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US 2026/0062376 A1Published application
Squaramide derivatives as cb1 allosteric modulators
AssigneeResearch Triangle Institute
InventorsYanan ZHANG, Thuy NGUYEN
Life of this patent
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Abstract
Squaramide-based cannabinoid 1 receptor (CB1R) allosteric modulators are described. Exemplary analogs may provide improved potencies and pharmacokinetic properties. Methods of using the analogs to treat diseases mediated by CB1R, such as substance abuse and obesity, are described.
Claims32
A compound of formula (I):
- wherein
- each R1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, NO2, CN, O—(C1-C6 alkyl), or N(R3)2;
- each R2 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, CN, NO2, OH, O—(C1-C6 alkyl), O-(5- to 13-membered cycloalkyl), N(R3)2, C(O)OH, C(O)C1-C6 alkyl, (C1-C6-alkyl)x-(5- to 13-membered aryl)-(R4)p, (C1-C6-alkyl)x-(5- to 13-membered heterocyclyl containing one, two, or three heteroatoms selected from N, O, or S)—(R4)p, (C1-C6-alkyl)x-(5- to 13-membered heteroaryl containing one, two, or three heteroatoms selected from N, O, or S)—(R4)P;
- each R3 is independently H or C1-6 alkyl;
- or two R3 groups and the nitrogen atom to which they are attached form a 5-7 atom heterocyclic ring which may contain one or two more additional heteroatoms selected from N, O, and S;
- each R4 is independently H, halo, C1-6 alkyl, or N(R5)2 wherein each R5 is independently H or C1-6 alkyl;
- each x independently is 0 or 1;
- Ring A is selected from (i) C3-6 cycloalkyl, (ii) C3-6 heterocyclyl having one, two, or three heteroatoms each selected from N, O, or S, (iii) C6 aryl, or (iv) C5-6 heteroaryl having one, two, or three heteroatoms each selected form N, O, or S;
- n is 0, 1, 2, 3, or 4;
- m is 0, 1, 2, or 3;
- o is 0, 1, 2, or 3;
- and
- p is 0, 1, 2, or 3,
- or a pharmaceutically acceptable salt or solvate thereof.
11 more elements
A compound selected from:
- 3-(Benzylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (9);
- 3-[(4-Chlorophenyl)amino]-4-[(2-phenylethyl)amino]cyclobut-3-ene-1,2-dione (10);
- 3-[(4-Chlorophenyl)amino]-4-[(3-phenylpropyl)amino]cyclobut-3-ene-1,2-dione (11);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (12);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (13);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (14);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(2-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (15);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (16);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(4-methoxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (17);
- 3-[(4-Chlorophenyl)amino]-4-({2-[2-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (18);
- 3-[(4-Chlorophenyl)amino]-4-({2-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (19);
- 3-[(4-Chlorophenyl)amino]-4-({2-[4-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (20);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(4-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (21);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(2-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (22);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (6);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(2-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (23);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3-fluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (24);
- 3-[(4-Chlorophenyl)amino]-4-({2-[3-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (25);
- 3-[(4-Chlorophenyl)amino]-4-({2-[4-(dimethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione (26);
- 4-[(2-{[2-(3-Chlorophenyl)ethyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]benzonitrile (27);
- 3-(Biphenyl-3-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (28);
- 3-{3-[6-(Pyrrolidin-1-yl)pyridin-2-yl]-phenyl}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (29);
- 3-[(4-Chlorophenyl)amino]-4-{[3-(thiophen-3-yl)phenyl]amino}cyclobut-3-ene-1,2-dione (31);
- 3-[(4-Chlorophenyl)amino]-4-[(4′-fluorobiphenyl-3-yl)amino]cyclobut-3-ene-1,2-dione (32);
- 3-(Biphenyl-4-ylamino)-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione (33);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(2-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(pyridin-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(pyridin-4-yl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(4-bromophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(thiophen-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-{[2-(A-acetylphenyl)ethyl]amino}-4-[(4-chlorophenyl)amino]cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3,4-dimethylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3-hydroxyphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(2,4-dichlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(piperidin-1-yl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-({2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}amino)cyclobut-3-ene-1,2-dione;
- 3-[(4-Chlorophenyl)amino]-4-{[2-(2,4-difluorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
- and
- 3-[(4-Chlorophenyl)amino]-4-({2-[4-(diethylamino)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione,
- or a pharmaceutically acceptable salt thereof.
38 more elements
A compound selected from
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (6);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(4-chlorophenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (12);
- 3-[(4-Chlorophenyl)amino]-4-{[2-(3-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (13);
- and
- 3-[(4-Chlorophenyl)amino]-4-{[2-(4-methylphenyl)ethyl]amino}cyclobut-3-ene-1,2-dione (14),
- or a pharmaceutically acceptable salt thereof.
3 more elements
Dependencies are inferred from the claim text.