Acylsulfonamides and processes for producing the same

1. A process for the preparation of an acylsulfonamide (3), the process comprising reacting a thioacid (1) with a sulfonyl azide (2) in the presence of a protein of the Bcl-2 family, wherein the thioacid (1), the sulfonyl azide (2), and the acylsulfonamide (3) correspond to Formulae (1), (2), and (3):

Z 1 is hydrocarbyl, substituted hydrocarbyl, heteroaryl, or heterocyclo; and

Z 2 is hydrocarbyl, substituted hydrocarbyl, heteroaryl, or heterocyclo.

2. The process of claim 1 wherein Z 1 is aryl, substituted aryl, or heteroaryl.

3. The process of claim 1 wherein Z 1 has the formula:

wherein

Z 10 , Z 11 , Z 12 , Z 13 , and Z 14 are independently hydrogen, hydroxyl, protected hydroxyl, halo, hydrocarbyl, substituted hydrocarbyl, heterocyclo, heteroaryl, alkoxy, alkenoxy, alkynoxy, aryloxy, arylalkoxy (heterocyclo)alkoxy, trihaloalkoxy, amino, amido, or cyano, or two of Z 10 , Z 11 , Z 12 , Z 13 , and Z 14 , together with the carbon atoms to which they are attached, form a fused carbocyclic (e.g., napthyl) or heterocyclic ring.

4. The process of claim 3 wherein Z 10 , Z 11 , Z 12 , Z 13 , and Z 14 are independently hydrogen, amino, alkoxy, nitro, or trihalomethoxy.

5. The process of claim 1 wherein Z 1 has the formula:

wherein

A is phenyl or a five- or six-membered aromatic carbocyclic or heterocyclic ring wherein from one to three carbon atoms may be replaced by a heteroatom selected from N, O, or S, and wherein A is substituted with Z 100 and Z 101 through ring carbon atoms or ring heteroatoms, and Z 100 and Z 101 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, heterocyclo(alkoxy), or halo.

6. The process of claim 1 wherein Z 1 is substituted or unsubstituted furyl, thienyl, pyridyl, oxazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidyl, purinyl, triazolyl, or thiazolyl.

7. The process of claim 1 wherein Z 1 is substituted or unsubstituted morpholino, pyran, tetrahydropyran, piperazinyl, piperidinyl, tetrahydropyridinyl, pyrrolidinyl, pyrrolinyl, 1,4-diazepanyl, or azepinyl.

8. The process of claim 1 wherein Z 1 is —(CH 2 ) x —Z 102 wherein Z 102 is hydrogen, hydroxyl, protected hydroxyl, heterocyclo, amino, amido, alkoxy, aryloxy, cyano, nitro, thiol, or an acetal, ketal, ester, ether, or thioether, and x is 1, 2, or 3.

9. The process of claim 1 wherein Z 1 is heteroaryl, heterocyclo, or has the formula:

wherein

Z 10 , Z 11 , Z 12 , Z 13 , and Z 14 are independently hydrogen, amino, alkoxy, nitro, or trihalomethoxy (e.g., trifluoromethoxy); or Z 1 is —(CH 2 ) x —Z 102 wherein Z 102 is hydrogen, hydroxyl, protected hydroxyl, heterocyclo, amino, amido, alkoxy, aryloxy, cyano, nitro, thiol, or an acetal, ketal, ester, ether, or thioether, and x is 1, 2, or 3.

10. The process of any one of claims 1 - 9 wherein Z 2 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkaryl, or aralkyl.

11. The process of any one of claims 1 - 9 wherein Z 2 has the formula:

wherein

Z 20 , Z 21 , Z 22 , Z 23 , and Z 24 are independently hydrogen, halo, hydrocarbyl, substituted hydrocarbyl, alkoxy, alkenoxy, alkynoxy, aryloxy, nitro, cyano, amino, or amido, or two of Z 20 , Z 21 , Z 22 , Z 23 , and Z 24 , together with the carbon atoms to which they are attached, form a fused carbocyclic or heterocyclic ring.

12. The process of claim 11 wherein Z 20 , Z 21 , Z 22 , Z 23 , and Z 24 are independently alkyl, substituted alkyl, amino, alkoxy, alkenoxy, alkynoxy, or aryloxy.

13. The process of any one of claims 1 - 10 wherein Z 2 is phenyl, substituted phenyl, napthyl, or substituted napthyl.

14. The process of any one of claims 1 - 10 wherein Z 2 may be —(CH 2 ) x —Z 200 wherein Z 200 is hydrogen, hydroxyl, protected hydroxyl, heterocyclo, amino, amido, alkoxy, aryloxy, cyano, nitro, thiol, or an acetal, ketal, ester, ether, or thioether, and x is 1, 2, or 3.

15. The process of any one of claims 1 - 9 wherein Z 2 is substituted or unsubstituted furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, purinyl, triazolyl, or thiazolyl.

16. The process of any one of claims 1 - 9 wherein Z 2 is substituted or unsubstituted morpholino, pyran, tetrahydropyran, piperazinyl, piperidinyl, tetrahydropyridinyl, pyrrolidinyl, pyrrolinyl, 1,4-diazepanyl, or azepinyl.

17. The process of any one of claims 1 - 16 wherein the protein is selected from Bcl-2, Bcl-X L , and Mcl-1.

18. The process of any one of claims 1 - 17 wherein the protein is Bcl-X L .

19. The process of any one of claims 1 - 17 wherein the protein is Mcl-1.