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US 2024/0174685 A1Published application
OX2R Compounds
AssigneeBoard of Regents, The University of Texas System
InventorsJef De Brabander, Daniel Rosenbaum, Qiren Liang, Wentian Wang
Life of this patent
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Abstract
Methods and compositions for agonizing a type-2 orexin receptor (OX2R) in a cell determined to be in need thereof, including the general method of (a) administering to a subject a cyclic guanidinyl OX2R agonist and (b) detecting a resultant enhanced wakefulness or increased resistance to diet-induced accumulation of body fat, or abbreviated recovery from general anesthesia or jet lag.
Claims19
A compound of formula (A):
- or a pharmaceutically acceptable salt thereof, wherein
- Y1, Y2, Y3, and Y4, are each independently N or CR6, wherein no more than two of Y1, Y2, Y3, and Y4 are N;
- W1 and W2 are each independently selected from aryl, heterocyclyl, or heteroaryl, which are each optionally substituted with one or more R10;
- L1 is C1-C6 alkylene or C2-C6 alkenylene, optionally substituted with one or more R7;
- L2 is C1-C6 alkylene or C2-C6 alkenylene, optionally substituted with one or more R8;
- R2 is selected O, NH, NR11;
- R6 is selected hydrogen, halogen, —CN, —NO2, —SC1—C6 alkyl, —COR9, —C1-C6 alkyl, —C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —C1-C6 haloalkoxy,
- R7 is selected from halogen, —OH, —NRaRb, —CN, —C1-C6 alkyl, —C1-C3 alkylene-OH, —C1-C3 alkylene-CN, —CH(OH)CH2CN, —C1-C3 alkylene-(C1-C6 alkoxy), —C1-C3 alkylene-(C1-C6 haloalkoxy), —C1-C3 alkylene-OCO(optionally substituted heterocyclyl), —C1-C3 alkylene-OCOR9, —C1-C3 alkylene-OCOORg, —C1-C3 alkylene-NRaRb, —C1-C3 alkylene-NRaCOR9, —C1-C3 alkylene-NRaCO(optionally substituted heterocyclyl), —C1-C3 alkylene-NRaCOORg, —C1-C3 alkylene-NRaCONRaRb, —C1-C3 alkylene-CONRaRb, —C1-C3 alkylene-CONR′Rd, —CONRaRb, —CONRcRd, —(C1-C3 alkylene)-O—(C1-C3 alkylene)-OH, —(C1-C3 alkylene)-O—(C1-C3 alkylene)-CN, —(C1-C3 alkylene)-O—(C1-C3 alkylene)-O—(C1-C4 alkyl), —(C1-C3 alkylene)-O—(C1-C3 alkylene)-O—(C1-C4 haloalkyl), —(C1-C3 alkylene)-O—(C1-C3 alkylene)-S—(C1-C3 alkyl), —C1-C3 alkylene-S(C1-C6 alkyl), —C1-C3 alkylene-SO(C1-C6 alkyl), —C1-C3 alkylene-SO2(C1-C6 alkyl), —C1-C3 alkylene-SO2R12, or hetercyclyl optionally substituted with R10;
- R8 is selected from —OH, —CN, —NO2, —CORg, oxo, —C1-C6 alkyl, C1-C6 alkylene-OH, —C1-C6 haloalkyl, —C3-C6 cycloalkyl,
- Ra and Rb are each independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, —CHO, —COOH, —CO(C1-C3 alkyl), —CO(C1-C3 haloalkyl), —CO(C3-C8 cycloalkyl), —CO(C2-C4 alkenyl), —CO(C1-C6 alkylene)-OH, —CO(C1-C6 alkylene)-(C1-C6 alkoxy), —CONReRf, —CO(C1-C3 alkylene)-NReRf, —CO(C1-C3 alkylene)-NReSRf, —CO(C1-C3 alkylene)-NReSORg, —CO(C1-C3 alkylene)-NReSO2Rf, —CO(C2-C3 alkenyl), —CO(C1-C3 haloalkyl), —CO(CH2)n(cycloalkyl), —CO(CH2)n(optionally substituted aryl), —CO(CH2)n(optionally substituted heterocyclyl), —CO(CH2)n(optionally substituted heteroaryl);Re and Rd together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring atom can contain up to 3 heteroatoms selected from N, O, or S;
- Re and Rf are each independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, or —C1-C6 alkylene-OH;
- Rg is H, —C1-C6 alkyl, —C3-C6 cycloalkyl, —C1-C6 haloalkyl, phenyl, or benzyl;
- R9 is —C1-C3 alkylene-OH, —C1-C3 alkylene-CN, —C1-C3 alkylene-(C1-C3 alkoxy), or —C1-C3 alkylene-NRaRb,
- R10 is halogen, —CN, oxo, —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —S—S—(C1-C6 alkyl), or optionally substituted phenyl;
- R11 is —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C3 alkylene-OH, —C1-C3 alkylene-(C1-C3 alkoxy), —COO(C1-C6 alkyl);
- alternatively, R11 and R7 together form a 5- to 7-membered ring, which is optionally substituted with R10;
- R12 is —OH, —C1-C6 alkyl, —C3-C6 cycloalkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, phenyl, benzyl, —NRaRb, —CONRaRb, or —NRaCORg;
- n is 0, 1, or 2.
15 more elements
A compound of formula (II):
- or a pharmaceutically acceptable salt thereof, wherein
- R1 is aryl or heteroaryl, optionally substituted with one or more R1a;
- R2 is aryl or heteroaryl, optionally substituted with one or more R2a;
- R3 is alkyl, cycloalkyl, aryl, -alkylaryl, heterocyclyl, or heteroaryl, optionally substituted with one or more R3a;
- and
- R1a, R2a, and R3a is each independently selected from halogen, —OH, —CN, —NO2, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —C3-C6 cycloalkyl, —S(C1-C6 alkyl), —SO(C1-C6 alkyl), —SO2(C1-C6 alkyl), —CORg, —NRaRb, —OCOR9, —OCOORg, —OCO(optionally substituted heterocyclyl), —NRaCOR9, —NRaCO(optionally substituted heterocyclyl), —NRaCOORg, —NRaCONRaRb, —CONRaRb, —CONReRd, heterocyclyl, heteroaryl, or aryl;
- Ra and Rb are each independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, —CHO, —CO(C1-C3 alkyl), —CO(C1-C6 alkylene)-OH, —CONReRf, —CO(C1-C3 alkylene)-NReRf, —CO(C1-C3 alkylene)-NReSRf, —CO(C1-C3 alkylene)-NReSORg, —CO(C1-C3 alkylene)-NReSO2Rf, —CO(C2-C3 alkenyl), —CO(C1-C3 haloalkyl), —CO(CH2)n(cycloalkyl), —CO(CH2)n(optionally substituted aryl), —CO(CH2)n(optionally substituted heterocyclyl), —CO(CH2)n(optionally substituted heteroaryl);
- Rc and Rd together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring atom can contain up to 3 heteroatoms selected from N, O, or S;
- Re and Rf are each independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, or —C1-C6 alkylene-OH;
- Rg is H, —C1-C6 alkyl, —C3-C6 cycloalkyl, —C1-C6 haloalkyl, phenyl, or benzyl;
- and
- R9 is —C1-C3 alkylene-OH, —C1-C3 alkylene-CN, —C1-C3 alkylene-(C1-C3 alkoxy), or —C1-C3 alkylene-NRaRb.
9 more elements
A compound of formula (VII):
- (VII)
- or a pharmaceutically acceptable salt thereof, wherein
- L1 is —NR7C(═O)—, —CONR7—, —CH2C(═O)—, —C(═O)CH2—, —OC(═O)—, —C(═O)O—, —SC(═O)—, —C(═O)S—, —NR7C(═O)—, —CH2NR7—, —CH2CH2—, —OCH2—, —CH2O—, —SCH2—, —CH2S—, —NR7SO2—, —SO2NR7—, —CH2SO2—, —SO2CH2—, —OSO2—, —SO2O—, —NR7—,
- L2 is —SO2—, —C(═O)—, —CH2—, —CH2CH2—, —CHR6—,
- W is arylene or heteroarylene, each optionally substituted with one or more R4;
- R1 is aryl or heteroaryl, each optionally substituted with one or more R4;
- R2 is selected NH2, or NHR11;
- R3 is halogen, —CN, —NO2, —SCH3, —COR5, —C1-C6 alkyl, —C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —C1-C6 haloalkoxy,
- R4 is halogen, —CN, —NO2, —SCH3, —COR5, —C1-C6 alkyl, —C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —C1-C6 haloalkoxy;
- R5 is H, —C1-C6 alkyl, —C3-C6 cycloalkyl, or —C1-C6 haloalkyl;
- R6 is selected halogen, —CN, —NO2, —SCH3, —COR5, —C1-C6 alkyl, —C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —C1-C6 haloalkoxy,
- R7 is —C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C3 alkylene-OH, —C1-C3 alkylene-(C1-C3 alkoxy), —COO(C1-C6 alkyl);
- and
- n is 0, 1, 2, 3, 4, or 5, or
- a compound of formula (VIII):
- or a pharmaceutically acceptable salt thereof, wherein
- R1 is alkyl, cycloalkyl, aryl, -alkylaryl, heterocyclyl, or heteroaryl, optionally substituted with one or more R1a;
- R2 is aryl or heteroaryl, optionally substituted with one or more R2a;
- R3 is H, or —OH, —CN, —NO2, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —C3-C6 cycloalkyl, aryl or heteroaryl, optionally substituted with one or more R3a
- R1a is each independently selected from halogen, —OH, —CN, —NO2, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —C3-C6 cycloalkyl, —S(C1-C6 alkyl), —SO(C1-C6 alkyl), —SO2(C1-C6 alkyl), —CORg, —NRaRb, —OCOR9, —OCOORg, —OCO(optionally substituted heterocyclyl), heterocyclyl, heteroaryl, or aryl
- R2a and R3a is each independently selected from halogen, —OH, —CN, —NO2, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C6 haloalkoxy, —C3-C6 cycloalkyl, —S(C1-C6 alkyl), —SO(C1-C6 alkyl), —SO2(C1-C6 alkyl), —CORg, —NRaRb, —OCOR9, —OCOORg, —OCO(optionally substituted heterocyclyl), —NRaCOORg, —NRaCONRaRb, —CONRaRb, —CONRcRd, heterocyclyl, heteroaryl, or aryl;
- Ra and Rb are each independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, —CHO, —CO(C1-C3 alkyl), —CO(C1-C6 alkylene)-OH, —CONReRf, —CO(C1-C3 alkylene)-NReRf, —CO(C1-C3 alkylene)-NReSRf, —CO(C1-C3 alkylene)-NReSORg, —CO(C1-C3 alkylene)-NReSO2Rf, —CO(C2-C3 alkenyl), —CO(C1-C3 haloalkyl), —CO(CH2)n(cycloalkyl), —CO(CH2)n(optionally substituted aryl), —CO(CH2)n(optionally substituted heterocyclyl), —CO(CH2)n(optionally substituted heteroaryl);
- Rc and Rd together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring atom can contain up to 3 heteroatoms selected from N, O, or S;
- Re and Rf are each independently selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, or —C1-C6 alkylene-OH;
- Rg is H, —C1-C6 alkyl, —C3-C6 cycloalkyl, —C1-C6 haloalkyl, phenyl, or benzyl;
- R9 is —C1-C3 alkylene-OH, —C1-C3 alkylene-CN, —C1-C3 alkylene-(C1-C3 alkoxy), or —C1-C3 alkylene-NRaRb;
- and
- X is, O or NH, or CH2 optionally substituted with —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —C1-C6 haloalkyl, —C1-C6 alkoxy, —C1-C6 haloalkoxy, o —C3-C6 cycloalkyl, —CORg, —NRaRb, or —OCOR9.
25 more elements
Dependencies are inferred from the claim text.