# US 12,110,287 B2 · Heterocyclic derivatives as Nav1.7 and Nav1.8 blockers

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- Number: US 12,110,287 B2
- Document ID: US12110287B2
- Status: Granted
- Kind: B2
- Application number: 17/417,182
- Filed: 2019-12-26
- Published: 2022-02-17
- Granted: 2024-10-08
- Earliest claimed: 2018-12-26
- Assignees: RaQualia Pharma Inc.
- Applicants: RaQualia Pharma Inc.
- Inventors: Tatsuya Yamagishi; Kiyoshi Kawamura; Yuji Shishido; Ryuichi Yamaguchi; Mikio Morita; Norikazu Gaja
- Web page: https://patentgrep.com/patent/US12110287B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 31/395: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to heterocyclic derivatives which have blocking activities of voltage gated sodium channels as the Nav1.7 and Nav1.8 channels, and which are useful in the treatment or prevention of disorders and diseases in which voltage gated sodium channels are involved. The invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which voltage gated sodium channels are involved.

## Claims

### Claim 1

A compound of the following formula (I):
wherein:
A is phenyl, pyridyl, or quinolyl;
R1 is selected from the group consisting of: C1-6 alkyl, —O—C1-6 alkyl, and fluorobenzyloxy; wherein the C1-6 alkyl or the —O—C1-6 alkyl, is substituted with one or more fluorines;
R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) —OC1-6 alkyl, and (6) —CN; wherein the C1-6 alkyl or the —O—C1-6 alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
P is 0, 1, 2, 3, or 4;
when p is two or more, each R2 is the same or different;
R1 and R2 may substitute anywhere on the A ring;
n is 1, 2, or 3;
Z is CH, CR3, or N;
R3 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, and (5) —O—C1-6 alkyl;
q is 0, 1, 2, or 3; when q is two or more, each R3 is the same or different;
R4 is selected from the group consisting of:
(1) C1-6 alkyl and (2) C3-7 cycloalkyl, wherein the C1-6 alkyl or the C3-7 cycloalkyl is unsubstituted or substituted with one or more substituents independently selected form the group consisting of: halogen, hydroxyl, C1-6 alkyl, —O—C1-6 alkyl, and C3-7 cycloalkyl;
R5a and R5b are independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, and (4) C1-6 alkyl, which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
R5a and R5b may substitute anywhere on the carbon atoms of the heterocyclic ring;
when R5a and R5b substitute at the same position, R5a may form a 3 to 6 membered cycloalkyl ring with R5b; and
R5c, is (1) hydrogen or (2) C1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound as described in claim 1, wherein the compound of the formula (I) is represented by a compound of the following formula (II):
wherein:
W is CH, CR2 or N;
R1 is selected from the group consisting of: —CF3, —CHF2, —OCF3, —OCH2CF3, and fluorobenzyloxy;
R2 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) —O—C1-6 alkyl, and (6) —CN;
n is 1, 2, or 3;
Z is CH, CR3, or N;
R3 is independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, and (5) —O—C1-6 alkyl;
R4 is selected from the group consisting of: (1) C1-6 alkyl and (2) C3-7 cycloalkyl, wherein the C1-6 alkyl or the C3-7 cycloalkyl is unsubstituted or substituted with one or more substituents independently selected form the group consisting of: halogen, hydroxyl, C1-6 alkyl, —O—C1-6 alkyl, and C3-7 cycloalkyl;
R5a and R5b are independently selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, and (4) C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
R5a and R5b may substitute anywhere on the carbon atoms of the heterocyclic ring;
when R5a and R5b substitute at the same position, R5a may form a 3 to 6 membered cycloalkyl ring with R5b;
R5c is (1) hydrogen or (2) C1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound as described in claim 1, wherein the compound of the formula (I) is represented by a compound of the following formula (III):
wherein:
W is CH or N;
R1 is —CF3 or —OCF3;
R2 is selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, (5) —O—C1-6 alkyl, and (6) —CN;
n is 1, 2, or 3;
Z is CH or N;
R3 is selected from the group consisting of:
(1) hydrogen, (2) halogen, (3) hydroxyl, (4) C1-6 alkyl, and (5) —O—C1-6 alkyl;
R4 is selected from the group consisting of: (1) C1-6 alkyl and (2) C3-7 cycloalkyl, wherein the C1-6 alkyl or the C3-7 cycloalkyl is unsubstituted or substituted with one or more substituents independently selected form the group consisting of: halogen and hydroxyl;
R5a and R5b are independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, and (4) C1-6 alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen and hydroxyl;
R5a and R5b may substitute anywhere on the carbon atoms of the heterocyclic ring;
when R5a and R5b substitute at the same position, R5a may form a 3 to 6 membered cycloalkyl ring with R5b;
R5c is (1) hydrogen or (2) C1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compound as described in claim 3 wherein:
W is N;
R1 is —CF3;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound as described in claim 1, which is selected from the group consisting of:
(S)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-methyl-6-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-methyl-6-propionamidoisonicotinamide;
(R)-2-isobutyramido-N-(1-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-methyl-6-propionamidoisonicotinamide;
(R)-2-propionamido-N-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-methyl-6-propionamido-N-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclobutanecarboxamido)pyrimidine-4-carboxamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-propionamidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-isobutyramidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclobutanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(S)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(S)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramidopyrimidine-4-carboxamide;
(S)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(S)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-propionamidoisonicotinamide;
(S)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(S)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)-2-acetamido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
N-((3R*,4R*)-1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-hydroxypiperidin-3-yl)-2-isobutyramidoisonicotinamide;
2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-methylpiperidin-3-yl)isonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-methylpiperidin-3-yl)-2-propionamidoisonicotinamide;
N-((3R,5S)-1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
(R)-2-propionamido-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
N-((3R*,4R*)-1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-hydroxypyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)-2-acetamido-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-2-isobutyramidoisonicotinamide;
2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-6-methylisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-6-methylisonicotinamide;
(R)-2-isobutyramido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-6-methylpyrimidine-4-carboxamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-ethoxy-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-6-methylisonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)-2-isobutyramido-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)-2-(cyclopropanecarboxamido)-6-methyl-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)-2-isobutyramido-6-methyl-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)—N-(1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
(R)-2-isobutyramido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-isobutyramido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
N-((3S,4R)-1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluoropiperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
N-((3S,4R)-1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-fluoropiperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclobutanecarboxamido)isonicotinamide;
(R)-2-butyramido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-pivalamidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(difluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-((4-fluorobenzyl)oxy)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)piperidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-((4-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-((4-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-2-(2-hydroxy-2-methylpropanamido)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(7-(trifluoromethyl)quinolin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-isobutyramido-N-(1-(7-(trifluoromethyl)quinolin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-methyl-6-propionamidoisonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-isobutyramidoisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)-2-methyl-6-propionamidoisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)-2-butyramido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-isobutyramido-6-methylpyrimidine-4-carboxamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-6-methylisonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)-2-acetamido-N-(1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)pyrimidine-4-carboxamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)piperidin-3-yl)pyrimidine-4-carboxamide;
(R)—N-(1-(3-fluoro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(3-fluoro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-methyl-6-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-6-methylisonicotinamide; and
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The compound as described in claim 5, which is selected from the group consisting of:
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-methyl-6-propionamidoisonicotinamide;
(R)-2-propionamido-N-(1-(5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclobutanecarboxamido)pyrimidine-4-carboxamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-propionamidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-isobutyramidopyrimidine-4-carboxamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclobutanecarboxamido)pyrimidine-4-carboxamide;
(R)-2-acetamido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-methylpiperidin-3-yl)isonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-6-methylpiperidin-3-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-2-isobutyramidoisonicotinamide;
2-acetamido-N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-6-methylisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)azetidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)piperidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)-2-isobutyramido-6-methyl-N-(1-(3-methyl-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)isonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
(R)-2-isobutyramido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-isobutyramido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-6-methylisonicotinamide;
(R)-2-butyramido-N-(1-(3-methoxy-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)isonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)piperidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)pyrrolidin-3-yl)-2-propionamidoisonicotinamide;
(R)—N-(1-(3-chloro-5-((4-fluorobenzyl)oxy)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)pyrrolidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-methyl-6-propionamidoisonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-propionamidoisonicotinamide;
(R)-2-acetamido-N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-6-methylisonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptan-7-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)-2-acetamido-N-(1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)isonicotinamide;
(R)-2-(cyclopropanecarboxamido)-N-(1-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)pyrimidine-4-carboxamide;
(R)—N-(1-(3-fluoro-4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)isonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)pyrimidine-4-carboxamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-isobutyramidoisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-isobutyramido-6-methylisonicotinamide;
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-propionamidoisonicotinamide; and
(R)—N-(1-(2-chloro-4-(trifluoromethoxy)phenyl)piperidin-3-yl)-2-(cyclopropanecarboxamido)-6-methylpyrimidine-4-carboxamide;
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 1, and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 7)

The pharmaceutical composition as described in claim 7, further comprising another pharmacologically active agent.

### Claim 9 (depends on 1)

A method for the treatment of a condition or disorder in which Nav1.7 and Nav1.8 channel blockers are involved in an animal or a human, which comprises administering to the animal or human in need of such treatment a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as described in claim 1;
wherein the condition or disorder is selected from the group consisting of: acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, nociceptive pain, pain associated with dysmenorrhea, pelvic pain, migraine, cluster headache, tension headache, peripheral neuropathic pain, sciatica, fibromyalgia, trigeminal neuralgia, herpetic neuralgia, general neuralgia, postherpetic neuralgia, radicular pain, back pain, head or neck pain, severe or intractable pain, breakthrough pain, postsurgical pain, cancer pain, causalgia, and chemo-induced pain.

### Claim 10 (depends on 1)

A process for preparing a pharmaceutical composition comprising mixing a compound or a pharmaceutically acceptable salt thereof, as described in claim 1, and a pharmaceutically acceptable carrier or excipient.