US 10,472,347 B2 · Aminopyrazine compounds with A2A antagonist properties

Abstract

Disclosed are compounds of Formula A and Formula A-1, or a salt thereof, and pharmaceutical formulations (pharmaceutical compositions) comprising those compounds, or a salt thereof; wherein “R1”, “RA-1”, “R2”, “R3”, and “Het” are defined herein above, which compounds are believed suitable for use in selectively antagonizing the A2a receptors, for example, those found in high density in the basal ganglia. Such compounds and pharmaceutical formulations are believed to be useful in treatment or management of neurodegenerative diseases, for example, Parkinson's disease, or movement disorders arising from use of certain medications used in the treatment or management of Parkinson's disease.

A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula A:

wherein:
“Het” is a moiety of the formula:
wherein “Ra1” and “Ra2” are, independently for each occurrence:
(a) —H;
or (b) lower alkyl which is optionally substituted with one or more moieties which are:
(i) halogen;
or (ii) lower alkoxy;
(A) one of R1 or R2 is lower alkyl or H and the other is;
(a) a linear, branched, mono-cyclic, or hi-cyclic-alkyl moiety of up to 10 carbon atoms, which is optionally substituted with one or more substituents which are independently:
(i) halogen;
(ii) —NR1gR2g, wherein R1g and R2g are, independently:
(ai) —H;
or (bi) lower alkyl;
(iii) —CN;
(iv) —OH;
(v) mono- or poly-cyclic heteroaryl comprising at least two carbon atoms and up to 3 heteroatoms which are, independently, N, O, or S and which is optionally substituted with:
(ai) lower alkyl, which moiety is optionally substituted with one or more moieties which are independently;
(aii) halogen;
(bii) lower alkoxy;
or
(cii) —OH
(bi) —NR1gR2g, wherein R1g and R2g are, independently:
(aii) —H;
or (bii) lower alkyl;
(ci) lower-alkoxy, which is optionally substituted in its alkyl portion with a halogen;
(di) halogen;
(ei) —OH;
(fi) heteroaryl;
(gi) heterocycloalkyl which is optionally substituted with one or more halogen atoms;
and wherein, if said heteroaryl comprises a single nitrogen heteroatom in the ring, optionally said ring nitrogen is present in the N-oxide oxidized form;
(vi) heteroarylone which is optionally substituted with one or more moieties which are, independently, a lower alkyl, which lower alkyl substituent is optionally fluorine substituted;
(vii) heteroarylaryl fused moiety, which is optionally substituted with one or more lower alkyl moieties, which lower alkyl moieties are optionally substituted with fluorine;
(viii) aryl, which is optionally substituted with one or more moieties which are independently:
(ai) lower alkyl which is optionally substituted with a halogen;
(bi) halogen;
(ci) —OH;
(di) lower alkoxy which is optionally halogen substituted;
or
(ei) —N(Ra8)2, wherein “Ra8” is independently —H or lower alkyl;
(ix) arylheteroaryl fused moiety, which is optionally substituted with one or more moieties which are lower alkyl;
(x) cycloalkylheteroaryl fused moiety;
(xi) linear, branched, or cyclic alkyl of up to 6 carbon atoms which is optionally substituted with one or more moieties which are independently:
(ai) —CN;
(bi) lower alkoxy;
or (ci) halogen;
(xii) a moiety of the formula “—C(O)—Ra12”, wherein “Ra12” is a moiety which is:
(ai) lower alkyl;
(bi) lower alkoxy;
(ci) heteroaryl;
or (di) aryl, and wherein said “Ra12” moiety is optionally substituted with one or more halogen moieties;
(xiii) a moiety of the formula “—O—Ra13”, wherein “Ra13” is lower alkyl or aryl;
(xiv) —OH;
(xv) heteroaryl-heterocycloalkyl fused moiety;
(b) heteroarylcycloalkyl fused moiety which is optionally substituted with:
(i) —OH;
or (ii) halogen;
(c) heterocycloalkyl, which is optionally substituted with one or more moieties which are independently:
(i) —F;
or (ii) heteroaryl;
(d) a compound of the Formula:
wherein “Rd1” is —H or lower alkyl, and wherein one of “Xd1” or “Xd2” is —CH2— and the other is —C(═O)—;
(e) arylheterocycloalkyl fused moiety;
(f) heterocycloalkylaryl fused moiety which is optionally substituted with —OH or halogen;
(g) heteroarylheterocycloalkyl fused moiety which is optionally substituted with —OH or halogen;
(h) arylcycloalkyl fused moiety, which is optionally substituted with one or more moieties which are, independently:
(i) —OH;
(ii) —CN;
(iii) halogen;
or
(iv) lower alkoxy;
(B) R1 and R2 taken together are a moiety of the formula —[(CRB1RB2)2)n]—, wherein, “n” is an integer of 3 to 6, and “RB1” and “RB2” are independently for each occurrence:
(a) lower alkyl;
(b) hydrogen;
(c) aryl;
or (d) halogen, thereby forming with the nitrogen to which they are bonded a heterocycloalkyl moiety;
or
(C) R1 and R2 taken together form an aryiheterocycloalkyl fused moiety;
and “R3” is:
selected from —CN, halogen, and lower alkyl, wherein said lower alkyl is unsubstituted or substituted with one or more moieties independently selected from OH and halogen.

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Aminopyrazine compounds with A2A antagonist properties

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Aminopyrazine compounds with A2A antagonist properties

Life of this patent

Abstract

Claims19