Asymmetric syntheses for spiro-oxindole compounds useful as therapeutic agents
View Patent ↗This invention is directed to asymmetric syntheses of certain spiro-oxindole derivatives, which are useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.
1. A method of preparing a compound of formula (I):
as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;
wherein:
p and r are each independently 1, 2, 3 or 4;
R 1 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 8 —C(O)R 5 , —R 8 —C(O)OR 5 , —R 8 —C(O)N(R 4 )R 5 , —S(O) 2 —R 5 , —R 9 —S(O) m —R 5 (where m is 0, 1 or 2), —R 8 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR 5 ) 2 , or —R 9 —O—R 9 —OR 5 ;
or R 1 is aralkyl substituted by —C(O)N(R 6 )R 7 where:
R 6 is hydrogen, alkyl, aryl or aralkyl; and
R 7 is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
or R 6 and R 7 , together with the nitrogen to which they are attached, form a N-heterocyclyl or a N-heteroaryl;
and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6 and R 7 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl;
or R 1 is aralkyl optionally substituted by one or more substituents selected from the group consisting of —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl;
or R 1 is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11 or —R 9 —N(R 10 )C(O)N(R 10 )R 11 where:
each R 10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl;
each R 11 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —N(R 4 )R 5 , —R 9 —OR 5 , or —R 9 —CN; and
R 12 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ;
and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 10 and R 11 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl;
or R 1 is heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , —R 8 —N(R 4 )R 5 , —R 8 —C(O)N(R 4 )R 5 , —R 8 —N(R 5 )C(O)R 4 , —R 8 —S(O) m R 4 (where m is 0, 1 or 2), —R 8 —CN, or —R 8 —NO 2 ;
each R 2 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —OS(O) 2 CF 3 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(═N—CN)N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
and wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 2 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —S(O) m R 4 , —R 8 —S(O) n N(R 4 )R 5 , —R 8 —C(O)R 4 , —R 8 —C(O)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , and —N(R 5 )S(O) n R 4 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
or any two adjacent R 2 's, together with the adjacent carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and the other R 2 's, if present, are as defined above;
each R 3 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —OS(O) 2 CF 3 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(N═C(R 4 )R 5 )N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
or any two adjacent R 3 's, together with the adjacent carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the other R 3 's, if present, are as defined above;
each R 4 and R 5 is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
or when R 4 and R 5 are each attached to the same nitrogen atom, then R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a N-heterocyclyl or a N-heteroaryl;
each R 8 is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and
each R 9 is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;
wherein the method comprises:
(a) treating a compound of formula (9):
where p, r, R 1 , R 2 and R 3 are as defined above for the compound of formula (I) and Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof, with a compound of formula (10):
Pg 2 OCH 2 X (10);
where Pg 2 is an oxygen protecting group and X is halo, under suitable C-alkylation conditions comprising the presence of a phase transfer catalyst selected from a quaternary ammonium salt of quinidine or a quaternary ammonium salt of cinchonine to provide a compound of formula (11):
where p, r, R 1 , R 2 and R 3 are each as defined above for the compound of formula (I) and Pg 1 and Pg 2 are each independently an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof;
(b) treating the compound of formula (11) under suitable recrystallization conditions to provide a compound of formula (12):
where p, r, R 1 , R 2 and R 3 are as defined above for the compounds of formula (I) and Pg 1 and Pg 2 are each independently an oxygen protecting group, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;
(g) treating the compound of formula (12) under suitable deprotecting conditions to provide a compound of formula (13):
where p, r, R 1 , R 2 and R 3 are as defined above for the compounds of formula (I), as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;
(h) treating the compound of formula (13) under suitable Mitsunobu reaction conditions to provide the compound of formula (I), as defined above, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein the compound of formula (I) is a compound of formula (Ia):
where q is 1 or 2 and p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I), as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.
3. The method of claim 2 wherein the compound of formula (Ia) is a compound of formula (Ia1):
as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 wherein the compound of formula (13) is a compound of formula (13a):
where q is 1 or 2 and p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I), as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 wherein the compound of formula (13a) is a compound of formula (13a1):
as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 wherein the compound of formula (12) is a compound of formula (12a):
where q is 1 or 2, Pg 1 and Pg 2 are each independently an oxygen protecting group and p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I), as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.
7. The method of claim 6 wherein the compound of formula (I2a) is a compound of formula (12a1):
where Pg 1 and Pg 2 are each independently an oxygen protecting group, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 wherein the compound of formula (11) is a compound of formula (11a):
where q is 1 or 2 and p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I) and Pg 1 and Pg 2 are each independently an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
9. The method of claim 8 wherein the compound of formula (11a) is a compound of formula (11a1):
where Pg 1 and Pg 2 are each independently an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 wherein the compound of formula (9) is a compound of formula (9a):
where q is 1 or 2 and p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I) and Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 wherein the compound of formula (9a) is a compound of formula (9a1):
where Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 further comprising a dehydoxylation step prior to treating the compound of formula (9) with a compound of formula (10), wherein the dehydroxylation step comprises treating a compound of formula (8):
where p, r, R 1 , R 2 and R 3 are each defined above in claim 1 for the compounds of formula (I) and Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof, under suitable dehydroxylation conditions to provide a compound of formula (9), as described above.
13. The method of claim 12 wherein the compound of formula (8) is a compound of formula (8a):
where q is 1 or 2, p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I) and Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 wherein the compound of formula (8a) is a compound of formula (8a1):
where Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
15. The method of claim 12 further comprising a protecting step prior to treating the compound of formula (8) under suitable dehydroxylation conditions, wherein the protecting step comprises treating a compound of formula (6):
where p, r, R 1 , R 2 , and R 3 are each as defined above in claim 1 for the compounds of formula (I), as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof, with a compound of formula (7):
Pg 1 X (7);
where X is halo and Pg 1 is an oxygen protecting group under suitable protecting conditions to provide a compound of formula (8), as described above.
16. The method of claim 15 wherein the compound of formula (6) is a compound of formula (6a):
where q is 1 or 2 and p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I), as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 wherein the compound of formula (6a) is a compound of formula (6a1):
as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof.
18. The method of claim 15 further comprising a Grignard addition step prior to treating the compound of formula (6) with a compound of formula (7), wherein the Grignard addition step comprises the following substeps:
(a) treating a compound of formula (4):
where r and R 3 are as described above for the compound of formula (I), with a Grignard reagent of formula (5):
RMgX (5);
where X is iodo, bromo or chloro and R is alkyl, under suitable conditions to form an intermediate Grignard addition product;
(b) treating a compound of formula (3):
where p, R 1 , R 2 are each as defined above in claim 1 for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, with the intermediate Grignard addition product formed in substep a) above under suitable Grignard reaction conditions to provide a compound of formula (6), as described above.
19. The method of claim 18 wherein the compound of formula (3) is a compound of formula (3a):
where p, R 1 and R 2 are each as defined above in claim 1 for the compounds of formula (I), or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 wherein the compound of formula (3a) is a compound of formula (3a1):
or a pharmaceutically acceptable salt thereof.
21. The method of claim 18 wherein the compound of formula (4) is a compound of formula (4a):
where q is 1 or 2.
22. The method of claim 21 wherein the compound of formula (4a) is a compound of formula (4a1):
23. The method of claim 18 further comprising a N-alkylation step prior to treating a compound of formula (3) with the intermediate Grignard addition product, wherein the N-alkylation step comprises treating a compound of formula (1):
where p and R 2 are each as defined above in claim 1 for the compounds of formula (I), or a pharmaceutically acceptable salt thereof, with a compound of formula (2):
X—R 1 (2);
where X is halo and R 1 is as defined above in claim 1 for the compounds of formula (I), under suitable N-alkylation conditions to provide a compound of formula (3), as described above.
24. The method of claim 23 wherein the compound of formula (1) is a compound of formula (1a):
or a pharmaceutically acceptable salt thereof.
25. The method of claim 23 wherein the compound of formula (2) is a compound of formula (2a):
where X is halo.
26. A method of preparing a compound of formula (I):
as an isolated (S)-enantiomer, or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;
wherein:
p and r are each independently 1, 2, 3 or 4;
R 1 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, —R 8 —C(O)R 5 , —R 8 —C(O)OR 5 , —R 8 —C(O)N(R 4 )R 5 , —S(O) 2 —R 5 , —R 9 —S(O) m —R 5 (where m is 0, 1 or 2), —R 8 —OR 5 , —R 8 —CN, —R 9 —P(O)(OR 5 ) 2 , or —R 9 —O—R 9 —OR 5 ;
or R 1 is aralkyl substituted by —C(O)N(R 6 )R 7 where:
R 6 is hydrogen, alkyl, aryl or aralkyl; and
R 7 is hydrogen, alkyl, haloalkyl, —R 9 —CN, —R 9 —OR 5 , —R 9 —N(R 4 )R 5 , aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
or R 6 and R 7 , together with the nitrogen to which they are attached, form a N-heterocyclyl or a N-heteroaryl;
and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 6 and R 7 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, —R 8 —CN, —R 8 —OR 5 , heterocyclyl and heteroaryl;
or R 1 is aralkyl optionally substituted by one or more substituents selected from the group consisting of —R 8 —OR 5 , —C(O)OR 5 , halo, haloalkyl, alkyl, nitro, cyano, aryl, aralkyl, heterocyclyl and heteroaryl;
or R 1 is —R 9 —N(R 10 )R 11 , —R 9 —N(R 12 )C(O)R 11 or —R 9 —N(R 10 )C(O)N(R 10 )R 11 where:
each R 10 is hydrogen, alkyl, aryl, aralkyl or heteroaryl;
each R 11 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 9 —OC(O)R 5 , —R 9 —C(O)OR 5 , —R 9 —C(O)N(R 4 )R 5 , —R 9 —C(O)R 5 , —R 9 —N(R 4 )R 5 , —R 9 —OR 5 , or —R 9 —CN; and
R 12 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 5 ;
and wherein each aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 10 and R 11 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, halo, haloalkyl, nitro, —R 8 —CN, —R 8 —OR 5 , —R 8 —C(O)R 5 , heterocyclyl and heteroaryl;
or R 1 is heterocyclylalkyl or heteroarylalkyl where the heterocyclylalkyl or the heteroarylalkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, alkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —OR 5 , —R 8 —C(O)OR 5 , —R 8 —N(R 4 )R 5 , —R 8 —C(O)N(R 4 )R 5 , —R 8 —N(R 5 )C(O)R 4 , —R 8 —S(O) m R 4 (where m is 0, 1 or 2), —R 8 —CN, or —R 8 —NO 2 ;
each R 2 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —OS(O) 2 CF 3 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(═N—CN)N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
and wherein each of the cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups for R 2 may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —S(O) m R 4 , —R 8 —S(O) n N(R 4 )R 5 , —R 8 —C(O)R 4 , —R 8 —C(O)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , and —N(R 5 )S(O) n R 4 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
or any two adjacent R 2 's, together with the adjacent carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, aryl, heterocyclyl and heteroaryl, and the other R 2 's, if present, are as defined above;
each R 3 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, haloalkenyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R 8 —CN, —R 8 —NO 2 , —R 8 —OR 5 , —R 8 —N(R 4 )R 5 , —N═C(R 4 )R 5 , —S(O) m R 4 , —OS(O) 2 CF 3 , —R 8 —C(O)R 4 , —C(S)R 4 , —C(R 4 ) 2 C(O)R 5 , —R 8 —C(O)OR 4 , —C(S)OR 4 , —R 8 —C(O)N(R 4 )R 5 , —C(S)N(R 4 )R 5 , —N(R 5 )C(O)R 4 , —N(R 5 )C(S)R 4 , —N(R 5 )C(O)OR 4 , —N(R 5 )C(S)OR 4 , —N(R 5 )C(O)N(R 4 )R 5 , —N(R 5 )C(S)N(R 4 )R 5 , —N(R 5 )S(O) n R 4 , —N(R 5 )S(O) n N(R 4 )R 5 , —R 8 —S(O) n N(R 4 )R 5 , —N(R 5 )C(═NR 5 )N(R 4 )R 5 , and —N(R 5 )C(N═C(R 4 )R 5 )N(R 4 )R 5 , wherein each m is independently 0, 1, or 2 and each n is independently 1 or 2;
or any two adjacent R 3 's, together with the adjacent carbon ring atoms to which they are directly attached, may form a fused ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the other R 3 's, if present, are as defined above;
each R 4 and R 5 is independently selected from group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
or when R 4 and R 5 are each attached to the same nitrogen atom, then R 4 and R 5 , together with the nitrogen atom to which they are attached, may form a N-heterocyclyl or a N-heteroaryl;
each R 8 is a direct bond or a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain; and
each R 9 is a straight or branched alkylene chain, a straight or branched alkenylene chain or a straight or branched alkynylene chain;
wherein the method comprises the following steps:
(a) treating a compound of formula (1):
where p and R 2 are as described above for the compound of formula (I), or a pharmaceutically acceptable salt thereof, with a compound of formula (2):
X—R 1 (2);
where R 1 is as defined above for the compound of formula (I) and X is halo, under suitable N-alkylation conditions to provide a compound of formula (3):
where p, R 1 and R 2 are as described above for the compound of formula (I), or a pharmaceutically acceptable salt thereof;
(b) treating the compound of formula (3) under suitable Grignard reaction conditions with an intermediate Grignard addition product formed from the treatment of a compound of formula (4):
where r and R 3 are as defined above for the compound of formula (I), with a Grignard reagent of formula (5):
RMgX (5);
where R is alkyl and X is iodo, bromo or chloro, under suitable conditions to form a compound of formula (6):
where p, r, R 1 , R 2 and R 3 are as defined above for the compound of formula (I), as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof;
(c) treating the compound of formula (6) with a compound of formula (7):
Pg 1 X (7);
where X is halo and Pg 1 is an oxygen protecting group under suitable protecting conditions to provide a compound of formula (8):
where p, r, R 1 , R 2 and R 3 are as defined above for the compound of formula (I) and Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof;
(d) treating the compound of formula (8) under suitable dehydroxylation conditions to provide a compound of formula (9):
where p, r, R 1 , R 2 and R 3 are as defined above for the compound of formula (I) and Pg 1 is an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof;
(e) treating the compound of formula (9) with a compound of formula (10):
Pg 2 OCH 2 X (10);
where Pg 2 is an oxygen protecting group and X is halo, under suitable C-alkylation conditions comprising the presence of a phase transfer catalyst selected from a quaternary ammonium salt of quinidine or a quaternary ammonium salt of cinchonine to provide a compound of formula (11):
where p, r, R 1 , R 2 and R 3 are each as defined above for the compound of formula (I) and Pg 1 and Pg 2 are each independently an oxygen protecting group, as a racemic mixture of enantiomers or as a non-racemic mixture of enantiomers, or a pharmaceutically acceptable salt thereof;
(f) treating the compound of formula (11) under suitable recrystallization conditions to provide a compound of formula (12):
where p, r, R 1 , R 2 and R 3 are as defined above for the compounds of formula (I) and Pg 1 and Pg 2 are each independently an oxygen protecting group, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;
(g) treating the compound of formula (12) under suitable deprotecting conditions to provide a compound of formula (13):
where p, r, R 1 , R 2 and R 3 are as defined above for the compounds of formula (I), as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof;
(h) treating the compound of formula (13) under suitable Mitsunobu reaction conditions to provide the compound of formula (I), as defined above, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer of greater than 80%, or a pharmaceutically acceptable salt thereof.