Biaryl substituted pyrazoles as sodium channel blockers
View Patent ↗Biaryl substituted pyrazole compounds are sodium channel blockers useful for the treatment of pain and other conditions. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treatment of conditions, including acute pain, chronic pain, visceral pain, inflammatory pain, and neuropathic pain, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more therapeutically active compounds.
1. A compound represented by Formula (I), (II), (III) or (IV):
or a pharmaceutically acceptable salt thereof, wherein
HET is one of the following heterocycles:
R 1 is
(a) H;
(b) C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 3 -C 6 -cycloalkyl, or C 1 -C 4 -alkyl-[C 3 -C 6 -cycloalkyl], any of which is optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, S(O) 0-2 —(C 1 -C 4 )alkyl, O—CONR a R b , NR a R b , N(R a )CONR a R b , COO—(C 1 -C 4 )alkyl, COOH, CN, CONR a R b , SO 2 NR a R b , N(R a )SO 2 NR a R b , —C(═NH)NH 2 , tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl;
(c) —O—C 1 -C 6 -alkyl, —O—C 3 -C 6 -cycloalkyl, —S—C 1 -C 6 -alkyl or —S—C 3 -C 6 -cycloalkyl, any of which is optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, S(O) 0-2 —(C 1 -C 4 )alkyl, O—CONR a R b , NR a R b , N(R a )CONR a R b , COO—(C 1 -C 4 )alkyl, COOH, CN, CONR a R b , SO 2 NR a R b , N(R a )SO 2 NR a R b , —C (═NH)NH 2 , tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl;
(d) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, or —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl;
(e) —OH;
(f) —O-aryl, or —O—C 1 -C 4 -alkyl-aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(R a ), v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO —OR a , viii) —C 0-4 alkyl)-NH—CO—OR a , ix) —(C 0-4 alkyl)-CO—N(R a )(R b ), x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a , xiii) —C 1-10 alkyl, and xiv) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a —, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—N(R a )—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C—;
(g) —OCON(R a )(R b ), or —OSO 2 N(R a )(R b );
(h) —SH, or —SCON(R a )(R b );
(i) NO 2 ;
(j) NR a R b , —N(COR a )R b , —N(SO 2 R a )R b , —N(R a )SO 2 N(R a ) 2 , —N(OR a )CONR a R b , —N(R a )SO 2 R a or —N(R a )CON(R a ) 2 ;
(k) —CH(OR a )R a , —C(OR b )CF 3 , —CH(NHR b )R a , —C(═O)R a , C(═O)CF 3 , —SOCH 3 , —SO 2 CH 3 , COOR a , CN, CONR a R b , —COCONR a R b , —SO 2 NR a R b , —CH 2 O—SO 2 NR a R b , SO 2 N(R a )OR a , —C(═NH)NH 2 , —CR a ═N—OR a , CH═CHCONR a R b ;
(l) —CONR a (CH 2 ) 0-2 C(R a )(R b )(CH 2 ) 0-2 CONR a R b ;
(m) tetrazolyl, tetrazolinonyl, triazolyl, triazolinonyl, imidazolyl, imidozolonyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrazolonyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, or phenyl, any of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)R a , v) C 1 -C 6 -alkyl, vi) —O—R a , vii) —NR a R b , viii) —C 0 -C 4 -alkyl-CO—OR a , ix) —(C 0 -C 4 -alkyl) -NH—CO—OR a , x) —(C 0 -C 4 -alkyl)-CO—NR a R b , xi) —S(O) 0-2 R a , xii)—SO 2 NR a R b , xiii) —NHSO 2 R a , xiv) —C 1 -C 4 -perfluoroalkyl, and xv) —O—C 1 -C 4 -perfluoroalkyl;
(n) —C(R a )═C(R b )—COOR a , or —C(R a )═C(R b )—CONR a R b ;
(o)
(p) piperidin-1-yl, morpholin-1-yl, pyrrolidin-1-yl, piperazin-1-yl or 4-susbstituted piperazin-1-yl, any of which is optionally substituted with 1-3 substituents selected from i) —CN, ii) —C(═O)(R a ), iii) C 1 -C 6 -alkyl, iv) —OR a , v) —NR a R b , vi) —C 0 -C 4 -alkyl -CO—OR a , vii) —(C 0 -C 4 -alkyl)-NH—CO—OR a , viii) —(C 0 -C 4 -alkyl)-CON(R a )(R b ), ix) —SR a , x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a xiii) —C 1 -C 4 -perfluoroalkyl and xiv) —O—C 1 -C 4 -perfluoroalkyl;
R a is
(a) H;
(b) C 1 -C 4 -alkyl, optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, S(O) 0-2 —(C 1 -C 4 )alkyl, —OCONH 2 , —OCONH(C 1 -C 4 alkyl), —OCON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —OCONHC 1 -C 4 alkyl-aryl), —OCON(C 1 -C 4 alkyl) (C 1 -C 4 alkyl-aryl), NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), NH(C 1 -C 4 alkyl-aryl), N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl-aryl), NHCONH 2 , NHCONH(C 1 -C 4 alkyl), NHCONH(C 1 -C 4 alkyl-aryl), —NHCON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), NHCON (C 1 -C 4 alkyl)(C 1 -C 4 alkyl-aryl), N(C 1 -C 4 alkyl)CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl)CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl-aryl), COO—(C 1 -C 4 -alkyl), COOH, CN, CONH 2 , CONH(C 1 -C 4 alkyl), CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), SO 2 NH 2 , SO 2 NH (C 1 -C 4 alkyl), SO 2 NH(C 1 -C 4 alkyl-aryl), SO 2 N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), NHSO 2 NH 2 , —C(═NH)NH 2 , tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl;
(c) C 0 -C 4 -alkyl-(C 1 -C 4 )-perfluoroalkyl; or
(d) —C 1 -C 4 -alkyl-aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(C 1 -C 4 -alkyl), v) —O(C 1 -C 4 -alkyl), vi) —N(C 1 -C 4 -alkyl)(C 1 -C 4 -alkyl), vii) —C 1-10 alkyl, and viii) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C—;
R b is
(a) H; or
(b) C 1 -C 6 -alkyl, optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, S(O) 0-2 —(C 1 -C 4 )alkyl, —OCONH 2 , —OCONH(C 1 -C 4 alkyl), NH 2 , NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), NHCONH 2 , NHCONH (C 1 -C 4 alkyl), —NHCON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), COO—(C 1 -C 4 -alkyl), COOH, CN, or CONH 2 ;
R 2 is:
(a) H;
(b) —C 1 -C 4 -alkyl, —C 3 -C 6 -cycloalkyl or —C 1 -C 4 -alkyl-(C 3 -C 6 )-cycloalkyl, optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, S(O) 0-2 —(C 1 -C 4 )alkyl, O—CONR a R b , NR a R b , N(R a )CONR a R b , COO—(C 1 -C 4 )alkyl, COOH, CN, CONR a R b , SO 2 NR a R b , N(R a )SO 2 NR a R b , —C(═NH)NH 2 , tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl;
(c) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl;
(d) aryl or —(C 1 -C 4 -alkyl)-aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(R a ), v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii) —(C 0-4 alkyl)-NH—CO—OR a , ix) —(C 0-4 alkyl)-CO—N(R a )(R b ), x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a , xiii) —C 1-10 alkyl, and xiv) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a —, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—N(R a )—, —C (O)—, —CH(OH)—, —C═C—, or —C≡C—;
(e) —C(═O)(R a ), —CONR a R b , COO—C 1 -C 4 )alkyl, —SO 2 R a , N(R a )COR a , —SO 2 N(R a )(R b );
R 3 is
(a) H;
(b) —C 1 -C 4 -alkyl, —C 3 -C 6 -cycloalkyl or —C 1 -C 4 -alkyl-(C 3 -C 6 )-cycloalkyl, optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, S(O) 0-2 -(C 1 -C 4 )alkyl, O—CONR a R b , NR a R b , N(R a )CONR a R b , COO—(C 1 -C 4 )alkyl, COOH, CN, CONR a R b , SO 2 NR a R b , N(R a )SO 2 NR a R b , —C(═NH)NH 2 , tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl or piperazinyl;
(c) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl;
(d) aryl or —(C 1 -C 4 -alkyl)-aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(R a ), v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii) —(C 0-4 alkyl)-NH—CO—OR a , ix) —(C 0-4 alkyl)-CO—N(R a )(R b ), x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a , xiii) —C 1-10 alkyl, and xiv) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a —, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—N(R a )—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C—;
(e) —O—C 1 -C 4 -alkyl, —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, —O-aryl or —O(C 1 -C 4 -alkyl)-aryl;
(f) —C(═O)(R a ), —SO 2 R a , —SO 2 N(R a )(R b ), CN, NR a R b , NO 2 , F, Cl, Br, I, OH, OCONR a R b , O(C 1 -C 4 -alkyl)CONR a R b , —OSO 2 NR a R b , COOR a , N(R a )COR a , or CONR a R b ;
R 4 and R 5 each independently is:
(a) H;
(b) —C 1 -C 6 -alkyl, —C 2 -C 6 -alkenyl, —C 2 -C 6 -alkynyl or —C 3 -C 6 -cycloalkyl, any of which is optionally substituted with one or more of the following substituents: F, CF 3 , —O—(C 1 -C 4 )alkyl, CN, —N(R a )(R b ), —N(R a )CO—(C 1 -C 4 )alkyl, COOR b , CON(R a )(R b ) or phenyl;
(c) —O—C 0 -C 6 -alkyl, —O-aryl, or —O—C 1 -C 4 -alkyl-aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(R a ), v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii) —(C 0-4 alkyl)-NH—CO—OR a , ix) —(C 0-4 alkyl)-CO—N(R a )(R b ), x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a , xiii) —C 1-10 alkyl, and xiv) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a —, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—N(R a )—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C—;
(d) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, or —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl; or
(e) CN, NH 2 , NO 2 , F, Cl, Br, I, OH, OCON(R a )(R b )O(C 1 -C 4 -alkyl)CONR a R b , —OSO 2 N(R a )(R b ), COOR b , CON(R a )(R b ), or aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(R a ), v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii) —(C 0-4 alkyl)-NH—CO—OR a , ix) —(C 0-4 alkyl)—CO—N(R a )(R b ), x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a , xiii) —C 1-10 alkyl, and xiv) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a —, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—N(R a )—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C; and
R 6 , R 7 and R 8 each independently is:
(a) H;
(b) C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl or C 3 -C 6 -cycloalkyl, any of which is optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, OCON(R a )(R b ), NR a R b , COOR a , CN, CONR a R b , N(R a )CONR a R b , N(R a )SO 2 NR a R b , SO 2 NR a R b , S(O) 0-2 (C 1 -C 4 -alkyl), —C(═NH)NH 2 , tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl, or piperazinyl;
(c) —O—C 1 -C 6 -alkyl, —O—C 3 -C 6 -cycloalkyl, —S—C 1 -C 6 -alkyl or —S—C 3 -C 6 -cycloalkyl, any of which is optionally substituted with one or more of the following substituents: F, CF 3 , OH, O—(C 1 -C 4 )alkyl, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , COOH, CN, CONH 2 , CONH(C 1 -C 4 -alkyl), CONH(C 1 -C 4 -alkyl) 2 , SO 2 NH 2 , SO 2 NH(C 1 -C 4 -alkyl), tetrazolyl, triazolyl, imidazolyl, oxazolyl, oxadiazolyl, isooxazolyl, thiazolyl, furyl, thienyl, pyrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, phenyl, piperidinyl, morpholinyl, pyrrolidinyl, or piperazinyl;
(d) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, or —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl;
(e) —O-aryl, or —O—C 1 -C 4 -alkyl-aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(R a ), v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii) —C 0-4 alkyl)-NH—CO—OR a , ix) —(C 0-4 alkyl)-CO—N(R a )(R b ), x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a , xiii) —C 1-10 alkyl, and xiv) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a —, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—N(R a )—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C; (f) CN, N(R a )(R b ), NO 2 , F, Cl, Br, I, —OR a , —SR a , —OCON(R a )(R b ), —OSO 2 N(R a )(R b ), COOR b , CON(R a )(R b ), —N(R a )CON(R a )(R b ), —N(R a )SO 2 N(R a )(R b ), C(OR b )R a , —C(OR a )CF 3 , C(NHR a )CF 3 , C(═O)R a , C(═O)CF 3 , —SOCH 3 , —SO 2 CH 3 , —NHSO 2 (C 1-6 -alkyl), —NHSO 2 -aryl, SO 2 N(R a )(R b ), —CH 2 OSO 2 N(R a )(R b ), SO 2 N(R b )—OR a , —C(═NH)NH 2 , —CR a ═N—OR a , CH═CH or aryl, wherein aryl is phenyl, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, triazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, or oxadiazolyl, any aryl of which is optionally substituted with 1-3 substituents selected from i) F, Cl, Br, I, ii) —CN, iii) —NO 2 , iv) —C(═O)(R a ), v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii) —(C 0-4 alkyl)-NH—CO—OR a , ix) —(C 0-4 alkyl)-CO—N(R a )(R b ), x) —S(O) 0-2 R a , xi) —SO 2 N(R a )(R b ), xii) —NR a SO 2 R a , xiii) —C 1-10 alkyl, and xiv) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a —, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(R a )—, —N(R a )—C(O)—, —N(R a )—C(O)—N(R a )—, —C(O)—, —CH(OH)—, —C═C—, or —C≡C; or when R 6 and R 7 are present on adjacent carbon atoms, R 6 and R 7 , together with the ring to which they are attached, may form a bicyclic aromatic ring selected from naphthyl, indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, and benzimidazolyl, any aromatic ring of which is optionally substituted with 1-4 independent substituents selected from i) halogen, ii) —CN, iii) —NO 2 , iv) —CHO, v) —O—C 1-4 alkyl, vi) —N(C 0-4 alkyl)(C 0-4 alkyl), vii) —C 0-4 alkyl-CO—O(C 0-4 alkyl), viii) —(C 0-4 alkyl)-NH—CO—O(C 0-4 alkyl), ix) —(C 0-4 alkyl)-CO—N(C 0-4 alkyl)(C 0-4 alkyl), x) —S(C 0-4 alkyl), xi) —S(O)(C 1-4 alkyl), xii) —SO 2 (C 0-4 alkyl), xiii) —SO 2 N(C 0-4 alkyl)(C 0-4 alkyl), xiv) —NHSO 2 (C 0-4 alkyl)(C 0-4 alkyl), xv) —C 1-10 alkyl and xvi) —C 1-10 alkyl in which one or more of the carbons can be replaced by a —N(C 0-6 alkyl)-, —O—, —S(O) 1-2 —, —O—C(O)—, —C(O)—O—, —C(O)—N(C 0-6 alkyl)-, —N(C 0-6 alkyl)-C(O)—, —N(C 0-6 alkyl)-C(O)—N(C 0-6 alkyl)-, —C(O)—, —CH(OH), —C═C—, or —C≡C—; with the proviso that R 1 , R 3 and R 6 are Not hydrogen at the same time.
2. The compound according to claim 1 represented by Formula (I), or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is other than H and is attached at the ortho position.
4. The compound according to claim 1 represented by Formula (II), or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is other than H and is attached at the ortho position.
6. The compound according to claim 1 represented by Formula (III), or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein
HET is
8. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein
HET is
9. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein
HET is
10. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein
HET is
11. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein
HET is
12. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is other than H and is attached at the ortho position.
13. The compound according to claim 1 represented by Formula (IV), or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein
HET is
15. The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein
HET is
16. The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein
HET is
17. The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein
HET is
18. The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein
HET is
19. The compound according to claim 13 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is other than H and is attached at the ortho position.
20. A compound represented by
or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 represented by
as indicated by the compound number herein:
Compd
R 8
R 7
R 6
R 4
R 3
R 1
1
H
H
CF 3
H
H
CH 3
2
H
H
OCF 3
H
H
CH 3
3
H
H
OCF 3
H
CH 3
H
4
H
H
CF 3
H
CH 3
H
5
H
H
CF 3
H
CH 3
CH 3
6
H
H
OCF 3
H
CH 3
CH 3
7
H
H
Cl
H
H
CF 3
8
H
H
Cl
H
CH 3
CONH 2
9
H
H
CF 3
H
CH 3
CONH 2
10
H
H
CF 3
H
CH 3
COOCH 3
11
H
H
CF 3
H
CH 3
COOH
12
H
H
Cl
H
t-Bu
COOH
13
H
H
OCF 3
H
CH 3
COOCH 3
14
H
H
OCF 3
H
CH 3
CONH 2
15
H
H
OCF 3
H
CH 3
COOH
16
H
H
OCF 3
H
COOEt
CH 3
17
H
H
CF 3
H
COOEt
CH 3
18
H
H
OCF 3
H
COOH
CH 3
19
H
H
CF 3
H
COOH
CH 3
20
H
H
OH
H
CH 3
CONH 2
21
H
H
0-Ph
H
CH 3
COOH
22
H
H
0-Ph
H
CH 3
COOMe
23
H
H
0-Ph
H
CH 3
COOEt
24
H
H
0-Ph
H
CH 3
CONH 2
25
H
H
CHO
H
CH 3
CONH 2
26
H
4-Cl
Cl
H
CH 3
CONH 2
27
H
4-CF 3
H
H
CH 3
CONH 2
28
H
3-CF 3
H
H
CH 3
CONH 2
29
5-Cl
3-Cl
H
H
CH 3
CONH 2
30
H
3-F
H
H
CH 3
CONH 2
31
5-CF 3
3-CF 3
H
H
CH 3
CONH 2
32
4-F
3-Cl
H
H
CH 3
CONH 2
33
H
4-Cl
H
H
CH 3
CONH 2
34
H
4-F
H
H
CH 3
CONH 2
35
4-Cl
3-Cl
H
H
CH 3
CONH 2
36
H
3-OCH 3
OCH 3
H
CH 3
CONH 2
37
H
3-Cl
CH 3
H
CH 3
CONH 2
38
H
5-Cl
OCH 3
H
CH 3
CONH 2
39
H
H
H
CH 3
CONH 2
40
H
H
H
CH 3
CONH 2
41
H
3-Ph
H
H
CH 3
CONH 2
42
H
H
H
CH 3
CONH 2
43
H
4-CH 2 OH
H
H
CH 3
CONH 2
44
H
H
H
H
CH 3
CONH 2
45
H
H
CH 3
H
CH 3
CONH 2
46
H
3-COOH
CH 3
H
CH 3
CONH 2
47
H
3-F
CH 3
H
CH 3
CONH 2
48
H
4-OPh
H
H
CH 3
CONH 2
49
H
3-Cl
H
H
CH 3
CONH 2
50
H
3-OEt
H
H
CH 3
CONH 2
51
H
H
F
H
CH 3
CONH 2
52
H
4-OEt
H
H
CH 3
CONH 2
53
H
6-F
F
H
CH 3
CONH 2
54
H
6-CH 3
CH 3
H
CH 3
CONH 2
55
H
4-t-Bu
H
H
CH 3
CONH 2
56
H
4-OCF 3
H
H
CH 3
CONH 2
57
H
4-COCH 3
H
H
CH 3
CONH 2
58
H
3-COCH 3
H
H
CH 3
CONH 2
59
H
3-CH 3
CH 3
H
CH 3
CONH 2
60
H
4-COOH
H
H
CH 3
CONH 2
61
H
4-CHO
H
H
CH 3
CONH 2
62
H
4-CF 3
CF 3
H
CH 3
CONH 2
63
H
6-CF 3
CF 3
H
CH 3
CONH 2
64
H
6-F
CF 3
H
CH 3
CONH 2
65
H
5-F
CF 3
H
CH 3
CONH 2
66
H
4-Cl
CF 3
H
CH 3
CONH 2
67
H
3-Cl
Cl
H
CH 3
CONH 2
68
H
H
OCH 2 CF 3
H
CH 3
CONH 2
69
H
H
OCF 3
F
CH 3
COOEt
70
H
H
OCF 3
F
CH 3
CONH 2
71
H
H
OCF 3
F
COOEt
CH 3
72
H
H
OCF 3
F
CONH 2
CH 3
73
H
3-Cl
Cl
F
CH 3
CONH 2
74
H
4-CF 3
CF 3
F
CH 3
CONH 2
75
H
H
OCF 3
F
CH 3
COOH
76
H
5-F
OH
H
CH 3
CONH 2
77
H
5-NMe 2
OCF 3
H
CH 3
CONH 2
78
H
4-F
CF 3
H
CH 3
COOH
79
H
4-CF 3
CF 3
H
CH 3
COOH
80
H
4-CF 3
F
H
CH 3
COOH
81
H
3-CF 3
CF 3
H
CH 3
COOH
82
H
H
OCF 3
H
CH 3
CF 3
83
H
H
OCF 3
H
t-Bu
CONH 2
84
H
H
OCF 3
H
OCH 2 CH 3
CH 3
85
H
5-F
CF 3
H
CH 3
COOH
86
H
3-Cl
Cl
H
CH 3
COOH
87
H
4-Cl
CF 3
H
CH 3
COOH
88
H
3-Cl
Cl
F
CH 3
COOH
89
H
6-Cl
Cl
H
CH 3
COOH
90
H
6-Cl
Cl
H
CH 3
CONH 2
91
H
6-F
CF 3
H
CH 3
COOH
92
H
H
CF 3
H
CH 3
COOH
93
H
6-CF 3
CF 3
H
CH 3
COOH
94
H
6-Cl
CF 3
H
CH 3
CONH 2
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 represented by
as represented by the compound number below:
Compd
R 6
R 3
R 2
R 1
1
Cl
H
CONH-t-Bu
H
2
Cl
H
CONH-Me
H
3
Cl
H
H
4
Cl
H
H
5
CF 3
H
COOEt
NH 2
6
CF 3
H
COOH
H
7
OCF 3
H
COOEt
H
8
OCF 3
H
COOH
NH 2
or a pharmaceutically acceptable salt thereof.
23. A compound represented by
or a pharmaceutically acceptable salt thereof.
24. A compound represented by
or a pharmaceutically acceptable salt thereof.
25. A compound represented by
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 is represented by
as represented by the compound number below:
Compound
R a
R b
1
—CH 2 CH 2 OH
H
2
—CH 2 CH 2 CH 2 OH
H
3
—CH(CH 2 OH) 2
H
4
—CH 3
H
5
—CH 2 CH 3
H
6
H
7
H
8
H
9
H
10
H
11
CH 3
12
CH 3
13
H
or a pharmaceutically acceptable salt thereof.
27. A compound represented by
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 1 represented by
as represented by the compound number below:
Compd
R 7
R 6
R 4
R 3
R 2
R 1
1
H
CF 3
H
CONH 2
H
CONH 2
2
H
OCF 3
H
CONH 2
H
CONH 2
3
4-CF 3
CF 3
H
CONH 2
H
CONH 2
4
5-F
CF 3
H
CONH 2
H
CONH 2
5
5-CF 3
OCF 3
H
CONH 2
H
CONH 2
6
H
OCHF 2
H
CONH 2
H
CONH 2
7
5-CF 3
CF 3
H
CONH 2
H
CONH 2
8
6-F
CF 3
H
CONH 2
H
CONH 2
9
4-F
OCH 2 CF 3 CF 3
H
CONH 2
H
CONH 2
10
6-CF 3
CF 3
H
CONH 2
H
CONH 2
11
H
OCH(CH 3 ) 2
H
CONH 2
H
CONH 2
12
3-OCF 3
OCH 2 CF 3 CF 3
H
CONH 2
H
CONH 2
13
3-CF 3
OCH 2 CF 3 CF 3
H
CONH 2
H
CONH 2
14
5-F
OCH 2 CF 3 CF 3
H
CONH 2
H
CONH 2
15
5-F
OCF 3
H
CONH 2
H
CONH 2
16
4-F
CF 3
H
CONH 2
H
CONH 2
17
H
CF 3
H
CONH-Et
H
CONH-Et
18
H
CF 3
H
CONH 2
H
CONH-Et
19
H
OCF 3
4-F
CONH 2
H
CONH 2
20
H
OCF 3
H
CONH-Et
H
CONH 2
21
H
OCF 3
H
COOEt
H
COOEt
22
H
CF 3
H
COOEt
H
COOEt
23
H
OCF 3
H
COOEt
H
CONH 2
24
H
CF 3
H
COOEt
H
CONH 2
25
4-CF 3
CF 3
H
COOEt
H
CONH 2
26
4-CF 3
CF 3
H
CONH 2
H
COOEt
27
H
OCF 3
H
CONH 2
H
COOEt
28
H
CF 3
H
CONH 2
H
COOEt
29
H
OCF 3
4-F
COOH
H
COOEt
30
H
OCF 3
4-F
COOH
H
CONH 2
31
H
OCF 3
4-F
CONH 2
H
COOEt
32
H
OCF 3
H
COOH
H
CONH 2
33
H
OCF 3
H
CH 3
COOMe
COOEt
34
H
OCF 3
H
CH 3
COOH
COOH
35
4-CF 3
CF 3
H
CH 3
COOH
COOH
36
H
OCF 3
H
CH 3
CONH 2
CONH 2
37
4-CF 3
CF 3
H
CH 3
CONH 2
CONH 2
38
H
CF 3
H
CH 3
COOH
COOH
39
H
CF 3
H
CH 3
CONH 2
CONH 2
40
5-CF 3
CF 3
H
CH 3
CONH 2
CONH 2
41
5-CF 3
CF 3
H
CH 3
COOH
COOH
42
H
CF 3
4-OCF 3
CH 3
COOMe
COOH
43
H
OCF 3
4-OCF 3
CH 3
CONH 2
CONH 2
44
H
CF 3
4-OCF 3
CH 3
CONH 2
CONH 2
45
H
OCF 3
4-F
CH 3
COOEt
COOEt
46
H
CF 3
4-F
CH 3
COOEt
COOEt
47
H
OCF 3
4-F
CH 3
COOEt
CONH 2
48
H
OCF 3
4-F
CH 3
CONH 2
CONH 2
49
H
CF 3
4-F
CH 3
COOEt
CONH 2
50
H
CF 3
4-F
CH 3
CONH 2
CONH 2
51
H
OCF 3
4-F
CH 3
COOH
COOH
52
H
Cl
H
H
CONH—Me
H
53
H
Cl
H
H
CONH 2
CF 3
54
H
OCF 3
H
H
COOEt
NH 2
55
H
CF 3
H
H
COOEt
NH 2
56
H
OCF 3
H
H
COOH
H
57
H
OCF 3
H
H
COOEt
H
58
4-CF 3
CF 3
H
H
COOEt
NH 2
59
H
OCF 3
H
H
COOH
NH 2
60
H
OCF 3
H
H
CONH 2
H
61
H
OCF 3
H
H
CONH 2
NH 2
62
H
OCF 3
H
CH 3
CONH 2
CH 3
63
H
Cl
H
H
CONH 2
H
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 represented by
as represented by the compound number below:
Compd
R 7
R 6
R 4
R 3
R 2
R 1
1
H
OCF 3
H
H
COOCH 3
H
2
H
CF 3
H
NH 2
CONH 2
H
3
H
OCF 3
H
NH 2
COOH
H
4
H
OCF 3
H
NH 2
CONH 2
H
5
H
CF 3
H
NH 2
COOH
H
6
H
OCF 3
H
H
COOEt
H
7
H
CF 3
H
H
COOEt
H
8
H
CF 3
H
H
CONH 2
9
H
OCF 3
F
H
COOEt
H
10
H
OCF 3
F
H
CONH 2
H
11
H
OCF 3
H
CH 3
COOEt
H
12
H
OCF 3
H
CH 3
COOH
H
13
H
OCF 3
H
CH 3
CONH 2
H
14
H
CF 3
H
CH 3
COOH
H
15
H
CF 3
H
CH 3
CONH 2
H
16
4-CF 3
CF 3
H
CH 3
COOH
H
17
4-CF 3
CF 3
H
CH 3
CONH 2
H
18
H
OCF 3
F
H
COCH
H
19
5-CF 3
CF 3
H
H
COOH
H
20
5-CF 3
CF 3
H
H
CONH 2
H
21
H
CF 3
H
CH 3
CONH 2
t-Bu
22
H
OCF 3
H
H
COOH
t-Bu
23
H
OCF 3
H
H
CONH 2
t-Bu
24
6-F
CF 3
H
H
CONH 2
H
25
6-F
CF 3
H
H
COOH
H
26
5-F
OCF 3
H
H
COOH
H
27
5-F
OCF 3
H
H
CONH 2
H
28
4-CF 3
CF 3
H
H
CONH 2
H
29
H
OCF 3
H
H
CONHNMe 2
H
or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
31. The pharmaceutical composition according to claim 27 , further comprising a second therapeutic agent selected from the group consisting of: i) opiate agonists, ii) opiate antagonists, iii) calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT receptor antagonists vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2 selective inhibitors, x) NK1 antagonists, xi) non-steroidal anti-inflammatory drugs, xii) selective serotonin reuptake inhibitors, xiii) selective serotonin and norepinephrine reuptake inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate, and xviii) neurontin.