Cyclic boronic acid ester derivatives and methods of making the same

1. A method of preparing a compound of formula (I):

wherein:

Y is a 1-4 atom alkylene or 2-4 atom alkenylene linker, optionally substituted by one or more substituents selected from the group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

R 1 is selected from a group consisting of —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , —CH(OH)C 1-9 alkylR 9 , —CH(OH)C 2-9 alkenylR 9 , —CH(OH)C 2-9 alkynylR 9 , —CH(OH)carbocyclyl-R 9 , —C(═O)R 9 , —C(═O)C 1-9 alkylR 9 , —C(═O)C 2-9 alkenylR 9 , —C(═O)C 2-9 alkynylR 9 , —C(═O)C 2-9 carbocyclyl-R 9 , —C(═O)NR 9 R 10 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)NR 9 R 10 , —N(R 9 )C(═O)OR 9 , —N(R 9 )C(═O)C(═NR 10 )R 9 , —N(R 9 )C(═O)C(═CR 9 R 10 )R 9 , —N(R 9 )C(═O)C 1-4 alkylN(R 9 )C(═O)R 9 , —N(R 9 )C(═NR 10 )R 9 , —C(═NR)NR 9 R 10 , —N═C(R 9 )NR 9 R 10 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 NR 9 R 10 , —N═CHR 9 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

R 6 is selected from a group consisting of H, —C 1-9 alkyl, C 2-9 alkenyl, —C 2-9 alkynyl, carbocyclyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , carbocyclyl-R 11 , —C(═O)OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , and -carbocyclyl-CO 2 R 9 , or alternatively:

(i) R 6 and an R 7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, or

(ii) R 6 is absent when the carbon to which it is attached is a ring atom in an aryl or heteroaryl ring;

each R 7 is independently selected from a group consisting of H, halo, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , and -carbocyclyl-CO 2 R 9 , or independently:

(i) R 6 and an R 7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, or

(ii) R 7 and an R 8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R 8 is independently selected from a group consisting of H, halo, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , -carbocyclyl-CO 2 R 9 , or independently:

(i) R 7 and an R 8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl,

(ii) a geminal R 7 and R 8 together form-C 2-9 alkenylenylCO 2 R 9 , or

(iii) each R 8 attached to a ring atom forming part of a substituted or unsubstituted aryl is absent;

each R 9 is independently selected from a group consisting of H, —C 1-9 alkyl, C 2-9 alkenyl, —C 2-9 alkynyl, carbocyclyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

each R 10 is independently selected from a group consisting of H, —C 1-9 alkyl, —OR 9 , —CH(═NH), —C(═O)OR 9 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

each R 11 is independently selected from a group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

X is selected from a group consisting of —CO 2 R 12 , and a carboxylic acid isostere;

R 12 is selected from a group consisting of H, C 1-9 alkyl, —(CH 2 ) 0-3 —R 11 , —C(R 13 ) 2 OC(O)C 1-9 alkyl, —C(R 13 ) 2 OC(O)R 11 , —C(R 13 ) 2 OC(O)OC 1-9 alkyl and —C(R 13 ) 2 OC(O)OR 11 ;

each R 13 is independently selected from a group consisting of H and C 1-4 alkyl; and

m is independently zero or an integer from 1 to 2,

wherein each C 1-9 alkyl, C 2-9 alkenyl, and C 2-9 alkynyl is independently optionally substituted;

the method comprising: deprotecting and cyclizing a pinanediol boronic ester to obtain a compound of formula (I).

2. The method of claim 1 , wherein the pinanediol boronic ester comprises a hydroxyl protecting group selected from the group consisting of trityl, t-butyldimethylsilyl, and benzyl.

3. The method of claim 1 , wherein the deprotection and cyclization comprises contacting the pinanediol boronic ester with a reagent selected from the group consisting of HCl, BCl 3 , BBr 3 , and CF 3 COOH.

4. The method of claim 1 , wherein the pinanediol boronic ester comprises a tert-butyldimethylsilyloxy (TBS) group and a tert-butyl ester group.

5. The method of claim 1 , wherein the pinanediol boronic ester derivative has the structure of formula (XII):

wherein:

R 2 and R 4 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; or alternatively, an R 2 and R 4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

R 3 and R 5 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

R a is selected from the group consisting of —R 9 , —NR 9 R 10 , —OR 9 , —C(═NR 10 )R 9 , —C(═CR 9 R 10 )R 9 , —C 1-4 alkylN(R 9 )C(═O)R 9 , —C 1-9 alkylR 11 , and —C(═NOR 9 )R 9′ ;

R 9′ is selected from the group consisting of C 1-9 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl; and

R 11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

6. The method of claim 5 , wherein the pinanediol boronic ester derivative is obtained by a step selected from coupling a bis-trimethylsilyl (TMS) 2 amine derivative with R a COOH, or reacting a bis-trimethylsilyl (TMS) 2 amine derivative with R a COCl.

7. The method of claim 6 , wherein the bis-trimethylsilyl amine derivative has the structure of formula (XI):

8. The method of claim 7 , wherein the bis-trimethylsilyl (TMS) 2 amine derivative is obtained by displacing a chloro group of a compound of formula (X):

9. The method of claim 8 , wherein displacing a chloro group is achieved in the presence of lithium bis(trimethylsilyl)amide.

10. The method of claim 8 , wherein the compound of formula (X) is obtained by homologation of a compound of formula (IX):

11. The method of claim 10 , wherein the homologation is achieved in the presence of dichloromethane and n-butyllithium.

12. The method of claim 1 , wherein the pinanediol boronic ester has the structure of formula (XLII):

13. The method of claim 12 , wherein the pinanediol boronic ester is obtained by reacting a bis-trimethylsilyl (TMS) 2 amine derivative having the following structure:

with a compound having the following structure:

14. The method of claim 13 , wherein the bis-trimethylsilyl (TMS) 2 amine derivative is obtained by displacing a chloro group of a compound of formula (XL):

15. The method of claim 14 , wherein the compound of formula (XL) is obtained by homologation of a compound of formula (XXXIX):

16. The method of claim 1 , wherein the pinanediol boronic ester has the structure of formula (XV):

wherein:

R 2 and R 4 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; or alternatively, an R 2 and R 4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

R 3 and R 5 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; and

R c is R 1 .

17. The method of claim 16 , wherein the pinanediol boronic ester is obtained by displacing a bromo group of a bromo-compound of formula (XIV):

18. The method of claim 17 , wherein displacing a bromo group is achieved using an agent selected from the group consisting of an α-alkoxy substituted alkyllithium agent, an organomagnesium reagent, a sodium salt of an alkyl derivative, and a sodium salt of an aryl carbamate derivative.

19. The method of claim 1 , wherein the pinanediol boronic ester has the structure of formula (XXV):

wherein:

R 2 and R 4 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; or alternatively, an R 2 and R 4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

R 3 and R 5 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

R a , R b , R c and R d are each independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

R′ is a hydroxyl protection group;

R″ is selected from a group consisting of H, C 1-9 alkyl, —(CH 2 ) 0-3 —R 11 , —C(R 13 ) 2 OC(O)C 1-9 alkyl, —C(R 13 ) 2 OC(O)R 11 , —C(R 13 ) 2 OC(O)OC 1-9 alkyl and —C(R 13 ) 2 OC(O)OR 11 ;

each R 13 is independently selected from a group consisting of H and C 1-4 alkyl; and

p and q are selected from 0, 1 or 2, such that the sum of p and q is 1 or 2.

20. The method of claim 19 , wherein the pinanediol boronic ester is obtained by Matteson homologation of a formula (XXIV):

21. The method of claim 1 , wherein the pinanediol boronic ester has the structure of formula (XXXIV):

wherein:

R 2 and R 4 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; or alternatively, an R 2 and R 4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

R 3 and R 5 are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

R a is selected from the group consisting of —R 9 , —NR 9 R 10 , —OR 9 , —C(═NR 10 )R 9 , —C(═CR 9 R 10 )R 9 , —C 1-4 alkylN(R 9 )C(═O)R 9 , —C 1-9 alkylR 11 , and —C(═NOR 9 )R 9′ ; and

R 9′ is selected from the group consisting of C 1-9 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl.

22. The method of claim 21 , wherein the pinanediol boronic ester is obtained by trans-esterification of a pinacol boronate of formula (XXXIII):

23. The method of claim 22 , wherein the trans-esterification is achieved by reacting the pinacol boronate with a pinane diol in the presence of tetrahydrofuran.

24. The method of claim 22 , wherein the pinacol boronate is obtained using iridium catalysis with a tert-butyldimethylsilyl compound of formula (XXXII):

25. The method of claim 1 , wherein the compound of formula (I) has the structure of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond with the proviso that the dashed and solid line can only be a double bond when n is 1;

R 2 and R 4 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

R 3 and R 5 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , with the proviso that if the bond represented by a dashed and solid line is a double bond then R 3 and R 5 are absent; and

n is independently zero or an integer from 1 to 2.

26. The method of claim 25 , wherein:

R 1 is selected from a group consisting of —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , —CH(OH)C 1-9 alkylR 9 , —CH(OH)C 2-9 alkenylR 9 , —CH(OH)C 2-9 alkynylR 9 , —C(═O)R 9 , —C(═O)C 1-9 alkylR 9 , —C(═O)C 2-9 alkenylR 9 , —C(═O)C 2-9 alkynylR 9 , —C(═O)NR 9 R 10 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)NR 9 R 10 , —N(R 9 )C(═O)OR 9 , —N(R 9 )C(═O)C(═NR 10 )R 9 , —N(R 9 )C(═O)C 1-4 alkylN(R 9 )C(═O)R 9 , —N(R 9 )C(═NR 10 )R 9 , —C(═NR 10 )NR 9 R 10 , —N═C(R 9 )NR 9 R 10 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 NR 9 R 10 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;

R 6 is selected from a group consisting of H, —C 1-9 alkyl, C 2-9 alkenyl, —C 2-9 alkynyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , —C(═O)OR 9 , and —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 , or alternatively R 6 and an R 7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R 7 is independently selected from a group consisting of H, —NR 9 R 10 , —OR 9 , and —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 , or independently, R 6 and an R 7 or independently an R 7 and an R 8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R 8 is independently selected from a group consisting of H, —NR 9 R 10 , —OR 9 , and —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 , or independently, an R 7 and an R 8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

each R 9 is independently selected from a group consisting of H, —C 1-9 alkyl, C 2-9 alkenyl, —C 2-9 alkynyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —(CH 2 ) 0-3 carbocyclyl, and substituted or unsubstituted heterocyclyl;

each R 10 is independently selected from a group consisting of H, —C 1-9 alkyl, —OR 9 , —CH(═NH), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; and

X is selected from a group consisting of —CO 2 H and a carboxylic acid isostere.

27. The method of claim 1 , wherein the compound of formula (I) has a structure of formula (IIIa) or (IIIb):

or a pharmaceutically acceptable salt thereof, wherein:

the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;

each R 2 and R 4 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

each R 3 and R 5 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , with the proviso that if the bond represented by a dashed and solid line is a double bond then R 3 and R 5 are absent.

28. The method of claim 1 , wherein the compound of formula (I) has the structure of formula (Iva), (IVb), or (IVc):

or a pharmaceutically acceptable salt thereof, wherein:

the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;

each R 2 and each R 4 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ;

each R 3 and each R 5 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , with the proviso that if the bond represented by a dashed and solid line is a double bond then the R 3 and R 5 attached to the carbon atoms bonded that bond are absent.

29. The method of claim 1 , wherein the compound of formula (I) has a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

30. The method of claim 1 , wherein the compound of formula (I) has a structure: