Compounds and methods for inhibiting mitotic progression

1. A process for preparing a compound of formula (A-1):

or a pharmaceutically acceptable salt thereof;

wherein:

Ring A is a substituted or unsubstituted 5- or 6-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring;

Ring B is a substituted or unsubstituted aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring;

Ring C is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;

R e is hydrogen, —OR 5 , —N(R 4 ) 2 , —SR 5 , or a C 1-3 aliphatic optionally substituted with R 3 or R 7 ;

each of R x and R y independently is hydrogen, fluoro, or an optionally substituted C 1-6 aliphatic; or R x and R y , taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloaliphatic ring;

each R 3 independently is selected from the group consisting of halo, —OH, —O(C 1-3 alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-3 alkyl), —CO 2 H, —CO 2 (C 1-3 alkyl), —C(O)NH 2 , and —C(O)NH(C 1-3 alkyl);

each R 4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S;

each R 5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; and

each R 7 independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group;

said process comprising step (e) of:

heating a compound of formula (x):

with a cyclodehydration reagent to afford the compound of formula (A-1).

2. The process of claim 1 , wherein the compound of formula (A-1) is a compound of formula (Va):

wherein:

R e is hydrogen;

each of R b2 and R b3 independently is selected from the group consisting of hydrogen, halo, C 1-3 aliphatic, C 1-3 fluoroaliphatic, and —OR 5 , where R 5 is hydrogen or C 1-3 aliphatic; and

each of R c1 and R c5 independently is selected from the group consisting of hydrogen, halo, C 1-3 aliphatic, C 1-3 fluoroaliphatic, and —OR 5 , where R 5 is hydrogen or C 1-3 aliphatic;

R g is selected from the group consisting of hydrogen, C 1-6 aliphatic, and R 2d ; and

each of R h and R k independently is hydrogen or R d .

3. The process of claim 2 , wherein each of R g , R h , and R k independently is selected from the group consisting of hydrogen, C 1-3 aliphatic, halo, —OR 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —C(═NR 4 )N(R 4 ) 2 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , and —N(R 4 )C(O)R 5 .

4. The process of claim 2 , wherein R g is hydrogen, and at least one of R h and R k is selected from the group consisting of —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )N(R 4 ) 2 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , and —N(R 4 )C(O)R 5 .

5. The process of claim 1 , further comprising step (d), prior to step (e), of treating a compound of formula (ix):

with

(i) an acid chloride in the presence of a base; or

(ii) a carboxylic acid in the presence of a coupling reagent

to afford the compound of formula (x).

6. The process of claim 5 , further comprising step (c), prior to (d), of reducing a compound of formula (viii):

(i) by hydrogenation in the presence of a metal catalyst; or

(ii) with a reducing agent

to afford the compound of formula (ix).

7. The process of claim 6 , further comprising the step (b), prior to step (c), of treating a compound of formula (vii) with a mono-substituted guanidine of formula (xix):

to afford the compound of formula (viii).

8. The process of claim 7 , further comprising the step (a), prior to step (b), of providing a compound of formula (vi):

and treating the compound of formula (vi) with N,N-dimethylformamide dimethyl acetal to prepare the compound of formula (vii) for use in step (b).

9. A process for preparing a compound of formula (A-1):

or a pharmaceutically acceptable salt thereof;

wherein:

Ring A is a substituted or unsubstituted 5- or 6-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring;

Ring B is a substituted or unsubstituted aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring;

Ring C is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring;

R e is hydrogen, —OR 5 , —N(R 4 ) 2 , —SR 5 , or a C 1-3 aliphatic optionally substituted with R 3 or R 7 ;

each of R x and R y independently is hydrogen, fluoro, or an optionally substituted C 1-6 aliphatic; or R x and R y , taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloaliphatic ring;

each R 3 independently is selected from the group consisting of halo, —OH, —O(C 1-3 alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-3 alkyl), —CO 2 H, —CO 2 (C 1-3 alkyl), —C(O)NH 2 , and —C(O)NH(C 1-3 alkyl);

each R 4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S;

each R 5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; and

each R 7 independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group;

said process comprising step (g) of cross-coupling a compound of formula (xviii):

with an organoboronic acid using palladium catalysis to afford the compound of formula (A-1).

10. The process of claim 9 , further comprising step (f), prior to step (g), of treating a compound of formula (xvii):

with a chlorinating reagent to afford the compound of formula (xviii).

11. The process of claim 10 , further comprising step (e), prior to step (f), of treating a compound of formula (xvi) with a mono-substituted guanidine of formula (xix):

to afford the compound of formula (xvii).

12. The process of claim 11 , further comprising step (d), prior to step (e), of treating a compound of formula (xv):

with N,N-dimethylformamide dimethyl acetal to afford the compound of formula (xvi).

13. The process of claim 12 , further comprising step (c), prior to step (d), of treating a compound of formula (xiv):

with a cyclodehydration reagent to afford the compound of formula (xv).

14. The process of claim 13 , further comprising step (b), prior to step (c), of treating a compound of formula (xiii):

with a dilute aqueous solution of an alkali-metal hydroxide to afford the compound of formula (xiv).

15. The process of claim 14 , further comprising step (a), prior to step (b), of providing a compound of formula (xii)

and condensing the compound of formula (xii) with a β-alanine ester to prepare the compound of formula (xiii).

16. The process of claim 9 , wherein the compound of formula (A-1) is a compound of formula (Va):

wherein:

R e is hydrogen;

each of R b2 and R b3 independently is selected from the group consisting of hydrogen, halo, C 1-3 aliphatic, C 1-3 fluoroaliphatic, and —OR 5 , where R 5 is hydrogen or C 1-3 aliphatic; and

each of R c1 and R c5 independently is selected from the group consisting of hydrogen, halo, C 1-3 aliphatic, C 1-3 fluoroaliphatic, and —OR 5 , where R 5 is hydrogen or C 1-3 aliphatic;

R g is selected from the group consisting of hydrogen, C 1-6 aliphatic, and R 2d ; and

each of R h and R k independently is hydrogen or R d .

17. The process of claim 16 , wherein each of R g , R h , and R k independently is selected from the group consisting of hydrogen, C 1-3 aliphatic, halo, —OR 5 , —CO 2 R 5 , —C(O)N(R 4 ) 2 , —SO 2 N(R 4 ) 2 , —C(═NR 4 )N(R 4 ) 2 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , and —N(R 4 )C(O)R 5 .

18. The process of claim 16 , wherein R g is hydrogen, and at least one of R h and R k is selected from the group consisting of —CO 2 R 5 , —C(O)N(R 4 ) 2 , —C(═NR 4 )N(R 4 ) 2 , —C(O)N(R 4 )C(═NR 4 )—N(R 4 ) 2 , —N(R 4 )C(═NR 4 )—N(R 4 )—C(O)R 5 , and —N(R 4 )C(O)R 5 .