Methods for preparing pyridazinone derivatives

Abstract

This disclosure describes a method for preparing dalone derivatives, comprising contacting a compound of formula (I) or a salt thereof: with a compound of formula (II) or a salt thereof: to form a compound of formula (III) or a salt thereof: . The compound of formula (III) may then be converted into a compound of formula (IV): , which can be used to prepare compounds for treating liver diseases or conditions, or lipid diseases or conditions.

Description

Technical Field

[0001] This invention relates to the preparation of tadalafil. Methods for ketone derivatives. Related applications

[0002] This application claims priority and interest in U.S. Application No. 63 / 104,898, filed October 23, 2020, and U.S. Application No. 63 / 150,616, filed February 18, 2020, the entire contents of which are incorporated herein by reference. Prior Technology

[0003] Thyroid hormones are essential for normal growth and development and for maintaining metabolic homeostasis. Circulating thyroid hormone levels are tightly regulated by feedback mechanisms within the hypothalamus / pituitary-thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism and hyperthyroidism clearly demonstrates the profound effects of thyroid hormones on cardiac function, weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0004] The development of thyroid hormone analogs that avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones will open new avenues for the treatment of patients with metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other conditions and diseases such as liver steatosis and nonalcoholic steatohepatitis (NASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, thyroid hormone resistance, and related conditions and diseases.

[0005] Development and preparation of tadalafil The need for novel approaches to using ketone compounds as thyroid hormone analogs remains urgent. Summary of the Invention

[0006] This invention partially provides synthetic thyroid hormone analogs such as thiazolinone. Methods for synthesizing ketone compounds and their salts. For example, the present invention provides methods for synthesizing thyroid hormone analogs such as ketones. Non-Grignard method for synthesizing ketone compounds and their salts. This invention also relates to the synthesis of ketones. Ketone compounds and their salt intermediates.

[0007] This invention provides a method for synthesizing compounds of formula V or Va: .

[0008] In one state sample, this disclosure provides a compound comprising formula (I), its tautomers, or a salt thereof: With compounds of formula (II) or their salts: Contact in a first organic solvent in the presence of a base to form a compound of formula (III) or a salt thereof: , in: R1 and R2 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -NO 2, -NR bR c, -NHS(=O) 2R a, -S(=O) 2NR bR c, -C(=O)R a, -OC(=O)R a, -C(=O)OR b, -OC(=O)OR b, -C(=O)NR bR c, -OC(=O)NR bR c, -NR bC(=O)NR bR c, -NR bC(=O)R a, -NR bC(=O)OR b, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C4-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C 6-alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R1 and R2 together forming a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted as needed with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl; Each R3 is independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -NO 2, -NR bR c, -NHS(=O) 2R a, -S(=O) 2NR bR c, -C(=O)R a, -OC(=O)R a, -C(=O)OR b, -OC(=O)OR b, -C(=O)NR bR c, -OC(=O)NR bR c, -NR bC(=O)NR bR c, -NR bC(=O)R a, -NR bC(=O)OR b, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C 6-Alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted as desired by one or more side oxygen groups, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl; Each Ra is independently a C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted as needed with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 haloalkyl; Each Rb is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted as needed with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 haloalkyl; Each Rc is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted as needed with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 haloalkyl; X-series halogens; and n is 0, 1, 2, 3, or 4.

[0009] In some specific embodiments, the first organic solvent comprises dimethylformamide (DMF), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), dichloromethane (DCM), dimethyl sulfoxide, or acetone.

[0010] In some specific embodiments, the alkali includes sodium carbonate (Na₂CO₃), sodium bicarbonate (NaHCO₃), potassium carbonate (K₂CO₃), and potassium bicarbonate (KHCO₃).

[0011] In some specific embodiments, the contact occurs at or above room temperature.

[0012] In one embodiment, this disclosure provides a method comprising contacting a 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: .

[0013] In some specific embodiments, the reducing agent comprises hydrogen (H2) gas and palladium (Pd / C) supported on carbon, H2 gas and Raney® nickel, H2 gas and platinum oxide (IV), ferrous chloride, or stannous chloride.

[0014] In some specific embodiments, the contact occurs at or above room temperature.

[0015] In one state sample, this disclosure provides a method comprising contacting a compound of formula (IV) or a salt thereof with R 4CH 2C(O)N(R 5)C(O)OCH 2CH 3 to form a compound of formula (V) or a salt thereof: , in: R-series hydrogen, deuterium, halogens, -CN, -OH, -OR a, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -NO 2, -NR bR c, -NHS(=O) 2R a, -S(=O) 2NR bR c、-C(=O)R a、-OC(=O)R a、-C(=O)OR b、 -OC(=O)OR b, -C(=O)NR bR c, -OC(=O)NR bR c, -NR bC(=O)NR bR c, -NR bC(=O)R a, -NR bC(=O)OR b, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C 1-C 6 alkyl, or C 1-C 6 haloalkyl substituted; and R 5 series hydrogen, deuterium, halogen, -CN, -OH, -OR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR bR c, -C(=O)R a, -OC(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C 1-C 6 alkyl, C 1-C 6 deuterated alkyl, 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 group is independently and as needed via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0016] In some specific embodiments, the method comprises contacting a compound of formula (IV) or a salt thereof with R4CH2C(O)N(R5)C(O)OCH2CH3 in the presence of an oxidant and an acid to form a compound of formula (IV-int) or a salt thereof: .

[0017] In some specific embodiments, the oxidant is sodium nitrite (NaNO₂) or potassium nitrite (KNO₂). In some specific embodiments, the acid is hydrochloric acid (HCl) or acetic acid (AcOH).

[0018] In some specific embodiments, the method includes contacting the compound of formula (IV-int) with a base to form the compound of formula (V). In some specific embodiments, the base is sodium acetate (NaOAc) or potassium acetate (KOAc).

[0019] In one embodiment, this disclosure provides a method comprising contacting a compound of formula (III) or a salt thereof with R6X to form a compound of formula (III-a) or a salt thereof: , in: R 6 series -CN, -OH, -OR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR bR c、-C(=O)R a、-OC(=O)R a、-C(=O)OR b、 -C(=O)NR bR c, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and as desired substituted with one or more side oxygen, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)Ra, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl; and The X series is defined in this paper as in equation (II).

[0020] In one embodiment, this disclosure provides a method comprising contacting a compound of formula (III-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: .

[0021] In some specific embodiments, the reducing agent comprises H2 gas and Pd / C, H2 gas and Rathalos nickel, H2 gas and platinum oxide (IV), ferrous chloride, or stannous chloride.

[0022] In some specific embodiments, the contact occurs at or above room temperature.

[0023] In one state sample, this disclosure provides a method comprising contacting a compound of formula (IV-a) or a salt thereof with R 4CH 2C(O)N(R 5)C(O)OCH 2CH 3 to form a compound of formula (Va) or a salt thereof: in: R-series hydrogen, deuterium, halogens, -CN, -OH, -OR a, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -NO 2, -NR bR c, -NHS(=O) 2R a, -S(=O) 2NR bR c、-C(=O)R a、-OC(=O)R a、-C(=O)OR b、 -OC(=O)OR b, -C(=O)NR bR c, -OC(=O)NR bR c, -NR bC(=O)NR bR c, -NR bC(=O)R a, -NR bC(=O)OR b, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and as needed substituted with one or more side oxygen, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl; and R-5 series hydrogen, deuterium, halogens, -CN, -OH, -ORα, -S(=O)RA, -S(=O) 2R a, -S(=O) 2NR bR c, -C(=O)R a, -OC(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0024] In some specific embodiments, the method comprises contacting a compound of formula (IV-a) or a salt thereof with R4CH2C(O)N(R5)C(O)OCH2CH3 in the presence of an oxidant and an acid to form a compound of formula (IV-a-int) or a salt thereof: .

[0025] In some specific embodiments, the oxidant is NaNO₂ or KNO₂. In some specific embodiments, the acid is HCl or AcOH.

[0026] In some specific embodiments, the method includes contacting a compound of formula (IV-a-int) with a base to form a compound of formula (Va). In some specific embodiments, the base is NaOAc or KOAc.

[0027] In some specific embodiments, the compound of formula (I) is 4-isopropyl tert-4-dimethyl ... -3,6-diol (compound 1-1), 4,5-dimethyl-1,2-dihydrodiol -3,6-dione (compound 2-1), 4-methyl-1,2-dihydrodione -3,6-dione (compound 3-1), 4-phenyl-1,2-dihydrodione -3,6-dione (compound 4-1), 4-(trifluoromethyl)-1,2-dihydrodione -3,6-dione (compound 5-1), 2,3,5,6,7,8-hexahydrophthalide -1,4-dione (compound 6-1), or 2,3-dihydrophthaloyl -1,4-Diketone (Compound 7-1):

[0028] In some specific embodiments, the compounds of formula (II) are 1,3-dichloro-2-fluoro-5-nitrobenzene (compounds 1-2): .

[0029] In some specific embodiments, the compound of formula (III) is 6-(4-amino-2,6-dichlorophenoxy)-5-isopropylpyridine. -3(2H)-ketones (compounds 1-3), 6-(2,6-dichloro-4-nitrophenoxy)-4-isopropyl ketones -3(2H)-ketones (compounds 1-4), 6-(2,6-dichloro-4-nitrophenoxy)-4,5-dimethylphenoxy -3(2H)-ketone (compound 2-2), 6-(2,6-dichloro-4-nitrophenoxy)-4-methylketone -3(2H)-ketone (compound 3-2), 6-(2,6-dichloro-4-nitrophenoxy)-5-methylketone -3(2H)-ketone (compound 3-3), 6-(2,6-dichloro-4-nitrophenoxy)-4-phenylketone -3(2H)-ketone (compound 4-2), 6-(2,6-dichloro-4-nitrophenoxy)-4-(trifluoromethyl) ketone -3(2H)-ketone (compound 5-2), 4-(2,6-dichloro-4-nitrophenoxy)-5,6,7,8-tetrahydrophthalide -1(2H)-ketone (compound 6-2), or 4-(2,6-dichloro-4-nitrophenoxy)phthalide -1(2H)-ketone (compound 7-2):

[0030] In some specific embodiments, the compound of formula (IV) is 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridine. -3(2H)-keto (Int. 7), 6-(4-amino-2,6-dichlorophenoxy)-4,5-dimethylketone -3(2H)-ketone (compounds 2-3), 6-(4-amino-2,6-dichlorophenoxy)-4-methylketone -3(2H)-ketone (compounds 3-4), 6-(4-amino-2,6-dichlorophenoxy)-5-methylketone -3(2H)-ketones (compounds 3-5), 6-(4-amino-2,6-dichlorophenoxy)-4-phenylketones -3(2H)-keto (compound 4-3), 6-(4-amino-2,6-dichlorophenoxy)-4-(trifluoromethyl) ketone -3(2H)-ketone (compound 5-3), 4-(4-amino-2,6-dichlorophenoxy)-5,6,7,8-tetrahydrophthaloyl -1(2H)-ketone (compound 6-3), 4-(4-amino-2,6-dichlorophenoxy)phthalide -1(2H)-ketone (compound 7-3), or 6-(4-amino-2,6-dichlorophenoxy)-5-isopropyl ketone -3(2H)-ketone (compound 8-1):

[0031] In some specific embodiments, the compound of formula (V) is 2-(3,5-dichloro-4-((5-isopropyl-6-sideoxy-1,6-dihydro-2-dichloro-4- ... -3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-trisyl) -6-formonitrile (MGL-3196).

[0032] In one state sample, this disclosure provides compounds having the following structures: Implementation

[0033] This invention provides a method for preparing tadalafil. Fermentation method for ketone derivatives. For example, compared to the preparation of ketones... The Grignard method for ketone derivatives, and the non-grignard method described herein, are advantageous, at least because they avoid the use of hazardous and expensive grignard reagents for the production of ketones. The demand for intermediates of ketone derivatives (such as MGL-3196).

[0034] This disclosure relates to one or more steps in the synthesis process according to the following procedures: 1, 2, and 3. Process 1: Process 2: Process 3:

[0035] In one state sample, this disclosure provides a compound comprising formula (I), its tautomers, or a salt thereof: With compounds of formula (II) or their salts: Contact in a first organic solvent in the presence of a base to form a compound of formula (III) or a salt thereof: , in: R1 and R2 are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -NO 2, -NR bR c, -NHS(=O) 2R a, -S(=O) 2NR bR c, -C(=O)R a, -OC(=O)R a, -C(=O)OR b, -OC(=O)OR b, -C(=O)NR bR c, -OC(=O)NR bR c, -NR bC(=O)NR bR c, -NR bC(=O)R a, -NR bC(=O)OR b, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C4-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R1 and R2 together to form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and as needed via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted; Each R3 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORα, -SH, -SRα, -S(=O)RA, -S(=O)2RA, -NO2, -NRbRc, -NHS(=O) 2R a, -S(=O) 2NR bR c, -C(=O)R a, -OC(=O)R a, -C(=O)OR b, -OC(=O)OR b, -C(=O)NR bR c, -OC(=O)NR bR c, -NR bC(=O)NR bR c, -NR bC(=O)R a, -NR bC(=O)OR b, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted; Each Ra is independently a C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted as needed with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 haloalkyl; Each Rb is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently, as needed, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH 3, C1-C6 alkyl, or C1-C6 haloalkyl substitution; Each Rc is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted as needed with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 haloalkyl; X-series halogens; and n is 0, 1, 2, 3, or 4.

[0036] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0037] In some specific embodiments, each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group in R1 is independently and as needed substituted with one, two, or three side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0038] In some specific embodiments, R1 is hydrogen or deuterium. In some embodiments, R1 is hydrogen.

[0039] In some specific embodiments, R1-based halogens, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C4-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C4-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted as needed by one or more side oxygen, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl.

[0040] In some specific embodiments, R1 is a C4-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclic alkyl; wherein each alkyl, cycloalkyl, and heterocyclic alkyl group is independently substituted as needed with one or more side oxygen, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl.

[0041] In some specific embodiments, R1 refers to C4-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclic alkyl; wherein each alkyl, cycloalkyl, and heterocyclic alkyl group is independently substituted with one or more halogens as desired. In some specific embodiments, R1 refers to C1-C6 deuterated alkyl.

[0042] In some specific embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl group.

[0043] In some specific embodiments, R1 is a C1-C6 alkyl group. In some embodiments, R1 is a methyl group. In some embodiments, R1 is an ethyl group. In some embodiments, R1 is a propyl group. In some embodiments, R1 is a butyl group. In some embodiments, R1 is an isopropyl group. In some embodiments, R1 is an isobutyl group. In some embodiments, R1 is a dibutyl group. In some embodiments, R1 is a tert-butyl group. In some embodiments, R1 is an pentyl group. In some embodiments, R1 is an isopentyl group. In some embodiments, R1 is a hexyl group. In some embodiments, R1 is an isohexyl group.

[0044] In some embodiments, R1 is a C1-C6 alkenyl group. In some embodiments, R1 is a C2 alkenyl group. In some embodiments, R1 is a C3 alkenyl group. In some embodiments, R1 is a C4 alkenyl group. In some embodiments, R1 is a C5 alkenyl group. In some embodiments, R1 is a C6 alkenyl group.

[0045] In some embodiments, R1 is a C2-C6 ynyl group. In some embodiments, R1 is a C2 ynyl group. In some embodiments, R1 is a C3 ynyl group. In some embodiments, R1 is a C4 ynyl group. In some embodiments, R1 is a C5 ynyl group. In some embodiments, R1 is a C6 ynyl group.

[0046] In some specific embodiments, each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group in R2 is independently and as needed substituted with one, two, or three lateral oxy groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0047] In some specific embodiments, R2 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R2 is hydrogen. In some embodiments, R2 is deuterium.

[0048] In some specific embodiments, each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group in R3 is independently substituted as needed with one, two, or three side oxygen groups, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl.

[0049] In some embodiments, R1 and R2 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. In some embodiments, R1 and R2 together form a cycloalkyl group. In some embodiments, R1 and R2 together form an aryl group. In some embodiments, R1 and R2 together form a heterocycloalkyl group. In some embodiments, R1 and R2 together form a heteroaryl group.

[0050] In some embodiments, R1 and R2 together form a cycloalkyl group. In some embodiments, R1 and R2 together form a 6-membered cycloalkyl group.

[0051] In some embodiments, R1 and R2 together form an aryl group. In some embodiments, R1 and R2 together form a 6-membered aryl group.

[0052] In some embodiments, each R3 is independently hydrogen, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, each R3 is independently a halogen, such as a halogen, fluorine, chlorine, bromine, and iodine. In some embodiments, one of the R3s is deuterium. In some embodiments, each R3 is independently hydrogen, deuterium, a halogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, each R3 is independently deuterium, a halogen, or a C1-C6 alkyl group. In some embodiments, each R3 is independently deuterium or a halogen.

[0053] In some embodiments, the X-series halogens are used. In some embodiments, the X-series fluorine is used. In some embodiments, the X-series chlorine is used. In some embodiments, the X-series bromine is used. In some embodiments, the X-series iodine is used.

[0054] In some embodiments, compounds of formula (I) are compounds of formula (Ia): , Its tautomers or salts, wherein R1 is as described in this paper for formula (I).

[0055] In some embodiments, compounds of formula (I) are compounds of formula (Ib): Its tautomers or salts, wherein R2 is as described herein with respect to formula (I).

[0056] In some embodiments, compounds of formula (II) are compounds of formula (II-a): Or its salts, wherein X and R3 are as described herein with respect to formula (II).

[0057] In some embodiments, compounds of formula (II) are compounds of formula (II-b): Or its salts, wherein X and R3 are as described herein with respect to formula (II).

[0058] In some embodiments, compounds of formula (II) are compounds of formula (II-c): Or its salts, wherein X is as described herein with respect to formula (II).

[0059] In some embodiments, compounds of formula (III) are compounds of formula (III-b): Or its salts, wherein R1, R3, and n are as described herein for equation (III).

[0060] In some embodiments, compounds of formula (III) are compounds of formula (III-d): Or its salts, wherein R2, R3, and n are as described herein for formula (III).

[0061] In some embodiments, compounds of formula (III) are compounds of formula (III-f): Or its salts, wherein R1, R2, and R3 are as described herein with respect to formula (III).

[0062] In some embodiments, compounds of formula (III) are compounds of formula (III-h): Or its salts, wherein R1 and R3 are as described herein with respect to formula (III).

[0063] In some specific embodiments, the compound of formula (I) is 4-isopropyl tert-4-dimethyl ... -3,6-diol (compound 1-1): .

[0064] In some specific embodiments, the compounds of formula (II) are 1,3-dichloro-2-fluoro-5-nitrobenzene (compounds 1-2): .

[0065] In some specific embodiments, the compound of formula (III) is 6-(2,6-dichloro-4-nitrophenoxy)-4-isopropylpyridine. -3(2H)-ketones (compounds 1-4): .

[0066] The first organic solvent used in the compound of formula (III) may comprise DMF, DMAC, DMSO, acetonitrile, THF, DCM, diacetone, or combinations thereof. In some specific embodiments, the first organic solvent used in the compound of formula (III) is DMF, DMAC, DMSO, acetonitrile, THF, DCM, diacetone, or combinations thereof. In some specific embodiments, the first organic solvent comprises DMF. In some specific embodiments, the first organic solvent is DMF.

[0067] The base used in the compound of formula (III) may comprise Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, or combinations thereof. In some specific embodiments, the base used in the compound of formula (III) is Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, or combinations thereof. In some specific embodiments, the base is added in solid form.

[0068] In some specific embodiments, the method further comprises contacting a 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: .

[0069] In some specific embodiments, the compound of formula (IV) is a compound of formula (IV-b): Or its salts, wherein R1, R3, and n are as described herein with respect to formula (IV).

[0070] In some specific embodiments, the compound of formula (IV) is a compound of formula (IV-d): Or its salts, wherein R2, R3, and n are as described herein with respect to formula (IV).

[0071] In some specific embodiments, the compound of formula (IV) is a compound of formula (IV-f): Or its salts, wherein R1, R2, and R3 are as described herein with respect to formula (IV).

[0072] In some embodiments, compounds of formula (IV) are compounds of formula (IV-h): Or its salts, wherein R1 and R3 are as described herein with respect to formula (IV-h).

[0073] In some specific embodiments, the compound of formula (IV) is 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridine. -3(2H)-keto (Int. 7): .

[0074] The second organic solvent used in the synthetic formula (IV) compound may comprise DMF, DMAC, DMSO, acetonitrile, THF, DCM, diacetone, or combinations thereof. The second organic solvent used in the synthetic formula (IV) compound is DMF, DMAC, DMSO, acetonitrile, THF, DCM, diacetone, or combinations thereof. In some specific embodiments, the second organic solvent comprises THF. In some specific embodiments, the second organic solvent is THF.

[0075] In some specific embodiments, the reducing agent used in the synthetic (IV) compound may comprise H₂ gas and Pd / C, H₂ gas and Rathalos nickel, H₂ gas and platinum oxide (IV), ferrous chloride, or stannous chloride. In some specific embodiments, the reducing agent used in the synthetic (IV) compound is H₂ gas and Pd / C, H₂ gas and Rathalos nickel, H₂ gas and platinum oxide (IV), ferrous chloride, or stannous chloride. In some specific embodiments, the reducing agent comprises H₂ gas and Pd / C. In some specific embodiments, the reducing agent is H₂ gas and Pd / C.

[0076] In some specific embodiments, the method further comprises contacting a compound of formula (IV) or a salt thereof with R 4CH 2C(O)N(R 5)C(O)OCH 2CH 3 to form a compound of formula (V) or a salt thereof: , in: R-series hydrogen, deuterium, halogens, -CN, -OH, -OR a, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -NO 2, -NR bR c, -NHS(=O) 2R a, -S(=O) 2NR bR c、-C(=O)R a、-OC(=O)R a、-C(=O)OR b、 -OC(=O)OR b, -C(=O)NR bR c, -OC(=O)NR bR c, -NR bC(=O)NR bR c, -NR bC(=O)R a, -NR bC(=O)OR b, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substitution; and R-5 series hydrogen, deuterium, halogens, -CN, -OH, -ORα, -S(=O)RA, -S(=O) 2R a, -S(=O) 2NR bR c, -C(=O)R a, -OC(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently, as needed, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0077] In some specific embodiments, each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group in R4 is independently, as needed, oxidized by one, two, or three side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0078] In some embodiments, R4 is a hydrogen, deuterium, or halogen.

[0079] In some specific embodiments, R4 series-CN.

[0080] In some specific embodiments, each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group in R5 is independently and as needed substituted with one or more side oxygen groups, deuterium, halogens, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0081] In some specific embodiments, R5 is a hydrogen atom or a C1-C6 alkyl group.

[0082] In some embodiments, R5-series hydrogen.

[0083] In some specific embodiments, the compound of formula (V) is a compound of formula (Vb): Or its salts, wherein R1, R3, R4, R5, and n are as described herein with respect to formula (V).

[0084] In some specific embodiments, the compound of formula (V) is a compound of formula (Vd): Or its salts, wherein R2, R3, R4, R5, and n are as described herein with respect to formula (V).

[0085] In some specific embodiments, the compound of formula (V) is a compound of formula (Vf): Or its salts, wherein R1, R2, R3, R4, and R5 are as described herein with respect to formula (V).

[0086] In some specific embodiments, the compound of formula (V) is a compound of formula (Vh): Or its salts, wherein R1, R3, R4, and R5 are as described herein with respect to formula (V).

[0087] In some specific embodiments, R 4CH 2C(O)N(R 5)C(O)OCH 2CH 3 is CNCH 2C(O)NHC(O)OCH 2CH 3.

[0088] In some specific embodiments, the compound of formula (V) is 2-(3,5-dichloro-4-((5-isopropyl-6-sideoxy-1,6-dihydro-2-dichloro-4- ... -3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-trisyl) -6-formonitrile (MGL-3196).

[0089] In some specific embodiments, prior to forming the (V) compound, the method further comprises contacting the (IV) compound or a salt thereof with R4CH2C(O)N(R5)C(O)OCH2CH3 as described above in the presence of an oxidant and an acid to form the (IV-int) compound or a salt thereof: .

[0090] In some embodiments, the oxidant used in the synthetic (IV-int) compound may include NaNO₂, KNO₂, or a combination thereof. In some embodiments, the oxidant used in the synthetic (IV-int) compound is Na₂CO₃, KNO₂, or a combination thereof. In some embodiments, the acid used in the synthetic (V-int) compound may include HCl, AcOH, or a combination thereof. In some embodiments, the acid used in the synthetic (V-int) compound is HCl, AcOH, or a combination thereof.

[0091] In some specific embodiments, the method further comprises contacting the compound of formula (IV-int) with a base to form the compound of formula (V). In some specific embodiments, the base used in the synthesis of the compound of formula (V) may comprise sodium acetate (NaOAc), potassium acetate (KOAc), or a combination thereof. In some specific embodiments, the base used in the synthesis of the compound of formula (V) is NaOAc, KOAc, or a combination thereof.

[0092] In some specific embodiments, the method further comprises contacting a compound of formula (III) or a salt thereof with R 6X to form a compound of formula (III-a) or a salt thereof: , in: R 6 series -CN, -OH, -OR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR bR c、-C(=O)R a、-OC(=O)R a、-C(=O)OR b、 -C(=O)NR bR c, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently, as needed, via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted; and The X series is defined in this paper as in equation (II).

[0093] In some specific embodiments, each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group in R6 is independently and as needed substituted with one, two, or three side oxygen groups, deuterium, halogen, -CN, -OH, -OR a, -NR bR c, -C(=O)R a, -C(=O)OR b, -C(=O)NR bR c, C1-C6 alkyl, or C1-C6 haloalkyl substituted.

[0094] In some specific embodiments, R is a C1-C6 alkyl group.

[0095] In some specific embodiments, compounds of formula (III-a) are compounds of formula (III-c): Or its salts, wherein R1, R3, R6, and n are as described herein with respect to formula (III-a).

[0096] In some specific embodiments, compounds of formula (III-a) are compounds of formula (III-e): Or its salts, wherein R2, R3, R6, and n are as described herein with respect to formula (III-a).

[0097] In some specific embodiments, the compound of formula (III-a) is a compound of formula (III-g): Or its salts, wherein R1, R2, R3, and R6 are as described herein with respect to formula (III-a).

[0098] In some specific embodiments, compounds of formula (III-a) are compounds of formula (III-i): Or its salts, wherein R1, R3, and R6 are as described herein with respect to formula (III-a).

[0099] In some specific embodiments, the method further comprises contacting a compound of formula (III-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: .

[0100] In some specific embodiments, the second organic solvent used in the synthetic formula (IV-a) compound may comprise DMF, DMAC, DMSO, acetonitrile, THF, DCM, diacetone, or combinations thereof. In some specific embodiments, the second organic solvent used in the synthetic formula (IV-a) compound is DMF, DMAC, DMSO, acetonitrile, THF, DCM, diacetone, or combinations thereof. In some specific embodiments, the second organic solvent comprises THF. In some specific embodiments, the second organic solvent is THF.

[0101] In some specific embodiments, the reducing agent used in the synthetic (IV-a) compound may comprise H₂ gas and Pd / C, H₂ gas and Rathalosin nickel, H₂ gas and platinum oxide (IV), ferrous chloride, or stannous chloride. In some specific embodiments, the reducing agent used in the synthetic (IV-a) compound is H₂ gas and Pd / C, H₂ gas and Rathalosin nickel, H₂ gas and platinum oxide (IV), ferrous chloride, or stannous chloride. In some specific embodiments, the reducing agent comprises H₂ gas and Pd / C. In some specific embodiments, the reducing agent is H₂ gas and Pd / C.

[0102] In some specific embodiments, the compound of formula (IV-a) is a compound of formula (IV-c): Or its salts, wherein R1, R3, R6, and n are as described herein with respect to formula (IV-a).

[0103] In some specific embodiments, the compound of formula (IV-a) is a compound of formula (IV-e): Or its salts, wherein R2, R3, R6, and n are as described herein with respect to formula (IV-a).

[0104] In some specific embodiments, the compound of formula (IV-a) is a compound of formula (IV-g): Or its salts, wherein R1, R2, R3, and R6 are as described herein with respect to formula (IV-a).

[0105] In some specific embodiments, the compound of formula (IV-a) is a compound of formula (IV-i): Or its salts, wherein R1, R3, and R6 are as described herein with respect to formula (IV-a).

[0106] In some specific embodiments, the method further comprises contacting a compound of formula (IV-a) or a salt thereof with R 4CH 2C(O)N(R 5)C(O)OCH 2CH 3 as described above to form a compound of formula (Va) or a salt thereof: .

[0107] In some specific embodiments, prior to forming the (Va) compound, the method comprises contacting the (IV-a) compound or a salt thereof with R4CH2C(O)N(R5)C(O)OCH2CH3 as described above in the presence of an oxidant and an acid to form the (IV-a-int) compound or a salt thereof: .

[0108] In some embodiments, the oxidant used in the synthetic (IV-a-int) compound may comprise NaNO₂, KNO₂, or a combination thereof. In some embodiments, the oxidant used in the synthetic (IV-a-int) compound is NaNO₂, KNO₂, or a combination thereof. In some embodiments, the acid used in the synthetic (IV-a-int) compound may comprise HCl, AcOH, or a combination thereof. In some embodiments, the acid used in the synthetic (IV-a-int) compound is HCl, AcOH, or a combination thereof.

[0109] In some specific embodiments, the method further comprises contacting the (IV-a-int) compound with a base to form the (Va) compound. In some specific embodiments, the base used in the synthesis of the (Va) compound may comprise NaOAc, KOAc, or a combination thereof. In some specific embodiments, the base used in the synthesis of the (Va) compound is NaOAc, KOAc, or a combination thereof.

[0110] In some specific embodiments, the compound of formula (Va) is a compound of formula (Vc): Or its salts, wherein R1, R3, R4, R5, R6, and n are as described herein for formula (Va).

[0111] In some specific embodiments, the compound of formula (Va) is a compound of formula (Ve): Or its salts, wherein R2, R3, R4, R5, R6, and n are as described herein for formula (Va).

[0112] In some specific embodiments, the compound of formula (Va) is a compound of formula (Vg): Or its salts, wherein R1, R2, R3, R4, R5, and R6 are as described herein with respect to formula (Va).

[0113] In some specific embodiments, the compound of formula (Va) is a compound of formula (Vi): Or its salts, wherein R1, R3, R4, R5, and R6 are as described herein with respect to formula (Va).

[0114] Specific examples of compounds of formula (V) or (Va) can be found in WO2019 / 240938, the contents of which are incorporated herein by reference.

[0115] In some embodiments, the compound can be contacted at room temperature, above room temperature, or below room temperature. In some embodiments, this contact occurs at room temperature.

[0116] In one state sample, this disclosure provides compounds having the following structures:

[0117] Examples of the compounds disclosed herein are shown in Table 1 below. [Medically acceptable salt] []

[0118] In some embodiments, the compounds described herein are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

[0119] In some specific embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic and organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some specific embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0120] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with inorganic salts, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucuronates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, transbutenedioates, glucoheptanoate, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dicitates, hydroxybenzoates, and γ-hydroxybutyric acid. Salts (g-hydroxybutyrate), hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, amygdalinate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, l-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0121] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, and citric acid. Benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, aryl sulfonic acid, methane sulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethane sulfonic acid, benzene sulfonic acid, 2-naphthalene sulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, gluconepic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid.

[0122] In some specific embodiments, those compounds described herein containing a free acid group react with: suitable bases, such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations; and with ammonia, or with pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Cl-4 alkyl)4, and the like.

[0123] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperidine. Compounds, and their similarities. It should be understood that the compounds described herein also include any quatemization of any basic nitrogen-containing group contained therein. In some specific embodiments, such quatemization is used to obtain water-soluble, oil-soluble, or dispersible products. [Pharmaceutical components and treatment methods] []

[0124] In some embodiments, this disclosure provides pharmaceutical compositions comprising one or more compounds of formula (V) or formula (Va) or salts thereof as active ingredients. In some embodiments, this disclosure provides pharmaceutical compositions comprising one or more compounds of formula (V) or formula (Va), pharmaceutically acceptable salts or solvates thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0125] In some embodiments, this disclosure provides pharmaceutical compositions comprising one or more compounds of formula (V) or formula (Va) prepared by the methods described herein, or salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0126] The pharmaceutical composition disclosed herein can be manufactured in a generally known manner, such as by conventional mixing, dissolving, granulation, sugar coating, grinding, emulsification, capsule filling, encapsulation, or freeze-drying processes. The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, which include excipients and / or adjuvants that facilitate the processing of the active ingredient into a pharmaceutically usable formulation. Of course, the appropriate formulation depends on the chosen route of administration.

[0127] In some specific embodiments, the pharmaceutical composition is formulated in gel form.

[0128] In some specific embodiments, the pharmaceutical composition is formulated in tablet form.

[0129] In some specific embodiments, the pharmaceutical composition is formulated in the form of pills.

[0130] In some specific embodiments, the pharmaceutical ingredients are formulated in capsule form.

[0131] In some specific embodiments, the pharmaceutical composition is prepared in solution form.

[0132] In some cases, this disclosure relates at least in part to a method of treating liver disease or condition or lipid disease or condition by administering a compound of formula (V) or formula (Va) or a salt thereof to an individual in need.

[0133] In some specific embodiments, the liver disease or condition treated by the method of the present invention is fatty liver disease.

[0134] In some specific embodiments, the liver disease or condition treated by the method of the present invention is nonalcoholic fatty liver disease (NAFLD). In some specific embodiments, the liver disease or condition treated by the method of the present invention is NASH.

[0135] In some specific embodiments, the lipid disorders or conditions treated by the method of the present invention are selected from the group consisting of: dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL. In some specific embodiments, hypercholesterolemia is heterozygous familial hypercholesterolemia (HeFH) or homozygous familial hypercholesterolemia (HoFH).

[0136] In some specific embodiments, the individual is at risk of developing the liver disease or condition described herein. In some specific embodiments, the individual is at risk of developing the lipid disease or condition described herein.

[0137] In some specific embodiments, the system comprises mammals. In some specific embodiments, the system comprises humans. definition

[0138] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Technical terms used in this specification are intended only to describe particular embodiments and are not intended to limit the scope of the invention.

[0139] When a range of values ​​is provided, it should be understood that the range includes both endpoints of the range, as well as all intermediate values.

[0140] Unless the context clearly indicates otherwise, the article "a / an" as used herein and in the claims of the appended patent application refers to one or more (i.e., at least one) grammatical objects of that article. For example, "ultrapure form" means one or more ultrapure forms.

[0141] The phrase "and / or" as used herein and in the claims should be understood to mean "either or both." Other elements may be present as needed, in addition to those specifically identified by the "and / or" clause. Therefore, as a non-limiting embodiment, in one embodiment, when used in conjunction with open-ended language such as "comprising," a reference to "A and / or B" may refer only to A (including elements other than B as needed); in another embodiment, only to B (including elements other than A as needed); and in yet another embodiment, to both A and B (including other elements as needed).

[0142] Unless otherwise expressly stated, the terms "approximately" and "about" are synonymous. In some embodiments, "approximately" and "about" refer to the listed amount, value, dose, or duration ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 2%, ± 1%, or ± 0.5%. In some embodiments, "approximately" and "about" refer to the listed amount, value, dose, or duration ± 5%. In some embodiments, "approximately" and "about" refer to the listed amount, value, dose, or duration ± 2%. In some embodiments, "approximately" and "about" refer to the listed amount, value, dose, or duration ± 1%.

[0143] As used herein and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when items are separated in a list, "or" or "and / or" should be interpreted as inclusive, that is, including at least one, but also more than one, and additional unlisted items as needed, among a number of elements or a list of elements. Only terms that clearly indicate the opposite, such as "only one of" or "exactly one of," or "consisting of" as used in the claims, will refer to including exactly one element among a number of elements or a list of elements. Generally speaking, when the preceding exclusive terms such as "either", "one of", "only one of", or "exactly one of", the term "or" as used in this article should only be interpreted as an exclusive choice (i.e., "one or the other, but not two").

[0144] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, or C6 alkyl groups. Examples of alkyl groups include portions having one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, secondary pentyl, or n-hexyl. In some embodiments, the straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., straight-chain C1-C6, branched C3-C6), while in another embodiment, the straight-chain or branched alkyl group has four or fewer carbon atoms.

[0145] As used herein, the term "alkenyl" includes an unsaturated aliphatic group with a similar length and possible substitutions to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some specific embodiments, the straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., straight-chain C2-C6, branched C3-C6). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

[0146] As used herein, the term "alkenyl" includes an unsaturated aliphatic group with a similar length and possible substitutions to the alkyl groups described above, but containing at least one triple bond. For example, "alkenyl" includes straight-chain alkenyl groups (e.g., ethynyl, propynyl, butynyl, pentyynyl, hexynyl, heptyynyl, octyynyl, nonynyl, decanynyl) and branched alkenyl groups. In some specific embodiments, the straight-chain or branched alkenyl groups have six or fewer carbon atoms in their backbone (e.g., straight-chain C2-C6, branched C3-C6). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5, or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0147] "Aminoalkyl" means an alkyl group as defined herein that has been substituted with one or more amino groups.

[0148] As used herein, the term "aryl" includes an aromatic group, comprising a "conjugated" or polycyclic system having one or more aromatic rings, and the ring structure containing no heteroatoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. Conveniently, aryl refers to phenyl.

[0149] As used herein, the term "contact" or "contacting" refers to an action that brings two or more reactants into close proximity, for example, causing two or more reactants to undergo a chemical reaction. In some embodiments, contact includes mixing two or more reactants. In some embodiments, contact is performed under conditions suitable for the formation of the desired reaction product from the two or more reactants.

[0150] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl.

[0151] "Deuteroalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by deuterium.

[0152] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine groups.

[0153] "Haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced by halogens.

[0154] Unless otherwise stated, as used herein, the term "heterocycloalkyl" means a saturated or unsaturated non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic (fused, bridged, or spirocyclic) system having one or more heteroatoms (such as O, N, S, P, or Se), for example 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or for example 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperidinyl... base, pyrrolidinyl, di Tetrahydrofuranyl, isoindolineyl, indolineyl, imidazolidineyl, pyrazolidineyl azole, iso Azoxyl, triazoxyl, ethylene oxide, aziridine, oxacyclobutyl, thiohexacyclobutyl, 1,2,3,6-tetrahydropyridyl, tetrahydropiperanyl, dihydropiperanyl, piperanyl, morpholinyl, tetrahydrothiopiperanyl, 1,4-diazacycloheptyl, 1,4-oxazacycloheptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azabicyclo[2.2.1]heptyl Spiro[3.3]heptyl, 2,6-diazespiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furan[3,4-b]pyridinyl]-yl, 3'H-spiro[ Cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8- Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, and the like. In the case of polycyclic non-aromatic rings, only one of these rings needs to be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthyl or 2,3-dihydroindole).

[0155] As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles composed of a carbon atom and one or more heteroatoms (e.g., 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or, for example, 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may be oxidized as needed (i.e., N→O and S(O)p, where p = 1 or 2). It should be noted that the total number of S and O atoms in an aromatic heterocycle is no more than 1. Examples of heteroaryl compounds include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetraazole, pyrazole, azole, isotonic azole, pyridine, pyridine ,despair Pyrimidines and similar compounds.

[0156] "Hydroxyalkyl" means an alkyl moiety as defined herein, substituted with one or more hydroxyl groups. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.

[0157] It should be understood that the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl (e.g., tricyclic, bicyclic), such as naphthalene and benzo[a]. azole, benzo[a] azole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthidine, indole, benzofuran, purine, benzofuran, dezapurine, indole .

[0158] As used herein, the term "pharmaceutically acceptable" means, within the bounds of reasonable medical judgment, those compounds, anions, cations, materials, components, carriers, and / or dosage forms that are suitable for use in human or animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and whose benefits / risks are commensurate with a reasonable ratio.

[0159] As used herein, the term "subject" may be used interchangeably with the term "individual with a need," both referring to an individual who has a disease or is at increased risk of developing a disease. "Subject" includes mammals. Mammals may be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. In some specific embodiments, the mammal is a human.

[0160] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and readily transform from one isomer to another. This transformation results in the formal migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solutions where tautomerization is possible, tautomers will reach chemical equilibrium. The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, electrons and hydrogen atoms are transferred simultaneously. Ring-chain tautomerism occurs when the aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic form, as seen in glucose.

[0161] It should be understood that the compounds disclosed herein can be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomeric form. It should be understood that some tautomers may have higher activity levels than others.

[0162] As used herein, the term "treating / treat" describes the handling and care of a patient for the purpose of combating a disease, condition, or symptom, and includes the administration of the compounds disclosed herein, or their pharmaceutically acceptable salts, polymorphs, or solvates, to alleviate or eliminate the symptoms or complications of the disease, condition, or symptom. The term "treat" may also include treatments in in vitro cell or animal models.

[0163] As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by the preparation of its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkali metal or organic salts of acidic residues (such as carboxylic acids); and the like. Pharmaceutically acceptable salts include, for example, known nontoxic salts or quaternary ammonium salts of parent compounds formed from nontoxic inorganic or organic acids. For example, such known non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids, such acids being selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glutamic acid, glycolic acid, glycollyrhanic acid, hexylresorcinic acid, hydroxamic acid, and hydrogen. Bromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, dihydroxynaphthic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, amine sulfonic acid, p-amine benzene sulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluene sulfonic acid, and commonly found amino acids such as glycine, alanine, phenylalanine, and arginine. Other examples of medically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, mucoconic acid, and the like. This disclosure also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., alkali metal ions, alkaline earth ions, aluminum ions); or when coordinated with an organic base (such as ethanolamine, diethanolamine, triethanolamine, thiocyanate, N-glucamine, and the like). In salt form, it should be understood that the ratio of the cation or anion of the compound to the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3. It should be understood that all references to pharmaceutically acceptable salts include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0164] Unless otherwise specified, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will be apparent from the various embodiments. The provided embodiments are illustrated and can be used to practice the different components and methods of this disclosure. The embodiments are not limited to the claimed disclosure. Based on this disclosure, those skilled in the art will recognize and employ other components and methods suitable for practicing this disclosure.

[0165] As used herein, the term "MGL-3196" is equivalent to 2-(3,5-dichloro-4-((5-isopropyl-6-sideoxy-1,6-dihydro- ... -3-yl)oxy)phenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-trisyl) -6-formonitrile (i.e., (or any of the following salts that are medically acceptable):

[0166] All publications and patent documents cited herein are incorporated herein by reference, as specifically and individually indicated that each such publication or document is incorporated herein by reference. The citation of publications and patent documents is not intended as an endorsement of any applicable prior art, nor does it constitute any endorsement of their content or date. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be implemented in various specific embodiments, and that the foregoing description and the following embodiments are for illustrative purposes and not for limiting the scope of the appended claims. Example

[0167] Unless otherwise stated, the analytical instruments and parameters used for the compounds described in the examples are as follows:

[0168] Nuclear magnetic resonance (NMR) spectroscopy was recorded on a Bruker NEO 600 MHz NMR spectrometer equipped with a 5 mm broadband observation probe. For 1H NMR, 16 scans were superimposed with 90-degree pulses and a 10-second cycle delay. For 13C NMR, 13C detection was accompanied by composite pulse decoupling of 1H. Unless otherwise noted, 256 scans were superimposed for 13C NMR data collection. Chemical shifts (δ) are reported in parts per million (ppm).

[0169] LC-MS chromatography and spectra were recorded using a Shimadzu LCMS-2020 ultra-high-speed mass spectrometer connected to a Shimadzu LC-2040C 3D liquid chromatography system.

[0170] XRPD data was collected using a Rigaku X-ray source: 30 kV, 15 mA; wavelength: Kα1; goniometer: MiniFlex goniometer; scan speed: 2.0000° / min; scan step: 0.02°; detector: Miniflex counter; scan range: 3.0000 to 45.0000.

[0171] Melting point values ​​were obtained using a TA Instruments Inc. DSC Q200.

[0172] abbreviation: ACN and MeCN Acetonitrile CDCl 3 Chloroform-d DCM dichloromethane DMF N,N-Dimethylformamide g gram HPLC High performance liquid chromatography mL milliliters MHz million Hertz THF Tetrahydrofuran [Example] [1] [:synthesis] [6-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-4-] [Isopropyl] [-2H-] [despair] [ ] [-3-] [ketone] [(Int. 7)] Synthesis of 6-(2,6-dichloro-4-nitro-phenoxy)-4-isopropyl-2H- pyroxyl -3-keto (compounds 1-4)

[0173] Potassium bicarbonate (2.34 g, 23.4 mmol) was added to a solution of compound 3-1 (3.0 g, 19.5 mmol) and compound 3-2 (2.9 g, 13.6 mmol) in DMF (60 mL), and the mixture was stirred at room temperature for two hours. The reaction was then quenched with water (180 mL). The resulting suspension was filtered. The filter cake was washed with water (60 mL) and dried under vacuum for 24 hours to obtain crude compound 1-4 (4.93 g), which was further purified by slurrying in ethyl acetate to give compound 1-4 as a grayish-white solid (3.51 g, purity 74.9%). Compound 1-3 (a regio-isomer of compound 1-4) was purified by column chromatography.

[0174] Compounds 1-4: ¹H NMR (600 MHz, CDCl₃) δ 8.31 (s, 2H), 7.16 (d, J = 0.8 Hz, 1H), 3.24 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H). ¹³C NMR (150 MHz, CDCl₃) δ 160.72, 154.89, 151.70, 150.85, 145.18, 130.55, 124.31, 119.65, 28.22, 20.75. LRMS:C 13H 12Cl 2N 3O 4 [M+H+] m / z = 344,C 13H 10Cl 2N 3O 4 [M+H-] m / z = 342. The crystalline solid systems of compounds 1-4 were obtained by recrystallization from a mixture of DCM and THF. Melting point: 270.82℃. The XRPD peak values ​​of compounds 1-4 are listed below (peak: 21-pts / parabolic filter, threshold = 3.0, cutoff = 0.1%, BG = 3 / 0.6, peak-to-peak = apex).

[0175] Compounds 1-3 (pure by HPLC): ¹H NMR (600 MHz, CDCl₃) δ 10.76 (s, ¹H, NH), 8.27 (s, 2H), 6.84 (s, ¹H), 3.16 (m, ¹H), 1.34 (d, J = 6.8 Hz, 6H). ¹³C NMR (150 MHz, CDCl₃) δ 161.98, 151.08, 150.64, 147.85, 145.42, 130.64, 128.36, 124.50, 28.63, 21.19. LRMS: C₁₃H₁₂Cl₂N₃O₄[M+H⁺] m / z = 344. Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H- pyroxene -3-Ketone (Int. 7)

[0176] Palladium (5%, 50 mg) loaded on carbon was added to a solution of compounds 1-4 (0.5 g, 1.5 mmol) in THF (25 mL). The solution was purged twice with nitrogen and then stirred for 5 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give Int. 7 (473 mg, 103.6%) as a grayish-white solid. ¹H NMR (600 MHz, CDCl₃) δ 7.05 (s, 1H), 6.64 (s, 2H), 3.18 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, CDCl 3) δ 160.53, 154.12, 152.89, 145.35, 137.15, 129.41, 120.44, 114.87, 28.29, 21.00. LRMS:C 13H 11Cl 2N 3O 2[M+H-] m / z = 312. [Example] [2.6-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-4,5-] [Dimethyl di ... [ ] [-3(2H)-] [ketone] [(2-3)] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-4,5-dimethylpyrazine -3(2H)- Ketone(2-2)

[0177] Potassium carbonate (118 mg, 0.86 mmol) was added to 4,5-dimethyl-1,2-dihydropyridine. 3,6-dione (compound 2-1, 80 mg, 0.57 mmol) and compound 1-2 (84 mg, 0.40 mmol) were reacted in a solution of DMF (2.0 mL) and the mixture was stirred at room temperature for 3 hours, followed by quenching with water (6.0 mL). The resulting suspension was filtered. The filter cake was washed with water (2.0 mL) and dried under vacuum for 24 hours to give crude compound 2-2 (114 mg), which was further purified by slurrying in ethyl acetate to give compound 2-2 (93 mg, yield: 49.5%) as a grayish-white amorphous solid. Compound 2-2: 1H NMR (600 MHz, CDCl 3) δ 10.72 (s, 1H, NH), 8.31 (s, 2H), 2.38 (s, 3H), 2.26 (s, 3H). 13C NMR (151 MHz, CDCl 3) δ 161.71, 151.52, 151.27, 145.28, 140.78, 133.08, 130.66, 124.47, 13.36, 13.00. LRMS:C 13H 10C l2N 3O 4[M+H +] m / z = 330. Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-4,5-dimethylpyrazine -3(2H)- Ketone(2-3)

[0178] Palladium (5%, 3.0 mg) supported on carbon was added to a solution of compound 2-2 (30 mg, 0.09 mmol) in THF (2.0 mL). The solution was purged twice with nitrogen and then stirred for 5 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give compound 2-3 (32 mg, 116%) as a grayish-white solid. Compound 2-3: 1H NMR (600 MHz, CDCl3) δ 6.69 (s, 2H), 2.34 (s, 3H), 2.20 (s, 3H). 13C NMR (151 MHz, CDCl 3) δ 163.28, 153.70, 148.80, 140.39, 137.37, 135.21, 130.01, 115.16, 13.25, 12.65. LRMS:C 12H 12Cl 2N 3O 2[M+H +] m / z = 300. [Example] [3.] [synthesis] [6-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-4-] [Methyl methyl ethyl ... [ ] [-3(2H)-] [ketone] [(3-4)] [and] [6-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-5-] [Methyl methyl ethyl ... [ ] [-3(2H)-] [ketone] [(3-5)] 6-(2,6-Dichloro-4-nitrobenzoxy)-4-methyldi ... -3(2H)- ketones (3-2) and 6-(2,6-dichloro-4-nitrophenoxy)-5-methyl ketones -3(2H)- Ketone (3-3)

[0179] Potassium carbonate (329 mg, 2.38 mmol) was added to 4-dimethyl-1,2-dihydrodihydrogenase. 3,6-dione (compound 3-1, 200 mg, 1.59 mmol) and compound 1-2 (233 mg, 1.11 mmol) were dissolved in DMF (4.0 mL) and the mixture was stirred at room temperature for 3 hours, followed by quenching with water (12.0 mL). The resulting suspension was filtered. The filter cake was washed with water (4.0 mL) and dried under vacuum for 24 hours to give crude compounds 3-2 / 3-3 (310 mg). Further purification by column chromatography yielded a grayish-white crystalline solid 3-2 (139 mg, yield: 27.8%) and a grayish-white amorphous solid 3-3 (74 mg, yield: 14.8%). Compound 3-2: ¹H NMR (600 MHz, DMSO-d⁶) δ 12.29 (s, ¹H, NH), 8.51 (s, 2H), 7.60 (s, ¹H), 2.14 (s, 3H). ¹³C NMR (151 MHz, DMSO-d⁶) δ 160.50, 150.44, 150.12, 145.35, 145.33, 129.31, 124.67, 122.37, 16.24. LRMS: C₁¹H₈Cl₂N₃O₂[M+H⁺] m / z = 316. Compound 3-3: ¹H NMR (600 MHz, DMSO-d⁶) δ 12.23 (s, ¹H, NH), 8.53 (s, 2H), 6.99 (s, ¹H), 2.31 (s, 3H). ¹³C NMR (151 MHz, DMSO-d⁶) δ 160.07, 150.45, 150.29, 145.36, 136.98, 131.82, 129.15, 124.67, 15.61. LRMS: C₁¹H₈Cl₂N₃O₂[M+H⁺] m / z = 316. Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-4-methylpyrazine -3(2H)- Ketone(3-4)

[0180] Palladium (5%, 2.5 mg) supported on carbon was added to a solution of compound 3-2 (25 mg, 0.08 mmol) in THF (2.0 mL). The solution was purged twice with nitrogen and then stirred for 5 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give compound 3-4 (21 mg, yield: 92.9%) as a grayish-white solid. Compound 3-4: 1H NMR (600 MHz, DMSO-d6) δ 12.11 (s, 1H, NH), 7.40 (s, 1H), 6.66 (s, 2H), 2.09 (s, 3H). 13C NMR (151 MHz, DMSO-d 6) δ 160.56, 151.37, 147.96, 144.14, 133.78, 127.84, 122.72, 112.88, 16.11. LRMS:C 11H 10C l2N 3O 2[M+H+] m / z = 286. Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-5-methylpyrazine -3(2H)- Ketones (3-5)

[0181] Palladium (5%, 1.5 mg) loaded on carbon was added to a solution of compound 3-3 (15 mg, 0.05 mmol) in THF (5.0 mL). The solution was purged twice with nitrogen and then stirred for 5 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give compound 3-5 (16 mg, yield: 107%) as a grayish-white solid. Compound 3-5: 1H NMR (600 MHz, CD 3OD) δ 6.89 (s, 1H), 6.70 (s, 2H), 2.35 (s, 3H). 13C NMR (151 MHz, CD 3OD) δ 163.52, 154.04, 148.90, 140.86, 137.19, 131.34, 129.90, 115.13, 16.60. LRMS:C 11H 10C l2N 3O 2[M+H+] m / z = 286. [Example] [4.] [synthesis] [6-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-4-] [Phenyleton] [ ] [-3(2H)-] [ketone] [(4-3)] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-4-phenylpyridine -3(2H)- Ketone(4-2)

[0182] Potassium carbonate (249 mg, 1.80 mmol) was added to 4-phenyl-1,2-dihydropyridine. 3,6-Diketone (compound 4-1, 226 mg, 1.20 mmol) and compound 1-2 (177 mg, 0.84 mmol) were reacted in a solution of DMF (5.0 mL) and the mixture was stirred at room temperature for 3 hours, followed by quenching with water (20 mL). The resulting suspension was filtered. The filter cake was washed with water (5.0 mL) and dried under vacuum for 24 hours to obtain crude compound 4-2 (177 mg), which was further purified by slurrying in ethyl acetate to give compound 4-2 (110 mg, yield: 24.2%) as a light brown crystalline solid. Compound 4-2: 1H NMR (600 MHz, CDCl 3) δ 11.02 (s, 1H, NH), 8.27 (m, 2H), 7.84 (m, 2H), 7.48 (m 3H), 7.43 (s, 1H). 13C NMR (151 MHz, CDCl 3) δ 160.66, 152.04, 151.01, 145.45, 144.52, 132.91, 130.77, 128.94, 128.92, 128.82, 124.56, 122.07. LRMS:C 16H 10Cl 2N 3O 2[M+H +] m / z = 378. Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-4-phenylpyridine -3(2H)- Ketone(4-3)

[0183] Palladium (5%, 3.0 mg) supported on carbon was added to a solution of compound 4-2 (30 mg, 0.08 mmol) in THF (2.0 mL). The solution was purged twice with nitrogen and then stirred for 5 hours under a hydrogen atmosphere at room temperature. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give compound 4-3 (23 mg, yield: 83.3%) as a light brown solid. Compound 4-3: 1H NMR (600 MHz, DMSO-d6) δ 7.85–7.84 (m, 2H), 7.56 (s, 1H), 7.50–7.48 (m, 3H), 6.71 (s, 2H). 13C NMR (151 MHz, DMSO-d 6) δ 152.41, 145.26, 139.33, 135.14, 127.44, 125.18, 121.47, 120.54, 120.21, 119.99, 114.46, 105.52. LRMS:C 16H 12C l2N 3O 2[M+H+] m / z = 348. [Example] [5.] [synthesis] [6-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-4-(] [Trifluoromethyl] [)] [despair] [ ] [-3(2H)-] [ketone] [(5-3)] Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-4-(trifluoromethyl ... -3(2H)- Ketone (5-2)

[0184] Sodium bicarbonate (46.7 mg, 0.56 mmol) was added to 4-(trifluoromethyl)-1,2-dihydropyridine at a temperature below 5.0 °C. 3,6-dione (compound 5-1, 100 mg, 0.56 mmol) and compound 1-2 (58.3 mg, 0.28 mmol) were dissolved in DMF (2.0 mL) and the mixture was stirred at room temperature for 4 days, after which the reaction was quenched with water (6.0 mL). The resulting suspension was filtered. The filter cake was washed with water (2.0 mL) and dried under vacuum for 24 hours to give crude compound 5-2 (109 mg), which was further purified by slurrying in ethyl acetate to give compound 5-2 (58 mg, yield: 28.3%) as a grayish-white solid. Compound 5-2: 1H NMR (600 MHz, DMSO-d6) δ 13.11 (s, 1H, NH), 8.55 (s, 2H), 8.38 (s, 1H). LRMS:C 11H 5Cl 2F 3N 3O 4[M+H +] m / z = 370). Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-4-(trifluoromethyl ... -3(2H)- Ketone (5-3)

[0185] Palladium (5%, 1.5 mg) supported on carbon was added to a solution of compound 5-2 (15 mg, 0.04 mmol) in THF (2.0 mL). The solution was purged twice with nitrogen and then stirred for 5 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness. After purification by column chromatography, compound 5-3 (6.1 mg, yield: 44.3%) was obtained as a grayish-white solid. Compound 5-3: 1H NMR (600 MHz, CDCl 3) δ 10.02 (s, 1H, NH), 7.60 (s, 1H), 6.63 (s, 2H). LRMS: C 11H 7Cl 2F 3N 3O 2 [M+H+] m / z = 340. [Example] [6.] [synthesis] [4-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-5,6,7,8-] [Tetrahydrophthaloyl] [ ] [-1(2H)-] [ketone] [(6-3)] Synthesis of 4-(2,6-dichloro-4-nitrophenoxy)-5,6,7,8-tetrahydrophthaloyl 1(2H)-keto(6-2)

[0186] Potassium carbonate (699 mg, 5.05 mmol) was added to 2,3,5,6,7,8-hexahydrophthalide. 1,4-Diketone (compound 6-1, 560 mg, 3.37 mmol) and compound 1-2 (495 mg, 2.36 mmol) were dissolved in DMF (5.0 mL) and the mixture was stirred at room temperature for 3 hours, after which the reaction was quenched with water (20 mL). The resulting suspension was filtered. The filter cake was washed with water (5.0 mL) and dried under vacuum for 24 hours to give crude compound 6-2 (821 mg), which was further purified by slurrying in ethyl acetate to give compound 6-2 as a grayish-white solid (722 mg, yield: 60.2%). Compound 6-2: ¹H NMR (600 MHz, DMSO-d⁶) δ 12.15 (s, ¹H, NH), 8.51 (s, 2H), 2.65 (t, J = 5.8 Hz, 2H), 2.44 (t, J = 5.8 Hz, 2H), 1.81–1.70 (m, 4H). ¹³C NMR (151 MHz, DMSO-d⁶) δ 159.90, 150.59, 149.67, 145.28, 141.37, 132.70, 129.28, 124.61, 23.03, 22.53, 20.26, 20.13. LRMS:C 14H 12Cl 2N 3O 4[M+H +] m / z = 356. Synthesis of 4-(4-amino-2,6-dichlorophenoxy)-5,6,7,8-tetrahydrophthalide -1(2H)- Ketone (6-3)

[0187] Palladium (5%, 2.5 mg) loaded on carbon was added to a solution of compound 6-2 (25 mg, 0.07 mmol) in THF (2.0 mL). The solution was purged twice with nitrogen and then stirred for 5 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give compound 6-3 (20 mg, yield: 87.3%) as a grayish-white solid. Compound 6-3: 1H NMR (600 MHz, CD 3OD) δ 6.70 (s, 2H), 2.73 (t, J = 4.9 Hz, 2H), 2.54 (t, J = 4.9 Hz, 2H), 1.88–1.78 (m, 4H). 13C NMR (151 MHz, CD 3OD) δ 163.02, 153.43, 148.52, 141.45, 137.42, 136.55, 130.03, 115.30, 31.04, 24.38, 22.03, 21.91. LRMS:C 14H 14Cl 2N 3O 2[M+H +] m / z = 326. [Example] [7.] [synthesis] [4-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)] [phthalide] [ ] [-1(2H)-] [ketone] [(7-3)] Synthesis of 4-(2,6-dichloro-4-nitrophenoxy)phthalide -1(2H)- Ketone (7-2)

[0188] Potassium carbonate (2.60 g, 18.50 mmol) was added to a solution of phthalic hydrazide (compound 7-1, 2.00 mg, 12.33 mmol) and compound 1-2 (1.81 g, 8.63 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction was then quenched with water (60 mL). The resulting suspension was filtered. The filter cake was washed with water (20 mL) and dried under vacuum for 24 hours to give crude compound 7-2 (2.98 g), which was further purified by slurrying in ethyl acetate to give compound 7-2 (2.2 g, yield: 50.7%) as a grayish-white solid. Compound 7-2: 1H NMR (600 MHz, DMSO-d6) δ 12.09 (s, 1H, NH), 8.55 (s, 2H), 8.32 (d, J = 7.5 Hz, 1H), 8.23 ​​(d, J = 7.8 Hz, 1H), 8.12–8.07 (m, 1H), 8.06–8.00 (m, 1H). 13C NMR (151 MHz, DMSO- d 6 ) δ 158.89, 150.39, 147.70, 145.43, 134.33, 133.40, 129.40, 129.09, 126.70, 124.63, 123.34, 122.77. LRMS:C 14H 8Cl 2N 3O 4[M+H +] m / z = 352. Synthesis of 4-(4-amino-2,6-dichlorophenoxy)phthalide -1(2H)- Ketone (7-3)

[0189] Palladium (5%, 10 mg) loaded on carbon was added to a solution of compound 7-2 (100 mg, 0.28 mmol) in THF (10 mL). The solution was purged twice with nitrogen and then stirred for 5 hours under a hydrogen atmosphere at room temperature. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give compound 7-3 (98 mg, yield: 107%) as a light brown solid. Compound 7-3: 1H NMR (600 MHz, DMSO-d6) δ 11.86 (s, 1H, NH), 8.28 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.05-8.01 (m, 1H), 8.00-7.95 (m, 1H), 6.71 (s, 2H), 5.64 (s, 2H, NH2). 13C NMR (151 MHz, DMSO-d 6) δ 158.88, 148.48, 148.03, 134.00, 133.90, 132.85, 128.88, 127.90, 126.46, 123.40, 123.37, 112.92. LRMS:C 14H 10Cl 2N 3O 2[M+H +] m / z = 322. [Example] [8.] [synthesis] [6-(4-)] [Amine] [-2,6-] [Dichlorophenoxy] [)-4-] [Isopropyl] [-2H-] [despair] [ ] [-3-] [ketone] [(8-1)]

[0190] Palladium (5%, 45 mg) loaded on carbon was added to a solution of compound 1-3 (450 mg, 1.31 mmol) in THF (25 mL). The solution was purged twice with nitrogen and then stirred for 5 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a diatomaceous earth mat and the filtrate was concentrated to dryness to give compound 8-1 (410 mg, 99.8%) as a grayish-white solid. Compound 8-1: 1H NMR (600 MHz, CDCl 3) δ 12.08 (s, NH), 6.79 (s, 1H), 6.68 (s, 2H), 3.05 (m, 1H), 1.27 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, CDCl 3) δ 160.92, 150.65, 148.46, 146.69, 134.17, 128.21, 128.02, 113.41, 28.24, 21.16. LRMS:C 13H 13Cl 2N 3O 2[M+H +] m / z = 314. equivalent

[0191] This invention may be practiced in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing specific embodiments should be considered illustrative in all respects and not limiting of the invention described herein. Consequently, the scope of this invention is indicated by the appended claims rather than by the foregoing description, and all variations in the same sense and scope as the claims are intended to be included.

Claims

1. A method comprising contacting a compound of formula (I), its tautomers, or salts: 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), its tautomers, or salts: and contacting a compound of formula (III), its tautomers, or salts: with a second organic solvent and a reducing agent to form a compound of formula (IV), its tautomers, or salts: wherein R1 and R2 are each independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRbRc, -NHS(=O)2Ra, -S(=O)2NRbRc, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRbRc, -OC(=O)NRbRc, -NRbC(=O)NRbRc, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C4-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R1 and R2 together to form cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and as needed via one or more side oxygen groups, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl substitution; each R3 is independently hydrogen, deuterium, halogen, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRbRc, -NHS(=O)2Ra, -S(=O)2NRbRc, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRbRc, -OC(=O)NRbRc, -NRbC(=O)NRbRc, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed substituted with one or more lateral oxygen groups, deuterium, halogens, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl; each Ra is independently C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed substituted with one or more lateral oxygen groups, deuterium, halogens, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 haloalkyl; each Rb is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently, as needed, substituted with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 Haloalkyl substitution; each Rc is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently, as needed, substituted with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -OCH3, -NH2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, or C1-C6 haloalkyl; X-series halogens; and n-series 0, 1, 2, 3, or 4.

2. The method of claim 1, further comprising contacting a compound of formula (IV), its tautomer, or salt with R4CH2C(O)N(R5)C(O)OCH2CH3 to form a compound of formula (V), its tautomer, or salt: , wherein: R4 series: hydrogen, deuterium, halogens, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRbRc, -NHS(=O)2Ra, -S(=O)2NRbRc, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRbRc, -OC(=O)NRbRc -NRbC(=O)NRbRc, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed substituted with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl; and R5 series hydrogen, deuterium, halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRbRc, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted as needed with one or more side oxygen, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl.

3. The method of claim 1, further comprising contacting a compound of formula (III), its tautomer, or salt with R6X to form a compound of formula (III-a), its tautomer, or salt: , wherein: R6 series: -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRbRc, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed substituted with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb. -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl substitution.

4. The method of claim 3, further comprising contacting a compound of formula (III-a), its tautomer or salt, with a second organic solvent and a reducing agent to form a compound of formula (IV-a), its tautomer or salt: .

5. The method of claim 4, further comprising contacting a compound of formula (IV-a), its tautomer, or salt with R4CH2C(O)N(R5)C(O)OCH2CH3 to form a compound of formula (Va), its tautomer, or salt: wherein: R4 series: hydrogen, deuterium, halogens, -CN, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -NO2, -NRbRc, -NHS(=O)2Ra, -S(=O)2NRbRc, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -OC(=O)ORb, -C(=O)NRbRc, -OC(=O)NRbRc -NRbC(=O)NRbRc, -NRbC(=O)Ra, -NRbC(=O)ORb, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently and as needed substituted with one or more side oxygen groups, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl; and R5 series hydrogen, halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRbRc, -C(=O)Ra, -OC(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted as needed with one or more side oxygen, deuterium, halogen, -CN, -OH, -ORa, -NRbRc, -C(=O)Ra, -C(=O)ORb, -C(=O)NRbRc, C1-C6 alkyl, or C1-C6 haloalkyl.

6. As in request item 1, where X is F.

7. As in request item 1, where R3 is Cl.

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

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

10. The method of claim 1, wherein the compound of formula (III) or its tautomers are compounds 1-3, 1-4, 2-2, 3-2, 3-3, 4-2, 5-2, 6-2, or 7-2:

11. The method of claim 1, wherein the compound of formula (IV) or its tautomers 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:

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

13. The method of claim 1, wherein the base comprises KHCO3 or K2CO3.

14. The method of claim 1, wherein the first organic solvent comprises THF.

15. The method of claim 1 or 4, wherein the reducing agent comprises H2 gas and Pd / C, H2 gas and Raney® nickel, H2 gas and platinum oxide (IV), ferrous chloride, or stannous chloride.

16. The method of claim 15, wherein the reducing agent comprises H2 gas and Pd / C.

17. The method of claim 1, wherein contact between the compound of formula (I), its tautomers or salts occurs at room temperature.

18. The method of claim 1, wherein contact of the compound of formula (I), its tautomers or salts occurs at a temperature above room temperature.

19. The method of claim 1 or 4, wherein contact of the compound of formula (III), its tautomers or salts occurs at room temperature.

20. The method of claim 1 or 4, wherein contact with the compound of formula (III), its tautomers or salts occurs above room temperature.

21. The method of claim 2, wherein the compound of formula (V) is 2-(3,5-dichloro-4-((5-isopropyl-6-sideoxy-1,6-dihydro-3-yl)oxy)phenyl)-3,5-sideoxy-2,3,4,5-tetrahydro-1,2,4-tri-6-carboxynitrile (MGL-3196).

22. The method of claim 4, wherein the second organic solvent comprises DMF, DMAC, DMSO, acetonitrile, THF, DCM, diacetone, or acetone.

23. A compound having the following structures: , , , , , , , , , , , , , , or.

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