Process for the synthesis of E1 activating enzyme inhibitors

1. A process comprising forming a compound of formula (I):

or a salt thereof;

wherein:

stereochemical configurations depicted at asterisk positions indicate relative stereochemistry;

R a is hydrogen or a hydroxyl protecting group; or R a taken together with R j and the intervening atoms forms a cyclic diol protecting group; or R a taken together with R m and the intervening atoms forms a cyclic diol protecting group;

R b is hydrogen, fluoro, C 1-4 aliphatic or C 1-4 fluoroaliphatic;

R c is hydrogen, fluoro, chloro, —OH, —O—R m or optionally substituted C 1-4 aliphatic;

R d is hydrogen, fluoro, C 1-4 aliphatic or C 1-4 fluoroaliphatic;

R e is hydrogen or C 1-4 aliphatic;

R e′ is hydrogen or C 1-4 aliphatic;

each R f is independently hydrogen, fluoro, C 1-4 aliphatic or C 1-4 fluoroaliphatic;

R g is chloro, fluoro, iodo or bromo;

R h is hydrogen, fluoro, C 1-4 aliphatic or C 1-4 fluoroaliphatic;

R h′ is hydrogen, fluoro, C 1-4 aliphatic or C 1-4 fluoroaliphatic;

R j is hydrogen or a hydroxyl protecting group; or R j taken together with R a and the intervening atoms forms a cyclic diol protecting group;

R k is hydrogen or C 1-4 aliphatic;

R m is a hydroxyl protecting group; or R m taken together with R a and the intervening atoms forms a cyclic diol protecting group;

said process comprising a step of combining a compound of formula (II), or a salt thereof, with a compound of formula (III) to afford a compound of formula (I);

wherein:

stereochemical configurations depicted at asterisk positions indicate relative stereochemistry;

each of variables R a , R b , R c , R d , R e , R e′ , R f , R g , R h , R h′ , R j , R k , and R m in formulas (II) and (III) is as defined in formula (I); and

R l is —CH 2 CHO.

2. The process of claim 1 , wherein each of R b , R d , R e , R e′ , R f , R h , R h′ , and R k is hydrogen.

3. The process of claim 1 , wherein:

said combining step comprises the step:

treating a compound of formula (II), or a salt thereof, with a compound of formula (III) in the presence of a base.

4. The process of claim 3 , wherein:

R g is chloro or fluoro; and

each of R b , R d , R e , R e′ , R f , R h , R h′ , and R k is hydrogen.

5. The process of claim 2 , further comprising a step of:

treating the compound of formula (I) with an amine of formula HNR n R o to form a compound of formula (V) or a salt thereof;

wherein:

stereochemical configurations depicted at asterisk positions indicate relative stereochemistry;

each of variables R a , R c , R d , R e , R e′ , R f , R h , R h′ , R k , and R m in formula (V) is as defined in formula (I);

R n is hydrogen or C 1-4 aliphatic; and

R o is optionally substituted C 1-10 aliphatic, aryl, heteroaryl or heterocyclic.

6. The process of claim 5 further comprising a step of:

sulfamoylating a compound of formula (V), wherein R j is hydrogen to form a compound of formula (VI), or a salt thereof;

wherein:

stereochemical configurations depicted at asterisk positions indicate relative stereochemistry; and

each of variables R a , R b , R c , R d , R e , R e′ , R f , R h , R h′ , R k , R m , R n , and R o in formula (VI) is as defined in formula (V).

7. The process of claim 6 , wherein the sulfamoylation step comprises the steps:

I-D) treating the compound of formula (V) with a sulfamoylating reagent R u N − —S(O) 2 X + ;

II-D) optionally treating the reaction mixture formed in step I-D) with an acid;

wherein:

R u is —C(O)OC(R v ) 2 (R w );

each R v is independently selected from hydrogen, optionally substituted C 1-10 aliphatic or optionally substituted aryl;

R w is optionally substituted C 1-10 aliphatic or optionally substituted aryl;

or one R v is optionally substituted C 1-10 aliphatic; and the other R v is taken together with R w to form an optionally substituted C 3-6 cycloaliphatic ring; and

X is a tertiary amine or nitrogen-containing heteroaryl.

8. The process of claim 5 , wherein:

HNR n R o is represented by a compound of formula (VIIa) and forms a compound of formula (Va);

wherein:

stereochemical configurations depicted at asterisk positions indicate relative stereochemistry;

each of variables R a , R b , R c , R d , R e , R e′ , R f , R h , R h′ , R k , and R m in formula (Va) is as defined in formula (V);

each R p independently is selected from the group consisting of

fluoro, —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), or a C 1-4 aliphatic or C 1-4 fluoroaliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y );

each R q independently is selected from the group consisting of

fluoro, —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), or a C 1-4 aliphatic or C 1-4 fluoroaliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ), provided that when two R q are attached to the same carbon atom, one must be selected from the group consisting of

fluoro, —CO 2 R 5x , —C(O)N(R 4x )(R 4y ), and C 1-4 aliphatic or C 1-4 fluoroaliphatic optionally substituted with —OR 5x , —N(R 4x )(R 4y ), —CO 2 R 5x , or —C(O)N(R 4x )(R 4y ); or two R q on the same carbon atom together form ═O or ═C(R 5x ) 2 ;

R 4x is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 6-10 ar(C 1-4 )alkyl, the aryl portion of which may be optionally substituted;

R 4y is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 6-10 ar(C 1-4 )alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring; or

R 4x and R 4y , taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S; and

each R 5x independently is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or an optionally substituted C 6-10 aryl or C 6-10 er(C 1-4 )alkyl.

9. The process of claim 8 further comprising a step of:

sulfamoylating a compound of formula (Va), wherein R j is hydrogen to form a compound of formula (VId);

wherein:

stereochemical configurations depicted at asterisk positions indicate relative stereochemistry; and

each of variables R a , R b , R c , R d , R e , R e′ , R f , R h , R h′ , R k , R m , R p , and R q in formula (VId) is as defined in formula (Va).

10. The process of claim 9 , wherein the sulfamoylation step comprises the steps:

I-D) treating the compound of formula (Va) with a sulfamoylating reagent R u N − —S(O) 2 X + ;

II-D) optionally treating the reaction mixture formed in step I-D) with an acid;

wherein:

R u is —C(O)OC(R v ) 2 (R w );

each R v is independently selected from hydrogen, optionally substituted C 1-10 aliphatic or optionally substituted aryl;

R w is optionally substituted C 1-10 aliphatic or optionally substituted aryl;

or one R v is optionally substituted C 1-10 aliphatic; and the other R v is taken together with R w to form an optionally substituted C 3-6 cycloaliphatic ring; and

X is a tertiary amine or nitrogen-containing heteroaryl.

11. The process of claim 10 wherein:

R c is hydrogen, OH or O—R m ;

R a is hydrogen or a hydroxyl protecting group selected from the group consisting of a silyl protecting group, optionally substituted aliphatic, —C(O)—R aa and —C(O)—O—R aa , or R a taken together with R m and the intervening atoms forms a cyclic diol protecting group —C(R aa )(R bb )—;

R m is a hydroxyl protecting group selected from the group consisting of a silyl protecting group, optionally substituted aliphatic, —C(O)—R aa and —C(O)—O—R aa ; or R m taken together with R a and the intervening atoms forms a cyclic diol protecting group —C(R aa )(R bb )—;

R aa is optionally substituted C 1-4 aliphatic or optionally substituted aryl; and

R bb is hydrogen or optionally substituted C 1-4 aliphatic.

12. The process of claim 6 , wherein the compound of formula (VI) has the structure of formula (VIb):

R o has the structure of formula (VII)-xx:

and R n , R a , R b , R c , and R d are all hydrogen.

13. The process of claim 12 wherein the sulfamoylation step comprises the steps:

I-D) treating the compound of formula (V) with a sulfamoylating reagent R u N − S(O) 2 X + ;

II-D) optionally treating the reaction mixture formed in step I-D) with an acid;

wherein:

R u is —C(O)OC(R v ) 2 (R w );

each R v is independently selected from hydrogen, optionally substituted C 1-10 aliphatic or optionally substituted aryl;

R w is optionally substituted C 1-10 aliphatic or optionally substituted aryl;

or one R v is optionally substituted C 1-10 aliphatic, and the other R v is taken together with R w to form a C 3-6 cycloaliphatic ring; and

X is a tertiary amine or nitrogen-containing heteroaryl.

14. The process of claim 13 wherein:

R u is —C(O)OCMe 3 ; and

X is triethylenediamine.