2-aryl cycloalkyl and heterocycloalkyl inhibitors of NAV1.8 for the treatment of pain
2-aryl cycloalkyl and heterocycloalkyl compounds inhibit the NAV1.8 sodium channel, providing targeted and effective pain relief by modulating neuronal activity, improving upon existing pain management strategies.
Patent Information
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- SITEONE THERAPEUTICS INC
- Filing Date
- 2025-01-23
- Publication Date
- 2026-07-16
AI Technical Summary
Current treatments for pain management, particularly targeting the NAV1.8 channel, are inadequate in providing effective and selective relief.
Development of 2-aryl cycloalkyl and heterocycloalkyl compounds that inhibit the NAV1.8 sodium channel, offering a targeted approach to pain relief by modulating neuronal activity.
These compounds provide selective and effective pain relief by inhibiting the NAV1.8 channel, addressing the limitations of existing pain management therapies.
Abstract
Description
example, in some embodiments, some embodiments, In some embodiments,
[0070] As used herein, solid and dashed rectangles are equivalent to solid and dashed wedges, respectively (Brecher, J. Pure Appl. Chern., Vol. 78, 10, pp-1897-1970, 2006). When used at the W1 and W2 positions, the solid and dashed rectangles denote relative stereochemistry, including in, for example, Compounds 1 and 3: where the stereochemistry is either (1R,2R) or (1S,2S) where the stereochemistry is either (1R,2S) or(lS,2R) unless context dictates otherwise. For example compound 34:
[0071] It will be apparent that certain structures recite specific stereochemistry at particular atoms.
[0072] Certain multicyclic structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any atom of the multicyclic ring, where chemically feasible and valency rules permitting. For example, this ring: depicts 0-2 R2 groups on a bicyclic ring; these R2 groups may be on a carbon in the cyclohexyl portion of the bicyclic ring and / or in the cyclopropyl portion of the bicyclic ring.
[0073] In one embodiment, provided herein is a compound of Formula (P-II): (P-II) wherein W1 is CH; W2 is CH orN; Lisa bond or is -C(O)NH- where the nitrogen of -C(O)NH- is attached to ring A; ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 5- to 10membered heterocyclic ring or N-oxide thereof; ring B is a 3- to 10-membered cycloalkylene optionally fused to a benzo group or a 5- to 10-membered heterocycloalkylene ring optionally fused to a benzo group; ring C is aryl, phenyl fused to HET, or phenyl fused to CYC, and where (R^n is substituted on any substitutable ring atom; R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; Ci-Ce haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-methoxy; halo-Ci-Cs alkoxy, in some embodiments, haloCi alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; and C2-C4 alkynyl, in some embodiments, ethynyl; R2, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; and aryl, in some embodiments, phenyl; R3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -C00H, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)NH2, -S(0)2NHR, O 11 -S(O)2Ci-C6-alkyl, HN J™Cl'C3'alky\ Ci-C6 alkoxy, -NH2, amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-Csalkyl, Cs-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, and wherein R is hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo; R3a, independently in each instance, is hydrogen, oxo, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; n is 0, 1,2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof and / or an isomer thereof; wherein the compound is not l-methyl-2-(3-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)quinolin-4(lH)-one; 2-(3-(4-methoxyphenyl)-l,2,3,4-tetrahydronaphthalen-2-yl)-l- methylquinolin-4(lH)-one; or 2-(3-(4-chlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-l-methylquinolin-4(lH)-one.
[0074] In one embodiment, the compound of Formula (I) is a compound of Formula (PI): R3 (P-I) wherein W1 is CH; W2 is CH orN; Lisa bond or is -C(O)NH- where the nitrogen of -C(O)NH- is attached to ring A; ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 6- to 10membered heterocyclic ring or N-oxide thereof; ring B is a 3- to 10-membered cycloalkylene optionally fused to a benzo group or a 5- to 10-membered heterocycloalkylene ring optionally fused to a benzo group; ring C is aryl, phenyl fused to HET, or phenyl fused to CYC, and where (R^n is substituted on any substitutable ring atom; R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; C1-C3 haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-methoxy; halo-Ci-Cs alkoxy, in some embodiments, haloCi alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; and C2-C4 alkynyl, in some embodiments, ethynyl; R2, independently in each instance, is selected from C1-C3 alkyl, in some embodiments, methyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; and aryl, in some embodiments, phenyl; R3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -COOH, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)NH2, -S(O)2NHR, O 11 -S(O)2Ci-C6-alkyl, HN J~CrC3'alkyl, Ci-C6 alkoxy, -NH2, amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-Csalkyl, Cs-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, and wherein R is hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo; R3a, independently in each instance, is hydrogen, oxo, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; n is 0, 1,2, 3, or 4; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
[0075] Embodiment Al: Provided herein is a compound according to any one of the following formulas: R3 wherein the ring C 2,3-dihydrobenzo[b][l,4]dioxin-5-yl is substituted with (K1)^ (LVII), wherein the ring C benzo[d][l,3]dioxole is substituted with (R1)^ (C); (CV); and (CVI); or a salt thereof, wherein W1, W2, L, ring A, ring B, ring C, R1, R2, R3, R3a, n, p, and q are as defined in the first aspect and any embodiments thereof.
[0076] Embodiment A2: Provided herein is a compound according to any one of the following formulas: or a salt thereof, wherein W1, W2, L, ring C, R1, R2, R3, n, and p are as defined in the first aspect and any embodiments thereof.
[0077] In one or more embodiments, the compound is according to Formula (X), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (XI), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (L), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (LI), wherein the ring C naphthyl is substituted with (R2)n, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (LII), wherein the ring C 2,3-dihydro-lH-inden-4-yl is substituted with (R2)n, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (LIII), wherein the ring C 2,3-dihydro-lH-inden-5-yl is substituted with (R2)n, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (LIV), wherein the ring C 1,2,3,4-tetrahydronaphthalen-5-yl is substituted with (R2)n, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (LV), wherein the ring C l,2,3,4-tetrahydronaphthalen-6-yl is substituted with (R1)^ or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (LVI), wherein the ring C 2,3-dihydrobenzo[b][l,4]dioxin-5-yl is substituted with (R2)n, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (LVII), wherein the ring C benzo[d][l,3]dioxole is substituted with (R’)n, or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (C), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (CI), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (CV), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (CVI), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (CVII), or a pharmaceutically acceptable salt thereof and / or an isomer thereof. In one or more embodiments, the compound is according to Formula (CVIII), or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
[0078] In some or any embodiments, provided herein is a compound of Formula (P-I) or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein ring A is phenyl substituted with R3, pyridyl substituted with R3, imidazopyridyl substituted with R3, benzimidazolyl substituted with R3, benzoxazolyl substituted with R3, oxazolopyridinyl substituted with R3, pyridinonyl (i.e. where R3 is oxo), pyrimidinonyl (i.e. where R3 is oxo), quinolinonyl (i.e. where R3 is oxo), or naphthyridinonyl (i.e. where R3 is oxo); where ring A is substituted with (R3a)q; in some embodiments, R3 is not -H; embedments, ring B is unsubstituted; designates attachment to W2; R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; C1-C3 haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-Ci alkoxy; halo-Ci-Cs alkoxy, in some embodiments, halo-Ci alkoxy or halo-C2 alkoxy; oxetanyl; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl or pyridazinyl; C2-C3 alkenyl, in some embodiments, vinyl; and C2-C3 alkynyl, in some embodiments, ethynyl; R2, independently in each instance, is selected from C1-C3 alkyl, in some embodiments, methyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; and aryl, in some embodiments, phenyl; R3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -COOH, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)NH2, -S(O)2NHR, O 11 -S(O)2Ci-C6-alkyl, HN-i-CrCralkyl, Ci-C6 alkoxy, -NH2, amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-C3alkyl, C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, and wherein R is hydrogen, C1-C3 alkyl, or Ca-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo; R3a, independently in each instance, is hydrogen, oxo, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; n is 0, 1,2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.
[0079] In some or any embodiments, provided herein is a compound of Formula (P-II) or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein ring A is phenyl substituted with R3, pyridyl or an N-oxide thereof substituted with R3, imidazopyridyl substituted with R3, benzimidazolyl substituted with R3, benzoxazolyl substituted with R3, benzoisoxazolyl substituted with R3, oxazolopyridinyl substituted with R3, pyridinonyl (i.e. where R3 is oxo), pyrimidinonyl (i.e. where R3 is oxo), pyridazinyl substituted with R3, isoindolinonyl (i.e. where R3 is oxo), indazolyl substituted with R3, indazolonyl (i.e. where R3 is oxo), benzoisothiazolyl substituted with R3, quinolinonyl (i.e. where R3 is oxo), naphthyridinonyl (i.e. where R3 is oxo); where ring A is substituted with (R3a)q; in some embodiments, R3 is not -H; substituted with (R^n, or substituted with (R’k; where * designates attachment to W2; R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; Ci-Ce haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-Ci alkoxy; halo-Ci-Cs alkoxy, in some embodiments, halo-Ci alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; and C2-C4 alkynyl, in some embodiments, ethynyl; R2, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or ethyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; and aryl, in some embodiments, phenyl; R3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -COOH, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)NH2, -S(0)2NHR, O 11 -S(O)2Ci-C6-alkyl, HN J»CrC3'alkyl, Ci-C6 alkoxy, -NH2, amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-C3alkyl, C3-C6- cycloalkyl, 3- to 6-membered heterocycloalkyl, and wherein R is hydrogen, C1-C3 alkyl, or Ca-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo; R3a, independently in each instance, is hydrogen, oxo, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; n is 0, 1,2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.
[0080] In some or any embodiments, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein ring A is phenyl substituted with R3, pyridyl or an N-oxide thereof substituted with R3, imidazopyridyl substituted with R3, benzimidazolyl substituted with R3, benzoxazolyl substituted with R3, benzoisoxazolyl substituted with R3, oxazolopyridinyl substituted with R3, pyridinonyl (i.e. where R3a is oxo) substituted with R3, pyrimidinonyl (i.e. where R3a is oxo) substituted with R3, pyridazinonyl (i.e. where R3a is oxo) substituted with R3, pyridazinyl substituted with R3, isoindolinonyl (i.e. where R3a is oxo) substituted with R3, indazolyl substituted with R3, indazolonyl (i.e. where R3a is oxo) substituted with R3, benzoisothiazolyl substituted with R3, quinolinonyl (i.e. where R3a is oxo) substituted with R3, naphthyri di nonyl (i.e. where R3a is oxo) or an N-oxide thereof substituted with R3; thiophenyl substituted with R3, where ring A is substituted with (R3a)q; in some embodiments, R3 is not -H; (R2)<>-2 I----(R2)o-2 (R2)o-^^^ (R2)o-7^ (rv2 o!).P ' , or foregoing structures, the upper is unsubstituted; (R1)n 2yO w2^r ring Cis , <QC (r2)o.“XX^ / (R2)o-2 / 7 ,,, (R2io.ry\j xXy (R^)o-2 ,, , \ X . X . X vA (R!,0JXX (rVaX , ,, ' ; where, in some embodiments of each of the *• is attached to L; or where in some embedments, ring B W2 J CO substituted with (R1^, substituted with (R^n, W2 / w2Z .. xoo < substituted with (Rx)n, ' W2 9 fo -—' substituted with (Rx)n, substituted with (R^n, w2 substituted with (R1)^ substituted with (R1)^ where * designates attachment to W2; R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl, ethyl, n-propyl, or isopropyl; halo, in some embodiments, fluoro, chloro, or bromo; Ci-Ce haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl or cyclobutyl; C1-C3 alkoxy, in some embodiments methoxy or ethoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-Ci alkoxy; halo-Ci-Cs alkoxy, in some embodiments, halo-Ci alkoxy or halo-C? alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; C2-C4 alkynyl, in some embodiments, ethynyl; and hydroxy; R2, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl ethyl, isopropyl, or tert-butyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl cyclobutyl, or cyclopentyl; cyano; -C(0)Ci-6alkyl; -C(O)Ci-6haloalkyl;-C(O)cyclohexyl; -C(O)aryl, in some embodiments, -C(O)phenyl; aryl, in some embodiments, phenyl or naphthyl; and 5- to 6-membered heteroaryl, in some embodiments, pyridinyl or pyrimidinyl; wherein the C3-C6 cycloalkyl, aryl, and heteroaryl, each alone or as part of another group, are optionally substituted with 1, 2, or 3 R2a groups independently selected from halo, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl; R3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -C00H, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)N(R)2, -S(0)2NHR, 0 0 fl * A r-S»n^N'r -S(O)2Ci-C6-alkyl, HN ~LCl'C3‘alkyl, JL , Ci-C6 alkoxy, -NH2, amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-Csalkyl, Cs-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6membered heteroaryl wherein each R is independently selected from hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo; R3a, independently in each instance, is hydrogen, oxo, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl; n is 0, 1,2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, or 3.
[0081] Additional embodiments of Formula (I), Formula (P-II), or (P-I) are where R1 is as provided in Embodiments 1-lg; ring A is as provided in Embodiments 2-2c; W1 is as provided in Embodiments 3-3b; W2 is as provided in Embodiments 3-3b; R2, independently in each instance, is as provided in Embodiments 4-4c; R3 is as provided in Embodiments 5-5d; R3a is as provided in Embodiment 6-6b; ring B is as provided in Embodiments 7-7f; ring C is as provided in Embodiments 8-8c; L is as provided in Embodiment 9-9a; n is as provided in Embodiments 10-10a and 13-13a-2; p is as provided in Embodiments 11-1 la and 13-13a-2; q is as provided in Embodiments 12-12a and 13-13a-2; and any combinations thereof.
[0082] Embodiment 1: In some or any embodiments, including Embodiment A, one R1 is Ci-Ce alkyl. In some or any embodiments, including embodiment A, one R1 is halo. In some or any embodiments, including embodiment A, one R1 is Ci-Ce haloalkyl. In some or any embodiments, including embodiment A, one R1 is C1-C3 haloalkyl. In some or any embodiments, including embodiment A, one R1 is cyano. In some or any embodiments, including embodiment A, one R1 is aryl. In some or any embodiments, including embodiment A, one R1 is C3-C6 cycloalkyl. In some or any embodiments, including embodiment A, one R1 is C1-C3 alkoxy. In some or any embodiments, including embodiment A, one R1 is deutero-Ci-Cs alkoxy. In some or any embodiments, including embodiment A, one R1 is halo-C1-C3 alkoxy. In some or any embodiments, including embodiment A, one R1 is 5- to 6membered heteroaryl. In some or any embodiments, including embodiment A, one R1 is C2-C3 alkenyl. In some or any embodiments, including embodiment A, one R1 is C2-C3 alkynyl. In some or any embodiments, including embodiment A, one R1 is C2-C4 alkenyl. In some or any embodiments, including embodiment A, one R1 is C2-C4 alkynyl.
[0083] Embodiment la: In some or any embodiments, including Embodiment A, at least one R1 is Ci-Ce alkyl. In some or any embodiments, including Embodiment A, at least one R1 is -CH3. In some or any embodiments, including Embodiment A, at least one R1 is Ci-Cealkoxy. In some or any embodiments, including Embodiment A, at least one R1 is -OCH3. In some or any embodiments, including Embodiment A, at least one R1 is Ci-Ce haloalkyl. In some or any embodiments, at least one R1 is -CF3. In some or any embodiments, including Embodiment A, at least one R1 is halo-Ci-Ce alkoxy. In some or any embodiments, including Embodiment A, at least one R1 is -OCF3. In some or any embodiments, including Embodiment A, at least one R1 is halogen. In some or any embodiments, including Embodiment A, at least one R1 is -Cl. In some or any embodiments, including Embodiment A, at least one R1 is -F. In some or any embodiments, including Embodiment A, at least one R1 is Cs-Ce-cycloalkyl. In some or any embodiments, including Embodiment A, at least one R1 is Cs-Ce-cycloalkylCi-Cs-alkyl.
[0084] Embodiment lb: In some or any embodiments, including Embodiment A, at least one R1 is methyl or propyl. In some or any embodiments, including Embodiment A, at least one R1 is methyl. In some or any embodiments, including Embodiment A, at least one R1 is propyl. In some or any embodiments, including Embodiment A, at least one R1 is n-propyl. In some or any embodiments, including Embodiment A, at least one R1 is isopropyl. In some or any embodiments, including Embodiment A, at least one R1 is fluoro, chloro, or bromo. In some or any embodiments, including Embodiment A, at least one R1 is fluoro. In some or any embodiments, including Embodiment A, at least one R1 is chloro. In some or any embodiments, including Embodiment A, at least one R1 is bromo. In some or any embodiments, including Embodiment A, at least one R1 is Ci haloalkyl. In some or any embodiments, including Embodiment A, at least one R1 is cyano. In some or any embodiments, including Embodiment A, at least one R1 is phenyl. In some or any embodiments, including Embodiment A, at least one R1 is cyclopropyl. In some or any embodiments, including Embodiment A, at least one R1 is methoxy. In some or any embodiments, including Embodiment A, at least one R1 is deutero-Ci alkoxy. In some or any embodiments, including Embodiment A, at least one R1 is halo-Ci alkoxy or halo-C? alkoxy. In some or any embodiments, including Embodiment A, at least one R1 is halo-Ci alkoxy. In some or any embodiments, including Embodiment A, at least one R1 is halo-C? alkoxy. In some or any embodiments, including Embodiment A, at least one R1 is oxetanyl, pyridinyl, or pyridazinyl. In some or any embodiments, including Embodiment A, at least one R1 is oxetanyl. In some or any embodiments, including Embodiment A, at least one R1 is pyridinyl. In some or any embodiments, including Embodiment A, at least one R1 is pyridazinyl. In some or any embodiments, including Embodiment A, at least one R1 is vinyl. In some or any embodiments, at least one R1 is ethynyl.
[0085] Embodiment lb-1: In some or any embodiments, including Embodiment A, at least one R1 is methyl, ethyl, n-propyl, or isopropyl. In some or any embodiments, including Embodiment A, at least one R1 is ethyl. In some or any embodiments, including Embodiment A, at least one R1 is cyclobutyl. In some or any embodiments, including Embodiment A, at least one R1 is ethoxy. In some or any embodiments, at least one R1 is hydroxy.
[0086] Embodiment 1c: In some or any embodiments, including Embodiment A, R1 is independently in each instance selected from methyl, ethyl, propyl, cyclopropyl, -F, -Cl, -Br, -OMe, -OEt, -O-propyl, -OCD3, -OCF3, -OCHF2, -OCH2CF3, -CF3, phenyl, -CN, oxetanyl, pyridyl, pyridazinyl, -CHCH2, and -CCH. In some or any embodiments, including Embodiment A, at least one R1 is methyl (or -Me). In some or any embodiments, including Embodiment A, at least one R1 is ethyl. In some or any embodiments, including Embodiment A, at least one R1 is propyl. In some or any embodiments, including Embodiment A, at least one R1 is cyclopropyl. In some or any embodiments, including Embodiment A, at least one R1 is -F. In some or any embodiments, including Embodiment A, at least one R1 is -Cl. In some or any embodiments, including Embodiment A, at least one R1 is -Br. In some or any embodiments, including Embodiment A, at least one R1 is -OMe. In some or any embodiments, at least one R1 is -OEt. In some or any embodiments, including Embodiment A, at least one R1 is -O-propyl. In some or any embodiments, including Embodiment A, at least one R1 is -OCD3. In some or any embodiments, including Embodiment A, at least one R1 is -OCF3. In some or any embodiments, including Embodiment A, at least one R1 is -OCHF2. In some or any embodiments, including Embodiment A, at least one R1 is -OCH2CF3. In some or any embodiments, including Embodiment A, at least one R1 is -CF3. In some or any embodiments, including Embodiment A, at least one R1 is phenyl. In some or any embodiments, including Embodiment A, at least one R1 is -CN. In some or any embodiments, including Embodiment A, at least one R1 is oxetanyl. In some or any embodiments, including Embodiment A, at least one R1 is pyridyl. In some or any embodiments, including Embodiment A, at least one R1 is pyridazinyl. In some or any embodiments, including Embodiment A, at least one R1 is -CHCH2. In some or any embodiments, at least one R1 is -CCH.
[0087] Embodiment Id: In some or any embodiments, including Embodiment A, R1 is independently in each instance selected from -Me, -Et, -CH(CH3)2, -F, -Cl, -Br, -OMe, -OEt, -OCH(CH3)2, -0CD3, z—N , , z\i U / / A_ -0CF3, -0CHF2, -OCH2CF3, -CF3, phenyl (or -Ph), -CN, , , \= / , \= / , -CHCH2, and -CCH. In some or any embodiments, including Embodiment A, at least one R1 is -CH(CH3)2. In some or any embodiments, at least one R1 is -OCH(CH3)2. In some or any embodiments, including Embodiment A, at least one R1 is °0> I in some or any ( / \\___ embodiments, at least one R1 is \= / . In some or any embodiments, including N—x , / / A__ Embodiment A, at least one R1 is \= / . In some or any embodiments, including | Embodiment A, at least one R1 is \= / . In some or any embodiments, at least one R1 is N-N , / / \\___
[0088] Embodiment le: In some or any embodiments, including Embodiment A, R1 is independently in each instance selected from -Me, propyl, -F, -Cl, -OMe, -OEt, -O-propyl, -OCD3, -OCF3, -OCHF2, -OCH2CF3, -CF3, phenyl, -CN, -CHCH2, and -CCH.
[0089] Embodiment If: In some or any embodiments, including Embodiment A, R1 is independently in each instance selected from -Me, -CH(CH3)2, -F, -Cl, -OMe, -OEt, -OCH(CH3)2, -OCD3, -0CF3, -0CHF2, -OCH2CF3, -CF3, phenyl, -CN, -CHCH2, and -CCH.
[0090] Embodiment 1g: In some or any embodiments, including Embodiments A and 1-If, one R1 is present. In some or any embodiments, including Embodiments A and 1-lf, two R1 are present. In some or any embodiments, including Embodiments A and 1-lf, three R1 are present.
[0091] Embodiment 2: In some or any embodiments including embodiments A-lg, ring A is phenyl substituted with R3 and optionally substituted with (R3a)q. In some or any embodiments including embodiments A-lg, ring A is a 5- to 10-membered heteroaryl orN-oxide thereof substituted with R3 and optionally substituted with (R3a)q. In some or any embodiments including embodiments A-lg, ring A is a 5- to 10-membered heteroaryl substituted with R3 and optionally substituted with (R3a)q. In some or any embodiments including embodiments A-lg, ring A is a 5- to 10-membered heteroaryl N-oxide substituted with R3 and optionally substituted with (R3a)q. In some or any embodiments including embodiments A-lg, ring A is a 6- to 10-membered heterocyclic ring or N-oxide thereof substituted with R3 and optionally substituted with (R3a)q.
[0092] Embodiment 2a: In some or any embodiments including embodiments A-lg, ring A is phenyl substituted with R3, pyridyl or an N-oxide thereof substituted with R3, imidazopyridyl substituted with R3, benzimidazolyl substituted with R3, benzoxazolyl substituted with R3, benzoisoxazolyl substituted with R3, oxazolopyridinyl substituted with R3, pyridinonyl (i.e. where R3a is oxo) substituted with R3, pyrimidinonyl (i.e. where R3a is oxo) substituted with R3, pyridazinonyl (i.e. where R3a is oxo) substituted with R3, pyridazinyl substituted with R3 substituted with R3, isoindolinonyl (i.e. where R3a is oxo) substituted with R3, indazolyl substituted with R3, indazolonyl (i.e. where R3a is oxo) substituted with R3, benzoisothiazolyl substituted with R3, quinolinonyl (i.e. where R3a is oxo) substituted with R3, naphthyridinonyl (i.e. where R3a is oxo) or an N-oxide thereof substituted with R3; thiophenyl substituted with R3, where ring A is substituted with (R3a)q; in some embodiments, R3 is not -H. In some or any embodiments including embodiments A-lg, ring A is pyridinonyl (i.e. where R3a is oxo) substituted with R3. In some or any embodiments including embodiments A-lg, ring A is pyrimidinonyl (i.e. where R3a is oxo) substituted with R3 In some or any embodiments including embodiments A-lg, ring A is pyridazinonyl (i.e. where R3a is oxo) substituted with R3. In some or any embodiments including embodiments A-lg, ring A is isoindolinonyl (i.e. where R3a is oxo) substituted with R3. In some or any embodiments including embodiments A-lg, ring A is indazolonyl (i.e. where R3a is oxo) substituted with R3. In some or any embodiments including embodiments A-lg, ring A is quinolinonyl (i.e. where R3a is oxo) substituted with R3. In some or any embodiments including embodiments A-lg, ring A is naphthyridinonyl (i.e. where R3a is oxo) or an N-oxide thereof substituted with R3. In some or any embodiments including embodiments A-lg, ring A is thiophenyl substituted with R3. In some or any embodiments including embodiments A-lg, ring A is substituted with (R3a)q. In some or any embodiments including embodiments A-lg, R3 is not -H.
[0093] Embodiment 2a-l: In some or any embodiments including embodiments A-lg, ring A is phenyl substituted with R3, pyridyl substituted with R3, imidazopyridyl substituted with R3, benzimidazolyl substituted with R3, benzoxazolyl substituted with R3, oxazolopyridinyl substituted with R3, pyridinonyl (i.e. where R3 is oxo), pyrimidinonyl (i.e. where R3 is oxo), quinolinonyl (i.e. where R3 is oxo), or naphthyridinonyl (i.e. where R3 is oxo); where ring A is substituted with (R3a)q; in some embodiments, R3 is not -H. In some or any embodiments including embodiments A-lg, ring A is phenyl substituted with R3. In some or any embodiments including embodiments A-lg, ring A is pyridyl substituted with R3. In some or any embodiments including embodiments A-lg, ring A is imidazopyridyl substituted with R3. In some or any embodiments including embodiments A-lg, ring A is benzimidazolyl substituted with R3. In some or any embodiments including embodiments A-lg, ring A is benzoxazolyl substituted with R3. In some or any embodiments including embodiments A-lg, ring A is oxazolopyridinyl substituted with R3. In some or any embodiments including embodiments A-lg, ring A is pyridinonyl (i.e. where R3 is oxo) substituted with R3. In some or any embodiments including embodiments A-lg, ring A is pyrimidinonyl (i.e. where R3 is oxo) substituted with R3. In some or any embodiments including embodiments A-lg, ring A is quinolinonyl (i.e. where R3 is oxo). In some or any embodiments including embodiments A-1g, ring A is naphthyri di nonyl (i.e. where R3 is oxo). In some or any embodiments including embodiments A-lg, ring A is substituted with (R3a)q. In some or any embodiments including embodiments A-lg, R3 is not -H.
[0094] Embodiment 2b: In some or any embodiments including embodiments A-lg, ring A is substituted with R3 and additionally with with one or more R3a, or N-oxide thereof substituted with R3 and additionally with with one or more R3a, substituted with R3 and additionally with with one or more R3a, R3a is oxo) substituted with R3 and additionally with with one or more R3a, substituted with R3 and additionally with with one or more R3a, R3 and additionally with with one or more R3a, substituted with R3 and O JM] L\; n additionally with with one or more R3a, H (i.e. where R3a is oxo) substituted with R3 and additionally with with one or more R3a, (i.e. where R3a is oxo) substituted with O with R3 and additionally with with one or more R3a, 0 (i.e. where R3a is oxo) or N-oxide thereof substituted with R3 and additionally with with one or more R3a, n'nh (i.e. where R3a is oxo) substituted with R3 and additionally with with one or more R3a, or substituted with R3 and additionally with with one or more R3a; and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is or N-oxide thereof substituted with R3 and additionally with with one or more R3a and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is (i.e. where R3a is oxo) substituted with R3 and additionally with with one or more R3a and where L designates attachment to L. In some or O any embodiments including embodiments A-lg, ring A is H (i.e. where R3a is oxo) substituted with R3 and and additionally with with one or more R3a where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is (i.e. where R3a is oxo) substituted with R3 and additionally with with one or more R3a and where L designates attachment to L. In some or any embodiments including O embodiments A-lg, ring A is H (i.e. where R3a is oxo) substituted with R3 and additionally with with one or more R3a and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is O (i.e. where R3a is oxo) or N-oxide thereof substituted with R3 and additionally with with one or more R3a and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is (i.e. where R3a is oxo) substituted with R3 and additionally with with one or more R3a and where L designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is substituted with R3 and where designates attachment to L.
[0095] Embodiment 2b-l: In some or any embodiments including embodiments A-lg, is substituted with (R3a)q; and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is substituted with R3 and (R3a)q, and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is substituted with R3 and (R3a)q, and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring substituted with R3 and (R3a)q, and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is O (i.e. where R3 is oxo) substituted with (R3a)q, and where L designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is N N H substituted with R3 and (R3a)q, and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is substituted with R3 and (R3a)q, and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is substituted with R3 and (R3a)q, and where designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is 0 H (i.e. where R3 is oxo) substituted with (R3a)q, and where L designates attachment to L. In some or any embodiments including embodiments A-lg, ring A is where R3 is oxo) substituted with (R3a)q, and where L designates attachment to L. In some O jmO or any embodiments including embodiments A-lg, ring A is H (i.e. where R3 is oxo) substituted with (R3a)q, and where designates attachment to L. In some or any A; , embodiments including embodiments A-lg, ring Ais substituted with R3 and (R3a)q, and where designates attachment to L. In some or any embodiments including O / o embodiments A-lg, ring A is H (i.e. where R3 is oxo) substituted with (R3a)q, and where designates attachment to L.
[0096] Embodiment 2c: In some or any embodiments including embodiments A-lg, ring O Ly^O \ A is not I and where designates attachment to L.
[0097] Embodiment 3: In some or any embodiments, including embodiments A-2al, W1 is CH and W2 is CH. In some or any embodiments, including embodiments A-2al, W1 is CH and W2 is N.
[0098] Embodiment 3a: In some or any embodiments, including embodiments A-2al, W1 is CRX and W2 is CH where Rx is C1-3 alkyl. In some or any embodiments, including embodiments A-2al, W1 is CH and W2 is CRX where Rx is C1-3 alkyl. In some or any embodiments, including embodiments A-21a, W1 is CRX and W2 is N where Rx is C1-3 alkyl. In some or any embodiments, including embodiments A-2al, W1 is N and W2 is CRX where Rx is C1-3 alkyl. In some or any embodiments, including embodiments A-2al, W1 is CRX and W2 is CRX where each Rx is C1-3 alkyl.
[0099] Embodiment 3b: In some or any embodiments, including embodiments A-2al, W1 is CRX and W2 is CH where Rx is methyl. In some or any embodiments, including embodiments A-2al, W1 is CH and W2 is CRX where Rx is methyl. In some or any embodiments, including embodiments A-2al, W1 is CRX and W2 is N where Rx is methyl. In some or any embodiments, including embodiments A-2al, W1 is N and W2 is CRX where Rx is methyl. In some or any embodiments, including embodiments A-2al, W1 is CRX and W2 is CRX where each Rx is methyl.
[00100] Embodiment 4: In some or any embodiments including embodiments A-3b, at least one R2 is Ci-Ce alkyl. In some or any embodiments including embodiments A-3b, at least one R2 is C1-C3 alkyl. In some or any embodiments including embodiments A-3b, at least one R2 is halogen. In some or any embodiments including embodiments A-3b, at least one R2 is C1-C3 haloalkyl. In some or any embodiments including embodiments A-3b, at least one R2 is C3-C6 cycloalkyl. In some or any embodiments including embodiments A-3b, at least one R2 is aryl.
[00101] Embodiment 4a-l: In some or any embodiments including embodiments A-3b, R2, independently in each instance, is -CH3, -F, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In some or any embodiments including embodiments A-3b, R2, independently in each instance, is selected from halo and C1-C3 haloalkyl. In some or any embodiments including embodiments A-3b, R2 is -CH3. In some or any embodiments including embodiments A-3b, R2 is -F. In some or any embodiments including embodiments A-3b, R2 is -CF3. In some or any embodiments including embodiments A-3b, R2 is -CH2CF3. In some or any embodiments including embodiments A-3b, R2 is cyclopropyl. In some or any embodiments including embodiments A-3b, R2 is cyclobutyl. In some or any embodiments including embodiments A-3b, R2 is cyclopropyl. In some or any embodiments including embodiments A-3b, R2 is cyclopentyl. In some or any embodiments including embodiments A-3b, R2 is cyclohexyl. In some or any embodiments including embodiments A-3b, R2 is phenyl.
[00102] Embodiment 4a-2: In some or any embodiments including embodiments A-3b, R2, independently in each instance, is -CH3, -CH2CH3, -F, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In some or any embodiments including embodiments A-3b, R2, is -CH2CH3.
[00103] Embodiment 4a-3: In some or any embodiments including embodiments A-3b, R2, independently in each instance, is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -F, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or naphthyl.
[00104] Embodiment 4b: In some or any embodiments including embodiments A-3b, at least one R2 is cyano. In some or any embodiments including embodiments A-3b, at least one R2 is -C(O)Ci-6alkyl. In some or any embodiments including embodiments A-3b, at least one R2 is -C(O)haloCi-6alkyl. In some or any embodiments including embodiments A-3b, at least one R2 is -C(O) C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R2a groups independently selected from halo, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some or any embodiments including embodiments A-3b, at least one R2 is -C(O)aryl optionally substituted with 1, 2, or 3 R2a groups independently selected from halo, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some or any embodiments including embodiments A-3b, at least one R2 is 5- to 6-membered heteroaryl. In some or any embodiments including embodiments A-3, at least one R2 is -C(O)CH3. In some or any embodiments including embodiments A-3b, at least one R2 is -C(O)CF3. In some or any embodiments including embodiments A-3b, at least one R2 is -C(O)cyclohexyl optionally substituted with 1, 2, or 3 R2a groups independently selected from halo, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some or any embodiments including embodiments A-3b, at least one R2 is -C(O)phenyl optionally substituted with 1, 2, or 3 R2a groups independently selected from halo, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl. In some or any embodiments including embodiments A-3b, at least one R2 is pyridinyl. In some or any embodiments including embodiments A-3b, at least one R2 is pyrimidinyl.
[00105] Embodiment 4c: In some or any embodiments, including Embodiments A-4a-3, one R2 is present. In some or any embodiments, including Embodiments A-4a-3, two R2 are present. In some or any embodiments, including Embodiments A-4a-3, three R2 are present.
[00106] Embodiment 5: In some or any embodiments including embodiments A-4c, R3 is H. In some or any embodiments including embodiments A-4c, R3 is -CN. In some or any embodiments including embodiments A-4c, R3 is halo. In some or any embodiments including embodiments A-4c, R3 is -OH. In some or any embodiments including embodiments A-4c, R3 is oxo. In some or any embodiments including embodiments A-4c, R3 is -B(OH)2. In some or any embodiments including embodiments A-4c, R3 is -COOH. In some or any embodiments including embodiments A-4c, R3 is Ci-Ce alkoxy carbonyl. In some or any embodiments including embodiments A-4c, R3 is Ci-Ce alkyl. In some or any embodiments including embodiments A-4c, R3 is hydroxy-Ci-Ce-alkyl. In some or any embodiments including embodiments A-4c, R3 is -C(=NH)NH2. In some or any embodiments including embodiments A-4c, R3 is -C(O)NH2. In some or any embodiments including embodiments A-4c, R3 is -S(O)2NHR, wherein R is hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl. In some or any embodiments including embodiments A-4c, R3 is -S(O)2NHR, wherein R is hydrogen. In some or any embodiments including embodiments A-4c, R3 is -S(O)2NHR, wherein R is C1-C3 alkyl. In some or any embodiments including embodiments A-4c, R3 is -S(O)2NHR, wherein R is Cs-Cscycloalkyl. In some or any embodiments including embodiments A-4c, R3 is -S(0)2Ci-o 11 Ce-alkyl. In some or any embodiments including embodiments A-4c, R3 is HN~«LCl °3 alkyl. In some or any embodiments including embodiments A-4c, R3 is Ci-Ce alkoxy. In some or any embodiments including embodiments A-4c, R3 is -NH2. In some or any embodiments including embodiments A-4c, R3 is amino-Ci-Cealkyl. In some or any embodiments including embodiments A-4c, R3 is amino-Ci-Cealkyl, wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo. In some or any embodiments including embodiments A-4c, R3 is amino-Ci-Cealkyl, wherein the alkyl in amino-Ci-Cealkyl is further substituted with 1, 2, 3, or 4 halo. In some or any embodiments including embodiments A-4c, R3 is -NHC(O)Ci-3alkyl. In some or any embodiments including embodiments A-4c, R3 is -NHC(O)NH2. In some or any embodiments including embodiments A-4b, R3 is -NHS(O)2NH2. In some or any embodiments including embodiments A-4c, R3 is -NHC(=NH)NH2. In some or any embodiments including embodiments A-4c, R3 is halo-Ci-Csalkyl. In some or any embodiments including embodiments A-4c, R3 is Cs-Ce-cycloalkyl. In some or any embodiments including embodiments l-4c, R3 is Cs-Ce-cycloalkyl optionally substituted with one -NH2. In some or any embodiments including embodiments A-4c, R3 is Cs-Ce-cycloalkyl substituted with one -NH2. In some or any embodiments including embodiments A-4c, R3 is 3- to 6-membered heterocycloalkyl. In some or any embodiments including embodiments A-4c, R3 is 3- to 6-membered heterocycloalkyl optionally substituted with one -NH2. In some or any embodiments including embodiments A-4c, R3 is 3- to 6-membered heterocycloalkyl substituted with one -NH2.
[00107] Embodiment 5a: In some or any embodiments including embodiments A-4c, R3 is -C(O)N(R)2 wherein each R is C1-3 alkyl. In some or any embodiments including embodiments A-4c, R3 is 5- to 6-membered heteroaryl.
[00108] Embodiment 5b: In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -CN, -OH, oxo, Ci-Ce alkoxycarbonyl, Ci-Ce alkyl, hydroxy-Ci-Ce-alkyl, -0 11 C(=NH)NH2, -C(O)NH2, -S(O)2NHR, -S(O)2Ci-C6-alkyl, HNJ»Cl'C3'alkyl, Ci-C6 alkoxy, -NH2, or amino-Ci-Cealkyl, and wherein R is hydrogen or Cs-Cscycloalkyl. In some or any embodiments, R3 is -CN, -OH, Ci-Ce alkoxycarbonyl, -C(O)NH2, -S(O)2NH2, -COOEt, or oxo. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -CN. In some or any embodiments including embodiments A-4b, R3 is not -H and R3 is -OH. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is oxo. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is Ci-Ce alkoxycarbonyl. In some or any embodiments including embodiments A-4c, R3 is -COOEt. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is Ci-Ce alkyl. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is hydroxy-Ci-Ce-alkyl. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -C(=NH)NH2. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -C(O)NH2. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -S(O)2NHR, wherein R is hydrogen or Cs-Cscycloalkyl. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 -S(O)2NH2. In some or any embodiments including embodiments A-4c, R3 is -S(O)2NH2. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -S(O)2Ci-C6-alkyl. In some or any o ii embodiments including embodiments A-4c, R3 is not -H and R3 is HN-~L~Cl C’ alkyl. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is Ci-Ce alkoxy. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -NH2. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is amino-Ci-Cealkyl.
[00109] Embodiment 5b-l: In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -CN, -OH, oxo, Ci-Ce alkoxycarbonyl, Ci-Ce alkyl, hydroxy-Ci-Ce-alkyl, o 11 -C(=NH)NH2, -C(O)NH2, -S(O)2NHR, -S(O)2Ci-C6-alkyl, HN™LCl'C3'alkyl, Ci-C6 alkoxy, -NH2, or amino-Ci-Cealkyl, and wherein R is alkyl. In some or any embodiments including embodiments A-4c, R3 is not -H and R3 is -S(O)2NHR, wherein R is alkyl.
[00110] Embodiment 5c: In some or any embodiments including embodiments A-4c, R3 is -CN, -OH, oxo, Ci-Ce alkoxy carbonyl, -C(O)NH2, o 11 -S(O)2NH2, -S(O)2Ci-Ce-alkyl, HN~l~Cl C3-alkyl or Ci-Ce alkoxy. In some or any embodiments, including embodiments A-4c, R3 is -CN, -OH, oxo, -COOEt, -C(O)NH2, 0 ii -S(O)2NH2, -S(O)2CH3, HNJ-CH\ or -OMe. In some or any embodiments including embodiments A-4b, R3 is -S(O)2CH3. In some or any embodiments including embodiments Ao ii 4c, R3 is HN J~CH3. In some or any embodiments including embodiments A-4b, R3 is -OMe.
[00111] Embodiment 5d: In some or any embodiments including embodiments A-4c, R3 is -COOH or -C(O)N(R)2. In some or any embodiments including embodiments A-4c, R3 is -COOH, C(O)NH2, or -C(O)N(CH3)2. In some or any embodiments including embodiments A-4c, R3 is -C(O)N(CH3)2. In some or any embodiments including embodiments A-4b, R3 is O 0 R k AA R-^N R . In some or any embodiments including embodiments A-4c, R3 is O 0 R Q A A H3C"?'N R —J-” . In some or any embodiments including embodiments A-4c, R3 is
[00112] Embodiment 6: In some or any embodiments including embodiments A-5d, at least one R3a is hydrogen. In some or any embodiments including embodiments A-5d, at least one R3a is oxo. In some or any embodiments including embodiments A-5d, at least one R3a is halogen. In some or any embodiments including embodiments A-5d, at least one R3a is C1-C3 alkyl. In some or any embodiments including embodiments A-5d, at least one R3a is C3-C6 cycloalkyl.
[00113] Embodiment 6a: In some or any embodiments including embodiments A-5d, at least one R3a is -H, halo, oxo, or C1-C3 alkyl. In some or any embodiments including embodiments A-5d, at least one R3a is -H, -F, oxo, or -CH3. In some or any embodiments including embodiments A-5d, at least one R3a is -F. In some or any embodiments including embodiments A-5d, at least one R3a is -CH3.
[00114] Embodiment 6b: In some or any embodiments, including Embodiments A-6a, one R3a is present. In some or any embodiments, including Embodiments A-6a, two R3a are present. In some or any embodiments, including Embodiments A-6a, three R3a are present.
[00115] Embodiment 7: In some or any embodiments including embodiments A-6b, ring B is a 3- to 10-membered cycloalkylene. In some or any embodiments including embodiments A-6b, ring B is a 3- to 11-membered cycloalkylene (in some embodiments, 3- to 10-membered cycloalkylene) optionally fused to a benzo group. In some or any embodiments including embodiments A-6b, ring B is a 3- to 11-membered cycloalkylene (in some embodiments, 3- to 10-membered cycloalkylene) fused to a benzo group. In some or any embodiments including embodiments A-6b, ring B is a 5- to 10-membered heterocycloalkylene ring. In some or any embodiments including embodiments A-6b, ring B is a 5- to 10-membered heterocycloalkylene ring optionally fused to a benzo group. In some or any embodiments including embodiments A-6b, ring B is a 5- to 10-membered heterocycloalkylene ring fused to a benzo group.
[00116] Embodiment 7a: In some or any embodiments including embodiments A-6b, ring B is a 3- to 11-membered cycloalkylene (in some embodiments, 3- to 10-membered cycloalkylene); or a 6-, 7-, or 10-membered heterocycloalkyl; where ring B is substituted with (R2)p. In some or any embodiments including embodiments A-6b, ring B is a 3- to 11membered cycloalkylene (in some embodiments, 3- to 10-membered cycloalkylene) where ring B is substituted with (R2)P. In some or any embodiments including embodiments A-6b, ring B is a 6-, 7-, or 10-membered heterocycloalkyl where ring B is substituted with (R2)P.
[00117] Embodiment 7b: In some or any embodiments including embodiments A-6b, ring embodiments A-6b, ring B is , where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment to ring C. In some or any embodiments including embodiments A-6b, ring B is substituted with (R2)P; and where L designates attachment to L, c designates attachment XL V-Nxy to ring C. In some or any embodiments including embodiments A-6b, ring Bis , where ring B is substituted with (R2)P; and where L designates attachment to L, c designates attachment to ring C. In some or any embodiments including embodiments A- 6b, ring Bis , where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment to ring C. In some or any embodiments including embodiments A-6b, ring B is , where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment to ring C, and designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is C, where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment to ring C. In some or any embodiments including / —\AL embodiments A-6b, ring Bis f c, where ring B is substituted with (R2)P; and where s L z* designates attachment to L, designates attachment to ring C. In some or any embodiments including embodiments A-6b, ring B is c , where ring B is substituted with (R2)P; and where L designates attachment to L, c designates attachment to ring C [ 1 XL In some or any embodiments including embodiments A-6b, ring Bis , where ring I B is substituted with (R2)P; and where designates attachment to L, designates attachment to ring C. In some or any embodiments including embodiments A-6b, ring B is Q-A , where ring B is substituted with (R2)P; and where A- designates attachment to L, designates attachment to ring C. In some or any embodiments including Z / "» embodiments A-6b, ring Bis , where ring B is substituted with (R2)P; and where designates attachment to L, designates attachment to ring C. In some or any embodiments including embodiments A-6b, ring B is c, where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment VVaA1 / r to ring C. In some or any embodiments including embodiments A-6b, ring Bis , where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment to ring C. In some or any embodiments including embodiments A- 6b, ring B is C , where ring B is substituted with (R2)P; and where L designates attachment to L, c designates attachment to ring C. In some or any embodiments I 7 Q including embodiments A-6b, ring B is or , where ring B is substituted with (R2)p; and where designates attachment to L, c designates attachment to ring C.
[00118] Embodiment 7b-l: In some or any embodiments including embodiments A-6b, W1 I W* f ; where ring B is substituted with (R2)P; and where designates AL R2 attachment to L, c designates attachment to ring C, and ' designates attachment to R2. w1 i w2 Ye In some or any embodiments including embodiments A-6b, ring Bis , where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment to ring C, and designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is , where ring B is substituted with (R2)P; and where designates attachment to L, c designates attachment to ring C, and designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is , where ring B is substituted with (R2)P; and where L designates attachment to L, c designates attachment to ring C, and ^wvw designates attachment to R2. In some or I I !^^w2 any embodiments including embodiments A-6b, ring Bis ' c, where ring B is substituted with (R2)p; and where designates attachment to L, c designates attachment to ring C, and designates attachment to R2. In some or any embodiments including i\L r / w < । embodiments A-6b, ring Bis ' c, where ring B is substituted with (R2)P; and where % L R2 designates attachment to L, c designates attachment to ring C, and ^~wx designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is , where ring B is substituted with (R2)P; and where designates attachment to R2 designates attachment to ring C, and designates attachment to R2. In some or R2 any embodiments including embodiments A-6b, ring B is w1 I w2 ' , where ring B is substituted with (R2)p; and where designates attachment to L, c designates attachment R2 to ring C, and designates attachment to R2. In some or any embodiments including r2a AL Z N W1 I I L ^W2 , embodiments A-6b, ring B is where L designates attachment to L, ' c, where ring B is substituted with (R2)P; and o r2 designates attachment to ring C, and vTwwwx designates attachment to R2. In some or any embodiments including embodiments A-6b, ring < w1 I I yN^w2 B is R C, where ring B is substituted with (R2)P; and where L designates R2 attachment to L, c designates attachment to ring C, and designates attachment to R2. R2 < Xw1 I 0 Vc In some or any embodiments including embodiments A-6b, ring Bis , where ring B is substituted with (R2)P; and where designates attachment to L, c designates R2 attachment to ring C, and designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is R2 , where ring B is substituted with (R2)p; and where designates attachment to L, c designates attachment to ring C, and •~ww» designates attachment to R2. In some or any embodiments including embodiments A- AL w1 I L w2 6b, ring B is ' c, where ring B is substituted with (R2)P; and where designates Xt R2 attachment to L, u designates attachment to ring C, and -~wwx designates attachment to R2. rx X w1 I k^w2 / c In some or any embodiments including embodiments A-6b, ring Bis , where ring B is substituted with (R2)P; and where designates attachment to L, c designates R2 attachment to ring C, and -wvwx designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is w1 I w2 Jr z* , where ring B is substituted with (R2)p; and where designates attachment to L, c designates attachment to ring C, and R2 •~ww» designates attachment to R2. In some or any embodiments including embodiments A- 6b, ring B is attachment to L, w1 i w2 y ' c, where ring B is substituted with (R2)P; and where designates o r2 u designates attachment to ring C, anddesignates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is W1 I w2 , where ring B is substituted with (R2)P; and where L designates attachment to L, c designates R2 attachment to ring C, and designates attachment to R2. In some or any embodiments w1 I ___XW2 C including embodiments A-6b, ring Bis , where ring B is substituted with (R2)p; and where XL designates attachment to L, c designates attachment to ring C, and R2 •"vvwx designates attachment to R2. In some or any embodiments including embodiments A I \L I L ,W2 6b, ring B is ' c, where ring B is substituted with (R2)P; and where X X. R2 designates attachment to L, c designates attachment to ring C, and • / www designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is R2 W1 I W2 f , where ring B is substituted with (R2)P; and where designates attachment to ~ R2 designates attachment to R2. In some or R2 / XL designates attachment to ring C, and any embodiments including embodiments A-6b, ring B is W1 I ,W2 ' c, where ring B is substituted with (R2)p; and where designates attachment to L, c designates attachment R2 designates attachment to R2. In some or any embodiments including to ring C, and R' embodiments A-6b, ring B is W1 I w2 ' c, where ring B is substituted with (R2)P; and \l ~ M I* designates attachment to L, v designates attachment to ring C, and designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is R , where ring B is substituted with (R2)P; and where L designates attachment to L, c designates attachment to ring C, and designates attachment to R2. In some or any embodiments including embodiments A-6b, ring B is substituted with (R2)p; and where designates attachment to L, c designates attachment to ring C, and JWVWV designates attachment to R2.
[00119] Embodiment 7b-2: In some or any embodiments including embodiments A-6b, R2 and where designates attachment to L, c designates attachment to ring C, and -ww« designates attachment to R2. In some or any embodiments including embodiments A-6b, ring / Q % L B is or , where ring B is substituted with (R2)P; and where designates r2 , attachment to L, designates attachment to ring C, and designates attachment to R2.
[00120] Embodiment 7c: In some or any embodiments including embodiments A-6b, ring B is (R2)o^0 (R2)o^ (r2)o-2 y (r2)o-2 y (R2)q-2 (R2)o-2 (r2)i (r2)^ r y n (R2)o-2 L 1 * (R2)o-2 I o 7 (r2)o-2 (R2)o-2 I---(R2)o-2 X <r2)<»-3 7 (R2)o-2 7 7 (R2)o-2 y ,, ,, (R2)o-2 I Ri , A / (R2)o-2 I I , 7 (R2)o-2 7 ,, , Y <r2)” x x _rNy 6AT rvy , (r2)o-2 l , / 7 n. y (r2)o.2 (r»i ,,,, (R2)i N J (R2)l-2 I N / (R2)l-2 jL J. , y ' y o 7 ,,, ^y (R2)oX^^ (R2)o^~^^ (R2)o^^ , , ,, / X^^y (r2)o-~ (R2)°-2yXX (r2)o-2 / ,, , , foregoing structures, the upper is attached to L.
[00121] Embodiment 7c-l: In some or any embodiments including embodiments A-6b, of the foregoing structures, the upper is attached to L.
[00122] Embodiment 7c-2: In some or any embodiments including embodiments A-6b, embodiments of each of the foregoing structures, the upper is attached to L.
[00123] Embodiment 7d: In some or any embodiments including embodiments A-6b, ring where designates attachment to L, and c designates attachment to ring C.
[00124] Embodiment 7e: In some or any embodiments including embodiments A-6b, ring B is not C % L c where designates attachment to L, designates attachment . r2 to ring C, and •"ww' designates attachment to R2.
[00125] Embodiment 7f: In some or any embodiments including embodiments A-6b, where L designates attachment to L, and c designates attachment to ring C. In some or any embodiments including embodiments A- 6b, where designates attachment to L, and designates attachment to ring C.
[00126] Embodiment 8: In some or any embodiments including embodiments A-7d, ring C is aryl substituted with (R1^. In some or any embodiments including embodiments A-7d, ring C is substituted with (R^n where r is 1 or 2 and where (R1)]! is substituted on any substitutable ring atom. In some or any embodiments including embodiments A-7d, ring C is phenyl ring fused to HET where Ring C substituted with (R1^.
[00127] Embodiment 8a: In some or any embodiments including embodiments A-7f, ring C is a 6- or 10-membered aryl, substituted with (R1)^ where designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is a 6- or 10-membered aryl, substituted with (R1^. In some or any embodiments including embodiments A-7f, ring C is W21 substituted with (R1^; where 5 designates attachment to W2. In some or any W2 embodiments including embodiments A-7f, ring C is , substituted with (R1^; where
[00128] designates attachment to W2. Embodiment 8a-l: In some or any embodiments including embodiments A-7f, w2 ring C is a 6- or 10-membered aryl, , or ; wherein ring C is substituted with (R1^; where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is a 6- or 10-membered aryl, substituted with (R1^. In w2 some or any embodiments including embodiments A-7f, ring C is , substituted with (R2)n; where 2 designates attachment to W2. In some or any embodiments including W2 embodiments A-7f, ring C is attachment to W2. W21 , substituted with (R1)^ where 2 designates
[00129] Embodiment 8b: In some or any embodiments including embodiments l-7f, ring Cis w (R1)n w substituted with (R2)n, W2 W2 substituted with (R2)n, w2 substituted with (R2)n, substituted with (R2)n, w2 w2' J J W21 substituted with (R2)n, or substituted with (R1)^ where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is (R1)n w2 , where 2 designates attachment to W2. In some or any embodiments including w embodiments A-7f, ring C is substituted with (R2)n, where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is W2 w2l substituted with (R1^, where 5 designates attachment to W2. In some or any W2 / embodiments including embodiments A-7f, ring C is substituted with (R^n, where 2 designates attachment to W2. In some or any embodiments including embodiments W2 cO w2i A-7f, ring C is substituted with (R1^, where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is substituted with (R2)n, where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is substituted with (R2)n where designates attachment to W2.
[00130] Embodiment 8c: In some or any embodiments including embodiments A-7f, where including embodiments A-7f, ring C is r1 , where designates attachment to W2. w2 R1 In some or any embodiments including embodiments A-7f, ring C is r1 , where w2 2 designates attachment to W2. In some or any embodiments including embodiments A-7d, R1 W2 1 ring C is R , where designates attachment to W2. In some or any w5 W21 embodiments including embodiments A-7f, where ring Cis R , where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is R1 W2 R1 yy2| , where 2 designates attachment to W2. In some or any embodiments R1 R1 including embodiments A-7f, ring C is 1 W2 R , where 2 designates attachment to R1 W2. In some or any embodiments including embodiments A-7f, ring C is R1 R1 w2i where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is r1 t 1 w2l R , where 2 designates attachment to W2. In some or any R1 □ 1 t w2 , W2 ? embodiments including embodiments A-7f, ring C is R , where 2 designates attachment to W2. In some or any embodiments including embodiments A-7f, ring C is R1 w2 1 w2I R where 2 designates attachment to W2.
[00131] Embodiment 9: In some or any embodiments including embodiments A-8c, L is a bond. In some or any embodiments including embodiments A-8c, L is -C(O)NH- where the nitrogen of -C(O)NH- is attached to ring A.
[00132] Embodiment 9a: In some or any embodiments including embodiments A-8c, L is O W H , where w indicates attachment to W1, and A indicates attachment to ring A
[00133] Embodiment 10: In some or any embodiments including embodiments A and 2-9a, n is 0. In some or any embodiments including embodiments A-lf and 2-9a, n is 1. In some or any embodiments including embodiments A-lf and 2-9a, n is 2. In some or any embodiments including embodiments A-lf and 2-9a, n is 3. In some or any embodiments including embodiments A-lf and 2-9a, n is 4.
[00134] Embodiment 10a: In some or any embodiments including embodiments A-lf and 2-9a, n is 1, 2, or 3.
[00135] Embodiment 11: In some or any embodiments including embodiments A-3 and 5-10a, p is 0. In some or any embodiments including embodiments A-4a and 5-10a, p is 1. In some or any embodiments including embodiments A-4a and 5-10a, p is 2. In some or any embodiments including embodiments A-4a and 5-10a, p is 3.
[00136] Embodiment 11-1: In some or any embodiments including embodiments A-3 and 5-10a, p is 4.
[00137] Embodiment Ila: In some or any embodiments including embodiments A-4a and 5-10a, p is 0, 1, or 2.
[00138] Embodiment 12: In some or any embodiments including embodiments A-5 and 7-11a, q is 0. In some or any embodiments including embodiments A-6a and 7-1 la, q is 1. In some or any embodiments including embodiments A-6a and 7-1 la, q is 2. In some or any embodiments including embodiments A-6a and 7-1 la, q is 3.
[00139] Embodiment 12a: In some or any embodiments including embodiments A-6a and 7-1 la, q is 0, 1, or 2.
[00140] Embodiment 13: In some or any embodiments including embodiments A-12a, n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0 or 1.
[00141] Embodiment 13a-l: In some or any embodiments including embodiments A-12a, n is 0, p is 2, and q is 1; n is 1, p is 0, and q is 1; n is 1, p is 1, and q is 1; n is 1, p is 2, and q is 1; n is 2, p is 0, and q is 1; n is 2, p is 2, and q is 1; n is 3, p is 0, and q is 1; n is 3, p is 1, and q is 1; n is 3, p is 2, and q is 1; n is 3, p is 3, and q is 0; or n is 3, p is 3, and q is 1.
[00142] Embodiment 13a-2: In some or any embodiments including embodiments A-12a, n is 2, p is 1, and q is 1.
[00143] Embodiment 14: In some or any embodiments, the compound is selected from any of:
[00144] Embodiment 14’: In some or any embodiments, the compound is selected from any of:
[00145] Embodiment 14a: In some or any embodiments, the compound is selected from any of:
[00146] Embodiment 14a’: In some or any embodiments, the compound is selected from any of:
[00147] Embodiment 14a-l: In some or any embodiments, the compound is selected from any of:
[00148] Embodiment 14a’-l: In some or any embodiments, the compound is selected from any of:
[00149] Embodiment 14b: In some or any embodiments, the compound is selected from any of: wherein Ar is aryl, phenyl fused to HET, or phenyl fused to CYC, and where (R1^ is substituted on any substitutable ring atom; R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; C1-C3 haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-methoxy; halo-Ci-Cs alkoxy, in some embodiments, halo-Ci alkoxy or halo-C2 alkoxy; 5- to 6membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; and C2-C4 alkynyl, in some embodiments, ethynyl.
[00150] Embodiment 14c: In some or any, the compound is selected from any of: f^N L II nh2 L if nh2 [ x 6' 0 6° V r^N NH NH jQ r~ jCl ,Me J Y^^s Y^^s Y^ x oz'NH x 6Z'NH x flpnh jT Jl i^nh 0 NH ' 0 Y^i^NH2 Y^XyNH2 Me OH NH2 X 0 rWr* 1 \ H MeO^y^F F ®,O0 ^®,O® N 1 11 r N K ,NH2 Y^yNH2 ^^^h2 JU Nh2 \ H x il \ n 6° 0 0 0 ^>1 r^N YY r^N II Me JL II Me 1 || Me . JL ,Me 6'"° x U0 x / "nh x Unh II1 Me [ |1 Me f |1 Me J^N NH X Qz NH X Qz NH rr° rr° n Y^^MeY^O Y-'™ VVH °® Me ^\ / nh2 vX^L / OH 1 / Me ' 1 \ f'Me Me Me Me M H Yjnh vCXf vOy y-OYn nh2 oh nh2
[00151] Embodiment 14c’: In some or any embodiments, the compound is selected from any of: Me
[00152] Embodiment 14d: In some or any embodiments, the compound is selected from any of:
[00153] Embodiment 14d’: In some or any embodiments, the compound is selected from any of:
[00154] Embodiment 15: In some or any embodiments, the compound is selected from any of: wherein R3 is hydrogen, -C(O)NH2, -C(O)N(CH3)2, or COOH.
[00155] Embodiment 15’: In some or any embodiments, the compound is selected from any of: O R3 F wherein R3 is hydrogen, -C(O)NH2, -C(O)N(CH3)2, or COOH.
[00156] Embodiment 16a: In some or any embodiments, the compound is selected from any of compounds 1-183, or a pharmaceutically acceptable salt and / or an isomer thereof, from Table A-l. Table A-l Compound No Structure 15 o XX k r ii nh2 QS o ° MeO^Y^F F 17 0 XX AX? / N — Sx \J H 6' NH2 MeO-^2^ 18 X XX? Gr« o' 'nh2 19 0 A X JL NH2 qX^a° MeO^'^^OCFa 21 o i^Gi JL X X NH2 CCC^Ao Jl / 1 MeO^^^OCFg 23 F\ a NH2 F7TB ?o MeO^^Xr F 24 FT 1 k JL ,NH2 Lx 1L°,o MeO^^Xr F Compound No Structure 37 O A^N fYoAynh= AAa ° F 38 O A^N AAa o MeO^y^F F 39 O r^N FC 1 JL 1 P U„ H 6' NH2 "TX MeO^Y^F F 41 O A^N fc II k il p 6' NH2 MeO^Y^F F 43 o A^n F\ A k k ,° IT H NH2 MeO^^Y^F F 45 2 < > CD \ / ° y }=\ m—<( ^IZ ' A W-. z^° I M 47 o A^n Il L if nh2 H "0 MeO^Y^F F Compound No Structure 48 a XTjL nh2 H 3' 'o MeO^Y^F F 49 0 MeO^Y^F F 50 CXI OY zie y—u. o=^ )=\ 7—\ O / \ ® C_y 51 a nh2 a °' MeO^Y^F F 53 Me 0 LJ. H 3' -0 MeO^Y^F F 54 Me. AJL zNH2 °' MeO^Y^F F 55 2 n JL II nh2 M A A °' MeO^Y^F F Compound No Structure 56 Me 0 n A A A ,nh2 t n / > 0 JO MeO^^^ 57 Me 0 N A Al / NH2 I A A °' 0 0 Al MeO^V^F F 58 Me 0 MeO^^ 59 0 Y^N f3c^a AA ,NH2 Wk °0 X A MeO^y^F F 60 0 Y^N II L if nh2 / ¾ 6 MecrAr F 61 ("A0 ® ' / m O z—“ A cn^ o I N> 62 Me O r^>\ AJXa 11 MeO^Y^F F Compound No Structure 63 0 r^N ll L if nh2 F3C^ N N 3 i 1 h 3^0 "XX MeO^y^F F 64 O r^N ll L if nh2 f3c^n^J% JI q' Mecry^F F 65 2 Ail ll L II nh2 U-A °' Cl 66 2 Ail ll L II nh2 H 6' 0 XX Cl^x?^C| 67 2 I^Jl ll L II nh2 M". A °z F3C^^ 70 O r^N Mecry^F F 71 0 [<^N ll L if nh2 fXX A. °' F XX MeO^y^F F Compound No Structure 72 Me O r^N F\ A JL X X nh2 :XY' J MeO^y^F F 73 o e JL X X nh2 kJ- jx °' IXL MeCT^^T 74 O Y^N f. Ji JX X XJ. H 6' 0 Tj MeO^y F 75 I^N AA-? r 1 6*'^ Xj 76 0 f^N F\ JL X^ X NH2 H 6 0 Tj F3C^^ 77 >-%_VC ■ < z o I 78 CXI X O. / z 0°°^ o 3 Compound No Structure 87 9 II L II nh2 n^^AsA H '0 MeO^J^F F 88 9 JI L II nh2 n^^sA H '0 MeO^^ 89 o AA r JI L H nh2 YxY A J MeO^^ 90 O r^N F II 1^ If NH2 F-fT^N^AsL °' Tj 91 O r^N F\ JL JA A NH2 kJ" Ak °' A J ci^y Cl 92 O r^N F\ A A. A NH2 fAt n^^sA H 3' -0 II 93 O r^N F\ A A A NH2 F^^^r n^^sA kJ" Ak °' A A CI^^T Compound No Structure 94 0 r^N F II jf NH2 XJ. H 6' 0 xOu Qr^ 95 o F\ JI X X nh2 H 6' 0 Xj f3co^^ 96 O f n if nh2 XX XX °' Xj 97 O F II jf NH2 JX °' X j 98 O r^N F\ JI X. X NH2 F^X^T N^^ / SX XX H 3' "0 Me\,XX Me 99 0 r^N F\ X X X 7NH2 \X XX °' XX F3C^^CF3 100 0 |<^N F II 1 Jf NH2 N^^;SX ^X" XX °' XX CI^^^^CFa Compound No Structure 101 O r^N F n if nh2 XX-J^CFs0' I J Cl 102 o f^n F n if nh2 Fnr n / S / ;sL U.„ °' 0 T J ci^y Cl 103 0 f^N F. II 1 jf NH2 XX h 6' 0 XX FsC^^F 104 o r^N F\ JL X X z^m2 XX h 6Z 0 XX f3c^^^ci 105 O r^N F II jf NH2 f-t^t XX Jk °' XX 106 O f^N F II jf NH2 XX xx °' o Xj ci^y F 107 0 F^N F\ X JX X / NH2 H O' 0 Xj f3c^o^^ Compound No Structure 108 0 r^N F II 1 jf NH2 h o 0 00 109 O r^N F II 1 if nh2 h 6' 0 JO 110 O r^N F II if NH2 H 6' 0 JO 111 0 r^N F. II 1 jf NH2 1^. h 6' 0 Ok 112 o F\ JI X NH2 M" °' ZQO 113 O r^N F\ X JX A NH2 Xj Cl 114 0 r^N F\ A A NH2 H 6' 0 Tj k^Q Compound No Structure 115 4-N NH2 HN-'X / -¼ F / >= / 0 FVy'N MeO^Y^ F 117 Z < > ® \ / O —\ )=\ / =Z -n—X / )iz I O=cn=O 1 z I bo 119 CN I Z 1 O=W=O 7—\ O / \ ® \ / 2 120 z=N NH2 N-A #— F j) 0 YX MeO^y^F F 121 ® \ / o=cn=o 1 z I 122 / =\ NH2 N-A #—x f ji o "Jul MeO^Y^F F Compound No Structure 123 n-A F / F^^O =N O ii -s-nh2 II o H II . MeO^y^ T F 124 N nh2 N'\ Fx J ' \ / / 0 FT^° MeO / J T F 125 F 0 II H 1 Me(J 1 F ^F 126 F J 0 xMe H ii MeCT F XF 127 F J 0 "n" H "Me MeCT F "f Compound No Structure 133 0 0 FEt°VS fVyk II H ZXX F 134 0 0 F^^y^N^Me MeO^^P^F F 135 0 0 MeO^^P^F F 136 0 0 cYr 'XX MeO^Y^F F 137 0 f XjlX 1 \ H 'XX MeO'Yx^F F Compound No Structure 138 0 F. AO II H "XX MeO^Y^F F 139 0 CN XX MeO^V^F F 140 CN I Z z—A oz / =\ o=< ZI\ / — 7—( O / \ ® < > 2 141 CN O Z-- 1 11 / / ^ Z-C / )—<' V U. II \__ / / ° )—\ o=^ ZI\ / -7—C O \ / ^ 142 0 xA^sx.F F X X J F-Y''^ II H "Xi MeO^y^F F Compound No Structure 154 O A^N fVAn^Anh2 Va ° F 155 v. / AA? fTX ^-2 CI^^^F F 156 O A^N fAAnXJ nh2 Va o C|A^A^f F 157 VJL IL? FTX D3CO^X^F F 158 fVAnAXnh2 Va ° D^O'JT F 159 O |<^N Aap FXl MXNH2 f2hco^^^f F 160 o A^n fW-nAynh! AX-.a o F2HCCTY^F F Compound No Structure 161 CM X CX / z ex zic y— u. oA 7—\ O / \ O \ / LL? 162 O r^N fWWyh, AAa ° F3CCTY^F F 163 XjXP Xi h °i ™2 MeO'yA F O r^N XXJ°H2 MeOjA F 164 O [A f. A JL zNH2 AJ, H '0 J 3 Me^y^F F 165 o r=^N F\ A JA A NH2 An A. °' J 3 Cl^y^F F 166 o F\ A A^ A / NH2 X JI f3c^y^f F Compound No Structure 174 O F II if NH2 fVt I J ci^y Cl 175 O r^N F. II JL if nh2 F^AAA^n^^^ / SA AA °' ° ci—O 176 O r^N F\ A JA A nh2 fA^At N^^sA A«ux °' Ij 177 O F. II if NH2 f-AAt n AnXX °' 178 o F\ A A NH2 fA^At n^^sA An^A °' 179 0 A^N F\ A A. A / NH2 fA^At n^^,sA v A °' IJ F3C^^ 180 0 A^N F\ A X A / NH2 f A^Ar N AnA °'
[00157] Embodiment 16b: In some or any embodiments, the compound is selected from any of compounds 184-211, or a pharmaceutically acceptable salt and / or an isomer thereof, from Table A-2. Table A-2 186 0 °yNH2 xx Me^y^F F 187 ~ o^nh2 o y F / Yj 1 \ H ZX1 Me'X^XX'F 188 CD, J1 CD \ / O --\ m—i>iz / =° y=\ ° 4 / / --\ z z I 189 O^NHo Oy f yvb Me''' Me^Y^F F 190 O \_ / ■n— / / 12 / =° y=\ ° m € Y? z z I N> 191 0 o^^2 qCg Me"' "'<^1 MeO^y^F F 192 ~ ck,nh2 o y Ao 1 \ H Me" ' Ci^Y^F F 193 0 °yNH2 qOu Me"' Me^y^F F 194 0 °yNH2 rVW Me j 1 MeO^Y^F F 195 CM I Z Z—A °^=<HX0 7—\ O / \ ® < > S 196 0 °yNH2 CI^Y^F F 197 CM X z Z— / \ 198 O^NH, Oy f. / vs FA / Xr'Nx^s^ II H ■ TZ.. 199 CM X Z z—A —C / <D / x O= / HT\ / — 7—( O / \ ® \ / ^ 200 CM X Z Z—A 7—\ O / \ ® \ / ^ 201 ~ o^nh2 o y f / yS F-SXy^N'^^ 1 \ H ^y^F F 207 o °yNH2 nW Me J 1 F F 208 CM I z z— oZ / =\ O=^ Zie / — 7—\ O / \ u < > ¢0 \__ / Q 209 0 O^NH2 / yS n J H Fi '-''A f jn MeO^\ss< / F F 210 CN T Z Z—A oz / =\ O=^ / — 7—C O / \ ® \ / ^ 211 CM X Z z—A / © 2
[00158] Embodiment 16c: In some or any embodiments, the compound is selected from any of compounds 212-723, or a pharmaceutically acceptable salt and / or an isomer thereof, from Table A-3. Table A-3 560 561 562 563 564 565 566 574 0 Y^N XA^ H 3' NH2 MeO^Y^F F 575 o Y^n A XA P M 1 H NH2 Me^ u Mel I 1 e MeO^y^F F 576 0 Y^N XA'? Y ^Yn M H 3' NH2 q.....XX MeO^Y^F F 577 0 Y^N XA'? Y^t^n IT H nh2 MeO^Y^F F 578 0 Y^N XA^ Y^t^n s^ M J H NH2 Me^ c'\Y'', YY u Me^ J1 e MeoX^F F 579 0 Y^N / \A XA^ Y 1 N s^ M 1 1 H NH2 Me M j[ e MeCTY^X F 580 0 o Y^n <> ,- zji JLX-? CiYi" o?'nh2 F XY MeO^Y^F F 658 CN I Z z—A oz / =\ ° \ ZI\ / “w\> / \ s '---4i I^-LL 659 2 \ / CD J----- C #xz / ° )=\ / ° z z I 660 ~ O^NH, Oy .Ao r^>"' 1 H F Me ^^ F 661 _ o^nh2 o y j / Vj 1 \ H Me^^^F 662 CN T Z Z—A OZ )=\ zrV ° \ ZI\ / / \ ^ 663 CM T Z Z—A oz / =\ / r^. ° \ ^~\ / / \ ^ 670 _ O^NH2 0 y Ao 1 1 H ^^r^F F 671 ~ O^NH, Ao II H ■ Ti 672 CM I z z— oz / =\ zrY ° \ ZX\ / 673 CM I Z Z—A —C / °' / \ z:c\ / — 674 CM I Z Z—A / °' / X / F~C °\ zx\ / 675 0 °yNH2 "" XY / ^ / 1^ f F 692 _ o^nh2 o Ao _____1 1 H / "jO Cl^y^F F 693 ~ O^NH2 o / yS ____1 \ H F 694 CN T Z Z—A \-- / o' / \ / r~L O=< ZI^ 695 z ( ) ® \ / m 4 / )—\ z z I ro 696 2 < ) CD \ / O / - 4 / 712 / ° p ■h 4 / )—\ z z I ro 697 0 °yNH2 o MeO'^^^F 0 0< ,nh2 'N R 710 Fn xi\r H MeCT o 0< .OMe r II N R J JI 711 Fn H T MeCT F F 0° XOH II II Fx [1 JI 712 F" H MeO^ o F "F O°- 1 'N\ Il H *N 713 R F" ^'i, 11 H N H fl MeCT [1 F 'F 0 °" r nh2 r N 714 J F J
[00159] In some or any embodiments, provided herein are: (a) compounds as described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 and pharmaceutically acceptable salts and compositions thereof; (b) compounds as described herein, e.g., of Formula (I), (P-II), or (P-I), and Compounds 1-723 and pharmaceutically acceptable salts and compositions thereof for use in the treatment of pain and / or conditions modulated by voltage-gated sodium channels; (c) processes for the preparation of compounds as described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 as described in more detail elsewhere herein; (d) pharmaceutical formulations comprising a compound as described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent; (e) a method for the treatment of a condition associated with voltage-gated sodium channel function in a subject that includes the administration of a therapeutically or prophylactically effective amount of a compound as described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 or its pharmaceutically acceptable salt or composition; (f) a method for the treatment of pain in a subject that includes the administration of a therapeutically or prophylactically effective amount of a compound as described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 or its pharmaceutically acceptable salt or composition; (g) pharmaceutical formulations comprising a compound as described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 or a pharmaceutically acceptable salt thereof together with one or more other effective agents for treating pain and / or conditions modulated by voltage-gated sodium channels, optionally in a pharmaceutically acceptable carrier or diluent; (h) a method for the treatment of pain in a subject that includes the administration of a therapeutically or prophylactically effective amount of a compound as described herein, e.g., of Formula (I), (P-II), or (P-I) Compounds 1-723 or its pharmaceutically acceptable salt or composition in combination and / or alternation with one or more agent for the treatment of pain and / or conditions modulated by voltage-gated sodium channels; (i) a method for the treatment of a condition associated with voltage-gated sodium channel function in a subject that includes the administration of a therapeutically or prophylactically effective amount of a compound as described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 or its pharmaceutically acceptable salt or composition in combination and / or alternation with one or more agent for the treatment of pain; and (j) use of any compound described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 or a composition comprising any compound described herein, e.g., of Formula (I), (P-II), or (P-I) and Compounds 1-723 or a pharmaceutically acceptable salt or composition for the treatment of a condition associated with voltage-gated sodium channel function described herein (e.g., pain), optionally in combination and / or alternation with one or more agent for the treatment of pain. Optically Active Compounds
[00160] It is appreciated that compounds provided herein have several chiral centers and may exist in and be isolated in optically active and racemic forms. It is to be understood that any racemic, optically-active, diastereomeric, tautomeric, or stereoisomeric form, mixture, or combination thereof, of a compound provided herein, which possess the useful properties described herein is within the scope of the invention. It being well known in the art how to prepare optically active forms (in some or any embodiments, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
[00161] In some or any embodiments, methods to obtain optically active materials are known in the art, and include at least the following. i) physical separation of crystals - a technique whereby macroscopic crystals of the individual stereoisomers are manually separated. This technique can be used if crystals of the separate stereoisomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual stereoisomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the stereoisomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an stereoisomerically pure or enriched synthetic precursor of the desired stereoisomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired stereoisomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations - a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions - this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the stereoisomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) stereospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired stereoisomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the stereoisomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and stereoisomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the stereoisomers are separated by virtue of preferential dissolution of one stereoisomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one stereoisomer of the racemate to pass through.
[00162] In some or any embodiments, provided is a composition of a compound that comprises a substantially pure designated stereoisomer of the compound. In some or any embodiments, in the methods and compounds, the compounds are substantially free of other stereoisomer. In some or any embodiments, a composition includes a compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by weight, of the designated stereoisomer, the remainder comprising other chemical species or stereoisomers. Isotopically Enriched Compounds
[00163] Also provided herein are isotopically enriched compounds.
[00164] Isotopic enrichment (in some or any embodiments, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. 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); WadeD, Chern. Biol. Interact. 117: 191 (1999).
[00165] Isotopic enrichment of a drug can be used, in some or any embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrees the production of deleterious metabolites in specific tissues and / or create a more effective drug and / or a safer drug for combination therapy, whether the combination therapy is intentional or not.
[00166] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C-H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). See, e.g., 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).
[00167] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.
[00168] Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T2O. Tritium decays slowly (half-life = 12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements, including, but not limited to, 13C or 14C for carbon, 33S, 34S, or 36S for sulfur, 15N for nitrogen, and 17O or 18O for oxygen, may lead to a similar kinetic isotope effect.
[00169] For example, the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching asserts that xenogens, when sequestered by Phase I enzymes, may bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity.
[00170] In some embodiments, the compounds described herein may be used as radiopharmaceuticals such as, for example, imaging agents. In one instance, radiopharmaceuticals are positron emission tomography (PET) imaging agents. In such embodiments, substitution of radionuclides (e.g., positron emitting isotopes) for atoms in the compounds allows for the syntheses of radiopharmaceuticals that can function as imaging agents. In some embodiments, radionuclides which can be substituted in the compounds described herein include, and are not limited to, 18F, nC, 13N, 15O, 76Br, and 124I. 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.
[00171] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. In some or any embodiments, such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and longterm toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses.
[00172] Therefore, isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacokinetic, pharmacologic, and / or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition. Preparation of Compounds
[00173] The compounds provided herein can be prepared, isolated or obtained by any method apparent to those of skill in the art. Compounds provided herein can be prepared according to the Exemplary Preparation Schemes provided below. Reaction conditions, steps and reactants not provided in the Exemplary Preparation Schemes would be apparent to, and known by, those skilled in the art.
[00174] Additional steps and reagents not provided in the Exemplary Preparation Scheme would be known to those of skill in the art. For example, intermediates and compounds could be prepared using the procedures known by one of ordinary skill in the art. Exemplary methods of preparation are described in detail in the Examples herein.
[00175] One of skill will understand that the order of steps for any process described herein may be changed. Other variations will be apparent to one of skill in the art and all such variations are contemplated within the scope of embodiments presented herein. Pharmaceutical Compositions and Methods of Administration
[00176] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration. Provided herein are pharmaceutical compositions comprising a compound of Formula (I), (P-II), or (P-I), as described herein in some and any embodiments, and a pharmaceutically acceptable carrier. In some embodiments, the composition is an oral or injectable composition. In some of such embodiments, the injectable composition is a subcutaneously injectable composition.
[00177] The methods provided herein encompass administering pharmaceutical compositions containing at least one compound as described herein, including a compound of Formula (I), (P-II), or (P-I) if appropriate in a salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent for the treatment of pain and / or conditions modulated by voltage-gated sodium channels.
[00178] In some or any embodiments, the second agent can be formulated or packaged with the compound provided herein. Of course, the second agent will only be formulated with the compound provided herein when, according to the judgment of those of skill in the art, such co-formulation should not interfere with the activity of either agent or the method of administration. In some or any embodiments, the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.
[00179] In clinical practice the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols). In some or any embodiments, the compound provided herein is administered orally.
[00180] Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.
[00181] These compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release.
[00182] Use may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin. These compositions can also comprise substances other than diluents, in some or any embodiments, wetting, sweetening or flavoring products.
[00183] The compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, in some or any embodiments, ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, in some or any embodiments, using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.
[00184] The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
[00185] The compositions can also be aerosols. For use in the form of liquid aerosols, the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active principle is finely divided and combined with a water-soluble solid diluent or vehicle, in some or any embodiments, dextran, mannitol or lactose.
[00186] In some or any embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers or excipients. In a specific embodiment and in this context, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
[00187] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and in some or any embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
[00188] Lactose free compositions provided herein can comprise excipients that are well known in the art and are listed, in some or any embodiments, in the U.S. Pharmacopeia (USP 36-NF 31 S2). In general, lactose free compositions comprise an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.
[00189] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelflife or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379 80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and / or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
[00190] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.
[00191] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. In some or any embodiments, suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
[00192] Further provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
[00193] The pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in some or any embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject. The formulation should suit the mode of administration. In a some or any embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, in some or any embodiments, an animal subject, such as a mammalian subject, in some or any embodiments, a human subject.
[00194] A pharmaceutical composition is formulated to be compatible with its intended route of administration. In some or any embodiments, routes of administration include, but are not limited to, parenteral, e.g., intrathecal, epidural, local or regional for peripheral nerve block, intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical (including administration to the eye, and in some embodiments to the cornea), transmucosal, intra-tumoral, intra-synovial, and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical (including administration to the eye, and in some embodiments to the cornea) administration to human beings. In a specific embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.
[00195] In some or any embodiments, dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (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 a subject, including suspensions (e.g., aqueous or nonaqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.
[00196] The composition, shape, and type of dosage forms provided herein will typically vary depending on their use. In some or any embodiments, a dosage form used in the initial treatment of pain may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, e.g, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
[00197] Generally, the ingredients of compositions are supplied either separately or mixed together in unit dosage form, in some or any embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
[00198] Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms can have 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 Forms
[00199] Pharmaceutical compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
[00200] In some or any embodiments, the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
[00201] Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. In some or any embodiments, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. In some or any embodiments, excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
[00202] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
[00203] In some or any embodiments, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
[00204] In some or any embodiments, excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
[00205] In some or any embodiments, fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
[00206] In some or any embodiments, suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103™ and Starch 1500 LM.
[00207] Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
[00208] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
[00209] 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 oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, in some or any embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. Delayed Release Dosage Forms
[00210] Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. In some or any embodiments, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500; each of which is incorporated herein by reference in its entirety. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, in some or any embodiments, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Thus, encompassed herein are unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel caps, and caplets that are adapted for controlled release.
[00211] All controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
[00212] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
[00213] In some or any embodiments, the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some or any embodiments, a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in a subject at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in the review by Langer (Science 249:15271533 (1990)). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. Parenteral Dosage Forms
[00214] In some or any embodiments, provided are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. In some or any embodiments, parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
[00215] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. In some or any embodiments, suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[00216] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms. Transdermal, Topical & Mucosal Dosage Forms
[00217] Also provided are 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 one of skill in the art. See, e.g.. Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
[00218] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, 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 to form lotions, tinctures, creams, emulsions, gels or ointments, which are nontoxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
[00219] Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients provided. In some or any embodiments, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
[00220] The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition. Dosage and Unit Dosage Forms
[00221] In human therapeutics, the doctor will determine the posology which the doctor considers most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the infection and other factors specific to the subject to be treated. In some or any embodiments, doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to 50 mg per day for an adult. In some or any embodiments, doses are from about 5 to about 400 mg per day or 25 to 200 mg per day per adult. In some or any embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated. In some or any embodiments, doses for subcutaneous administration are from about 1 to about 50 mg per day, or from about 1 to about 25 mg per day, or from about 1 to about 10 mg per day, or from about 1 to about 20 mg per day, or from about 5 to about 25 mg per day, or from about 5 mg to about 20 mg per day, or from about 10 to about 20 mg per day. In some or any embodiments, doses for oral administration are from about 5 to about 250 mg per day, from about 5 to 200 mg per day, or from about 50 mg to about 100 mg per day, or from about 75 mg to about 1125 mg per day, or from about 10 mg to about 200 mg per day. In some embodiments, the mg / day amounts are for an adult. In further aspects, provided are methods of treating a condition associated with voltage-gated sodium channel function and / or pain in a subject by administering, to a subject in need thereof, a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The amount of the compound or composition which will be therapeutically or prophylactically effective in the treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
[00222] In some or any embodiments, exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). For compositions provided herein, in some or any embodiments, the dosage administered to a subject is 0.01 mg / kg to 3 mg / kg of the subject’s body weight, or 0.10 mg / kg to 3 mg / kg of the subject’s body weight, based on weight of the active compound. In some or any embodiments, the dosage administered to a subject is between 0.20 mg / kg and 2.00 mg / kg, or between 0.30 mg / kg and 1.50 mg / kg of the subject’s body weight. In some embodiments, the dosage is administered subcutaneously to a subject and is between about 0.01 mg / kg to 1 mg / kg (inclusive), or between about 0.03 mg / kg to 0.5 mg / kg (inclusive) of the subject’s body weight, based on weight of the active compound. In some embodiments, the dosage is administered orally to a subject and is between about 0.10 mg / kg to 5 mg / kg (inclusive) of the subject’s body weight, or between about 0.10 mg / kg to 2 mg / kg (inclusive) of the subject’s body weight, based on weight of the active compound.
[00223] In some or any embodiments, the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day. In some or any embodiments, the daily dose is administered twice daily in equally divided doses. In some or any embodiments, the daily dose is administered thrice daily in equally divided doses. In some or any embodiments, the daily dose is administered four times daily in equally divided doses. In some or any embodiments, a daily dose range should be 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, or from about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response.
[00224] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. In some or any embodiments, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.
[00225] In some or any embodiment, the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is 0.1 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 10 mg / kg, or 15 mg / kg or more of a subject’s body weight. In another embodiment, the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is a unit dose of 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, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 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.
[00226] In some or any embodiments, treatment or prevention can be initiated with one or more loading doses of a compound or composition provided herein followed by one or more maintenance doses. In such embodiments, the loading dose can be, for instance, about 6 to about 40 mg per day, or about 10 to about 20 mg per day for one day to five weeks. The loading dose can be followed by one or more maintenance doses. In some or any embodiments, each maintenance does is, independently, about from about 1 mg to about 20 mg per day, between about 2.5 mg and about 15 mg per day, or between about 2.5 and about 8 mg per day. Maintenance doses can be administered daily and can be administered as single doses, or as divided doses.
[00227] In some or any embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age. In some or any embodiments, a sufficient amount of a compound or composition provided herein is administered to achieve a steady-state concentration in blood or serum of the subject of from about 100 to about 1000 ng / mL, from about 150 to about 800 ng / mL, or from about 300 to about 600 ng / mL. In some or any embodiments, loading doses can be administered to achieve steady-state blood or serum concentrations of about 300 to about 2000 ng / mL, or about 400 to about 800 ng / mL for one to five days. In some or any embodiments, maintenance doses can be administered to achieve a steady-state concentration in blood or serum of the subject of from about 100 to about 1000 ng / mL, from about 150 to about 800 ng / mL, or from about 300 to about 600 ng / mL. In some or any embodiments, administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least 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.
[00228] In some or any embodiments, provided herein are unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail herein. In some or any embodiments, the unit dosage comprises 1 to 1000 mg, 1 to 100 mg or 10 to 50 mg active ingredient. In particular embodiments, the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient. Such unit dosages can be prepared according to techniques familiar to those of skill in the art.
[00229] In some or any embodiments, dosages of the second agents to be used in a combination therapy are provided herein. In some or any embodiments, dosages lower than those which have been or are currently being used to treat pain are used in the combination therapies provided herein. The recommended dosages of second agents can be obtained from the knowledge of those of skill in the art. For those second agents that are approved for clinical use, recommended dosages are described in, for example, Hardman etaL, eds., 1996, Goodman & Gilman’s The Pharmacological Basis Of Therapeutics 9th Ed, Mc-Graw-Hill, New York; Physician’s Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ; which are incorporated herein by reference in their entirety.
[00230] In various embodiments, the therapies (e.g., a compound provided herein and the second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart. In various embodiments, the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In some or any embodiments, two or more therapies are administered within the same patient visit. In other embodiments, the compound provided herein and the second agent are administered concurrently.
[00231] In other embodiments, the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
[00232] In some or any embodiments, administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same agent may be repeated and the administration may be separated by at least 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.
[00233] In some or any embodiments, a compound provided herein and a second agent are administered to a patient, in some or any embodiments, a subject, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise. In some or any embodiments, the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In some or any embodiments, the compound provided herein and the second active agent exert their effect at times which overlap. Each second active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound provided herein is administered before, concurrently or after administration of the second active agent.
[00234] In some or any embodiments, the compound provided herein and the second agent are cyclically administered to a patient. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second agent and / or third agent (e.g., a second and / or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improve the efficacy of the treatment.
[00235] In some or any embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered 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.
[00236] In other embodiments, courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent. In some or any embodiments, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
[00237] The second agent can act additively or synergistically with the compound provided herein. In some or any embodiments, the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition. In another embodiment, a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions. In still another embodiment, a compound provided herein is administered prior to or subsequent to administration of a second agent. Also contemplated are administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral. In some or any embodiments, when the compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited. Kits
[00238] Also provided are kits for use in methods of treatment of pain and / or a condition associated with voltage-gated sodium channel function or a pain-related disorder. The kits can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating the pain or a pain-related disorder. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a compound or composition provided herein, or a second agent or composition, can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the subject for at least 1 day. In some or any embodiments, a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.
[00239] In some or any embodiments, suitable packaging is provided. As used herein, “packaging” includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and / or a second agent suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents. Methods of Use
[00240] Provided herein is a method for treating a condition associated with voltage-gated sodium channel function and / or pain in a subject, which comprises contacting the subject with a therapeutically or prophylactically effective amount of a compound of Formula (I), (P-II) or (P-I) including a single enantiomer, a mixture of an enantiomeric pair, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers; or a pharmaceutically acceptable salt thereof.
[00241] Provided herein is a method for the treatment of a condition associated with voltagegated sodium channel function in a subject, comprising the administration of a therapeutically or prophylactically effective amount of a compound of Formula (I), (P-II), or (P-I) described herein or a pharmaceutical composition described herein.
[00242] In some embodiments, the subject is a human. In a group of embodiments, the condition is pain or the condition is associated with pain. In some embodiments, the condition is pain. In some embodiments, the condition is associated with pain. In some embodiments, the pain is nociceptive pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the pain is refractory to other forms of pain medications.
[00243] In a group of embodiments, the condition is selected from the group consisting of erythromelalgia, diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, postherpetic neuralgia, cancer pain, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, and postsurgical pain. In a group of embodiments, the condition is selected from the group consisting of epilepsy, Parkinson’s disease, a mood disorder, psychosis, amyotropic lateral sclerosis, glaucoma, ischemia, a spasticity disorder, and obsessive compulsive disorder.
[00244] In some or any embodiments, provided herein are methods for treating pain and / or a condition associated with voltage-gated sodium channel function in a subject. In some or any embodiments, the methods encompass the step of administering to the subject in need thereof an amount of a compound effective for the treatment pain and / or a condition associated with voltage-gated sodium channel function in combination with a second agent effective for the treatment or prevention of pain and / or a condition associated with voltage-gated sodium channel function. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In some or any embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.
[00245] In some or any embodiments, provided herein are methods for treating a condition associated with voltage-gated sodium channel function in a subject. In some or any embodiments, the methods encompass the step of administering to the subject in need thereof a therapeutically or prophylactically effective amount of a compound effective for the treatment of a condition associated with voltage-gated sodium channel function in combination with a second agent effective for the treatment of a condition associated with voltage-gated sodium channel function. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In some or any embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.
[00246] In some or any embodiments, provided herein is of inhibiting NAV1.8 comprising contacting NAV1.8 with a compound of Formula (I), (P-II), or (P-I) and Compounds 1-723.
[00247] In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is associated with a condition or is a condition selected from acute pain, anal fissures, back pain, chronic pain, dental pain, joint pain, neck pain, neuropathic pain, obstetric pain, post-herpetic neuralgia, shingles, tension headaches, trigeminal blepharospasm, pain associated with cardiac arrythmia, focal dystonia, hyperhidrosis, muscle spasms, urinary bladder relaxation, visceral pain, sympathetically maintained pain, myositis pain, musculoskeletal pain, lower back pain, pain from sprains and strains, pain associated with functional bowel disorders, non-cardiac chest pain, pain associated with irritable bowel syndrome, pain associated with myocardial ischemia, toothache pain, pain from dysmenorrhea, erythromelalgia, diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional pain syndrome, trigeminal neuralgia, multiple sclerosis, osteoarthritis, postherpetic neuralgia, cancer, cluster headache, migraine, sciatica, endometriosis, fibromyalgia, dry eye syndrome, (acute) corneal injuries or abrasions, comeal infections, pain associated with Parkinson’s disease, pain associated with ALS, and surgery (in some embodiments, postsurgery; in some embodiments, ocular surgery). In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is pain in an acute care setting, including postsurgery (post-surgical pain). In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is pain in an acute care setting, including post-surgery and the compound is administered intravenously. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is ocular pain. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is ocular pain and the compound is administered topically. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is subacute pain or chronic pain. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is subacute pain or chronic pain and the compound is administered subcutaneously. In some or any embodiments, the pain to be reduced, ameliorated, treated, or prevented is subacute pain or chronic pain and the compound is administered orally.
[00248] In some or any embodiments, the condition associated with voltage-gated sodium channel function is selected from itch, cough, epilepsy, Parkinson’s disease, a mood disorder, psychosis, amyotrophic lateral sclerosis (ALS), cardiac arrhythmia, glaucoma, ischemia, a spasticity disorder, and obsessive compulsive disorder. In some or any embodiments, the condition associated with voltage-gated sodium channel function is selected from pain, itch, cough, glaucoma, and ischemia. In some or any embodiments, the condition associated with voltage-gated sodium channel function is selected from pain, itch, and cough. In some or any embodiments, the condition associated with voltage-gated sodium channel function is pain.
[00249] In some or any embodiments, the compounds described herein are used for delaying the onset of pain, or reducing the severity or duration of pain. In some or any embodiments, the compounds described herein are used for the reduction of the severity or duration of pain associated with voltage-gated sodium channel function. In some embodiments, the compounds described herein are used for delaying or preventing onset of pain.
[00250] In some or any embodiments, the compounds described herein are used for prevention of pain or of a condition associated with voltage-gated sodium channel function.
[00251] In some or any embodiments, the compounds described herein are used for treatment of pain or of a condition associated with voltage-gated sodium channel function. Assay Methods
[00252] Compounds can be assayed for efficacy in treating pain and / or a condition associated with voltage-gated sodium channel function according to any assay known to those of skill in the art. Exemplary assay methods are provided elsewhere herein. Second Therapeutic Agents
[00253] In some or any embodiments, the compounds and compositions provided herein are useful in methods of treatment of pain and / or a condition associated with voltage-gated sodium channel function, that comprise further administration of a second agent effective for the treatment of pain and / or a pain-related disorder and / or a condition associated with voltagegated sodium channel function. The second agent can be any agent known to those of skill in the art to be effective for the treatment of pain and / or a pain-related disorder and / or a condition associated with voltage-gated sodium channel function, including those currently approved by the United States Food and Drug Administration, or other similar body of a country foreign to the United States. In some or any embodiments, the second agent is a local anesthetic (in some or any embodiments, a steroid), an opioid, a vasoconstrictor, a glucocorticoid, adrenergic drugs (in some or any embodiments, alpha agonists or mixed central-peripheral alpha-2- agonists), vanilloids, an anti-inflammatory agent (e.g. NSAID, or an anti-inflammatory agent associated with ocular conditions, including cyclosporine and lifitegrast) or a chemical permeation enhancer. In some embodiments, the second agent is an inhibitor of Nav 1.8. In some or any embodiments, chemical permeation enhancers include anionic surfactants, cationic surfactants, nonionic surfactants. In some or any embodiments, the second agent is bupivacaine, levobupivicaine, tetracaine, ropivacaine, epinephrine, phenylephrine, clonidine, sodium lauryl sulfate, sodium octyl sulfate, dodecyltrimethylammonium bromide, octyltrimethylammonium bromide, polyoxyethylene (20) sorbitan monolaurate, and / or polyoxyethylene (20) sorbitan monooleate.
[00254] In some or any embodiments, a compound provided herein is administered in combination with one second agent. In further embodiments, a compound provided herein is administered in combination with two second agents. In still further embodiments, a compound provided herein is administered in combination with two or more second agents.
[00255] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). The use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.
[00256] As used herein, the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and / or less frequent administration of said therapies to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.
[00257] The active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an agent effective in the treatment of pain and / or a pain-related disorder and / or a condition associated with voltage-gated sodium channel function. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially. The dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the pain or a pain-related disorder to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. EXAMPLES
[00258] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: ESI (electrospray ionization); g (grams); mg (milligrams); mL or ml (milliliters); pL (microliters); pM (micromolar); HATU (hexafluorophosphate azabenzotri azole tetramethyl uronium); hr or hrs (hours); Hz (Hertz); MHz (megahertz); mmol (millimoles); MS (mass spectrometry); N (normality when referring to acid); psi (pounds per square inch); HPLC (high pressure liquid chromatography); Prep-HPLC (preparatory high pressure liquid chromatography); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); and DMSCkf (deuterated dimethylsulfoxide).
[00259] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in0 C (degrees Celsius). All reactions are conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.
[00261] Step 1: base (in some embodiments, EtsN, NaH), X-CO2R (in some embodiments, dimethyl carbonate, diethyl carbonate), solvent (in some embodiments, THF, DMF); Step 2: base (in some embodiments, iPr2NEt, EtsN, NaH, Tf20, solvent (in some embodiments, di chloromethane, THF); Step 3: boronic acid or boronic ester, base (in some embodiments, sodium carbonate, potassium carbonate), catalyst (in some embodiments, palladium acetate, palladium chloride), solvent (in some embodiments, EtOH, water, DMF); Step 4: hydrogen, catalyst (in some embodiments, Pd / C, Raney Ni), solvent (in some embodiments, MeOH, EtOH); Step 5: base (in some embodiments, LiOH, NaOH), solvent (in some embodiments, water, THF); Step 6: amine (in some embodiments, 3-aminobenzene-1-sulfonamide, 4-aminopyridine-1-sulfonamide, 4-amino-3-acetyl-pyridine), coupling agent (in some embodiments, HATU, HBTU, POCI3) or oxalyl chloride, catalyst (in some embodiments, DMAP, DMF), base (in some embodiments, iPr2NEt, EtsN), solvent (in some embodiments, dichloromethane, DMF).
[00262] General Scheme 2
[00263] Step 1: X-Ar (in some embodiments, 1 -bromo-3,4-difluoro-2-methoxybenzene), base (in some embodiments, potassium phosphate), catalyst (in some embodiments, copper iodide), solvent (in some embodiments, DMSO); Step 2: base (in some embodiments, LiOH, NaOH), solvent (in some embodiments, water, THF, MeOH); Step 3: amine (in some embodiments, 3-aminobenzene-1-sulfonamide, 4-aminopyridine-l-sulfonamide, 4-amino-3-acetyl-pyridine), coupling agent (in some embodiments, HATU, HBTU, POCI3) or oxalyl chloride, catalyst (in some embodiments, DMAP, DMF), base (in some embodiments, iPr2NEt, EtsN), solvent (in some embodiments, dichloromethane, DMF).
[00264] General Scheme 3
[00265] Step 1: amine (in some embodiments, 4-amino-3-acetyl-pyridine), coupling agent (in some embodiments, HATU, HBTU, POCI3) or oxalyl chloride, catalyst (in some embodiments, DMAP, DMF), base (in some embodiments, iPr2NEt, EtsN), solvent (in some embodiments, dichloromethane, DMF); Step 2: base (in some embodiments, NaOH, NaOlBu, KOH), solvent (in some embodiments, THF, water, DMSO, DMF). Synthetic Examples Compound 1 Synthesis of rac-(1R, 2R)-2-phenyl-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide Compound 3 Synthesis of rac-(lR,2S)-2-phenyl-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide Synthesis of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l-carboxylate O OTf
[00266] To a stirred solution of ethyl 2-oxocyclopentane-l-carboxylate (3.0 g, 19.2 mmol) in di chloromethane (30 mL) were added trifluoromethanesulfonic anhydride (6.4 mL, 38 mmol), and diisopropylethylamine (10 mL, 57 mmol) at -78 °C and the reaction mixture was stirred at room temperature for 12 hours. After reaction completion, saturated sodium bicarbonate was added followed by extraction with dichloromethane. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography using 30-40% ethyl acetate in hexane to afford ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1 -ene-1 -carboxylate. Synthesis of ethyl 2-phenylcyclopent-l-ene-l-carboxylate O
[00267] To a solution of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l-carboxylate (2.0 g, 6.9 mmol) and phenylboronic acid (1.0 g, 8.2 mmol) in ethanol (4 mL), acetonitrile (4 ml) was added water (2 mL) was added sodium carbonate (1.5 g, 13.8 mmol). The reaction mixture was degassed with nitrogen for 10 minutes. Palladium acetate (0.016 g, 0.7 mmol) and bis(diphenylphosphino)butane (0.58 g, 1.38 mmol) were added and reaction mixture degassed with nitrogen for 5 minutes and heated under stirring at 100 °C for 12 hours. After reaction completion, the reaction mixture was concentrated, water was added, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography using 30-40% ethyl acetate in hexane to afford ethyl 2-phenylcyclopent-l-ene-1-carboxylate as a colorless oil. Synthesis of ethyl 2-phenylcyclopentane-l-carboxylate O
[00268] To a solution of ethyl 2-phenylcyclopent-l-ene-l-carboxylate (1.0 g, 4.6 mmol) in methanol (10 mL) was added 10% palladium on charcoal (0.48 g, 0.46 mmol). The reaction mixture was stirred under hydrogen atmosphere (50 psi) for 12 hours at room temperature. After reaction completion, the reaction mixture was filtered through a through a pad of Celite®, filtered, then concentrated to obtain ethyl 2-phenylcyclopentane-l-carboxylate as a colorless oil. Synthesis of rac-(lR,2R)-2-phenylcyclopentane-l-carboxylic acid and rac-(lR,2S)-2-phenylcyclopentane-1-carboxylic acid
[00269] To a solution of ethyl 2-phenylcyclopentane-l-carboxylate (0.80 g, 3.7 mmol) in methanol (4 mL), tetrahydrofuran (4 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.60 g, 14.6 mmol). The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated, and the residue was acidified with 17V hydrochloric acid then extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified by reversed phase Prep-HPLC to afford rac-(l / ?,2A)-2-phenylcyclopentane-1-carboxylic acid and rac-(lA,25)-2-phenylcyclopentane-l-carboxylic acid. Synthesis of rac-(1R, 2R)-2-phenyl-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide To a solution of rac-(lA,2A)-2-phenylcyclopentane-l-carboxylic acid (0.3 g, 1.6 mmol) in di chloromethane (6 mL) under nitrogen atmosphere was added oxalyl chloride (0.16 g, 1.9 mmol) followed by 1-2 drops of 7V,7V-dimethylformamide at 0 °C. After 1 hour stirring at room temperature, the reaction mixture was concentrated. The residue was dissolved in di chloromethane (6 mL) and was added to a solution of 3-aminobenzene-1-sulfonamide (0.32 g, 1.9 mmol) and diisopropylethylamine (1.5 mL, 8 mmol) in dichloromethane (6 mL) at 0 °C. The reaction mixture was stirred for 1 hour at room temperature. After reaction completion, water was added then extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated. The residue was purified by reversed phase Prep-HPLC to afford rac-(lA,2A)-2-phenyl-A-(3-sulfamoylphenyl)cyclopentane-l-carboxamide. MS (ESI) m / z 343.3 [M - H]’; 'H NMR (400 MHz, DMSO-d6) 8 10.15 (s, 1H), 8.15 (s, 1H), 7.68-7.65 (m, 1H), 7.45-7.42 (m, 2H), 7.32-7.25 (m, 6H), 7.19-7.15 (m, 1H), 3.403.36 (m, 1H), 2.93-2.86 (m, 1H), 2.17-2.10 (m, 2H), 1.84-1.69 (m, 4H). Synthesis of rac-(lS!R,2R2S)~ 2-phenyl-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide
[00270] To a stirred solution of rac-(lMA,2A25)-2-phenylcyclopentane-1-carboxylic acid (0.20 g, 0.95 mmol) in dichloromethane (4 mL) was added HATU (0.54 g, 1.4 mmol) and DMAP (0.057 g, 0.47 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated. The residue was dissolved in acetonitrile (4 mL) and added to a solution of 3-aminobenzenesulfonamide (0.19 g, 1.1 mmol) in acetonitrile (4 mL) and heated at 80 °C for 16 hours. After reaction completion, the reaction mixture was concentrated, water was added, then extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified by reversed phase Prep-HPLC to afford rac-(151A,2A25)-2-phenyl-A-(3-sulfamoylphenyl)cyclopentane-l-carboxamide. MS (ESI): m / z 345.20 [M + H]+; *HNMR (400 MHz, DMSO-d6) 6 9.85 (s, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.417.36 (m, 3H), 7.32 (br s, 2H), 7.24-7.22 (m, 2H), 7.18-7.14 (m, 2H), 7.08-7.04 (m, 1H), 3.433.37 (m, 1H), 3.22-3.17 (m, 1H), 2.17-2.01 (m, 5H), 1.92-1.75 (m, 1H). Compound 5 Synthesis of rac-(lR,2R)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide Compound 7 Synthesis of rac-(lR, 2S)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide Synthesis of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l-carboxylate O OTf
[00271] To a stirred solution of ethyl 2-oxocyclopentane-l-carboxylate (1 g, 6.4 mmol) in di chloromethane (20 mL) was added A,A-diisopropylethylamine (2.48 g, 19.2 mmol) and trifluoromethanesulfonic anhydride (3.61 g, 12.8 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, water was added extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated. The residue was purified using flash column chromatography with a gradient of 10% ethyl acetate in hexane to afford ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1 -ene-1 -carboxylate. Synthesis of ethyl 2-(2-methoxyphenyl)cyclopent-l-ene-l-carboxylate o
[00272] To a stirred solution of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l-carboxylate (2 g, 6.62 mmol) in acetonitrile (30 mL) and ethanol (20 mL), (2-methoxyphenyl)boronic acid (1.51 g, 9.92 mmol), l,4-bis(diphenylphosphino)butane (56.4 mg, 0.132 mmol) and palladium bis(acetate) (0.015 mg, 0.066 mmol) were added at 0-5 °C. To the reaction mixture, an aqueous solution of sodium carbonate (2.1 g, 19.8 mmol) in water (10 mL) was added and the reaction mixture was slowly warmed to room temperature and then heated at 100 °C for 16 hours. After reaction completion, the reaction mixture was cooled to room temperature, diluted with water, then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 20-30% ethyl acetate in heptane to afford ethyl 2-(2-methoxyphenyl)cyclopent-l-ene-l -carboxylate. Synthesis of ethyl 2-(2-methoxyphenyl)cyclopentane-l-carboxylate o
[00273] To a stirred solution of ethyl 2-(2-methoxyphenyl)cyclopent-l-ene-l-carboxylate (3 g, 12.2 mmol) in methanol (60 mL), 10% Pd / C (3 g, 2.82 mmol) was added and the reaction mixture was stirred for 16 hours at room temperature. After reaction completion, the reaction mixture was filtered through a pad of Celite®, filtered, then concentrated. The residue was purified by column chromatography using 5-10% ethyl acetate in heptane to afford ethyl 2-(2-methoxyphenyl)cyclopentane-1 -carboxylate. Synthesis of rac-(lR,2R)-2-(2-methoxyphenyl)cyclopentane-l-carboxylic acid and rac-(1R, 2S)-2-(2-methoxyphenyl)cyclopentane-l-carboxylic acid
[00274] To a stirred solution of ethyl 2-(2-methoxyphenyl)cyclopentane-l-carboxylate (2.5 g, 10.1 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL), a solution of lithium hydroxide (2.41 g, 101 mmol) in water (10 mL) was added. The reaction mixture was stirred at 80 °C for 16 hours. After reaction completion, the reaction mixture was concentrated. The residue was neutralized with IN hydrochloric acid then extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to afford rac-(lA,2A)-2-(2-methoxyphenyl)cyclopentane-l-carboxylic acid and rac-(lA,25)-2-(2- methoxyphenyl)cyclopentane-1 -carboxylic acid. Synthesis of rac-(lR,2R)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide
[00275] To a stirred solution of (lA,2A)-2-(2-methoxyphenyl)cyclopentane-l-carboxylic acid (0.4 g, 1.82 mmol) in dichloromethane (20 mL), HATU (1.04 g, 2.72 mmol) and N,N-dimethyl-4-pyridylamine (0.111 g, 0.908 mmol) were added at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was concentrated and the residue was dissolved in acetonitrile (20 mL). To the solution was added 3-aminobenzenesulfonamide (0.375 g, 2.18 mmol) and the reaction mixture was heated at 80 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to get rac-(lA,2A)-2-(2-methoxyphenyl)-A-(3-sulfamoylphenyl)cyclopentane-l-carboxamide was obtained. MS (ESI): m / z 373.3 [M - H]’; 1HNMR(400MHz, DMSO-d6) 8 10.12 (s, 1H), 8.16 (s, 1H), 7.69-7.66 (m ,1H), 7.45-7.43 (m, 2H), 7.31 (br s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 3.71 (s, 3H), 3.68-3.61 (m, 1H), 3.04-2.98 (m, 2H), 2.09-2.07 (m, 2H), 1.83-1.80 (m, 3H), 1.67-1.60 (m, 1H). Synthesis of rac-(lR, 2S)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclopentane-l-carboxamide To a stirred solution of rac-(U?,25)-2-(2-methoxyphenyl)cyclopentane-l-carboxylic acid (0.13 g, 0.59 mmol) in dichloromethane (20 mL), HATU (0.337 g, 0.885 mmol) and A, A-dimethyl-4-pyridylamine (0.036 g, 0.295 mmol) were added at 0-5 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was concentrated and the residue was dissolved in acetonitrile (20 mL).
[00276] To the solution was added 3-aminobenzenesulfonamide (0.375 g, 2.18 mmol) and the reaction mixture was heated at 80 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to get rac-(U?,25)-2-(2-methoxyphenyl)-A-(3-sulfamoylphenyl)cyclopentane-l-carboxamide was obtained. MS (ESI): m / z 373.30 [M - H]’; 'HNMR (400 MHz, DMSO-d6) 8 9.63 (s, 1H), 7.88 (br s, ,1H), 7.38-7.31 (m, 3H), 7.28 (br s, 2H), 7.16 (d, J = 6.8 Hz, 1H), 7.07-7.04 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.62-3.55 (m, 1H), 3.27-3.22 (m, 1H), 2.22-2.18 (m, 1H), 1.99-1.96 (m, 3H), 1.84-1.78 (m, 1H), 1.69-1.63 (m, 1H). Compound 9 Synthesis of rac-(1R, 2R)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide Compound 11 Synthesis of rac-(lR, 2S)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide Synthesis of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate o
[00277] To a stirred solution of ethyl 2-oxocyclohexane-l-carboxylate (3 g, 17.6 mmol) in di chloromethane (30 mL) was added A-A-ethylbis(isopropyl)amine (6.83 g, 52.9 mmol) and trifluoromethanesulfonic anhydride (7.46 g, 26.4 mmol) dropwise at -78 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, ice cold water was added followed by extraction with dichloromethane. The organic layer dried over sodium sulfate, filtered, then concentrated. The residue was purified using flash column chromatography with a gradient of 10% ethyl acetate in hexane to afford ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate. Synthesis of ethyl 2 '-methoxy-3,4,5,6-tetrahydro-[1,1 '-biphenyl / -2-carboxylate O
[00278] To a stirred solution of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate (1 g, 3.31 mmol) in acetonitrile (15 mL) and ethanol (10 mL), (2-methoxyphenyl)boronic acid (0.754 g, 4.96 mmol), l,4-bis(diphenylphosphino)butane (0.028 g, 0.066 mmol) and palladium bis(acetate) (0.007 g, 0.033 mmol) were added at 0-5 °C. To the reaction mixture, an aqueous solution of sodium carbonate (1.05 g, 9.92 mmol) in water (5 mL) was added and the reaction mixture was slowly warmed to room temperature and heated at 100 °C for 16 hours. After reaction completion, the reaction mixture was cooled to room temperature, diluted with water followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography with a gradient of 20-30% ethyl acetate in heptane to afford ethyl 2'-methoxy-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-carboxylate. Synthesis of ethyl 2-(2-methoxyphenyl)cyclohexane-l-carboxylate O
[00279] To a stirred solution of ethyl 2'-methoxy-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-carboxylate (1 g, 3.84 mmol) in methanol (20 mL), 10% Pd / C (1 g, 0.94 mmol) was added and the reaction mixture was stirred for 16 hours at room temperature. After reaction completion, the reaction mixture was filtered through a pad of Celite®, then concentrated. The residue was purified by column chromatography with a gradient of 5-10% ethyl acetate in heptane to afford ethyl 2-(2-methoxyphenyl)cyclohexane-l-carboxylate. Synthesis of rac-(lR,2R)-2-(2-methoxyphenyl)cyclohexane-l-carboxylic acid and rac-(1R, 2S)-2-(2-methoxyphenyl)cyclohexane-l-carboxylic acid
[00280] To a stirred solution of ethyl 2-(2-methoxyphenyl)cyclohexane-l-carboxylate (1.2 g, 4.57 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) a solution of lithium hydroxide (1.1 g, 45.7 mmol) in water (5 mL) was added. The reaction mixture was stirred at 80 °C for 16 hours. After reaction completion, the reaction mixture was concentrated. The residual aqueous solution was neutralized with IN hydrochloric acid followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to afford rac-(lA,2A)-2-(2-methoxyphenyl)cyclohexane-l-carboxylic acid and rac-(l A,25)-2-(2- methoxyphenyl)cyclohexane-1 -carboxylic acid. Synthesis of rac-(1R, 2R)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide
[00281] To a stirred solution of rac-(lA,2A)-2-(2-methoxyphenyl)cyclohexane-l-carboxylic acid (0.12 g, 0.512 mmol) in dichloromethane (10 mL), HATU (0.292 g, 0.768 mmol) and N,N-dimethyl-4-pyridylamine (0.031 g, 0.256 mmol) were added at 0-5 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated then dissolved in acetonitrile (10 mL) and 3-aminobenzenesulfonamide (0.106 g, 0.615 mmol) was added. The reaction mixture was heated at 80 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The organic layers were washed with brine, combined, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain rac-(lA,2A)-2-(2-methoxyphenyl)-A-(3-sulfamoylphenyl)cyclohexane-l-carboxamide was obtained. MS (ESI): m / z 389.10 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 8 10.10 (s, 1H), 8.06 (s, 1H), 7.58-7.55 (br s, ,1H), 7.42-7.37 (m, 2H), 7.28 (br s, 2H), 7.24-7.22 (m, 1H), 7.09-7.05 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 3.76 (s, 3H), 3.29-3.26 (m, 1H), 2.91-2.87 (m, 1H), 2.02-1.98 (m, 1H), 1.77-1.64 (m, 3H), 1.60-1.51 (m, 1H), 1.45-1.41 (m, 2H), 1.39-1.36 (m, 1H). Synthesis of rac-(lR, 2S)-2-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide
[00282] To a stirred solution of rac-(lA,25)-2-(2-methoxyphenyl)cyclohexane-l-carboxylic acid (0.2 g, 0.854 mmol) in dichloromethane (10 mL), HATU (0.487 g, 1.28 mmol) and N,N-dimethyl-4-pyridylamine (0.052 g, 0.427 mmol) were added at 0-5 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated then dissolved in acetonitrile (10 mL) and 3-aminobenzenesulfonamide (0.176 g, 1.02 mmol) was added and the reaction mixture was heated at 80 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The organic layers were washed with brine, combined, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain rac-(lA,25)-2-(2-methoxyphenyl)-A-(3-sulfamoylphenyl)cyclohexane-l-carboxamide was obtained. MS (ESI): m / z 387.30 [M - H]’; 'H NMR (400 MHz, DMSO-d6) 6 9.72 (s, 1H), 8.06-8.05 (m, 1H), 7.497.46 (m, 1H), 7.41-7.35 (m, 2H), 7.30 (br s, 2H), 7.23-7.21 (m, 1H), 7.12-7.07 (m, 1H), 6.93- 6.91 (m, 1H), 6.78-6.77 (m, 1H), 3.81 (s, 3H), 3.22-3.18 (m, 1H), 2.99-2.97 (m, 1H), 2.73-2.64 (m, 1H), 1.99-1.87 (m, 2H), 1.82-1.70 (m, 2H), 1.54-1.51 (m, 1H), 1.44-1.39 (m, 2H). Compound 13 Rac-(1R, 2R)-2-(3,4-dijluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide Compound 15 Rac-(1R, 2S)-2-(3,4-dijluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide Synthesis of ethyl 2-(((trijluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate O
[00283] To a stirred solution of ethyl 2-oxocyclohexanecarboxylate (2 g, 11.8 mmol) in di chloromethane (20 mL) were added A,A-diisopropylethylamine (4.56 g, 35.3 mmol) and trifluoromethanesulfonic anhydride (6.63 g, 23.5 mmol) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was quenched with ice cold water followed by extraction with di chloromethane. The organic layers were dried over sodium sulfate, filtered, concentrated. The residue was purified using flash column chromatography with a gradient of 10% ethyl acetate in hexane to afford ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate. Synthesis of ethyl 34'-difluor o-2 '-methoxy-3,4,5,6-tetrahydro-[1,1 '-biphenyl]-2-carboxylate
[00284] To a stirred solution of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate (1 g, 3.31 mmol) in acetonitrile (15 mL) and ethanol (10 mL), (3,4-difluoro-2-methoxyphenyl)boronic acid (0.754 g, 4.96 mmol), l,4-bis(diphenylphosphino)butane (0.028 g, 0.066 mmol) and palladium acetate (0.007 g, 0.033 mmol) were added at 0-5 °C. To the reaction mixture, an aqueous solution of sodium carbonate (1.05 g, 9.92 mmol) in water (5 mL) was added and the reaction mixture was slowly warmed to room temperature. The reaction mixture was heated at 100 °C for 16 hours. After reaction completion, the reaction mixture was diluted with water, then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was to afford residue was purified by column chromatography with a gradient of 20-30% ethyl acetate in heptane to afford ethyl 3',4'-difluoro-2'-methoxy-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-carboxylate. Synthesis of ethyl 2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-l-carboxylate O
[00285] To a stirred solution of ethyl 3',4'-difluoro-2'-methoxy-3,4,5,6-tetrahydro-[l,T-biphenyl]-2-carboxylate (1.2 g, 4.05 mmol) in methanol (50 mL), 10% Pd / C (1 g) was added at room temperature and the reaction mixture was stirred for 16 hours at room temperature under hydrogen atmosphere. After reaction completion, the reaction mixture was filtered through a pad of Celite®, filtered, then concentrated. The residue was purified by column chromatography using 10-20% ethyl acetate in hexane to obtain ethyl 2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-1 -carboxylate. Synthesis of rac-(lR,2R)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-l-carboxylic acid and rac-(1R, 2S)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-l-carboxylic acid
[00286] To a stirred solution of ethyl 2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-l-carboxylate (1.2 g, 4.57 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) a solution of lithium hydroxide monohydrate (1.1 g, 26.22 mmol) in water (5 mL) was added. The reaction mixture was stirred at 80 °C for 16 hours. After reaction completion, the reaction mixture was concentrated. The resulting aqueous solution was neutralized with IN hydrochloric acid followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep.-HPLC to afford (1A,27?)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-1 -carboxylic acid and (lR,2S)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-l-carboxylic acid. Synthesis of rac-(lR,2R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl) cyclohexane-1 -carboxamide
[00287] To a stirred solution of afford rac-(lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-1 -carboxylic acid (0.12 g, 0.44 mmol) in dichloromethane (10 mL), oxalyl chloride (0.11 g, 0.89 mmol) and 1 drop of NA-di methyl form am ide were added at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 2 hours. After reaction completion, the reaction mixture was concentrated. The residue was added to a mixture of 3-aminobenzenesulfonamide (0.09 g, 0.53 mmol) and NA-diisopropylethylamine (0.23 g, 1.8 mmol) in dichloromethane (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. After reaction completion, water was added followed by extraction with di chloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to afford rac-(l R, 2A)-2-(3,4-difluoro-2-methoxyphenyl)-A-(3-sulfamoylphenyl)cy cl ohexane-1 -carboxamide. MS (ESI): m / z 425.20 [M + H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.12 (br s, 1H), 8.01 (s, 1H), 7.60-7.57 (m, 1H), 7.42-7.39 (m, 2H), 7.27 (br s, 2H), 7.10-7.07 (m, 2H), 3.89 (s, 3H), 3.22-3.20 (m, 1H), 2.85-2.77 (m, 1H), 2.03-2.01 (m, 1H), 1.85-1.71 (m, 3H), 1.601.51 (m, 1H), 1.46-1.28 (m, 3H). Synthesis of rac-(lR,2S)-N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-dijluoro-2-methoxyphenyl)cyclohexane-l-carboxamide
[00288] To a stirred solution of rac-(lA,25)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-1-carboxylic acid (0.12 g, 0.44 mmol) and 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide (0.25 g, 0.53 mmol) in pyridine (5 mL) was added phosphorus oxychloride (0.34 g, 2.2 mmol) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate followed by extraction with ethyl acetate. The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, then concentrated. The residue was used in the next step without any further purification. Synthesis of rac-(lR,2S)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl) cyclohexane-1 -carboxamide
[00289] To a stirred solution of rac-(lA,25)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)cyclohexane-l-carboxamide (0.2 g, 0.276 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (0.6 mL) at 0-5 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, then extracted with di chloromethane. The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain rac-(l A,25)-2-(3,4-difluoro-2-methoxyphenyl)-A-(3-sulfamoylphenyl)cy cl ohexane-1-carboxamide. MS (ESI): m / z 425.20 [M + H]+; 'H NMR (400 MHz, DMSO-d6): 8 9.83 (br s, 1H), 8.05-8.04 (m, 1H), 7.50-7.48 (m, 1H), 7.43-7.37 (m, 2H), 7.27 (br s, 2H), 7.07-7.01 (m, 2H), 3.95 (s, 3H), 3.17-3.13 (m, 1H), 2.90-2.87 (m, 1H), 2.67-2.56 (m, 1H), 1.97-1.94 (m, 1H), 1.90-1.83 (m, 1H), 1.82-1.68 (m, 2H), 1.53-1.42 (m, 3H). Synthesis of N,N-bis(2,4-dimethoxybenzyl)-3-nitrobenzenesulfonamide
[00290] To a stirred solution of bis(2,4-dimethoxybenzyl)amine (5 g, 10 mmol) in di chloromethane (100 ml) was added tri ethylamine (7.87 mL, 56.4 mmol) at room temperature and stirred for 5 minutes. The reaction mixture was cooled to 0-5 °C and m- (chlorosulfonyl)nitrobenzene (5 g, 22.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After reaction completion, water was added followed by extraction with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, fdtered, then concentrated. The residue was used in the next step without any further purification. Synthesis of 3-amino-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide
[00291] To a stirred solution of A,A-bis(2,4-dimethoxybenzyl)-3-nitrobenzenesulfonamide (5 g, 9.95 mmol) in ethanol (75 mL) was added ammonium chloride (5.32 g, 99.5 mmol) in water (25 mL) and zinc dust (6.51 g, 99.5 mmol) at room temperature. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was concentrated, and water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was triturated ethyl acetate and pentane to 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide. MS (ESI): m / z 473.40 [M + H]+; 'H NMR (400 MHz, DMSO-d6): 8 7.19 (t, J = 7.6 Hz, 1H), 7.08-7.03 (m, 1H), 6.99-6.95 (m, 2H), 6.856.83 (m, 1H), 6.79-6.77 (m, 1H), 6.45-6.35 (m, 4H), 5.58 (br s, 2H), 4.15 (s, 4H), 3.70 (s, 6H), 3.57 (s, 6H). Compound 17 Synthesis of (S)-l-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)pyrrolidine-2-carboxamide Synthesis of methyl (2-methoxyphenyl)-L-prolinate
[00292] A solution of methyl (5)-2-pyrrolidinecarboxylate hydrochloride (14.2 g, 85.5 mmol) and o-iodom ethoxybenzene (2 g, 8.55 mmol) in dimethylformamide (20 mL) was degassed with nitrogen for 10 minutes followed by addition of cesium carbonate (27.8 g, 85.5 mmol), copper iodide (163 mg, 0.86 mmol) and 2-isobutyrylcyclohexanone (288 mg, 1.71 mmol). The reaction mixture was degassed for 5 minutes and heated under stirring at 100 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by silica column chromatography using 20% ethyl acetate in hexane to methyl (2-methoxyphenyl)-L-prolinate. Synthesis of (2-methoxyphenyl)-L-proline O
[00293] To a solution of methyl (2-methoxyphenyl)-L-prolinate (250 mg, 1.06 mmol) in tetrahydrofuran (3 mL) and methanol (0.5 mL), a solution of lithium hydroxide monohydrate (223 mg, 5.31 mmol) in water (1.5 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated, diluted with water, acidified with IN HC1 solution (pH~5), followed by extraction with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was triturated with diethyl ether and / / -pentane to afford crude (2-methoxyphenyl)-L-proline as brown oily liquid was used in the next step without any further purification. Synthesis of (S)-l-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)pyrrolidine-2-carboxamide
[00294] To a stirred solution of (2-methoxyphenyl)-L-proline (250 mg, 1.13 mmol) in dimethylformamide (5 mL) was added 3-aminobenzenesulfonamide (214 mg, 1.24 mmol) and HATU (644 mg, 1.69 mmol) at room temperature. The reaction mixture was cooled to 0 °C and 4-methylmorpholine (206 mg, 2.03 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. After reaction completion, water was added followed by extraction with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC (5)-l-(2-methoxyphenyl)-A-(3-sulfamoylphenyl)pyrrolidine-2-carboxamide was obtained MS (ESI): m / z 376.25 [M + H]+; 1H NMR (400 MHz, DMSO-d6): 8 9.96 (s, 1H), 8.19 (s, 1H), 7.81-7.79 (m, 1H), 7.46 (d, J = 5.2 Hz, 2H), 7.32 (br s, 2H), 6.86-6.80 (m, 2H), 6.74-6.69 (m, 2H), 4.44-4.41 (m, 1H), 3.57 (s, 3H), 3.55-3.50 (m, 1H), 3.25-3.21 (m, 1H), 1.96-1.86 (m, 1H), 1.48-1.24 (m, 3H). Compound 18 Synthesis of l-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)pyrrolidine-2-carboxamide Synthesis of methyl (2-methoxyphenyl)prolinate O
[00295] To a solution of methyl 2-pyrrolidinecarboxylate hydrochloride (14.9 g, 89.7 mmol) and o-iodomethoxybenzene (3 g, 12.8 mmol) in dimethylformamide (50 mL) was added triethylamine (1.3 g, 12.8 mmol). The reaction mixture was degassed with nitrogen for 10 minutes followed by addition of cesium carbonate (41.8 g, 128 mmol), copper iodide (1.22 g, 6.41 mmol) and 2-isobutyrylcyclohexanone (1.08 g, 6.41 mmol). The reaction mixture was degassed for 5 minutes and heated under stirring at 100 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by silica gel column chromatography using 15-20% ethyl acetate in heptane to obtain methyl (2-methoxyphenyl)prolinate. Synthesis of (2-methoxyphenyl)proline O
[00296] To a solution of methyl (2-methoxyphenyl)prolinate (150 mg, 0.64 mmol) in tetrahydrofuran (1.8 mL) and methanol (0.3 mL), a solution of lithium hydroxide monohydrate (134 mg, 5.59 mmol) in water (0.9 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated, diluted with water, acidified with IN HC1 solution (pH~5) followed by extraction with ethyl acetate (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, then concentrated. The residue was purified by trituration with diethyl ether and n-pentane to afford (2-methoxyphenyl)proline. Synthesis of l-(2-methoxyphenyl)-N-(3-sulfamoylphenyl)pyrrolidine-2-carboxamide
[00297] To a stirred solution of (2-methoxyphenyl)proline (250 mg, 1.13 mmol) and 3-aminobenzenesulfonamide (214 mg, 1.24 mmol) in dimethylformamide (5 mL) was added HATU (644 mg, 1.69 mmol) at room temperature. The reaction mixture was cooled to 0 °C and 4-methylmorpholine (206 mg, 2.03 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. After reaction completion, water was added followed by extraction with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC to obtain l-(2-methoxyphenyl)-A-(3- sulfamoylphenyl)pyrrolidine-2-carboxamide. MS (ESI): m / z 376.2 [M + H]+; 'H NMR (400 MHz, DMSO-d6): 8 9.96 (s, 1H), 8.20 (s, 1H), 7.83-7.76 (m, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.36 (br s, 2H), 6.85-6.80 (m, 2H), 6.74-6.72 (m, 2H), 4.44-4.41 (m, 1H), 3.65 (s, 3H), 3.603.54 (m, 1H), 3.27-3.22 (m, 1H), 2.28-2.19 (m, 1H), 1.97-1.91 (m, 3H). Compound 19 Synthesis of rac-(1R, 2R)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)-N-(3- sulfamoylphenyl) cyclohexane-1 -carboxamide Compound 21 Synthesis of rac-(IR, 2S)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)-N-(3- sulfamoylphenyl) cyclohexane-1 -carboxamide Synthesis of ethyl 2'-methoxy-4'-(trifluoromethoxy)-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-carboxylate
[00298] To a stirred solution of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate (1 g, 3.3 mmol) in acetonitrile (15 mL) and ethanol (10 mL), (2-methoxy-4-(trifluoromethoxy)phenyl)boronic acid (1.17 g, 5 mmol), l,4-bis(diphenylphosphino)butane (0.028 g, 0.066 mmol) and palladium acetate (0.007 g, 0.033 mmol) were added at 0-5 °C. To the reaction mixture, an aqueous solution of sodium carbonate (1.05 g, 9.9 mmol) in water (5 mL) was added and the reaction mixture was slowly warmed to room temperature and then heated at 100 °C for 16 hours. After reaction completion, the reaction mixture was diluted with water followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography with a gradient of 20-30% ethyl acetate in heptane to afford ethyl 2'-methoxy-4'-(trifluoromethoxy)-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-carboxylate. Synthesis of ethyl 2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-l-carboxylate
[00299] To a stirred solution of ethyl 2'-methoxy-4'-(trifluoromethoxy)-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-carboxylate (3.0 g, 8.71 mmol) in methanol (100 mL), then 10% Pd / C was added and the reaction mixture was stirred for 16 hours at room temperature under hydrogen atmosphere. After reaction completion, the reaction mixture was filtered through a pad of Celite®, filtered, then concentrated. The residue was purified by column chromatography using 10-20% ethyl acetate in hexane to obtain ethyl 2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-1 -carboxylate. Synthesis of rac-(lR,2R)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-l-carboxylic acid and rac-(lR, 2S)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-l-carboxylic acid
[00300] To a stirred solution of ethyl 2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-l-carboxylate (4.0 g, 11.5 mmol) in methanol (40 mL) and tetrahydrofuran (40 mL) a solution of lithium hydroxide (1.61 g, 67 mmol) in water (40 mL) was added. The reaction mixture was stirred at 80 °C for 16 hours. After reaction completion, the reaction mixture was concentrated and the aqueous solution was neutralized with IN hydrochloric acid, followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to afford rac-(lA,2A)-2-(2-methoxy-4- (trifluoromethoxy)phenyl)cyclohexane-l-carboxylic acid and rac-(lR,2S)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-1 -carboxylic acid. Synthesis of rac-(lR,2R)-N-(3-(N,N-bis(3,4-dimethylbenzyl)sulfamoyl)phenyl)-2-(2-methoxy-4-(trijluoromethoxy)phenyl) cyclohexane-1 -carboxamide
[00301] To a stirred solution of rac-((lA,2A)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-l-carboxylic acid (0.2 g, 0.628 mmol) in di chloromethane (10 mL), and oxalyl di chloride (0.16 g, 1.26 mmol), 1 drop of N,N-dimethylformamide were added at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 2 hours. After 2 hours, the reaction mixture was concentrated, then the residue was dissolved in di chloromethane (10 mL). This solution was added dropwise into a mixture of 3-amino-NA-bis(2,4-dimethoxybenzyl)benzenesulfonamide (0.356 g, 0.754 mmol), N,N-diisopropylethylamine (0.406 g, 3.14 mmol) and dichloromethane (10 mL) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 2 hours. After reaction completion, the reaction mixture was diluted with water, then extracted in di chloromethane. The organic layers were washed with brine, dried over sodium sulfate, fdtered, then concentrated. The residue was used in the next step without any further purification. Synthesis of rac-(IR, 2R)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)-N-(3-sulfamoylphenyl) cyclohexane-1-carboxamide
[00302] To a stirred solution of rac-(lA,2A)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-1-carboxamide (0.4 g, 0.52 mmol) in di chloromethane (20 mL) was added trifluoroacetic acid (1.5 mL) at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate followed by extraction with di chloromethane. The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain rac-(lA,2A)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)-A-(3- sulfamoylphenyl)cyclohexane-l-carboxamide. MS (ESI): m / z 473.30 [M + H]+; 1HNMR(400 MHz, DMSO-d6): 8 10.14 (br s, 1H), 8.06 (s, 1H), 7.56-7.54 (m, 1H), 7.43-7.38 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.28-3.25 (m, 1H), 2.88 (d, J= 8.8 Hz, 1H), 2.03-2.00 (m, 1H), 1.84-1.74 (m, 3H), 1.57-1.50 (m, 1H), 1.41-1.33 (m, 2H), 1.24-1.22 (m, 1H). Synthesis of rac-(1R, 2S)-2-(2-methoxy-4-(trijluoromethoxy)phenyl)-N-(3-sulfamoylphenyl) cyclohexane-1 -carboxamide
[00303] To a stirred solution of rac-(lA,25)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)cyclohexane-l-carboxylic acid (0.2 g, 0.63 mmol) in di chloromethane (10 mL), and oxalyl dichloride (0.16 g, 1.26 mmol) was added 1 drop of N,N-dimethylformamide were added at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 2 hours. After 2 hours, the reaction mixture was concentrated and the residue was dissolved in di chloromethane (10 mL). This solution was added dropwise into a mixture of m-aminobenzenesulfonamide (0.13 g, 0.754 mmol), MA-diisopropylethylamine (0.325 g, 2.51 mmol) and dichloromethane (10 mL) at 0-5 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with di chloromethane. The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain rac-(lA,25)-2-(2-methoxy-4-(trifluoromethoxy)phenyl)-A-(3-sulfamoylphenyl)cyclohexane-l-carboxamide. MS (ESI): m / z 471.30 [M - H]’; 'H NMR (400 MHz, DMSO-d6): 6 9.76 (br s, 1H), 8.07 (s, 1H), 7.43-7.38 (m, 3H), 7.31-7.29 (m, 3H), 6.92 (d, J = 1.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.19-3.15 (m, 1H), 2.98 (br s, 1H), 2.72-2.63 (m, 1H), 1.97-1.95 (m, 1H), 1.90-1.87 (m, 1H), 1.76-1.71 (m, 2H), 1.52-1.50 (m, 1H), 1.46-1.40 (m, 2H). Compound 23 l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-N-(3-sulfamoylphenyl)piperidine-2- carboxamide Synthesis of 1-(tert-butyl) 2-methyl 4,4-dijluoropiperidine-l,2-dicarboxylate
[00304] To a stirred solution of 1-(tert-butyl) 2-methyl 4-oxopiperidine-l,2-dicarboxylate (5 g, 19.40 mmol) in di chloromethane (50 mL) was added diethylaminosulfur trifluoride (12.8 mL, 97.20 mmol) dropwise at -78 °C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was added dropwise to a saturated aqueous solution of sodium bicarbonate, followed by extraction with di chloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was adsorbed on silica gel and purified by column chromatography using 20-30% ethyl acetate in hexane as an eluent to obtain 1-(tert-butyl) 2-methyl 4,4-difluoropiperidine-l,2-dicarboxylate. Synthesis of methyl 4,4-difluoropiperidine-2-carboxylate
[00305] To a stirred solution of 1-(tert-butyl) 2-methyl 4,4-difluoropiperidine-l,2-dicarboxylate (1.5 g, 5.37 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (4.5 mL) at 0-5 °C and the reaction mixture was stirred for 16 hours at room temperature. After reaction completion, water was added, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 40-50% ethyl acetate in hexane as an eluent to obtain methyl 4,4-difluoropiperidine-2-carboxylate. Synthesis of methyl l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylate
[00306] To a stirred solution of methyl 4,4-difluoropiperidine-2-carboxylate (0.6 g, 3.35 mmol) and 1 -bromo-3,4-difluoro-2-methoxybenzene (0.896 g, 4.02 mmol) in dimethyl sulfoxide (12 mL) were added potassium phosphate (1.42 g, 6.7 mmol) and copper iodide (0.159 g, 0.837 mmol) at room temperature then stirred for 10 minutes. The reaction mixture was heated at 100 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 30-40% ethyl acetate in hexane as an eluent to obtain methyl 1-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylate. Synthesis of l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylic acid
[00307] To a stirred solution of methyl l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylate (0.060 g, 0.018 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added an aqueous solution of lithium hydroxide monohydrate (0.044 g, 1.05 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 16 hours. After reaction completion, the reaction mixture was concentrated, the aqueous solution was neutralized with IN hydrochloric acid, followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated to obtain 1-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylic acid. Synthesis of N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-dijluoropiperidine-2-carboxamide OMe
[00308] To a stirred solution of l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylic acid (0.05 g, 0.163 mmol) and 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide (0.092 g, 0.019 mmol) in pyridine (2 mL) was added phosphoryl trichloride (0.125 g, 0.814 mmol) at 0-5 °C and the reaction mixture was stirred at 0-5 °C for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain N-(3-(N,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxamide. Synthesis of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-N-(3-sulfamoylphenyl)piperidine-2-carboxamide
[00309] To a stirred solution of A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxamide (0.08 g, 0.105 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.4 mL) at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with di chloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-A-(3-sulfamoylphenyl)piperidine-2-carboxamide. MS (ESI): m / z 462.30 [M + H]+; 'H NMR(400MHz, DMSO-d6): 8 10.32 (br s, 1H), 8.11 (s, 1H), 7.62-7.60 (m, 1H), 7.50-7.44 (m, 2H), 7.34 (br s, 2H), 7.10-7.04 (m, 1H), 6.98-6.96 (m, 1H), 4.37 (t, J = 6.0 Hz, 1H), 3.99 (s, 3H), 3.67-3.62 (m, 1H), 3.05-2.99 (m, 1H), 2.43-2.37 (m, 2H), 2.31-2.17 (m, 2H). Compound 24 Synthesis of rac-(lR,2R,5S)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)-5-(trijluoromethyl)cyclohexane-l -carboxamide Compound 26 Synthesis of rac-(lR,2S,5R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)cyclohexane-l-carboxamide Synthesis of methyl 2-oxo-5-(trifluoromethyl)cyclohexane-l-carboxylate
[00310] To a stirred solution of 60% sodium hydride in mineral oil (960 mg, 24 mmol) in tetrahydrofuran (40 mL) was added dimethyl carbonate (3.87 mL, 36 mmol) at 0 °C. The reaction mixture was heated at 60 °C for 30 minutes. The reaction mixture was cooled to 0 °C and a solution of 4-(trifluoromethyl)cyclohexanone (2 g, 12 mmol) in THF was added. The reaction mixture was heated under stirring at 60 °C for 12 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, then concentrated. The residue was purified by silica gel column chromatography using 10% ethyl acetate in hexane as an eluent to obtain methyl 2-oxo-5-(trifluoromethyl)cyclohexane-l-carboxylate. Synthesis of methyl 5-(trifluoromethyl)-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate
[00311] To a stirred solution of 60% sodium hydide in mineral oil (428 mg, 10.7 mmol) in di chloromethane (30 mL) was added methyl 2-oxo-5-(trifluoromethyl)cyclohexane-l-carboxylate (2 g, 8.92 mmol) at 0 °C and stirred for 30 minutes. The reaction mixture was cooled to 0 °C and trifluoro(trifluoromesyloxysulfonyl)methane (1.8 mL, 10.7 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 12 hours. After reaction completion, water was added followed by extraction with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain methyl 5-(trifluoromethyl)-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1 -ene-1 -carboxylate. Synthesis of methyl 3 ',4'-difluoro-2 '-methoxy-4-(trifluoromethyl)-3,4,5,6-tetrahydro-[1,1 -biphenyl]-2-carboxylate
[00312] A solution of methyl 5-(trifluoromethyl)-2- (((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate (4 g, 11.2 mmol), (3,4-difluoro-2-methoxyphenyl)boronic acid (3.17 g, 16.8 mmol) in acetonitrile (30 mL) and ethanol (10 mL) was degassed with nitrogen for 10 minutes followed by addition of sodium carbonate (3.57 g, 33.7 mmol) in water (10 mL), l,4-bis(diphenylphosphino)butane (dppb, 955 mg, 2.24 mmol) and palladium acetate (252 mg, 1.12 mmol). The reaction mixture was degassed for 5 minutes and heated under stirring at 100 °C for 12 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue purified by silica gel column chromatography using 10% ethyl acetate in hexane as an eluent to obtain methyl 3',4'-difluoro-2'-methoxy-4-(trifluoromethyl)-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-carboxylate. Synthesis of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxylate
[00313] To a stirred solution of methyl 3',4'-difluoro-2'-methoxy-4-(trifluoromethyl)-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-carboxylate (2.8 g, 7.99 mmol) in methanol (100 mL), was added 10% palladium on carbon at room temperature. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. After reaction completion, the reaction mixture was filtered through a pad of Celite® then concentrated. The residue was purified by column chromatography using 10-20% ethyl acetate in hexane as an eluent to obtain methyl 2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cy cl ohexane-1 -carboxylate. Synthesis of rac-( 1R,2R,55)-2-(3,4-difluoro-2-methoxyphenyl)-5- (trifluoromethyl)cyclohexane-l-carboxylic acid and rac-(lR,2S,5R)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxylic acid
[00314] To a solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-1 -carboxylate (1.2 g, 3.41 mmol) in tetrahydrofuran (10 mL) and methanol (2 mL) a solution of lithium hydroxide monohydrate (1.43 g, 34.1 mmol) in water (4 mL) was added. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated, acidified with IN hydrochloric acid (pH~6), followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC to obtain rac-(lA,2A,55)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-1-carboxylic acid and rac-(lA,25,5A)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-1 -carboxylic acid. Synthesis of rac-(lR,2R,5S)-N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4- difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide
[00315] To a stirred solution of rac-(lA,2A,55)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxylic acid (150 mg, 443 pmol) and 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide (251 mg, 532 pmol) in Pyridine (5 mL) was added phosphoryl trichloride (207 pL, 2.22 mmol) at 0-5 °C and the reaction mixture was stirred for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,2A,55)-A-(3-(A,A-bis(2,4- dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide. DMB is a 2,4-dimethoxybenzyl (DMB) group. Synthesis of rac-(lR,2R,5S)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)cyclohexane-l -carboxamide
[00316] To a stirred solution of rac-(lA,2A,55)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)-5- (trifluoromethyl)cyclohexane-l-carboxamide (160 mg, 0.2 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (0.8 mL) at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with di chloromethane. The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain rac-(lR,2R, 55)-2-(3,4-difluoro-2-methoxyphenyl)-A-(3 -sulfamoylphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide.
[00317] MS (ESI): m / z 491.3 [M-H]+; 'H NMR (400 MHz, DMSO-d6): 10.25 (br s, 1H), 7.99 (s, 1H), 7.63-7.60 (m, 1H), 7.45-7.39 (m, 2H), 7.31 (br s, 2H), 7.14-7.10 (m, 2H), 3.88 (s, 3H), 3.28-3.22 (m, 1H), 3.12-3.09 (m, 1H), 2.78-2.75 (m, 1H), 2.18-2.14 (m, 1H), 1.99-1.91 (m, 2H), 1.87-1.80 (m, 1H), 1.67-1.64 (m, 1H), 1.54-1.49 (m,lH). Synthesis of rac-(lR,2S,5R)-N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide
[00318] To a stirred solution of rac-(lA,25,5A)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxylic acid (150 mg, 0.44 mmol) and 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide (251 mg, 0.53 mmol) in pyridine (4 mL) was added phosphoryl trichloride (0.207 mL, 2.22 mmol) at 0-5 °C and the reaction mixture was stirred at 0-5 °C for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,2£,5A)-A-(3-(7V,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide. Synthesis of rac-((1R,2S, 5R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide
[00319] To a stirred solution of rac-(lA,2£,5A)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)-5- (trifluoromethyl)cyclohexane-l-carboxamide (150 mg, 189 pmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.6 mL) at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with di chloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC to obtain rac-(lA,25,5A)-2-(3,4-difluoro-2-methoxyphenyl)-A-(3-sulfamoylphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide. MS (ESI): m / z 491.30 [M - H]+; 'H NMR (400 MHz, DMSO-d6): 10.24 (br s, 1H), 8.02 (s, 1H), 7.58-7.54 (m, 1H), 7.44-7.39 (m, 2H), 7.31 (br s, 2H), 7.27-7.24 (m, 1H), 7.13-7.07 (m, 1H), 4.03 (brs, 1H), 3.81 (s, 3H), 3.09-3.04 (m, 1H), 2.61-2.51 (m, 1H), 2.13-2.03 (m, 1H), 1.98-1.83 (m, 3H), 1.71-1.68 (m, 1H), 1.35-1.29 (m, 1H). Compound 28 Synthesis of rac-(1R, 2R)-2-(3,4-dijluoro-2-methoxyphenyl)-5,5-difluor o-N-(2- sulfamoylpyridin-4-yl) cyclohexane-1 -carboxamide Me Compound 30 Synthesis of rac-(lR,2S)-2-(4-fluoro-3-methylphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide Me Synthesis of ethyl 4'-fluor o-3 '-methyl-3,4,5,6-tetrahydro-[1,1 '-biphenyl]-2-carboxylate O Me
[00320] To a stirred solution of ethyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate (4 g, 13.9 mmol) in acetonitrile (25 mL, 479 mmol) and ethanol (15 mb, 257 mmol), (4-fluoro-3-methylphenyl)boronic acid (3.21 g, 20.85 mmol) were added, 1,4-bis(diphenylphosphino)butane (1.78 g, 4.16 mmol) and palladium acetate (467 mg, 2.08 mmol) at room temperature. To the reaction mixture, an aqueous solution of sodium carbonate (4.41 g, 41.6 mmol) in water (10 mL) was added and the reaction mixture was heated at 100 °C for 16 hours. After reaction completion, the reaction mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 10-20% ethyl acetate in hexane as an eluent to obtain 2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxylate (1.5 g, 6.04 mmol). Synthesis of ethyl 2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxylate O Me
[00321] To a stirred solution of ethyl 2-(4-fluoro-3-tolyl)-l-cyclohexene-l-carboxylate (2 g, 7.62 mmol) in methanol (30 mL), 10% Pd / C (0.2 g) was added at room temperature and the reaction mixture was stirred for 16 hours at room temperature under hydrogen atmosphere. After reaction completion, the reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated to obtain ethyl 2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxylate, which was taken for next step without any purification. Synthesis of (lR,2R)-2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxylic acid and (1R,2S)~ 2-(4-fluoro-3-tolyl)cyclohexanecarboxylic acid O 0 Me Me
[00322] To a stirred solution of ethyl 2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxylate (1.7 g, 6.43 mmol) in tetrahydrofuran (10 mL) was added lithium hydroxide mono hydrate (770 mg, 18.35 mmol) in water (5 mL) and methanol (5 mL) was added then the reaction mixture was stirred for 16 hours at 75 °C. After reaction completion, the reaction mixture was concentrated, neutralized with IN hydrochloric acid, followed by extraction with ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC to afford rac-(lA,2A)-2-(4-fluoro-3- methylphenyl)cyclohexane-l-carboxylic tolyl)cyclohexanecarboxylic acid. acid and rac-(lA,25)-2-(4-fluoro-3- Synthesis of rac-(lR,2R)-N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-f1uoro- 3-methylphenyl)cyclohexane-l-carboxamide Me
[00323] To a stirred solution rac-(lA,27?)-2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxylic acid (0.1 g, 0.423 mmol) and 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide (240 mg, 0.508 mmol) in pyridine (3 mL) was added phosphoryl trichloride (0.2 mL, 2.14 mmol) at 0-5 °C and the reaction mixture was stirred for 1 hour. After reaction completion, ice cold water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,2A)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-fluoro-3 methylphenyl)cyclohexane-l- carb oxamide. Synthesis of rac-(1R, 2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluor o-N-(2-sulfamoylpyridin-4-yl) cyclohexane-1 -carboxamide
[00324] To a solution of rac-(lA,2A)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxamide (250 mg, 0.362 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) at 0 °C and the reaction mixture was stirred at 45 °C for 12 hours. After reaction completion, the reaction mixture was concentrated. The residue was purified by Prep-HPLC to obtain rac-(17?,27?)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluoro-A-(2-sulfamoylpyridin-4-yl)cyclohexane-l-carboxamide. MS (ESI): m / z 389.20 [M - H]’; 'H NMR (400 MHz, DMSO-d6): 8 10.04 (br s, 1H), 8.04 (s, 1H), 7.58-7.54 (m, 1H), 7.43-7.38 (m, 2H), 7.30 (br s, 2H), 7.11 (t, J = 8.0 Hz, 1H), 6.99-6.93 (m, 2H), 2.84-2.81 (m, 1H), 2.66 (dt, J = 11.6, 3.2 Hz, 1H), 2.11 (s, 3H), 1.97-1.95 (m, 1H), 1.87-1.76 (m, 3H), 1.57-1.47 (m, 1H), 1.46-1.33 (m, 3H). Synthesis of rac-(lR,2S)-N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-fluoro- 3-methylphenyl)cyclohexane-l-carboxamide Me
[00325] To a stirred solution of rac-(lA,2S)-2-(4-fluoro-3-methylphenyl)cyclohexane-l-carboxylic acid (0.1 g, 0.423 mmol) and 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide (240 mg, 0.508 mmol) in pyridine (3 mL) was added phosphoryl trichloride (0.2 mL, 2.14 mmol) at 0-5 °C and the reaction mixture was stirred for 1 hour. After reaction completion, ice cold water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,25)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-fluoro-3 methylphenyl)cyclohexane-l- carb oxamide. Synthesis of rac-(lR,2S)-2-(4-fluoro-3-methylphenyl)-N-(3-sulfamoylphenyl)cyclohexane-l-carboxamide
[00326] To a stirred solution of rac-(lA,25)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(4-fluoro-3 methylphenyl)cyclohexane-l- carboxamide (150 mg, 217 pmol) in dichloromethane (20 mL) was added trifluoroacetic acid (0.6 mL) at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with di chloromethane. The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by preparative HPLC to obtain rac-(17?,25)-2-(4-fluoro-3-methylphenyl)-A-(3-sulfamoylphenyl)cyclohexane-l-carboxamide. MS (ESI): m / z 391.20 [M + H]+; 'H NMR (400 MHz, DMSO-d6): 8 9.85 (br s, 1H), 8.05 (s, 1H), 7.54-7.51 (m, 1H), 7.44-7.38 (m, 2H), 7.28 (br s, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.02-6.99 (m, 2H), 2.95 (br s, 1H), 2.91-2,87 (m, 1H), 2.58-2.57 (m, 1H), 2.12 (s, 3H), 1.96-1.94 (m, 1H), 1.91-1.84 (m, 1H), 1.80-1.71 (m, 2H), 1.62-1.61 (m, 1H), 1,60-1.50 (m, 1H), 1.401.38 (m, 1H). Compound 39 Synthesis of rac-(1R, 2R, 55)-2-(3,4-difluoro-2-methoxyphenyl)-N-(2-sulfamoylpyridin-4-yl)-5- (trijluoromethyl)cyclohexane-l -carboxamide Compound 41 Synthesis of rac-(lR,25,5R)-2-(3,4-dijluoro-2-methoxyphenyl)-N-(2-sulfamoylpyridin-4-yl)-5- (trifluor omethyl)cyclohexane-l -carboxamide Synthesis of rac-(lR,2R,5S)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluor omethyl)cyclohexane-l -carboxamide O Iv N ^DMB ” oz V "% DMB MeO^V^F F
[00327] To a stirred solution of rac-(lA,2A,55)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxylic acid (80 mg, 236 pmol) and 4-amino-7V,7V-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (134 mg, 0.28 pmol) in pyridine (3 mL) was added phosphoryl trichloride (0.1 mL, 1.18 mmol) at 0-5 °C. The reaction mixture was stirred for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,2A,5S)-7V-(2-(7V,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide. Synthesis of rac-(1R, 2R, 55)-2-(3,4-difluoro-2-methoxyphenyl)-N-(2-sulfamoylpyridin-4-yl)-5-(trijluoromethyl)cyclohexane-l -carboxamide
[00328] To a stirred solution of rac-( lR,2R,5S)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5- (trifluoromethyl)cyclohexane-l-carboxamide (110 mg, 0.12 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC to obtain rac-(lA,2A,55)-2-(3,4-difluoro-2-methoxyphenyl)-A-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)cyclohexane-l-carboxamide. MS (ESI): m / z494.10 [M + H]+; 'H NMR (400 MHz, DMSO-d6): 10.67 (s, 1H), 8.48 (d, J= 5.2 Hz, 1H), 8.04 (d, J= 2.0 Hz, 1H), 7.62 (dd, J= 5.2, 2.0 Hz, 1H), 7.39 (br s, 2H), 7.15-7.08 (m, 1H), 7.06-7.02 (m, 1H), 3.90 (s, 3H), 3.29-3.23 (m, 1H), 3.14-3.09 (m, 1H), 2.80-2.77 (m, 1H), 2.22-2.18 (m, 1H), 2.01-1.92 (m, 2H), 1.90-1.81 (m, 1H), 1.68-1.65 (m, 1H), 1.58-1.52 (m, 1H). Synthesis of (1R,2S,5R)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide
[00329] To a stirred solution of rac-(lA,25,5A)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxylic acid (110 mg, 325 pmol) and 4-amino-A,A-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (154 mg, 325 pmol) in pyridine (2.93 mL) was added phosphoryl trichloride (0.152 mL, 1.63 mmol) at 0-5 °C. The reaction mixture was stirred for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,25',5A)-A-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)261yridine-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)cyclohexane-l-carboxamide as pale-yellow solid. Synthesis of rac-(lR,2S,5R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(2-sulfamoylpyridin-4-yl)-5-(trijluoromethyl)cyclohexane-l -carboxamide
[00330] To a stirred solution of rac-( lR,2S,5R)-N-(2-(N,N-bis(2,4- dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5- (trifluoromethyl)cyclohexane-l-carboxamide (0.1 g, 0.12 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (1 mL) at 0-5 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC to obtain rac-(lA,25,5A)-2-(3,4-difluoro-2-methoxyphenyl)-A-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)cyclohexane-l-carboxamide. MS (ESI): m / z 494.30 [M + H]+. 'HNMR (400 MHz, DMSO-d6): 10.69 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.06 (d, J = 1.4 Hz, 1H), 7.58 (dd, J= 5.4, 1.7 Hz, 1H), 7.38 (br s, 2H), 7.25-7.21 (m, 1H), 7.14-7.08 (m, 1H), 4.05-4.02 (m, 1H), 3.80 (s, 3H), 3.14-3.08 (m, 1H), 2.61-2.60 (m, 1H), 2.10-1.69 (m, 4H), 1.72-1.69 (m, 1H), 1.37-1.28 (m, 1H). Synthesis of 4-amino-N,N-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide
[00331] To a stirred solution of 4-bromo-AfA-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (1 g, 1.86 mmol) in l-methyl-2-pyrrolidinone (10 mL) was added copper(II) acetylacetonate (146 mg, 0.558 mmol), 2-acetylcyclohexanone (157 mg, 1.12 mmol), ammonium acetate (1.43 g, 18.6 mmol) and cesium carbonate (1.82 g, 5.58 mmol). The reaction mixture was stirred at room temperature for 10 minutes, followed by heating at 90 °C for 16 hours. After reaction completion, the reaction mixture was diluted with water followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 40-50% ethyl acetate in hexane as an eluent to obtain 4-amino-A,A-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide. Compound 43 Synthesis of rac-(1R, 2R)-2-(3,4-dijluoro-2-methoxyphenyl)-5,5-difluor o-N-(2-sulfamoylpyridin-4-yl) cyclohexane-1 -carboxamide Compound 45 Synthesis of rac-(lR,2S)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluoro-N-(2- sulfamoylpyridin-4-yl) cyclohexane-1 -carboxamide Synthesis of methyl 5,5-difluoro-2-oxocyclohexane-l-carboxylate
[00332] To a stirred solution of 60% sodium hydride in mineral oil (2.48 g, 59.6 mmol) in tetrahydrofuran (50 mL) was added dimethyl carbonate (4.79 mL, 44.7 mmol) at 0 °C and heated under stirring at 60 °C for 30 minutes. A solution of 4,4-difluorocyclohexanone (2 g, 14.9 mmol) in THF was added at 0 °C and the reaction mixture was heated under stirring at 60 °C for 12 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, then concentrated to obtain methyl 5,5-difluoro-2-oxocyclohexanecarboxylate. Synthesis of methyl 5,5-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate
[00333] To a solution of 60% sodium hydride in mineral (0.5 g, 12.5 mmol) in di chloromethane (18 mL) was added methyl 5,5-difluoro-2-oxocyclohexanecarboxylate (2 g, 10.4 mmol) and the reaction mixture was stirred for 30 minutes. The reaction mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (2.1 mL, 12.5 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 12 hours. After reaction completion, water was added, followed by extraction with di chloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain methyl 5,5-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-1-carboxylate. Synthesis of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluoro-l-cyclohexene-l -carboxylate
[00334] To a stirred solution of methyl 5,5-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate (2 g, 6.17 mmol) and (3,4-difluoro-2-methoxyphenyl)boronic acid (1.74 g, 9.25 mmol) in acetonitrile (11 mL) and ethanol (7.5 mL ) were added l,4-bis(diphenylphosphino)butane (789 mg, 1.85 mmol) and palladium acetate (208 mg, 0.93 mmol). The reaction mixture was purged with argon for 10 minutes. An aqueous solution of disodium carbonate (1.96 g, 18.5 mmol) in water (3.73 mL) was added and the reaction mixture was heated at 100 °C for 16 hours. After reaction completion, the reaction mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 10-20% ethyl acetate in hexane as an eluent to obtain methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluoro-l-cy cl ohexene-1-carboxylate. Synthesis of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexanecarboxylate
[00335] To a stirred solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluoro-l-cyclohexene-1-carboxylate (1.4 g, 4.4 mmol) in methanol (50 mL) were added 10% palladium on carbon at room temperature and the reaction mixture was stirred for 16 hours at room temperature under hydrogen atmosphere. After reaction completion, the reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated to obtain the product methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexanecarboxylate. Synthesis of rac-(lR, 2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l- carboxylic acid and rac-(lR, 25)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane- 1-carboxylic acid
[00336] To a stirred solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexanecarboxylate (1.4 g, 4.37 mmol) in tetrahydrofuran (7.82 mL) and methanol (1.3 mL) was added lithium hydroxide monohydrate (1.83 g, 43.7 mmol) in water (3.91 mL). The reaction mixture was heated to 40 °C and stirred for 12 hours. After reaction completion, the reaction mixture was concentrated, acidified with IN hydrochloric acid (pH~6), followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated. The residue was purified by Prep-HPLC to obtain rac-fl / ?,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylic acid and rac-(17?,25)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylic acid. Synthesis of rac-(1R, 2R)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxamide o
[00337] To a stirred solution of rac-flA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-1-carboxylic acid (120 mg, 0.392 mmol) and 4-amino-A,A-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (223 mg, 0.47 mmol) in pyridine (1 mL) was added phosphoryl trichloride (0.3 g, 1.96 mmol) at 0-5 °C. The reaction mixture was stirred for 1 hour at room temperature. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,2A)-A-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)266yridine-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-1-carboxamide. Synthesis of rac-(1R, 2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluor o-N-(2-sulfamoylpyridin-4-yl) cyclohexane-1 -carboxamide
[00338] To a solution of rac-(lA,2A)-A-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-1-carboxamide (120 mg, 0.16 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (1 ml) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated. The residue was purified by Prep-HPLC method to afford rac-(lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluoro-A-(2-sulfamoylpyridin-4-yl)cyclohexane-l-carboxamide. MS (ESI): m / z 462.30 [M + H]+; 'HNMR (400 MHz, DMSO-d6): 6 10.70 (s, 1H), 8.48 (d, J= 5.6 Hz, 1H), 8.02 (d, J= 1.6 Hz, 1H), 7.57 (dd, J= 5.6, 2.0 Hz, 1H), 7.39 (br s, 2H), 7.12-7.08 (m, 2H), 3.90 (s, 3H), 3.41-3.60 (m, 1H), 3.19-3.14 (m, 1H), 2.44-2.42 (m, 1H), 2.23-2.09 (m, 3H), 1.84-1.81 (m, 1H), 1.62-1.60 (m, 1H). Synthesis of rac-(lR,2S)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxamide o
[00339] To a stirred solution of rac-(lA,25)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-1-carboxylic acid (80 mg, 0.26 mmol) and 4-amino-A,A-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide (148 mg, 0.31 mmol) in pyridine (0.89 mL) was added phosphoryl trichloride (0.2 g, 1.31 mmol) at 0-5 °C. The reaction mixture was stirred at room temperature for 4 hours. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,25)-A-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-1-carboxamide. Synthesis of rac-(lR,2S)-2-(3,4-dijluoro-2-methoxyphenyl)-5,5-difluoro-N-(2-sulfamoylpyridin-4-yl) cyclohexane-1 -carboxamide
[00340] To a solution of (1 A,25)-A-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxamide (50 mg, 65.6 pmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (0.2 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated. The residue was purified by prep-HPLC method to afford rac-(lA,25)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluoro-A-(2-sulfamoylpyridin-4-yl)cyclohexane-l-carboxamide. MS (ESI): m / z 462.20 [M + H]+. 'H NMR (400 MHz, DMSO-d6): b 10.53 (s, 1H), 8.47 (d,J=5.6Hz, 1H), 8.07 (d,J= 1.6Hz, 1H), 7.50 (dd, J= 5.2Hz, 1.6 Hz, 1H), 7.37 (br s, 2H), 7.24-7.21 (m, 1H), 7.11-7.04 (m, 1H), 3.91 (s, 3H), 3.44-3.42 (m, 1H), 3.28-3.27 (m, 1H) 2.71-2.63 (m, 1H), 2.44-2.42 (m, 2H), 2.14-2.03 (m, 2H), 1.84-1.81 (m, 1H). Compound 81 Synthesis of rac-(lR,2R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)cycloheptane-l-carboxamide Compound 83 Synthesis of rac-(lR,2S)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3- sulfamoylphenyl)cycloheptane-l-carboxamide Synthesis of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohept-l-ene-l-carboxylate 0 CjytJMe ^OTf
[00341] To a stirred solution of 60% sodium hydride in mineral oil (564 mg, 14.1 mmol) in di chloromethane (40 mL) was added methyl 2-oxocycloheptanecarboxylate (2 g, 11.8 mmol) at 0 °C and stirred for 30 minutes. The reaction mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (2.37 mL, 14.1 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. After reaction completion, water was added, followed by extraction with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohept-1 -ene-1 -carboxylate. Synthesis of methyl 2-(3,4-difluoro-2-methoxyphenyl)cyclohept-l-ene-l -carboxylate O
[00342] To a stirred solution of methyl 2-(((trifluoromethyl)sulfonyl)oxy)cyclohept-l-ene-1-carboxylate (650 mg, 2.15 mmol) in acetonitrile (6.5 mL) and ethanol (4.33 mL) were added (3,4-difluoro-(3,4-difluoro-2-methoxyphenyl)boronic acid (606 mg, 3.23 mmol), 1,4-bis(diphenylphosphino)butane (18.3 mg, 43 pmol) and palladium acetate (4.83 mg, 0.0215 mmol) at room temperature. To the reaction mixture, an aqueous solution of disodium carbonate (684 mg, 6.45 mmol) in water (1.95 mL) was added and the reaction mixture was heated at 100 °C for 16 hours. After reaction completion, the reaction mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 20-30% ethyl acetate in hexane as an eluent to obtain methyl 2-(3,4-difluoro-2-methoxyphenyl)cyclohept-l-ene-1-carboxylate. Synthesis of methyl 2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carboxylate
[00343] To a stirred solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-l-cycloheptene-1-carboxylate (3.5 g, 11.8 mmol) in methanol (50 mL) were added 10% palladium on carbon and the reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. After reaction completion, the reaction mixture was filtered through a pad of Celite® and the filtrate concentrated to obtain 2-(3,4-difluoro-2-methoxyphenyl)cy cl oheptane-1-carboxylate. Synthesis of rac-(lR,2R)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carboxylic acid and rac-(lR,2S)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carboxylic acid
[00344] To a stirred solution of methyl 2-(3,4-difluoro-2- methoxyphenyl)cycloheptanecarboxylate (2 g, 6.7 mmol) and lithium hydroxide monohydrate (2.81 g, 67 mmol) in tetrahydrofuran (12 mL), water (6 mL) and methanol (2 mL) at room temperature. The reaction mixture was heated to 80 °C and stirred for 12 hours. After reaction completion, the reaction mixture was concentrated, acidified with IN hydrochloric acid (pH~6), followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, concentrated. The residue was purified by prep-HPLC to obtain rac-(lA,27?)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptanecarboxylic acid and rac-( 1R,2S)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptanecarboxylic acid. Synthesis of rac-(lR,2R)-N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4- difluoro-2-methoxyphenyl)cycloheptane-l-carboxamide
[00345] To a stirred solution of rac-(lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptanecarboxylic acid (0.2 g, 703 pmol) and 3-amino-7V,7V-bis(2,4-dimethoxybenzyl)benzenesulfonamide (399 mg, 0.84 mmol) in pyridine (3 mL) was added phosphoryl trichloride (539 mg, 3.52 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue purified by silica gel column chromatography using 50% ethyl acetate in hexane as an eluent to obtain rac-(lA,2A)-A-(3-(A,A-bis(2,4- dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carboxamide. Synthesis of rac-(lR,2R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)cycloheptane-l-carboxamide
[00346] To a solution of rac-(lA,2A)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carboxamide (140 mg, 0.18 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. After reaction completion, the reaction mixture was concentrated. The residue was purified by prep-HPLC method to afford rac-(l / ?,2A)-2-(3,4-difluoro-2-methoxyphenyl)-A-(3-sulfamoylphenyl)cycloheptane-l-carboxamide. MS (ESI): m / z 439.3 [M + H]+; 'H NMR (400 MHz, DMSO-d6): 8 10.01 (s, 1H), 7.99 (s, 1H), 7.58-7.54 (m, 1H), 7.43-7.48 (m, 2H), 7.30 (br s, 2H), 7.07-7.01 (m, 2H), 3.89 (s, 3H), 3.47-3.41 (m, 1H), 2.95-2.89 (m, 1H), 1.96-1.90 (m, 1H), 1.82-1.72 (m, 3H), 1.70-1.65 (m, 4H), 1.59-1.54 (m, 2H). Synthesis of rac-(lR,2S)-N-(3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carboxamide
[00347] To a stirred solution of rac-(lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptanecarboxylic acid (80 mg, 0.28 mmol) and 3-amino-A,A-bis(2,4-dimethoxybenzyl)benzenesulfonamide (160 mg, 034 mmol) in pyridine (1.2 mL) was added phosphoryl trichloride (216 mg, 1.41 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac-(lA,25)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carb oxamide. Synthesis of rac-(lR,25)-2-(3,4-dijluoro-2-methoxyphenyl)-N-(3-sulfamoylphenyl)cycloheptane-l-carboxamide
[00348] To a solution of (lA,25)-A-(3-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)phenyl)-2-(3,4-difluoro-2-methoxyphenyl)cycloheptane-l-carboxamide (0.1 g, 0.135 mmol) in di chloromethane (10 mL) was added trifluoroacetic acid (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. After reaction completion, the reaction mixture was concentrated. The residue was purified by Prep-HPLC method to afford rac-(lA, 25)-2-(3,4-difluoro-2-methoxyphenyl)-7V-(3-sulfamoylphenyl)cycloheptane-l-carboxamide. MS (ESI): m / z 437.2 [M-H]’; 'H NMR (400 MHz, DMSO-d6): 8 9.76 (s, 1H), 7.94 (s, 1H), 7.47-7.36 (m, 3H), 7.19 (br s, 2H), 7.05-6.97 (m, 2H), 3.92 (s, 3H), 3.47-3.43 (m, 1H), 2.92-2.87 (m, 1H), 2.45-2.39 (m, 1H), 2.03-1.98 (m, 1H), 1.91-1.84 (m, 4H), 1.70-1.67 (m, 1H), 1.51-1.43 (m, 3H). The following compounds were prepared using similar procedures as described above: 1, 3, 5, 7, 9, 11, 13, 15, 19, 21, 24, 26, 28, 30, 32, 34, 37, 38, 39, 41, 43, 45, 47, 53, 54, 63, 65, 66, 70, 81, 83, 117, 138, 139, 140, 141, 148, 153, 154, 155, 156, 183, 184, 185, 186, 187, 188,189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 207, 208, 209, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 222, 223, 224, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 264, 265, 266, 267, 268, 269, 270, 271, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 291, 292, 294, 295, 298, 299, 300, 301,302, 303, 304, 305, 306, 307, 308, 311, 312, 313, 314, 315, 317, 318, 319, 320, 321, 322, 323, 328, 329, 330, 331, 332, 334, 335, 336, 337, 338, 339, 340, 341, 342, 344, 345, 346, 348, 350, 351, 352, 357, 358, 359, 362, 363, 364, 364, 366, 367, 368, 369, 370, 371, 373, 374, 375, 376, 377, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 420, 423, 424, 425, 426, 427, 428, 429, 431, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 457, 462, 463, 464, 467, 468, 469, 470, 471, 472, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 505, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 540, 541, 544, 545, 546, 549, 550, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 627, 628, 629, 630, 631, 633, 634, 635, 636, 637, 638, 639, 640, 641, 643, 644, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724 Compound 140 Synthesis of methyl 5,5-difluoro-2-oxocyclohexane-1-carboxylate O To a stirred solution of 4,4-difluorocyclohexan-l-one (850 g, 6.34 mol) in THF (10V) was added NaH (304 g, 12.7 mol) between 0-10 °C. The reaction was stirred between 0-10 °C for 30 minutes, followed by the addition of dimethyl carbonate (1.7 kg, 19 mol). The reaction mixture was warmed to room temperature and stirred for 16 hours. After reaction completion, the reaction mixture was added to an aqueous solution of citric acid and n-heptane was added. The organic layer was separated, and the aqueous phase was extracted with MTBE. Another batch was set up using the same procedure. The organic layers were combined, washed with brine, filtered, then concentrated. The residue was purified by distillation to give methyl 5,5-difluoro-2-oxocyclohexane-l-carboxylate (1.9 kg, 72%). Synthesis of methyl 5,5-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate To a stirred solution of methyl 5,5-difluoro-2-oxocyclohexane-l-carboxylate (950 g, 2.9 mol) was added TEA (445 g, 4.4 mol) and DCM (10V). The reaction mixture was cooled between -50 and -30 °C then TfzO (1 kg, 3.5 mol) was added dropwise. The reaction mixture was stirred between -50 and -30°C for 30 minutes, then the reaction mixture was warmed to room temperature. Water was added to the reaction mixture and the organic layer was separated. The aqueous phase was extracted with DCM. Another batch was set up using the same procedure. The organic layers were combined then filtered using silica gel to give methyl 5,5-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-l-carboxylate (3 kg, 86%). Synthesis of methyl 34,4,4'-tetrafluor o-2 '-methoxy-3,4,5,6-tetrahydro-[1,1 '-biphenyl]-2-carboxylate To a stirred solution of methyl 5,5-difluoro-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-l-ene-1-carboxylate (1.23 kg, 3.85 mol) was added dioxane (10V), water (2V), (3,4-difluoro-2-methoxyphenyl)boronic acid (760 g, 4 mol), and K3PO4 (2.5 kg, 11.6 mol). The atmosphere was replaced with nitrogen then Pd(dppf)2C12 was added. The reaction mixture was heated to 100 °C and stirred for 2 hours. After reaction completion, water and MTBE was added to the reaction mixture. The organic layers separated, and the aqueous phase was extracted with MTBE. Another batch was set up using the same procedure. The organic layers were combined, washed with water, extracted with n-pentane, filtered using silica gel, then concentrated to give methyl 3(4,4,4Metrafhioro-2'-methoxy-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-carboxylate (2.9 kg, 91%). Synthesis of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylate To a stirred solution of methyl 3(4,4,4'-tetrafluoro-2'-methoxy-3,4,5,6-tetrahydro-[l,r-biphenyl]-2-carboxylate (1.9 kg, 6 mol) was added Raney Ni and MeOH (7.5V). The atmosphere was replaced with hydrogen (1 MPa) and the reaction mixture was stirred at 105 °C for 16 hours. After reaction completion, the reaction mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated to give methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylate (1 kg, 96%). Synthesis of rac-(lR, 2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-dijluorocyclohexane-l- carboxylic acid O F To a stirred solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylate (920 g, 2.9 mol) was added MeOH (6V) and 30% NaOMe in MeOH (11.5 mol). The reaction mixture was heated to 70 °C and stirred for 16 hours. After reaction completion, 20% aqueous NaOH (11.5 mol) was added to the reaction mixture and the reaction mixture was stirred for 2 hours. After reaction completion, the reaction mixture was concentrated. 3M HC1 was added dropwise to the residue to adjust the pH to 1~2 at 10-25 °C. The mixture was extracted with ethyl acetate. The organic layers were combined and concentrated to give rac-(lA,27?)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylic acid (845 g, 96%). Synthesis of (1R, 2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylic acid To a solution of rac-(lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylic acid (660 g, 2.2 mol) in EtOH (10V) was added L-l-phenylethylamine (1.1 eq). The reaction mixture was stirred at room temperature for 30 minutes. After reaction completion, the reaction mixture was filtered. The solid was dissolved in water, acidified using 2M HC1, then extracted with DCM. The organic layers were combined, washed with water, then concentrated. The residue was dried at 55 °C for 16 hours to give (lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylic acid (250 g, 38%) Synthesis of (1R, 2R)-N-(3-acetylpyridin-4-yl)-2-(3,4-dijluoro-2-methoxyphenyl)-5,5-dijluorocyclohexane-l-carboxamide To a solution of (lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxylic acid (225 g, 735 mmol) in DMF (20V) was added HATU (420 g, 1.1 mol). The reaction mixture was stirred for 30 minutes, then DIPEA (475 g, 3.7 mol) and 1-(4-aminopyridin-3-yl)ethan-l-one (120 g, 880 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After reaction completion, water was added to the reaction mixture followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, then concentrated. The residue was purified by column chromatography to give (lA,2A)-7V-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-l-carboxamide (270 g, 98%). Synthesis of 2-((lR,2R)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)-l,6-naphthyridin-4 (1H) -one To a solution of (lA,2A)-7V-(3-acetylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexane-1-carboxamide (283 g, 667 mol) in DMAc (25 V) was added K3PO4 (700 g, 3.3 mol). The reaction mixture was heated at 135 °C and stirred for 16 hours. After reaction completion, the reaction mixture was filtered using Celite. Water was added to the filtrate and the solution was extracted using ethyl acetate. The organic layers were combined, washed with brine, then concentrated. MTBE was added to the residue and the solution was stirred for 2 hours. The mixture was filtered to give 2-((lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)-l,6-naphthyridin-4(l / 7)-one (202 g, 99%). Synthesis of 2-((1R2R)-2-(3,4-dijluoro-2-methoxyphenyl)-5,5-dijluorocyclohexyl)-4-oxo-l, 4-dihydro-l,6-naphthyridine-5-carboxamide To a solution of 2-((lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)-l,6-naphthyridin-4(l / 7)-one (180 g, 440 mmol) in formamide (10V), NHPI (72 g, 440 mmol), and TFA (100 g, 890 mmol). The reaction mixture was heated at 75 °C then CAN (485 g, 880 mmol) was added in three batches. After reaction completion, water was added to the reaction mixture. 2M HC1 was used to acidify the reaction mixture followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, filtered, then concentrated. IPA was added to the residue and the mixture was stirred for 2 hours. The mixture was filtered, and the precipitate was purified by chiral SFC to give 2-((lA,2A)-2-(3,4-difluoro-2-methoxyphenyl)-5,5-difluorocyclohexyl)-4-oxo-l,4-dihydro-l,6-naphthyridine-5-carboxamide (48.5 g, 99%). Compound 163 (R)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-N-(2-sulfamoylpyridin-4-yl)piperidine-2- carboxamide (S)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-N-(2-sulfamoylpyridin-4-yl)piperidine-2-carboxamide Synthesis of methyl l-(3,4-dijluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylate To a stirred solution of methyl 4,4-difluoro-2-piperidinecarboxylate and 1 -bromo-3,4-difluoro-2-methoxybenzene in dimethyl sulfoxide were added potassium phosphate and copper iodide at room temperature. The reaction mixture was stirred for 10 minutes then heated at 100 °C for 16 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography to give methyl 1-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-2-piperidinecarboxylate. Synthesis of l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylic acid To a stirred solution of methyl l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylate in tetrahydrofuran and methanol was added an aqueous solution of lithium hydroxide in water. The reaction mixture was stirred at room temperature for 16 hours. After reaction completion, the reaction mixture was concentrated and the remaining aqueous solution was neutralized with IM hydrochloric acid, followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, then concentrated to give 1 -(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylic acid. Synthesis of N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-l-(3,4-dijluoro-2-methoxyphenyl)-4,4-dijluoropiperidine-2-carboxamide To a stirred solution of l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxylic acid and 2 4-amino-7V,7V-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide in pyridine was added phosphoryl chloride at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 1 hour. After reaction completion, the reaction mixture was diluted with water, neutralized with saturated aqueous solution of sodium bicarbonate, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to give 7V-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxamide. Synthesis (5)-1-(3,4-dijluoro-2-methoxyphenyl)-4,4-dijluoro-N-(2-sulfamoylpyridin-4-yl)piperidine-2-carboxamide and (R)-l-(3,4-dijluoro-2-methoxyphenyl)-4,4-dijluoro-N-(2-sulfamoylpyridin-4-yl)piperidine-2-carboxamide To a stirred solution of A-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoropiperidine-2-carboxamide in dichloromethane was added trifluoroacetic acid at 0-5 °C. The reaction mixture was stirred for 16 hours at room temperature. After reaction completion, water was added to the reaction mixture. The solution was neutralized with saturated aqueous solution of sodium bicarbonate then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by prep HPLC to obtain 4-[ 1-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-2-piperidylcarbonylamino]-2-pyridinesulfonamide, which was further purified by chiral SFC to give 4-[(S)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-2-piperidylcarbonylamino]-2-pyridinesulfonamide and 4-[(A)-l-(3,4-difluoro-2-methoxyphenyl)-4,4-difluoro-2-piperidylcarbonylamino]-2-pyridinesulfonamide. Peak-1: *HNMR (400 MHz, DMSO-d6): 3 10.70 (br s, 1H), 8.52 (d, J= 5.44, 1H), 8.16 (s, 1H), 7.65-7.63 (m, 1H), 7.41 (br s, 2H), 7.11-7.04 (m, 1H), 6.97-6.93 (m, 1H), 7.31(br s, 2H), 4.45 (t, J = 5.8 Hz, 1H), 3.97 (s, 3H), 3.72-3.66 (m, 1H), 3.12-3.06 (m, 1H), 2.19-2.15 (m, 2H). MS (ESI): m / z 463.30 [M + H]+. Peak-2 *HNMR (400 MHz, DMSO-d6): 3 10.70 (br s, 1H), 8.52 (d, J= 5.44, 1H), 8.16 (s, 1H), 7.65-7.63 (m, 1H), 7.41 (br s, 2H), 7.11-7.04 (m, 1H), 6.97-6.93 (m, 1H), 7.31(br s, 2H), 4.45 (t, J = 5.8 Hz, 1H), 3.97 (s, 3H), 3.79-3.66 (m, 1H), 3.12-3.06 (m, 1H), 2.19-2.12 (m, 2H). MS (ESI): m / z 463.30 [M + H]+. The following compounds were prepared using similar procedures as described above: 17, 18, 23, 59, 87, 88, 89, 163, 164, 165, 166, 168, 169, 170, 173, 174, 177, 178, 179, 180, 181, 182. 221, 272, 316, 333, 355, 356, 379, 392, 393, 418, 419, 430, 473, 485, 565, 587, 588, 599, 614 Compound 353 and Compound 354 Synthesis of ethyl (E)-3-(3,4-dijluoro-2-methoxyphenyl)acrylate Amixture of 1-bromo-3,4-difluoro-2-methoxybenzene, ethyl (E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate, potassium phosphate and [l,l-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) in dioxane and water was degassed and purged with nitrogen for 3 times, the reaction mixture was stirred at 80 °C for 12 hours under nitrogen atmosphere. After reaction completion, the reaction mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 0-10% ethyl acetate in hexane as an eluent to obtain ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate as a white solid. Synthesis of rac-ethyl (1R, 2R)-34 '-difluoro-2 '-methoxy-1,2,3,6-tetrahydro-[l, 1 '-biphenyl]-2-carboxylate A solution of toluene and ethyl (£)-3-(3,4-difluoro-2-methoxyphenyl)acrylate and buta-1,3-diene in 1.9 M hexane was pumped (4 mL / min) to flow reactor (HC, Coils reactor, 3.175 mm, 130 mL, 280 °C) with backpressure of 4.6 MPa. The residence time of flow reactor 1 was 30 min. The reaction mixture was collected with a bottle. After reaction completion, the reaction mixture was concentrated. The residue was purified by prep HPLC to obtain rac-ethyl (1 7?,2£)-3',4'-difluoro-2'-methoxy-l,2,3,6-tetrahydro-[l,T-biphenyl]-2-carboxylate as a colorless oil. Synthesis of rac-ethyl (3R, 4R)-4-(3,4-difluoro-2-methoxyphenyl) bicyclo[4.1.0]heptane-3-carboxylate O To a solution of rac-ethyl (l£,2£)-3',4'-difluoro-2'-methoxy-l,2,3,6-tetrahydro-[l,r-biphenyl]-2-carboxylate in 1,2-di chloroethane was dropwise added IM di ethylzinc at 0 °C under nitrogen atmosphere. Chloroiodomethane was dropwise added. The reaction mixture was stirred at 0 °C for 30 minutes and warmed to room temperature for 16 hours. After reaction completion, water was added followed by extraction with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by prep HPLC to obtain rac-ethyl (3A,4A)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3-carboxylate as a colorless oil. Synthesis of rac-(3R, 4R)-4-(3,4-dijluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3- carboxylic acid To a solution of rac-ethyl (3A,4A)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3-carboxylate in ethanol and tetrahydrofuran was added lithium hydroxide in water. The reaction mixture was heated at 80 °C for 16 hours. After reaction completion, the reaction mixture was concentrated and the resulting aqueous solution was acidified with IN hydrochloric acid followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtained rac-(3A,4A)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3-carboxylic acid as a light yellow oil. Synthesis of rac-(3R, 4R)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3- carboxamide To a solution of rac-(3A,4A)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3-carboxylic acid and ammonium chloride in dimethylformamide (3 mL) was added HATU and triethylamine. The mixture was stirred at 50 °C for 5 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 0-50% ethyl acetate in hexane as an eluent to obtain rac-(3A,47?)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3-carboxamide as a white solid. Synthesis of rac- (3R,4R)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-4-(3,4-difluoro-2-methoxyphenyl) bicyclo [4.1.0]heptane-3-carboxamide OMe F To a solution of rac-(3A,4A)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3-carboxamide and 4-bromo-A,A-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide in dioxane was added BrettPhos Pd G3 and cesium carbonate. The mixture was stirred at 100 °C for 4 hours under nitrogen atmosphere. After reaction completion, the reaction mixture was cooled to room temperature, diluted with water, followed by extraction with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography obtain rac-(3A,4A)-N-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1,0]heptane-3-carboxamide. Synthesis of rac-(IS, 3R, 4R, 6R)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-sulfamoylpyridin-4-ylfbicyclo[4.1.0]heptane-3-carboxamide andrac- (lR,3R,4R,6S)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-sulfamoylpyridin-4-yl)bicyclo[4.1.0]heptane-3-carboxamide To a solution of rac-(3A,4A)-N-(2-(A,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-4-(3,4-difluoro-2-methoxyphenyl)bicyclo[4.1.0]heptane-3-carboxamide in dichloromethane was added 2,2,2-trifluoroacetic acid. The reaction mixture was stirred at 40 °C for 1 hour. After reaction completion, the reaction mixture was purified by prep HPLC to afford rac-(15,37?,4A,6A)-4-(3,4-difluoro-2-methoxyphenyl)-N-(2-sulfamoylpyridin-4-yl)bicyclo[4.1.0]heptane-3-carboxamide as a white solid and rac-(\R,3R,4R,65)-4-(3,4- difluoro-2-methoxyphenyl)-A-(2-sulfamoylpyridin-4-yl)bicyclo[4.1.0]heptane-3-carboxamide as a white solid. Compound 353: *HNMR (400 MHz, DMSO-d6): ¢5 10.55 (s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.00 (d, J= 2.0 Hz, 1H), 7.56 (dd, J= 2.0, 5.6 Hz, 1H), 7.37 (br. s., 2H), 7.11 - 7.02 (m, 2H), 3.89 (d, J= 0.8 Hz, 3H), 3.03 - 2.92 (m, 1H), 2.83 - 2.71 (m, 1H), 2.49 - 2.41 (m, 1H), 2.01 -1.93 (m, 1H), 1.80 - 1.71 (m, 1H), 1.70 - 1.60 (m, 1H), 1.14-1.00 (m, 2H), 0.77 - 0.65 (m, 1H), 0.27 - 0.18 (m, 1H). MS (ESI): m / z 438.1 [M + H]+. Compound 354: *HNMR (400 MHz, DMSO-d6): 3 10.57 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 2.0, 5.6 Hz, 1H), 7.36 (br. s., 2H), 7.07 - 7.00 (m, 1H), 6.98 - 6.91 (m, 1H), 3.92 (s, 3H), 3.12-3.02 (m, 1H), 2.74 - 2.65 (m, 1H), 2.28 - 2.15 (m, 2H), 2.06 - 1.97 (m, 1H), 1.40 - 1.29 (m, 1H), 1.13 - 0.99 (m, 2H), 0.77 - 0.65 (m, 1H), 0.24 - 0.14 (m, 1H). MS (ESI): m / z 438.1 [M + H]+ The following compounds were prepared using similar procedures as described above: 36, 71, 210, 258, 259, 260, 261, 262, 263, 293, 324, 325, 326, 327, 353, 354, 421, 422, 456, 458, 459, 504, 506, 507, 536, 537, 538, 539, 542, 543, 547, 548, 551, 552, 553, 625, 626, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665 Compound 372 Synthesis of rac-2-methyl-N-(quinolin-8-yl)cyclohexanecarboxamide To a solution of rac-2-methylcyclohexanecarboxylic acid and quinolin-8-amine in dimethylformamide was added HATU and diisopropylethylamine. The mixture was stirred at room temperature for 5 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography to obtain rac-2-methyl-A-(quinolin-8-yl)cyclohexanecarboxamide. Synthesis of rac-(lS,2R, 65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methyl-N-(quinolin-8-yl)cyclohexanecarboxamide To a solution of rac-2-methyl-A-(quinolin-8-yl)cyclohexanecarboxamide in tertbutyl alcohol was added diacetoxypalladium and silver carbonate. The reaction mixture was stirred at 80 °C for 12 hours. After reaction completion, the reaction mixture was cooled to room temperature, filtered, then concentrated. The residue was purified by column chromatography using 0-30% ethyl acetate in hexane as an eluent to obtain rac-(\S,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methyl-A-(quinolin-8-yl)cyclohexanecarboxamide. Synthesis of rac-(lS,2R, 6S)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid To a solution of rac-(fS,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methyl-A-(quinolin-8-yl)cyclohexanecarboxamide in methylbenzene and water was added trifluoromethanesulfonic acid. The reaction mixture was stirred at 100 °C for 5 hours. After reaction completion, the reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC to obtain rac-(\S,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid. Synthesis of rac-((lS,2R, 6S)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexyl)methanol Me F To a solution of rac-(\S,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid in tetrahydrofuran was added borane dimethyl sulfide complex at 0 °C. The reaction mixture was stirred at 70 °C for 3 hours. After reaction completion, the reaction mixture was added methanol (25 mL) dropwise at 0 °C then stirred at 80 °C for 3 hours. The reaction mixture was concentrated. The residue was purified by column chromatography to obtain rac-((l 5,2A, 65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexyl)methanol. Synthesis of rac-(lS,2R, 6S)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarbaldehyde Me O aa MeO^Y^F F To a solution of methyl rac-((15,2A,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexyl)methanol in dichloromethane was added Dess-Martin at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After reaction completion, a mixed solution of sodium sulfite and sodium bicarbonate was added. Then the mixture was extracted by di chloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtained rac-(15,2A,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarbaldehyde. Synthesis of racflR,2R,6S)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarbaldehyde To a solution of rac-(15,2A,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarbaldehyde in methyl alcohol was added potassium hydroxide. The reaction mixture was stirred at room temperature for 0.5 hour. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain rac- (15,27?,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid as a yellow oil. Synthesis of rac-(lR,2R,6S)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid Me O To a solution of rac-(fS,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid in tert-butyl alcohol and water was added 2-methyl-2-butene and sodium dihydrogen phosphate and 80% sodium hypochlorite. The mixture was stirred at room temperature for 0.5 hour. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated to obtain racflR,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid. Synthesis of rac-(lR, 2R, 65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxamide Me O To a solution of racf 17?,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxylic acid and ammonium chloride in dimethylformamide was added HATU and triethylamine. The mixture was stirred at 50 °C for 3 hours. After reaction completion, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, then concentrated. The residue was purified by column chromatography using 10-100% ethyl acetate in hexane as an eluent to obtain rac-(17?,27?,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methy 1 cy cl ohexanecarb oxami de. Synthesis of rac-(lR,2R,6S)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxamide OMe F To a solution of rac-(fR,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methylcyclohexanecarboxamide and 4-bromo-A,A-bis(2,4-dimethoxybenzyl)pyridine-2-sulfonamide in dioxane was added BrettPhos-Pd-Gs and cesium carbonate. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen atmosphere. After reaction completion, the reaction mixture was concentrated. The residue was purified by column chromatography to obtain rac-(lR,2R)-N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-3-methyl cy cl ohexanecarb oxami de. Synthesis of rac-(lR, 2R, 65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methyl-N-(2-sulfamoylpyridin-4-yl)cyclohexanecarboxamide To a solution of rac-(lA,2A)-A-(2-(7V,A-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-3-methylcyclohexanecarboxamide (70.0 mg, 94.6 pmol) in formic acid (10 mL). The reaction mixture was stirred at 50 °C for 2 hours. After reaction completion, the reaction mixture was purified by prep-HPLC to afford rac-(\R,2R,65)-2-(3,4-difluoro-2-methoxyphenyl)-6-methyl-A-(2-sulfamoylpyridin-4-yl)cyclohexanecarboxamide as a white solid. 'HNMR (400 MHz, DMSO-d6): 6 10.47 (br s, 1H), 8.46 (d, J= 5.6 Hz, 1H), 8.02 (s, 1H), 7.67 - 7.59 (m, 1H), 7.37 (s, 2H), 7.23 - 7.00 (m, 2H), 3.84 (s, 3H), 3.29 - 3.23 (m, 1H), 2.48 - 2.42 (m, 1H), 1.85 - 1.64 (m, 4H), 1.56 - 1.40 (m, 1H), 1.38 - 1.25 (m, 1H), 1.21 - 1.08 (m, 1H), 0.95 - 0.87 (m, 3H). MS (ESI): m / z 440.1 [M + H]+. The following compounds were prepared using similar procedures as described above: 309, 310, 360, 361, 372, 466 Compound Characterization Data Compound 1 XH NMR (400 MHz, DMSO-d6) 8 10.15 (s, 1H), 8.15 (s, 1H), 7.68-7.65 (m, 1H), 7.45-7.42 (m, 2H), 7.32-7.25 (m, 6H), 7.19-7.15 (m, 1H), 3.40-3.36 (m, 1H), 2.93-2.86 (m, 1H), 2.172.10 (m, 2H), 1.84-1.69 (m, 4H). MS (ESI) m / z 343.3 [M - H]’ Compound 3 'H NMR (400 MHz, DMSO-d6) 6 9.85 (s, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.41-7.36 (m, 3H), 7.32 (br s, 2H), 7.24-7.22 (m, 2H), 7.18-7.14 (m, 2H), 7.08-7.04 (m, 1H), 3.43-3.37 (m, 1H), 3.22-3.17 (m, 1H), 2.17-2.01 (m, 5H), 1.92-1.75 (m, 1H). MS (ESI): m / z 345.20 [M + H]+. Compound 5 XH NMR (400 MHz, DMSO-d6) 6 10.12 (s, 1H), 8.16 (s, 1H), 7.69-7.66 (m ,1H), 7.45-7.43 (m, 2H), 7.31 (br s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H), 3.71 (s, 3H), 3.68-3.61 (m, 1H), 3.04-2.98 (m, 2H), 2.09-2.07 (m, 2H), 1.83-1.80 (m, 3H), 1.67-1.60 (m, 1H) MS (ESI): m / z 373.3 [M - H]’ Compound 7 XH NMR (400 MHz, DMSO-d6) 6 9.63 (s, 1H), 7.88 (br s, ,1H), 7.38-7.31 (m, 3H), 7.28 (br s, 2H), 7.16 (d, J = 6.8 Hz, 1H), 7.07-7.04 (m, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 3.75 (s, 3H), 3.62-3.55 (m, 1H), 3.27-3.22 (m, 1H), 2.22-2.18 (m, 1H), 1.99-1.96 (m, 3H), 1.84-1.78 (m, 1H), 1.69-1.63 (m, 1H) MS (ESI): m / z 373.30 [M - H]’ Compound 9 XH NMR (400 MHz, DMSO-d6) 8 10.10 (s, 1H), 8.06 (s, 1H), 7.58-7.55 (br s, ,1H), 7.42-7.37 (m, 2H), 7.28 (br s, 2H), 7.24-7.22 (m, 1H), 7.09-7.05 (m, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 3.76 (s, 3H), 3.29-3.26 (m, 1H), 2.91-2.87 (m, 1H), 2.02-1.98 (m, 1H), 1.77-1.64 (m, 3H), 1.60-1.51 (m, 1H), 1.45-1.41 (m, 2H), 1.39-1.36 (m, 1H). MS (ESI): m / z 389.10 [M+H]+ Compound 11 XH NMR (400 MHz, DMSO-d6) 6 9.72 (s, 1H), 8.06-8.05 (m, 1H), 7.49-7.46 (m, 1H), 7.417.35 (m, 2H), 7.30 (br s, 2H), 7.23-7.21 (m, 1H), 7.12-7.07 (m, 1H), 6.93-6.91 (m, 1H), 6.786.77 (m, 1H), 3.81 (s, 3H), 3.22-3.18 (m, 1H), 2.99-2.97 (m, 1H), 2.73-2.64 (m, 1H), 1.991.87 (m, 2H), 1.82-1.70 (m, 2H), 1.54-1.51 (m, 1H), 1.44-1.39 (m, 2H). MS (ESI): m / z 387.30 [M-H]’ Compound 13 'HNMR (400 MHz, DMSO-d6): 8 10.12 (br s, 1H), 8.01 (s, 1H), 7.60-7.57 (m, 1H), 7.427.39 (m, 2H), 7.27 (br s, 2H), 7.10-7.07 (m, 2H), 3.89 (s, 3H), 3.22-3.20 (m, 1H), 2.85-2.77 (m, 1H), 2.03-2.01 (m, 1H), 1.85-1.71 (m, 3H), 1.60-1.51 (m, 1H), 1.46-1.28 (m, 3H). MS (ESI): m / z 425.20 [M + H]+ Compound 15 'HNMR (400 MHz, DMSO-d6): 6 9.83 (br s, 1H), 8.05-8.04 (m, 1H), 7.50-7.48 (m, 1H), 7.43-7.37 (m, 2H), 7.27 (br s, 2H), 7.07-7.01 (m, 2H), 3.95 (s, 3H), 3.17-3.13 (m, 1H), 2.902.87 (m, 1H), 2.67-2.56 (m, 1H), 1.97-1.94 (m, 1H), 1.90-1.83 (m, 1H), 1.82-1.68 (m, 2H), 1.53-1.42 (m, 3H). MS (ESI): m / z 425.20 [M + H]+ Compound 17 'H NMR (400 MHz, DMSO-d6): 6 9.96 (s, 1H), 8.19 (s, 1H), 7.81-7.79 (m, 1H), 7.46 (d, J = 5.2 Hz, 2H), 7.32 (br s, 2H), 6.86-6.80 (m, 2H), 6.74-6.69 (m, 2H), 4.44-4.41 (m, 1H), 3.57 (s, 3H), 3.55-3.50 (m, 1H), 3.25-3.21 (m, 1H), 1.96-1.86 (m, 1H), 1.48-1.24 (m, 3H). MS (ESI): m / z 376.25 [M + H]+ Compound 18 'HNMR (400 MHz, DMSO-d6): 6 9.96 (s, 1H), 8.20 (s, 1H), 7.83-7.76 (m, 1H), 7.46 (d, J= 8.0 Hz, 2H), 7.36 (br s, 2H), 6.85-6.80 (m, 2H), 6.74-6.72 (m, 2H), 4.44-4.41 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.27-3.22 (m, 1H), 2.28-2.19 (m, 1H), 1.97-1.91 (m, 3H) MS (ESI): m / z 3162 [M + H]+ Compound 19 'HNMR (400 MHz, DMSO-d6): 8 10.14 (br s, 1H), 8.06 (s, 1H), 7.56-7.54 (m, 1H), 7.437.38 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.28-3.25 (m, 1H), 2.88 (d, J = 8.8 Hz, 1H), 2.03-2.00 (m, 1H), 1.84-1.74 (m, 3H), 1.57-1.50 (m, 1H), 1.41-1.33 (m, 2H), 1.24-1.22 (m, 1H). MS (ESI): m / z 473.30 [M + H]+ Compound 21 'HNMR (400 MHz, DMSO-d6): 6 9.76 (br s, 1H), 8.07 (s, 1H), 7.43-7.38 (m, 3H), 7.31-7.29 (m, 3H), 6.92 (d, J = 1.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.19-3.15 (m, 1H), 2.98 (br s, 1H), 2.72-2.63 (m, 1H), 1.97-1.95 (m, 1H), 1.90-1.87 (m, 1H), 1.76-1.71 (m, 2H), 1.52-1.50 (m, 1H), 1.46-1.40 (m, 2H). MS (ESI): m / z 471.30 [M - H]’ Compound 23 'H NMR (400 MHz, DMSO-d6): 3 1016 (br s, 1H), 8.15 (s, 1H), 7.60-7.59 (m, 1H), 7.45-7.42 (m, 2H), 7.31 (br s, 2H), 7.07-7.00 (m, 1H), 6.70-6.84 (m, 1H),4.16-4.13 (m, 1H), 3.98 (s, 3H), 3.64-3.61 (m, 1H), 2.76-2.72 (m, 1H), 1.99-1.93 (m, 2H), 1.73-1.65 (m, 3H), 1.53 (br s, 1H). MS (ESI): m / z 426.30 [M + H]+. Compound 24 'HNMR (400 MHz, DMSO-d6): 10.25 (br s, 1H), 7.99 (s, 1H), 7.63-7.60 (m, 1H), 7.45-7.39 (m, 2H), 7.31 (br s, 2H), 7.14-7.10 (m, 2H), 3.88 (s, 3H), 3.28-3.22 (m, 1H), 3.12-3.09 (m, 1H), 2.78-2.75 (m, 1H), 2.18-2.14 (m, 1H), 1.99-1.91 (m, 2H), 1.87-1.80 (m, 1H), 1.67-1.64 (m, 1H), 1.54-1.49 (m,lH). MS (ESI): m / z 491.3 [M-H]+. Compound 26 'HNMR (400 MHz, DMSO-d6): 10.24 (br s, 1H), 8.02 (s, 1H), 7.58-7.54 (m, 1H), 7.44-7.39 (m, 2H), 7.31 (br s, 2H), 7.27-7.24 (m, 1H), 7.13-7.07 (m, 1H), 4.03 (brs, 1H), 3.81 (s, 3H), 3.09-3.04 (m, 1H), 2.61-2.51 (m, 1H), 2.13-2.03 (m, 1H), 1.98-1.83 (m, 3H), 1.71-1.68 (m, 1H), 1.35-1.29 (m, 1H). MS (ESI): m / z 491.30 [M - H]+. Compound 28 'HNMR (400 MHz, DMSO-d6): 8 10.04 (br s, 1H), 8.04 (s, 1H), 7.58-7.54 (m, 1H), 7.437.38 (m, 2H), 7.30 (br s, 2H), 7.11 (t, J = 8.0 Hz, 1H), 6.99-6.93 (m, 2H), 2.84-2.81 (m, 1H), 2.66 (dt, J= 11.6, 3.2 Hz, 1H), 2.11 (s, 3H), 1.97-1.95 (m, 1H), 1.87-1.76 (m, 3H), 1.57-1.47 (m, 1H), 1.46-1.33 (m, 3H). MS (ESI): m / z 389.20 [M - H]’ Compound 30 1H NMR (400 MHz, DMSO-d6): 6 9.85 (br s, 1H), 8.05 (s, 1H), 7.54-7.51 (m, 1H), 7.44-7.38 (m, 2H), 7.28 (br s, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.02-6.99 (m, 2H), 2.95 (br s, 1H), 2.912,87 (m, 1H), 2.58-2.57 (m, 1H), 2.12 (s, 3H), 1.96-1.94 (m, 1H), 1.91-1.84 (m, 1H), 1.801.71 (m, 2H), 1.62-1.61 (m, 1H), 1,60-1.50 (m, 1H), 1.401.38 (m, 1H). MS (ESI): m / z 391.20 [M + H]+ Compound 32 'HNMR (400 MHz, DMSO-d6): 6 9.76 (br s, 1H), 8.07 (s, 1H), 7.43-7.38 (m, 3H), 7.31-7.29 (m, 3H), 6.92 (d, J = 1.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 3.19-3.15 (m, 1H), 2.98 (br s, 1H), 2.72-2.63 (m, 1H), 1.97-1.95 (m, 1H), 1.90-1.87 (m, 1H), 1.76-1.71 (m, 2H), 1.52-1.50 (m, 1H), 1.46-1.40 (m, 2H). MS (ESI): m / z 471.30 [M - H]’ Compound 34 'HNMR (400 MHz, DMSO-d6): 3 9.82 (br s, 1H), 7.97 (s, 1H), 7.52-7.47 (m, 1H), 7.41 (m, 2H), 7.31-7.28 (m, 2H), 7.08-7.01 (m, 1H), 6.92-6.82 (m, 2H), 3.77 (s, 3H), 3.22-3.11 (m, 1H), 2..68-2.61 (m, 1H), 1.99-1.90 (m, 1H), 1.89-1.72 (m, 2H), 1.68-1.38 (m, 4H), 0.58 (d, J = 6.5 Hz, 3H). MS (ESI): m / z 403.40 [M + H]+ Compound 36 'H NMR (400 MHz, DMSO-d6): 3 10.30 (br s, 1H), 8.14-8.13 (m, 1H), 7.78-7.74 (m, 1H), 7.51-7.46 (m, 1H), 7.34 (br s, 2H), 7.27-7.23 (m, 2H), 6.99-6.93 (m, 2H), 4.79 (t, J = 4.8 Hz, 1H), 4.70 (d, J = 4.3 Hz, 1H), 4.06 (t, J = 5.3 Hz, 1H), 3.10 (d, J = 6.2 Hz, 1H), 1.72-1.61 (m, 2H), 1.40-1.32 (m, 2H). MS (ESI): m / z 403.30 [M+ H] + Compound 37 XH NMR (400 MHz, DMSO-d6): 3 10.54 (s, 1H), 8.40 (d, J =5.5 Hz, 1H), 8.07 (d, J= 1.8 Hz, 1H), 8.03 (br s, 1H), 7.61-7.60 (m, 2H), 7.14-7.07 (m, 2H), 3.90 (s, 3H), 3.41-3.35 (m, 1H), 3.19-3.14 (m, 1H), 2.44-2.41 (m, 1H), 2.23-2.03 (m, 3H), 1.84-1.81 (m, 1H), 1.62-1.60 (m, 1H). MS (ESI): m / z 426.30 [M + H]+. Compound 38 XH NMR (400 MHz, DMSO-d6): 3 10.40 (s, 1H), 8.39 (d, J= 5.5 Hz, 1H), 8.12 (d,J= 1.8 Hz, 1H), 8.05 (br s, 1H), 7.61 (br s, 1H), 7.56-7.54 (m, 1H), 7.24-7.21 (m, 1H), 7.10-7.0, 3.92 (s, 3H), 3.45-3.43 (m, 1H), 3.28-3.27 (m, 1H), 2.70-2.63 (m, 1H), 2.42-2.39 (m, 1H), 2.142.01 (m, 2H), 1.84-1.82 (m, 1H). MS (ESI): m / z 426.30 [M + H]+. Compound 39 'H NMR (400 MHz, DMSO-d6): 10.67 (s, 1H), 8.48 (d, J= 52 Hz, 1H), 8.04 (d, J= 2.0 Hz, 1H), 7.62 (dd, J= 52, 2.0 Hz, 1H), 7.39 (br s, 2H), 7.15-7.08 (m, 1H), 7.06-7.02 (m, 1H), 3.90 (s, 3H), 3.29-3.23 (m, 1H), 3.14-3.09 (m, 1H), 2.80-2.77 (m, 1H), 2.22-2.18 (m, 1H), 2.01-1.92 (m, 2H), 1.90-1.81 (m, 1H), 1.68-1.65 (m, 1H), 1.58-1.52 (m, 1H) MS (ESI): m / z 494.10 [M + H]+ Compound 41 XH NMR (400 MHz, DMSO-d6): 10.69 (s, 1H), 8.47 (d, J= 5.4 Hz, 1H), 8.06 (d, J= 1.4 Hz, 1H), 7.58 (dd, J= 5.4, 1.7 Hz, 1H), 7.38 (br s, 2H), 7.25-7.21 (m, 1H), 7.14-7.08 (m, 1H), 4.05-4.02 (m, 1H), 3.80 (s, 3H), 3.14-3.08 (m, 1H), 2.61-2.60 (m, 1H), 2.10-1.69 (m, 4H), 1.72-1.69 (m, 1H), 1.37-1.28 (m, 1H) MS (ESI): m / z 494.30 [M + H]+. Compound 43 'H NMR (400 MHz, DMSO-d6): 3 10.68 (br s, 1H), 8.48 (d, J= 5.4 Hz, 1H), 8.01 (d, J= 1.6 Hz, 1H), 7.57-7.08 (m, 5H), 3.91 (s, 3H), 3.41-3.35(m, 1H), 3.19-3.14 (m, 1H), 2.44 (br s, 1H), 2.23-2.01 (m, 3H), 1.84-1.81 (m, 1H), 1.62-1.60 (m, 1H). MS (ESI): m / z 462.30 [M + H]+. Compound 45 XH NMR (400 MHz, DMSO-d6): 3 10.53 (s, 1H), 8.47 (d, J =5.6 Hz, 1H), 8.07 (d, J= 1.6 Hz, 1H), 7.50 (dd, J= 52 Hz, 1.6 Hz, 1H), 7.37 (br s, 2H), 7.24-7.21 (m, 1H), 7.11-7.04 (m, 1H), 3.91 (s, 3H), 3.44-3.42 (m, 1H), 3.28-3.27 (m, 1H) 2.71-2.63 (m, 1H), 2.44-2.42 (m, 2H), 2.14-2.03 (m, 2H), 1.84-1.81 (m, 1H). MS (ESI): m / z 462.20 [M + H]+. Compound 47 1H NMR (400 MHz, DMSO-d6): 5 10.72 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.57 (dd, J = 5.2, 2.0 Hz, 1H), 7.38 (br s, 2H), 7.20-7.08 (m, 2H), 4.21-4.18 (m, 1H), 3.97-3.92 (m, 4H), 3.54-3.51 (m, 2H), 3.50-3.42 (m, 1H), 3.18-3.11 (m, 1H), 1.69-1.56 (m, 2H). MS (ESI): m / z 428.30 [M + H]+ Compound 53 MS (ESI): m / z 440.5 [M + H]+ Compound 54 1H NMR (400 MHz, DMSO-d6) 5 10.24 (s, 1H), 8.02 (s, 1H), 7.59 - 7.56 (m, 1H), 7.45 -7.39 (m, 2H), 7.32 (s, 2H), 7.12 - 7.07 (s, 2H), 3.90 (s, 3H), 3.21 - 3.07 (m, 3H), 2.84 (d, J= 11.20 Hz, 1H), 2.23 (s, 3H), 2.11 - 2.01 (m, 2H), 1.70- 1.66 (dd,J= 12.80 & 3.20 Hz, 1H), 1.58 - 1.48 (m, 1H). MS (ESI): m / z 440.30 [M + H]+ Compound 55 MS (ESI): m / z 440.3 [M + H]+ Compound 59 MS (ESI): m / z 495.2 [M + H]+ Compound 63 1H NMR (400 MHz, DMSO-d6) 5 10.29 (s, 1H), (s, 1H), 8.00 (s, 1H), 7.59 - 7.56 (m, 1H), 7.45 - 740 (m, 2H), 7.31 (s, 2H), 7.14 - 7.09 (m, 2H), 3.90 (s, 3H), 3.13 - 3.11 (m, 1H), 3.00 (d,J=9.6Hz, 1H), 2.63 - 2.53 (m, 3H), 1.69- 1.63 (m, 1H), 1.55 - 1.53 (m, 1H). MS (ESI): m / z 506.40 [M + H]’ Compound 64 MS (ESI): m / z 507.13 [M + H]’ Compound 65 MS (ESI): m / z 393.3 [M + H]+ Compound 66 MS (ESI): m / z 427.3 [M + H]+ Compound 70 XH NMR (400 MHz, DMSO-d6): 3 10.51 (s, 1H), 8.46 (d,J=5.6Hz, 1H), 8.02 (d, J =2.0 Hz, 1H), 7.59 (dd, J= 2.0, 5.6 Hz, 1H), 7.33 (br s, 2H), 7.12 - 7.04 (m, 2H), 3.93 - 3.88 (m, 3H), 3.30 - 3.21 (m, 1H), 3.07 - 2.97 (m, 1H), 2.08 - 1.97 (m, 1H), 1.95 - 1.85 (m, 1H), 1.78 -1.62 (m, 1H), 1.56 - 1.39 (m, 1H), 1.25 - 1.20 (m, 1H), 1.03 - 0.87 (m, 1H), 0.43 - 0.30 (m, 4H). MS (ESI): m / z 452.1 [M + H] + Compound 71 XH NMR (400 MHz, DMSO-d6): d 10.69 (br. s., 1H), 8.47 (d, J= 5.6 Hz, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.68 - 7.56 (m, 1H), 7.36 (br. s., 2H), 7.23 - 7.02 (m, 2H), 3.96 - 3.87 (m, 3H), 3.61 - 3.50 (m, 1H), 3.03 - 2.91 (m, 1H), 2.25 - 2.15 (m, 2H), 2.14 - 1.99 (m, 3H), 1.84 - 1.69 (m, 1H) MS (ESI): m / z 462.1 [M + H] + Compound 81 'HNMR (400 MHz, DMSO-d6): 8 10.01 (s, 1H), 7.99 (s, 1H), 7.58-7.54 (m, 1H), 7.43-7.48 (m, 2H), 7.30 (br s, 2H), 7.07-7.01 (m, 2H), 3.89 (s, 3H), 3.47-3.41 (m, 1H), 2.95-2.89 (m, 1H), 1.96-1.90 (m, 1H), 1.82-1.72 (m, 3H), 1.70-1.65 (m, 4H), 1.59-1.54 (m, 2H). MS (ESI): m / z 439.3 [M + H]+. Compound 83 'HNMR (400 MHz, DMSO-d6): 6 9.76 (s, 1H), 7.94 (s, 1H), 7.47-7.36 (m, 3H), 7.19 (br s, 2H), 7.05-6.97 (m, 2H), 3.92 (s, 3H), 3.47-3.43 (m, 1H), 2.92-2.87 (m, 1H), 2.45-2.39 (m, 1H), 2.03-1.98 (m, 1H), 1.91-1.84 (m, 4H), 1.70-1.67 (m, 1H), 1.51-1.43 (m, 3H). MS (ESI): m / z 437.2 [M-H]’. Compound 87 'H NMR (400 MHz, DMSO-d6): 3 1016 (br s, 1H), 8.15 (s, 1H), 7.60-7.59 (m, 1H), 7.45-7.42 (m, 2H), 7.31 (br s, 2H), 7.07-7.00 (m, 1H), 6.70-6.84 (m, 1H),4.16-4.13 (m, 1H), 3.98 (s, 3H), 3.64-3.61 (m, 1H), 2.76-2.72 (m, 1H), 1.99-1.93 (m, 2H), 1.73-1.65 (m, 3H), 1.53 (br s, 1H). MS (ESI): m / z 426.30 [M + H]+. Compound 88 'HNMR (400 MHz, DMSO-d6): 3 9.93 (br s, 1H), 8.13 (s, 1H), 7.60-7.56 (m, 1H), 7.45-7.40 (m, 2H), 7.31(br s, 2H), 7.12-7.11 (m, 1H), 6.97-6.92 (m, 2H), 6.87-6.82 (m, 1H), 4.14 (t, J = 5.4 Hz, 1H), 3.82 (s, 3H), 3.57-3.54 (m, 1H), 2.80-2.76 (m, 1H), 1.92-1.90 (m, 2H), 1.69-1.61 (m, 3H), 1.57-1.54 (m, 1H). MS (ESI): m / z 390.30 [M + H]+. Compound 89 'H NMR (400 MHz, DMSO-d6): 6 10.17 (br s, 1H), 8.11 (s, 1H), 7.63-7.60 (m, 1H), 7.487.43 (m, 2H), 7.33(br s, 2H), 7.15-7.13 (m, 1H), 7.00-6.95 (m, 2H), 6.87-6.83 (m, 1H), 4.39 (t, J = 5.7 Hz, 1H), 3.82 (s, 3H), 3.68-3.64 (m, 1H), 3.80-3.04 (m, 1H), 2.49-2.33 (m, 2H), 2.14-2.07 (m, 3H). MS (ESI): m / z 426.30 [M + H]+. Compound 117 'H NMR (400 MHz, DMSO-d6): 3 12.36 (br s, 1H), 7.95 (br m, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.39 (br s, 1H), 7.16 (br s, 1H), 7.10 (m, 1H), 7.02-6.96 (m, 1H), 3.79 (s, 3H), 3.60 (br m, 2H), 2.49-2.41 (m, 2H), 2.21-2.06 (m, 2H), 1.90-1.87 (m, 1H), 1.78 (br m, 1H). MS (ESI): m / z 422.40 [M + H]+ Compound 138 'HNMR (400 MHz, DMSO-d6): ¢511.66 (br s, 1H), 9.02 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.35 (d, J = 5.8 Hz, 1H), 7.13-7.03 (m, 2H), 6.11 (s, 1H), 3.80-3.60 (m, 4H), 3.28-3.20 (m, 1H), 2.49-2.40 (m, 2H), 2.21-2.06 (m, 2H), 1.91-1.88 (m, 1H), 1.77-1.73 (m, 1H). MS (ESI): m / z 407.40 [M + H]’. Compound 139 'HNMR (400 MHz, DMSO-d6): 3 12.02 (s, 1H), 8.63 (d, J= 5.2 Hz, 1H), 7.64 (d, J= 5.6 Hz, 1H), 7.20 - 6.98 (m, 2H), 6.24 (s, 1H), 3.82 (s, 3H), 3.71 - 3.53 (m, 1H), 3.31 - 3.24 (m, 1H), 2.48 - 2.35 (m, 2H), 2.23 - 2.02 (m, 2H), 1.95 - 1.84 (m, 1H), 1.82 - 1.61 (m, 1H). MS (ESI): m / z 432.2 [M + H] +. Compound 140 'HNMR (400 MHz, DMSO-d6): ¢5 11.59 (s, 1H), 8.41 (d, J= 4.8 Hz, 1H), 7.39 (br s, 1H), 7.34 (d, J= 5.5 Hz, 1H), 7.19-7.14 (m, 2H), 7.09-7.04 (m, 1H), 6.08 (s, 1H), 3.83 (s, 3H), 3.60 (br s, 1H), 3.27-3.22 (m, 1H), 2.42-2.38 (m, 2H), 2.19-2.07 (m, 2H), 1.92-1.88 (m, 1 H), 1.75-1.60 (m, 1H). MS (ESI): m / z 450.4 [M + H]+ Compound 141 'HNMR (400 MHz, DMSO-d6): 3 12.20 (s, 1H), 8.62 - 8.46 (m, 1H), 7.78 - 7.50 (m, 3H), 7.17 - 7.14 (m, 1H), 7.09 - 7.02 (m, 1H), 6.34 (s, 1H), 3.84 (s, 3H), 3.72 - 3.53 (m, 1H), 3.39 - 3.25 (m, 1H), 2.47 - 2.36 (m, 2H), 2.25 - 2.04 (m, 2H), 1.96 - 1.85 (m, 1H), 1.81 - 1.59 (m, 1H) MS (ESI): m / z 486.0 [M + H] + Compound 148 'HNMR (400 MHz, DMSO-d6): 3 13.39 (br s, 1H), 11.97 (br s, 1H), 7.40 (d, J= 7.6 Hz, 1H), 7.26 - 7.10 (m, 1H), 7.07 - 6.95 (m, 1H), 6.70 - 6.61 (m, 1H), 6.57 (d, J= 7.2 Hz, 1H), 3.72 (s, 3H), 3.60 - 3.53 (m, 2H), 2.45 - 2.35 (m, 1H), 2.30 - 2.23 (m, 1H), 2.20 - 2.08 (m, 2H), 1.89 - 1.62 (m, 2H). MS (ESI): m / z 423.3 [M + H] + Compound 153 'H NMR (400 MHz, DMSO-d6): 8 10.69 (s, 1H), 8.47 (dd, J = 5.2, 0.4 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 5.2, 2.0 Hz, 1H), 7.38 (br s, 2H), 7.22-7.15 (m, 1H), 7.09-7.06 (m, 1H), 3.28-3.24 (m, 1H), 3.16-3.14 (m, 1H), 2.45-2.41 (m, 1H), 2.29-2.28 (m, 3H), 2.23-2.14 (m, 1H), 2.08-2.07 (m, 2H), 1.86-1.82 (m, 1H), 1.60-1.54 (m, 1H). MS (ESI): m / z 446.30 [M + H]+ Compound 154 'H NMR (400 MHz, DMSO-d6): 3 10.52 (s, 1H), 8.40 (d, J= 5.5 Hz, 1H), 8.07 (d, J= 2.0 Hz, 1H), 8.02 (br s, 1H), 7.61-7.55 (m, 2H), 7.14-7.07 (m, 2H), 3.91-3.90 (m, 3H), 3.41-3.34 (m, 1H), 3.19-3.13 (m, 1H), 2.39-2.38 (m, 1H), 2.23-2.01 (m, 3H), 1.84-1.76 (m, 1H), 1.681.52 (m, 1H). MS (ESI): m / z 426.30 [M + H]+. Compound 155 'HNMR (400 MHz, DMSO-d6): 6 10.77 (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.58(dd, J = 5.6, 2.0 Hz, 1H), 7.47-7.39 (m, 3H), 7.28-7.25 (m, 1H), 3.54-3.49 (m, 1H), 3.28-3.19 (m,lH), 2.27-2.12 (m, 3H), 1.92-1.88 (m, 1H), 1.54 (br m, 1H). MS (ESI): m / z 466.3 [M + H]+ Compound 156 'HNMR (400 MHz, DMSO-d6): 3 11.67-11.65 (m, 1H), 9.02 (s, 1H), 8.52 (d, J = 5.7 Hz, 1H), 7.37 (d, J = 5.8 Hz, 1H), 6.73-6.58 (m, 2H), 56.00-5.98 (m, 1H), 3.80-3.51 (m, 5H), 2.40-2.30 (m, 2H), 2.29-2.01 (m, 3H), 1.90-1.78 (m, 1H). MS (ESI): m / z 407.4 [M + H]+. Compound 164 'HNMR (400 MHz, DMSO-d6): 8 8.43 (d, J = 5.3 Hz, 1H), 6 8.01 (d, J = 1.5 Hz, 1H), 7.537.52 (m, 1H), 7.19-7.12 (m, 1H), 7.07-7.04 (m, 1H), 4.09-4.07 (m, 1H), 3.25-3.23 (m, 1H), 2.78-2.73 (m, 1H), 2.30-2.29 (m, 3H), 2,23-2,17 (m, 2H). Compound 165 'HNMR (400 MHz, DMSO-d6): 3 10.68 (br s, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 5.5, 2.0 Hz, 1H), 7.43-7.37 (3H), 7.24-7.20 (m, 1H), 4.37 (t, J = 6.1 Hz, 1H), 3.69-3.66 (m, 1H), 3.02-2.96 (m, 1H), 2.57-2.56 (m, 2H), 2.20-2.15 (m, 2H). MS (ESI): m / z 467.30 [M + H]+ Compound 166 'H NMR (400 MHz, DMSO-d6): 3 10.73 (br s, 1H), 8.52 (d, J = 5.4 Hz, 1H), 8.08 (br s, 1H), 7.79-7.71 (m, 1H), 7.59 (dd, J = 5.4, 2.0 Hz, 1H), 7.42 (br s, 3H), 4.21-4.18 (m, 1H), 3.213.07 (m, 1H), 2.90 (br s, 1H), 2.59-2.57 (m, 2H), 2.19-2.02 (m, 2H). MS (ESI): m / z 501.30 [M + H]+ Compound 168 'H NMR (400 MHz, DMSO-d6): 3 10.75 (br s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.18 (d,J = 1.8 Hz, 1H), 7.71 (dd, J= 5.5, 2.0 Hz, 1H), 7.41 (brs, 2H), 7.10 (t, J= 8.30 Hz, 1H), 6.92-6.90 (m, 1H), 6.89-6.87 (m, 2H), 4.74-4.72 (m, 1H), 3.79-3.72 (m, 1H), 3.66-3.63 (m, 1H), 2.722.61 (m, 1H), 2.59 (br s, 1H), 2.20-2.13 (m, 2H). MS (ESI): m / z 477.3 [M+ H] + Compound 169 'H NMR (400 MHz, DMSO-d6): 3 10.69 (brs, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.18 (d,J = 1.8 Hz, 1H), 7.69 (dd, J= 5.5, 2.0 Hz, 1H), 7.39 (br s, 2H), 6.69 (t, J= 8.2 Hz, 1H), 6.54 (d, J= 7.7 Hz, 1H), 6.44 (dd, J= 1.1, 0.8 Hz, 1H), 4.68 (t, J= 5.1 Hz, 1H), 3.78-3.68 (m, 1H), 3.473.44 (m, 1H), 2.15-2.07 (m, 2H), 1.65 (s, 3H), 1.53 (s, 3H), 1.26-1.23 (m, 2H) MS (ESI): m / z 469.10 [M + H]+ Compound 170 'HNMR (400 MHz, DMSO-d6): 3 10.68 (br s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.19 (d, J = 1.72 Hz, 1H) 7.72-7.70 (dd, J = 5.4, 2.0 Hz, 1H), 6.75 (t, J = 8.3 Hz, 1H), 6.59-6.53 (m, 2H), 5.95 (dd, J = 7.5, 1.0 Hz, 2H), 4.70 (t, J = 4.9 Hz, 1H), 3.73-3.67 (m, 1H), 3.52-3.49 (m, 1H), 2.63-2.58 (m, 1H), 2.44-2.39 (m, 1H), 2.15-2.03 (m, 2H). MS (ESI): m / z 441.30 [M + H]+. Compound 173 'H NMR (400 MHz, DMSO-d6): 3 10.64 (s, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 5.6 Hz, 1H), 7.60 (dd, J = 5.6, 2.0 Hz, 1H), 7.43-7.35 (m, 4H), 7.28-7.24 (m, 1H), 7.08-7.04 (m, 1H), 4.38 (t, J = 6.0 Hz, 1H), 3.71-3.66 (m, 1H), 2.99-2.94 (m, 1H), 2.46-2.45 (m, 2H, merged with the solvent signal), 2.24-2.15 (m, 2H). MS (ESI): m / z 431.20 [M + H]+. Compound 174 XH NMR (400 MHz, DMSO-d6): 3 10.67 (brs, 1H), 8.51 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 5.4, 2.0 Hz, 1H), 7.40 (br s, 2H), 7.36-7.20 (m, 3H), 4.40 (t, J = 6.1 Hz, 1H), 3.75-3.70 (m, 1H), 3.30-2.98 (m, 1H), 2.56-2.54 (m, 1H), 2.20-2.16 (m, 2H). MS (ESI): m / z 465.00 [M + H]+ Compound 177 'H NMR (400 MHz, DMSO-d6): 3 10.75 (br s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 7.72 (dd, J = 7.7, 1.6 Hz, 1H), 7.67 (dd, J = 5.5, 2.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.41 (br s, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.19-7.13 (m, 1H), 4.65 (t, J = 5.3 Hz, 1H), 3.39-3.37 (m, 1H), 2.71-2.62 (m, 1H), 2.59-2.55 (m, 1H), 2.26-2.20 (m, 2H), 2.18-2.15 (m, 2H). MS (ESI): m / z 422.30 [M + H] Compound 178 'H NMR (400 MHz, DMSO-d6): 3 10.56 (br s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.35 (br s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 6.0 Hz, 1H), 7.04-7.01 (m, 1H), 4.09-4.06 (m, 1H), 3.14-3.12 (m, 1H), 2.87-2.80 (m, 2H), 2.77-2.71 (m, 2H), 2.27 (br s, 1H), 2.19-2.11 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H). MS (ESI): m / z 425.15 [M+H]+ Compound 179 XH NMR (400 MHz, DMSO-d6): 3 10.60 br (s, 1H), 8.48 (d, J = 5.6 Hz, 1H), 8.05 (d, J = 1.6 Hz 1H), 7.73-7.71 (m, 1H), 7.68-7.61 (m, 2H), 7.60-7.55 (m, 1H), 7.41 (br s, 2H), 7.38-7.31 (m, 1H), 4.28-4.17 (m, 1H), 3.39-3.36 (m, 1H), 2.86-2.79 (m, 1H), 2.53-2.51 (m, 1H), 2.442.35 (m, 1H), 2.18-2.08 (m, 2H). MS (ESI): m / z 465.30 [M + H]+ Compound 180 ‘H-NMR (400 MHz, DMSO-d6): 8 10.65 (br s, 1H), 8.54 (d, J = 5.4 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 7.76 (dd, J = 5.5, 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.40 (br s, 2H), 7.12 (d, J = 8.8 Hz, 2H), 5.01-4.99 (m, 1H), 3.98-3.95 (m, 1H), 3.59-3.52 (m, 1H), 2.83 (br m, 1H), 2.562.52 (m, 1H), 2.11-2.03 (brm, 2H). MS (ESI): m / z 465.30 [M + H]+ Compound 181 XH NMR (400 MHz, DMSO-d6): 3 10.63 (br s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.59-7.49 (m, 3H), 7.41 (br s, 2H), 4.18-4.15 (m, 1H), 3.37 (br s, 1H), 2.87-2.80 (m, 1H), 2.48-2.32 (m, 2H), 2.34-2.12 (m, 2H). MS (ESI): m / z 483.30 [M + H]+ Compound 182 'H NMR (400 MHz, DMSO-d6): 3 10.62 (brs, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.11 (d, J = 1.7 Hz, 1H), 7.60 (dd, J = 5.4, 1.9 Hz, 1H), 7.46-7.39 (m, 4H), 7.15 (dt, J = 8.4, 2.96 Hz, 1H), 4.32 (t, J = 6.1 Hz, 1H), 3.64-3.61 (m, 1H), 2.96-2.90 (m, 1H), 2.16-2.07 (m, 2H). MS (ESI): m / z 449.30 [M + H]+. Compound 183 'HNMR (400 MHz, DMSO-t / 6): 3 9.94 (br s, 1H), 8.54 (d, J= 5.6 Hz, 1H), 8.18 (d, J= 2.0 Hz, 1H), 7.82 (dd, J= 2.0, 5.6 Hz, 1H), 7.40 (br s, 2H), 7.12 - 6.81 (m, 2H), 3.87 - 3.66 (m, 4H), 2.92 - 2.73 (m, 1H), 2.34 - 2.02 (m, 4H), 1.79 - 1.54 (m, 1H), 1.25 - 1.11 (m, 3H) MS (ESI): m / z 476.0 [M + H] + Compound 184 'HNMR (400 MHz, DMSO-d6): 5 11.62 (br s, 1H), 8.42 (d, J = 5.8 Hz, 1H), 7.44-7.33 (m, 4H), 7.20 (br s, 1H), 6.07 (s, 1H), 3.76-3.71 (m, 1H), 3.36 (br m, 1H), 2.49-2.42 (m, 2H), 2.22-2.01 (m, 2H), 1.98-1.91 (m, 1H), 1.69-1.60 (m, 1H). Compound 185 'H NMR (400 MHz, DMSO-d6): ¢5 11.61 (brs, 1H), 8.41 (d, J = 5.7 Hz, 1H), 7.54-7.7.51-(m, 1H), 7.41 (br s, 1H), 7.34 (dd, J = 5.8 Hz, 1H), 7.28 (dd, J = 8.8, 2.6 Hz, 1H), 7.20 (br s, 1H), 7.17-7.13 (m, 1H), 6.05 (s, 1H), 3.74-3.68 (m, 1H), 3.33-3.17 (m, 1H), 2.67-2.55 (m, 1H), 2.43-2.37 (m, 1H), 2.30-2.02 (m, 2H), 2.00-1.90 (m, 1H), 1.71-1.59 (m, 1H). MS (ESI): m / z 436.30 [M + H]+ Compound 186 'HNMR (400 MHz, DMSO-d6): 5 11.70 (s, 1H), 8.39 (d, J = 4.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.17-7.11 (m, 3H), 6.11 (s, 1H), 3.54-3.48 (m, 1H), 3.26-3.25 (m, 1H), 2.42-2.39 (m, 1H), 2.22-2.09 (m, 6H), 1.93-1.90 (m, 1H), 1.59-1.56 (m, 1H). MS (ESI): m / z 434.05 [M + H]+ Compound 187 'HNMR (400 MHz, DMSO-d6): 5 11.53 (br s, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.39-7.29 (m, 3H), 7.17 (s, 1H), 6.91-6.85 (m, 2H), 6.11 (s, 1H), 3.47-3.42 (m, 1H), 3.32-3.28 (m, 1H), 2.41-2.38 (m, 2H), 2.28 (s, 3H), 2.19-2.05 (m, 2H), 1.92-1.88 (m, 1H), 1.59-1.56 (m, 1H). MS (ESI): m / z 416.20 [M + H]+. Compound 188 'HNMR (400 MHz, CD3OD): 3 8.45 (d, J= 6.0 Hz, 1H), 7.46 (d, J= 5.2 Hz, 1H), 7.18 -6.96 (m, 1H), 6.94 - 6.77 (m, 1H), 6.23 (s, 1H), 3.90 (s, 3H), 3.78 - 3.58 (m, 1H), 3.27 - 3.22 (m, 1H), 2.56 - 2.43 (m, 1H), 2.41 - 2.19 (m, 2H), 1.98 - 1.86 (m, 1H), 1.82 - 1.54 (m, 1H), 1.11 (d, J= 6.8 Hz, 3H). MS (ESI): m / z 464.1 [M + H] + Compound 189 'HNMR (400 MHz, DMSO-d6): 3 11.62 (br. s., 1H), 8.41 (d, J= 5.6 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J= 5.6 Hz, 1H), 7.20 (s, 1H), 7.16-7.10 (m, 2H), 6.15 (s, 1H), 3.61 -3.50(m, 1H), 3.29 - 3.22 (m, 1H), 2.48 - 2.31 (m, 3H), 2.23 (d, J= 2.0 Hz, 3H), 1.93 - 1.81 (m, 1H), 1.43 -1.28 (m, 1H), 1.02 (d, J= 2.0 Hz, 3H) MS (ESI): m / z 448.2 [M + H] + Compound 190 'HNMR (400 MHz, DMSO-t / e): 5 8.47 (d, J= 6.0 Hz, 1H), 7.47 (d, J= 6.0 Hz, 1H), 7.32 -7.24 (m, 1H), 7.24 - 7.10 (m, 1H), 6.22 (s, 1H), 3.90 - 3.72 (m, 1H), 3.49 - 3.33 (m, 1H), 2.57 - 2.47 (m, 1H), 2.47 - 2.28 (m, 1H), 2.17 - 2.03 (m, 2H), 1.96 - 1.89 (m, 1H), 1.57 - 1.47 (m, 1H), 1.38 - 1.32 (m, 1H), 1.00 (t, J= 7.6 Hz, 3H) MS (ESI): m / z 482.3 [M + H]+ Compound 191 'H NMR (400 MHz, DMSO-d6): 3 11.50 (br s, 1H), 8.40 (d, J= 6.0 Hz, 1H), 7.58 - 7.29 (m, 2H), 7.26 - 6.83 (m, 3H), 5.91 (s, 1H), 3.80 (s, 3H), 3.53 - 3.45 (m, 1H), 3.02 - 2.83 (m, 1H), 1.99 (m, 1H), 1.86 (m, 1H), 1.77 (m, 3H), 1.22 - 1.08 (m, 2H), 0.95 (d, J= 6.0 Hz, 3H). MS (ESI): m / z 428.1 [M + H]+ Compound 192 XH NMR (400 MHz, DMSO-t / 6): 3 8.52 - 8.40 (m, 1H), 7.54 - 7.43 (m, 1H), 7.30 - 7.23 (m, 1H), 7.21 -7.11 (m, 1H), 6.14-6.03 (m, 1H), 3.72 -3.60 (m, 1H), 3.02-2.91 (m, 1H), 2.18 -2.10 (m, 1H), 2.01 - 1.85 (m, 3H), 1.81 - 1.75 (m, 1H), 1.29 - 1.21 (m, 2H), 1.07 - 0.98 (m, 3H) MS (ESI): m / z 432.1 [M + H]+ Compound 193 XH NMR (400 MHz, DMSO-t / e): 5 11.52 (br s, 1H), 8.40 (d, J= 6.0 Hz, 1H), 7.40 (d, J= 5.6 Hz, 2H), 7.26 - 7.04 (m, 3H), 5.94 (s, 1H), 3.35 - 3.27 (m, 1H), 3.01 - 2.89 (m, 1H), 2.20 (s, 3H), 2.04 - 1.92 (m, 1H), 1.90 - 1.59 (m, 4H), 1.25 - 1.00 (m, 2H), 0.92 (d, J= 6.4 Hz, 3H). MS (ESI): m / z 412.2 [M + H]+ Compound 194 'H NMR (400 MHz, DMSO-d6) 3...
Claims
1. A compound of Formula (I)R3(I)whereinW1 is CRX;W2 is CRxorN;each Rx is H or C1-3 alkyl;Lisa bond or is -C(0)NH- where the nitrogen of -C(0)NH- is attached to ring A;ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 5- to 10membered heterocyclic ring or N-oxide thereof;ring B is a 3- to 11-membered cycloalkylene optionally fused to a benzo group or a 5- to 10-membered heterocycloalkylene ring optionally fused to a benzo group;ring C is aryl, phenyl fused to HET, or phenyl fused to CYC, and where (R^n is substituted on any substitutable ring atom;R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl, ethyl, n-propyl, or isopropyl; halo, in some embodiments, fluoro, chloro, or bromo; Ci-Ce haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl or cyclobutyl; C1-C3 alkoxy, in some embodiments methoxy or ethoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-methoxy; halo-Ci-Cs alkoxy, in some embodiments, halo-Ci alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; C2-C4 alkynyl, in some embodiments, ethynyl; and hydroxy;R2, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl, ethyl, isopropyl, or tert-butyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in someembodiments, cyclopropyl, cyclobutyl, or cyclopentyl,; cyano; -C(0)Ci-6alkyl; -C(O)Ci-ehaloalkyl; -C(O)C3-6 cycloalkyl; -C(O)aryl, and aryl, in some embodiments, phenyl or naphthyl; and 4- to 6-membered heteroaryl, in some embodiments, pyridinyl or pyrimidinyl; wherein the C3-C6 cycloalkyl, aryl, and heteroaryl, each alone or as part of another group, are optionally substituted with 1, 2, or 3 R2a groups independently selected from halo, -CN, Ci-Ce alkyl, and Ci-Ce haloalkylR3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -C00H, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)N(R)2, -S(0)2NHR,0 o 9S 1111 1 HhC I xCi-C3-alkyl R । "N R-S(O)2Ci-Ce-alkyl, , —L- , Ci-Ce alkoxy, -NH2,amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-Csalkyl, Cs-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl wherein each R is independently selected from hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo;R3a, independently in each instance, is hydrogen, oxo, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl;n is 0, 1,2, 3, or 4;p is 0, 1,2, 3, or 4;q is 0, 1, 2, or 3;or a pharmaceutically acceptable salt thereof and / or an isomer thereof; wherein the compound is not l-methyl-2-(3-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl)quinolin-4(lH)-one; 2-(3-(4-methoxyphenyl)-l,2,3,4-tetrahydronaphthalen-2-yl)-l-methylquinolin-4(lH)-one; or 2-(3-(4-chlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)-l-methylquinolin-4(lH)-one.
2. The compound of claim 1, whereinW1 is CH;W2 is CH orN;ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 5- to 10membered heterocyclic ring or N-oxide thereof;ring B is a 3- to 10-membered cycloalkylene optionally fused to a benzo group or a 5- to 10-membered heterocycloalkylene ring optionally fused to a benzo group;R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; C1-C3 haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-methoxy; halo-Ci-Cs alkoxy, in some embodiments, haloCi alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; and C2-C4 alkynyl, in some embodiments, ethynyl;R2, independently in each instance, is selected from C1-C3 alkyl, in some embodiments, methyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; and aryl, in some embodiments, phenyl;R3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -C00H, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)NH2, -S(0)2NHR,0 11-S(O)2Ci-C6-alkyl, HN_l_Cl’C3’alky\ Ci-C6 alkoxy, -NH2, amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-Csalkyl, Cs-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, and wherein R is hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo;p is 0, 1, 2, or 3;or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
3. The compound of claim 2, whereinW1 is CH;W2 is CH orN;ring A is phenyl; a 5- to 10-membered heteroaryl or N-oxide thereof; or a 6- to 10membered heterocyclic ring or N-oxide thereof;ring B is a 3- to 10-membered cycloalkylene optionally fused to a benzo group or a 5- to 10-membered heterocycloalkylene ring optionally fused to a benzo group;R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; C1-C3 haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-methoxy; halo-Ci-Cs alkoxy, in some embodiments, haloCi alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; and C2-C4 alkynyl, in some embodiments, ethynyl;R2, independently in each instance, is selected from C1-C3 alkyl, in some embodiments, methyl; halo, in some embodiments, fluoro or chloro; C1-C3 haloalkyl, in some embodiments, C1-C2 haloalkyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; and aryl, in some embodiments, phenyl;R3 is selected from -H, -CN, halo, -OH, oxo, -B(0H)2, -C00H, Ci-Ce alkoxycarbonyl, Ci-C6 alkyl, hydroxy-Ci-C6-alkyl, -C(=NH)NH2, -C(0)NH2, -S(0)2NHR,O 11-S(O)2Ci-C6-alkyl, HN J„Cl'C3'alky\ Ci-C6 alkoxy, -NH2, amino-Ci-C6alkyl, -NHC(O)Ci-3alkyl, -NHC(0)NH2, -NHS(O)2NH2, -NHC(=NH)NH2, halo-Ci-Csalkyl, Cs-Ce-cycloalkyl, 3- to 6-membered heterocycloalkyl, and wherein R is hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl; where the Cs-Cecycloalkyl and the 3- to 6-membered heterocycloalkyl are optionally substituted with one -NH2; and wherein the alkyl in amino-Ci-Cealkyl is optionally further substituted with 1, 2, 3, or 4 halo;p is 0, 1, 2, or 3;or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R1, independently in each instance, is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -F, -Cl, -Br, -OMe, -OEt, -O-propyl, -OCD3, -OCF3, -OCHF2, -OCH2CF3, -CF3, phenyl, -CN, oxetanyl, pyridyl, pyridazinyl, -CHCH2, -CCH, and hydroxy.
5. The compound of any one of claim 1-4, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R1, independently in each instance, is selected from methyl, ethyl, propyl, cyclopropyl, -F, -Cl, -Br, -OMe, -OEt, -O-propyl, -OCD3, -OCF3, -OCHF2, -OCH2CF3, -CF3, phenyl, -CN, oxetanyl, pyridyl, pyridazinyl, -CHCH2, and -CCH.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R1, independently in each instance, is selected from -Me, -Et, -CH(CH3)2, -F, -Cl, -Br, -OMe, -OEt, -OCH(CH3)2, -OCD3, -OCF3,7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein n is 1, 2, or 3; in some embodiments n is 1; in some embodiments n is 2; or in some embodiments n is 3.
8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R2, independently in each instance, is selected from -CH3, -CH2CH3, -CH(CH3)2, C(CH3)3, -F, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyano, -C(O)Ci-6alkyl, -C(O)Ci-6haloalkyl, -C(O)cyclohexyl, -C(O)phenyl, phenyl, napthyl, pyridinyl, and pyrimidinyl; wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (alone or as part of -C(O)cyclohexyl), phenyl (alone or as part of -C(O)phenyl), napthyl, pyridinyl, and pyrimidinyl, are optionally substituted with 1, 2, or 3 R2a groups independently selected from halo, -CN, Ci-Ce alkyl, and Ci-Ce haloalkyl.
9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R2, independently in each instance, is selected from -CH3, -F, -CF3, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; in some embodiments, R2, independently in each instance, is selected from halo and C1-C3 haloalkyl; wherein Ar is aryl, phenyl fused to HET, or phenyl fused to CYC, and where (R^n is substituted on any substitutable ring atom; R1, independently in each instance, is selected from Ci-Ce alkyl, in some embodiments, methyl or propyl; halo, in some embodiments, fluoro, chloro, or bromo; C1-C3 haloalkyl, in some embodiments, Ci haloalkyl; cyano; aryl, in some embodiments, phenyl; C3-C6 cycloalkyl, in some embodiments, cyclopropyl; C1-C3 alkoxy, in some embodiments methoxy; deutero-Ci-Cs alkoxy, in some embodiments, deutero-methoxy; halo-Ci-Cs alkoxy, in some embodiments, halo-Ci alkoxy or halo-C2 alkoxy; 5- to 6-membered heteroaryl, in some embodiments, pyridinyl, or pyridazinyl; 4- to 6-membered heterocyclic, in some embodiments, oxetanyl; C2-C4 alkenyl, in some embodiments, vinyl; and C2-C4 alkynyl, in some embodiments, ethynyl.
10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein p is 0, 1, or 2; in some embodiments p is 0; in some embodiments p is 1; or in some embodiments p is 2.
11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R3 is not -H and R3 is selected from -CN, -OH, oxo, Ci-Ce alkoxycarbonyl, Ci-Ce alkyl, hydroxy-Ci-Ce-alkyl,0II-C(=NH)NH2, -C(O)N(R)2, -S(O)2NHR, -S(O)2Ci-C6-alkyl, HN J~CrC3'alkyl,O fl R R , Ci-Ce alkoxy, -NH2, amino-Ci-Cealkyl, and 5- to 6-memberedheteroaryl wherein each R is independently hydrogen, C1-C3 alkyl, or Cs-Cscycloalkyl.
12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R3 is not -H and R3 is selected from -CN, -OH, oxo, Ci-Ce alkoxycarbonyl, Ci-Ce alkyl, hydroxy-Ci-Ce-alkyl,o II-C(=NH)NH2, -C(O)NH2, -S(O)2NHR, -S(O)2Ci-C6-alkyl, HN™LCl'C3'alkyl, Ci-C6 alkoxy, -NH2, and amino-Ci-Cealkyl, and wherein R is hydrogen or Cs-Cscycloalkyl; in some embodiments, R3 is selected from -CN, -OH, Ci-Ce alkoxycarbonyl, -C(O)NH2, -S(O)2NH2, -COOEt, and oxo.
13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R3 is selected from -CN, -OH, oxo, Ci-Ce o iialkoxycarbonyl, -C(0)NH2, -S(O)2NH2, -S(O)2Ci-C6-alkyl, ^-1-01-03-311^ and Ci-Ce alkoxy; in some embodiments, R3 is selected from -CN, -OH, oxo, -COOEt, o ii-C(O)NH2, -S(O)2NH2, -S(O)2CH3, HN™LCH3, and -OMe.
14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein R3a, independently in each instance, is -H, halo, oxo, or C1-C3 alkyl; in some embodiments, R3a, independently in each instance, is -H, -F, oxo, or -CH3.
15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein q is 0, 1, or 2; in some embodiments q is 0; in some embodiments q is 1; or in some embodiments q is 2.
16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein ring A is phenyl substituted with R3, pyridyl or an N-oxide thereof substituted with R3, imidazopyridyl substituted with R3, benzimidazolyl substituted with R3, benzoxazolyl substituted with R3, benzoisoxazolyl substituted with R3, oxazolopyridinyl substituted with R3, pyridinonyl (i.e. where R3a is oxo) substituted with R3, pyrimidinonyl (i.e. where R3a is oxo) substituted with R3, pyridazinonyl (i.e. where R3a is oxo) substituted with R3, pyridazinyl substituted with R3, isoindolinonyl (i.e. where R3a is oxo) substituted with R3, indazolyl substituted with R3, indazolonyl (i.e. where R3a is oxo) substituted with R3, benzoisothiazolyl substituted with R3, quinolinonyl (i.e. where R3a is oxo) substituted with R3,naphthyridinonyl (i.e. where R3a is oxo) or an N-oxide thereof substituted with R3; thiophenyl substituted with R3, where ring A is substituted with (R3a)q; in some embodiments, R3 is not -H.
17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein ring A is phenyl substituted with R3, pyridyl substituted with R3, imidazopyridyl substituted with R3, benzimidazolyl substituted with R3, benzoxazolyl substituted with R3, oxazolopyridinyl substituted with R3, pyridinonyl (i.e. where R3 is oxo), pyrimidinonyl (i.e. where R3 is oxo), quinolinonyl (i.e. where R3 is oxo), or naphthyridinonyl (i.e. where R3 is oxo); where ring A is substituted with (R3a)q; in some embodiments, R3 is not -H.
18. The compound of any one of the preceding claims, or a pharmaceutically acceptablesalt thereof and / or an isomer thereof, wherein ring A is issubstituted withsubstituted with R3,OJM]lY^nwith R3, H (i.e. where R3a is oxo) substituted with R3,(i.e. whereR3a is oxo) substituted with R3,(i.e. where R3a is oxo) substituted withoxide thereof substituted with R3,(i.e. where R3a is oxo) substituted withsubstituted with R3; where ring A is substituted with (R3a)q; and wheredesignates attachment to L.
19. The compound of any one of the preceding claims, or a pharmaceutically acceptablesalt thereof and / or an isomer thereof, wherein ring A is(i.e. where R3 is oxo),substituted with R3, or(i.e. where R3 is oxo); wherering A is substituted with (R3a)q; and where L designates attachment to L.
20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein ring B is a 3- to 11-membered cycloalkylene (in an embodiment, 3- to 10-membered cycloalkylene); or a 6-, 7-, or 10membered heterocycloalkyl; where ring B is substituted with (R2)P.
21. The compound of any one of the preceding claims, or a pharmaceutically acceptableattachment to L, c designates attachment to ring C, and designatesattachment to R2.
22. The compound of any one of the preceding claims, or a pharmaceutically acceptableorW1IW*z' ; where ring B is substituted with (R2)P; and wheredesignates attachment to L, designates attachment to ring C, anddesignates attachment to R2.
23. The compound of any one of the preceding claims, or a pharmaceutically acceptablesalt thereof and / or an isomer thereof, wherein ring C is 6- or 10-membered aryl,w2designates attachment to W2.; wherein ring C is substituted with (R1)^ where24. The compound of any one of the preceding claims, or a pharmaceutically acceptable(R1)nsalt thereof and / or an isomer thereof, wherein ring C issubstituted with (R^n,W2withW2W2(R%w2substituted with (R1)^ orsubstituted with (R^n,w2substituted with0.substituted with (R1)^substitutedsubstituted with (R1)^ wheredesignates attachment to W2.
25. The compound of any one of the preceding claims, or a pharmaceutically acceptablesalt thereof and / or an isomer thereof, wherein ring C issubstituted with (R2)n,W2substituted with (R2)n,with (R2)n,W2substituted with (R2)n,substituted with (R1)^ where ' designates attachment to W2.
26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein W2 is CRT27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein W2 is CH.
28. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein W2 is N.
29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein W1 is CH.
30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; and q is 0 or 1.
31. The compound of any one of the preceding claims, or a pharmaceutically acceptablesalt thereof and / or an isomer thereof, wherein when ring C isin someembodiments, ring C is selected from the group consistingdesignates attachment to W2.
32. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein Lisa bond.
33. The compound of any one of the preceding claims, or a pharmaceutically acceptableOsalt thereof and / or an isomer thereof, wherein L is W H ; where w indicates attachment to W1, and A indicates attachment to ring A.
34. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (X):(X)or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
35. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (XI):(XI)or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
36. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (L):R3(L)or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
37. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (LI):(LI)or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein the ring C naphthyl is substituted with (R^.
38. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (LII):(LII)or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein the ring C 2,3-dihydro-lH-inden-4-yl is substituted with (R1^.
39. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (LIII):(LIII)or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein the ring C 2,3-dihydro-lH-inden-5-yl is substituted with (R1^.
40. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (LIV):R3q(LIV)or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein the ring C l,2,3,4-tetrahydronaphthalen-5-yl is substituted with (R1^.
41. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (LV):(LV)or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein the ring C l,2,3,4-tetrahydronaphthalen-6-yl is substituted with (R1^.
42. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (LVI):(LVI)or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein the ring C 2,3-dihydrobenzo[b][l,4]dioxin-5-yl is substituted with (R1^.
43. The compound of any one of claims 1 to 33, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (LVII):(LVII),or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein the ring C benzo[d][l,3]dioxole is substituted with (R1^.
44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein45. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, wherein46. The compound of any one of claims 1 to 34 and 36, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (CV):(CV)or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
47. The compound of any one of claims 1 to 34 and 36, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (CVI):(CVI)or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
48. The compound of any one of claims 1 to 32, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (CVII):(CVII)or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
49. The compound of any one of claims 1 to 32, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof and / or an isomer thereof, is a compound of Formula (CVIII):(CVIII)or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
50. A compound of Table A-l, Table A-2, or Table A-3 or a pharmaceutically acceptable salt thereof and / or an isomer thereof.
51. A pharmaceutical composition comprising the compound of any one of preceding claims, or a pharmaceutically acceptable salt thereof and / or an isomer thereof, and a pharmaceutically acceptable carrier.
52. The pharmaceutical composition of claim 51, wherein the composition is an oral or injectable composition, optionally wherein the injectable composition is a subcutaneously injectable composition.
53. A method for the treatment of a condition associated with voltage-gated sodium channel function, including Nav1.8, in a subject, comprising administering a therapeutically or prophylactically effective amount of the compound of any one of claims 1-50 or the pharmaceutical composition of claim 51 or 52.
54. The method of claim 53, wherein the subject is a human.
55. The method of claim 53 or 54, wherein the condition is pain or wherein the condition is associated with pain.
56. The method of claim 53 or 54, wherein the condition is pain.
57. The method of claim 53 or 54, wherein the condition is associated with pain.
58. The method of any one of claims 53-57, wherein the condition is selected from the group consisting of pain associated with erythromelalgia, pain associated with diabetic peripheral neuropathy, paroxysmal extreme pain disorder, complex regional painsyndrome, pain associated with trigeminal neuralgia, pain associated with multiple sclerosis, pain associated with arthritis (including osteoarthritis), pain associated with postherpetic neuralgia, cancer pain, pain associated with cluster headache, pain associated with migraine, pain associated with sciatica, pain associated with endometriosis, pain associated with fibromyalgia, postsurgical pain, subacute pain, chronic pain, pain and / or discomfort associated with dry eye syndrome, pain associated with (acute) corneal injuries or abrasions, acute ocular pain, chronic ocular pain, pain associated with corneal infections, 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, a mood disorder, psychosis, pain associated with amyotropic lateral sclerosis, glaucoma, ischemia, a spasticity disorder, and obsessive compulsive disorder.
59. The method of claim 53 or 54, wherein the condition is selected from the group consisting of acute pain, subacute pain, post-surgical pain, and ocular pain.
60. A method of inhibiting NAV1.8 comprising contacting NAV1.8 with a compound of any one of claims 1-50.