Aminopyrazine compounds with A2A antagonist properties

Patent metadata

Field	Value
Publication number	US-10472347-B2
Application number	US-201515525788-A
Country	US
Kind code	B2
Filing date	Nov 13, 2015
Priority date	Nov 18, 2014
Publication date	Nov 12, 2019
Grant date	Nov 12, 2019

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 “R 1 ”, “R A-1 ”, “R 2 ”, “R 3 ”, 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.

First claim

The invention claimed is:

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

wherein:
“Het” is a moiety of the formula:

wherein “R a1 ” and “R a2 ” 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 R 1 or R 2 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) —NR 1g R 2g , wherein R 1g and R 2g 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) —NR 1g R 2g , wherein R 1g and R 2g 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(R a8 ) 2 , wherein “R a8 ” 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)—R a12 ”, wherein “R a12 ” is a moiety which is: (ai) lower alkyl; (bi) lower alkoxy; (ci) heteroaryl; or (di) aryl, and wherein said “R a12 ” moiety is optionally substituted with one or more halogen moieties;
(xiii) a moiety of the formula “—O—R a13 ”, wherein “R a13 ” 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 “R d1 ” is —H or lower alkyl, and wherein one of “X d1 ” or “X d2 ” is —CH 2 — 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) R 1 and R 2 taken together are a moiety of the formula —[(CR B1 R B2 ) 2 ) n ]—, wherein, “n” is an integer of 3 to 6, and “R B1 ” and “R B2 ” 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) R 1 and R 2 taken together form an aryiheterocycloalkyl fused moiety; and “R 3 ” 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.

2. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula A-1:

wherein:
R A-1 is lower alkyl;
“Het” is a moiety of the formula:

wherein “R a1 ” and “R a2 ” 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; and

“R 3 ” is: (a) —CN; (b) halogen; (c) lower alkyl which is optionally substituted with one or more moieties which are: (i) —OH; or (ii) halogen.

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein “Het” is:

wherein “R a1 ” and “R a2 ” 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.

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein “Het” is:

wherein “R a1 ” and “R a2 ” 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, and X 1 is [—CH═] or [—N═].

5. A compound of claim 3 having the Formula:

wherein —R 3 is:

wherein
R 4 is (i) linear, branched or cyclic alkyl of up to four carbon atoms, wherein said alkyl is optionally substituted with one or more fluorine atoms; (ii) halogen; (iii) —O—R 4a , wherein R 4a is linear, branched or cyclic alkyl of up to four carbon atoms; or (iv) —N(R 4b ) 2 wherein R 4b is independently for each occurrence linear, branched or cyclic alkyl of up to four carbon atoms;

wherein Z is —CH 2 .N—, or is —CH—,

or a pharmaceutically acceptable salt thereof.

6. The following compounds of claim 2 :
methyl 3-amino-6-chloro-5-(1H-pyrazol-1-yl)pyrazine-2-carboxylate;
ethyl 3-amino-6-methyl-5-(2H-1,2,3-triazol-2-yl)pyrazine-2-carboxylate,

or a pharmaceutically acceptable salt thereof.

7. The following compounds of claim 3 , or a pharmaceutically acceptable salt thereof:
3-amino-6-methyl-N-[(3-methylpyridin-2-yl)methyl]-5-(1,3-oxazol-

Assignees

• Merck Sharp & Dohme

Inventors

• Kuang Rongze
• Ting Pauline
• Ali Amjad
• Wu Heping
• Berlin Michael
• Stamford Andrew
• Wang Hongwu
• Zhou Gang
• Kim David
• Deng Qiaolin
• Lim Yeon-Hee
• Yu Younong

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D241/26

  with nitrogen atoms directly attached to ring carbon atoms · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title