Method of making tetrahydronaphthyridinyl nonanoic acid compounds

1. A method of making a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, comprising:

Step 1: reacting Compound A:

wherein “Ac” refers to an acetyl group and is a substituent on W, with Compound B:

wherein X 1 is halogen, and R 21 , R 22 , R 23 , and R 31 are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl, to form Compound 1:

and

Step 2: reducing Compound 1:

optionally in the presence of a catalyst, to form the compound of formula I:

wherein:

Q is

X is CR 4 or N;

Y is CR 4 or N;

R 1 is H, F, Cl, C 1 -C 4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C 1 -C 4 alkoxy substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms;

R 2 and R 3 are each independently H, F, CH 2 F, CHF 2 , or CF 3 , provided that one of R 2 and R 3 is not H;

each R 4 is independently H, CH 2 F, CHF 2 , or CF 3 ; and

R 51 and R 52 are each independently H, F, or C 1 ;

W is fused to the pyridyl moiety at positions 1 and 2, and W is a 5- to 7-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of N, O, and S;

n is 1 or 2; and

R and R′ are each independently H or F, or R and R′, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or heterocyclic ring.

2. The method of claim 1 , wherein n is 1.

3. The method of claim 1 , wherein R and R′ are each H.

4. The method of claim 1 , wherein Q is

5. The method of claim 1 , wherein R 51 and R 52 are each H.

6. The method of claim 1 , wherein X is N and Y is CR 4 .

7. The method of claim 1 , wherein at least one R 4 is CF 3 .

8. The method of claim 1 , wherein R 1 is H.

9. The method of claim 1 , wherein Q is

10. The method of claim 1 , wherein

is selected from the group consisting of

11. The method of claim 1 , further comprising one or more steps selected from:

Step A1: reacting Compound 2:

with Compound 3:

wherein W′ is an unsaturated, partially saturated, or aromatic 5- to 7-membered ring optionally comprising 1-4 heteroatoms selected from the group consisting of N, O, and S, to form Compound 4:

Step A2: reducing Compound 4:

optionally in the presence of a catalyst, followed by a reaction with acetic anhydride to form Compound 5:

and

Step A3: converting Compound 5:

to Compound A:

12. The method of claim 1 , further comprising one or more steps selected from:

Step B1: reacting Compound 6a:

with Compound 7:

to form Compound 8a:

Step B2: converting Compound 8a:

to Compound 9a:

wherein X 1 is halogen; and

Step B3: reacting Compound 9a:

with a phosphine compound

to form Compound B1:

13. The method of claim 1 , further comprising one or more steps selected from:

Step C1: reacting Compound 6b:

with Compound 7:

to form Compound 8b:

Step C 2 : converting Compound 8b:

to Compound 9b:

wherein X 1 is halogen;

Step C 3 : reacting Compound 9b:

with a phosphine compound

to form Compound B2:

14. The method of claim 1 , wherein Step 1 comprises:

1a. adding a non-nucleophilic base to Compound B to generate a mixture; and

1b. adding Compound A to the mixture from Step 1a.

15. The method of claim 1 , wherein Step 2 comprises:

2a. adding H 2 to Compound 1 in the presence of a protic solvent;

2b. adding a base to the reaction mixture from Step 2a; and

2c. adding an acid to the reaction mixture from Step 2b.

16. The method of claim 11 , wherein:

Step A1 comprises:

A1a. adding n-butyllithium to dimethyl methylphosphonate;

A1b. adding Compound 2 to the mixture from Step A1a; and

A1c. adding Compound 3 to the mixture from Step A1b;

Step A2 comprises:

A2a. adding H 2 to Compound 4 in the presence of a protic solvent; and

A2b. adding 4-(dimethylamino)pyridine to the reaction mixture from Step A2a; and

Step A3 comprises:

adding Dess-Martin periodinane to Compound 5.

17. The method of claim 12 , wherein:

Step B1 comprises:

adding Compound 6a, a chiral ligand, and a metal catalyst to Compound 7; and

Step B2 comprises:

B2a. adding a metal halide and silyl halide to Compound 8a to generate a mixture; and

B2b. adding a protic solvent to the mixture from Step B2a.

18. The method of claim 13 , wherein:

Step C1 comprises:

adding Compound 6b, a chiral ligand, and a metal catalyst to Compound 7; and

Step C 2 comprises:

C2a. adding a metal halide and silyl halide to Compound 8b; and

C2b. adding a protic solvent to the mixture from Step C2a.