Sulfonamide compounds and uses as TNAP inhibitors

1. A method for treating pathological calcification or vascular calcification in a mammal comprising administering to the mammal with pathological calcification or vascular calcification a tissue-nonspecific alkaline phosphatase (TNAP) inhibitor compound of Formula I, or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, or N-oxide 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 halogen, —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 , 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:

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:

3. The method of claim 1 , wherein X 1 is ═C(R 2 )—.

4. 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 .

5. The method of claim 1 , wherein A is selected from:

wherein:

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

wherein:

R 17 and R 18 are independently hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted phenyl, or R 17 and R 18 together with the nitrogen atom to which they are attached form an optionally substituted heterocycloamino; and

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.

6. 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 .

7. The method of claim 6 , 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.

8. The method of claim 6 , 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.

9. The method of claim 8 , wherein the optionally substituted heterocycloamino is an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted morpholine, or an optionally substituted piperazine.

10. The method of claim 6 , 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.

11. The method of claim 6 , wherein:

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

12. The method of claim 1 , wherein the vascular calcification is an arterial calcification.

13. 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.

14. The method of claim 1 , wherein the vascular calcification is associated with chronic renal disease, end-stage renal disease, or pre- or post-dialysis uremia.

15. The method of claim 1 , wherein the pathological calcification is associated with 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.

16. The method of claim 1 wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, metabolite, or N-oxide thereof.

17. The method of claim 16 , wherein the compound is:

or a pharmaceutically acceptable salt, polymorph, solvate, tautomer, metabolite, or N-oxide thereof.