METHODS FOR PREPARING PYRIDAZINONE DERIVATIVES

1 . A method comprising contacting a compound of formula (I), a tautomer or a salt thereof:

with a compound of formula (II) or a salt thereof:

in a first organic solvent in the presence of a base, to form a compound of formula (III) or a salt thereof:

wherein:

R 1 and R 2 are each independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 4 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R 1 and R 2 come together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R 3 is independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , —SH, —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —NH 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R b is independently hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —NH 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

each R C is independently hydrogen, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —NH 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

X is halogen; and

n is 0, 1, 2, 3, or 4.

2 . The method of claim 1 , further comprising contacting the compound of formula (III) or a salt thereof with a second organic solvent and a reducing agent to form a compound of formula (IV) or a salt thereof:

3 . The method of claim 2 , further comprising contacting the compound of formula (IV) or a salt thereof with R 4 CH 2 C(O)N(R 5 )C(O)OCH 2 CH 3 to form a compound of formula (V) or a salt thereof:

wherein:

R 4 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and

R 5 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

4 . The method of claim 1 , further comprising contacting the compound of formula (III) or a salt thereof with R 6 X to form a compound of formula (III-a) or a salt thereof:

wherein:

R 6 is —CN, —OH, —OR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

5 . The method of claim 4 , further comprising contacting the compound of formula (M-a) or a salt thereof with a second organic solvent and a reducing agent to form a compound of formula (IV-a) or a salt thereof:

6 . The method of claim 5 , further comprising contacting the compound of formula (IV-a) or a salt thereof with R 4 CH 2 C(O)N(R 5 )C(O)OCH 2 CH 3 to form a compound of formula (V-a) or a salt thereof:

wherein:

R 4 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —NO 2 , —NR b R c , —NHS(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —OC(═O)OR b , —C(═O)NR b R c , —OC(═O)NR b R c , —NR b C(═O)NR b R c , —NR b C(═O)R a , —NR b C(═O)OR b , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR′, —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and

R 5 is hydrogen, halogen, —CN, —OH, —OR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR b R c , —C(═O)R a , —OC(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OR a , —NR b R c , —C(═O)R a , —C(═O)OR b , —C(═O)NR b R c , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

7 . The method of claim 1 , wherein X is F.

8 . The method of claim 1 , wherein R 3 is Cl.

9 . The method of claim 1 , wherein the compound of formula (I) is compound 1-1, compound 2-1, compound 3-1, compound 4-1, compound 5-1, compound 6-1, or compound 7-1:

10 . The method of claim 1 , wherein the compound of formula (II) is compound 1-2:

11 . The method of claim 1 , wherein the compound of formula (III) is compound 1-3, compound 1-4, compound 2-2, compound 3-2, compound 3-3, compound 4-2, compound 5-2, compound 6-2, or compound 7-2:

12 . The method of claim 2 , wherein the compound of formula (IV) or the salt thereof is Int. 7, compound 2-3, compound 3-4, compound 3-5, compound 4-3, compound 5-3, compound 6-3, compound 7-3, or compound 8-1:

13 . The method of claim 1 , wherein the first organic solvent comprises DMF, DMAC, DMSO, acetonitrile, THF, DCM, dioxane, or acetone.

14 . The method of claim 1 , wherein the base comprises KHCO 3 or K 2 CO 3 .

15 . (canceled)

16 . The method of claim 2 , wherein the reducing agent comprises H 2 gas and Pd/C, H 2 gas and Raney® nickel, H 2 gas and platinum (IV) oxide, ferrous chloride, or stannous chloride.

17 . (canceled)

18 . The method of claim 1 , wherein the contacting occurs at room temperature or above room temperature.

19 . (canceled)

20 . The method of claim 2 , wherein the contacting occurs at room temperature or above room temperature.

21 . (canceled)

22 . The method of claim 3 , wherein the compound of formula (V) is 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (MGL-3196).

23 . The method of claim 5 , wherein the second organic solvent comprises DMF, DMAC, DMSO, acetonitrile, THF, DCM, dioxane, or acetone.

24 . A compound having the structure of