HETEROARYL AMIDES USEFUL AS INHIBITORS OF VOLTAGE-GATED SODIUM CHANNELS

• US 20090099233A1
• Filed: 10/10/2008
• Published: 04/16/2009
• Est. Priority Date: 10/11/2007
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Wilson, Dean, Krenitsky, Paul, Termin, Andreas, Joshi, Pramod
• Granted Patent: US 8,519,137 B2
• Time in Patent Office: Days
• US Class Current: 514/326
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 249/10 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 263/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 285/12 : 1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention relates to compounds useful as inhibitors of voltage-gated sodium 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

1-59. -59. (canceled)

60. A compound of formula I″

;

or a pharmaceutically acceptable salt thereof, wherein;

Ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x occurrences of R³;

X¹, X², X³ and X⁴ are each independently nitrogen or C—

R⁴ provided that X¹, X², X³ and X⁴ are not all simultaneously nitrogen;

each R² is independently hydrogen, or C_1-6 aliphatic, wherein up to two carbon atoms other than the atom attached to the nitrogen atom is optionally replaced with O, S, NR^N, or C(O);

x is 0-4;

each occurrence of R^N is independently selected from hydrogen or a C_1-6 aliphatic group optionally substituted with 1-3 independent occurrences of —

R^J, oxo, thioxo, —

CO₂R^J, —

OR^J, —

N(R^J)₂, —

SR^J, —

NO₂, halogen, —

CN, —

C_1-4haloalkyl, —

C_1-4haloalkoxy,—

C(O)N(R^J)₂, —

NR^JC(O)R^J, —

SO₂R^J, —

SO₂N(R^J)₂, —

NR_JSO₂R^J, —

NR^JCON(R^J)₂, —

NR^JCO₂R^J, —

COR^J, —

OCOR^J, —

OCON(R^J)₂, —

SOR^J, —

NR^JSO₂N(R^J)₂, —

COCOR^J, —

COCH₂COR^J, —

OP(O)(OR^J)₂, —

P(O)(OR^J)₂, —

PO(OR^J)(R^J), —

P(O)(R^J)₂, or —

OP(O)(R^J)₂;

wherein

R^J is hydrogen or unsubstituted C_1-6 aliphatic;

each occurrence of R³ and R⁴ is independently Q-R^X;

Q is a bond or is a C_1-6 aliphatic chain wherein up to three methylene units of Q are optionally and independently replaced by —

NH—

, —

NR—

, —

O—

, —

S—

, —

CO₂—

, —

OC(O)—

, —

C(O)CO—

, —

C(O)—

, —

C(S)—

, —

C(O)NH—

, —

C(O)NR—

, —

C(═

N—

CN)—

, —

NHCO—

, —

NRCO—

, —

NHC(O)O—

, —

NRC(O)O—

, —

SO₂NH—

, —

SO₂NR—

, —

NHSO₂—

, —

NRSO₂—

, —

NHC(O)NH—

, —

NRC(O)NH—

, —

NHC(O)NR—

, —

NRC(O)NR, —

OC(O)NH—

, —

OC(O)NR—

, —

NHSO₂NH—

, —

NRSO₂NH—

, —

NHSO₂NR—

, —

NRSO₂NR—

, —

SO—

or —

SO₂—

;

wherein

Q is optionally substituted with 1-3 independent occurrences of R^Q;

each occurrence of R^X is independently selected from —

R′

, halogen, —

NO₂, —

CN, —

OR′

, —

SR′

, —

N(R′

)₂, —

NR′

C(O)R′

, —

NR′

C(O)N(R′

)₂, —

NR′

CO₂R′

, —

C(O)R′

, —

CO₂R′

, —

OC(O)R′

, —

C(O)N(R′

)₂, —

OC(O)N(R′

)₂, —

SOR′

, —

SO₂R′

, —

SO₂N(R′

)₂, —

NR′

SO₂R′

, —

NR′

SO₂N(R′

)₂, —

C(O)C(O)R′

, —

C(O)CH₂C(O)R′

, —

OP(O)(OR′

)₂, —

P(O)(OR′

)₂, —

PO(OR)(R′

), —

P(O)(R′

)₂, or —

OP(O)(R′

)₂;

each occurrence of R is independently selected from hydrogen or a C_1-6 aliphatic group optionally substituted with 1-3 independent occurrences of —

R^T, -T-Ar¹, halogen, oxo, thioxo, —

OR^T, —

SR^T, —

N(R^T)₂, —

NO₂, —

C_1-4haloalkyl, —

C_1-4haloalkoxy, —

CN, —

CO₂R^T, —

COR^T, —

CON(R^T)₂, —

OCOR^T, —

NR^TCOR^T, —

SO₂R^T, —

SO₂N(R^T)₂, or —

NR^TSO₂R^T;

wherein

each R^T is independently hydrogen or unsubstituted C_1-6 aliphatic;

or

any two R^T groups, on the same substituent or different substituents, together with the atom(s) to which each group is bound, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring, or a 5-6 membered monocyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein said monocyclic ring is optionally substituted with 1-3 independent occurrences of —

R^R, -T-Ar¹, halogen, oxo, thioxo, —

OR^R, —

SR^R, —

N(R^R)₂, —

NO₂, —

C_1-4haloalkyl, —

C_1-4haloalkoxy, —

CN, —

CO₂R^R, —

COR^R, CON(R^R)₂, —

OCOR^R, —

NR^RCOR^R, —

SO₂R^R, —

SO₂N(R^R)₂, or —

NR^RSO₂R^R;

wherein each R^R is independently hydrogen or unsubstituted C_1-6 aliphatic;

T is (CH₂)_w;

w is 0-2;

Ar¹ is selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aryl ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein

Ar¹ is optionally substituted with 1-3 independent occurrences of —

R^W, oxo, thioxo, —

CO₂R^W, —

OR^W, —

N(R^W)₂, —

SR^W, —

NO₂, halogen, —

CN, —

C_1-4haloalkyl, —

C_1-4haloalkoxy, —

C(O)N(R^W)₂, —

NR^WC(O)R^W, —

SO₂R^W, —

SO₂N(R^W)₂, —

NR^WSO₂R^W, —

NR^WCON(R^W)₂, —

NR^WCO₂R^W, —

COR^W, —

OCOR^W, —

OCON(R^W)₂, —

SOR^W, —

NR^WSO₂N(R^W)₂, —

COCOR^W, —

COCH₂COR^W, —

OP(O)(OR^W)₂, —

P(O)(OR^W)₂, —

PO(OR^W)(R^W), —

P(O)(R^W)₂, or —

OP(O)(R^W)₂;

wherein R^W is hydrogen or unsubstituted C_1-6 aliphatic;

R^Q is selected from halogen, —

R^S, —

N(R^S)₂, —

SR^S, —

OR^S, C_3-10 cycloaliphatic, C_6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, —

C_1-4haloalkoxy, —

C_1-4haloalkyl, —

NO₂, —

CN, —

CF₃, —

OCF₃, —

CO₂R^S, —

COR^S, —

OC(O)R^S or —

NR^SC(O)R^S;

wherein R^S is hydrogen or unsubstituted C_1-6 aliphatic;

or

any two R^Q or two R^S groups, or any combination of an R^Q group with an R^S group on the same substituent or different substituents, together with the atom(s) to which each group is bound, optionally form a 3-8 membered saturated or partially unsaturated monocyclic ring, or a 5-6 membered monocyclic aryl ring;

each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein any of said monocyclic ring is optionally substituted with 1-3 independent occurrences of R^O, halogen, oxo, thioxo, —

OR^O, —

SR^O, —

N(R^O)₂, —

NO₂, —

C_1-4haloalkyl, —

C_1-4haloalkoxy, —

CN, —

CO₂R^O, —

COR^O, —

CON(R^O)₂, —

OCOR^O, —

NR^OCOR^O, —

SO₂R^O, —

SO₂N(R^O)₂, or —

NR^OSO₂R^O;

wherein

R^O is hydrogen or unsubstituted C_1-6 aliphatic;

each occurrence of R′

is independently selected from hydrogen or a C_1-8 aliphatic, C_6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms, or wherein R and R′

taken together with the atom(s) to which they are bound, or two occurrences of R′

taken together with the atom(s) to which they are bound, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein said C_1-8 aliphatic, C_6-10 aryl, heteroaryl ring or heterocyclyl ring is optionally substituted with 1-3 independent occurrences of R^I, halogen, oxo, thioxo, —

OR^I, —

SR^I, —

N(R^I)₂, —

NO₂, —

C_1-4haloalkyl, —

C_1-4haloalkoxy, —

CN, —

CO₂R^I, —

COR^I, —

CONHR^I, —

OCOR^I, —

NR^ICOR^I, —

SO₂R^I, —

SO₂N(R^I)₂, or —

NR^ISO₂R^I;

wherein

R^I is hydrogen or unsubstituted C_1-6 aliphatic.

61. The compound according to claim 60, wherein ring B is an optionally substituted 6-membered heteroaryl ring.

62. The compound according to claim 61, wherein ring B is selected from:

63. The compound according to claim 60, wherein ring B is an optionally substituted 5-membered heteroaryl ring.

64. The compound according to claim 63, wherein ring B is selected from:

65. The compound according claim 64, wherein ring B is selected from:

66. The compound according to claim 60, wherein x is 1-3.

67. The compound according to claim 66, wherein x is 1-3, and each R³ is independently selected from hydrogen, halogen, CN, CF₃, NO₂, or an optionally substituted group selected from C_1-6 aliphatic, C_1-6 cycloaliphatic, C_6-10 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

C(O)R′

, —

COOR′

, —

NRCOR′

, —

CON(R′

)₂, —

S(O)₂R′

, or —

S(O)₂N(R′

)₂.

68. The compound according to claim 67, wherein x is 1-2 and each R³ is methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl or an optionally substituted group selected from C_1-6 aliphatic, C_6-10 aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl or aralkyl.

71. The compound according to claim 60, wherein radical:

72. The compound according to claim 60, wherein each R⁴ is hydrogen.

73. The compound according to claim 60, wherein each R⁴, when present, is independently selected from hydrogen, halogen, CN, NO₂, or an optionally substituted group selected from C_1-6 aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

C(O)R′

, —

COOR′

, —

NR′

COR′

, —

CON(R′

)₂, or —

S(O)₂N(R′

)₂.

74. The compound according to claim 60, wherein in SO₂N(R²)₂, both R² are hydrogen.

69-70. -70. (canceled)

75-86. -86. (canceled)

87. A compound selected from Table 1.

88-104. -104. (canceled)