US 12,570,687 B2Granted

Triterpenoid compounds, pharmaceutical compositions thereof, and their use for treating a nuclear receptor subfamily 4 group a member 1-mediated disease

AssigneeNucMito Pharmaceuticals Co. Ltd.

InventorsXiaokun Zhang, Ying Su, Guobin Xie, Zhenfei Huang, Ziwen Chen, Yuqi Zhou, Duo Zhang, Zhiping Zeng, Siwei Yan

Life of this patent

Estimating the term…

Abstract

Disclosed herein are triterpenoid compounds, for example, a compound of Formula (I), and pharmaceutical compositions thereof. Also disclosed herein are methods of their use for treat.

Claims26

Dependent claims

A compound of Formula (I):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,
wherein:
R1 is (i) —C(O)NR1bR1c, —C(R1a)═NR1b, —C(R1a)═NOR1b, —C(O)R1a, —C(O)OR1a, —C(O)ONR1bR1c, —C(O)OP(OR1a)(OR1b), —C(O)N(CN)R1b, —C(O)N(R1b)OR1c, —C(O)SR1a, —C(═NR1a)NR1bR1c, —C(S)R1a, —C(S)OR1a, —C(S)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)SR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)R1b, —NR1aC(═NR1d)NR1bR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)N1aR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —SC(O)R1a, —SC(O)NR1bR1c, —S(O)R1a, —S(O)2R1a, —S(O)2OR1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
(ii) hydrogen, deuterium, azido, cyano, halo, isocyanato, isothiocyanato, or nitro;
or (iii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R2 is —O—C1-6 alkyl, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, or heteroaryl;
or R2 and R3 together with the carbon atoms to which they are attached form monocyclic heterocyclylene;
R3 and R4 together with the carbon atom to which they are attached form ═CO, ═CR1aR1c, ═CR1aCN, ═NR1b, ═NOR1b, ═NNR1aC(O)R1d, —NNR1aC(O)NR1bR1c, or heterocyclylene;
or R3 is C1-6 alkyl, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)SR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)R1b, —NR1aC(═NR1d)NR1bR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, or —NR1aS(O)2NR1bR1c;
and R4 is hydrogen or R3;
or R3, R4, and R5 together with the carbon atoms to which they are attached form unsaturated heterocyclylene;
or R3, R5, and R6 together with the carbon atoms to which they are attached form unsaturated heterocyclylene;
R5 and R6 together with the carbon atom to which they are attached form ═CO, ═CR1aR1c, ═CR1aCN, ═NR1b, ═NOR1b, or heterocyclylene;
or R5 is C1-6 alkyl, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)SR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)R1b, —NR1aC(═NR1d)NR1bR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, or —NR1aS(O)2NR1bR1c;
and R6 is hydrogen or R5;
and
each R1a, R1b, R1c, and R1d is independently C1-6 alkyl, hydrogen, deuterium, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl;
or R1b and R1c together with the N atom to which they are attached form heterocyclyl;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) deuterium, azido, cyano, halo, isocyanato, isothiocyanato, and nitro;
(b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Qa;
and (c) —C(O)Ra, —C(O)ORa, —C(O)NR1bR1c, —C(O)SRa, —C(NRa)NRbRc, —C(S)Ra, —C(S)ORa, —C(S)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(O)SR, —OC(═NRa)NRbRc, —OC(S)Ra, —OC(S)ORa, —OC(S)NRbRc, —OPO3RaRd, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(O)SRd, —NRaC(═NRd)NRbRc, —NRaC(S)Rd, —NRaC(S)ORd, —NRaC(S)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa;
or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Qa;
wherein each Qa is independently selected from:
(a) deuterium, azido, cyano, halo, isocyanato, isothiocyanato, and nitro;
(b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(O)SRe, —OC(═NRe)NRfRg, —OC(S)Re, —OC(S)ORe, —OC(S)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORf, —NReC(O)NRfRg, —NReC(O)SRf, —NReC(═NRh)NRfRg, —NReC(S)Rh, —NReC(S)ORf, —NReC(S)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or (iii) R and Rg together with the N atom to which they are attached form heterocyclyl.

29 more elements

A compound of:

(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A1;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-(methoxy-d3)-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A2;
(2R,4aS,6aS,12bR,14aS,14bR)-9-(acetyloxy)-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A3;
methyl (2R,4aS,6aS,12bR,14aS,14bR)-9-(1H-indol-3-yl)-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A4;
methyl (2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A5;
1H-1,2,3-benzotriazol-1-yl (2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A6;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-N,2,4a,6a,9,12b,14a-heptamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A7;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carbonyl fluoride A8;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A9;
(2R,4aS,6aS,9S,12bR,14aS,14bR)—N-ethyl-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A10;
benzyl (2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A11;
(2R,4aS,6aS,9S,12bR,14aS,14bR)—N-propyl-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A12;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-N,N,2,4a,6a,9,12b,14a-octamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A13;
(4S,6bS,8aS,11R,12aR,12bS,14aR)-11-(hydroxymethyl)-4-methoxy-4,6b,8a,11,12b,14a-hexamethyl-4,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydropicene-2,3-dione A14;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-ethoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A28;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carbonitrile A39;
(4S,6bS,8aS,11R,12aR,12bS,14aR)-11-(aminomethyl)-4-methoxy-4,6b,8a,11,12b,14a-hexamethyl-4,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydropicene-2,3-dione A40;
(4S,6bS,8aS,11R,12aR,12bS,14aR)-11-amino-4-methoxy-4,6b,8a,11,12b,14a-hexamethyl-4,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydropicene-2,3-dione A41;
1-((2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicen-2-yl)urea A42;
(2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A15;
benzyl (2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A16;
(2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-N,2,4a,6a,9,12b,14a-heptamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A17;
(3R,4S,6bS,8aS,11R,12aR,12bS,14aR)-3-hydroxy-11-(hydroxymethyl)-4-methoxy-4,6b,8a,11,12b,14a-hexamethyl-2,3,4,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-hexadecahydropicen-2-one A18;
(2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carbaldehyde A19;
methyl (2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A20;
(2R,4aS,6aR,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12b,13,14,14a,14b-icosahydropicene-2-carboxylic acid A21;
methyl (2R,4aS,6aR,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12b,13,14,14a,14b-icosahydropicene-2-carboxylate A22;
(3R,4S,6bS,8aS,11R,12aR,12bS,14aR)-4-methoxy-4,6b,8a,11,12b,14a-hexamethyl-11-(methylcarbamoyl)-2-oxo-2,3,4,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-hexadecahydropicen-3-yl butyrate A23;
methyl (2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-(butyryloxy)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A24;
methyl (2R,4aS,6aS,9S,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10-(methylamino)-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A26;
benzyl (2R,4aS,6aS,9S,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10-(methylamino)-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A27;
methyl (2R,4aS,6aS,12bR,14aS,14bR)-9,10-dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A35;
methyl (2R,4aS,6aS,9S,10S,12bR,14aS,14bR)-10-(butyryloxy)-11-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A25;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-10,11-dihydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A29;
(2R,4aS,6aS,9S,10Z,12bR,14aS,14bR)-10-(cyanomethylidene)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A30;
(2R,4aS,6aS,9S,10E,12bR,14aS,14bR)-10-(cyanomethylidene)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A31;
methyl (2R,4aS,6aS,10Z,12bR,14aS,14bR)-10-(cyanomethylidene)-9-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A33;
methyl (2R,4aS,6aS,10E,12bR,14aS,14bR)-10-(cyanomethylidene)-9-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A34;
(2R,4aS,6aS,9S,10E,12bR,14aS,14bR)-10-(cyanomethylidene)-11-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A36;
methyl (2R,4aS,6aS,11E,12bR,14aS,14bR)-11-(cyanomethylidene)-9-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-10-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A37;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-10-(cyanomethyl)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A38;
(6bS,8aS,11R,12aR,12bS,14aR)-16a-hydroxy-4a,6b,8a,11,12b,14a-hexamethyl-16-oxo-2,3,4a,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a,16,16a-octadecahydropiceno[3,4-b][1,4]dioxine-11-carboxylic acid A43;
(2R,4aS,6aS,9S,12bR,14aS,14bR)—N-(2-hydroxyethyl)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A44;
(2R,4aS,6aS,9S,12bR,14aS,14bR)—N-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A45;
(2R,4aS,6aS,14bR,16aS,16bR)-13a-hydroxy-9-methoxy-2,4a,6a,9,14b,16a-hexamethyl-2,3,4,4a,5,6,6a,9,11,12,13a,14b,15,16,16a,16b-hexadecahydro-1H-piceno[2,3-b][1,4]oxazine-2-carboxylic acid A46;
(2R,4aS,6aS,14bR,16aS,16bR)—N,13a-dihydroxy-9-methoxy-2,4a,6a,9,14b,16a-hexamethyl-2,3,4,4a,5,6,6a,9,11,12,13a,14b,15,16,16a,16b-hexadecahydro-1H-piceno[2,3-b][1,4]oxazine-2-carboxamide A47;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-11-(hydroxyimino)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A48;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-10-(2-carbamoylhydrazono)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A49;
(2R,4aS,6aS,9S,10S,12bR,14aS,14bR)-10-hydroxy-11-(hydroxyimino)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A50;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-10-(acetamidoimino)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A51;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-10-{[(pyridin-4-yl)formamido]imino}-1,2,3,4,4a,5,6,6a,9,10,11,12b,13, 14,14a,14b-hexadecahydropicene-2-carboxylic acid A52;
(2R,4aS,6aS,9S,12bR,14aS,14bR)-10-(2-benzoylhydrazono)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid A53;
(4S,6bS,8aS,11R,12aR,12bS,14aR)-4-methoxy-4,6b,8a,11,12b,14a-hexamethyl-3-oxo-4,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-3H-spiro[picene-2,2′-[1,3]dioxolane]-11-carboxylic acid A54;
(2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A55;
(3R,4S,6bS,8aS,11R,12aR,12bS,14aR)-3-hydroxy-4-methoxy-4,6b,8a,11,12b,14a-hexamethyl-11-(morpholine-4-carbonyl)-4,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydropicen-2(3H)-one A56;
(2R,4aS,6aS,9S,10R,12bR,14aS,14bR)—N,10-dihydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxamide A57;
methyl (2R,4aS,6aS,14bR,16aS,16bR)-9-methoxy-2,4a,6a,9,14b,16a-hexamethyl-11-oxo-1,3,4,4a,5,6,6a,9,9a,11,12,14b,15,16,16a,16b-hexadecahydro-2H-piceno[3,2-b][1,4]oxazine-2-carboxylate A58;
(2R,4aS,6aS,9S,10Z,12bR,14aS,14bR)-10-(cyanomethylidene)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadeca-hydropicene-2-carboxamide A59;
benzyl (2R,4aS,6aS,9S,10Z,12bR,14aS,14bR)-10-(cyanomethylidene)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadeca-hydropicene-2-carboxylate A60;
benzyl (2R,4aS,6aS,9S,10E,12bR,14aS,14bR)-10-(cyanomethylidene)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylate A61;
(2R,4aS,6aS,9S,10R,12bR,14aS,14bR)-10-hydroxy-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicene-2-carbonitrile A62;
or
N-[(2R,4aS,6aS,9S,12bR,14aS,14bR)-9-methoxy-2,4a,6a,9,12b,14a-hexamethyl-10,11-dioxo-1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydropicen-2-yl]acetamide A63;
or a diastereomer, a mixture of diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

62 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/753,684Filed 14 Sep 2020 · us provisional application
Priority: 12 Sep 2019
Published: US 2022/0324903 A113 Oct 2022
Granted: 10 Mar 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07J 63/008
Steroids in which the cyclopentahydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms: expansion of ring…
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/16
Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles: agglomerates;…
A61P 35/00
Antineoplastic agents

Family

Application62/899,671Us provisional application · filed 12 Sep 2019
US 2022/0324903 A1Pre-grant publication · published 13 Oct 2022
US 12,570,687 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Disclosed herein are triterpenoid compounds, for example, a compound of Formula (I), and pharmaceutical compositions thereof. Also disclosed herein are methods of their use for treat.

A compound of Formula (I):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof;
or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,
wherein:
R1 is (i) —C(O)NR1bR1c, —C(R1a)═NR1b, —C(R1a)═NOR1b, —C(O)R1a, —C(O)OR1a, —C(O)ONR1bR1c, —C(O)OP(OR1a)(OR1b), —C(O)N(CN)R1b, —C(O)N(R1b)OR1c, —C(O)SR1a, —C(═NR1a)NR1bR1c, —C(S)R1a, —C(S)OR1a, —C(S)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)SR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)R1b, —NR1aC(═NR1d)NR1bR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)N1aR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —SC(O)R1a, —SC(O)NR1bR1c, —S(O)R1a, —S(O)2R1a, —S(O)2OR1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c;
(ii) hydrogen, deuterium, azido, cyano, halo, isocyanato, isothiocyanato, or nitro;
or (iii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R2 is —O—C1-6 alkyl, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, or heteroaryl;
or R2 and R3 together with the carbon atoms to which they are attached form monocyclic heterocyclylene;
R3 and R4 together with the carbon atom to which they are attached form ═CO, ═CR1aR1c, ═CR1aCN, ═NR1b, ═NOR1b, ═NNR1aC(O)R1d, —NNR1aC(O)NR1bR1c, or heterocyclylene;
or R3 is C1-6 alkyl, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)SR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)R1b, —NR1aC(═NR1d)NR1bR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, or —NR1aS(O)2NR1bR1c;
and R4 is hydrogen or R3;
or R3, R4, and R5 together with the carbon atoms to which they are attached form unsaturated heterocyclylene;
or R3, R5, and R6 together with the carbon atoms to which they are attached form unsaturated heterocyclylene;
R5 and R6 together with the carbon atom to which they are attached form ═CO, ═CR1aR1c, ═CR1aCN, ═NR1b, ═NOR1b, or heterocyclylene;
or R5 is C1-6 alkyl, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(O)SR1a, —OC(═NR1a)NR1bR1c, —OC(S)R1a, —OC(S)OR1a, —OC(S)NR1bR1c, —OP(O)(OR1a)OR1d, —OS(O)R1a, —OS(O)2R1a, —OS(O)2OR1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)SR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)R1b, —NR1aC(═NR1d)NR1bR1c, —NR1aC(S)R1d, —NR1aC(S)OR1d, —NR1aC(S)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, or —NR1aS(O)2NR1bR1c;
and R6 is hydrogen or R5;
and
each R1a, R1b, R1c, and R1d is independently C1-6 alkyl, hydrogen, deuterium, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl;
or R1b and R1c together with the N atom to which they are attached form heterocyclyl;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) deuterium, azido, cyano, halo, isocyanato, isothiocyanato, and nitro;
(b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Qa;
and (c) —C(O)Ra, —C(O)ORa, —C(O)NR1bR1c, —C(O)SRa, —C(NRa)NRbRc, —C(S)Ra, —C(S)ORa, —C(S)NRbRc, —ORa, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(O)SR, —OC(═NRa)NRbRc, —OC(S)Ra, —OC(S)ORa, —OC(S)NRbRc, —OPO3RaRd, —OS(O)Ra, —OS(O)2Ra, —OSO3Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(O)SRd, —NRaC(═NRd)NRbRc, —NRaC(S)Rd, —NRaC(S)ORd, —NRaC(S)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Qa;
or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Qa;
wherein each Qa is independently selected from:
(a) deuterium, azido, cyano, halo, isocyanato, isothiocyanato, and nitro;
(b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl;
and (c) —C(O)Re, —C(O)ORe, —C(O)NRfRg, —C(O)SRe, —C(NRe)NRfRg, —C(S)Re, —C(S)ORe, —C(S)NRfRg, —ORe, —OC(O)Re, —OC(O)ORe, —OC(O)NRfRg, —OC(O)SRe, —OC(═NRe)NRfRg, —OC(S)Re, —OC(S)ORe, —OC(S)NRfRg, —OS(O)Re, —OS(O)2Re, —OS(O)NRfRg, —OS(O)2NRfRg, —NRfRg, —NReC(O)Rh, —NReC(O)ORf, —NReC(O)NRfRg, —NReC(O)SRf, —NReC(═NRh)NRfRg, —NReC(S)Rh, —NReC(S)ORf, —NReC(S)NRfRg, —NReS(O)Rh, —NReS(O)2Rh, —NReS(O)NRfRg, —NReS(O)2NRfRg, —SRe, —S(O)Re, —S(O)2Re, —S(O)NRfRg, and —S(O)2NRfRg;
wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium;
(ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
or (iii) R and Rg together with the N atom to which they are attached form heterocyclyl.

29 more elements

Facts

Application

17/753,684Filed 14 Sep 2020 · us provisional application

Priority

12 Sep 2019

Published

US 2022/0324903 A113 Oct 2022

Granted

10 Mar 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07J 63/008
Steroids in which the cyclopentahydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms: expansion of ring…
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/16
Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles: agglomerates;…
A61P 35/00
Antineoplastic agents