Sulfonamide compounds and uses as TNAP inhibitors

1. A method of inhibiting tissue-nonspecific alkaline phosphatase (TNAP) activity in a subject with vascular calcification, ectopic ossification in spinal ligaments, ankylosis, osteoarthritis, or pathological calcification comprising administering a compound of Formula I, or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide thereof, to the subject in need thereof:

wherein:

Y 1 is a bond, and Y 2 is —N(R 6 )—;

L 1 and L 2 are each a bond;

X 1 is ═N— or ═C(R 2 )—;

X 2 is ═N— or ═C(R 3 )—;

R 1 and R 4 are independently selected from the group consisting of —F, —Cl, —Br, —CN, —C(O)—N(R 7 )—R 8 , —C(O)—O—R 9 , —OMe, —OCF 3 , optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;

R 2 , R 3 , and R 5 are hydrogen;

R 6 is hydrogen;

R 7 and R 8 are independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted phenyl,

or R 7 and R 8 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloamino;

R 9 is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted phenyl; and

A is —C(O)—N(R 7 )—R 8 , or —C(O)—O—R 9 ;

or A is an optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl, wherein A is selected from:

R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, —CN, —OH, —C(O)—O—R 19 , optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;

R 19 is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted phenyl; and

R 15 is hydrogen or optionally substituted alkyl.

2. The method of claim 1 , wherein:

the vascular calcification is an arterial calcification.

3. The method of claim 1 , wherein:

the vascular calcification is associated with diabetes mellitus I, diabetes mellitus II, idiopathic infantile arterial calcification (IIAC), Kawasaki disease, obesity, or increased age.

4. The method of claim 1 , wherein:

the vascular calcification is associated with chronic renal disease.

5. The method of claim 1 , wherein:

the pathological calcification is ankylosing spondylitis, tumoral calcinosis, fibrodysplasia ossificans progressiva, progressive osseous heteroplasia, pseudoxanthoma elasticum, ankylosis, osteoarthritis, general arterial calcification in infancy (GACI), arterial calcification due to deficiency of CD73 (ACDC), Keutel syndrome, peritoneal calcification, heterotopic calcification in amputees, tibial artery calcification, bone metastasis, prosthetic calcification, or Paget's disease of bone.

6. The method of claim 1 , wherein:

Y 1 is a bond and Y 2 is —N(R 6 )—;

X 2 is ═C(R 3 )—;

L 1 is a bond;

L 2 is a bond; and

R 6 is hydrogen as shown in Formula Ie:

7. The method of claim 1 , wherein:

X 1 is ═C(R 2 )—.

8. The method of claim 1 , wherein:

R 4 is optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, —C(O)—N(R 7 )—R 8 , or —C(O)—O—R 9 .

9. The method of claim 1 , wherein:

R 1 and R 4 are independently selected from the group consisting of —F, —Cl, —Br, —CN, —OMe, and —OCF 3 .

10. The method of claim 1 , wherein:

A is optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl, wherein A is selected from:

R 12 and R 13 are independently selected from the group consisting of hydrogen, halogen, —CN, —OH, —C(O)—O—R 19 , optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkoxy, haloalkyl, haloalkoxy, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl;

R 19 is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted phenyl; and

R 15 is hydrogen or optionally substituted alkyl.

11. The method of claim 1 , wherein:

A is

 wherein R 12 and R 13 are independently selected from the group consisting of hydrogen, —F, —CN, —OH, —OMe, and —C(O)—O—Me;

or A is —C(O)—O—R 9 ;

or A is —C(O)—N(R 7 )—R 8 .

12. The method of claim 11 , wherein:

A is —C(O)—O—R 9 , wherein R 9 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted phenyl.

13. The method of claim 11 , wherein:

A is —C(O)—N(R 7 )—R 8 , wherein R 7 and R 8 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloamino.

14. The method of claim 13 , wherein:

the optionally substituted heterocycloamino is an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted morpholine, or an optionally substituted piperazine.

15. The method of claim 11 , wherein:

A is —C(O)—N(R 7 )—R 8 , wherein R 7 is hydrogen and R 8 is optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted phenyl.

16. The method of claim 11 , wherein:

A is —C(O)—N(R 7 )—R 8 , wherein R 7 and R 8 are hydrogen.

17. A method of inhibiting tissue-nonspecific alkaline phosphatase (TNAP) activity in a subject with vascular calcification, ectopic ossification in spinal ligaments, ankylosis, osteoarthritis, or pathological calcification comprising administering one of the following compounds to the subject in need thereof:

or a pharmaceutically acceptable salt thereof.