# US 7,745,629 B2 · Bicyclic derivatives as modulators of ion channels

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- Number: US 7,745,629 B2
- Document ID: US7745629B2
- Status: Granted
- Kind: B2
- Application number: 11/432,997
- Filed: 2006-05-12
- Published: 2008-05-22
- Granted: 2010-06-29
- Earliest claimed: 2005-05-16
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: Andreas Termin; Nicole Zimmermann; Tara Leanne Knoll; Gabriel Martinez-Botella; Esther Martinborough
- Web page: https://patentgrep.com/patent/US7745629B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 23/00: Anaesthetics
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to bicyclic compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

## Claims

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt thereof;
wherein:
ring Z is a 5-7 membered unsaturated or aromatic ring having at least one ring heteroatom selected from O, S, N, or NH; wherein Z is optionally fused to ring A;
wherein A is an optionally substituted 5-7 membered unsaturated or aromatic ring; and wherein Z or Z taken together with said fused ring A is substituted with up to z occurrence of RZ;
z is 0 to 4;
each RZ is independently selected from R1, R2, R3, R4, or R5;
q is 1 or 2;
Q is a bond or a C1-C6 straight or branched saturated alkylidine chain, wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR2—, —CONR2NR2—, —CO2—, —OCO—, —NR2CO2—, —O—, —NR2CONR2—, —OCONR2—, —NR2NR2—, —NR2NR2CO—, —NR2CO—, —S—, —SO, —SO2—, —NR2—, —SO2NR2—, NR2SO2—, —NR2SO2NR2—, or a spirocycloalkylene moiety;
RQ is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from O, S, N, or NH, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from O, S, N, or NH; wherein RQ is optionally substituted with up to 4 substituents independently selected from R1, R2, R3, R4, or R5;
RM and RN are independently R2;
R1 is oxo, ═NN(R6)2, ═NN(R7)2, ═NN(R6R7), R6, or (CH2)—Y;
n is 0, 1, or 2;
Y is halo, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6, SO2R6, NH2, NHR6, N(R6)2, NR6R8, COOH, COOR6, or OR6; or two R1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R2 is hydrogen or C1-C6 aliphatic, wherein each R2 is optionally substituted with up to 2 substituents independently selected from R1, R4, or R5;
R3 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 substituents, independently selected from R1, R2, R4, or R5;
R4 is OR5, OR6, OC(O)R6, OC(O)R5, OC(O)OR6, OC(O)OR5, OC(O)N(R6)2, OC(O)N(R5)2, OC(O)N(R6R5), OP(O)(OR6)2, OP(O)(OR5)2, OP(O)(OR6)(OR5), SR6, SR5, S(O)R6, S(O)R5, SO2R6, SO2R5, SO2N(R6)2, SO2N(R5)2, SO2NR5R6, SO3R6, SO3R5, C(O)R5, C(O)OR5, C(O)R6, C(O)OR6, C(O)N(R6)2, C(O)N(R5)2, C(O)N(R5R6), C(O)N(OR6)R6, C(O)N(OR5)R6, C(O)N(OR6)R5, C(O)N(OR5)R5, C(NOR6)R6, C(NOR6)R5, C(NOR5)R6, C(NOR5)R5, N(R6)2, N(R5)2, N(R5R6), NR5C(O)R5, NR6C(O)R6, NR6C(O)R5, NR6C(O)OR6, NR5C(O)OR6, NR6C(O)OR5, NR5C(O)OR5, NR6C(O)N(R6)2, NR6C(O)NR5R6, NR6C(O)N(R5)2, NR5C(O)N(R6)2, NR5C(O)NR5R6, NR5C(O)N(R5)2, NR6SO2R6, NR6SO2R5, NR5SO2R5, NR6SO2N(R6)2, NR6SO2NR5R6, NR6SO2N(R5)2, NR5SO2NR5R6, NR5SO2N(R5)2, N(OR6)R6, N(OR6)R5, N(OR5)R5, N(OR5)R6, P(O)(OR6)N(R6)2, P(O)(OR6)N(R5R6), P(O)(OR6)N(R5)2, P(O)(OR5)N(R5R6), P(O)(OR5)N(R6)2, P(O)(OR5)N(R5)2, P(O)(OR6)2, P(O)(OR5)2, or P(O)(OR6)(OR5);
R5 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, optionally substituted with up to 3 R1 substituents;
R6 is H or C1-C6 aliphatic, wherein R6 is optionally substituted with a R7 substituent;
R7 is a C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring, and each R7 is optionally substituted with up to 2 substituents independently selected from H, C1-C6 aliphatic, or (CH2)m—Z′ wherein m is 0-2;
Z′ is selected from halo, CN, NO2, C(halo)3, CH(halo)2, CH2(halo), —OC(halo)3, —OCH(halo)2, —OCH2(halo), OH, S—(C1-C6) aliphatic, S(O)—(C1-C6) aliphatic, SO2—(C1-C6)aliphatic, NH2, NH—(C1-C6)aliphatic, N((C1-C6)aliphatic)2, N((C1-C6)aliphatic)R8, COOH, C(O)O(—(C1-C6)aliphatic), or O—(C1-C6)aliphatic;
R8 is acetyl, C6-C10 aryl sulfonyl, or C1-C6 alkyl sulfonyl; and
provided that said compound is not N-[4-cyano-5-(methylthio)-1H-pyrazol-3-yl]-1,2-dihydro-1-methyl-2-oxo-4-(trifluoromethyl)-6-quinolinesulfonamide.

### Claim 2 (depends on 1)

The compound according to claim 1, Z is an optionally substituted ring selected from:

### Claim 3 (depends on 1)

The compound according to claim 1, wherein A is phenyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein z is 0-2.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein each RZ is independently selected from R1, R2, or R5.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein each RZ is independently selected from a hydrogen, halo, OR6, a C1-C6 aliphatic, or an optionally substituted group independently selected from C3-C8 cycloaliphatic, C6-C10 aryl, C3-C8 heterocyclic, or C5-C10 heteroaryl ring; wherein said cycloaliphatic, said aryl, said heterocyclic, or said heteroaryl is optionally substituted with up to 3 substituents independently selected from R1, R2, R4, or R5.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein each RZ is independently selected from hydrogen, halo, O(C1-C6 alkyl), C1-C6 alkyl, C3-C8 cycloalkyl, or phenyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein RM is hydrogen.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein RN is hydrogen.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein Q is selected from a bond, or a C1-C6 straight or branched alkylidene chain, wherein up to two methylene units of said alkylidene is independently replaced by O, S, OCO, NH, N(C1-C4 alkyl), or a spirocycloalkylene group.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein Q is —X2—(X1)p—,
wherein:
X2 is a bond or C1-C6 aliphatic, optionally substituted with up to two substituents independently selected from R1, R4, or R5;
p is 0 or 1; and
X1 is O, S, or NR2.

### Claim 12 (depends on 11)

The compound according to claim 11, wherein X2 is a bond, C1-C6 alkyl, or C2-C6 alkylidene, and said alkyl and alkylidene are independently and optionally substituted with R1 or R4.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein X2 is selected from a bond, —CH2—, —CH2—CH2—, —(CH2)3—, —C(Me)2-, —CH(Me)-, —CH(Ph)—, —CH2—CH(Me)-, —CH(Et)-, or —CH(i-Pr)—.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein RQ is an optionally substituted phenyl or naphthyl.

### Claim 15 (depends on 14)

The compound according to claim 14, wherein RQ is optionally substituted with up to 3 substituents independently selected from halo, cyano, trifluoromethyl, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, trifluoromethoxy, C(O)NH2, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(O)C1-4 alkyl, or C(O)C1-4 alkyl.

### Claim 16 (depends on 15)

The compound according to claim 15, wherein RQ is selected from:

### Claim 17 (depends on 1)

The compound according to claim 1, wherein RQ is an optionally substituted 3-8 membered cycloaliphatic ring.

### Claim 18 (depends on 17)

The compound according to claim 17, wherein RQ is an optionally substituted ring selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

### Claim 19 (depends on 1)

The compound according to claim 1, wherein RQ is an optionally substituted 5-6 membered monocyclic, unsaturated, partially substituted, or aromatic ring containing up to 3 heteroatoms independently selected from O, S, N, or NH.

### Claim 20 (depends on 19)

The compound according to claim 19, wherein RQ is an optionally substituted ring selected from:

### Claim 21 (depends on 20)

The compound according to claim 20, wherein RQ is optionally fused to an optionally substituted phenyl ring.

### Claim 22 (depends on 1)

The compound according to claim 1, wherein RQ is an optionally substituted 8-10-membered bicyclic, heterocyclic or heteroaromatic, ring.

### Claim 23 (depends on 22)

The compound according to claim 22, wherein RQ is an optionally substituted ring selected from:

### Claim 24 (depends on 19)

The compound according to claim 19 or claim, wherein RQ is selected from pyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, piperidin-1-yl, 3-methyl-piperidin-1-yl, 4-methyl-piperidin-1-yl, 4,4-difluoropiperidin-1-yl, 4,5-dimethyl-4-morpholin-1-yl, 2,6-dimethyl-morpholin-4-yl, indol-1-yl, 4-fluoro-indol-1-yl, 5-chloro-indol-1-yl, 7-chloro-indol-1-yl, tetrahydroquinolin-1-yl, 7-trifluoromethyl-tetrahydroquinolin-1-yl, 6-methyl-tetrahydroquinolin-1-yl, 6-chloro-tetrahydroquinolin-1-yl, tetrahydro-isoquinolin-2-yl, 7-chloro-tetrahydro-isoquinolin-2-yl, 7-trifluoromethyl-tetrahydro-isoquinolin-2-yl, 7-fluoro-tetrahydro-isoquinolin-2-yl, 6-methyl-tetrahydro-isoquinolin-2-yl, 8-trifluoromethyl-quinolin-4-yl, pyridine-3-yl, or pyridine-4-yl.

### Claim 25 (depends on 1)

The compound according to claim 1, wherein said compound is selected from formula I-A or formula I-C:

### Claim 26

A compound selected from
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

A pharmaceutical composition comprising a compound according to any one of claims 1-26, and a pharmaceutically acceptable carrier, adjuvant, or a vehicle.