IP Library › Granted Patent US 12,195,445

Granted Patent B2

US 12,195,445 · App. 17/752,419 · Granted Jan 14, 2025

2-amino-N-heteroaryl-nicotinamides as Na

Inventors: Ashok Arasappan (Bridgewater, NJ); Ian M. Bell (Harleysville, PA); Michael J. Breslin (Drexel Hill, PA); Christopher James Bungard (Lansdale, PA); Christopher S. Burgey (Ambler, PA); Harry R. Chobanian (Westfield, NJ); Jason M. Cox (Rancho Santa Fe, CA); Anthony T. Ginnetti (Perkasie, PA); Deodial Guy Guiadeen (Chesterfield, NJ); Kristen L. G. Jones (Oreland, PA); Mark E. Layton (Harleysville, PA); Hong Liu (Hillsborough, NJ); Jian Liu (Norristown, PA); James J. Perkins (Churchville, PA); Shawn J. Stachel (Perkasie, PA); Linda M. Suen-Lai (Philadelphia, PA); Zhe Wu (Blue Bell, PA)

Assignee: Merck Sharp & Dohme LLC

C07D401/12 C07D401/14 C07D409/14 C07D413/14 C07D417/14 C07D471/04 C07D471/08 C07D487/04 C07D491/04 C07D491/048 C07D495/04

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,195,445
App. No.: 17/752,419
Granted: Jan 14, 2025
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Na v 1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Na v 1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.

Claims (311)

1. A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein

A is selected from:

(1) pyridine,

(2) pyrimidine,

(3) pyrazine,

(4) indazole,

(5) imidazo[1,2-a]pyridine,

(6) pyrrolo[3,2-c]pyridine,

(7) pyrrolo[2,3-b]pyridine,

(8) pyrazole,

(9) thiophene, and

(10) 1,2,4-oxadiazole,

wherein A is unsubstituted or substituted with one to four substituents selected from R a , provided that both A and B are not pyridine;

B is selected from:

(1) pyrazine,

(2) pyridine,

(3) pyrimidine, and

(4) pyridazine,

wherein each B is unsubstituted or substituted with one to three substituents selected from R b ;

R 1 is selected from:

(1) —SO 3 H,

(2) —SO 2 NH 2,

(3) —SO 2 C 1-6 alkyl,

(4) —SO 2 NH—C 1-6 alkyl,

(5) —SO 2 C 3-6 cycloalkyl,

(6) —C(O)NH 2,

(7) —CO 2 H,

(8) —CN,

(9) halogen,

(10) —OH, and

(11) —OC 1-6 alkyl,

wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d ;

R 2 is hydrogen;

R 3 is selected from:

(1) cyclohexane,

(2) cycloheptane,

(3) pyrrolidine,

(4) azetidine,

(5) piperidine,

(6) piperazine,

(7) azepane,

(8) morpholine,

(9) thiomorpholine,

(10) oxazepane,

(11) isoindoline,

(12) dihydroisoquinoline,

(13) azabicyclo[2.2.1]heptane,

(14) azabicyclo[3.1.1]heptane,

(15) azabicyclo[4.1.0]heptane,

(16) azabicyclo[3.2.1]octane,

(17) azabicyclo[3.2.0]heptane,

(18) azaspiro[2.5]octane,

(19) dihydrothieno[3,2-c]pyridine,

(20) dihydroimidazo[1,2-a]pyrazine, and

(21) hexahydrofuro[3,2-b]pyrrole,

wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c ;

each R a is selected from:

(1) —OC 1-6 alkyl,

(2) halogen,

(3) —OH,

(4) oxo,

(5) —CN,

(6) —C 3-6 cycloalkyl, and

(7) —C 2-5 cycloheteroalkyl,

wherein halogen is F or C 1 , and wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to six substituents selected from halogen, OH, NH 2 , NH(C 1-6 alkyl) and N(C 1-6 alkyl) 2 ;

each R b is independently selected from the group consisting of:

(1) —CF 3 ,

(2) —CHF 2 ,

(3) —OCHF 2 ,

(4) OCH 2 CF 3 ,

(5) —OCF 3 ,

(6) CN,

(7) halogen,

(8) —Si(C 1-6 alkyl) 3 ,

(9) —C 1-6 alkyl,

(10) —OC 1-6 alkyl,

(11) —C 3-6 cycloalkyl,

(12) —C 2-6 cycloheteroalkyl,

(13) —C 2-6 alkyl-C 3-6 cycloalkyl,

(14) —C 2-6 alkynyl-C 3-6 cycloalkyl, and

(15) heteroaryl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R f ;

each R c is independently selected from:

(1) —CF 3 ,

(2) —CH 2 CF 3 ,

(3) —CHF 2 ,

(4) —OCHF 2 ,

(5) —OCF 3 ,

(6) CN,

(7) OXO,

(8) —OH,

(9) halogen,

(10) —C 1-6 alkyl,

(11) —C 2-6 alkenyl,

(12) —C 2-6 alkynyl,

(13) —C 3-6 cycloalkyl,

(14) —C 2-6 cycloheteroalkyl,

(15) —C 1-6 alkyl-C 3-6 cycloalkyl,

(16) —C 1-6 alkyl-C 2-6 cycloheteroalkyl,

(17) —C 1-6 alkyl-aryl,

(18) —C 1-6 alkyl-heteroaryl,

(19) —C 1-6 alkenyl-C 3-6 cycloalkyl,

(20) —C 1-6 alkenyl-aryl,

(21) —C 1-6 alkenyl heteroaryl,

(22) —C 1-6 alkenyl-C 2-6 cycloheteroalkyl,

(23) —C 2-6 alkynyl-C 3-6 cycloalkyl,

(24) —C 2-6 alkynyl-C 2-6 cycloheteroalkyl,

(25) —C 2-6 alkynyl-aryl,

(26) —C 2-6 alkynyl heteroaryl,

(27) —OC 1-6 alkyl,

(28) —OC 2-6 alkenyl,

(29) —OC 2-6 alkynyl,

(30) —OC 3-6 cycloalkyl,

(31) —OC 2-6 heterocycloalkyl,

(32) —OC 1-6 alkyl-cycloalkyl,

(33) —OC 1-6 alkyl-cycloheteroalkyl,

(34) —OC 1-6 alkyl-aryl,

(35) —OC 1-6 alkyl-heteroaryl,

(36) —S(O) m R L ,

(37) —S(O)R L ,

(38) —S—R L ,

(39) —C 1-6 alkyl-S(O) m R L ,

(40) —C(O)R L ,

(41) —C(O)C 1-6 alkyl-R L ,

(42) —OC(O)R L ,

(43) —CO 2 R L ,

(44) aryl, and

(45) heteroaryl,

wherein each R c is unsubstituted or substituted with one to five substituents selected from R g ;

R d is independently selected from:

(1) hydrogen,

(2) halogen,

(3) OH,

(4) OXO,

(5) —C 1-6 alkyl,

(6) —OC 1-6 alkyl,

(7) NH 2 ,

(8) NH(C 1-6 alkyl), and

(9) N(C 1-6 alkyl) 2 ;

each R f is selected from:

(1) halogen,

(2) —C 1-6 alkyl,

(3) —OH,

(4) —OC 1-6 alkyl,

(5) —OC 3-6 cycloalkyl,

(6) —OC 2-6 cycloheteroalkyl,

(7) CN,

(8) —NH 2 ,

(9) —NH(C 1-6 alkyl),

(10) —NH(C 3-6 cycloalkyl),

(11) —NH(C 2-6 cycloheteroalkyl),

(12) —N(C 1-6 alkyl) 2 ,

(13) —N(C 3-6 cycloalkyl) 2 , and

(14) —N(C 2-6 cycloheteroalkyl) 2 ,

wherein each alkyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each R g is selected from:

(1) halogen,

(2) C 1-6 alkyl,

(3) —OH,

(4) —OC 1-6 alkyl,

(5) —S(O)m-C 1-6 alkyl,

(6) —CN,

(7) —CF 3 ,

(8) —OCHF 2 , and

(9) —OCF 3 ,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each R L is selected from:

(1) —C 1-6 alkyl,

(2) —C 2-6 alkenyl,

(3) —C 3-6 cycloalkyl,

(4) —C 2-6 cycloheteroalkyl,

(5) aryl, and

(6) heteroaryl,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from: —C 1-6 alkyl, —C 3-6 cycloalkyl, —OH, —OC 1-6 alkyl, —OC 3-6 cycloalkyl, halogen, cyano, and —S(O) 2 CH 3 ; and

and each m is independently 0, 1 or 2.

2. The compound according to claim 1 wherein A is pyridine, wherein pyridine is unsubstituted or substituted with one to four substituents selected from R a ,

provided that both A and B are not pyridine;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein B is selected from:

(1) pyridine,

(2) pyrimidine, and

(3) pyridazine,

wherein each B is unsubstituted or substituted with one to three substituents selected from R b ;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein R 1 is selected from:

(1) —SO 2 NH 2 ,

(2) —C(O)NH 2 , and

(3) —OH;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R 3 is selected from:

(1) pyrrolidine,

(2) azetidine,

(3) piperidine,

(4) piperazine,

(5) azepane,

(6) morpholine,

(7) thiomorpholine,

(8) oxazepane,

(9) isoindoline,

(10) dihydroisoquinoline,

(11) azabicyclo[2.2.1]heptane,

(12) azabicyclo[3.1.1]heptane,

(13) azabicyclo[4.1.0]heptane,

(14) azabicyclo[3.2.1]octane,

(15) azabicyclo[3.2.0]heptane,

(16) azaspiro[2.5]octane,

(17) dihydrothieno[3,2-c]pyridine,

(18) dihydroimidazo[1,2-a]pyrazine, and

(19) hexahydrofuro[3,2-b]pyrrole,

wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c ;

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 3 is selected from:

(1) piperidine,

(2) azepane, and

(3) morpholine,

wherein R 3 is unsubstituted or substituted with one to six substituents selected from R c ;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein

A is selected from:

(1) pyridine,

(2) pyrimidine,

(3) pyrazine,

(4) indazole,

(5) imidazo[1,2-a]pyridine,

(6) pyrrolo[3,2-c]pyridine,

(7) pyrrolo[2,3-b]pyridine,

(8) pyrazole,

(9) thiophene, and

(10) 1,2,4-oxadiazole,

wherein A is unsubstituted or substituted with one to four substituents selected from R a ,

provided that both A and B are not pyridine;

B is selected from:

(1) pyridine,

(2) pyrimidine, and

(3) pyridazine,

wherein each B is unsubstituted or substituted with one to four substituents selected from R b ;

R 1 is selected from:

(1) —SO 3 H,

(2) —SO 2 NH 2 ,

(3) —SO 2 C 1-6 alkyl,

(4) —SO 2 NH—C 1-6 alkyl,

(5) —SO 2 C 3-6 cycloalkyl,

(6) —C(O)NH 2 ,

(7) —CO 2 H,

(8) —CN,

(9) halogen,

(10) —OH, and

(11) —OC 1-6 alkyl,

wherein each alkyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R d ;

R 2 is hydrogen;

R 3 is selected from:

(1) pyrrolidine,

(2) azetidine,

(3) piperidine,

(4) piperazine,

(5) azepane,

(6) morpholine,

(7) thiomorpholine,

(8) oxazepane,

(9) isoindoline,

(10) dihydroisoquinoline,

(11) azabicyclo[2.2.1]heptane,

(12) azabicyclo[3.1.1]heptane,

(13) azabicyclo[4.1.0]heptane,

(14) azabicyclo[3.2.1]octane,

(15) azabicyclo[3.2.0]heptane,

(16) azaspiro[2.5]octane,

(17) dihydrothieno[3,2-c]pyridine,

(18) dihydroimidazo[1,2-a]pyrazine, and

(19) hexahydrofuro[3,2-b]pyrrole,

wherein R 3 is unsubstituted or substituted with one to eight substituents selected from R c ;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 wherein

B is pyridine, wherein pyridine is unsubstituted or substituted with one to three substituents selected from R b ;

R 1 is selected from:

(1) —SO 2 NH 2 ,

(2) —C(O)NH 2 , and

(3) —OH;

R 2 is hydrogen;

R 3 is selected from:

(1) piperidine,

(2) azepane, and

(3) morpholine,

wherein R 3 is unsubstituted or substituted with one to six substituents selected from R c ;

or a pharmaceutically acceptable salt thereof.

10. A compound selected from:

1) 2-(4,4-difluoropiperidin-1-yl)-N-(6-sulfamoylpyrazin-2-yl)-5-(trifluoromethyl)-nicotinamide;

2) 2-(4,4-difluoropiperidin-1-yl)-N-(4-hydroxypyrimidin-2-yl)-5-(trifluoromethyl)-nicotinamide;

3) 2-(4,4-difluoroazepan-1-yl)-N-[1-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;

4) 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl-N-[1-(methylsulfonyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide;

5) 5-chloro-2-(4,4-difluoroazepan-1-yl)-4,6-dimethyl-N-[1-(methylsulfonyl)-1H-pyrazol-4-yl]pyridine-3-carboxamide;

6) N-{1-[(2-aminoethyl)sulfonyl]-1H-pyrazol-4-yl}-5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methylpyridine-3-carboxamide;

7) 2-(4,4-difluoroazepan-1-yl)-N-[1-(methylsulfonyl)-1H-indazol-3-yl]-5-(trifluoromethyl)-pyridine-3-carboxamide;

8) 2-(4,4-difluoroazepan-1-yl)-N-[1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-5-(trifluoromethyl)pyridine-3-carboxamide;

9) N-[1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl]-2-(4,4-difluoroazepan-1-yl)-5-(trifluoro-methyl)pyridine-3-carboxamide;

10) N-[5-cyclopropyl-1-(methylsulfonyl)-1H-pyrazol-4-yl]-2-(4,4-difluoroazepan-1-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

11) 2-cyclopropyl-4-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyrimidine-5-carboxamide;

12) 6-cyclopropyl-3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)pyridazine-4-carboxamide;

13) 2-(azepan-1-yl)-N-(3-cyano-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide;

14) 2-(azepan-1-yl)-N-(2-methyl-5-sulfamoylthiophen-3-yl)-5-(trifluoro-methyl)pyridine-3-carboxamide;

15) 4-(4,4-difluoroazepan-1-yl)-2-methyl-N-(2-sulfamoylpyridin-4-yl)pyrimidine-5-carboxamide;

16) 3-(4,4-difluoroazepan-1-yl)-N-(2-sulfamoylpyridin-4-yl)-6-(trifluoromethyl)-pyridazine-4-carboxamide; and

17) 2-(azepan-1-yl)-N-(3-bromoimidazo[1,2-a]pyridin-6-yl)-5-(trifluoromethyl)-pyridine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A method of treating a disorder, condition or disease that is responsive to the inhibition of Nav1.8 channel activity in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

13. The method of claim 12 wherein the disorder is selected from: pain disorder, a cough disorder, an acute itch disorder or chronic itch disorder.

14. The method of claim 13 wherein the disorder is a pain disorder.

15. The method of claim 14 wherein the pain disorder is selected from: acute pain, inflammatory pain, or neuropathic pain.

Assignments (2)

MERGER Recorded May 24, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 060004/0784 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 24, 2022

From: ARASAPPAN, ASHOK; CHOBANIAN, HARRY R; COX, JASON M; GUIADEEN, DEODIAL GUY; LIU, HONG; LIU, JIAN; BELL, IAN M.; BRESLIN, MICHAEL J.; BUNGARD, CHRISTOPHER JAMES; BURGEY, CHRISTOPHER S.; GINNETTI, ANTHONY T.; JONES, KRISTEN L.G.; LAYTON, MARK E.; PERKINS, JAMES J.; STACHEL, SHAWN J.; SUEN-LAI, LINDA M.; WU, ZHE

To: MERCK SHARP & DOHME CORP.

Reel/Frame 060389/0190 →

Continuity (3)

Division 16669598 · Oct 31, 2019

Provisional Application 62754742 · Nov 2, 2018

Related Publication 20220289710A1 · Sep 15, 2022

References Cited (99)

US 8202877B2 · Maechling et al. · 2012 [cited by applicant]

US 8519137B2 · Joshi et al. · 2013 [cited by applicant]

US 8703768B2 · Bleicher · 2014 [cited by examiner]

US 9051270B2 · Hadida-Ruah et al. · 2015 [cited by applicant]

US 9108903B2 · Hadida-Ruah et al. · 2015 [cited by applicant]

US 9163042B2 · Anderson et al. · 2015 [cited by applicant]

US 9783501B2 · Tadida-Ruah et al. · 2017 [cited by applicant]

US 20070249579A1 · Wang et al. · 2007 [cited by applicant]

US 20100298267A1 · Maechling et al. · 2010 [cited by applicant]

US 20140213592A1 · Chilov et al. · 2014 [cited by applicant]

BR 112020000553A2 · 2020 [cited by applicant]

EP 3470404A1 · 2019 [cited by applicant]

JP 6431779A · 1989 [cited by applicant]

JP 2008519034A · 2008 [cited by applicant]

JP 2012517966A · 2012 [cited by applicant]

JP 2017522346A · 2017 [cited by applicant]

JP 2017214290A · 2017 [cited by applicant]

JP 2020526561A · 2020 [cited by applicant]

WO 2005013914A2 · 2005 [cited by applicant]

WO 2006016316A1 · 2006 [cited by applicant]

WO 2006050476A2 · 2006 [cited by applicant]

WO 2007127635A2 · 2007 [cited by applicant]

WO 2009049180A2 · 2009 [cited by applicant]

WO 2009049181A1 · 2009 [cited by applicant]

WO 2009049183A1 · 2009 [cited by applicant]

WO 2010043315A1 · 2010 [cited by applicant]

WO WO2010043052A1 · 2010 [cited by examiner]

WO 2010094406A1 · 2010 [cited by applicant]

WO WO2011043371A1 · 2011 [cited by examiner]

WO WO2011154327A1 · 2011 [cited by examiner]

WO 2012085650A1 · 2012 [cited by applicant]

WO 2013061205A2 · 2013 [cited by applicant]

WO 2014058691A1 · 2014 [cited by applicant]

WO 2014068988A1 · 2014 [cited by applicant]

WO 2014120808A1 · 2014 [cited by applicant]

WO 2014120815A1 · 2014 [cited by applicant]

WO 2014120820A1 · 2014 [cited by applicant]

WO 2014209841 · 2014 [cited by applicant]

WO 2015010065A1 · 2015 [cited by applicant]

WO 2015089361A1 · 2015 [cited by applicant]

WO 2016016316A1 · 2016 [cited by applicant]

WO 2016039448A1 · 2016 [cited by applicant]

WO 2017209322A1 · 2017 [cited by applicant]

WO 2018050677A1 · 2018 [cited by applicant]

WO 2018213426A1 · 2018 [cited by applicant]

WO 2019014352A1 · 2019 [cited by applicant]

Hanisak et al. Bioorganic and Medicinal Chemistry Letters (2016), 26(17), 4250-4255. [cited by examiner]

Bagal, Sharan K. et al., Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain, ACS Med. Chem. Lett., 2015, 650-654, 6. [cited by applicant]

Baker et al., Involvement of Na + Channels in Pain Pathways, Trends in Pharmacological Sciences, 2001, 27-31, 22, No. 1. [cited by applicant]

Bashford, Katherine E. et al., The Bohlmann-Rahtz route to functionalised pyridine scaffolds and their use in library synthesis, Tetrahedron Letters, 2003, 1627-1629, 44(8). [cited by applicant]

Belkouch, Mounir et al., Functional up-regulation of Nav1.8 sodium channel in Aβ afferent fibers subjected to chronic peripheral inflammation, Journal of Neuroinflammation, 2014, 1-17, 11:45. [cited by applicant]

Bennett, David L. et al., Painful and painless channelopathies, Lancet Neurol., 2014, 587-599, 13(6). [cited by applicant]

Black, Joel A. et a., Multiple Sodium Channel Isoforms and Mitogen-Activated Protein Kinases Are Present in Painful Human Neuromas, Ann Neurol, 2008, 644-653, 64(6). [cited by applicant]

Black, Joel A. et al., Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis, Proc. Natl. Acad. Sci. USA… [cited by applicant]

Carter et al., Advances in the Management of Neuropathic Pain, Physical Medicine and Rehabilitation Clinics of North America, 2001, 447-459, 12(2). [cited by applicant]

Catterall, William A. et al., The chemical basis for electrical signaling, Nature Chemical Biology, 2017, 455-463, 13(5). [cited by applicant]

Colloca, Luana et al., Neuropathic pain, Nature Reviews Disease Primers, 2017, 1-19, 3:17002. [cited by applicant]

Coward, K et al., Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states, Pain, 2000, 41-50, 85. [cited by applicant]

Emery, Edward C. et al., Novel SCN9A Mutations Underlying Extreme Pain Phenotypes: Unexpected Electrophysiological and Clinical Phenotype Correlations, Journal of Neuroscience, 2015, 7674-7681, 35(20). [cited by applicant]

Flaxman et al., Years Lived with Disability (YLDs) for 1160 Sequelae of 289 Diseases and Injuries 1990-2010: A Systematic Analysis for the Global Burden of Disease Study 2010, Lancet, 2012, 2163-2196, 380. [cited by applicant]

Goldin et al., Nomenclature of Voltage-Gated Sodium Channels, Neuron, 2000, 365-368, 28. [cited by applicant]

Goldin, Diveristy of Mammalian Voltage-Gated Sodium Channels, Ann NY Acad Sci., 1999, 38-50, 30, 868. [cited by applicant]

Han, Chongyang et al., The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability, J Neurol Neurosurg Psychiatry, 2014, 499-505, 85(5). [cited by applicant]

Han, Chongyang, et al., Sodium channel Nav1.8, Emerging links to human disease, Neurology, 2016, 473-483, 86. [cited by applicant]

Huang, Jianying et al., Small-Fiber Neuropathy Nav1.8 Mutation Shifts Activation to Hyperpolarized Potentials and Increases Excitability of Dorsal Root Ganglion Neurons, Journal of Neuroscience, 2013, 14087-14097, 33(35… [cited by applicant]

Ikoma et al., The Neurobiology of Itch, Nature Reviews, 2006, 535-547, 7. [cited by applicant]

Jarvis, Michael F. et al., A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat, PNAS, 2007, 8520-8525, 104. [cited by applicant]

Kers, Inger et al., Structure and activity relationship in the (S)-N-chroman-3-ylcarboxamide series of voltage-gated sodium channel blockers, Bioorganic & Medicinal Chemistry Letters, 2012, 5618-5624, 22(17). [cited by applicant]

Kist, Andreas M. et al., SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing, PLOS One, 2016, pp. 1-19, 11(9):e0161789. [cited by applicant]

Kort, Michael E. et al., Discovery and Biological Evaluation of 5-Aryl-2-furfuramides, Potent and Selective Blockers of the Nav1.8 Sodium Channel with Efficacy in Models of Neuropathic and Inflammatory Pain, J. Med. Che… [cited by applicant]

Liu, Yang et al., VGLUT2-Dependent Glutamate Release from Nociceptors Is Required to Sense Pain and Suppress Itch, Neuron, 2010, 543-556, 68(3). [cited by applicant]

Luo, Jialie et al., Molecular and cellular mechanisms that initiate pain and itch, Cellular and Molecular Life Sciences, 2015, 3201-3223, 72. [cited by applicant]

McGaraughty, Steve et al., A Selective Nav1.8 Sodium Channel Blocker, A-803467 [5-(4-Chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], Attenuates Spinal Neuronal Activity in Neuropathic Rats, JPET, 2008, 1204-12… [cited by applicant]

McMahon et al., Itching for an Explanation, Trends Neuroscience, 1992, 497-501, 15. [cited by applicant]

Miyazaki, Tohru et al., Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators, Bioorganic & Medicinal Chemistry Letters, 2019, 815-820, 29(23). [cited by applicant]

Nair, Parameswaran et al., Airway Hyperresponsiveness in Asthma: Measurement and Clinical Relevance, J Allergy Clin Immunol Pract, 2017, 649-659, 5(3). [cited by applicant]

Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority, or the Declaration, mailed Feb. 3, 2020, 7 pages. [cited by applicant]

Payne, Claire Elizabeth et al., A novel selective and orally bioavailable NAv1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability, British Journal of Pharmacology, 2015, 2654-2670, 17… [cited by applicant]

Riol-Blanco, Lorena et al., Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation, Nature, 2014, 157-161, 510. [cited by applicant]

Roostaei, Tina et al., Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis, Neurology, 2016, 410-417, 86(5). [cited by applicant]

Schmelz et al., Specific C-Receptors for Itch in Human Skin, J. of Neuroscience, 1997, 8003-8008, 17(20). [cited by applicant]

Schreiber, Anne K. et al., Diabetic neuropathic pain: Physiopathology and treatment, World Journal of Diabetes, 2015, 432-444, 6(3). [cited by applicant]

Shields, Shannon D. et al., A Channelopathy Contributes to Cerebellar Dysfunction in a Model of Multiple Sclerosis, Ann Neurol, 2012, 186-194, 71(2). [cited by applicant]

Shields, Shannon D. et al., Oral Administration of PF-01247324, a Subtype-Selective Nav1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis, PLoS One, 2015, 1-8, 10(3). [cited by applicant]

Sun, Shaoyi et al., The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Nav1.7, Bioorganic & Medicinal Chemistry Letters, 2014, 4397-4401, 24(18). [cited by applicant]

Talbot, Sebastien et al., Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation, Neuron, 2015, 341-354, 87(2). [cited by applicant]

Van Loey et al., Itching Following Burns: Epidemiology and Predictors, British J. Dermatology, 2008, 95-100, 158. [cited by applicant]

Wood, John N et al., Voltage-gated sodium channels, Current Opinion in Pharmacolgoy, 2001, 17-21, 1. [cited by applicant]

Yiangou, Y. et al., SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves, FEBS Letters, 2000, 249-252, 467. [cited by applicant]

Yu et al., Overview of the Voltage-Gated Sodium Channel Family, Genome Biology, 2003, 207, 4. [cited by applicant]

Zeng, Chao et al., Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studie… [cited by applicant]

Zhang, Xu-Feng et al., A-887826 is a structurally novel, potent and voltage-dependent Nav1.8 sodium channel blocker that attenuates neuropathic tactile allodynia in rats, Neuropharmacology, 2010, 201-207, 59. [cited by applicant]

Meurice, Nathalie et al., Structural Conservation in Band 4.1, Ezrin, Radixin, Moesin (FERM) Domains as a Guide to Identify Inhibitors of the Proline-Rich Tyrosine Kinase 2, J. Med. Chem., 2010, 669-677, 53. [cited by applicant]

Meurice, Nathalie et al., Supporting Information—Structural conservation in FERM domains as a guide to identify inhibitors of the focal adhesion kinase Pyk2, Journal of Medicinal Chemistry, 2010, S1-S18, 53. [cited by applicant]

Vlaar, Cornelis P. et al., Design, synthesis and biological evaluation of new carbazole derivatives as anti-cancer and anti-migratory agents, Bioorganic & Medicinal Chemistry Letters, 2018, 884-890, 26. [cited by applicant]

CAS RN. 1022814-74-9 (May 27, 2008 Entered STN), 1 page. [cited by applicant]

Camille G. Wermuth, Molecular Variations Based on Isosteric Replacements, The Practice of Medicinal Chemistry, Chapter 13, 189-214, 2003. [cited by applicant]

RN-2176589-55-0 dated Feb. 20, 2018, RN-2186126-31-6 dated Mar. 7, 2018, RN-2190063-54-6 dated Mar. 13, 2018, RN-2209817-54-7 dated Apr. 10, 2018, RN-2061218-61-7 dated Jan. 29, 2017 (3 pages). [cited by applicant]

Search result of STN:RN 21753353-22-5 dated Feb. 18, 2018, RN 2175797-30-3 dated Feb. 19, 2018, RN 2176276-62-1 dated Feb. 19, 2018, RN 2177313-40-3 dated Feb. 21, 2018, RN 2177393-26-7 dated Feb. 21, 2018, RN 1192603-9… [cited by applicant]

Cited By (1)

US 12,612,383