N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists

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Quick Facts

Patent No.: US 7,259,157
App. No.: 10/114,685
Granted: Aug 21, 2007
Kind: B2

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Abstract

Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are effective as NMDA NR2B antagonists useful for relieving pain.

Claims (36)

1. A compound having the Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

NonAr is a nonaromatic 6 membered ring containing 1 nitrogen ring atom, wherein the remaining ring atoms are carbon;

A is a phenyl optionally substituted with 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-7 cycloalkyl, —CF 3 , halogen, —OH, —CN, imidazolyl, —C 0-4 alkyl-N(C 0-5 alkyl)(C 0-5 alkyl), —O—C 1-4 alkyl, —C(O)—C 0-4 alkyl, —C(O)—O—C 0-4 alkyl, —O—C(O)—C 0-4 alkyl, —O—C(O)—C 0-4 alkylphenyl, —C 0-4 alkyl—N(C 0-5 alkyl)-C(O)—C 0-4 alkyl, —C 0-4 alkyl-N(C 0-5 alkyl)-C(O)—O—C 0-4 alkyl, —C 0-4 alkyl-N(C 0-5 alkyl)-C(O)—O—C 1-4 alkyl, or —NHSO 2 —C 1-4 alkyl, —O—C 1-4 alkylphenyl, or hydroxyiminoethyl; any alkyl optionally substituted with 1–6 —OH or halogen; or

A is pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiophenyl, thiazolyl, thiadiazolyl, oxazolyl, or isoxazolyl, each optionally substituted with 1–3 substituents, each substituent independently is —C 1-4 alkyl, —C 3-7 cycloalkyl, —CF 3 , halogen, —OH, —CN, —C 1-4 alkoxyl, phenyl, —C 0-4 alkyl-N(C 0-5 alkyl)(C 0-5 alkyl), —C 1-4 hydroxyalkyl; or

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with 1–5 substituents; each substituent independently is —C 1-4 alkyl, —C 3-7 cycloalkyl, —CF 3 , halogen, —OH, —CN, phenyl, pyrrolidinyl, azepanyl, —C 1-4 hydroxyalkyl, —C 1-4 alkoxy, (CH 3 ) 2 N—(CH 2 ) 2 —NH—, —SO 2 —C 1-4 alkyl, —C 0-4 alkyl-N(C 0-5 alkyl)(C 0-5 alkyl), —C 0-4 alkyl-N(C 3-6 cycloalkyl)(C 0-5 alkyl), —C 0-4 alkyl-N(C 0-5 alkyl)(C 1-4 alkyloxyC 1-4 alkyl), —N(C 0-5 alkyl)-C 0-4 alkyl-phenyl(C 1-4 alkoxyl) 0-3 , —N(C 0-5 alkyl)—C 0-4 alkylthiaphenyl, dimethoxyphenyl-CH 2 —NH—; any phenyl optionally substituted with 1–5 —OH, halogen, or C 1-4 alkyl; any alkyl optionally substituted with 1–5 —OH or halogen; or the substituent taken with a neighboring bond is ═O; or

A is pyrrolophenyl, pyrazolophenyl, triazolophenyl, pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl, benzoxazolonyl, oxodihydrobenzoxazolyl, indolinonyl, oxadihydroquinolinyl, oxatetrahydroquinolinyl, or purinyl, each optionally substituted with 1–5 substituents, each substituent independently is —C 1-4 alkyl, —C 3-7 cycloalkyl, —CF 3 , halogen, —OH, or —CN;

B is aryl(CH 2 ) 0-3 —O—(CH 2 ) 0-2 —C(O)—, heteroaryl(CH 2 ) 1-3 —O—(CH 2 ) 0-2 —C(O)—, indanyl(CH 2 ) 0-3 —O—(CH 2 ) 0-2 —C(O)—, aryl-cyclopropyl-C(O)—(CH 2 ) 0-2 —, heteroaryl(CH 2 ) 1-3 —C(O)—, aryl(CH 2 ) 1-3 —, heteroaryl(CH 2 ) 1-3 —, aryl(CH 2 ) 1-3 —NH—C(O)—, aryl(CH 2 ) 1-3 —NH—C(NCN)—, aryl(CH 2 ) 1-3 —SO 2 —, aryl(CH 2 ) 0-3 —S—(CH 2 ) 0-2 —C(O)—, or heteroaryl(CH 2 ) 1-3 —SO 2 — wherein any of the aryl or heteroaryl is optionally substituted by 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, phenyl, —O—C 1-4 alkylphenyl, —S(O)—C 1-4 alkyl, bromo, fluoro, chloro, or 2 substituents together form methylene dioxy; any (CH 2 ) optionally is substituted with C 1-2 alkyl; or

B is

wherein the phenyl is optionally substituted by 1–3 substituents, each substituent independently is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, trifluoromethyl, bromo, fluoro, or chloro; and

X is H, OH, F, C 1-4 alkyl, C 1-4 alkoxy, —N(C 0-5 alkyl)(C 0-5 alkyl), phenyl, or ═O.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

A is a phenyl optionally substituted with 1–5 substituents, each substituent independently is C 1-4 alkyl, C 3-7 cycloalkyl, —CF 3 , halogen, —OH, —CN, imidazolyl, —C 0-4 alkyl-N(C 0-5 alkyl)(C 0-5 alkyl), —O—C 1-4 alkyl, —C(O)—C 0-4 alkyl, —C(O)—O—C 0-4 alkyl, —O—C(O)—C 0-4 alkyl, —O—C(O)—C 0-4 alkylphenyl, —C 0-4 alkyl-N(C 0-5 alkyl)-C(O)—C 0-4 alkyl, —C 0-4 alkyl-N(C 0-5 alkyl)-C(O)—O—C 0-4 alkyl, —C 0-4 alkyl-N(C 0-5 alkyl)-C(O)—O—C 1-4 alkyl, or —NHSO 2 —C 1-4 alkyl, —O—C 1-4 alkylphenyl, or hydroxyiminoethyl; any alkyl optionally substituted with 1–6 —OH or halogen.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

A is pyridyl, pyradazinyl, pyrimidinyl, or pyrazinyl, each optionally substituted with 1–3 substituents, each substituent independently is —C 1-4 alkyl, —C 3-7 cycloalkyl, —CF 3 , halogen, —OH, —CN, phenyl, —C 1-4 hydroxyalkyl, —C 1-4 alkoxy, (CH 3 ) 2 N—(CH 2 ) 2 —NH—, —C 0-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl), dimethoxyphenyl-CH 2 —NH—, or the substituent taken with a neighboring bond is ═O.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein

A is pyrrolophenyl, pyrazolophenyl, triazolophenyl, pyridinoimidazolyl, naphthyridinyl, tetrahydrocyclopentopyrazolyl, quinolinyl, pyrimidinopyrazololyl, benzothiazolyl, benzoimidazolyl, or purinyl, each optionally substituted with 1–3 substituents, each substituent independently is —C 1-4 alkyl, —C 3-7 cycloalkyl, —CF 3 , halogen, —OH, or —CN.

6. The compound according to claim 1 , wherein said compound is