WO2011056985A2

WO2011056985A2 - Substituted heterocyclic compounds

Info

Publication number: WO2011056985A2
Application number: PCT/US2010/055467
Authority: WO
Inventors: Matthew Abelman; Nancy Chu; Robert Jiang; Jeff Zablocki
Original assignee: Gilead Sciences, Inc.
Priority date: 2009-11-04
Filing date: 2010-11-04
Publication date: 2011-05-12
Also published as: WO2011056985A3

Abstract

The present invention relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula (I) as further described herein. The invention also relates to methods for the preparation of the compounds, and to pharmaceutical compositions containing such compounds.

Description

SUBSTITUTED HETEROCYCLIC COMPOUNDS

FIELD

[0001] The present invention relates to novel compounds and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. The invention also relates to methods for their preparation, and to pharmaceutical compositions containing such compounds.

SUMMARY

[0002] Accordingly, in typical embodiments the present invention provides novel compounds thAt function as late sodium channel blockers. In typical embodiments the compounds of the invention have the structure shown in Formula (I):

wherein:

C* is carbon,

R₁ is -L1 -R18 or is -R19, wherein:

L1 is -Lk-, or -Lk'-O-Lk'-, wherein Lk is C₁-C₆ alkylene optionally substituted with 1 or 2 groups independently selected from hydroxyl and C₁-C₃ alkyl; and each Lk' independently is C₂-C₆ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups;

R18 is hydrogen, hydroxyl, -CF₃, -CN, C₁-C₃ alkoXy, -O- R20, -C(O)-R20, -C(O)-O-R20, -S(=O)₂-CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂-R24, -C(O)-N(R20)-S(=O)₂- R26, tetrazolyl; cycloalkyl, phenyl, or heteroaryl; wherein said cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, optionally substituted alkyl, C₁-C₃ alkoxy, -O-R20, -C(O)-O-R20, -S(=O)₂- CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂- R24, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -R25-hydroxyl, -R25-C₁-C₃ alkoxy, -R25-O-R20, -R25- C(O)-O-R20, -R25-S(=O)2-CH3, -R25-C(O)-N(R20)(R22), -R25- N(R20)-C(O)-R24, -R25-N(R20)-S( =O)₂-R24, -R25-C(O)-N(R20)- S(=O)₂-R26, -R25-tetrazolyl, -R25-cycloalkyl, -R25-phenyl, or - R25-heteroaryl; and

R19 is hydrogen, cycloalkyl, phenyl, or heteroaryl; wherein said cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, -CN, optionally substituted alkyl, C₁-C₃ alkoxy, -C(O)-O-R20, -S(=O)₂- CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂- R24, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -R25-hydroxyl, -R25-C₁-C₃ alkoxy, -R25-C(O)-O-R20, - R25-S(=O)₂-CH₃, -R25-C(O)-N(R20)(R22), -R25-N(R20)-C(O)- R24, -R25-N(R20)-S(=O)₂-R24, -R25-C(O)-N(R20)-S(=O)₂-R26, - R25-tetrazolyl, -R25-cycloalkyl, -R25 -phenyl, or -R25-heteroaryl; R₂ and R₃ are each independently hydrogen or C₁-C₃ alkyl, or

R₂ and R₃, taken together with the carbon to which they are both attached, form an optionally substituted cycloalkyl; or

R and R₃, taken together, is selected from:

a) a'-Qa*-R32-Qa*-b', wherein each Qa* is independently selected from -0-, -NH-, and -S-; R32 is C₂-C₅ alkylene optionally substituted with -R20; and a' and b' are each single covalent bonds to C*;

b) a'-N(R30)-C(O)-R33-b', wherein R30 is hydrogen or optionally substituted alkyl, R33 is C₁-C₅ alkylene optionally substituted with -R20, and a' and b' are each single covalent bonds to C*; or c) a'-R34-Qb*-R34-b', wherein Qb* is independently selected from

-0-, -N(R30)-, and -S-; each R34 is independently C1-C4 alkylene optionally substituted with -R20; R30 is hydrogen or optionally substituted alkyl, and a' and b' are each single covalent bonds to c*;

D designates the phenyl ring in Formula (I) to which R₇, R«, and R are attached,

R₇ and Rg are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -N0₂, -CF₃, -O-CF3, -CN, -O-R20, - S-R20, -N(R20)(R22), -S(=O)-R22, -S(=O)₂R22, -S(O)₂-N(R20)(R22), -S(=O)₂-O-R20, -N(R20)-C(O)-R22, -N(R20)-C(O)-O-R22, -N(R20)-C(O)-N(R20)(R22), -C(O)-R20, - C(O)-O-R20, -C(O)-N(R20)(R22), and -N(R20)-S(=O)₂-R22, wherein each optional alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituent is further optionally substituted with halo, -NO2, -CF₃, -O-CF3, -N(R20)(R22), -C(O)-R20, -C(O)-O-R20, -C(O)- N(R20)(R22), -CN, -O-R20, or optionally substituted alkyl; or

R₇ and R₈, taken together, is a'-Qc*-R35-Qd*-R36-b', wherein Qc* and Qd* are each independently selected from covalent bond, -0-, -NH-, and -S-; R35 is C₁-C₄ alkylene optionally substituted with -R20; R36 is covalent bond or-CHR20-; a' is a first single covalent bond to phenyl ring D, and b' is a second single covalent bond to phenyl ring D at a position that is ortho to the a'; wherein Qd* and R36 are not both covalent bond; or

R₇ and R₈, taken together with phenyl ring D, form a fused bicyclic heteroaryl selected from benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiphenyl,

benzo[c]thiophenyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl,

benzothiazolyl, benzoxadiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or quinazolinyl;

R₉ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -N0₂, -CF₃, -O-CF3, -CN, -O-R20, -S-R20, - N(R20)(R22), -S(=O)-R22, -S(=O)₂R22, -S(=O)₂-N(R20)(R22), -S(=O)₂-O-R20, - N(R20)-C(O)-R22, -N(R20)-C(O)-O-R22, -N(R20)-C(O)-N(R20)(R22), -C(O)-R20, - C(O)-O-R20, -C(O)-N(R20)(R22), and -N(R20)-S(=O)₂-R22, wherein each optional alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituent is further optionally substituted with halo, -NO₂, -CF₃, -O-CF3, -N(R20)(R22), -C(O)-R20, -C(O)-O-R20, -C(O)- N(R20)(R22), -CN, -O-R20, or optionally substituted alkyl;

X₂ is -N= or -C(R16)=, wherein R16 is selected from hydrogen, halo, -O-R20, -alkyl, -CF₃, -CN, -N(R20)(R22), or -L3-R38, wherein L3 is -Lj- or -Lj'-O-Lj'-, wherein Lj is C₁-C₆ alkylene optionally substituted with 1 or 2 groups independently selected from hydroxyl and C₁-C₃ alkyl; and each Lj* independently is C₂-C₆ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups;

R38 is hydrogen, hydroxyl, -CF₃, -CN, C₁-C₃ alkoxy, -O- R20, -C(O)-O-R20, -N(R20)-S(=O)₂-R24, -C(O)-N(R20)-S(=O)₂- R26, tetrazolyl, phenyl, or heteroaryl; wherein said phenyl, or heteroaryl is optionally substituted with 1 , 2, or 3 groups

independently selected from hydroxyl, halo, optionally substituted alkyl, C₁-C₃ alkoxy, -O-R20, -C(O)-O-R20, -S(=O)₂-CH₃, -C(O)- N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂-R24, -C(O)- N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -R25- hydroxyl, -R25-C₁-C₃ alkoxy, -R25-O-R20, -R25-C(O)-O-R20, - R25-S(=O)₂-CH₃, -R25-C(O)-N(R20)(R22), -R25-N(R20)-C(O)- R24, -R25-N(R20)-S(=O)₂-R24, -R25-C(O)-N(R20)-S(=O)₂-R26, - R25-tetrazolyl, -R25-cycloalkyl, -R25-phenyl, or -R25-heteroaryl; and

Xi and X₃ each are independently -N= or -C(R17)=, wherein R17 is hydrogen, halo, cyano, optionally substituted alkyl, or -N(R20)(R22);

each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C₁-C₁₅ alkyl, C₂-C₁₅ alkenyl, C₂-C₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, -CN, lower alkoxy, -CF₃, aryl, and heteroaryl;

R24 is optionally substituted alkyl or optionally substituted aryl;

R25 is C₁-C₃ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups; and

R26 is optionally substituted alkyl or optionally substituted cycloalkyl.

[0003] In certain embodiments the invention provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of the invention (e.g. a compound of Formula (I) ) and at least one pharmaceutically acceptable excipient. [0004] Some embodiments provide a method of using the compounds of the invention (e.g. a compound of Formula (I) ) in the treatment of a disease or condition in a mammal that is amenable to treatment by a late sodium channel blocker. The compounds of the invention and their therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of certain diseases, such as, cardiovascular diseases such as atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, recurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, and intermittent claudication.. Such diseases may also include diabetes, and conditions related to diabetes, e.g. diabetic peripheral neuropathy. Such diseases may also include conditions affecting the neuromuscular system resulting in pain, seizures, or paralysis.

BREIF DESCRIPTION OF THE DRAWINGS

[0005] These and other features of the invention will be understood from the description of representative embodiments of the method herein and the disclosure of illustrative materials for carrying out the method, taken together with the Figures, wherein

[0006] Figure 1 shows a typical response due to activation of Nay 1.5 sodium channel in a sodium current assay.

[0007] Figure 2 is a plot of sodium current measured with and without Tefluthrin.

[0008] Figure 3 illustrates hERG channel activation upon application of the indicated potential.

[0009] Figure 4 shows peak INa plotted as a function of experiment time. Stimulation at 3 Hz is indicated. Calculation of UDB corrects for the decrease in peak in the absence of test compound.

DETAILED DESCRIPTION

[0010] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. [0011] The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

[0012] The term "substituted alkyl" refers to:

1) an alkyl group as defined above, having 1 , 2, 3, 4 or 5 substituents, (typically 1, 2, or 3 substituents) selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,

heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - SO-alkyl, -SO-aryl,-SO-heteroaryl, -S0₂-alkyl, S0₂-aryl and -S0₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)„R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

2) an alkyl group as defined above that is interrupted by 1 -10 atoms (e.g. 1, 2, 3, 4, or 5 atoms) independently chosen from oxygen, sulfur and NRa-, where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O)„R, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

3) an alkyl group as defined above that has both 1 , 2, 3, 4 or 5

substituents as defined above and is also interrupted by 1 -10 atoms (e.g. 1 , 2, 3, 4, or 5 atoms) as defined above.

[0013] The term "lower alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

[0014] The term "substituted lower alkyl" refers to lower alkyl as defined above having 1 to 5 substituents (typically 1, 2, or 3 substituents), as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substituted alkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined above.

[0015] The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, typically having from 1 to 20 carbon atoms (e.g. 1-10 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms). This term is exemplified by groups such as methylene (-CH₂-), ethylene (-CH₂CH₂-), the propylene isomers (e.g., -CH₂CH₂CH₂- and-CH(CH₃)CH₂-), and the like.

[0016] The term "lower alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, typically having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0017] The term "substituted alkylene" refers to:

(1) an alkylene group as defined above having 1, 2, 3, 4, or 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,

(2) an alkylene group as defined above that is interrupted by 1-10 groups (e.g. 1, 2, 3, 4, or 5 groups) independently chosen from -0-, -S-, sulfonyl, -C(O)-, - C(O)0-, -C(O)N-, and -NRa-, where Ra is chosen from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl; or

(3) an alkylene group as defined above that has both 1 , 2, 3, 4 or 5 substituents as defined above and is also interrupted by 1-10 groups as defined above. Examples of substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene (- CH(NH₂)CH₂-), methylaminoethylene (-CH(NHMe)CH₂-), 2-carboxypropylene isomers(-CH₂CH(C0₂H)CH2-), ethoxyethyl (-CH2CH2O-CH2CH2-),

ethylmethylaminoethyl (-CH₂CH₂-N(CH₃)-CH₂CH2-)_> l-ethoxy-2-(2-ethoxy- ethoxy)ethane (-CH2CH2O-CH2CH2-OCH2CH2-OCH2CH2-), and the like.

[0018] The term "aralkyl" refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein. 'Optionally substituted aralkyl" refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4- methoxyphenyl)propyl, and the like.

[0019] The term "alkoxy" refers to the group R-0-, where R is optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y is optionally substituted alkylene and Z is optionally substituted alkenyl, optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and

cycloalkenyl are as defined herein. Typical alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n- pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.

[0020] The term "lower alkoxy" refers to the group R-O- in which R is optionally substituted lower alkyl as defined above. This term is exemplified by groups such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, and the like.

[0021] The term "alkylthio" refers to the group R-S-, where R is as defined for alkoxy.

[0022] The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group typically having from 2 to 20 carbon atoms (more typically from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon double bonds, e.g. 1, 2, or 3 carbon-carbon double bonds. Typical alkenyl groups include ethenyl (or vinyl, i.e. -CH=CH₂), 1 -propylene (or ally!, -CH₂CH=CH₂), isopropylene (-C(CH₃)=CH₂), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is attached to nitrogen, the double bond cannot be alpha to the nitrogen.

[0023] The term "lower alkenyl" refers to alkenyl as defined above having from 2 to 6 carbon atoms.

[0024] The term "substituted alkenyl" refers to an alkenyl group as defined above having 1 , 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, - SO₂-alkyl, SO₂-aryl and - SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0025] The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon, typically having from 2 to 20 carbon atoms (more typically from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1 to 6 carbon-carbon triple bonds e.g. 1 , 2, or 3 carbon- carbon triple bonds. Typical alkynyl groups include ethynyl (-C≡CH), propargyl (or propynyl, -C≡CCH3), and the like. In the event that alkynyl is attached to nitrogen, the triple bond cannot be alpha to the nitrogen.

[0026] The term "substituted alkynyl" refers to an alkynyl group as defined above having 1 , 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, - SO₂-alkyl, SO₂-aryl and - SO₂-heteroaryL Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)„R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0027] The term "aminocarbonyl" refers to the group -C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)„R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0028] The term "ester" or "carboxyester" refers to the group -C(O)OR, where R is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, which may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O)„Ra, in which Ra is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0029] The term "acylamino" refers to the group -NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(O)_nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0030] The term "acyloxy" refers to the groups -OC(O)-alkyl, -OC(O)-cycloalkyl, - OC(O)-aryl, -OC(O)-heteroaryl, and -OC(O)-heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0031] The term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl, and anthryl). Typical aryls include phenyl, fluorenyl, naphthyl, anthryl, and the like.

[0032] Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with 1 , 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,

alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,

heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, - S0₂-alkyl, S0₂-aryl and -SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)„R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. [0033] The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above. The term "arylthio" refers to the group R-S-, where R is as defined for aryl.

[0034] The term "amino" refers to the group -NIな.

[0035] The term "substituted amino" refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl,

aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and - S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0036] The term "carboxyalkyl" refers to the groups -C(O)0-alkyl, -C(O)0-cycloalkyl, where alkyl and cycloalkyl are as defined herein, and may be optionally further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or - S(O)_nR, in which R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0037] The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and

bicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example indan, and the like.

[0038] The term "substituted cycloalkyl" refers to cycloalkyl groups having 1 , 2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, - S0₂-alkyl, SCVaryl and -S0₂-heteroaryl. The term "substituted cycloalkyl" also includes cycloalkyl groups wherein one or more of the annular carbon atoms of the cycloalkyl group is a carbonyl group (i.e. an oxygen atom is oxo to the ring). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

[0039] The term "halogen" or "halo" refers to fluoro, bromo, chloro, and iodo.

[0040] The term "acyl" denotes a group -C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0041] The term heteroaryl" refers to a group comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within at least one ring. The term heteroaryl" is generic to the terms "aromatic heteroaryl" and "partially saturated

heteroary '. The term "aromatic heteroaryl" refers to a heteroaryl in which at least one ring is aromatic. Examples of aromatic heteroaryls include pyrrole, thiophene, pyridine, quinoline, pteridine. The term "partially saturated heteroaryl" refers to a heteroaryl having a structure equivalent to an underlying aromatic heteroaryl which has had one or more double bonds in an aromatic ring of the underlying aromatic heteroaryl saturated. Examples of partially saturated heteroaryls include dihydropyrrole, dihydropyridine, 1,2,3,4- tetrahydronaphthalene.

[0042] Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents (typically 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl (an alkyl ester), arylthio, heteroaryl, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, aralkyl, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -S0₂-alkyl, S0₂-aryl and -S0₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazole, or benzothienyl). Examples of nitrogen heterocyclyls and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogen containing heteroaryl compounds.

[0043] The term "heteroaryloxy" refers to the group heteroaryl-O-.

[0044] The term "heterocyclyl" refers to a monoradical saturated group having a single ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.

[0045] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5 substituents (typically 1, 2, or 3 substituents), selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,

heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, - SO₂-alkyl, SO₂-aryl and -SO₂-heteroaryl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)_nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

Heterocyclic groups can have a single ring or multiple condensed rings. Preferred

heterocyclics include tetrahydrofuranyl, morpholino, piperidinyl, and the like.

[0046] The term "thiol" refers to the group -SH.

[0047] The term "substituted alkylthio" refers to the group -S-substituted alkyl.

[0048] The term "heteroarylthiol" refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above. [0049] The term "sulfoxide" refers to a group -S(O)R, in which R is alkyl, aryl, or heteroaryl. "Substituted sulfoxide" refers to a group -S(O)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

[0050] The term "sulfone" refers to a group -S(O)2R, in which R is alkyl, aryl, or heteroaryl. "Substituted sulfone" refers to a group -S(0>2R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.

[0051] The term "keto" refers to a group -C(O)-. The term "thiocarbonyl" refers to a group -C(S)-. The term "carboxy" refers to a group -C(O)-OH.

[0052] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

[0053] A "substituted" group includes embodiments in which a monoradical substituent is bound to a single atom of the substituted group (e.g. forming a branch), and also includes embodiments in which the substituent may be a diradical bridging group bound to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.

[0054] A compound of a given Formula (e.g. the "compound of Formula (I)") is intended to encompass the compounds of the invention as disclosed, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, hydrates, polymorphs, and prodrugs of such compounds. Additionally, the compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or di astereoi som ers . The number of stereoisomers present in any given compound of a given Formula depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.

[0055] "Isomers" are different compounds that have the same molecular formula. [0056] "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space.

[0057] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate.

[0058] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0059] The absolute stereochemistry is specified according to the Cahn Ingold Prelog R S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) that they rotate the plane of polarized light at the wavelength of the sodium D line.

[0060] The term "therapeutically effective amount" refers to an amount that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0061] The term "treatment" or "treating" means any treatment of a disease in a mammal, including:

(i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop;

(ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or

(iii) relieving the disease, that is, causing the regression of clinical symptoms.

[0062] In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0063] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.

[0064] Specific examples of suitable amines include, by way of example only,

isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0065] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0066] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0067] "Coronary diseases" or "cardiovascular diseases" refer to diseases of the

cardiovasculature arising from any one or more than one of, for example, heart failure (including congestive heart failure, diastolic heart failure and systolic heart failure), acute heart failure, ischemia, recurrent ischemia, myocardial infarction, arrhythmias, angina (including exercise-induced angina, variant angina, stable angina, unstable angina), acute coronary syndrome, diabetes, and intermittent claudication.

[0068] "Intermittent claudication" means the pain associated with peripheral artery disease. "Peripheral artery disease" or PAD is a type of occlusive peripheral vascular disease (PVD). PAD affects the arteries outside the heart and brain. The most common symptom of PAD is a painful cramping in the hips, thighs, or calves when walking, climbing stairs, or exercising. The pain is called intermittent claudication. When listing the symptom intermittent claudication, it is intended to include both PAD and PVD

[0069] Arrhythmia refers to any abnormal heart rate. Bradycardia refers to abnormally slow heart rate whereas tachycardia refers to an abnormally rapid heart rate. As used herein, the treatment of arrhythmia is intended to include the treatment of supra ventricular tachycardias such as atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia, atrial tachycardia, and the ventricular tachycardias (VTs), including idiopathic ventricular tachycardia, ventricular fibrillation, pre-excitation syndrome, and Torsade de Pointes (TdP),

[0070] Where a given group (moiety) is described herein as being attached to a second group and the site of attachment is not explicit, the given group may be attached at any available site of the given group to any available site of the second group. For example, a "lower alkyl-substituted phenyl", where the attachment sites are not explicit, may have any available site of the lower alkyl group attached to any available site of the phenyl group. In this regard, an "available site" is a site of the group at which a hydrogen of the group may be replaced with a substituent.

NOMENCLATURE

[0071] Names of compounds of the present invention are provided using ACD/Name software for naming chemical compounds (Advanced Chemistry Development, Inc., Toronto). Other compounds or radicals may be named with common names, or systematic or non-systematic names. The naming and numbering of the compounds of the invention is illustrated with a representative compound of Formula (I)

which is named 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one.

[0072] The inhibition of the Na_vl .5 late current may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion. Compounds described herein, e.g. compounds which have a structure given by Formula (I), have now been found to be sodium channel blockers that are effective for the inhibition of the Na_vl .5 late current. In particular embodiments, the compounds provide for inhibition of the Na_vl .5 late current and are selective for the sodium channel with little hERG inhibition.

[0073] Accordingly, in typical embodiments the present invention provides compounds that function as sodium channel blockers. In typical embodiments the compounds of the invention have the structure shown in Formula (I):

wherein:

C* is carbon,

R₁ is -Ll-R18 or is -R19 wherein:

LI is -Lk--, or -Lk'-O-Lk'-, wherein Lk is C₁-C₆ alkylene optionally substituted with 1 or 2 groups independently selected from hydroxyl and C₁-C₃ alkyl; and each Lk' independently is C₂-C₆

alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups;

Rl 8 is hydrogen, hydroxyl, -CF₃, -CN, C₁-C₃ alkoxy, -O- R20, -C(O)-R20, -C(O)-O-R20, -S(0)₂-CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂-R24, -C(O)-N(R20)-S(=O)₂- R26, tetrazolyl; cycloalkyl, phenyl, or heteroaryl; wherein said cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, optionally substituted alkyl, C₁-C₃ alkoxy, -O-R20, -C(O)-O-R20, -S(=O)₂- CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂- R24, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -R25-hydroxyI, -R25-C₁-C₃ alkoxy, -R25-O-R20, -R25- C(O)-O-R20, -R25-S(=O)₂-CH₃, -R25-C(O)-N(R20)(R22), -R25- N(R20)-C(O)-R24, -R25-N(R20)-S(=O)₂-R24, -R25-C(O)-N(R20)- S(=O)₂-R26, -R25-tetrazolyl, -R25-cycloalkyl, -R25-phenyl, or - R25-heteroaryl; and

R19 is hydrogen, cycloalkyl, phenyl, or heteroaryl; wherein said cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, -CN, optionally substituted alkyl, C₁-C₃ alkoxy, -C(O)-O-R20, -S(=O)₂- CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂- R24, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -R25-hydroxyl, -R25-C₁-C₃ alkoxy, -R25-C(O)-O-R20, - R25-S(=O)₂-CH₃, -R25-C(O)-N(R20)(R22), -R25-N(R20)-C(O)- R24, -R25-N(R20)-S(=O)₂-R24, -R25-C(O)-N(R20)-S(=O)₂-R26, - R25-tetrazolyl, -R25-cycloalkyl, -R25-phenyl, or -R25-heteroaryl; R₂ and R₃ are each independently hydrogen or C₁-C₃ alkyl, or

R₂ and R₃, taken together, is selected from: d) a'-Qa*-R32-Qa*-b', wherein each Qa* is independently selected from -0-, -NH-, and -S-; R32 is C2-C5 alkylene optionally substituted with -R20; and a' and b' are each single covalent bonds to C*;

e) a'-N(R30)-C(O)-R33-b', wherein R30 is hydrogen or optionally substituted alkyl, R33 is C1-C5 alkylene optionally substituted with -R20, and a' and b' are each single covalent bonds to C*; or a'-R34-Qb*-R34-b% wherein Qb* is independently selected from -0-, -N(R30)-, and -S-; each R34 is independently C1-C4 alkylene optionally substituted with -R20; R30 is hydrogen or optionally substituted alkyl, and a' and b' are each single covalent bonds to C*;

D designates the phenyl ring in Formula (I) to which R₇, Rg, and R9 are attached,

R₇ and Rg are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -NO2, -CF3, -O-CF3, -CN, -O-R20, - S-R20, -N(R20)(R22), -S(=O)-R22, -S(=O)₂R22, -S(=O)₂-N(R20)(R22), -S(=O)₂-O-R20, -N(R20)-C(O)-R22, -N(R20)-C(O)-O-R22, -N(R20)-C(O)-N(R20)(R22), -C(O)-R20, - C(O)-O-R20, -C(O)-N(R20)(R22), and -N(R20)-S(=O)₂-R22, wherein each optional alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituent is further optionally substituted with halo, -N0₂, -CF₃, -O-CF3, -N(R20)(R22), -C(O)-R20, -C(O)-O-R20, -C(O)- N(R20)(R22), -CN, -O-R20, or optionally substituted alkyl; or

R₇ and Rg. taken together, is a'-Qc*-R35-Qd*-R36-b', wherein Qc* and Qd* are each independently selected from covalent bond, -0-, -NH-, and -S-; R35 is C1-C4 alkylene optionally substituted with -R20; R36 is covalent bond or-CHR20-; a' is a first single covalent bond to phenyl ring D, and b' is a second single covalent bond to phenyl ring D at a position that is ortho to the a'; wherein Qd* and R36 are not both covalent bond; or

R₇ and Rg, taken together with phenyl ring D, form a fused bicyclic heteroaryl selected from benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiphenyl, benzo[c]thiophenyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl,

R9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -N0₂, -CF₃, -O-CF3, -CN, -O-R20, -S-R20, - N(R20)(R22), -S(=O)-R22, -S(=O)₂R22, -S(=O)₂-N(R20)(R22), -S(=O)₂-O-R20, - N(R20)-C(O)-R22, -N(R20)-C(O)-O-R22, -N(R20)-C(O)-N(R20)(R22), -C(O)-R20, - C(O)-O-R20, -C(O)-N(R20)(R22), and -N(R20)-S(=O) -R22, wherein each optional alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituent is further optionally substituted with halo, -NO2, -CF₃, -O-CF3, -N(R20)(R22), -C(O)-R20, -C(O)-O-R20, -C(O)- N(R20)(R22), -CN, -O-R20, or optionally substituted alkyl;

X₂ is -N= or-C(R16)=, wherein R16 is selected from hydrogen, halo, -O-R20, -alkyl, -CF₃, -CN, -N(R20)(R22), or -L3-R38, wherein

L3 is -Lj-, or -Lj'-O-Lj'-, wherein Lj is C₁-C₆ alkylene optionally substituted with 1 or 2 groups independently selected from hydroxyl and C₁-C₃ alkyl; and each Lj' independently is C₂-C₆ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups;

Xi and X3 each are independently -N= or-C(Rl 7)=, wherein R17 is hydrogen, halo, cyano, optionally substituted alkyl, or -N(R20)(R22);

each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C1-C15 alkyl, C₂-C₁₅ alkenyl, C₂-C₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, -CN, lower alkoxy, -CF3, aryl, and heteroaryl; R24 is optionally substituted alkyl or optionally substituted aryl;

R26 is optionally substituted alkyl or optionally substituted cycloalkyl.

[0074] In typical embodiments the compounds of the invention have the structure shown in Formula (I):

wherein:

C* is carbon,

Ri is -L1-R18 or is -R19, wherein:

LI is -Lk- wherein Lk is C]-C₆ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups;

R18 is hydrogen, hydroxyl, -CF₃, -CN, C₁-C₃ alkoxy, -O-R20, - C(O)-R20, -C(O)-O-R20, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -C(O)- N(R20)-S(=O)₂-R26, tetrazolyl, phenyl, or heteroaryl; wherein said phenyl, or heteroaryl is optionally substituted with 1 , 2, or 3 groups independently selected from hydroxyl, halo, optionally substituted alkyl, C₁-C₃ alkoxy, - O-R20, -C(O)-O-R20, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted phenyl, or optionally substituted heteroaryl; and

RI 9 is hydrogen, phenyl, or heteroaryl; wherein said phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, -CN, optionally substituted alkyl, C₁-C₃ alkoxy, -C(O)-O-R20, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted phenyl, or optionally substituted heteroaryl;

R₂ and R₃ are each independently hydrogen or C₁-C₃ alkyl, or R₂ and R₃, taken together with the carbon to which they are both attached, form an optionally substituted cycloalkyl; or

R₂ and R₃, taken together, is selected from:

a) a'-Qa*-R32-Qa*-b', wherein each Qa* is independently selected from -0-, -NH-, and -S-; R32 is C2-C5 alkylene; and a' and b' are each single covalent bonds to C*; or

b) a'-R34-Qb*-R34-b', wherein Qb* is independently selected from -0-, -N(R30)-, and -S-; each R34 is independently C₁-C alkylene; R30 is hydrogen or optionally substituted alkyl, and a' and b' are each single covalent bonds to C*;

D designates the phenyl ring in Formula (I) to which R7, Rg, and R9 are attached,

R₇, R«, and R9 are each independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, halo, -CF₃, -O-CF3, -CN, -O-R20, -N(R20)(R22), - C(O)-R20, and -C(O)-N(R20)(R22), wherein each optional alkyl, aryl, and heteroaryl substituent is further optionally substituted with halo, -CF₃, -O-CF3, -CN, -N(R20)(R22), - C(O)-R20, -O-R20, or optionally substituted alkyl;

X2 is-C(R16)=, wherein R16 is selected from hydrogen, halo, -O-R20, -alkyl, -CF3, -CN, -N(R20)(R22), or -L3-R38, wherein

L3 is -Lj- wherein Lj is C₁-C₆ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups; and

R38 is hydrogen, hydroxyl, -CF₃, C₁-C₃ alkoxy, -O-R20, -C(O)-0- R20, -C(O)-N(R20)-S(=O)₂-R26, or tetrazolyl;

X₁ and X₃ each are independently -C(R17)=, wherein R17 is hydrogen, halo, cyano, or optionally substituted alkyl;

each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C₁-C₁₅ alkyl, and aryl, wherein the alkyl and aryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, -CN, alkyl, lower alkoxy, and -CF3;

R24 is optionally substituted alkyl or optionally substituted aryl; and

R26 is optionally substituted alkyl or optionally substituted cycloalkyl.

[0075] In typical embodiments the compounds of the invention have the structure shown in Formula (I):

wherein:

C* is carbon,

R₁ is -L1-R18 or is -R19, wherein:

LI is -Lk- wherein Lk is C₁-C₃ alkylene optionally substituted with 1 or 2 methyl groups;

R₁₈ is hydrogen, hydroxy., -CF₃, C₁-C₃ alkoxy, -C(O)-O-R20, or heteroaryl; wherein said heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, optionally substituted alkyl, C₁-C₃ alkoxy, -O-R20, or -C(O)-O-R20;

R19 is hydrogen;

R₂ and R₃ are each independently hydrogen or C₁-C₃ alkyl, or

R₂ and R₃, taken together, is a'-Qa*-R32-Qa*-b\ wherein each Qa* is -0-; R32 is C₂- C₃ alkylene; and a' and b' are each single covalent bonds to C*;

D designates the phenyl ring in Formula (I) to which R₇, R₈, and R₉ are attached, R₇, Rg, and R9 are each independently selected from the group consisting of hydrogen, alkyl, halo, -CF₃, -CN, -O-R20, -C(O)-R20, and -C(O)-N(R20)(R22);

X2 is-C(R16)=, wherein R16 is hydrogen;

X₁ and X₃ each are independently -C(R 17)=, wherein RI 7 is hydrogen;

each instance of R20 and R22 is independently selected from hydrogen, C₁-C₃ alkyl, or optionally substituted phenyl.

[0076] In typical embodiments, each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C_1-15 alkyl, C_2-15 alkenyl, C_2-15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or di-alkylamino, C_1-6 alkyl-O-, -CF3, aryl, and heteroaryl. In some embodiments, each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or di-alkylamino, C_1-6 alkyl-O-, -CF3, aryl, and heteroaryl. In certain embodiments, each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C₁-C₆ alkyl, and aryl, wherein the alkyl and aryl moieties are optionally substituted with from 1 or 2 substituents independently selected from halo, alkyl, amino, C_1-6 alkyl-O-, -CF3, and -O-CF3.

Further embodiments:

[0077] In typical embodiments, the compounds provided by the present invention are effective in the treatment of conditions known to respond to administration of late sodium channel blockers, including cardiovascular diseases such as atrial and ventricular

arrhythmias, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induced angina, congestive heart disease, and myocardial infarction. In some embodiments, compounds provided by the present invention which function as late sodium channel blockers may be used in the treatment of diseases affecting the neuromuscular system resulting in pain, seizures, or paralysis, or in the treatment of diabetes and disease states related to diabetes, such as diabetic peripheral neuropathy.

[0078] Certain compounds of the invention may also possess a sufficient activity in modulating neuronal sodium channels and may have appropriate pharmacokinetic properties such that they may active with regard to the central and/or peripheral nervous system.

Consequently, some compounds of the invention may also be of use in the treatment of pain of neuropathic origin.

[0079] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a hydrate of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g. a compound of Formula (I), such as a compound of Formula (I) named herein.

Pharmaceutical Compositions

[0080] Compounds provided in accordance with the present invention are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be

administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's

Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.)

[0081] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

[0082] One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for

administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0083] Sterile injectable solutions are prepared by incorporating a compound according to the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0084] Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0085] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents. [0086] The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer- coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902514; and 5,616,345.

Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of

pharmaceutical agents.

[0087] The compositions are preferably formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable

pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0088] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [0089] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0090] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0091] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

SYNTHETIC REACTION PARAMETERS

[0092] The terms "solvent," "inert organic solvent" or "inert solvent" refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0093] The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

SYNTHESIS OF EXAMPLE COMPOUNDS

[0094] The compounds of the invention may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein, e.g. compounds having structures described by Formula (I), may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers.

GENERAL SYNTHESES:

[0095] Typical embodiments of compounds in accordance with the present invention may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments of the present invention, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.

EXAMPLE 1

Example 1 A: General method for synthesis of compounds of Formula (I) Scheme I

[0096] Starting material compounds 2 are generally available commercially or may be synthesized using published methods. Referring to Scheme I, to a suspension of 2 in hot H₂0 was added slowly a solution of Br₂ and Br in H₂0. The reaction mixture was heated with stirring for 1 to 60 hours (h), preferably heated to reflux for ca 20 h. After completion, the reaction mixture was cooled, sonicated, filtered. The insoluble solid was washed with H₂0 and an organic solvent, preferably hexane, ether or a mixture of EtOAc and hexane, dried to afford compound 3, which was usually fine for the next step reaction. In case it was not pure enough, or the solid did not form, a traditional column chromatography would be used to give relatively pure 3.

[0097] Compound 3 was coupled with arylboronic acid or pinacol ester in a combined solvent of aqueous base such as sodium bicarbonate and organic solvent like DMF or DME. Palladium catalyst such as Ph(PPh₃)4 or PdCl₂(PPh₃)₂ was used under conventional heating at a temperature between 25°C and 150°C for 1 to 24 h, or microwave heating at a temperature between 100°C and 200°C, preferably at around 140°C for 5 to 40 min. The reaction mixture was usually diluted with ethyl acetate, and filtered through a layer of celite. The combined filtrate was washed with water or IN NanCCb, 30% aqueous NH₄CI, brine, dried and concentrated. The residue was purified by precipitation from an organic solvent such as methanol or Et₂0, followed by washing and drying, or by column chromatography via silica gel. It could also be purified by preparative HPLC eluting with a gradient solvent of MeCN and H₂0 (2% to 98%) to afford compound of Formula (I). Example IB: General method for synthesis of compounds of Formula (I)

[0098] Starting material compounds 5 are generally available commercially or may be synthesized using published methods. Compound 5 was treated with a base such as NaH or potassium carbonate in a polar solvent such as DMF or THF, excess R|-C1 or R_t-Br was added at a temperature between 0°C and 160°C, preferably at around 25°C for 1 to 40 h. Conventional work up and re-crystallization, or column chromatography purification via silica gel, or preparative HPLC separation was used to afford compound 6. To a solution of 6 in a non-polar solvent, preferably benzene or toluene, was added PCI 5 and heated at a temperature between 0°C and 120°C, preferably at around 50°C for 1 to 40 h. The solvent was removed in vacuo, and the residue was further purified by column chromatography to afford compound 7. To a solution of 7 in AcOH was added slowly excess activated zinc, and the resulting mixture was stirred further for 5 min to 6 h. The zinc was filtered off and washed with AcOH and EtOAc. The filtrate was concentrated in vacuo, and concentrated NaHCC*3 was added to quench the acid. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with 30% NH₄CI and brine, dried over MgS0₄ and concentrated in vacuo. The residue was purified by column chromatography to afford compound 8. Finally, compound of Formula (I) where both R2 and R3 are hydrogens was synthesized via a similar Suzuki-Miyaura coupling as that in Scheme I.

EXAMPLE 2 Example 2A: Synthesis of a compound of Formula (I) via microwave heating method

[0100] To a solution of 101 (212 mg, 1.00 mmol) and 4-fluorophenylboronic acid (168 mg, 1.20 mmol) in DMF (2.5 mL) was added NaHC0₃ (252 mg, 3.00 mmol) and H₂O (0.5 mL). The reaction mixture was stirred for 5 min under an atmosphere of dry N₂. PdC.₂(PPh₃)₂ (35 mg, 0.05 mmol) was added, the resulting mixture in a 5 mL Biotage microwave vial was heated using microwave irradiation at 150°C for 20 min. Cooled, diluted with EtOAc (10 mL), filtered through a layer of rightly packed celite, washed with 10% DMF in EtOAc (60 mL), transferred to a separation funnel, organic phase was washed with 1N Na₂CO₃ (30 mL), 30% NH₄CI (30 mL) and brine (30 mL), dried and concentrated. To this crude product was added MeOH (3 mL), sonicated, filtered, washed with cold MeOH (5 mL), dried to afford white solid 102 (120 mg, 0.53 mmol, 53%), LCMS mz 228.1 (M+H), anal HPLC >97% in purity. ^!H NMR (400 MHz; CDC1₃) 57.88 (s, 1H); 7.45-7.55 (m, 2H); 7.41 (d, J = 0.8 Hz, 1H); 7.39 (dd, J = 7.8 and 0.8 Hz, 1H); 7.05-7.16 (m, 2H); 6.92 (d, J - 7.8 Hz, 1H); 3.60 (s, 2H).

Example 2B: Synthesis of a compound of Formula (I) via conventional heating method

[0101] To a solution of 101 (6.362 g, 30.0 mmol) and 4-fluorophenylboronic acid (5.037 g, 36.0 mmol) in DMF (90 mL) was added NaHCO₃ (10.090 g, 120.0 mmol) and H₂O (10 mL). The reaction mixture was stirred for 10 min under an atmosphere of dry N₂. Pd(PPh₃)4 (866 mg, 0.75 mmol) was added, the resulting mixture was heated at 88°C. In ca 4 h, 101 disappeared in the reaction mixture (LCMS). Cooled, diluted with EtOAc (180 mL), filtered through a thick layer of tightly packed celite, washed with 10% DMF in EtOAc (360 mL), transferred to a separation funnel, organic phase was washed with IN Na₂C0₃ (150 mL), 30% NH₄CI (150 mL) and brine (150 mL), dried (Na_sS0₄) and concentrated. To this crude product was added warm (40°C) MeOH (15 mL), sonicated, filtered, washed with MeOH (25 mL), dried to afford 102 (2.590 g, 11.4 mmol, 39%), LCMS mz 228.1 (M+H), anal HPLC >95% in purity.

[0102] The filtrate from MeOH washed was concentrated in vacuo. The solid was recrystallized from EtOAc to give first crop of 102 (2.128 g, 9.36 mmol, 31%), LCMS mz 228.1 (M+H), anal HPLC >98% in purity. Further recrystallization afforded another 600 mg of 102 at a purity of 96%. Overall yield was 78%. 1H NMR (400 MHz; CDCI3) of the combined compound 102: 57.90 (s, 1H); 7.45-7.55 (m, 2H); 7.36-7.44 (m, 2H); 7.05-7.16 (m, 2H); 6.92 (d, J = 7.8 Hz, 1H); 3.60 (s, 2H).

EXAMPLE 3

Example 3: Synthesis of further compounds of Formula (I)

[0103] Similarly, following the above procedures, but optionally replacing 4- fluorophenylboronic acid with other optionally substituted aryl boronic acids, or optionally replacing simple 5-bromoindolin-2-one with other substituted 5-bromoindolin-2-one, or optionally replacing the conventional heating with microwave heating, and vice versa, the following compounds of Formula (I) were prepared:

[0104] 5-(3-fluorophenyl)-1,3-dihydro-2H-indol-2-one;

[0105] 5-[4-(trifluoromethyl)phenyl]- 1 ,3-dihydro-2H-indol-2-one;

[0106] 5-(3,4-difluorophenyl)-l ,3-dihydro-2H-indol-2-one;

[0107] 1 -methyl-5-[3-(trifluoromethyl)phenyl]-l ,3-dihydro-2H-indol-2-one;

[0108] 5-(3-chloro-4-fluorophenyl)-1,3-dihydro-2H-indol-2-one;

[0109] 5-[4-(trifluoromethoxy)phenyl]-l ,3-dihydro-2H-indol-2-one;

[0110] 5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one;

[0111] 5-(2,5-dimethoxyphenyl)-l ,3-dihydro-2H-indol-2-one;

[0112] 5-[4-fluoro-3-(trifluoromethyl)phenyl]-l ,3-dihydro-2H-indol-2-one;

[0113] 5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one;

[0114] 5-[4-chloro-2-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one;

[0115] 5-(2,4-difluorophenyl)- 1 ,3-dihydro-2H-indoI-2-one;

[011 ] 5-[2,4-bis(trifluoromethyl)phenyl]- 1 ,3-dihydro-2H-indol-2-one;

[0117] 5-(2-fluorophenyl)- 1 ,3 -dihydro-2H-indol-2-one;

[0 18] 5-(3-methoxyphenyl)- 1 ,3-dihydro-2H-indol-2-one; [0119] 5-(6-methoxypyridin-3-yl)-l ,3-dihydro-2H-indol-2-one;

[0120] 5-(2, 1 ,3 -benzoxadiazol-5-yl)- 1 ,3-dihydro-2H-indol-2-one;

[0121] 5-(3-nitrophenyl)- 1 ,3-dihydro-2H-indol-2-one.

EXAMPLE 4

Example: Synthesis of compounds of Formula (I)

[0122] Procedure to compound 301 To a solution of 5-bromoisatin (2.260 g, 10.0 mmol) in anhydrous DMF (20 ml) was added K₂CO₃ (1.520 g, 11.0 mmol), stirred at room temperature for 25 min. To the above mixture was added ethyl 2-chloroacetate (2.451 g, 20.0 mmol), stirred at room temperature for 72 h. The reaction was diluted with EtOAc ( 80 mL), washed with H₂O (40 mL), 30% NH₄CI (40 mL), brine (40 mL), dried over Na₂SO₄, and concentrated. To the crude product was added Et₂O (20 mL), sonicated, filtered, washed with Et₂0 (40 mL), and dried to afford 301 (2.495 g, 8.0 mmol, 80%). LCMS mz 311.9 (M+H), 313.9 (M+2+H), anal HPLC > 94% in purity, ¹H NMR (400 MHz; CDC1₃) δ7.76 (d, J = 2.0 Hz, 1H); 7.70 (dd, J = 8.6 and 2.0 Hz, 1H); 6.70 (d, J = 8.6 Hz, 1H); 4.48 (s, 2H); 4.25 (q, J = 7.1 Hz, 2H); 1.92 (t, J = 7.1 Hz, 3H).

[0123] Procedure to compound 302 To a solution of 301 (1.561 g, 5.0 mmol) in a mixture of benzene (25 mL) and DMF (3 mL) was added PCI₅ (2.337 g, 11.5 mmol) at room temperature and stirred for 10 min. It was then heated at 80°C for 18 h under an atmosphere of dry N₂. The solvent was removed in vacuo, and the residue was further purified by column chromatography via silica gel, eluted with CH₂CI₂ to afford compound 302 (1.156 g, 31.5 mmol, 63%). LCMS mz 367.8 (M+H), 389.8 (M+Na), anal HPLC > 98% in purity, ^lH NMR (400 MHz; CDCI₃) δ7.79 (d, J = 2.0 Hz, 1H); 7.52 (dd, J = 8.3 and 2.1 Hz, 1H); 6.66 (d, J = 8.4 Hz, 1H); 4.46 (s, 2H); 4.23 (q, J = 7.1 Hz, 2H); 1.27 (t, J = 7.1 Hz, 3H).

[0124] Procedure to compound 303 To a solution of 301 (807 mg, 2.2 mmol) in AcOH (20 mL) was added slowly activated zinc (1.500 g, 21.9 mmol), and the resulting was stirred further for 30 min. The zinc was filtered off and washed with AcOH (10 mL) and EtOAc (20 mL). The filtrate was concentrated in vacuo, and 2N NaHCOj (30 mL, 60 mmol) was added and stirred until there was no bubble from the reaction. The resulting mixture was extracted with EtOAc (3 x 30 mL), and the combined organic layers were washed with 30% H₄CI (50 mL) and brine (50 mL), dried over MgSO₄ and concentrated in vacuo to afford, without further purification, compound 303 (603 mg, 2.0 mmol, 91%). LCMS mz 367.8 (M+H), 389.8 (M+Na), anal HPLC > 98% in purity, ¹H NMR (400 MHz; CDCI3) 67.40 (s, 1H); 7.38 (m, 1H); 6.60 (d, J = 8.6 Hz, 1H); 4.45 (s, 2H); 4.22 (q, J = 7.1 Hz, 2H); 3.63 (s, 2H); 1.27 (t, J = 7.1 Hz, 3H).

[0125] Procedure to compound 304 To a solution of 303 (298 mg, 1.00 mmol) and 4-(trifluoromethoxy)phenylboronic acid (247 mg, 1.20 mmol) in DMF (2.5 mL) was added NaHCC>3 (420 mg, 5.00 mmol) and H₂0 (0.5 mL). The reaction mixture was stirred for 5 min under an atmosphere of dry N₂. Pd(PPh₃) (59 mg, 0.05 mmol) was added, the resulting mixture in a 5 mL Biotage microwave vial was heated using microwave irradiation at 150°C for 30 min. After cooling, the mixture was diluted with EtOAc (10 mL), filtered through a layer of tightly packed celite, washed with 10% DMF in EtOAc (60 mL), transferred to a separation funnel, organic phase was washed with IN Na₂CO₃ (30 mL), 30% NH₄CI (30 mL) and brine (30 mL), dried and concentrated. The crude product was purified by preparative HPLC with a gradient MeCN/H₂0 (5-98%) to afford compound 304 (205 mg, 0.54 mmol, 54%). LCMS mz 380.0 (M+H), 402.0 (M+Na), anal HPLC > 95% in purity, ¹H NMR (400 MHz; CDCI3) 57.53 (m, 2H); 7.45 (m, 2H); 7.20-7.30 (m, 2H); 6.78 (m, 1H); 4.50 (s, 2H); 4.24 (m, 2H); 3.67 (s, 2H); 1.27 (m, 3H).

[0126] Procedure to compound 305 To a solution of 304 (76 mg, 0.20 mmol) in MeOH (2 mL) was added IN LiOH (4 mL, 4.00 mmol). The resulting mixture was stirred for 18 h under an atmosphere of dry N₂. The reaction mixture was acidified to PH 4, extracted with EtOAc (4 x 20 mL), combined organic layers were washed with 30% NH₄CI (30 mL) and brine (30 mL), dried and concentrated to afford compound 304 (65 mg, 0.18 mmol, 90%). LCMS mz 352.0 ( +H), 373.9 (M+Na), anal HPLC ca 90% in purity, 1H NMR (400 MHz; CDC1₃) δ8.09 (m, 1H); 7.40-7.60 (m, 4H); 7.20-7.35 (m, 1H); 6.83 (m, 1H); 4.55 (s, 2H); 3.68 (s, 2H).

EXAMPLE 5

Example 5: Synthesis of further compounds of Formula (I)

[0127] Similarly, following the above procedures, but optionally replacing 4- (trifluoromethoxy)phenylboronic acid with other optionally substituted aryl boronic acids, or optionally replacing simple 5-bromoindolin-2-one with other substituted 5-bromoindolin-2- one, or optionally replacing the conventional heating with microwave heating, and vice versa, the following compounds of Formula (I) were prepared:

[0128] ethyl (5-bromo-2,3 -dioxo-2,3-dihydro- 1 H-indol- 1 -yl)acetate;

[0129] ethyl {2-oxo-5-[4-(trifluoromemoxy)phenyl]-2,3-<iihydro-1H-indol- 1 -yl } acetate;

[0130] ethyl {2-oxo-5-[3-( fluoromethoxy)phenyl]-2,3-dihydro-1H-indol-1-yl}acetate;

[0131] ethyl (5-bromo-2-oxo-2,3-dihydro-l H-indol- l-yl)acetate;

[0132] ethyl {2,3-dioxo-5-[4-(trifluoromemoxy)phenyI]-2,3-dihydro-1H-indol-1-yl}acetate;

[0133] {2-oxo-5-[4-(trifluoromethoxy)phenyl]-2,3-dihydro- 1 H-indol- 1 -yl} acetic acid;

[0134] ethyl [5-(4-fluorophenyl)-2-oxo-2,3-dihydro-l H-indol- l-yl]acetate;

[0135] 5-bromo- 1 -(pyridin-3-ylmethyl)- 1 H-indole-2,3 -dione;

[0136] 5-(4-fluorophenyl)-l -(pyridin-3-ylmethyl)- 1 H-indole-2,3-dione;

[0137] 3,3-dichloro-5-(4-fluorophenyl)-l -(pyridin-3-ylmethyl)-l ,3-dihydro-2H-indol-2- one;

[0138] tert-butyl (5-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate;

[0139] 5-(4-fluorophenyl)- 1 H-indole-2,3-dione. EXAMPLE 6

Example 6: Synthesis of compounds of Formula (I)

[0140] Procedure to compound 401 and 402 To a solution of 101 (45 mg, 0.20 mmol) and benzyl isocyanate (29 mg, 0.22 mmol) in acetone (2 mL) was added N,N- diisopropylethylamine (252 mg, 3.00 mmol) in a 5 mL Biotage microwave vial. The reaction mixture was stirred for 5 min under an atmosphere of dry N₂. It was then heated using microwave irradiation at 120°C for 30 min. Cooled, concentrated, the residue was taken up with EtOAc (40 mL), washed with 0.1 N HCl (20 mL), 30% NH₄CI (30 mL) and brine (30 mL), dried and concentrated. The crude product was purified by preparative HPLC with a gradient MeCN/H₂0 (5-98%) to afford compound 401 (10 mg, 0.02 mmol, 10%). LCMS mz 494.1 (M+H), 516.1 (M+Na), anal HPLC ca 92% in purity, Ή NMR (400 MHz; CDC1₃) 67.40-7.55 (m, 6H); 7.30-7.37 (m, 2H); 7.20-7.30 (m, 3H); 7.10-7.20 (m, 2H); 7.00-7.10 (m, 2H); 6.68 (d, J = 8.6 Hz, 1H); 6.48 (s, 1H); 4.84 (d, J = 5.5 Hz, 1H); 4.43 (d, J = 5.5 Hz, 1H);

3.43 (bs, 2H); 2.88 (bs, 2H).

[0141] The preparative HPLC with a gradient MeCN/H₂0 (5-98%) also afforded compound 402 (22 mg, 0.08 mmol, 40%). LCMS mz 268.0 (M+H), 290.0 (M+Na), anal HPLC ca 92% in purity, Ή NMR (400 MHz; CDC1₃) 67.67 (s, 1H); 7.63 (s, 1H); 7.50 (m, 2H); 7.36 (dd, J - 8.0 and 1.8 Hz, 1H); 7.12 (m, 2H); 6.90 (d, J = 8.2 Hz, 1H); 2.64 (s, 3H);

2.44 (s, 3H).

[0142] The names of the compounds include:

[0143] N,N'-dibenzyl-5-(4-fluorophenyl)-2-oxo-2,3-dihydro- 1 H-indole- 1 ,3 -dicarboxamide;

[0144] 5-(4-fluorophenyl)-3-(propan-2-ylidene)- 1 ,3-dihydro-2H-indol-2-one. EXAMPLE 7

Example 7: Synthesis of compounds of Formula (I)

102 601

[0145] Procedure to compound 601 and 602 A reaction vial (10 mL capacity) was charged with compound 102 (35 mg, 0.15 mmol) and anhydrous Ac₂0 (2.0 mL) and heated at 90°C for 6 h. After cooling, 2N NaHC0₃ (20 mL, 40 mmol) was added and stirred until there was no bubble from the reaction. The resulting mixture was extracted with EtOAc (3 x 30 mL), and the combined organic layers were washed with 30% NH₄CI (50 mL) and brine (50 mL), dried over MgSC>4 and concentrated in vacuo The crude product was purified by by preparative HPLC with a gradient MeCN/H₂0 (5-98%) to give 601 (19 mg, 0.07 mmol, 47%). LCMS mz 270.0 (M+H), anal HPLC 98%. 1H NMR (400 MHz; CDC1₃) 58.28 (d, J = 8.3 Hz, 1H); 7.40-7.60 (ra, 4H); 7.13 (t, J = 8.8 Hz, 2H); 3.78 (s, 3H); 2.70 (s, 3H).

[0146] The preparative HPLC with a gradient MeCN H₂0 (5-98%) also afforded compound 602 (15 mg, 0.04 mmol, 28%). LCMS mz 354.0 (M+H), 376.0 (M+Na), anal HPLC 98%, Ή NMR (400 MHz; CDCI3) 58.34 (d, J = 9.0 Hz, 1H); 7.76 (d, J = 2.0 Hz, 1H); 7.45-7.56 (m, 3H); 7.15 (t, J = 8.7 Hz, 2H); 2.74 (s, 3H); 2.72 (s, 3H); 2.41 (s, 3H).

[0147] The names of the compounds include:

[0148] 1 -acetyl-5-(4-fiuorophenyl)-l ,3-dihydro-2H-indol-2-one;

[0149] 1 ,3,3 -triacetyl-5-(4-fluorophenyl)- 1 ,3-dihydro-2H-indol-2-one.

EXAMPLE 8

Example 8 A: Synthesis of compounds of Formula (D - spirocvcles

[0150] The biphenyl bromo amide above, prepared by the standard coupling of commercial a, B- unsaturated cyclic acids with the biphenylamine, can be ring closed using a catalytic palladium (zero) intramolecular Heck cyclization. The resulting spiro ring system can be further manipulated by hydrogenation to provide the saturated ring system.

Example 8B: Synthesis of compounds of Formula (I) - spirocvcles

Leading Reference: Overman, L E., et al. J.Org. Chem. 1987, 52, 4130-4133.

[0151] Another application of the intramolecular Heck cyclization is shown above. The starting materials are easily prepared from the biphenylaniline and the commercial fused cyclohexylmaleic anhydride. Subjection of the bromobiphenylamide to catalytic

palladium(zero) and subsequent ring formation should provide the unsaturated carboxylic acid which can form new amides or esters. Hydrogenation of the unsaturation in the newly created spiro ring system would then provide the fully saturated cyclohexyl ring. EXAMPLE 9

Example 9: Synthesis of compounds of Formula (D - spirocvcles

Leading Reference: Jarrahpour, Aliasghar et al. Tetrahedron Lett. 2007, 48, 7140-7143

[0152] Another method for the preparation of oxindole spiro ring systems, which has a number of literature precedents, is the application of the Staudinger like reaction on the alpha imine of an oxindole, generated from reaction of an amine with the biphenylisatin. The Staudinger reaction entails the in situ formation of a ketene which undergoes [2+2] cycloadditon with the isatin derived imine to form a spiro azetidinone.

EXAMPLE 10

Example 10: Synthesis of compounds of Formula fl) - spirocvcles

[0153] Another aspect of the biphenyl isatins, as shown above, is that they can form spiro 5-membered hetero ring systems very easily. There are many optically active glycols commercially available that could be utilized and even some diethyl tartrates that would make for some novel dioxolanes. Likewise, one can use ethylamino alcohols or ethylamino thiols to form the spiro ring system. EXAMPLE 11

Example 11 : Synthesis of compounds of Formula (I) - spirocvcles

[0154] Utilizing the known preference for oxindoles to bisalkylate at the three position, we would alkylate with methyl 2-bromoacetoacetate. The resulting diester can then be subjected to ammonia, an aniline or alkyl primary amine and the subsequent ring closure

would provide a novel spiro cyclic imide.

EXAMPLE 11

Example 11 : Synthesis of compounds of Formula (D - spirocvcles

avorov

vide

s

[0155] Another aspect of the isatin arylimine, as previously shown to engage in Staudinger reactions, can also participate in a Pavorov reaction, and acid catalysed formation of quinolines. In a one pot sequence the biphenyl isatin is subjected to an appropriately substituted aniline and ethylvinyl ether ( or N-vinylpyrollidone or trimethylsilyl acetylene) as the two carbon electron rich olefin. Condensation and cylization should provide the newly formed spiro oxindole quinoline ready for final manipulation, such as elimination of the ethoxy group to the olefin. EXAMPLE 12

Example 12: Preparation of a compound of Formula (I)

[0156] Similarly, by essentially following the procedures set out in Examples 1 through 11 above, but optionally altering the selection of the starting materials to select compounds having the necessary substituents to result in the indicated products (e.g. the products in the table below), or using other synthetic methods known in the art, the following compounds were prepared:

Table 1:

ID

(PT-nnn) Name of Compound

PT-001 5-(3-fluorophenyI)-l ,3-dihydro-2H-indol-2-one

PT-002 5-[3-(trifluoromethyI)phenyl]-l ,3-dihydro-2H-indol-2-one

PT-003 5-(4-fluorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-004 5-(3-fluorophenyl)-1-methyl-l ,3-dihydro-2H-indol-2-one

PT-005 5-[4-(trifluoromethyI)phenyI]-l ,3-dihydro-2H-indol-2-one

PT-006 5-(3,4-difluorophenyl)-l ,3-dihydro-2H-indol-2-one

P -007 1 -raethyl-5-[3-(trifluoromethyI)phenyl]-l ,3-dihydro-2H-indol-2-one

PT-008 5-(3-chloro-4-fluorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-009 5-[4-(trifluoromethoxy)phenyl]- 1 ,3-dihydro-2H-indol-2-one

PT-010 5-[4-chloro-3-(trifluoromethyI)phenyl3-l ,3-dihydro-2H-indol-2-one

PT-011 5-(2,5-dimethoxyphenyl)-l ,3-dihydro-2H-indol-2-one

PT-012 5-[4-fluoro-3-(trifluoromethyI)phenyl]-1,3-dihydro-2H-indol-2-one

PT-013 5-(2,3-dihydro-l ,4-benzodiox.in-6-yl)-l ,3-dihydro-2H-indol-2-one

PT-014 5-[4-chloro-2-(trifluoromethyI)phenyl]-l ,3-dihydro-2H-indol-2-one

PT-015 5-(2,4-difluorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-016 5-[2,4-bis(trifluoromethyI)phenyl]-l ,3-dihydro-2H-indol-2-one

PT-017 5-(2-fluorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-018 5-(3-methoxypheny])-l ,3-dihydro-2H-indol-2-one

PT-019 5-<2,l ,3-benzoxadiazol-5-yl)- 1 ,3-dihydro-2H-indo1-2-one

PT-020 5-(3-nitrophenyl)-l ,3-dihydro-2H-indol-2-one

T-021 7-bromo-5-{4-fluorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-022 6-chloro-5-(4-fluorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-023 6-chloro-5-[3-(trifluoromethyI)phenyl]-1,3-dihydro-2H-indoJ-2-one

PT_024 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

PT-025 5-{4-fluoro-2-methoxyphenyl)-l ,3-dihydro-2H-indol-2-one

PT-026 5-[4-methoxy-2-{trifluoromethyI)phenyl]- 1 ,3-dihydro-2H-indol-2-one

PT-027 5-(3,4-difluorophenyl)-7-fluoro-l ,3-dihydro-2H-indol-2-one

PT-028 ethyl [5-(3,4-difluorophenyl)-2-oxo-2,3-dihydro-l H-indol-1 -yl]acetate

PT-029 ethyl [5-(3,4-difluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetate PT-030 ethyl {2-oxo-5-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-1H-indol-1-yl}acetate

PT-031 ethyl {2-oxo-5-[3-(trifluoromethoxy)phenyl]-2,3-dihydro-l H-indol-1 -yl} acetate

PT-032 {2-oxo-5-[4-(trifluoromethoxy)phenyI]-2,3-dihydro-1H-indol-l -yl}acetic acid

PT-033 5-(4-fluoro-3-methyIphenyl)-l ,3-dihydro-2H-indol-2-one

P -034 ethyl [5-{4-fluorophenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate

PT-035 5-(4-chlorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-036 6-chloro-5-{4-chlorophenyl)-l ,3-dihydro-2H-indol-2-one

PT-037 1 -acetyl-5-(4-fluorophenyl)-l ,3-dihydro-2H-iiidol-2-one

TESTING

[0157] Activity testing is conducted in the Examples below using methods described herein and those well known in the art.

Sodium current screening assays:

[0158] The late sodium current (Late INa) and peak sodium current (Peak INa) assays are performed on an automated electrophysiology platform, PatchXpress 7000A (MDS

Analytical Technologies, Sunnyvale, CA), which uses the whole cell patch clamp technique to measure currents through (he cell membrane of up to 16 cells at a time. The assay uses an HEK293 (human embryonic kidney) cell line heterologously expressing the wild-type human cardiac sodium channel, hNa_v1.5, purchased from Millipore (Billerica, MA). No beta subunits were coexpressed with the Na channel alpha subunit. Cells are maintained with standard tissue culture procedures and stable channel expression is maintained with 400 μg/ml Geneticin in the culture medium. Cells isolated for use on PatchXpress are incubated for 5 minutes in Versene IX and then for 2 minutes in 0.0125% Trypsin-EDTA (both at 37 °C) to ensure that 80-90% of the cells are single and not part of a cell cluster. Experiments are carried out at 24-27 °C.

[0159] For both the Late INa and Peak INa assays, series resistance compensation is set to 50% and whole-cell compensation is performed automatically. Currents are low-pass filtered at 10 kHz and digitized at 31.25 kHz. Currents through open sodium channels are automatically recorded and stored in the DataXpress2 database (MDS Analytical

Technologies, Sunnyvale, CA). Analysis is performed using DataXpress2 analysis software and data are compiled in Excel. [0160] Compound stocks are routinely made in glass vials to 10 mM in dimethyl sulfoxide (DMSO). In some cases, when compounds are not soluble in DMSO, they are made in 100% ethanol. Stocks are sonicated as necessary. The extracellular solution for screening Late INa is composed of: 140 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mM MgCl₂, and 5 mM HEPES with pH adjusted to 7.4 using NaOH. The extracellular solution for screening Peak INa is composed of: 20 mM NaCl, 120 mM N-methyl-D glucamine, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mM MgC^, and 5 mM HEPES with pH adjusted to 7.4 using HCl. The intracellular solution used to perfuse the inside of the cells for both the Late INa and Peak INa assays contains: 120 mM CsF, 20 mM CsCl, 5 mM EGTA, 5 mM HEPES and pH adjusted to 7.4 with CsOH. Compounds are diluted in extracellular solution to 10 μΜ in glass vials and then transferred to glass well plates before robotic addition to the cells. The ONa extracellular solution used at the end of each experiment for the Late INa and Peak INa assays to measure baseline current contains: 140 mM N-methyl-D-glucamine; 4 mM KCl; 1.8 mM CaCl₂; 0.75 mM MgCl₂; 5 mM HEPES and pH was adjusted to 7.4 with HCl.

Late INa Screening Assay:

[0161] For the Late INa assay, sodium channels are activated every 10 seconds (0.1 Hz) by depolarizing the cell membrane to -20 mV for 250 milliseconds (ms) from a holding potential of -120 mV. In response to a -20 mV voltage step, typical Na_vl .5 sodium currents activate rapidly to a peak negative current and then inactivate nearly completely within 3-4 ms (see Figure 1).

[0162] All compounds are tested to determine their activity in blocking the late sodium current. Late INa current is generated by adding 10 μΜ Tefluthrin (pyrethroid) to the extracellular solution while recording Na currents. In Figure 2 the black traces (designated by the arrow, 101) are Na current measured before addition of Tefluthrin and the gray traces (designated by the arrow, 102) are measured after Tefluthrin addition. For some

experiments, 50 nM ATX II (sea anemone toxin), another late INa activator, was used to generate the late component. Bom activators generate late components that are large enough that block of the late component by compounds can be measured easily. For the purposes of the screening, late INa is defined as the mean current between 225 ms and 250 ms after stepping to -20 mV to activate Na channels. After establishing the whole cell recording configuration, late INa activators are added to each well 4 times over a 16-17 minute period so that the late component of the Na current reaches a stable value. Compounds are then added (typically at 10 μΜ), in the presence of late INa activator, with 3 additions over the course of 7 or 8 minutes. Measurements are made typically at the end of exposure to the third compound addition. Baseline current in the absence of Na⁺ ions is measured at the end of each experiment (after two additions of ONa solution-see above) and is used to calculate the percent block by compound.

Peak INa Screening Assay:

[0163] Compounds were also evaluated for their effect in several other assays, including their effect on Peak INa. In some cases, the effect on Peak INa was measured using data from the Late INa assay. However, peak currents were often too large to make this possible, requiring a separate assay to evaluate the effect on peak INa. Since the peak INa can be very large, introducing artifacts in the recording, the concentration of Na⁺ in the bath is reduced to 20 mM and a nonpermeant cation is added to compensate for the Na⁺ that was omitted from the standard extracellular solution (see above). The peak INa assay uses a holding potential of -100 mV and a 20 ms test pulse to 0 mV to activate the channel. As in the Late INa assay, stepping the voltage to 0 mV causes a rapid increase in negative Na current through hNavl .5 that inactivates within a few ms. No late INa activator is added for the peak assay.

[0164] For the separate peak INa assay, both tonic (TB) block and use-dependent (UDB) block of peak inward sodium current by 10 uM compound are determined. TB is block of the channel in the resting state, before the channel opens. TB is simulated in this assay by stimulating the channel to open at a low frequency (0.1 Hz). This is done in order to measure the control current amplitude and monitor current rundown, enabling correction for rundown in the calculation of percent block for TB. UDB is measured by stimulating the channel to open at a higher frequency (3 Hz) and is used to determine accumulated block in activated states by compound. Activating the channel at this higher frequency typically also decreases the peak current some even in the absence of compound. Therefore, the assay is designed to measure the use-dependent decrease in peak both in the absence and in the presence of compound, and the calculation of UDB corrects the decrease in current measured in the presence of compound for the decrease in current in the absence of compound (Figure 4).

[0165] After establishing the whole cell recording configuration, currents are allowed to stabilize for 6-10 minutes while channels are activated briefly at 0.1 Hz. This is followed by a 2 minute stimulation at 3 Hz and then a 2 minute stimulation at 0.1 Hz before addition of compound. Compound is added 3 times over a period of 2 to 3 minutes and channels are exposed to compound for 8 to 9 minutes before another round of high frequency stimulation at 3 Hz for 2 minutes. As with the late INa assay, ONa extracellular solution is added two times at the end to establish the baseline current and demonstrate the quality of solution exchange and the recording. hERG Screening Assay:

[0166] Compounds were screened to test their activity in blocking the hERG potassium channel. The hERG channel is heterologously expressed in a CHO (Chinese Hamster Ovary) cell line. Cells are maintained with standard tissue culture procedures and stable channel expression is maintained with 500 μg ml G418 in the culture medium. Cells are harvested for testing on the PatchXpress automated patch clamp with Accumax (Innovative Cell Technologies, San Diego, CA) to isolate single cells.

[0167] The following solutions are used for electrophysiological recordings. The external solution contains: 2 mM CaCl₂; 2 mM MgCl₂; 4 mM KCl; 150 mM NaCl; 10 mM Glucose; 10 mM HEPES (pH 7.4 with 1M NaOH, osmolality). The internal solution contains: 140 mM KCl, 10 mM MgCl₂, 6 mM EGTA, 5 mM HEPES, 5 mM ATP (pH adjusted to 7.25 with KOH).

[0168] hERG channels are activated when the voltage is stepped to +20 mV from the -80 mV holding potential (see Figure 3). During a 5 second step at +20 mV, the channels activate and then largely inactivate, so the currents are relatively small. Upon returning to - 50 mV from +20 mV, hERG currents transiently become much larger as inactivation is rapidly removed and then the channel closes. The first step to -50 mV for 300 ms is used as a baseline for measuring the peak amplitude during the step to -50 mV after channel activation. The peak current at -50 mV is measured both under control conditions and after addition of compound.

[0169] All compounds are prepared as 10 mM DMSO stocks in glass vials. Stock solutions are mixed by vigorous vortexing and sonication for about 2 minutes at room temperature. For testing, compounds are diluted in glass vials using an intermediate dilution step in pure DMSO and then further diluted to working concentrations in external solution. Dilutions are prepared no longer than 20 minutes before use. [0170] After achieving the whole-cell configuration, cells are monitored for 90 seconds to assess stability and washed with external solution for 66 seconds. The voltage protocol described above is then applied to the cells every 12 seconds and throughout the whole procedure. Only cells with stable recording parameters and meeting specified health criteria are allowed to enter the compound addition procedure.

[0171] External solution containing 0.1% DMSO (vehicle) is applied to the cells first to establish the control peak current amplitude. After allowing the current to stabilize for 3 to 5 minutes, 1 μΜ and then 10 μΜ test compounds are applied. Each compound concentration is added 4 times and cells are kept in test solution until the effect of the compound reaches steady state or for a maximum of 12 minutes. After addition of test compound, a positive control (1 μΜ Cisapride) is added and must block >95% of the current for the experiment to be considered valid. Washout in the external solution compartment is performed until the recovery of the current reaches steady state. Data are analyzed using DataXpress, Clampfit (Molecular Devices, Inc., Sunnyvale) and Origin 7 (Originlab Corp.)

L-type Calcium Channel Activity Well-Plate Assay:

[0172] Cell Culture: IMR-32 (human neuroblastoma) cells were obtained from The American Type Culture Collection. The cells were maintained in MEM supplemented with 10% fetal bovine serum, 2 mM of L-glutamine, 100 IU/ml of penicillin, 50 μ τϊ of streptomycin, 1% of sodium pyruvate, 1% of sodium bicarbonate and 1% of non-essential amino acid. The cells were cultured at 37°C in a humidified 5% C0₂ 95% air incubator. Culture medium was changed every two days and cells were recultivated when they reached 70-80% confluent.

[0173] Assay: IMR-32 cells were seeded on a Microtest 96-well Assay Plate (BD

FALCON™) at a density of 200,000 cells/well in 200 μΐ culture medium for overnight. The culture medium was removed, and replaced by 120 μΐ Ca-4 dye (MDS Analytical

Technologies, Sunnyvale, CA) in HBSS (lx Hank's Balanced Salt solution plus 20 mM HEPES, pH 7.4) containing 2 mM probenecid. Cells were then incubated for 1 hour at 37 ⁰ in incubator. Testing compounds were diluted from 5 μΜ - 50 μΜ in HBSS, and 40 μΐ were added in cells before assay. L-type calcium channel activities (Max - Min) were measured after addition of 40 μΐ of 1 μΜ (-)Bay K 8644 plus 50 mM KCl (final concentration) using FlexStation (Molecular Devices) immediately after addition of testing compounds. The inhibition of L-type calcium channel activity by compounds was then calculated. [0174] Compounds were tested using the described assay methods. Data are shown in Table 2 below. Data are shown for results obtained by testing the listed compounds at a concentration of 10 μΜ in the late INa and Peak INa assays, and at 1 μM and 10 μM for the hERG and L-type calcium channel assays.

[0175] The assay results shown in Table 15 establish that compounds tested showed activity as modulators of late sodium current, for example by inhibiting (or reducing) the late sodium current. (Note that zeroes in the above table may indicate the results were below the level of detection.)

[0176] It is generally desirable that the effects of a compound be specific for the late sodium current and show little or no activity with respect to one or more other ion channels. Thus, in some embodiments, a compound having an activity of reducing late sodium current will also exhibit little or no activity with regard to the peak sodium current. In particular embodiments, a compound having an activity of reducing late sodium current will also exhibit little or no activity with regard to the hERG potassium channel. In some

embodiments, a compound having an activity of reducing late sodium current will also exhibit little or no activity with regard to the L-type calcium channel. For example, a given compound may provide a 30% (or greater, e.g. more than 40%, more than 50%, more than 60%, more than 70%, more than 80%) reduction in late sodium current in the assay described herein, and the same compound may exhibit little or no activity for one or more of the peak sodium current, the hERG potassium channel, and the L-type calcium channel. In this regard, a compound having "little" effect will typically show less then a 30% reduction (e.g. less than a 20% reduction, less than a 15% reduction, less than a 10% reduction) in the given activity (e.g. Peak INa, hERG, L-type calcium), when measured using the assay described herein. In this regard, "no" effect means that any activity measured will differ from the control by less than the standard error of the measurement. The assays conducted to measure activities in this regard should be performed as described above, with the compound at a concentration of 10 μΜ (or at the upper limit of solubility, if less).

[0177] In particular embodiments, a compound will exhibit a high selectivity for the late sodium current modulatory activity as compared to the activity in one or more other ion channels. The selectivity of a compound may be determined by determining the percentage reduction in late sodium current due to the compound, as measured by the assay described above. The percentage reduction in one other ion channel activity, such as the hERG potassium channel or L-type calcium channel, due to the compound is determined as described above. The selectivity is determined by taking the ratio of (percentage reduction in late sodium current) to (percentage reduction in one other ion channel activity). The assays conducted to measure activities in this regard should be performed as described above, with the compound at a concentration of 10 μΜ (or at the upper limit of solubility, if less). In particular embodiments, the selectivity of a compound of the invention will be at least 5:1, e.g. at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 12:1, at least 15:1, at least 20: 1 , or at least 25: 1 , when comparing the percentage reduction in late sodium current versus percentage reduction of one of the peak sodium current, the hERG potassium channel current, or the L-type calcium channel.

Claims

CLAIMS What is claimed is:

1. A compound having the structure shown in Formula (I):

wherein:

C* is carbon,

Ri is -Ll-Rl 8 or is -R19, wherein:

LI is -Lk-, or -Lk'-O-Lk'-, wherein Lk is C₁-C₆ alkylene optionally substituted with 1 or 2 groups independently selected from hydroxyl and C₁-C₃ alkyl; and each Lk' independently is C₂-C₆ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups;

Rl 8 is hydrogen, hydroxyl, -CF3, -CN, C₁-C₃ alkoxy, -O- R20, -C(O)-R20, -C(O)-O-R20, -S(=O)₂-CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂-R24, -C(O)-N(R20)-S(=O)₂- R26, tetrazolyl; cycloalkyl, phenyl, or heteroaryl; wherein said cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1 , 2, or 3 groups independently selected from hydroxyl, halo, optionally substituted alkyl, C₁-C₃ alkoxy, -O-R20, -C(O)-O-R20, -S(=O)₂- CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂- R24, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -R25-hydroxyl, -R25-C₁-C₃ alkoxy, -R25-O-R20, -R25- C(O)-O-R20, -R25-S(=O)₂-CH₃, -R25-C(O)-N(R20)(R22), -R25- N(R20)-C(O)-R24, -R25-N(R20)-S(=O)₂-R24, -R25-C(O)-N(R20)- S(0)₂-R26, -R25-tetrazolyl, -R25-cycloalkyl, -R25-phenyl, or - R25-heteroaryl; and

R19 is hydrogen, cycloalkyl, phenyl, or heteroaryl; wherein said cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, -CN, optionally substituted alkyl, C|-C₃ alkoxy, -C(O)-O-R20, -S(=O)₂- CH₃, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -N(R20)-S(=O)₂- R24, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, -R25-hydroxyl, -R25-C₁-C₃ alkoxy, -R25-C(O)-O-R20, - R25-S(=O)₂-CH₃, -R25-C(O)-N(R20)(R22), -R25-N(R20)-C(O)- R24, -R25-N(R20)-S(=O)₂-R24, -R25-C(O)-N(R20)-S(=O)₂-R26, - R25-tetrazolyl, -R25-cycloalkyl, -R25-phenyl, or -R25-heteroaryl; R₂ and R₃ are each independently hydrogen or C|-C₃ alkyl, or

R₂ and R₃, taken together, is selected from:

g) a'-Qa*-R32-Qa*-b', wherein each Qa* is independently selected from -0-, -NH-, and -S-; R32 is Q2-C5 alkylene optionally substituted with -R20; and a' and b' are each single covalent bonds to C*;

h) a'-N(R30)-C(O)-R33-b' , wherein R30 is hydrogen or optionally substituted alkyl, R33 is C 1 -C5 alkylene optionally substituted with -R20, and a' and b' are each single covalent bonds to C*; or i) a'-R34-Qb*-R34-b', wherein Qb* is independently selected from -0-, -N(R30)-, and -S-; each R34 is independently C1-C4 alkylene optionally substituted with -R20; R30 is hydrogen or optionally substituted alkyl, and a¹ and V are each single covalent bonds to C*;

D designates the phenyl ring in Formula (I) to which R , Rg, and R9 are attached, R₇ and Rg are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -N0₂, -CF₃, -0-CF₃, -CN, -O-R20, - S-R20, -N(R20)(R22), -S(=O)-R22, -S(=O)₂R22, -S(=O)₂-N(R20)(R22), -S(=O)₂-O-R20, -N(R20)-C(O)-R22, -N(R20)-C(O)-O-R22, -N( 20)-C(O)-N(R20)(R22), -C(O)-R20, - C(O)-O-R20, -C(O)-N(R20)(R22), and -N(R20)-S(=O)₂-R22, wherein each optional alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituent is further optionally substituted with halo, -N0₂, -CF₃, -O-CF3, -N(R20)(R22), -C(O)-R20, -C(O)-O-R20, -C(O)- N(R20)(R22), -CN, -O-R20, or optionally substituted alkyl; or

R₇ and Rg, taken together, is a'-Qc*-R35-Qd*-R36-b\ wherein Qc* and Qd* are each independently selected from covalent bond, -0-, -NH-, and -S-; R35 is C|-C₄ alkyl ene optionally substituted with -R20; R36 is covalent bond or-CHR20-; a' is a first single covalent bond to phenyl ring D, and b' is a second single covalent bond to phenyl ring D at a position that is ortho to the a'; wherein Qd* and R36 are not both covalent bond; or

R9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, -N0₂, -CF₃, -O-CF3, -CN, -O-R20, -S-R20, - N(R20)(R22), -S(=O)-R22, -S(=O)₂R22, -S(=O)₂-N(R20)(R22), -S(=O)₂-O-R20, - N(R20)-C(O)-R22, -N(R20)-C(O)-O-R22, -N(R20)-C(O)-N(R20)(R22), -C(O)-R20, - C(O)-O-R20, -C(O)-N(R20)(R22), and -N(R20)-S(=O)₂-R22, wherein each optional alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl substituent is further optionally substituted with halo, -N0₂, -CF₃, -O-CF3, -N(R20)(R22), -C(O)-R20, -C(O)-O-R20, -C(O)- N(R20)(R22), -CN, -O-R20, or optionally substituted alkyl;

X₂ is -N- or -C(R16)=, wherein Rl 6 is selected from hydrogen, halo, -O-R20, -alkyl, -CF₃, -CN, -N(R20)(R22), or -L3-R38, wherein

L3 is -Lj-, or -Lj'-O-Lj'-, wherein Lj is C_\-C_b alkylene optionally substituted with 1 or 2 groups independently selected from hydroxyl and C₁-C₃ alkyl; and each Lj' independently is C₂-C₆ alkylene optionally substituted with 1 or 2 C|-C₃ alkyl groups;

R38 is hydrogen, hydroxyl, -CF₃, -CN, C₁-C₃ alkoxy, -O- R20, -C(O)-O-R20, -N(R20)-S(=O)₂-R24, -C(O)-N(R20)-S(=O)₂- R26, tetrazolyl, phenyl, or heteroaryl; wherein said phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups

Xi and X3 each are independently— N= or-C(R17)=, wherein R17 is hydrogen, halo, cyano, optionally substituted alkyl, or -N(R20)(R22);

each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C₁-Ci5 alkyl, C₂-Cu alkenyl, C2-C15 alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, -CN, lower alkoxy, -CF₃, aryl, and heteroaryl;

R24 is optionally substituted alkyl or optionally substituted aryl;

R2S is C₁-C₃ alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups; and

R26 is optionally substituted alkyl or optionally substituted cycloalkyl.

2. A compound having the structure shown in Formula (I):

wherein:

C* is carbon,

Ri is -L1-R18 or is -R19, wherein:

LI is -Lk- wherein Lk is Cj-Ce alkylene optionally substituted with 1 or 2 C1-C₃ alkyl groups;

RI 8 is hydrogen, hydroxy., -CF₃, -CN, C₁-C₃ alkoxy, -O-R20, - C(O)-R20, -C(O)-O-R20, -C(O)-N(R20)(R22), -N(R20)-C(O)-R24, -C(O)- N(R20)-S(=O)₂-R26, tetrazolyl, phenyl, or heteroaryl; wherein said phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxy., halo, optionally substituted alkyl, C1-C₃ alkoxy, - O-R20, -C(O)-O-R20, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted phenyl, or optionally substituted heteroaryl; and

R19 is hydrogen, phenyl, or heteroaryl; wherein said phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from hydroxyl, halo, -CN, optionally substituted alkyl, C₁-C₃ alkoxy, -C(O)-O-R20, -C(O)-N(R20)-S(=O)₂-R26, tetrazolyl, optionally substituted phenyl, or optionally substituted heteroaryl;

R₂ and R₃ are each independently hydrogen or C₁-C₃ alkyl, or

R₂ and R₃, taken together, is selected from: c) a'-Qa*-R32-Qa*-b\ wherein each Qa* is independently selected from -0-, -NH-, and -S-; R32 is C2-C5 alkylene; and a' and b' are each single covalent bonds to C*; or

d) a'-R34-Qb*-R34-b', wherein Qb* is independently selected from -0-, -N(R30)-, and -S-; each R34 is independently C1-C4 alkylene; R30 is hydrogen or optionally substituted alkyl, and a' and b' are each single covalent bonds to C*;

D designates the phenyl ring in Formula (I) to which R ,な, and R9 are attached,

R₇, R_g, and R9 are each independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, halo, -CF₃, -O-CF3, -CN, -O-R20, -N(R20)(R22), - C(O)-R20, and -C(O)-N(R20)(R22), wherein each optional alkyl, aryl, and heteroaryl substituent is further optionally substituted with halo, -CF₃, -O-CF3, -CN, -N(R20)(R22), - C(O)-R20, -O-R20, or optionally substituted alkyl;

X₂ is-C(R16)=, wherein R16 is selected from hydrogen, halo, -O-R20, -alkyl, -CF₃, -CN, -N(R20)(R22), or -L3-R38, wherein

L3 is -Lj— wherein Lj is Ci-Ce alkylene optionally substituted with 1 or 2 C₁-C₃ alkyl groups; and

Xi and X₃ each are independently -C(R17)-, wherein R17 is hydrogen, halo, cyano, or optionally substituted alkyl;

each instance of R20 and R22 is independently selected from the group consisting of hydrogen, C₁-C15 alkyl, and aryl, wherein the alkyl and aryl moieties are optionally substituted with from 1 to 3 substituents independently selected from halo, -CN, alkyl, lower alkoxy, and -CF₃;

R24 is optionally substituted alkyl or optionally substituted aryl; and

R26 is optionally substituted alkyl or optionally substituted cycloalkyl.

3. A compound of the invention having the structure shown in Formula (I):

wherein:

C* is carbon,

Ri is -Ll-Rl 8 or is -R19, wherein:

R18 is hydrogen, hydroxy., -CF₃, C₁-C₃ alkoxy, -C(O)-O-R20, or heteroaryl; wherein said heteroaryl is optionally substituted with 1 , 2, or 3 groups independently selected from hydroxyl, halo, optionally substituted alkyl, C₁-C₃ alkoxy, -O-R20, or -C(O)-O-R20;

R19 is hydrogen;

R₂ and R₃ are each independently hydrogen or C₁-C₃ alkyl, or

R2 and R₃, taken together with the carbon to which they are both attached, form an optionally substituted cycloalkyl; or

R₂ and R₃, taken together, is a'-Qa*-R32-Qa*-b', wherein each Qa* is -0-; R32 is C₂- C₃ alkylene; and a' and b' are each single covalent bonds to C*;

D designates the phenyl ring in Formula (I) to which R₇, Rg, and R9 are attached, R₇, Re, and R9 are each independently selected from the group consisting of hydrogen, alkyl, halo, -CF₃, -CN, -O-R20, -C(O)-R20, and -C(O)-N(R20)(R22);

X2 is-C(R16)=, wherein R16 is hydrogen;

X) and X3 each are independently -C(R17)=, wherein R17 is hydrogen;

each instance of R20 and R22 is independently selected from hydrogen, C1.C3 alkyl, or optionally substituted phenyl.

4. A compound named in Table 1.

5. A pharmaceutical formulation comprising a compound according to any of claims 1 - 4 or a pharmaceutically acceptable salt, ester, hydrate, polymorph, prodrug or tautomeric form thereof, and at least one pharmaceutically acceptable excipient.

6. A method of treating a disease state in a mammal that is alleviable by treatment with an agent capable of reducing late sodium current, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound according to any of claims 1 - 4.

7. The method of claim 6, wherein the disease state is a cardiovascular disease selected from one or more of atrial and ventricular arrhythmias, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, acute heart failure), Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, ischemia, recurrent ischemia, reperfusion injury, myocardial infarction, acute coronary syndrome, peripheral arterial disease, and intermittent claudication.

8. The method of claim 7, wherein the disease state is diabetes or diabetic peripheral neuropathy.

9. The method of claim 7, wherein the disease state results in one or more of neuropathic pain, seizures, or paralysis.