMR (400MHz, DMSO-d6): 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=6.0Hz,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-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide Synthesis of 2,6-dichloroquinoline-3-carboxylic acid

[0368] Silver nitrate (1.2 g, 7.1 mmol) was added to a stirred solution of 2,6-dichloroquinoline-3-carboxaldehyde (1.0 g, 4.4 mmol) in ethanol (30 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, an 80% aqueous solution of sodium hydroxide (0.88 g, 22 mmol) in ethanol was added dropwise, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the solvent was rotary evaporated, diluted with water, acidified with 1N hydrochloric acid solution, and then 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 a grayish-white solid. Synthesis of methyl 2,6-dichloroquinoline-3-carboxylic acid

[0369] At room temperature, potassium carbonate (1.5 g, 11 mmol) and iodomethane (0.6 mL, 9.3 mmol) were added to a solution of 2,6-dichloroquinoline-3-carboxylic acid (0.9 g, 3.7 mmol) in N,N-dimethylformamide (9 mL). The mixture was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with ice water and then 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-carboxylic acid as a pale yellow solid. Synthesis of methyl 6-chloro-2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxylate

[0370] At room temperature, 4,4-difluoroazacycloheptane hydrochloride (0.63 g, 4.7 mmol) and potassium carbonate (1.7 g, 12.5 mmol) were added to a stirred solution of methyl 2,6-dichloroquinoline-3-carboxylate (0.8 g, 3.1 mmol) in N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 80 °C for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with ice 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 rapid column chromatography using a 50-70% ethyl acetate / hexane gradient to give methyl 6-chloro-2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxylate as a yellow solid. Synthesis of 6-chloro-2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxylic acid

[0371] Lithium hydroxide (0.19 g, 4.5 mmol) was added to a stirred solution of methyl 6-chloro-2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxylic acid (0.8 g, 2.3 mmol) in a mixture of methanol (8 mL), tetrahydrofuran (8 mL), and water (8 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was rotary evaporated, diluted with water, acidified with 1N hydrochloric acid, and then 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-difluoroazacycloheptan-1-yl)quinoline-3-carboxylic acid as a yellow solid. Synthesis of 6-chloro-2-(4,4-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide

[0372] At 0 °C, 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 to a stirred solution of 6-chloro-2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxylic acid (0.33 g, 0.88 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solvent was rotary evaporated and diluted with acetonitrile (3 mL). The mixture was then refluxed with 0.18 g (1.1 mmol) of 3-aminobenzenesulfonamide for 16 hours. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with water and then 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 rapid column chromatography using a 50-70% ethyl acetate / hexane gradient to give 6-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide as a yellow solid. MS (ESI): Calculated value [M+H] + :495.11, measured value:495.20.

[0373] 1 H NMR (400MHz, DMSO-d6): δ10.99(s,1H),8.31(d,J=6.0Hz,2H),7.95(s,1H),7.85-7.83(m,1H),7.65-7.62(m,2H),7.60-7.5 5(m,2H),7.42(brs,2H),3.76-3.74(m,2H),3.61(t,J=6.0Hz,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-difluoroazacycloheptan-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide Synthesis of 2,7-dichloroquinoline-3-carboxylic acid

[0374] Silver nitrate (1.2 g, 7.1 mmol) was added to a stirred solution of 2,7-dichloroquinoline-3-carboxaldehyde (1.0 g, 4.4 mmol) in ethanol (20 mL). A solution of sodium hydroxide (0.9 g, 22 mmol) in water (3 mL) was added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth filter, and the solvent was removed by rotary evaporation to obtain a crude mixture. The crude mixture was diluted with water, acidified with 1N hydrochloric acid solution, and then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. The crude product was ground with diethyl ether and pentane to obtain 2,7-dichloroquinoline-3-carboxylic acid, a grayish-white solid. Synthesis of 7-chloro-2-(4,4-difluoroazacycloheptane-1-yl)quinoline-3-carboxylic acid

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

[0376] Under a nitrogen atmosphere, oxaloyl chloride (0.15 g, 1.0 mmol) was added to a solution of 7-chloro-2-(4,4-difluoroazacycloheptan-1-yl)quinoline-3-carboxylic acid (0.30 g, 0.90 mmol) in dichloromethane (6 mL), followed by the addition of 1-2 drops of N,N-dimethylformamide at 0 °C. The mixture was then allowed to react at room temperature for 1 hour. After the reaction was complete, the solvent was removed under a nitrogen atmosphere. The crude mixture was dissolved in dichloromethane (6 mL), and 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) was added to the resulting solution at 0 °C. The mixture was then stirred at room temperature for another 1 hour. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was quenched with water and then extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain the crude product. The crude residue was purified by rapid column chromatography, eluting with a 40-50% ethyl acetate / hexane gradient to give 7-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-N-(3-aminosulfonylphenyl)quinoline-3-carboxamide, a light brown solid. MS (ESI): Calculated value [M+H] + :495.11, measured value:495.15.

[0377] 1 H NMR (400MHz, DMSO-d6): δ10.98(s,1H),8.37(s,1H),8.30(s,1H),7.88-7.83(m,2H),7.64(d,J=1.6Hz,1H),7.58-7.54(m,2H),7.42(s ,2H),7.32(dd,J=2.4,8.8Hz,1H),3.77-3.74(m,2H),3.60(t,J=5.6Hz,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-difluoroazacycloheptane-1-yl)quinoxaline-2-carboxamide Synthesis of 3-chloroquinoxaline-2-carboxylic acid

[0378] A mixture of 3-hydroxyquinoxaloline-2-carboxylic acid (2 g, 9.6 mmol) and phosphorus oxychloride (20 mL) was slowly heated to 120 °C and maintained for 5 hours. After the reaction was complete, the reaction mixture was quenched with ice water and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude residue was ground with n-pentane and diethyl ether to give 3-chloroquinoxaloline-2-carboxylic acid as a yellow solid. Synthesis of 3-(4,4-difluoroazacycloheptane-1-yl)quinoxaloline-2-carboxylic acid

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

[0380] Under a nitrogen atmosphere, oxaloyl chloride (0.15 g, 2.7 mmol) and one drop of N,N-dimethylformamide were added to a solution of 3-(4,4-difluoroazacycloheptan-1-yl)quinoxaloline-2-carboxylic acid (0.4 g, 1.4 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was evaporated under a nitrogen atmosphere. The crude mixture was dissolved in dichloromethane (10 mL), and 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) was added to the resulting solution at 0 °C, and the mixture was st...

Claims

1. Compound represented by formula (I): in, R 1 , at each occurrence, is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two R's 1 Connect to on adjacent ring carbon atoms in the ring, and together with the adjacent carbon atoms to which it is attached, form * indicates The common carbon atom, and any remaining R 1 Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, halogenated C1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: R 3 substituted and optionally (R 3a ) q Substituted C6-C 10 Aryl; R 3 substituted and optionally (R 3a ) q substituted 5 to 10 atoms consisting of heteroaryl; optionally (R 3a ) q1 Replaced Optionally (R 3a ) q1 Replaced or optionally (R 3a ) q1 Replaced W 1 is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 -C-, W 2 With W 3 The virtual bond between is a double bond, and is a partially unsaturated carbocyclic ring of 5 to 8 atoms, a benzocyclic ring, a partially unsaturated heterocyclic ring of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One of them is -C- and the other is -N-, W 2 With W 3 The virtual bond between is a single bond, and is a 5 or 6-atom heterocyclic ring optionally containing an additional N atom and wherein the remaining ring atoms are C; R 2 , at each occurrence, is independently H, halogen, C1-C6 alkyl, or halogenated C1-C6 alkyl; or Two R's 2 are respectively connected to adjacent carbon atoms and together with the carbon atoms connected thereto form a carbon ring consisting of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogen and C1-C6 alkyl; and the remaining R 2 , at each occurrence, is independently H, halogen, or C1-C6 alkyl; or Two R's 2 are all connected to the same carbon atom and together with the carbon atom to which they are connected form a carbon ring consisting of 3 to 7 atoms, the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogen and C1-C6 alkyl; and the remaining R 2 , at each occurrence, is independently H, halogen, or C1-C6 alkyl; R 3 is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6-alkyl, halogenated C1-C3-alkyl, C3-C6-cycloalkyl, heterocycloalkyl composed of 3 to 6 atoms, or wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the 3 to 6 atoms consisting of heterocycloalkyl are each optionally substituted by one -NH2; and wherein the alkyl in amino-C1-C6 alkyl is optionally further substituted by 1, 2, 3 or 4 halogens; R 3a , at each occurrence, is independently H, halogen, C1-C3 alkyl, or C3-C6 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 pharmaceutically acceptable salt and / or an isomer thereof; Provided that the compound is not: 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt 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 pharmaceutically 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 pharmaceutically acceptable salt 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 pharmaceutically acceptable salt and / or an isomer thereof; or 2-(4,4-difluoroazepan-1-yl)-N-(3-sulfamoylphenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide, or a pharmaceutically acceptable salt and / or an isomer thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is R 3 substituted and optionally (R 3a ) q Substituted C6-C 10 Aryl, optionally wherein A is replaced by R 3 substituted and optionally (R 3a ) q Substituted phenyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is R 3 Substituted phenyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is in Indicates connection to R 3 .

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is in Indicates connection to R 3 .

6. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is R 3 substituted and optionally (R 3a ) q substituted heteroaryl groups of 5 to 10 atoms, or wherein A is replaced by R 3 substituted and optionally (R 3a ) q substituted 9-atom heteroaryl, or wherein A is replaced by R 3 substituted and optionally (R 3a ) q A substituted 10-atom heteroaryl group.

7. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is 8. The compound according to claim 1 or 6, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is R 3 substituted and optionally (R 3a ) q substituted 5 to 6 atoms of heteroaryl, or wherein A is replaced by R 3 substituted and optionally (R 3a ) q substituted 5-atom heteroaryl, or wherein A is replaced by R 3 substituted and optionally (R 3a ) q A substituted 6-atom heteroaryl group.

9. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is 10. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is selected from the group consisting of:

11. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is selected from the group consisting of: in Indicates connection to R 3 .

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 is H, -OH, -B(OH)2, -COOH, hydroxy-C1-C3 alkyl, -C(=NH)NH2, -C(O)NH2, NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C3 alkyl, halogenated C1-C3 alkyl, C3-C6-cycloalkyl, heterocycloalkyl composed of 3 to 6 atoms, or wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the 3 to 6 atoms composed of heterocycloalkyl are each optionally substituted by one -NH2; and wherein the alkyl in amino-C1-C3 alkyl is optionally further substituted by 1, 2, 3 or 4 halogens.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 is -C(O)NH2, -NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, or wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl.

14. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is pyrazolyl, and R 3 It's H.

15. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is pyridyl, and R 3 It is -S(O)2NHR, where R is H.

16. The compound according to claim 1, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: A is pyridyl, and R 3 It is -C(O)NH2.

17. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 It is -C(O)NH2.

18. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 It is -NH2.

19. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 is -S(O)2NHR, optionally wherein R is C1-C3 alkyl, or optionally wherein R is C3-C5 cycloalkyl.

20. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 It is -S(O)2NH2.

21. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 It is -S(O)2C1-C6-alkyl.

22. The compound according to any one of claims 1 to 13 and 21, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 It is -S(O)2CH3.

23. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 yes 24. The compound according to any one of claims 1 to 13 and 23, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 3 yes 25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: yes Where W 4 is O or S; One R 1 It can be R as shown in the above ring 1a ;and R 1a is H, halogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl; or a pharmaceutically acceptable salt and / or an isomer thereof.

26. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: yes One R 1 It can be R as shown in the above ring 1a ;and R 1a is H, halogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl.

27. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: yes Where W 4 is O or S; One R 1 It can be R as shown in the above ring 1a ;and R 1a is H, halogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl.

28. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: yes One R 1 It can be R as shown in the above ring 1a ;and R 1a is H, halogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl.

29. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: yes One R 1 It can be R as shown in the above ring 1a ;and R 1a is H, halogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl.

30. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: yes Where R 1a is H, halogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-cycloalkylC1-C3-alkyl.

31. The compound according to any one of claims 27 to 30, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 1a It's H.

32. The compound according to any one of claims 27 to 30, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 1a It's a halogen.

33. A compound according to any one of claims 27 to 30, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 1a It is C1-C6-alkyl.

34. The compound according to any one of claims 27 to 30, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein: R 1a It is C3-C6-cycloalkyl.

35. The compound according to any one of claims 27 to 30, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: R 1a It is C3-C6-cycloalkylC1-C3-alkyl.

36. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: There exists an R 1 , and R 1 Not for H.

37. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: There are two R 1 , and each R 1 are each independently not H.

38. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: There are three R 1 , and each R 1 are each independently not H.

39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 1 is a C1-C6 alkyl group, optionally wherein at least one R 1 It is -CH3.

40. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 1 is a C1-C6 alkoxy group, optionally wherein at least one R 1 It is -OCH3.

41. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 1 is a C1-C6 haloalkyl group, optionally wherein at least one R 1 It is -CF3.

42. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 1 It's a halogen.

43. A compound according to any one of claims 1 to 38 and 42, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 1 It is –Cl.

44. A compound according to any one of claims 1 to 38 and 42, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 1 Yes – F.

45. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 1 is a halogenated C1-C6 alkoxy group, optionally wherein at least one R 1 Yes - OCF3.

46. ​​A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: Each R 1 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and halogen.

47. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: Each R 1 They are H respectively.

48. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: Two R's 1 Connect to on adjacent ring carbon atoms in the ring, and together with the adjacent carbon atoms to which it is attached, form * indicates The common carbon atom, and any remaining R 1 Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, halo-substituted C1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl.

49. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: There exists an R 2 , and R 2 Not for H.

50. The compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: There are two R 2 , and each R 2 are each independently not H.

51. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: There are three R 2 , and each R 2 are each independently not H.

52. A compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 2 It's a halogen.

53. A compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 2 Yes – F.

54. A compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 2 It is a C1-C6 alkyl group.

55. A compound according to any one of claims 1 to 51 and 54, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: At least one R 2 It is -CH3.

56. A compound according to any one of claims 1 to 48, 50 and 51, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: Two R's 2 are respectively connected to adjacent carbon atoms and together with the carbon atoms connected thereto form a carbon ring consisting of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogen and C1-C6 alkyl; and the remaining R 2 , in each case, independently H, halogen, or C1-C6 alkyl; or wherein two R 2 are all connected to the same carbon atom and together with the carbon atom to which they are connected form a carbon ring consisting of 3 to 7 atoms, the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogen and C1-C6 alkyl; and the remaining R 2 , at each occurrence, is independently H, halogen, or C1-C6 alkyl.

57. A compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: Each R 2 Each is independently selected from C1-C6 alkyl and halogen.

58. A compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: Each R 2 They are H respectively.

59. A compound according to any one of claims 1 to 58, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: m is 1 or 2.

60. The compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: m is 2.

61. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: W 1 Yes - N =.

62. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: W 1 It is -C(H)=.

63. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: W 1 It is -C(C1-C6 alkyl)=.

64. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt and / or an isomer thereof, wherein: W 1 It is -C(C1-C6alkoxy)=.

65. The compound according to claim 1, or a pharmaceutically acceptable salt and / or isomer thereof, selected from the group consisting of compounds provided in Table A.

66. A pharmaceutical composition comprising the compound according to any one of claims 1 to 65, or a pharmaceutically acceptable salt 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, optionally wherein the injectable composition is a subcutaneous injectable composition.

68. Treat subjects with voltage-gated sodium channel function including Na V 1.8 A method for treating a disease related to the present invention, the method comprising administering a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 65 or a pharmaceutical composition according to any one of claims 66 to 67.

69. The method of claim 68, wherein: The subject is a human.

70. The method of claim 68 or 69, wherein: The condition is pain, or wherein the condition is associated with pain.

71. The method of claim 68 or 69, wherein: The condition is pain.

72. The method of claim 68 or 69, wherein: The condition is associated with pain.

73. The method according to any one of claims 68 to 72, wherein: 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 headaches, pain associated with migraines, pain associated with sciatica, pain associated with endometriosis, pain associated with fibromyalgia, postoperative pain, subacute pain, chronic pain, 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, pain associated with ocular surgery, pain associated with epilepsy, pain associated with Parkinson's disease, mood disorders, psychosis, pain associated with amyotrophic lateral sclerosis, glaucoma, ischemia, spasticity, and obsessive-compulsive disorder.

74. The method of claim 68 or 69, wherein: The condition is selected from the group consisting of acute pain, subacute pain, postoperative pain, and ocular pain.

75. Inhibition of NA V 1.8 method, which includes making NA V 1.8 Contacting with a compound according to any one of claims 1 to 65.

76. A compound represented by any of the following general formulas, or a salt and / or an isomer thereof: in, R 1 , at each occurrence, is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, haloC1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; or Two R's 1 Connect to on adjacent ring carbon atoms in the ring, and together with the adjacent carbon atoms to which it is attached, form * indicates The common carbon atom, and any remaining R 1 Each is independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, halogenated C1-C6 alkoxy, C3-C6-cycloalkyl, and C3-C6-cycloalkylC1-C3-alkyl; A is: R 3 substituted and optionally (R 3a ) q Substituted C6-C 10 Aryl; R 3 substituted and optionally (R 3a ) q substituted 5 to 10 atoms consisting of heteroaryl; optionally (R 3a ) q1 Replaced Optionally (R 3a ) q1 Replaced or optionally (R 3a ) q1 Replaced W 1 is -N=, -C(H)=, -C(halogen)=, -C(C1-C6 alkyl)=, -C(cyclopropyl)=, or -C(C1-C6 alkoxy)=; W 2 and W 3 -C-, W 2 With W 3 The virtual bond between is a double bond, and is a partially unsaturated carbocyclic ring of 5 to 8 atoms, a benzocyclic ring, a partially unsaturated heterocyclic ring of 5 to 7 atoms, or a heteroaromatic ring of 5 or 6 atoms; or W 2 and W 3 One of them is -C- and the other is -N-, W 2 With W 3 The virtual bond between is a single bond, and is a 5 or 6-atom heterocyclic ring optionally containing an additional N atom and wherein the remaining ring atoms are C; R 2 , at each occurrence, is independently H, halogen, C1-C6 alkyl, or halogenated C1-C6 alkyl; or Two R's 2 are respectively connected to adjacent carbon atoms and together with the carbon atoms connected thereto form a carbon ring consisting of 3 to 7 atoms, wherein the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogen and C1-C6 alkyl; and the remaining R 2 , at each occurrence, is independently H, halogen, or C1-C6 alkyl; or Two R's 2 are all connected to the same carbon atom and together with the carbon atom to which they are connected form a carbon ring consisting of 3 to 7 atoms, the ring is optionally substituted by 1, 2 or 3 groups independently selected from halogen and C1-C6 alkyl; and the remaining R 2 , at each occurrence, is independently H, halogen, or C1-C6 alkyl; R 3 is H, -OH, -B(OH)2, -COOH, hydroxyalkyl, -C(=NH)NH2, -C(O)NH2, -NH2, -NHC(O)C 1-3 Alkyl, -NHC(O)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, -S(O)2NHR, -S(O)2C1-C6-alkyl, amino-C1-C6-alkyl, halogenated C1-C3-alkyl, C3-C6-cycloalkyl, heterocycloalkyl composed of 3 to 6 atoms, or wherein R is H, C1-C3 alkyl, or C3-C5 cycloalkyl; wherein the C3-C6 cycloalkyl and the 3 to 6 atoms consisting of heterocycloalkyl are each optionally substituted by one -NH2; and wherein the alkyl in amino-C1-C6 alkyl is optionally further substituted by 1, 2, 3 or 4 halogens; R 3a , at each occurrence, is independently H, halogen, C1-C3 alkyl, or C3-C6 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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