Thyroid hormone receptor beta agonist compounds

Abstract

Provided herein are compounds, preferably thyroid hormone receptor beta, THRbeta, agonist compounds, compositions thereof, and methods of making the same, and methods of agonizing THRbeta, and methods for treating conditions mediated by THRbeta.

Description

[0001] Cross-referencing of related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 722,312, filed August 24, 2018, and U.S. Provisional Application No. 62 / 867,117, filed June 26, 2019, the disclosures of each of which are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This invention relates to compounds, preferably thyroxine receptor β (THRβ) agonist compounds, compositions thereof, methods for their preparation, methods for agonizing THRβ, and methods for treating THRβ-mediated conditions. Background Technology

[0004] The beneficial effects of using self-derived T3 / T4 endogenous ligands or analogues of these endogenous ligands to treat hyperthyroidism or hypothyroidism have been described in the references (Richardson Hill Jr., S. et al., *Journal of Clinical Investigation*, 1960, 39, 523-533). These early studies and similar follow-up studies established the heart as the primary organ for assessing the side effects of both hyperthyroidism and hypothyroidism (Klein, I. et al., *Circulation*, 2007, 1725-1735). Specifically, tachycardia, hypertrophy, arrhythmias, and atrial fibrillation are serious problems. Additionally, increased bone turnover leading to decreased bone mineral density has also been noted. Negative effects in the heart and bones have been associated with the activating effect of the THRα isoform, while the beneficial effect of the THR activating effect in the liver is largely associated with the THRβ isoform (Sinha, RA et al., *Nature Review: Endocrinology*, 2018, 14, 259-269).

[0005] Diseases or conditions associated with THRβ include nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. There is a need for thyroid hormone analogs, such as those that act as THRβ agonists, and preferably those that avoid the unwanted effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones, for example, for the treatment of patients with nonalcoholic steatohepatitis (NASH). Specifically, there is a need to develop novel thyroid hormone analogs that are selective agonists of THRβ, and preferably those that avoid the unwanted effects associated with the agonist effect of THRα while maintaining the beneficial effects of thyroid hormones, for example, for the treatment of patients with nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia. Summary of the Invention

[0006] In one aspect, this document provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] Ring A together with the carbonyl (ketone) group within the ring forms a 5-membered heterocycle containing 1 to 3 cyclic heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted with 1 to 2 C1-C3 alkyl or C3-C4 cycloalkyl groups, and wherein the carbonyl (ketone) group is not adjacent to the atom bonded to X.

[0010] R 1 C1-C4 alkyl, C3-C5 cycloalkyl, CON(R) groups optionally substituted with 1 to 5 halogenated or hydroxyl groups are used. 10 )2 or NR 10 COR 10 ;

[0011] R 2 It is H or C1-C3 alkyl;

[0012] L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 CN, CHR 11 or C(R) 11 )R 11 ;

[0013] R 3 and R 4 Independently, it can be Cl, Br, methyl, or ethyl;

[0014] R 5 It can be H, a halogen, a C1-C4 alkyl group, or a C3-C4 cycloalkyl group;

[0015] Or R 5 With R 4 Together with intercalated atoms, they form 5 to 7-membered cycloalkyl groups or 5 to 7-membered heterocycles containing 1 to 2 cyclic heteroatoms;

[0016] X represents non-existent, O, or NR. 12 C(O)NR 12 NR 12 C(O), CR 12 R 12 OCR 12 R 12 CR 12 R 12 O, NR 12 CR 12 R 12 CR 12 R 12 NR 12 SO2NR 12 or NR 12 SO2;

[0017] Each R 10 Independently, it is a C1-C3 alkyl group or H;

[0018] Each R 11 Independently, it is a C1-C2 alkyl group optionally substituted with 1 to 5 halogen groups.

[0019] Or two Rs 11 The groups, together with the carbon atoms they bond to, form cyclopropyl or cyclobutyl rings; and

[0020] Each R 12 It can be H or methyl on its own.

[0021] In some embodiments, the compound is a compound of formula (IIA) or (IIB):

[0022]

[0023] Where R 1 R 2 R 3 R 4 R 5 X and L are defined as for compounds of formula (I).

[0024] In some embodiments, the compound is a compound of formula (VD):

[0025]

[0026] Where R 1 R 2 R 3 R 4 and R 5 As defined in claim 1.

[0027] In some embodiments, R 1 It is a C1-C4 alkyl group, or a C3-C5 cycloalkyl group, optionally substituted with one or two halogen or hydroxyl groups. In some embodiments, R 1 It is isopropyl, tert-butyl, HO-CH(CH3)-, HO-CH(CH2CH3)-, HO-C(CH3)2-, HO-CH2CH(CH3)-, cyclopropyl or

[0028] In some embodiments, R 2 It can be H or -CH3.

[0029] In some embodiments, R 3 It is chlorine or -CH3.

[0030] In some embodiments, R 4 It is chlorine or -CH3; or R 5 With R 4 Together with intercalated atoms, they form 5 to 6-membered cycloalkyl groups. In some embodiments, R 5 With R 4 Together with intercalated atoms, they form a cyclopentyl group. In some embodiments, R 5 It is H or fluorine.

[0031] In some embodiments, X is a key. In some embodiments, X is an NR. 12 C(O), OCR 12 R 12 or NR 12 CR 12 R 12 ; and each R 12 Independently, it is H or methyl. In some embodiments, X is -OCH2-, -NHCH2-, -NHC(O)-, -N(CH3)CH2-, or -N(H)CH(CH3)-.

[0032] In some embodiments, L is O, CH2, SO2, CO, or CHR. 11 or C(R) 11 )R 11 ; and each R 11 It is independently methyl or ethyl. In some embodiments, L is O, CH2, SO2, or CO.

[0033] In some embodiments, this document provides compounds selected from those in Table 1, or pharmaceutically acceptable salts thereof.

[0034] In one aspect, this document provides a pharmaceutical composition comprising the compounds provided herein and at least one pharmaceutically acceptable excipient.

[0035] In one aspect, this document provides a method for contacting thyrotropin receptor β (THRβ), comprising contacting said THRβ with an effective amount of a compound or a pharmaceutical composition provided herein.

[0036] In one aspect, this document provides a method for treating a patient with a THRβ-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In some embodiments, the condition is nonalcoholic steatohepatitis (NASH). Detailed Implementation

[0037] definition

[0038] As used herein, unless otherwise indicated herein, the following definitions shall apply. Furthermore, if any term or symbol used herein is not defined as set forth below, it shall have its general meaning in the relevant technical field.

[0039] The word "comprising" is intended to mean that a composition or method includes the elements listed herein, but does not exclude other elements. When "consisting substantially of" is used to define a composition or method, it should mean the exclusion of other elements that are of any significant importance to the composition. For example, a composition consisting substantially of elements as defined herein should not exclude other elements that do not substantially affect the fundamental and novel features of the invention claimed herein. "Constitutes" should mean the exclusion of other ingredients and substantial method steps beyond trace amounts (e.g.) listed herein. Examples defined by each of these transitional terms are within the scope of the invention.

[0040] The “effective amount” or dose of a compound or composition refers to the amount of the compound or composition that, based on the disclosure herein, optionally leads to the desired result. The effective amount can be determined in cell cultures or laboratory animals using standard pharmaceutical procedures, such as (but not limited to) determining the LD50. 50 (The dose that would cause death in 50% of the population) and ED 50 (The effective dose in 50% of the population).

[0041] As used herein, the term "excipient" means an inert or inactive substance that can be used to produce a drug or pharmaceutical product (e.g., a tablet containing a compound of the present invention as an active ingredient). The term "excipient" can include a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or emulsion, lubricant, solution for non-enteral administration, material for chewable tablets, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Adhesives include, for example, carbomer, polyvinylpyrrolidone, xanthan gum, etc.; coatings include, for example, cellulose phthalate acetate, ethyl cellulose, gellan gum, maltodextrin, enteric coating, etc.; compression / encapsulation aids include, for example, calcium carbonate, glucose, fructose DC (DC = "directly compressible"), honey DC, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose or microcrystalline cellulose), starch DC, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, starch hydroxyacetic acid, etc. Sodium, etc.; creams or emulsions including (e.g.) maltodextrin, carrageenan, etc.; lubricants including (e.g.) magnesium stearate, stearic acid, sodium stearate fumarate, etc.; materials for chewable tablets including (e.g.) glucose, fructose DC, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents including (e.g.) carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners including (e.g.) aspartame, glucose, fructose DC, sorbitol, sucrose DC, etc.; and wet granulation agents including (e.g.) calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0042] "Patient" refers to a mammal, including both humans and non-human mammals. Examples of patients include (but are not limited to) mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to humans.

[0043] "Pharmaceutical acceptable" means safe and non-toxic, preferably for use in vivo, and more preferably for human administration.

[0044] "Pharmaceutically acceptable salt" refers to a salt that is pharmaceutically acceptable. The compounds described in this article can be administered as pharmaceutically acceptable salts.

[0045] A "prodrug" is a compound that, upon administration, is metabolized or otherwise converted into a biologically active compound (or drug) or a compound with at least one more active property. A prodrug is chemically modified in a way that reduces or eliminates its activity relative to the drug, but such modification results in the production of the corresponding drug through metabolism or other biological processes upon administration. Compared to the active drug, a prodrug may have altered metabolic stability or transport properties, fewer side effects or lower toxicity, or improved flavor (e.g., see reference Nogrady, 1985, *Medicinal Chemistry: A Biochemical Approach*, Oxford University Press, New York, pp. 388–392, incorporated herein by reference). Prodrugs can be synthesized from reactants, in addition to using the corresponding drug. For the purposes of illustration and not limitation, prodrugs include carboxylic acid esters, linear and cyclic phosphate esters and phosphoramides and amino phosphate esters, carbamates, preferably phenolic carbamates (i.e., carbamates in which the hydroxyl group is part of an aryl or heteroaryl moiety, wherein the aryl and heteroaryl moiety may optionally be substituted), etc.

[0046] “Salt” refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain acidic functional groups, these salts include (but are not limited to) alkali metals, alkaline earth metals, and ammonium salts. As used herein, ammonium salts include salts containing protonated nitrogen groups and alkyl nitrogen groups. Exemplary and non-limiting cations suitable for pharmaceutically acceptable salts based on naturally occurring amino acids include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations. When the compounds used herein contain basic functional groups, these salts include (but are not limited to) salts of organic acids (e.g., carboxylic acids and sulfonic acids) and inorganic acids (e.g., hydrogen halides, sulfuric acid, phosphoric acid), etc. Exemplary and non-limiting anions suitable for pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, hydrogen sulfate, monovalent, divalent, and trivalent phosphates, methanesulfonate, toluenesulfonate, etc.

[0047] The "therapeutic effective amount" or dose of a compound or composition refers to the amount of the compound or composition that reduces or inhibits symptoms or prolongs the survival of a patient. This result may require multiple doses of the compound or composition.

[0048] In the context of this invention, “treatment” refers to 1) preventing the disease from occurring in patients who are susceptible to the disease or who have not yet shown symptoms of the disease; 2) suppressing the disease or preventing its progression; or 3) improving the disease or causing its remission. As used herein, “treatment” is a method for achieving a favorable or desired outcome (including clinical outcomes). For the purposes of this invention, favorable or desired outcomes include (but are not limited to) one or more of the following: reducing one or more symptoms arising from the disease or condition; gradually reducing the severity of the disease or condition; stabilizing the disease or condition (e.g., preventing or delaying the worsening of the disease or condition); delaying the onset or recurrence of the disease or condition; delaying or slowing the progression of the disease or condition; improving the state of the disease or condition; providing relief from the disease or condition (whether partial or complete); reducing the dosage of one or more other drugs required to treat the disease or condition; enhancing the effect of another drug used to treat the disease or condition; delaying the progression of the disease or condition; increasing the patient's quality of life; and / or prolonging the patient's survival. "Treatment" also includes the reduction of the pathological consequences of the said disease or condition. The method of the present invention is intended to treat any one or more of these aspects.

[0049] An "isotope isomer" of a compound is a compound in which one or more atoms of the compound have been replaced by isotopic substitutions of those same atoms. For example, where H has been replaced by D or T, or 12 C has 11 C substitution or 14 N has 15 Nitrogen substitution. For example (but not limited to), D substitution can lead to a decrease in metabolic rate and thus a prolonged half-life in some instances. T substitution for H can provide radioligands suitable for binding studies. Short-lived isotopes. 11 C replacement 12 C can provide ligands suitable for positron emission tomography (PET) scans. 15 N displacement 14 N provides access via 15 Compounds detected / monitored by NNMR spectroscopy. For example, an isotopic isomer of the compound containing -CH2CH3, but containing -CD2CD3 instead of -CH2CH3.

[0050] Unless a specific isotope of an element is indicated in the formula, this invention includes all isotopic forms of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (where H may be...). 2H, i.e., D). Isotopes may have isotopic substitutions at any or all positions in the structure, or may have atoms present in natural abundance at any or all positions in the structure.

[0051] "Stereoisomers" refer to compounds in which the constituent atoms differ in stereoisomeric origin (e.g., but not limited to, in terms of chirality of one or more stereocenters) or are associated with the cis or trans configuration of carbon-carbon or carbon-nitrogen double bonds. Stereoisomers include enantiomers and diastereomers.

[0052] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol-ketone and imine-enamine tautomers, or heteroaryl tautomers containing ring atoms bound to the ring-NH- and ring=N- moieties, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles.

[0053] "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. For example, the term includes straight-chain or branched-chain hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). x Alkyl refers to an alkyl group having x carbon atoms.

[0054] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least 1 to 2 vinyl (>C=C<) unsaturated sites. These groups are exemplified, for example, by vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers. x Alkenyl refers to an alkenyl group having x carbon atoms.

[0055] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1 to 2 alkynyl (-C≡C-) unsaturated sites. Examples of such alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH). x The alkynyl group refers to an alkynyl group having x carbon atoms.

[0056] "Substituted alkyl" refers to an alkyl group having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclic. Amino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0057] "Substituted alkenyl" refers to an alkenyl group having 1 to 3 substituents selected from the group consisting of, and preferably 1 to 2 substituents: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocycloalkylamino, carboxyl, carboxyl ester, (carboxyl ester)amino. (Carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamine, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein and provided that any hydroxyl or thiol substitution is not bonded to a vinyl (unsaturated) carbon atom.

[0058] "Substituted alkynyl" refers to an alkynyl group having 1 to 3 substituents selected from the group consisting of, and preferably 1 to 2 substituents: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocycloalkylamino, carboxyl, carboxyl ester, (carboxyl ester) The following groups are included: amino, (carboxylate)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein and provided that any hydroxyl or thiol substitution does not bind to an alkyne carbon atom.

[0059] "Alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined herein. For example, alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, and n-pentoxy.

[0060] "Substituted alkoxy" refers to the group -O- (substituted alkyl), wherein the substituted alkyl is as defined herein. Preferred substituted alkyl groups in -O- (substituted alkyl) include halogenated alkyl and, more specifically, halogenated methyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0061] “Acyl” refers to the group HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl groups include "acetyl" CH3C(O)-.

[0062] "Acylamine group" refers to the -NR group. 30 C(O)alkyl, -NR 30 C(O) substituted alkyl group, -NR 30 C(O)cycloalkyl, -NR 30 C(O) substituted cycloalkyl, -NR 30 C(O) alkenyl, -NR 30 C(O) substituted alkenyl, alkoxy, substituted alkoxy-NR 30 C(O) ynyl group, -NR 30 C(O) substituted alkynyl group, -NR 30 C(O) aryl, -NR 30 C(O) substituted aryl, -NR 30 C(O) heteroaryl, -NR 30 C(O) substituted heteroaryl, -NR 30 C(O) heterocycles and -NR 30 C(O) substituted heterocyclic ring, wherein R 30 The alkyl group is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl; and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

[0063] “Acyloxy” refers to the group alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0064] "Amine group" refers to the -NH2 group.

[0065] "Substituted amino group" refers to the -NR group. 31 R 32 , where R 31 and R 32 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, arylamine, substituted arylamine, heteroarylamine, substituted heteroarylamine, cycloalkylamine, substituted cycloalkylamine, heterocycloalkylamine, substituted heterocycloalkylamine, sulfonylamine and substituted sulfonyl, wherein R 31 and R 32 The nitrogen atoms that are optionally bonded to them are linked together to form heterocycles or substituted heterocycle groups, provided that R is present. 31 and R 32 Neither of them is hydrogen, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. When R 31 It is hydrogen and R 32 When R is alkyl, the substituted amino group is sometimes referred to herein as an alkylamino group. 31 and R 32 When the amino group is alkyl, the substituted amino group is sometimes referred to as dialkylamino group in this text. When referring to a monosubstituted amino group, it means R 31 Or R 32 It consists of hydrogen, but not both groups are hydrogen. When referring to a disubstituted amino group, it means R 31 Or R 32 Neither of them is hydrogen.

[0066] "Aminocarbonyl" refers to the group -C(O)NR 33 R 34 , where R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0067] "Aminothiocarbonyl" refers to the group -C(S)NR 33 R 34 , where R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0068] "aminocarbonylamino" refers to the -NR group. 30 C(O)NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0069] "aminothiocarbonylamino" refers to the -NR group. 30 C(S)NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0070] "Aminocarbonyloxy group" refers to the group -OC(O)NR 33 R 34 , where R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0071] "Aminosulfonyl" refers to the group -SO2NR 33 R34 , where R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0072] "Aminosulfonyloxy" refers to the group -O-SO2NR 33 R 34 , where R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0073] "Aminosulfonylamino group" refers to the -NR group. 30 -SO2NR 33 R 34 , where R 30 It is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or substituted cycloalkyl, and R 33 and R 34 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0074] "Amino group" refers to the group -C (=NR) 35 )NR 33 R 34 , where R 33 R 34 and R 35 The group is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle, wherein R 33 and R 34 The nitrogen atoms optionally bonded to them are linked together to form heterocycles or substituted heterocyclic groups, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0075] "Arl" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms, which has a single ring (e.g., phenyl(Ph)) or multiple fused rings (e.g., naphthyl or anthracene), the fused rings of which may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.), provided that the bonding site is located at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0076] "Substituted aryl" refers to an aryl group selected from 1 to 5 of the group consisting of, preferably 1 to 3, or more preferably 1 to 2 substituents: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamine The substituents are: alkyl, heterocyclic alkylamine, substituted heterocyclic alkylamine, carboxyl, carboxyl ester, (carboxyl ester)amine, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclic alkyl, substituted heterocyclic alkylthio, heterocyclic alkylthio, substituted heterocyclic alkylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, sulfonylamine, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0077] "Aryloxy group" refers to the -O-aryl group, where aryl groups are defined herein, and for example, include phenoxy and naphthoxy groups.

[0078] "Substituted aryl group" refers to the group -O- (substituted aryl), where the substituted aryl group is as defined herein.

[0079] "Arylthio" refers to the group -S-aryl, where aryl is as defined in this article.

[0080] "Substituted arylthio" refers to the group -S- (substituted aryl), where the substituted aryl group is as defined herein.

[0081] "Arylamine group" refers to the -NR group. 37 (aryl), where aryl is as defined in this paper and R 37 It is hydrogen, alkyl, or substituted alkyl.

[0082] "Substituted arylamine group" refers to the -NR group. 37 (Substituted aryl), where R 37 It is hydrogen, alkyl, or substituted alkyl, wherein the substituted aryl group is as defined herein.

[0083] "Carbonyl" refers to the divalent group -C(O)-, which is equivalent to -C(=O)-.

[0084] "Carboxyl group" refers to -COOH or its salt.

[0085] "Carboxylic ester" or "carboxylic acid ester" refers to the group -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-ynyl, -C(O)O-substituted alkenyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic and -C(O)O-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0086] "(Carboxylate)amine group" refers to the -NR group. 30 -C(O)O-alkyl, -NR 30 -C(O)O-substituted alkyl group, -NR 30 -C(O)O-alkenyl, -NR 30 -C(O)O- substituted alkenyl groups, -NR 30 -C(O)O-alkynyl group, -NR 30 -C(O)O- substituted alkynyl group, -NR 30 -C(O)O-aryl, -NR 30 -C(O)O-substituted aryl, -NR 30 -C(O)O-cycloalkyl, -NR 30 -C(O)O-substituted cycloalkyl, -NR 30 -C(O)O-heteroaryl, -NR 30 -C(O)O-substituted heteroaryl, -NR 30 -C(O)O- heterocycles and -NR 30 -C(O)O- substituted heterocyclic ring, where R 30 It is an alkyl or hydrogen, and wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle are as defined herein.

[0087] "(Carboxyl ester)oxy" refers to the group -OC(O)O-alkyl, -OC(O)O-substituted alkyl, -OC(O)O-alkenyl, -OC(O)O-substituted alkenyl, -OC(O)O-ynyl, -OC(O)O-substituted alkenyl, -OC(O)O-aryl, -OC(O)O-substituted aryl, -OC(O)O-cycloalkyl, -OC(O)O-substituted cycloalkyl, -OC(O)O-heteroaryl, -OC(O)-substituted heteroaryl, -OC(O)O-heterocyclic and -OC(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0088] "Cyano" refers to the group -C≡N.

[0089] "Cycloalkyl" refers to saturated or unsaturated but non-aromatic cycloalkyl groups having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, having monocyclic or polycyclic rings, including fused, bridged, and spirocyclic systems. x A cycloalkyl group refers to a cycloalkyl group having x number of cyclic carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more rings may be aryl, heteroaryl, or heterocyclic, provided that the bonding site is through a non-aromatic, non-heterocyclic saturated carbon ring. "Substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5, preferably 1 to 3, substituents selected from the group consisting of: oxo, thion, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidine, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl) The substituents are ester, amino, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidinyl, substituted guanidinyl, halogen, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclicoxy, substituted heterocyclicoxy, heterocyclicthio, substituted heterocyclicthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

[0090] “Cycloalkoxy” refers to -O-cycloalkyl.

[0091] "Substituted cycloalkoxy" refers to -O- (substituted cycloalkyl).

[0092] "Cycloalkylamine" refers to the -NR group. 37 (cycloalkyl), where R 37 It is hydrogen, alkyl, or substituted alkyl.

[0093] "Substituted cycloalkylamine group" refers to the -NR group. 37 (substituted cycloalkyl), wherein R 37 Hydrogen, alkyl or substituted alkyl and substituted cycloalkyl as defined herein.

[0094] “Cycloalkylthio” refers to -S-cycloalkyl.

[0095] "Substituted cycloalkyl thio" refers to -S- (substituted cycloalkyl).

[0096] "Guidinyl" refers to the group -NHC(=NH)NH2.

[0097] "Substituted guanidine group" refers to -NR 36 C(=NR 36 )N(R 36 )2, where each R 36 The group consisting of two R atoms independently chosen from the group consisting of: hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle bonded to a common guanidinium atom. 36 The groups are optionally linked to the nitrogen atoms to form heterocycles or substituted heterocycles, provided that at least one R group is present. 36 It is not hydrogen, and the substituents therein are as defined herein.

[0098] "Halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine, with fluorine or chlorine being preferred.

[0099] "Hydroxy group" refers to the -OH group.

[0100] "Zehnderm" refers to one or more carbon atoms that have undergone the following reactions: -O-, -S-, SO2, -NR-. Q -、 or Partially substituted alkyl groups, wherein R Q It is an H or C1-C6 alkyl group. "Substituted azayl group" refers to an azaylynyl group having 1 to 3 substituents (and preferably 1 to 2 substituents) selected from the substituents disclosed for the substituted azayl group.

[0101] "Heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. These heteroaryls may have a monocyclic ring (e.g., pyridyl or furanyl) or multiple fused rings (e.g., indoleazinyl or benzothiopheneyl), wherein the fused rings may be aromatic or non-aromatic and / or contain heteroatoms, provided that the bonding site is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5- or 6-membered heteroaryls, such as pyridyl, pyrroleyl, thiopheneyl, and furanyl. Other preferred heteroaryls include 9- or 10-membered heteroaryls, such as indoleyl, quinolinyl, quinolinoneyl, isoquinolinyl, and isoquinolinoneyl.

[0102] "Substituted heteroaryl" refers to a heteroaryl group selected from 1 to 5 of the same group of substituents as defined for substituted aryl, preferably 1 to 3, or more preferably substituted by 1 to 2 substituents.

[0103] "Heteroaryloxy" refers to -O-heteroaryl.

[0104] "Substituted heteroaryl group" refers to the group -O- (substituted heteroaryl group).

[0105] "Heteroarylthio" refers to the -S-heteroaryl group.

[0106] "Substituted heteroarylthio" refers to the group -S- (substituted heteroaryl).

[0107] "Heteroarylamine" refers to the -NR group. 37 (Heteroarylene), of which R 37 It is hydrogen, alkyl, or substituted alkyl.

[0108] "Substituted heteroarylamine group" refers to the -NR group. 37 (Substituted heteroaryl), where R 37 Hydrogen, alkyl or substituted alkyl and substituted heteroaryl as defined herein.

[0109] "Heterocycle" or "heterocyclic" or "heterocyclic alkyl" or "heterocyclyl" refers to a saturated or partially saturated, but non-aromatic, group having 1 to 10 cyclic carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms, and 1 to 4 cyclic heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen, preferably 1 to 3 heteroatoms, and more preferably 1 to 2 heteroatoms. C xHeterocyclic alkyl refers to a heterocyclic alkyl group having x number of ring atoms (including cyclic heteroatoms). Heterocyclic rings comprise monocyclic or multiple fused rings, including fused, bridged, and spirocyclic systems. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided that the bonding site is through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, sulfinyl, or sulfonyl moiety.

[0110] "Heterocyclic group" refers to a divalent saturated or partially saturated, but non-aromatic group, having 1 to 10 cyclic carbon atoms and 1 to 4 cyclic heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. "Substituted heterocyclic group" refers to a heterocyclic group substituted with 1 to 5, or preferably 1 to 3, of the same substituents as defined for substituted cycloalkyl groups.

[0111] "Substituted heterocycle" or "substituted heterocyclic alkyl" or "substituted heterocyclic group" refers to a heterocyclic group substituted with 1 to 5, or preferably 1 to 3, of the same substituents as defined for substituted cycloalkyl.

[0112] "Heterocyclic group" refers to the -O-heterocyclic group.

[0113] "Substituted heterocyclic group" refers to the group -O- (substituted heterocyclic group).

[0114] "Heterocyclic thio group" refers to the -S-heterocyclic group.

[0115] "Substituted heterocyclic thio group" refers to the group -S- (substituted heterocyclic group).

[0116] "Heterocyclic amino group" refers to the -NR group. 37 (heterocyclic group), where R 37 It is hydrogen, alkyl, or substituted alkyl.

[0117] "Substituted heterocyclic amino group" refers to the -NR group. 37 (Substituted heterocyclic group), where R 37 Hydrogen, alkyl or substituted alkyl and substituted heterocyclic groups as defined herein.

[0118] Examples of heterocyclic and heteroaryl groups include (but are not limited to) aza-butyl, pyrroloyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indoleyl, isoindoleyl, indoleyl, dihydroindoleyl, indazoleyl, purineyl, quinolinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, cenyl, pteridinyl, carbazoleyl, carbolinyl, phenanthridineyl, acridineyl, phenanthiazolyl, isothiazolyl, phenazinyl. Isoxazolyl, phenoxazinyl, phenthiazinyl, imidazodinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimide, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, thiazolyl, thiazolyl, thiophenyl, benzo[b]thiophenyl, morpholinyl, thiomorpholinyl (also known as thiomorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

[0119] "Nitro" refers to the group -NO2.

[0120] "O-group" refers to an atom (=O) or (O).

[0121] "Spiral ring system" refers to a bicyclic system that has a single ring carbon atom shared by the two rings.

[0122] "Sulinate" refers to the divalent group -S(O)- or -S(=O)-.

[0123] "Sulfoyl" refers to the divalent group -S(O)2- or -S(=O)2-.

[0124] "Substituted sulfonyl" refers to groups such as -SO2-alkyl, -SO2-substituted alkyl, -SO2-OH, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cycloalkyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl groups include, for example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2- groups. Preferred substituted alkyl groups on the -SO2- substituted alkyl group include halogenated alkyl groups and, more specifically, halogenated methyl groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0125] "Substituted sulfinyl" refers to the groups -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cycloalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocyclic, -SO-substituted heterocyclic, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfinyl groups include, for example, methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on substituted alkyl-SO- include halogenated alkyl groups and, more specifically, halogenated methyl groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0126] "Sulfooxy" or "substituted sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-OH, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cycloalkyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0127] "Sulfonylamine group" refers to the -NR group. 37 (Substituted sulfonyl group), where R 37 It is hydrogen, alkyl or substituted alkyl and substituted sulfonyl as defined herein.

[0128] "Thioacyl" refers to the group HC(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0129] "Mercapto" or "thiol" refers to the -SH group.

[0130] "Formyl group" refers to the group -C(O)H.

[0131] "Thiocarbonyl" refers to the divalent group -C(S)-, which is equivalent to -C(=S)-.

[0132] "Thione" refers to the atom (=S).

[0133] "alkylthio" refers to the -S-alkyl group, where alkyl is as defined in this article.

[0134] "Substituted alkyl thio" refers to the group -S- (substituted alkyl), wherein the substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S- (substituted alkyl) include halogenated alkyl groups and, more specifically, halogenated methyl groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, etc.

[0135] "Vinyl" refers to the unsaturated hydrocarbon group -CH=CH2 derived from ethylene.

[0136] As used throughout this specification, the terms "optional" or "optionally" mean that the events or conditions described below may occur but are not necessarily to occur, and the description includes instances where said events or conditions occur and instances where said events or conditions do not occur. For example, "nitrogen atoms are optionally oxidized to provide an N-oxide (N→O) moiety" means that said nitrogen atoms may be oxidized but are not necessarily oxidized, and the description includes cases where said nitrogen atoms are not oxidized and cases where said nitrogen atoms are oxidized.

[0137] The term "optionally substituted" refers to a substituted or unsubstituted group. The substituted group may be substituted with one or more substituents, for example, 1, 2, 3, 4, or 5 substituents. Preferably, the substituents are selected from the functional groups provided herein. In some more preferred embodiments, the substituents are selected from oxo groups, halogen groups, -CN, NO2, and -CO2R. 100 -OR 100 -SR 100 -SOR 100 -SO2R 100 -NR 101 R 102 -CONR 101 R 102 -SO2NR 101 R 102 C1-C6 alkyl, C1-C6 alkoxy, -CR 100 =C(R) 100 )2、-CCR 100 C3-C 10 cycloalkyl, C4-C 10 Heterocyclic group, C6-C14 Aryl and C5-C 12 heteroaryl, wherein each R 100 Independently hydrogen or C1-C8 alkyl; C3-C 12 cycloalkyl; C4-C 10 Heterocyclic group; C6-C 14 Aryl; or C2-C 12 Heteroaryl; wherein each alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with 1 to 3 halogroups, 1 to 3 C1-C6 alkyl groups, 1 to 3 C1-C6 haloalkyl groups, or 1 to 3 C1-C6 alkoxy groups. More preferably, the substituents are selected from the group consisting of: chlorine, fluorine, -OCH3, methyl, ethyl, isopropyl, cyclopropyl, -OCF3, -CF3, and -OCHF2.

[0138] R 101 and R 102 Independently hydrogen; optionally substituted with -CO2H or its esters, C1-C8 alkyl, C1-C6 alkoxy, oxo, -CR 103 =C(R) 103 )2、-CCR、C3-C 10 cycloalkyl, C3-C 10 Heterocyclic group, C6-C 14 Aryl or C2-C 12 heteroaryl, wherein each R 103 Independently hydrogen or C1-C8 alkyl; C3-C 12 cycloalkyl; C4-C 10 Heterocyclic group; C6-C 14 Aryl; or C2-C 12 Heteroaryl; wherein each cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with 1 to 3 alkyl groups or 1 to 3 halogen groups, or R 101 and R 102 Together with the nitrogen atoms they bind with, they form 5 to 7-membered heterocycles.

[0139] Unless otherwise indicated herein, nomenclature for substituents not explicitly defined herein is achieved by naming the terminal portion of the functional group, followed by the adjacent functional group at the point of contact. For example, the substituent “alkoxycarbonylalkyl” refers to the group (alkoxy)-C(O)-(alkyl)-.

[0140] It should be understood that polymers defined by substituents in all the substituted groups as defined above (e.g., substituted aryl groups having substituted aryl groups as substituents, which themselves are substituted aryl groups, etc.) are not intended to be included herein. In these cases, the maximum number of such substituents is three. That is, each of the above definitions is subject to the following limitations, for example, substituted aryl is limited to -substituted aryl - (substituted aryl) - substituted aryl.

[0141] It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., substituted methyl groups with four fluoro groups). These unacceptable substitution patterns are well known to skilled technicians.

[0142] It should be understood that, for clarity, certain features of the invention described in the text of a single embodiment may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the text of a single embodiment may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups represented by variables are expressly included in the invention and disclosed herein as if each combination and each such combination were individually and expressly disclosed herein to the extent that these combinations comprise compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all sub-combinations of chemical groups listed in the embodiments describing these variables are also expressly included in the invention and disclosed herein as if each chemical group and each such sub-combination were individually and expressly disclosed herein.

[0143] compound

[0144] In one aspect, this paper provides compounds of formula (I):

[0145]

[0146] Or its tautomers or N-oxides, or isotopic isomers of each of them, or prodrugs of each of the above, or stereoisomers of the above, or pharmaceutically acceptable salts of each of the foregoing, or solvates of each of the foregoing, wherein:

[0147] Ring A together with the carbonyl (ketone) group within the ring forms a 5-membered heterocycle containing 1 to 3 cyclic heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted by 1 to 2 substituents selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl, and wherein the carbonyl (ketone) group is not adjacent to the atom bonded to X.

[0148] R 1 It is a C1-C4 alkyl group; optionally substituted with 1 to 5 halogen groups (preferably fluorine) or hydroxyl groups; C3-C5 cycloalkyl group, CON(R)10 )2 or NR 10 COR 10 , where each R 10 Independently, it is a C1-C3 alkyl group or H;

[0149] R 2 It is H or C1-C3 alkyl;

[0150] L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 CN (e.g., C(Me)CN), CHR 11 or C(R) 11 )R 11 , where each R 11 C1-C2 alkyl groups optionally substituted with 1 to 5 halogen groups (preferably fluorine), or 2 R groups. 11 The groups, together with the carbon atoms they bond to, form cyclopropyl or cyclobutyl rings;

[0151] R 3 and R 4 Each of these is independently Cl, Br, Me, or an ethyl group;

[0152] R 5 It is H, a halogen, a C1-C4 alkyl group (preferably CH3) or a C3-C4 cycloalkyl group, or R. 5 With R 4 Together with intercalated atoms, they form 5- to 7-membered cycloalkyl groups or 5- to 7-membered heterocycles containing 1 to 2 cyclic heteroatoms; and

[0153] X is non-existent (i.e., X is a key), or is 0 or NR. 12 C(O)NR 12 NR 12 C(O), CR 12 R 12 OCR 12 R 12 CR 12 R 12 O, NR 12 CR 12 R 12 CR 12 R 12 NR 12 SO2NR 12 or NR 12 SO2, where each R 12 It can be H or methyl on its own.

[0154] In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt.

[0155] In one embodiment, the compound of formula (I) is a compound of formula (IIA):

[0156]

[0157] The variables are defined as shown in equation (I).

[0158] In one embodiment, the compound of formula (I) is a compound of formula (IIB):

[0159]

[0160] The variables are defined as shown in equation (I).

[0161] In one embodiment, the compound of formula (I) is a compound of formula (IIIA).

[0162]

[0163] The variables are defined as shown in equation (I).

[0164] In one embodiment, the compound of formula (I) is a compound of formula (IIIB):

[0165]

[0166] The variables are defined as shown in equation (I).

[0167] In one embodiment, the compound of formula (I) is a compound of formula (IIIC):

[0168]

[0169] The variables are defined as shown in equation (I).

[0170] In one embodiment, the compound of formula (I) is a compound of formula (IIID):

[0171]

[0172] The variables are defined as shown in equation (I).

[0173] In one embodiment, the compound of formula (I) is a compound of formula (IVA):

[0174]

[0175] The variables are defined as shown in equation (I).

[0176] In one embodiment, the compound of formula (I) is a compound of formula (IVB):

[0177]

[0178] The variables are defined as shown in equation (I).

[0179] In one embodiment, the compound of formula (I) is a compound of formula (IVC):

[0180]

[0181] The variables are defined as shown in equation (I).

[0182] In one embodiment, the compound of formula (I) is a compound of formula (IVD):

[0183]

[0184] The variables are defined as shown in equation (I).

[0185] In one embodiment, the compound of formula (I) is a compound of formula (VA):

[0186]

[0187] The variables are defined as shown in equation (I).

[0188] In one embodiment, the compound of formula (I) is a compound of formula (VB):

[0189]

[0190] The variables are defined as shown in equation (I).

[0191] In one embodiment, the compound of formula (I) is a compound of formula (VC):

[0192]

[0193] The variables are defined as shown in equation (I).

[0194] In one embodiment, the compound of formula (I) is a compound of formula (VD):

[0195]

[0196] The variables are defined as shown in equation (I).

[0197] In one embodiment, the compound of formula (I) is a compound of formula (VIA):

[0198]

[0199] The variables are defined as shown in equation (I).

[0200] In one embodiment, the compound of formula (I) is a compound of formula (VIB):

[0201]

[0202] The variables are defined as shown in equation (I).

[0203] In one embodiment, the compound of formula (I) is a compound of formula (VIC):

[0204]

[0205] The variables are defined as shown in equation (I).

[0206] In one embodiment, the compound of formula (I) is a compound of formula (VID):

[0207]

[0208] The variables are defined as shown in equation (I).

[0209] In one embodiment, the compound of formula (I) is a compound of formula (VIIA):

[0210]

[0211] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0212] In one embodiment, the compound of formula (I) is a compound of formula (VIIB):

[0213]

[0214] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0215] In one embodiment, the compound of formula (I) is a compound of formula (VIIC):

[0216]

[0217] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0218] In one embodiment, the compound of formula (I) is the compound of formula (VIID):

[0219]

[0220] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0221] In one embodiment, the compound of formula (I) is a compound of formula (VIIIA):

[0222]

[0223] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0224] In one embodiment, the compound of formula (I) is a compound of formula (VIIIB):

[0225]

[0226] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0227] In one embodiment, the compound of formula (I) is a compound of formula (VIIIC):

[0228]

[0229] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0230] In one embodiment, the compound of formula (I) is a compound of formula (VIIID):

[0231]

[0232] Where R 2 It is H or methyl, and the variable is defined as in formula (I).

[0233] In one embodiment, the compound of formula (I) is a compound of formula (IXA), (IXB), (IXC), (IXD), (IXE), or (IXF):

[0234]

[0235] The variables are defined as in formula (I). In some embodiments, the compound is a compound of formula (IXA). In some embodiments, the compound is a compound of formula (IXB). In some embodiments, the compound is a compound of formula (IXC). In some embodiments, the compound is a compound of formula (IXD). In some embodiments, the compound is a compound of formula (IXE). In some embodiments, the compound is a compound of formula (IXF).

[0236] In one embodiment, ring A, together with the carbonyl (ketone) group within the ring, forms a 5-membered heterocycle containing 1 to 3 cyclic heteroatoms selected from the group consisting of N, O, and S, wherein the ketone group is not adjacent to the atom bonded to X. In one embodiment, ring A, together with the carbonyl (ketone) group within the ring, forms a 5-membered heterocycle containing 1 to 3 cyclic heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted with 1 to 2 C1-C3 alkyl or C3-C4 cycloalkyl groups, and wherein the ketone group is not adjacent to the atom bonded to X. In one embodiment, the 5-membered heterocycle contains 1 to 3 cyclic heteroatoms selected from the group consisting of N and O. In some embodiments, ring A, together with the carbonyl (ketone) group within the ring, is a In some embodiments, ring A together with the carbonyl (ketone) group within the ring is

[0237] In one embodiment, R 1 It is a C1-C4 alkyl group. In some embodiments, R 1 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl. In some embodiments, R 1 It is a C3-C4 alkyl group. In one embodiment, R 1 It is isopropyl. In some embodiments, R... 1 It is tert-butyl. In one embodiment, R... 1 It is a C1-C4 alkyl group optionally substituted with 1 to 5 halogen groups (preferably fluorine). In some embodiments, R 1 It is a C1-C4 alkyl group optionally substituted with one or two halogen groups (e.g., fluorine or chlorine). In one embodiment, R 1 It is a C1-C4 alkyl group optionally substituted with 1 to 5 halogen or hydroxyl groups. In some embodiments, R 1 It is a C2-C4 alkyl group optionally substituted with 1 to 5 halogen or hydroxyl groups. In some embodiments, R 1 It is a C1-C4 alkyl group optionally substituted with one or two halogen or hydroxyl groups. In one embodiment, R 1 It is a C1-C4 alkyl group optionally substituted with 1 to 5 hydroxyl groups. In some embodiments, R 1 It is a C1-C4 alkyl group optionally substituted with one or two hydroxyl groups. In some embodiments, R 1 It is a C1-C4 alkyl group substituted with one hydroxyl group. In some embodiments, R 1 It is a C1-C4 alkyl group optionally substituted with one or two halogen or hydroxyl groups. In some embodiments, R 1 For HO-CH(CH3)-. In some embodiments, R 1 For HO-CH(CH2CH3)-. In some embodiments, R 1It is HO-C(CH3)2-. In some embodiments, R 1 It is HO-CH2CH(CH3)-. In one embodiment, R 1 It is a C3-C5 cycloalkyl group. In some embodiments, R 1 It is a monocyclic C3-C5 cycloalkyl group. In some embodiments, R 1 It is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 1 It is cyclopropyl. In some embodiments, R 1 It is a fused bicyclic C3-C5 cycloalkyl group. In some embodiments, R 1 For bridging bicyclic C3-C5 cycloalkyl groups. In some embodiments, R 1 for In one embodiment, R 1 For CON(R) 10 )2. In one embodiment, R 1 For NR 10 COR 10 .

[0238] In one embodiment, each R 10 Independently, each R is a C1-C3 alkyl group. In some embodiments, each R 10 Independently, it is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, each R... 10 methyl. In one embodiment, each R... 10 For H. In some embodiments, an R 10 For H and another R 10 It is a C1-C3 alkyl group. In some embodiments, one R 10 For H and another R 10 It is a methyl group.

[0239] In one embodiment, R 2 For H. In one embodiment, R 2 It is a C1-C3 alkyl group. In some embodiments, R 2 It is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 2 methyl. In some embodiments, R 2 It can be H or -CH3.

[0240] In one embodiment, L is O. In one embodiment, L is CH2. In one embodiment, L is S. In one embodiment, L is SO. In one embodiment, L is SO2. In one embodiment, L is CO. In one embodiment, L is CHF. In one embodiment, L is CF2. In one embodiment, L is C(R) 11)CN. In one embodiment, L is C(Me)CN. In another embodiment, L is CHR 11 or C(R) 11 )R 11 , where each R 11 It is a C1-C2 alkyl group independently and optionally substituted with 1 to 5 halogen groups (preferably fluorine), or 2 R groups. 11 The groups, together with the carbon atoms they are bonded to, form a cyclopropyl or cyclobutyl ring. In one embodiment, L is CHR. 11 In one embodiment, L is C(R) 11 )R 11 In one embodiment, each R 11 Independently, each R is a C1-C2 alkyl group, i.e., methyl or ethyl. In one embodiment, each R 11 It is a C1-C2 alkyl group independently substituted with 1 to 5 halogen groups (preferably fluorine). In one embodiment, the two R groups... 11 The groups, together with the carbon atoms they are bonded to, form a cyclopropyl or cyclobutyl ring. In some embodiments, L is O, CH2, SO2, CO, or CHR. 11 or C(R) 11 )R 11 And each R 11 It is independently methyl or ethyl. In some embodiments, L is O, CH2, SO2, or CO.

[0241] In one embodiment, R 3 For Cl. In one embodiment, R 3 For Br. In one embodiment, R 3 For Me. In one embodiment, R 3 It is ethyl. In some embodiments, R 3 It is Cl or -CH3. In one embodiment, R 4 For Cl. In one embodiment, R 4 For Br. In one embodiment, R 4 For Me. In one embodiment, R 4 It is ethyl. In one embodiment, R... 3 and R 4 Each is Cl. In some embodiments, R 3 and R 4 Each is a methyl group. In some embodiments, R 3 For Cl and R 4 methyl. In some embodiments, R 3 Methyl and R 4 It is Cl.

[0242] In one embodiment, R 5 For H. In one embodiment, R5 It is a halogen group. In some embodiments, R 5 It is fluorine, chlorine, or bromine. In some embodiments, R 5 It is fluorine. In one embodiment, R... 5 It is a C1-C4 alkyl group. In some embodiments, R 5 It is a C1-C3 alkyl group. In some embodiments, R 5 It is methyl, ethyl, n-propyl, or isopropyl. In one embodiment, R... 5 CH3. In some embodiments, R 5 It is H or -CH3. In one embodiment, R 5 It is a C3-C4 cycloalkyl group. In some embodiments, R 5 It is cyclopropyl. In some embodiments, R 5 It is cyclobutyl. In one embodiment, R 4 With R 5 Together with intercalated atoms, they form 5 to 7-membered cycloalkyl groups. In some embodiments, R 4 With R 5 Together with intercalated atoms, they form cyclopentyl or cyclohexyl groups. In some embodiments, R 4 With R 5 Together with intercalated atoms, they form a cyclopentyl group. In one embodiment, R... 4 With R 5 Together with intercalated atoms, they form a 5- to 7-membered heterocycle containing 1 to 2 cyclic heteroatoms. Preferred heteroatoms include any one or more of N, O, and S.

[0243] In one embodiment, X is non-existent (i.e., X is a key). In one embodiment, X is 0. In one embodiment, X is NR. 12 In one embodiment, X is C(O)NR 12 In one embodiment, X is NR. 12 C(O). In one embodiment, X is NR. 12 SO2. In one embodiment, X is SO2NR. 12 In one embodiment, X is NR. 12 C(O). In one embodiment, X is CR. 12 R 12 In one embodiment, X is an OCR. 12 R 12 In one embodiment, X is CR 12 R 12 O. In one embodiment, X is CR 12 R 12 NH. In one embodiment, X is NR. 12 CR 12 R12 In some embodiments, X is NR. 12 C(O), OCR 12 R 12 or NR 12 CR 12 R 12 And each R 12 Independently, it is H or methyl. In some embodiments, X is N(CH3)CH2. In one embodiment, X is CR. 12 R 12 NR 12 In one embodiment, X is NH. In one embodiment, X is CH2. In one embodiment, X is OCH2. In one embodiment, X is CH2O. In one embodiment, X is NHCH2. In one embodiment, X is CH2NH. In one embodiment, X is NHC(O). In one embodiment, X is C(O)NH. In one embodiment, X is SO2NH. In one embodiment, X is NHSO2. In some embodiments, X is OCH2, NHCH2, NHC(O), N(CH3)CH2, or N(H)CH(CH3). In one embodiment, R 12 For H. In one embodiment, R 12 Methyl. In some embodiments, all R in a given portion are methyl. 12 Groups (e.g., OCR) 12 R 12 ) is H. In some embodiments, all R in a given part 12 Groups (e.g., OCR) 12 R 12 ) is methyl. In some embodiments, R in a given portion 12 Groups (e.g., OCR) 12 R 12 ) is a combination of H and methyl.

[0244] In one aspect, this document provides compounds of formula (I), wherein said compounds have any one or more of the following characteristics:

[0245] (I) Ring A together with the carbonyl group within the ring is:

[0246] (i) or

[0247] (ii)

[0248] (II)R 1 for:

[0249] (iii) C1-C4 alkyl groups optionally substituted with 1 to 5 halogenated or hydroxyl groups; or

[0250] (iv) C3-C5 cycloalkyl groups;

[0251] (III)R 2 It is H or C1-C3 alkyl;

[0252] (IV)R 3 It is Cl or methyl;

[0253] (V)R 4 It is Cl or methyl;

[0254] (VI)R 5 It can be H, a halogroup, or a C1-C4 alkyl group;

[0255] (VII)R 5 With R 4 Together with intercalated atoms, they form 5 to 7-membered cycloalkyl groups or 5 to 7-membered heterocycles containing 1 to 2 cyclic heteroatoms;

[0256] (VIII)X is:

[0257] (v) key; or

[0258] (vi)NR 12 C(O), OCR 12 R 12 or NR 12 CR 12 R 12 , where each R 12 Independently H or methyl; and

[0259] (IX)L can be O, CH2, SO2 or CO.

[0260] In one variation, (I) applies. In one variation, (II) applies. In one variation, (III) applies. In one variation, (IV) applies. In one variation, (V) applies. In one variation, (VI) applies. In one variation, (VII) applies. In one variation, (VIII) applies. In one variation, (IX) applies. In one aspect of the variation, (I), (II), (III), (IV), (V), (VI), (VIII), and (IX) apply. In another aspect of the variation, (I), (II), (III), (IV), (VII), (VIII), and (IX) apply. In one variation, (i), (iii), and (vi) apply. In one variation, (ii), (iii), and (v) apply. In one variation, (i), (iii), and (vi) apply. In one variation, (i), (iv), and (vi) apply. In one variation, (i), (iii), (VII) and (vi) apply.

[0261] In some embodiments, the compound of formula (I) is a agonist of THRβ. In some embodiments, the compound of formula (I) is a agonist of THRβ and has higher selectivity than THRα. In some embodiments, the compound of formula (I) has at least 2 times the selectivity for THRβ compared to THRα. In some embodiments, the compound of formula (I) has at least 5 times the selectivity for THRβ compared to THRα. In some embodiments, the compound of formula (I) has at least 10 times the selectivity for THRβ compared to THRα. In some embodiments, the compound of formula (I) has at least 20 times the selectivity for THRβ compared to THRα. In some embodiments, the compound of formula (I) has at least 50 times the selectivity for THRβ compared to THRα. In some embodiments, the compound of formula (I) has at least 75 times the selectivity for THRβ compared to THRα. In some embodiments, the compound of formula (I) has at least 100 times the selectivity for THRβ compared to THRα. In some embodiments, the compound of formula (I) exhibits at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times selectivity for THRβ compared to THRα. In any such embodiment, in one aspect, the selectivity is assessed via a biochemical analysis, such as the TR-FRET analysis described in Example B1.

[0262] Throughout this specification, it should be understood that each description, variation, embodiment, or aspect of a part may be combined with each description, variation, embodiment, or aspect of other parts, to the extent that each and every combination described is explicitly and individually enumerated. For example, each description, variation, embodiment, or aspect provided herein with respect to ring A of formula (I) may be combined with R 1 R 2 R 3 R 4 R 5 R 10 R 11 R 12Each description, variation, embodiment, or aspect of X and L is described to the extent that each and each combination is explicitly and individually enumerated. It should also be understood that all descriptions, variations, embodiments, or aspects of formula (I), when applicable, are equally applicable to other formulas described in detail herein, and are described to the extent that each and each description, variation, embodiment, or aspect is listed individually for all formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I), when applicable, are equally applicable to any of the formulas described in detail herein, such as formulas (IIA), (IIB), (IIIA)-(IIID), (IVA)-(IVD), (VA)-(VD), (VIA)-(VID), (VIIA)-(VIID), (VIIIA)-(VIIID), and (IXA)-(IXF), and are described to the extent that each and each description, variation, embodiment, or aspect is listed individually for all formulas.

[0263] In some embodiments, this document provides compounds selected from the compounds in Table 1, or pharmaceutically acceptable salts thereof. Although some compounds described in this disclosure (including those in Table 1) are presented as specific stereoisomers and / or in non-stereochemical forms, it should be understood that any or all stereochemical forms of any of the compounds of this invention (including those in Table 1), including any enantiomers or diastereomers, and any tautomers or other forms described herein, are permissible.

[0264] In one embodiment, this document provides a selection of compounds listed in Table 1 below:

[0265] Table 1

[0266]

[0267]

[0268]

[0269] Or its tautomers or N-oxides, or isotopic isomers of each of them, or prodrugs of each of the above, or stereoisomers of the above, or pharmaceutically acceptable salts of each of the foregoing, or solvates of each of the foregoing.

[0270] In some embodiments, this document provides a selection of those compounds listed in Table 1 or their pharmaceutically acceptable salts.

[0271] This invention also includes all salts of the compounds mentioned herein, such as pharmaceutically acceptable salts. This invention also includes any or all of the stereochemical forms of the compounds described herein (including any enantiomers or diastereomers and any tautomers or other forms, such as N-oxides, solvates, prodrugs, or isotopes). Unless the stereochemistry is explicitly indicated in the chemical structure or name, the structure or name is intended to encompass all possible stereoisomers of the compounds described herein. Furthermore, in the case of a particular stereochemical form being described, it should be understood that other stereochemical forms are also included in this invention. All forms of the compounds are also included in this invention, such as crystalline or amorphous forms of the compounds. Compositions of the compounds of this invention are also intended to include, for example, compositions of substantially pure compounds, including their particular stereochemical forms. Compositions containing mixtures of the compounds of this invention in any ratio are also included in this invention, including mixtures of two or more stereochemical forms of the compounds of this invention in any ratio, such that racemic, non-racemic, enantiomerically enriched, and scaly mixtures of the compounds are included in this invention.

[0272] Synthesis method

[0273] Scheme 1: General Synthesis of Biaryl-Ether Core

[0274]

[0275] Where R 1 R 3 R 4 and R 5 As defined for compounds of formula (I); T is Br, CN or NH2; and PG and G are suitable protecting groups.

[0276] The biarylene-ether core of the compounds disclosed in this article can be prepared as outlined in Scheme 1. 3,6-Dichloropyridazine and general formula R 1 The reaction of -CO2H compounds with ammonium persulfate provides R 1 Substituted dichloropyridazine compounds can then be reacted with phenol derivatives, hydrolyzed, and optionally N protected to provide the desired intermediate compound.

[0277] Option 1': Alternative synthesis of pyridazine

[0278]

[0279] Where R 1 As defined for compounds of formula (I).

[0280] Scheme 1' provides an alternative synthesis of pyridazines for the preparation of compounds of formula (I) disclosed herein. 3,6-Dichloro-1,2,4,5-tetraazine and R... 1The reaction of substituted acetylene provides R 1 Substituted dichloropyridazine compounds.

[0281] Option 1a: Achieve G=alkyl and T=NH2

[0282]

[0283] Where R 1 R 3 R 4 and R 5 As defined for compounds of formula (I); and G is a suitable protecting group.

[0284] Scheme 1a outlines the synthesis of compounds where G is an alkyl group and T is NH2. Compounds with a biaryl-ether core containing an amine moiety can be protected with phthalimide, N-alkylated, and then deprotected to provide the desired intermediate compound.

[0285] Option 2:

[0286]

[0287] Where R 1 R 3 R 4 R 5 and R 12 As defined for compounds of formula (I); and PG, G and G1 are suitable protecting groups.

[0288] Scheme 2 outlines the synthesis of certain compounds of formula (I) disclosed herein. For example, compounds having a biaryl-ether core with an amine moiety, as provided in Scheme 1a, can be N-alkylated and subjected to a second amine derivatization, followed by reaction with NH2OH, treatment with a carbonyl transfer reagent, and optionally deprotection to provide the desired compound.

[0289] Option 2a:

[0290]

[0291] Where R 1 R 3 R 4 R 5 and R 12 As defined for compounds of formula (I); and PG and G1 are suitable protecting groups.

[0292] Scheme 2a outlines the alternative synthesis of certain compounds of formula (I) disclosed herein. Compounds having a biaryl-ether core with an amine moiety can be N-alkylated, protected with an amine group, reacted with NH2OH, treated with a carbonyl transfer reagent, and optionally deprotected or hydrolyzed to provide the desired compound.

[0293] Option 3:

[0294]

[0295] Where R 1 R 3 R 4 R 5 And ring A as defined for compounds of formula (I); and G and G1 are suitable protecting groups.

[0296] Scheme 3 illustrates the synthesis of certain compounds of formula (I). The reaction of a biaryl-ether derivative containing an amine moiety with a carboxylic acid derivative of ring A provides amide bond formation to form the desired compound.

[0297] Option 4:

[0298]

[0299] Where R 1 R 3 R 4 R 5 and R 12 As defined for compounds of formula (I); and G and PG are suitable protecting groups.

[0300] Scheme 4 shows the synthesis of certain compounds of formula (I). Palladium-mediated hydroxylation of a bromine-containing biaryl-ether derivative, followed by O-alkylation, reaction with NH2OH, treatment with a carbonyl transfer reagent, and optionally deprotection or hydrolysis, provides the desired compound.

[0301] Option 5:

[0302]

[0303] Where R 1 R 3 R 4 and R 5 As defined for compounds of formula (I); and G is a suitable protecting group.

[0304] Scheme 5 shows the synthesis of certain compounds of formula (I). Treatment of a cyano-containing biaryl-ether derivative with NH₂OH, followed by treatment with a carbonyl transfer reagent, yields the desired compound.

[0305] Option 6:

[0306]

[0307] Where R 1 R 3 R 4 and R 5 As defined for compounds of formula (I).

[0308] Scheme 6 shows the synthesis of certain compounds of formula (I). A biaryl-ether derivative containing a cyano group is treated with NH₂OH, followed by treatment with a carbonyl transfer reagent and hydrolysis to provide the desired compound.

[0309] Option 7:

[0310]

[0311] Where R 1 R 3 R 4 and R 5 As defined for compounds of formula (I); and G is a suitable protecting group.

[0312] Scheme 7 shows the synthesis of certain compounds of formula (I). Diazotization / iodination of a biaryl-ether derivative containing an amino group, followed by stigma coupling, reaction with NH2OH, and then optionally deprotection, provides the desired compound.

[0313] The foregoing illustratively illustrates the synthesis of certain compounds provided herein, and examples are provided below. The variables listed in the foregoing schemes are defined for compounds of formula (I) or variations thereof, embodiments, or aspects. Based on the guidance provided herein and the synthetic methods familiar to those skilled in the art, the synthesis of other compounds provided herein will be readily apparent to those skilled in the art.

[0314] In cases where a specific enantiomer of a compound is required, this can be accomplished using any suitable conventional procedure for separating or resolving enantiomers from the corresponding mixture of enantiomers. Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers (e.g., a racemic mixture) with a suitable chiral compound. The diastereomeric derivative can then be separated by any convenient means, such as by crystallization, and the desired enantiomer can be recovered. In another analytical method, the racemic mixture can be separated using chiral high-performance liquid chromatography. Alternatively, the desired specific enantiomer can be obtained using any of the methods described herein with the help of a suitable chiral intermediate.

[0315] In cases where it is necessary to obtain a specific isomer of a compound or to purify the product of a reaction in other ways, chromatography, recrystallization, and other conventional separation procedures may also be used with intermediates or final products.

[0316] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also anticipated. Solvates contain stoichiometric or non-stoichiometric solvents and are typically formed during the crystallization process. When the solvent is water, hydrates are formed, or when the solvent is an alcohol, alkoxides are formed. Polymorphs comprise different crystalline accumulations of the same elemental composition of the compound. Polymorphs typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and / or solubility. Various factors (e.g., recrystallization solvents, crystallization rates, and storage temperatures) can cause single-crystal predominance.

[0317] It should be understood that the synthetic methods disclosed herein can be modified to obtain various compounds of the present invention by selecting appropriate reagents and starting materials. It should also be understood that, where protection of certain active or incompatible groups (e.g., amines or carboxylic acids) is required, (for example) the formulas provided herein are intended to include compounds in which such active or incompatible groups are in a suitably protected form. For a general description of protecting groups and their uses, see PGM Woods and TW Greene, Greene's Protective Groups in Organic Synthesis, 4th ed., Wiley-Interscience, New York, 2006.

[0318] Pharmaceutical compositions and formulations

[0319] This invention comprises pharmaceutical compositions comprising any of the compounds described in detail herein. Therefore, this invention includes pharmaceutical compositions comprising the compounds of this invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention are available in forms suitable for oral, buccal, non-enteric, nasal, topical, or rectal administration, or suitable for inhalation administration.

[0320] In one aspect, compounds as described in detail herein may be in purified form, and compositions comprising compounds in purified form are described in detail herein. Compositions comprising compounds as described in detail herein or salts thereof are provided, such as compositions of substantially pure compounds. In some embodiments, compositions comprising compounds as described in detail herein or salts thereof are in substantially pure form. In one variation, “substantially pure” means that the composition contains no more than 35% impurities, wherein the impurities represent compounds other than the majority of the compounds or salts thereof that constitute the composition. For example, compositions of substantially pure compounds selected from Table 1 are intended to contain no more than 35% impurities, wherein the impurities represent compounds other than the compounds or salts thereof. In one variation, compositions of substantially pure compounds or salts thereof are provided, wherein the composition contains no more than 25% impurities. In another variation, compositions of substantially pure compounds or salts thereof are provided, wherein the composition contains or does not exceed 20% impurities. In yet another variation, compositions of substantially pure compounds or salts thereof are provided, wherein the composition contains or does not exceed 10% impurities. In yet another variation, compositions of substantially pure compounds or salts thereof are provided, wherein the composition contains or does not exceed 5% impurities. In another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains or does not exceed 3% impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided, wherein the composition contains or does not exceed 1% impurities. In yet another variation, a composition of a substantially pure compound or a salt thereof is provided herein, wherein the composition contains or does not exceed 0.5% impurities. In still other variations, a composition of a substantially pure compound means that the composition contains no more than 15%, or preferably no more than 10%, or more preferably no more than 5%, or even more preferably no more than 3%, and most preferably no more than 1% impurities, which may be compounds in different stereochemical forms. For example (but not limited to), a composition of a substantially pure (S) compound means that the composition contains no more than 15%, or no more than 10%, or no more than 5%, or no more than 3%, or no more than 1% of the compound in the (R) form.

[0321] In one variation, the compounds described herein are synthetic compounds prepared for administration to an individual (e.g., a human). In another variation, compositions comprising compounds in substantially pure form are provided. In yet another variation, the invention includes pharmaceutical compositions comprising compounds described in detail herein and pharmaceutically acceptable carriers or excipients. In yet another variation, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are applicable to any compound or form thereof described in detail herein.

[0322] The compound can be formulated for any available route of delivery, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), non-enteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compound can be formulated with suitable carriers to provide delivery forms, which include (but are not limited to) lozenges, tablets, capsules (e.g., hard gelatin capsules or soft, flexible gelatin capsules), flat capsules, tablets, lozenges, gels, dispersions, suppositories, ointments, pastes (ointments), powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gelling agents, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs.

[0323] One or more of the compounds described herein can be used to prepare formulations, such as pharmaceutical formulations, by combining the compounds as active ingredients or by combining the compounds with pharmaceutically acceptable carriers, such as those mentioned above. The carriers may take various forms depending on the therapeutic form of the system (e.g., transdermal patches versus oral tablets). Additionally, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, and salts, buffers, coating agents, or antioxidants for adjusting osmotic pressure. Formulations containing the compounds may also contain other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st edition (2005), which is incorporated herein by reference.

[0324] The compounds described herein can be administered to an individual (e.g., a human) in the form of recognized oral compositions, such as lozenges, coated lozenges, and gel capsules, emulsions, or suspensions in hard or soft shells. Examples of carriers that can be used to prepare these compositions are lactose, corn starch or derivatives thereof, talc, stearates or salts thereof, etc. Acceptable carriers for gel capsules with soft shells are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, modifiers, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0325] Any of the compounds described herein can be formulated into tablets in any of the dosage forms described herein.

[0326] This document also describes compositions comprising the compounds provided herein. In one variation, the composition comprises the compound and a pharmaceutically acceptable carrier or excipient. In another variation, this document provides compositions of substantially pure compounds.

[0327] Methods of use / treatment

[0328] The compounds and compositions described in detail herein, such as pharmaceutical compositions containing any of the formulas provided herein (or pharmaceutically acceptable salts thereof) and pharmaceutically acceptable carriers or excipients, may be used in methods of administration and treatment as provided herein. For screening purposes and / or for quality control analysis, the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering the compounds or compositions to cells.

[0329] In one aspect, this article provides a method for contacting thyrotropin receptor β (THRβ), comprising contacting an effective amount of the compound provided herein, or an effective amount of a pharmaceutical composition provided herein, with THRβ.

[0330] In one aspect, this article provides a method for treating a patient with a condition mediated by THRβ, comprising administering to the patient in need a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein.

[0331] The methods for treating THRβ-mediated conditions (including, but not limited to, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and their respective symptoms and manifestations) are well known to skilled technicians and are applicable to the treatment of such conditions with the compounds or compositions provided herein.

[0332] In one aspect, this document provides a method for acting thyroxine receptor β (THRβ), comprising contacting an effective amount of a compound provided herein or a salt thereof, such as a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein with THRβ. In one aspect, this document provides a method for selectively acting THRβ relative to THRα, comprising contacting an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition provided herein with THRβ. In one aspect, the method selectively acts THRβ at a rate at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times higher than THRα. In any of these embodiments, in one aspect, selectivity is assessed via a biochemical analysis, such as the TR-FRET analysis described in Example B1.

[0333] In one aspect, this invention provides a method for treating a THRβ-mediated disease or condition in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, the disease or condition is a liver disease or condition. In one aspect, this invention provides a method for treating a liver disease or condition in a patient in need associated with suboptimal THRβ agonist effects, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound selectively agonizes THRβ relative to THRα.

[0334] In one aspect, this invention provides a method for treating non-alcoholic fatty liver disease in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or a composition provided herein. In one aspect, this invention provides a method for treating non-alcoholic steatohepatitis (NASH) in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or a composition provided herein. In one aspect, this invention provides a method for treating metabolic syndrome in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or a composition provided herein. In one aspect, this invention provides a method for treating dyslipidemia in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or a composition provided herein. In one aspect, this invention provides a method for treating hypertriglyceridemia in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or a composition provided herein. In one aspect, this article provides a method for treating hypercholesterolemia in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or a composition provided herein.

[0335] In any of the embodiments described herein, a patient suffering from a disease or condition associated with the activating effect of THRβ may include (but is not limited to) a patient suffering from underlying hypothyroidism.

[0336] In another aspect, methods are provided to delay the onset and / or development of a THRβ-mediated disease or condition in patients (e.g., humans) at risk of developing such a disease or condition. It should be understood that delayed development can be included in prevention in cases where the individual does not develop the disease or condition. In one aspect, an individual at risk of developing a THRβ-mediated disease or condition has one or more risk factors for developing such a disease or condition, such as age, increased waist circumference, high body mass index, or the presence of associated comorbidities.

[0337] In one aspect, this invention provides a method for delaying the onset and / or development of non-alcoholic fatty liver disease in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of non-alcoholic steatohepatitis (NASH) in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of metabolic syndrome in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of dyslipidemia in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, this invention provides a method for delaying the onset and / or development of hypertriglyceridemia in patients in need, comprising administering to the patient a therapeutically effective amount of a compound or composition provided herein. In one aspect, this article provides a method for delaying the onset and / or development of hypercholesterolemia in patients in need, comprising administering to said patient a therapeutically effective amount of a compound or composition provided herein.

[0338] In one aspect, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for use in treatment. In some embodiments, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising this compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non-alcoholic fatty liver disease. In some embodiments, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising this compound or a pharmaceutically acceptable salt thereof, for use in the treatment of non-alcoholic steatohepatitis (NASH). In some embodiments, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising this compound or a pharmaceutically acceptable salt thereof, for use in the treatment of metabolic syndrome. In some embodiments, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising this compound or a pharmaceutically acceptable salt thereof, for use in the treatment of dyslipidemia. In some embodiments, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising this compound or a pharmaceutically acceptable salt thereof, for use in the treatment of hypertriglyceridemia. In some embodiments, a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of hypercholesterolemia.

[0339] In another embodiment, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for manufacturing an agent for treating non-alcoholic fatty liver disease. In another embodiment, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for manufacturing an agent for treating non-alcoholic steatohepatitis (NASH). In another embodiment, this document provides a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for manufacturing an agent for treating metabolic syndrome. In some embodiments, the agent is used to treat dyslipidemia. In some embodiments, the agent is used to treat hypertriglyceridemia. In some embodiments, the agent is used to treat dyslipidemia. In some embodiments, the agent is used to treat hypercholesterolemia.

[0340] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or about 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about 21, 18, 15, 10, 5, 4, 3, 2, or 1 year old.

[0341] Administration and method of administration

[0342] The dosage of the compound described herein, or its stereoisomers, tautomers, solvates, or salts, administered to an individual (e.g., a human) may vary depending on the specific compound or its salts, the method of administration, and the specific disease or condition being treated, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), metabolic syndrome, hypertriglyceridemia, dyslipidemia, or hypercholesterolemia. In some embodiments, the amount of the compound, or its stereoisomers, tautomers, solvates, or salts, is a therapeutically effective amount.

[0343] The compounds or their salts provided herein can be administered to individuals via various routes, including intravenous, intramuscular, subcutaneous, oral, and transdermal routes.

[0344] In one aspect, the effective amount of the compound may be a dose between about 0.01 and about 100 mg / kg. The effective amount or dose of the compound of the present invention may be determined by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and progression of the disease to be treated, the individual's health status, condition, and weight. Illustrative doses are in the range of about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 g to 7 g daily.

[0345] In one aspect, any of the methods provided herein may include administering to an individual a pharmaceutical composition containing an effective amount of the compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient.

[0346] The compounds or compositions provided herein may be administered to an individual for the desired period or duration according to an effective dosing regimen, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer, and in some variations, this may be the duration of the individual's life. In one variation, the compound may be administered on a daily or intermittent schedule. The compound may be administered to an individual continuously (e.g., at least once daily) for a given period. The dosing frequency may also be less than once daily, for example, about once a week. The dosing frequency may be greater than once daily, for example, twice or three times daily. The dosing frequency may also be intermittent, including "pause periods" (e.g., dosing once daily for seven days, followed by a seven-day break, repeated for any 14-day period, such as about two months, about four months, about six months, or more). Any of the dosing frequencies may be used with any of the compounds described herein in conjunction with any of the doses described herein.

[0347] Products and sets

[0348] The present invention further provides articles comprising, in suitable packaging, the compounds described herein or salts thereof, the compositions described herein, or one or more unit doses described herein. In some embodiments, the articles are used in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, wide-mouth bottles, flexible packaging, etc. The articles may be further sterilized and / or sealed.

[0349] The present invention further provides a kit for carrying out the methods of the invention, the kit comprising one or more compounds described herein or a composition comprising compounds described herein. The kit may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kit may be used for any one or more of the uses described herein, and therefore may contain instructions for treating any of the diseases described herein (e.g., for treating non-alcoholic steatohepatitis (NASH)).

[0350] Kits generally include suitable packaging. A kit may contain one or more containers containing any of the compounds described herein. Individual components (if more than one component is present) may be packaged in separate containers, or, where cross-reactivity and shelf life permit, some components may be combined in one container.

[0351] Kits may be available in unit dose form, in bulk (e.g., multi-dose packs), or in subunit doses. For example, kits may be provided herein containing sufficient doses of the compounds disclosed herein and / or additional pharmaceutically active compounds suitable for the diseases described in detail herein to provide effective treatment to an individual over an extended period (e.g., one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or more). Kits may also include multi-unit doses of compounds and instructions for use, packaged in sufficient quantities for storage and use in pharmacies (e.g., hospital pharmacies and multi-dose pharmacies).

[0352] The kit may optionally include a set of instructions for use (generally written instructions for use), although electronic storage media containing instructions for use (e.g., disks or optical discs) are also acceptable, relating to the use of the components of the method of the invention. The instructions for use included in the kit generally include information about the components and their application to an individual.

[0353] Exemplary Examples

[0354] The present invention is further described by the following embodiments. Where appropriate and practical, each feature of the embodiments may be combined with any of the features in other embodiments.

[0355] Example 1: A compound of formula (Ia):

[0356]

[0357] Or its tautomers or N-oxides, or isotopic isomers of each of them, or prodrugs of each of the above, or stereoisomers of the above, or pharmaceutically acceptable salts of each of the foregoing, or solvates of each of the foregoing, wherein:

[0358] Ring A together with the carbonyl (ketone) group within the ring forms a 5-membered heterocycle containing 1 to 3 cyclic heteroatoms selected from N, O and S, wherein the heterocycle is optionally substituted with 1 to 2 C1-C3 alkyl or C3-C4 cycloalkyl groups, and wherein the carbonyl (ketone) group is not adjacent to the atom bonded to X.

[0359] R 1 It is a C1-C4 alkyl group; optionally substituted with 1 to 5 halogen groups (preferably fluorine); C3-C5 cycloalkyl group, CON(R) 10 )2 or NR 10 COR 10 , where each R 10 Independently, it is a C1-C3 alkyl group or H;

[0360] R 2 It is H or C1-C3 alkyl;

[0361] L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 CN, CHR 11 or C(R) 11 )R 11 , where each R 11 C1-C2 alkyl groups optionally substituted with 1 to 5 halogen groups (preferably fluorine), or 2 R groups. 11 The groups, together with the carbon atoms they bond to, form cyclopropyl or cyclobutyl rings;

[0362] R 3 and R 4 Each of these is independently Cl, Br, Me, or an ethyl group;

[0363] R 5 It is H, halogen, C1-C4 alkyl or C3-C4 cycloalkyl, or R 5 With R 4 Together with intercalated atoms, they form 5 to 7-membered cycloalkyl groups or 5 to 7-membered heterocycles containing 1 to 2 cyclic heteroatoms;

[0364] X is non-existent (i.e., X is a key), or is 0 or NR. 12 C(O)NR 12 NR 12 C(O), CR 12 R 12 OCR 12 R 12 CR 12 R 12 O, NR 12 CR 12 R 12 CR 12 R 12 NR12 SO2NR 12 NR 12 SO2, where each R 12 It can be H or methyl on its own.

[0365] Example 2: The compound according to Example 1 is a compound of formula (IIA), (IIB), (IIIA), (IIIB), (IIIC), (IVA), (IVB), (IVC), (IVA), (VB), (VC), (VIA), (VIB), or (VIC):

[0366]

[0367]

[0368] The variables are defined as in Example 1.

[0369] Example 3: The compound according to Example 1 is a compound of formula (VIIA), (VIIB), (VIIC), (VIIIA), (VIIIB), or (VIIIC):

[0370]

[0371] Where R 2 It is H or methyl, and the remaining variables are as defined in Example 1.

[0372] Example 4: The compound according to Example 1, wherein R 1 It is isopropyl.

[0373] Example 5: The compound according to Example 1, wherein R 2 For H.

[0374] Example 6: The compound according to Example 1, wherein R 3 It is chlorine.

[0375] Example 7: The compound according to Example 1, wherein R 4 It is chlorine.

[0376] Example 8: The compound according to Example 1, wherein R 5 It is hydrogen.

[0377] Example 9: The compound according to Example 1, wherein X is a bond.

[0378] Example 10: The compound according to Example 1, wherein X is CHR 11 OCHR 11 NR 11 CHR11 NR 11 CH2, CHR 11 NH, CHR 11 NR 11 NHCR 11 R 11 C(O)NR 12 NR 12 C(O), SO2NR 12 or NR 12 SO2, where R 12 As defined in Example 1.

[0379] Example 11: The compound according to Example 1, wherein X is NH, CH2, OCH2, CH2O, NHCH2, CH2NH, C(O)NH, NHC(O), SO2NH or NHSO2.

[0380] Example 12: The compound according to Example 1, wherein -X- is -NH-CH2-, -NHC(O)- or -O-CH2-.

[0381] Example 13: The compound according to Example 1, wherein -L- is O.

[0382] Example 14: A compound selected from those listed in Table 1.

[0383] Example 15: A pharmaceutical composition comprising the compound of Example 1 and at least one pharmaceutically acceptable excipient.

[0384] Example 16: A method of stimulating thyroxine receptor β (THRβ) comprising contacting an effective amount of the compound of Example 1 or an effective amount of the composition of Example 15 with THRβ.

[0385] Example 17: A method of treating a patient with a THRβ-mediated condition, comprising administering to the patient a therapeutically effective amount of the compound of Example 1 or a therapeutically effective amount of the composition of Example 15.

[0386] Example

[0387] It should be understood that the present invention has been described by way of example only, and those skilled in the art can utilize many variations in the combination and arrangement of parts without departing from the spirit and scope of the invention.

[0388] The chemical reactions described in the examples herein are readily applicable to the preparation of many other compounds disclosed herein, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplary compounds according to the invention can be successfully carried out by modifications readily apparent to those skilled in the art, for example, by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art besides those described herein, or by routine modifications to the reaction conditions, reagents, and initial materials. Alternatively, other reactions described herein or known in the art will be recognized as suitable for the preparation of other compounds of the present invention.

[0389] The following abbreviations may be used in connection with this application.

[0390] abbreviation

[0391] Ac: Acetyl group

[0392] ACN: Acetonitrile

[0393] Boc: tert-butoxycarbonyl

[0394] Bu: Butyl

[0395] DBA: Diphenylmethyleneacetone

[0396] DMAP: Dimethylaminopyridine

[0397] DMF: Dimethylformamide

[0398] DMF-DMA: Dimethylformamide dimethyl acetal

[0399] DMSO: Dimethyl sulfoxide

[0400] DSC: Disuccinimide Carbonate

[0401] Et: Ethyl

[0402] Me: Methyl

[0403] Pr: Propyl

[0404] Py or Pyr: Pyridine

[0405] rt: room temperature

[0406] SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride

[0407] SFC: Supercritical Fluid Chromatography

[0408] TEA: Triethylamine

[0409] THF: Tetrahydrofuran

[0410] TFA: Trifluoroacetic acid

[0411] t-Bu Xphos: 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl

[0412] Synthesis Example

[0413] Option A: 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (compound 1e)

[0414]

[0415] 3,6-Dichloro-4-isopropylpyridazine (1a). Sulfuric acid (19.75 g, 201.37 mmol, 10.73 mL) was added to a mixture of 3,6-dichloropyridazine (10 g, 67.12 mmol), 2-methylpropionic acid (6.21 g, 70.48 mmol, 6.54 mL), and AgNO3 (5.70 g, 33.56 mmol, 5.64 mL) in 200 mL of H2O at 60 °C. Then, a solution of ammonium persulfate (45.95 g, 201.37 mmol) in 100 mL of H2O was added dropwise to the mixture at 75 °C, and the resulting mixture was stirred for 30 min at 75 °C. TLC showed that the reaction was complete. After cooling, the mixture was adjusted to pH 9-10 with NH3·H2O. The mixture was then extracted with ethyl acetate (200 mL x 2), the organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to produce 1a. This product can be used directly in the next step. (For [M+1]) + The calculated MS quality requirement value for (C7H8Cl2N2) is m / z 191.1, and the measured LCMS value is m / z 191.1. 1 HNMR (400MHZ, CDCl3) δ7.38 (s, 1H), 3.24-3.31 (m, 1H), 1.31 (d, J = 6.8HZ, 6H).

[0416] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)oxy)aniline (1b). K₂CO₃ (9.32 g, 67.41 mmol) and CuI (1.93 g, 10.11 mmol) were added to a solution of 4-amino-2,6-dichlorophenol (3 g, 16.85 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (3.22 g, 16.85 mmol) in DMSO (30 mL). The mixture was then degassed and washed three times with N₂, and stirred at 90 °C under N₂ atmosphere for 16 h. TLC and LCMS showed complete consumption of the initial material and the required MS was detected. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (1000 mL * 2) and H₂O (500 mL). The combined organic phases were washed with brine (50 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10:1 to 3:1, according to TLC) to produce 1b. [M+1] + (C 13 H 12 The MS quality requirement value (m / z) calculated by Cl3N3O is 332.0, and the measured LCMS value (m / z) is 332.0. 1 H NMR (400MHZ, DMSO) δ7.66 (s, 1H), 6.67-6.76 (m, 2H), 5.67 (s, 2H), 3.11-3.21 (m, 1H), 1.28 (d, J = 6.85HZ, 6H).

[0417] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1c). NaOAc (3.21 g, 39.08 mmol) was added to a mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1b) (2.6 g, 7.82 mmol) and isobenzofuran-1,3-dione (1.16 g, 7.82 mmol) in HOAc (5 mL). The mixture was stirred at 120 °C for 6 hours. LCMS showed complete consumption of the initial material and the required MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solids were dissolved in water and the pH was adjusted to 9 with a saturated NaHCO3 solution (10 mL). The mixture was then partitioned between ethyl acetate (30 mL x 2) and H2O (30 mL). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The solid was diluted in ethyl acetate (10 mL), and then petroleum ether (50 mL) was added to the mixture in portions. The mixture was filtered to collect the solid. The solid was dried to produce 1c. [M+1] + (C 21 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O4 is 444.0, and the measured LCMS value (m / z) is 444.1. 1 H NMR(400MHZ,DMSO)δ12.21(s,1H),7.98-8.06(m,2H),7.90-7.97(m,2H),7 .78-7.83(m,2H), 7.46(s,1H), 3.03-3.10(m,1H), 1.20(d,J=6.85HZ,6H).

[0418] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1d). A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1c) (500 mg, 1.13 mmol) in DMF-DMA (4 mL) was stirred for 2.5 h at 110 °C. TLC showed complete consumption of the initial material and the formation of two new spots. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (10 mL x 2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to produce 1d. The product was used directly in the next step without further purification.

[0419] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1e). A mixture of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (1d) (700 mg, 1.53 mmol) and but-1-amine (335.13 mg, 4.58 mmol) in MeOH (10 mL) was stirred for 1 hour at 70 °C. TLC (petroleum ether:ethyl acetate = 1:1, P1:R) f =0.6) and LCMS showed that the initial material was completely consumed and the required MS was detected. The mixture was concentrated in vacuum to produce a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 1:1, P1:R) f =0.6) Purification to produce 1e. For [M+1] + (C 14 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O2 is 328.1, and the measured LCMS value (m / z) is 328.2. 1 H NMR (400MHZ, CD3OD) δ7.22 (s, 1H) 6.70 (s, 1H) 3.52 (s, 3H) 3.17 (dt, J = 13.81, 7.13Hz, 1H) 1.43 (s, 2H) 1.25 (d, J = 6.58Hz, 6H).

[0420] Example 1: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0421]

[0422] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)-acetonitrile (1f). 2-bromoacetonitrile (438.58 mg, 3.66 mmol, 243.65 μL), NaI (219.23 mg, 1.46 mmol), and K₂CO₃ (202.13 mg, 1.46 mmol) were added to a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1e) in ACN (4 mL). The mixture was then sealed in a tube and stirred at 100 °C for 16 hours. LC-MS showed complete consumption of the initial material and the required MS was detected. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (5 mL * 3). The combined filtrate was concentrated to dryness to produce a residue. The residue was analyzed by preparative TLC (petroleum ether:ethyl acetate = 1:1, P1:R). f =0.5) Purification to produce 1f, which is a yellow oil. For [M+1] + (C 16 H 16 The MS quality requirement value (m / z) calculated for Cl2N4O2 is 367.1, and the measured LCMS value (m / z) is 366.8. 1 H NMR (400MHZ, CDCl3) δ7.04 (s, 1H), 6.72 (s, 2H), 4.13 (d, J = 6.85HZ, 2H), 3.54 (s, 3H), 3.21-3.28 (m, 1H), 1.26 (d, J = 6.85HZ, 5H).

[0423] (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)carbamate tert-butyl ester (1 g). Boc2O (374.41 mg, 1.72 mmol, 394.12 μL) and DMAP (69.86 mg, 571.85 μL) were added to a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (1 f) (210 mg, 571.85 μL) in THF (3 mL). The mixture was stirred at 40 °C for 3 hours. TLC (petroleum ether:ethyl acetate = 1:1, P1:R) f=0.9) and LCMS showed that the initial material was completely consumed and the required MS was detected. The mixture was partitioned twice between ethyl acetate (10 mL*2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to produce a residue. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1, P1:R f =0.5) Purification to produce 1g. For [M+1] + (C 21 H 24 The MS quality requirement value (m / z) calculated for Cl2N4O4 is 467.1, and the measured LCMS value (m / z) is 467.0. 1 H NMR (400MHZ, CDCl3) δ7.45 (s, 2H), 4.61 (s, 2H), 3.43 (s, 3H), 3.13 (dt, J = 13.8, 6.8HZ, 1H), 1.45 (s, 9H), 1.22 (d, J = 6.8HZ, 6H).

[0424] (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (1 h). NH₂OH·HCl (297.39 mg, 4.28 mmol) and NaOAc (351.06 mg, 4.28 mmol) were added to a solution of (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (1 g) (250 mg, 534.94 μmol) in DMF (3 mL). The mixture was stirred at 80 °C for 1 h. LCMS showed complete consumption of the initial material and the required MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL x 2) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce a yellow solid (260 mg, crude) over 1 hour. This product could be used directly in the next step without further purification. [M+1] + (C 21 H 27 The MS quality requirement value (m / z) calculated by Cl2N5O5 is 500.1, and the measured value (m / z) of LCMS is 500.1.

[0425] (3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (1i). DSC (173.04 mg, 675.49 μol, 1.3 equivalents) and TEA (105.16 mg, 1.04 mmol, 144.65 μL) were added to a solution of (Z / E)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-tert-butyl carbamate (1h) (260 mg, 519.61 μol) in THF (3 mL). The mixture was stirred at 60°C for 16 hours. (TLC: dichloromethane:methanol = 10:1, P1:R) f =0.3) and LCMS showed that the initial material was completely consumed and the required MS was detected. The mixture was partitioned between ethyl acetate (10 mL*2) and H2O (3 mL). The combined organic phase was washed with brine (5 mL*3), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to produce a residue. The residue was analyzed by preparative TLC (SiO2, DCM:MeOH = 10:1, P1:R f =0.3) Purification to produce 1i. For [M+1] + (C 22 H 25 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 526.1, and the measured LCMS value (m / z) is 526.2. 1 H NMR (400MHZ, CD3OD) δ7.54 (s, 2H), 7.32 (s, 1H), 4.77 (s, 2H), 3.48 (s, 3H), 3.18 (dt, J = 13.6, 6.84HZ, 1H), 1.46 (s, 9H), 1.27 (d, J = 6.8HZ, 6H).

[0426] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 1). A solution of (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate tert-butyl (1i) (170 mg, 322.97 μmol) in HCl / EtOAc (2 mL) was stirred for 2 hours at 25 °C. LC-MS and HPLC showed complete consumption of the initial material and detection by MS. The mixture was diluted with water (0.5 mL) and the pH was adjusted to 8 with NaHCO3 (5 mL). The mixture was then partitioned into 10 mL portions of ethyl acetate, twice. The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce a residue. The residue was purified by preparative HPLC (FA) column: Luna C18 100 x 30 5 u; mobile phase: [water (0.2% FA)-ACN]; B%: 25% to 60%, 12 min] to produce Example 1. [M+1] + (C 17 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 426.1, and the measured LCMS value (m / z) is 426.0. 1 H NMR (400MHZ, CD3OD) δ7.23 (s, 1H), 6.76 (s, 2H), 4.88 (s, 139H), 4.28 (s, 2H), 3.50 (s, 3H), 3.12-3.21 (m, 1H), 1.25 (d, J = 7.06HZ, 6H).

[0427] Example 2: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0428]

[0429] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)acetonitrile (2a). Cs₂CO₃ (66.54 mg, 204.23 μol) and MeI (193.26 mg, 1.36 mmol, 84.76 μL) were added to a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (1f) (50 mg, 136.15 μol) in THF (2 mL). The mixture was stirred at 100 °C in a sealed tube for 16 hours. TLC and LCMS showed approximately 30% of the remaining 1f of the reactant, and the desired MS concentration was determined. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (5 mL * 3). The combined filtrate was concentrated to dryness to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, according to TLC) to produce 2a. [M+1] + (C 17 H 18 The MS quality requirement value (m / z) calculated by Cl2N4O2 is 381.1, and the measured LCMS value (m / z) is 381.0. 1 H NMR (400MHZ, CDCl3) δ7.03 (d, J = 0.7HZ, 1H), 6.82 (s, 2H), 4.19 (s, 2H), 3.54 (s, 3H), 3.28-3.20 (m, 1H), 3.05 (s, 3H), 1.27-1.25 (m, 6H).

[0430] (Z)-2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)-N'-hydroxyacetamidine (2b). NH₂OH·HCl (75.82 mg, 1.09 mmol) and NaOAc (89.51 mg, 1.09 mmol) were added to a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)acetonitrile (2a) (52 mg, 136.39 μmol) in DMF (2 mL). The mixture was stirred at 80 °C for 6 hours. TLC showed complete consumption of reactant 2a, and LCMS showed a main peak with the desired MS. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (5 mL * 3). The combined filtrate was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO₂, DCM:MeOH = 10:1, according to TLC) to produce 2b. For [M+1] + (C 17 H 21 The MS quality requirement value (m / z) calculated by Cl2N5O3 is 414.1, and the measured value (m / z) of LCMS is also 414.1.

[0431] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 2). DSC (21.70 mg, 84.72 μol) and TEA (33.97 mg, 335.75 μol, 46.73 μL) were added to a solution of (Z / E)-2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(methyl)amino)-N'-hydroxyacetamidine (2b) (30 mg, 65.17 μol) in THF (2 mL). The mixture was stirred at 80 °C for 2 hours. TLC and LCMS showed complete consumption of 2b, and the required MS was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was examined by HPLC and then purified by preparative HPLC (column: Waters Atlantis T3 150*30*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 40% to 70%, 13 min) to produce Example 2. For [M+1] + (C 18 H 19The MS quality requirement value (m / z) calculated by Cl2N5O4 is 440.1, and the measured value (m / z) of LCMS is 440.1. 1 H NMR (400MHZ, CD3OD) δ7.24 (s, 1H), 6.92 (s, 2H), 4.48 (s, 2H), 3.49 (s, 3H), 3.17 (td, J = 7.2, 13.9HZ, 1H), 3.05 (s, 3H), 1.26 (d, J = 6.8HZ, 6H).

[0432] Example 3: P1 and P2: 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one

[0433]

[0434] 2-((3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)propionitrile (3a). A mixture of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1e) (0.2 g, 609.40 μmol, 1 equivalent), K₂CO₃ (168.44 mg, 1.22 mmol), NaI (182.69 mg, 1.22 mmol), and 2-bromopropionitrile (816.44 mg, 6.09 mmol) in CH₃CN (5 mL) was added to a sealed tube and heated to 90 °C for 16 hours. LCMS showed the desired MS and STM values ​​for 1e. The mixture was filtered and washed with ethyl acetate (10 mL * 2). The combined filtrate was washed with brine (20 mL) and the organic phase was concentrated to produce 3a (0.25 g, crude), which can be used directly in the next step. [M+1] + (C 17 H 18 The MS quality requirement value (m / z) calculated by Cl2N4O2 is 381.1, and the measured LCMS value (m / z) is 381.0.

[0435] (1-Cyanoethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (3b). A mixture of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)propionitrile (3a) (0.25 g, 655.73 μol), Boc2O (429.33 mg, 1.97 mmol, 451.93 μL) and DMAP (80.11 mg, 655.73 μol) in THF (5 mL) was heated to 50 °C for 1 hour. LCMS showed the desired MS, and TLC showed new spots. The mixture was concentrated, and the residue was purified by preparative TLC (petroleum ether: ethyl acetate = 3:1) to produce 3b. Regarding [M+1] + (C 22 H 26 The MS quality requirement value (m / z) calculated by Cl2N4O4 is 481.1, and the measured LCMS value (m / z) is 481.3. 1 H NMR (400MHz, CDCl3) δ7.31 (s, 2H), 7.07 (s, 1H), 3.51 (s, 3H), 3.30-3.23 (m, 1H), 3.20 (q, J = 7.0Hz ,1H), 2.03(s,3H), 1.75(d,J=7.0Hz,3H), 1.57(s,4H), 1.51-1.43(m,9H), 1.28(d,J=6.8Hz,6H).

[0436] (Z / E)-(1-amino-1-(hydroxyimino)propyl-2-yl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (3c). A mixture of (1-cyanoethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (3b) (80 mg, 166.19 μmol), NH₂OH·HCl (92.39 mg, 1.33 mmol), and NaOAc (109.07 mg, 1.33 mmol) in DMF (3 mL) was heated to 80 °C for 5 hours. LCMS showed the desired MS, TLC (petroleum ether:ethyl acetate = 1:1, R f =0.47) showed a new point. The mixture was filtered and washed with ethyl acetate (10 mL * 2). The filtrate was washed with brine (10 mL * 2). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to produce 3c. For [M+1]+ (C 22 H 29 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 514.2, and the measured LCMS value (m / z) is 514.0.

[0437] (3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)tert-butyl carbamate (3d). A mixture of (Z / E)-(1-amino-1-(hydroxyimino)propyl-2-yl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (3c) (39 mg, 75.82 μol), DSC (25.25 mg, 98.56 μol) and TEA (15.34 mg, 151.63 μol, 21.11 μL) in THF (4 mL) was heated to 60 °C for 2 hours. The mixture was then heated to reflux for 4 hours. (TLC: Petroleum ether:ethyl acetate = 1:1, R...) f =0) indicates the reaction is complete, and the mixture is concentrated to produce 3d (70mg, crude), which can be used directly in the next step. For [M+1] + (C 23 H 27 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 540.1, and the measured LCMS value (m / z) is 540.2.

[0438] 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one (Example 3). TFA (0.5 mL) was added to a solution of (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)carbamate (3d) (70 mg, 129.53 μmol) in DCM (2 mL), and the mixture was stirred at 25 °C for 50 min. LC-MS showed that the reaction was complete, and the desired MS was detected. The mixture was then concentrated under vacuum. The residue was purified by preparative HPLC (FA) (column: Waters Atlantis T3 150*30*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 40% to 80%, 13 min) to produce 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one Example 3. For [M+1] + (C 18 H 19 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 440.0, and the measured LCMS value (m / z) is 440.1. 1 HNMR (400MHz, CD3OD) δ7.25 (d, J=0.8Hz, 1H), 6.78 (s, 2H), 4.55 (q, J=6.8Hz, 1H ), 3.52 (s, 3H), 3.23-3.13 (m, 1H), 1.60 (d, J = 6.8Hz, 3H), 1.27 (d, J = 7.0Hz, 6H).

[0439] SFC separation: 3-(1-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)ethyl)-1,2,4-oxadiazol-5(4H)-one (Example 3) (17.17 mg, 39.00 μmol, 1 equivalent) was separated by SFC ([monitoring] Instrument: Thaler SFC80 preparative SFC; Column: Chiralpak AS-H, 250*30 mm id10u; Mobile phase: A is CO2 and B is MeOH (0.1% ammonia); Gradient: B% = 40%; Flow rate: 70 g / min; Wavelength: 220 nm; Column temperature: 40 °C; System back pressure: 100 bar) to produce Example-P1; for [M+1] + (C18 H 19 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 440.1, and the measured LCMS value (m / z) is 440.0. 1 ¹H NMR (400MHz, CD₃OD) δ 7.23 (d, J = 0.8Hz, 1H), 6.75 (s, 2H), 4.48 (q, J = 6.8Hz, 1H), 3.51 (s, 3H), 3.17 (td, J = 6.6, 13.6Hz, 1H), 1.58 (d, J = 6.8Hz, 3H), 1.26 (d, J = 7.2Hz, 6H) and example - P2; for [M+1] + (C 18 H 19 The MS quality requirement value (m / z) calculated for Cl2N5O4 is 440.1, and the measured LCMS value (m / z) is 440.0. 1 ¹H NMR (400MHz, CD₃OD) δ 7.23 (s, 1H), 6.75 (s, 2H), 4.48 (q, J = 6.8Hz, 1H), 3.51 (s, 3H), 3.17 (quintet, J = 6.8Hz, 1H), 1.58 (d, J = 6.8Hz, 3H), 1.26 (d, J = 6.8Hz, 6H).

[0440] Example 4: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0441]

[0442] (Z / E)-2-amino-2-(hydroxyimino)ethyl acetate (4a). NH₂OH·HCl (2.63 g, 37.85 mmol) and Na₂CO₃ (2.67 g, 25.23 mmol) were added to a solution of ethyl cyanoformate (2.5 g, 25.23 mmol, 2.48 mL) in EtOH (25 mL). The mixture was stirred at 25 °C for 2 hours. TLC showed the reaction was complete. LCMS showed a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H₂O (5 mL) and extracted with EtOAc (20 mL x 5). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by recrystallization from MTBE:petroleum ether = 1:1 (20 mL) at 70 °C to produce 4a. [M+1] +The calculated MS quality requirement value for (C4H8N2O3) is m / z 133.1, and the measured LCMS value is m / z 133.1. 1 H NMR (400MHz, CDCl3) δ8.90 (br s, 1H), 5.12 (br s, 2H), 4.34 (q, J = 7.1Hz, 2H), 1.36 (t, J = 7.2Hz, 3H).

[0443] Ethyl (Z)-2-amino-2-(((ethoxycarbonyl)oxy)imino)ethyl acetate (4b). TEA (2.30 g, 22.71 mmol, 3.16 mL) and ethyl chloroformate (903.56 mg, 8.33 mmol, 792.59 μL) were added to a solution of ethyl (Z / E)-2-amino-2-(hydroxyimino)ethyl acetate (4a) (1 g, 7.57 mmol) in DCM (5 mL). The mixture was stirred at 0 °C for 1 hour. TLC indicated that 5a was completely consumed and a new spot formed. According to TLC, the reaction was complete. The reaction mixture was concentrated under reduced pressure to produce 4b (1.34 g, crude). 1 H NMR (400MHz, CDCl3) δ5.44 (br s, 2H), 4.40 (q, J = 7.2Hz, 2H), 4.34 (q, J = 7.2Hz, 2H), 1.42-1.38 (m, 3H), 1.38-1.34 (m, 3H).

[0444] Ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylate (4c). A solution of (Z / E)-2-amino-2-(((ethoxycarbonyl)oxy)imino)ethyl acetate (4b) (1.34 g, 6.56 mmol) in AcOH (5 mL) was degassed and washed three times with N2, and then the mixture was stirred at 120 °C under N2 atmosphere for 10 h. LC-MS showed complete consumption of 4b and a main peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH and then 4c (1.03 g, crude) was obtained. The crude product was ready for use in the next step without further purification. [M-1] - The MS quality requirement value (m / z) calculated for (C5H6N2O4) is 157.0, and the LCMS measured value (m / z) is also 157.0.

[0445] 5-O-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (4d). LiOH (36.35 mg, 1.52 mmol, 1.2 equivalent) was added to a solution of ethyl 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (4c) (200 mg, 1.26 mmol, 1 equivalent) in MeOH (1 mL) and H₂O (0.2 mL). The mixture was stirred at 25 °C for 1 hour. TLC showed complete consumption of reactant 4 and the formation of a new spot. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was diluted with HCl (1 M, 5 mL) to adjust the pH to 4–6 and then extracted with EtOAc (5 mL x 4). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce 4d (114 mg, crude). The crude product was used in the next step without further purification. Regarding [M+1] + The MS quality requirement value for (C5H6N2O4) is 159.0, but the LCMS did not measure the m / z value. 1 HNMR (400MHz, DMSO) δ4.35 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H).

[0446] 5-Oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e). (COCl)₂ (128.82 mg, 1.01 mmol, 88.84 μL) and DMF (6.18 mg, 84.58 μL, 6.51 μL) were added to a solution of 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (4d) (110 mg, 845.77 μol) in THF (3 mL). The mixture was stirred at 25 °C for 1 hour. A few drops of the reaction mixture were quenched with MeOH for monitoring. TLC indicated complete consumption of 4d and the formation of a new spot. The mixture was concentrated under reduced pressure to produce 4e (155 mg, crude). The crude product was used in the next step without further purification.

[0447] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 4). TEA (18.50 mg, 182.82 μol, 25.45 μL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (13.57 mg, 91.41 μol) were added to a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (1e) (20 mg, 60.94 μol) in THF (3 mL). The mixture was stirred at 25 °C for 0.5 h. LCMS showed complete consumption of 1e and the required MS was detected. The reaction mixture was quenched by adding MeOH (1 mL) at 25 °C and then concentrated under reduced pressure to produce a residue. The residue was examined by HPLC and purified by preparative HPLC (column: Ultimate C18 150*25 mm*5 μm; mobile phase: [water (10 mm NH4HCO3)-ACN]; B%: 30% to 55%, 10 min) to produce Example 4. For [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated by Cl2N5O5 is 440.0, and the measured LCMS value (m / z) is also 440.0. 1 H NMR (400MHz, CD3OD) δ7.93 (s, 2H), 7.31 (s, 1H), 3.51 (s, 3H), 3.19 (quind, J = 7.0, 13.8Hz, 1H), 1.27 (d, J = 6.8Hz, 6H).

[0448] Example 5: 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0449]

[0450] 2-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)acetonitrile (5a). K₂CO₃ (119.67 mg, 865.87 μol) and NaI (129.79 mg, 865.87 μol) were added to a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1b) (180 mg, 432.94 μol) and 2-bromoacetonitrile (259.65 mg, 2.16 mmol, 144.25 μL) in ACN (2 mL). The mixture was stirred at 100 °C in a sealed tube for 16 hours. LC-MS showed complete consumption of reactant 1b and the required MS was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, according to TLC) to produce 4a. [M+1] + (C 15 H 13 The MS quality requirement value calculated by Cl3N4O is 371.0 m / z, and the measured LCMS value is 371.0 m / z. 1 H NMR (400MHz, CD3Cl) δ7.25 (s, 1H), 6.66 (s, 2H), 4.83-4.77 (m, 1H), 4.05 (d, J = 6.4Hz, 2H), 3.29 (td, J = 6.8, 13.6Hz, 1H), 1.37 (d, J = 6.8Hz, 6H).

[0451] (Cyanomethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)carbamate tert-butyl (5b). DMAP (51.00 mg, 417.45 μol) and Boc2O (248.48 mg, 1.14 mmol, 261.55 μL) were added to a solution of 2-((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)amino)acetonitrile (5a) (172 mg, 379.50 μol) in THF (10 mL). The mixture was stirred at 40 °C for 2 hours. TLC indicated that reactant 5a was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, according to TLC) to produce 5b. [M+1] + (C 20 H 21 The MS quality requirement value (m / z) calculated by Cl3N4O3 is 471.1, and the measured value (m / z) of LCMS is also 471.1. 1H NMR (400MHz, CD3Cl) δ7.38 (s, 2H), 7.24 (s, 1H), 4.48 (s, 2H), 3.29 (td, J = 6.7, 13.6Hz, 1H), 1.53 (s, 9H), 1.37 (d, J = 6.8Hz, 6H).

[0452] (Z / E)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (5c). NH₂OH·HCl (170.87 mg, 2.46 mmol) and NaOAc (201.70 mg, 2.46 mmol) were added to a solution of (cyanomethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (5b) (145 mg, 307.36 μmol) in DMF (2 mL). The mixture was stirred at 80 °C for 6 hours. TLC showed complete consumption of reactant 5b. LCMS showed a main peak with the desired MS concentration. The suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (5 mL x 3). The combined filtrate was washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1, according to TLC) to produce 5c. [M+1] + (C 20 H 24 The MS quality requirement value (m / z) calculated by Cl3N5O4 is 504.1, and the measured LCMS value (m / z) is also 504.1. 1 H NMR (400MHz, CD3Cl) δ7.37(s,2H), 7.21(s,1H), 5.11(br s,2H), 4.23(s,2H), 3.28(td,J=7.0,13.8Hz,1H), 2.09(s,1H), 1.49(s,9H), 1.36(d,J=6.8Hz,6H).

[0453] (3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (5d). DSC (29.69 mg, 115.89 μol) and TEA (33.97 mg, 335.75 μol, 46.73 μL) were added to a solution of (Z / E)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (5c) (50 mg, 89.15 μol) in THF (2 mL). The mixture was stirred at 80 °C for 1 hour. LCMS showed complete consumption of 5c and the required MS was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1, according to TLC) to produce 5d. For [M+1] + (C 21 H 22 The MS quality requirement value (m / z) calculated by Cl3N5O5 is 530.1, and the measured value (m / z) of LCMS is also 530.1.

[0454] 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 5). NaOAc (75.66 mg, 922.40 μmol) was added to a solution of ((3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate)5d (68 mg, 115.30 μmol) in AcOH (3 mL). The mixture was stirred at 110 °C for 3 hours. LC-MS showed the consumption of the reactant 5d and the required MS was detected. The reaction mixture was concentrated under reduced pressure to remove AcOH and then a residue was generated. The residue was examined by HPLC and purified by preparative HPLC (column: Waters Xbridge preparative OBD C18 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 30% to 65%, 13 min) to produce Example 5. For [M+1] + (C 16 H 15 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 412.0, and the measured value (m / z) of LCMS is also 412.0. 1H NMR (400MHz, DMSO) δ12.11 (s, 1H), 7.31 (s, 1H), 6.79 (s, 2H), 6.66 (brt, J = 6.0Hz ,1H), 4.27(d,J=6.2Hz,2H), 3.02(td,J=7.0,13.6Hz,1H), 1.17(d,J=6.8Hz,6H).

[0455] Example 6: 3-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)-1,2,4-oxadiazol-5(4H)-one

[0456]

[0457] 6-(4-bromo-2,6-dichlorophenoxy)-3-chloro-4-isopropylpyridazine (6a). A mixture of 4-bromo-2,6-dichlorophenol (3.04 g, 12.56 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (2 g, 10.47 mmol) in pyridine (10 mL) was stirred for 48 hours at 130 °C in a 100 mL autoclave. LC-MS showed complete consumption of the initial material of 1a and the required MS was determined. The mixture was diluted with toluene (30 mL) and concentrated under vacuum. The residue was partitioned between ethyl acetate (30 mL x 2) and H2O (10 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 100:1) to produce 6a. Regarding [M+1] + (C 13 H 10 The MS quality requirement value (m / z) calculated by BrCl3N2O is 394.9, and the measured value (m / z) of LCMS is also 394.9. 1 H NMR (400MHz, DMSO) δppm 7.98-8.04(m,1H)7.92-7.97(m,1H)7.84(s,1H)3.11-3.29(m,1H)1.23-1.47(m,6H).

[0458] 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (6b). A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-3-chloro-4-isopropylpyridazine (6a) (1 g, 2.52 mmol) and NaOAc (827.59 mg, 10.09 mmol) in AcOH (10 mL) was stirred for 18 hours at 120 °C. LC-MS showed complete consumption of the initial material and the required MS was determined. The mixture was concentrated under vacuum. The solid was dissolved in water and the pH was adjusted to 9 with saturated NaHCO3 (2 mL). The mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to produce 6b. The product was used directly in the next step without further purification. [M+1] + (C 13 H 11 The MS quality requirement value (m / z) calculated by BrCl2N2O2 is 376.9, and the measured value (m / z) by LCMS is also 376.9. 1 HNMR(400MHz,DMSO)δppm 12.22(br s,1H)7.91-8.02(m,2H)7.39(s,1H)2.97-3.11(m,1H)2.87-2.95(m,1H)1.29(d,J=6.72Hz,1H)1.15-1.23(m,6H).

[0459] 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (6c). A mixture of 3-(4-bromo-2,6-dichlorophenoxy)-5-isopropyl-1H-pyridazine-6-one (6b) (500 mg, 1.32 mmol) in DMF-DMA (22.42 g, 188.19 mmol, 25.00 mL) was stirred for 16 hours at 105 °C. LC-MS showed complete consumption of the initial material and detection of the required MS. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate (10 mL x 2) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1:0 to 30:1) to produce 6c. [M+1] + (C 14 H 13 The MS quality requirement value (m / z) calculated by BrCl2N2O2 is 391.0, and the measured value (m / z) by LCMS is also 391.0. 1H NMR (400MHz, DMSO) δppm 7.96 (s, 2H) 7.41 (s, 1H) 3.32 (s, 1H) 3.08 (dt, J = 13.67, 6.84Hz, 1H) 2.50 (br d, J = 3.53Hz, 8H) 1.18 (d, J = 7.06Hz, 5H) 1.23 (br s,1H).

[0460] 6-(2,6-Dichloro-4-hydroxyphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (6d). A mixture of 6-(4-bromo-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (6c) (170 mg, 433.59 μmol), KOH (31.63 mg, 563.67 μmol), t-Bu Xphos (27.62 mg, 65.04 μmol), and Pd2(dba)3 (39.70 mg, 43.36 μmol) in dioxane (8 mL) and H2O (8 mL) was degassed and washed three times with N2. The mixture was then stirred at 100 °C under N2 atmosphere for 3.5 h. TLC showed complete consumption of 6c, and MS was determined by LCMS. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (5 mL x 3). The combined filtrate was concentrated to produce a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 1:1, according to TLC) to produce 6d. For [M+1] + (C 14 H 14 The MS quality requirement value (m / z) calculated for Cl2N2O3 is 329.0, and the measured MS value (m / z) is also 329.0. ¹H NMR (400MHz, CDCl3) δ 7.06 (s, 1H), 6.93 (s, 2H), 6.45 (br s, 1H), 3.55 (s, 3H), 3.25 (td, J = 6.8, 13.6Hz, 1H), 1.27 (d, J = 6.8Hz, 6H).

[0461] 2-(3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)acetonitrile (6e). K₂CO₃ (50.38 mg, 364.54 μol) and 2-bromoacetonitrile (21.86 mg, 182.27 μol, 12.15 μL) were added to a solution of 6-(2,6-dichloro-4-hydroxyphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (6d) (40 mg, 121.51 μol) in acetone (2 mL). The mixture was stirred at 20 °C for 2 hours. TLC showed complete consumption of 6d and the formation of a new spot. The suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOH (5 mL x 3). The combined filtrate was concentrated to dryness to produce a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 1:1) to produce a yellow solid containing 6e. [M+1] + (C 16 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O3 is 368.0, and the actual MS measured value (m / z) is also 368.0. 1 H NMR (400MHz, CDCl3) δ7.04 (s, 3H), 4.80 (s, 2H), 3.53 (s, 3H), 3.25 (td, J = 6.8, 13.4Hz, 1H), 1.27 (d, J = 6.8Hz, 6H).

[0462] (Z / E)-2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)N'-hydroxyacetamidine (6f). NH₂OH·HCl (57.37 mg, 825.61 μmol) and NaOAc (67.72 mg, 825.61 μmol) were added to a solution of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)acetonitrile (6e) (38 mg, 103.20 μmol) in DMF (2 mL). The mixture was stirred at 80 °C for 6 hours. TLC showed complete consumption of 6e, and LCMS showed a main peak with the desired MS concentration. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with brine (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce 6f (66.3 mg, crude). This product was ready for use in the next step without further purification. [M+1] + (C 16 H 18The MS quality requirement value (m / z) calculated by Cl2N4O4 is 401.0, and the measured value (m / z) by LCMS is 401.2.

[0463] 3-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 6). DSC (44.02 mg, 171.85 μL) and TEA (26.75 mg, 264.38 μL, 36.80 μL) were added to a solution of (Z / E)-2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenoxy)-N'-hydroxyacetamidine (6f) (66.3 mg, 132.19 μL) in THF (2 mL). The mixture was stirred at 60 °C for 4 hours. LCMS showed complete consumption of 6f and the required MS was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Waters Xbridge preparative OBDC18 150*30 5u; mobile phase: [water (0.04% NH3H2O)-ACN]; B%: 5% to 35%, 10 min) to produce Example 6. For [M+1] + (C 17 H 16 The MS quality requirement value (m / z) calculated by Cl2N4O5 is 427.1, and the measured value (m / z) of LCMS is also 427.1. 1 HNMR (400MHz, CD3OD) δ7.30 (s, 1H), 7.24 (s, 2H), 5.10 (s, 2H), 3.49 (s, 3H), 3.19 (quind, J = 7.0, 13.8Hz, 1H), 1.27 (d, J = 6.8Hz, 6H).

[0464] Example 7: 5-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one

[0465]

[0466] 6-(2,6-Dichloro-4-iodophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (7a). NaNO₂ (12.61 mg, 182.82 μol) was added to a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (1e) (50 mg, 152.35 μol) in HCl (5 M, 304.70 μL) at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. A solution of KI (50.58 mg, 304.70 μol) in H₂O (1.5 mL) was then added to the mixture, and the mixture was stirred again at 20 °C for 16 h. TLC indicated complete consumption of reactant 1e. LCMS showed complete consumption of reactant 1e and the formation of a main peak with the desired MS. The reaction mixture was extracted with EtOAc (5 mL x 4). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was analyzed by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1, product R). f =0.80, purified according to TLC to produce 7a. For [M+1] + (C 14 H 12 The MS quality requirement value (m / z) calculated by Cl2N2O2 is 438.9, and the measured value (m / z) of LCMS is also 438.9. 1 H NMR (400MHz, CDCl3) δ7.71 (s, 2H), 7.04 (s, 1H), 3.52 (s, 3H), 3.25 (td, J = 7.0, 13.4Hz, 1H), 1.26 (d, J = 6.8Hz, 6H).

[0467] Ethyl propargyl 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)propargyl acid (7b). A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (7a) (25 mg, 56.94 μmol), ethyl propargyl acid (12.29 mg, 125.26 μmol), Pd(PPh3)2Cl2 (4.00 mg, 5.69 μmol), CuI (2.17 mg, 11.39 μmol), and Cs2CO3 (37.10 mg, 113.88 μmol) in THF (5 mL) was degassed and washed three times with N2. The mixture was then stirred in a microwave at 110 °C for 0.5 h. TLC indicated that reactant 7a was completely consumed and formed numerous spots. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (5 mL x 3). The combined filtrate was concentrated to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1, according to TLC) to produce 7b. [M+1] + (C 19 H 18 The MS quality requirement value (m / z) calculated by Cl2N2O4 is 409.1, and the measured value (m / z) of LCMS is also 409.1. 1 HNMR (400MHz, CDCl3) δ7.61 (s, 2H), 7.06 (s, 1H), 4.32 (q, J = 7.0Hz, 2H), 3.51 (s, 3 H), 3.25 (quind, J=6.8, 13.8Hz, 1H), 1.37 (t, J=7.2Hz, 3H), 1.27 (d, J=6.8Hz, 6H).

[0468] 5-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (Example 7). NH₂OH·HCl (13.50 mg, 194.22 μmol) and KOH (16.35 mg, 291.33 μmol) were added to a solution of ethyl 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)propynate (7b) (27 mg, 48.56 μmol) in MeOH (3 mL). The mixture was stirred at 25 °C for 16 hours. TLC showed complete consumption of reactant 7b. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was examined by HPLC and purified by preparative HPLC (column: Waters Xbridge preparative OBD C18 150*30 5u; mobile phase: [water (0.04% NH₃H₂O)-ACN]; B%: 5% to 35%, 10 min) to produce Example 7. [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated by Cl2N3O4 is 396.0, and the measured LCMS value (m / z) is also 396.0. 1 H NMR (400MHz, CDCl3) δ7.76 (s, 2H), 7.08 (s, 1H), 6.25 (s, 1H), 3.52 (s, 3H), 3.31-3.22 (m, 1H), 1.28 (d, J = 6.8Hz, 6H).

[0469] Example 8: 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one

[0470]

[0471] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)acetamide (8a). NaOAc (863.18 mg, 10.52 mmol) was added to a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (1b) (1 g, 3.01 mmol) in AcOH (10 mL). The mixture was stirred at 100 °C for 16 h. LCMS showed a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with water (20 mL) and 1N NaOH was added to adjust the pH to 9–10. The suspension was extracted with EtOAc (10 mL x 4), the combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce 8a (1.55 g, crude). The product was ready for use in the next step without further purification. Regarding [M+1] + (C 15 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O3 is 356.1, and the measured LCMS value (m / z) is also 356.1.

[0472] 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (8b). An aqueous solution of NaOH (1M, 21.26 mL) was added to a solution of N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)acetamide (8a) (1.55 g, 3.48 mmol) in MeOH (20 mL). The mixture was stirred at 120 °C for 4 hours. LC-MS showed a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (20 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 5:1 to 1:5, according to TLC) to produce 8b. Regarding [M+1] + (C 13 H 13 The MS quality requirement value (m / z) calculated by Cl2N3O2 is 314.0, and the measured value (m / z) of LCMS is also 314.0. 1 H NMR (400MHz, DMSO) δ12.11(s,1H), 7.25(s,1H), 6.64(s,2H), 5.60(s,2H), 3.07-2.94(m,1H), 1.19-1.12(m,7H).

[0473] 6-(2,6-Dichloro-4-iodophenoxy)-4-isopropylpyridazine-3(2H)-one (8c). NaNO₂ (65.89 mg, 954.91 μol) was added to a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (8b) (250 mg, 795.76 μol) in HCl (967.11 mg, 7.96 mmol, 948.14 μL, 30% purity) at 0 °C, and the mixture was stirred for 0.5 h. Then, a solution of KI (264.19 mg, 1.59 mmol) in H₂O (5 mL) was added to the mixture. The mixture was then stirred again at 20 °C for 16 h. LC-MS showed a main peak with the desired MS concentration. The reaction mixture was extracted with EtOAc (10 mL x 4). The assembled organic layer was washed, dried with Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was analyzed by preparative TLC (SiO2, petroleum ether:ethyl acetate = 3:1, product R...). f =0.60, purified according to TLC to produce 8c. For [M+1] + (C 13 H 11 The MS quality requirement value (m / z) calculated by Cl2IN2O2 is 424.9, and the measured value (m / z) of LCMS is also 424.9. 1 H NMR (400MHz, CDCl3) δ10.50-10.29(m,1H), 7.75-7.69(m,2H), 7.13-7.08(m,1H), 3.30-3.14(m,1H), 1.28-1.25(m,6H).

[0474] 6-(2,6-Dichloro-4-iodophenoxy)-4-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (8d). 2-(chloromethoxy)ethyl-trimethylsilane (58.84 mg, 352.90 μL, 62.46 μL) was added to a mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropylpyridazine-3(2H)-one (8c) (50 mg, 117.63 μL), DIPEA (30.41 mg, 235.27 μL, 40.98 μL) in DMF (4 mL). The mixture was degassed and washed three times with N2, and stirred at 25 °C under N2 atmosphere for 2 hours. TLC indicated complete consumption of 8c. LCMS showed a main peak with the desired MS concentration. The reaction mixture was quenched by adding water (5 mL) and then extracted with EtOAc (6 mL x 3). The combined organic layers were concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 5:1, according to TLC) to produce 8d. For [M+1] + (C 19 H 25 The MS quality requirement value (m / z) calculated by Cl2IN2O3Si is 555.0, and the measured LCMS value (m / z) is 555.0. 1 H NMR (400MHz, CD3OD) δ7.78-7.61(m,2H), 7.13-7.00(m,1H), 5.28-5.16(m,2H), 3.58-3. 50(m,2H), 3.32-3.18(m,1H), 1.31-1.23(m,6H), 0.91-0.83(m,2H), 0.01-0.11(m,9H).

[0475] Ethyl 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazine-3-yl)oxy)phenyl)propynate (8e). A mixture of 6-(2,6-dichloro-4-iodophenoxy)-4-isopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (8d) (18 mg, 32.41 μmol), ethyl propynate (7.00 mg, 71.31 μmol, 7.00 μL), Pd(PPh3)2Cl2 (2.28 mg, 3.24 μmol), CuI (1.23 mg, 6.48 μmol), and Cs2CO3 (21.12 mg, 64.83 μmol) in THF (4 mL) was degassed and washed three times with N2, and then stirred in a microwave at 110 °C for 0.5 h. TLC indicated complete consumption of 8d and formation of numerous spots. LCMS showed the formation of a main peak with the desired MS. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (5 mL x 3). The combined filtrate was concentrated to dryness to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 8:1, according to TLC) to produce 8e. [M+1] + (C 24 H 30 The MS quality requirement value (m / z) calculated by Cl2N2O5Si is 525.1, and the measured value (m / z) of LCMS is also 525.1. 1 H NMR (400MHz, CD3OD) δ7.61-7.57(m,2H), 7.08-7.06(m,1H), 5.19-5.17(m,2H), 4.35-4.28(m,2H), 3.57-3. 50(m,2H), 3.31-3.19(m,1H), 1.38-1.34(m,3H), 1.28-1.25(m,6H), 0.89-0.84(m,2H), -0.03-0.06(m,9H).

[0476] 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (8f). Ethyl 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)propynate (8e) (5 mg, 9.51 μmol) in MeOH (2 mL) was added to NH₂OH·HCl (2.64 mg, 38.06 μmol) and KOH (3.20 mg, 57.09 μmol). The mixture was stirred at 25 °C for 5 hours. TLC indicated complete consumption of 8e. LCMS showed the formation of a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H₂O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 3:2, according to TLC) to produce 8f. For [M+1] + (C 22 H 27 The MS quality requirement value (m / z) calculated by Cl2N3O5Si is 512.1, and the measured value (m / z) of LCMS is also 512.1. 1 HNMR (400MHz, CD3OD) δ7.78-7.73(m,2H), 7.12-7.08(m,1H), 6.29-6.24(m,1H), 5.23-5.20(m,2H) , 3.59-3.52(m,2H), 3.33-3.22(m,1H), 1.30-1.27(m,6H), 0.90-0.85(m,2H), -0.05-0.10(m,9H).

[0477] 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (Example 8). A solution of 5-(3,5-dichloro-4-((5-isopropyl-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoxazol-3(2H)-one (8f) (4 mg, 7.81 μmol) in TFA (2 mL) was stirred for 4 hours at 25 °C. LCMS showed complete consumption of 8f and the required MS was detected. The mixture was then concentrated under vacuum. The residue was examined by HPLC and purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.2% FA)-ACN]; B%: 30% to 60%, 12 min) to produce Example 8. For [M+1] + (C 16 H 13 The MS quality requirement value (m / z) calculated by Cl2N3O4 is 382.0, and the measured value (m / z) of LCMS is also 382.0. 1 H NMR (400MHz, CD3OD) δ7.91-7.86(m,2H), 7.37-7.35(m,1H), 6.48-6.46(m,1H), 3.20-3.14(m,1H), 1.33-1.24(m,6H).

[0478] Example 9: 3-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]phenyl]-4H-1,2,4-oxadiazol-5-one

[0479]

[0480] 3,5-Dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yl)oxybenzonitrile (9a). A mixture of 3,5-dichloro-4-hydroxybenzonitrile (1a) (100 mg, 531.88 μmol) and 3,6-dichloro-4-isopropyl-pyridazine (101.62 mg, 531.88 μmol) in Py (3 mL) was stirred for 36 hours at 130 °C. LC-MS showed complete consumption of 1a and the required MS was detected. The mixture was diluted with toluene (5 mL x 3) and concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 5:1) to produce 9a. [M+1] + (C 14 H 10 The MS quality requirement value calculated by Cl3N3O is 342.0 m / z, and the measured LCMS value is 342.1 m / z. 1HNMR (400MHZ, CD3OD) δ 8.02 (s, 2H), 7.67 (s, 1H), 3.47-3.50 (m, 1H), 3.32-3.39 (m, 1H), 1.37 (d, J = 6.84HZ, 6H).

[0481] (Z / E)-3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-N'-hydroxybenzoamide (9b). NH₂OH·HCl (97.36 mg, 1.40 mmol) and NaOAc (114.93 mg, 1.40 mmol) were added to a solution of 3,5-dichloro-4-(6-chloro-5-isopropylpyridazin-3-yl)oxy-benzonitrile (9a) (60 mg, 175.13 μmol) in DMF (2 mL). The mixture was stirred at 80 °C for 1 hour. LCMS showed complete consumption of the initial material and the required MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL x 2) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to yield 9b. [M+1] + (C 14 H 13 The MS quality requirement value (m / z) calculated by Cl3N4O2 is 375.0, and the measured LCMS value (m / z) is also 375.0.

[0482] 3-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (9c). DSC (53.19 mg, 207.65 μol) and TEA (32.33 mg, 319.46 μol, 44.46 μL) were added to a solution of (Z / E)-3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-N'-hydroxybenzoamide (9b) (60 mg, 159.73 μol) in THF (3 mL). The mixture was stirred at 60 °C for 16 hours. LCMS showed complete consumption of the initial material and the required MS was detected. The mixture was concentrated under vacuum to produce 9c (60 mg, crude). The product was used directly in the next step without further purification. For [M+1] + (C 15 H 11 The MS quality requirement value (m / z) calculated by Cl3N4O3 is 401.0, and the measured LCMS value (m / z) is also 401.0.

[0483] 3-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (Example 9). NaOAc (49.02 mg, 597.56 μmol) was added to a solution of 3-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (9c) (60 mg, 149.39 μmol) in HOAc (3 mL). The mixture was stirred at 120 °C for 16 hours. LCMS showed complete consumption of the initial material and the required MS was detected. The mixture was concentrated under vacuum to produce a residue. The residue was purified by preparative HPLC (column: Waters Atlantis T3 150*30*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 35% to 75%, 13 min) to produce Example 9. For [M+1] + (C 15 H 12 The MS quality requirement value (m / z) calculated by Cl2N4O4 is 383.0, and the measured LCMS value (m / z) is also 383.0. 1 H NMR (400MHZ, CD3OD) δ7.93 (s, 2H), 7.38 (d, J = 0.8HZ, 1H), 3.17 (spt, J = 6.8HZ, 1H), 1.29 (d, J = 6.8HZ, 6H).

[0484] Example 10: 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H)-one

[0485]

[0486] 3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzonitrile (10a). NaOAc (38.31 mg, 467.01 μmol) was added to a solution of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)benzonitrile (9a) (40 mg, 116.75 μmol) in HOAc (4 mL). The mixture was stirred at 120 °C for 16 h. LCMS showed complete consumption of the initial material and the required MS was determined. The mixture was concentrated under vacuum. The solid was dissolved in water and the pH was adjusted to 9 with NaHCO3 (4 mL). The mixture was then partitioned into 10 mL portions of ethyl acetate twice. The combined organic phase was washed with brine (5 mL x 3), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to produce 10a (34 mg, crude). Regarding [M+1] + (C 14 H 11 The MS quality requirement value (m / z) calculated for Cl2N3O2 is 324.0, and the measured LCMS value (m / z) is 324.2. 1 HNMR (400MHZ, DMSO) δ12.28(s,1H), 8.27-8.35(m,2H), 7.44(s,1H), 3.27-3.44(m,25H), 2.98-3.10(m,1H), 1.15-1.23(m,6H).

[0487] 3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzonitrile (10b). A mixture of 3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzonitrile (10a) (34 mg, 104.89 μmol) in DMF-DMA (2 mL) was stirred for 5 hours under reflux at 110 °C. LC-MS showed complete consumption of the initial material and the required MS was detected. The mixture was concentrated under vacuum. The residue was partitioned twice between ethyl acetate (10 mL) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce the residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to produce 10b. Regarding [M+1] + (C 15 H 13 The MS quality requirement value (m / z) calculated for Cl2N3O2 is 338.0, and the measured LCMS value (m / z) is also 338.0. 1H NMR (400MHZ, CD3OD) δ 8.00 (s, 2H), 7.38 (s, 1H), 3.48 (s, 3H), 3.14-3.25 (m, 1H), 1.28 (d, J = 6.85HZ, 6H).

[0488] (Z)-3,5-dichloro-N'-hydroxy-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzomid (10c). NH2OH·HCl (41.10 mg, 591.39 μmol) and NaOAc (48.51 mg, 591.39 μmol) were added to a solution of 3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)benzonitrile (10b) (25 mg, 73.92 μmol) in DMF (2 mL). The mixture was stirred at 80 °C for 1 hour. LCMS showed complete consumption of 10b and the required MS was detected. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned between ethyl acetate (10 mL) and H2O (3 mL). The combined organic phases were washed with brine (5 mL x 3), dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce 10c (25 mg, crude). The product could be used directly in the next step without further purification. [M+1] + (C 15 H 16 The MS quality requirement value (m / z) calculated by Cl2N4O3 is 371.1, and the measured value (m / z) of LCMS is 371.2.

[0489] 3-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-1,2,4-oxadiazol-5(4H)-one (Example 10). DSC (22.43 mg, 87.55 μol) and TEA (13.63 mg, 134.69 μol, 18.75 μL) were added to a solution of (Z)-3,5-dichloro-N'-hydroxy-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3yl)oxy)benzamidin (10c) (25 mg, 67.35 μol) in THF (3 mL). The mixture was stirred at 60 °C for 16 hours. LCMS showed complete consumption of the initial material and the required MS was detected. The mixture was concentrated under vacuum to produce a residue. The residue was purified by preparative HPLC (column: Waters Atlantis T3 150*30*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30% to 70%, 13 min) to produce Example 10. For [M+1] +(C 16 H 14 The MS quality requirement value (m / z) calculated for Cl2N4O4 is 397.0, and the measured LCMS value (m / z) is also 397.0. 1 H NMR (400MHZ, CD3OD) δ7.92-7.98 (m, 2H), 7.37 (d, J = 0.73HZ, 1H), 3.48 (s, 3H), 3.12-3.26 (m, 1H), 1.28 (d, J = 6.85HZ, 6H).

[0490] Option B: 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazine-3(2H)-one (compound 11d)

[0491]

[0492] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)-2-methylaniline (11a). K₂CO₃ (575.75 mg, 4.17 mmol) and CuI (119.01 mg, 624.86 μmol) were added to a mixture of 4-amino-2,6-dichloro-3-methylphenol (0.2 g, 1.04 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (198.97 mg, 1.04 mmol) in DMSO (5 mL) at 25 °C. The mixture was then stirred at 90 °C for 16 hours. The mixture was added to H₂O (25 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The mixture was washed with petroleum ether (5 mL) and filtered. The filter cake is concentrated in a vacuum to produce 11a.

[0493] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)isoindoline-1,3-dione (11b). NaOAc (378.63 mg, 4.62 mmol) was added to a mixture of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-2-methylaniline (11a) (0.4 g, 1.15 mmol) and isobenzofuran-1,3-dione (170.92 mg, 1.15 mmol) in AcOH (10 mL) at 25 °C. The mixture was then stirred at 120 °C for 12 hours. LCMS showed that the reaction was complete. The mixture was concentrated to obtain a residue, which was then extracted with ethyl acetate (50 mL x 2) by adding H₂O (20 mL). The combined organic phase was washed with brine (50 mL x 2), dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was washed with MTBE (5 mL) and filtered. The filter cake was concentrated to produce 11b. [M+1] + (C 22 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O4 is 458.1, and the measured value (m / z) of LCMS is also 458.1.

[0494] 2-(3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)isoindoline-1,3-dione (11c). A mixture of 2-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]-2-methyl-phenyl]isoindoline-1,3-dione (11b) (0.37 g, 807.34 μmol) in DMF-DMA (5 mL) was stirred for 4 hours at 105 °C. LC-MS showed the reaction was complete. The mixture was added to H₂O (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce 11c. The crude product was used directly in the next step. Regarding [M+1] + (C 22 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O4 is 472.1, and the measured value (m / z) of LCMS is also 472.1.

[0495] 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (11d). Butyl-1-amine (2M, 1.40 mL) was added to a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]isoindoline-1,3-dione (11c) (440 mg, 931.57 μmol) in MeOH (1 mL) at 70 °C. The mixture was stirred at 70 °C for 1 hour. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to produce 11d. [M+1] + (C 22 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O4 is 342.1, and the measured value (m / z) of LCMS is also 342.1. 1 H NMR (400MHz, CD3OD) δ7.22 (s, 1H), 6.77 (s, 1H), 3.50 (s, 3H), 3.20-3.14 (m, 1H), 2.20 (s, 3H), 1.25 (d, J = 6.8Hz, 6H).

[0496] Example 11: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0497]

[0498] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 11). TEA (18.50 mg, 182.82 μol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (13.57 mg, 91.41 μol) were added to a solution of 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (11d) (20.85 mg, 60.94 μol) in THF (3 mL). The mixture was stirred at 25 °C for 0.5 h. TLC showed consumption over 11 days. The reaction mixture was quenched at 25°C with the addition of MeOH (1 mL) and then concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Ultimate C18 150*25mm*5μm; mobile phase: [water (10 mm NH4HCO3)-ACN]; B%: 20% to 50%, 10 min) to produce Example 11. For [M+1] + (C 18 H 17 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 454.1, and the measured LCMS value (m / z) is also 454.1. 1 H NMR (400MHz, CD3OD) δ7.77 (s, 1H), 7.31 (d, J = 0.7Hz, 1H), 3.49 (s, 3H), 3.23-3.11 (m, 1H), 2.38 (s, 3H), 1.27 (d, J = 6.8Hz, 6H).

[0499] Example 12: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2-methylphenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0500]

[0501] 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-aniline]acetonitrile (12a). 2-bromoacetonitrile (87.62 mg, 730.52 μol, 48.68 μL), NaI (43.80 mg, 292.21 μol), and K₂CO₃ (40.39 mg, 292.21 μol) were added to a solution of 6-(4-amino-2,6-dichloro-3-methylphenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (11d) in ACN (1 mL). The mixture was stirred at 100 °C for 16 hours. The suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (5 mL * 3). The combined filtrate was concentrated to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1) to produce (12a). 1 HNMR (400MHz, CDCl3) δ7.04 (s, 1H), 6.71 (s, 1H), 4.20 (d, J = 6.6Hz, 2H), 4.13 (q, J = 7 .2Hz,1H), 4.08-4.01(m,1H), 3.53(s,3H), 3.31-3.16(m,1H), 2.27(s,3H), 1.59(br s,4H), 1.38-1.15(m,8H).

[0502] N-(cyanomethyl)-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]carbamate tert-butyl (12b). Boc₂O (94.45 mg, 432.78 μL, 99.42 μL) and DMAP (17.62 mg, 144.26 μL) were added to a solution of 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-aniline]acetonitrile (12a) (55 mg, 144.26 μL) in THF (1 mL). The mixture was stirred at 40 °C for 1 hour. LCMS showed complete consumption of the initial material and the required MS was detected. The mixture was partitioned twice between ethyl acetate (10 mL) and H₂O (3 mL). The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 3:1) to produce 12b. [M+1] + (C 22 H 26The MS quality requirement value (m / z) calculated by Cl2N4O4 is 481.1, and the measured LCMS value (m / z) is also 481.1. 1 H NMR (400MHz, CDCl3) δ7.04(d,J=1.0Hz,1H), 4.57-4.27(m,2H), 3.48(brs,3H), 3.28-3.16(m,1H), 2.29(s,3H), 1.66-1.47(m,10H), 1.38(br s,6H).

[0503] N-[(2Z)-2-amino-2-hydroxyimino-ethyl]-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl] tert-butyl carbamate (12c). NH₂OH·HCl (46.19 mg, 664.77 μmol) and NaOAc (54.53 mg, 664.77 μmol) were added to a solution of N-(cyanomethyl)-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl] tert-butyl carbamate (12b) (40 mg, 83.10 μmol) in DMF (1 mL). The mixture was stirred at 80 °C for 1 hour. The residue was partitioned twice between ethyl acetate (10 mL) and H₂O (3 mL). The combined organic phases were washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1) to yield 12c. [M+1] + (C 22 H 29 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 514.2, and the measured LCMS value (m / z) is also 514.2. 1 H NMR (400MHz, CDCl3) δ7.16 (s, 1H), 7.05 (d, J = 1.0Hz, 1H), 5.27 (br s,2H), 3.50(s,3H), 3.33-3.17(m,1H), 2.25(s,4H), 1.39(s,8H), 1.28-1.26(m,7H).

[0504] N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]-N-[(5-oxo-4H-1,2,4-oxadiazol-3-yl)methyl] tert-butyl carbamate (12d). DSC (25.90 mg, 101.09 μol) and TEA (15.74 mg, 155.52 μol, 21.65 μL) were added to a solution of N-[(2Z)-2-amino-2-hydroxyimino-ethyl]-N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl] tert-butyl carbamate (12c) (40 mg, 77.76 μol) in THF (1 mL). The mixture was stirred at 60 °C for 16 hours. LCMS showed complete consumption of the initial material and the required MS was detected. The mixture was partitioned twice between ethyl acetate (10 mL) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (SiO₂, DCM:MeOH = 5:1) to produce 12d. [M+1] + (C 22 H 29 The MS quality requirement value (m / z) calculated by Cl2N5O5 is 540.1, and the measured value (m / z) of LCMS is also 540.1.

[0505] 3-[[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-aniline]methyl]-4H-1,2,4-oxadiazol-5-one (Example 12). HCl / EtOAc (2M, 27.76 μL) was added to a solution of N-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-2-methyl-phenyl]-N-[(5-oxo-4H-1,2,4-oxadiazol-3-yl)methyl]carbamate tert-butyl (12d) (30 mg, 55.51 μL) in EtOAc (1 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (HCl conditions) to produce Example 12. Regarding [M+1] + (C 22 H 29 The MS quality requirement value (m / z) calculated by Cl2N5O5 is 440.1, and the measured LCMS value (m / z) is 440.2. 1H NMR (400MHz, CD3OD) δ7.24 (s, 1H), 6.72 (s, 1H), 4.37 (s, 2H), 3.48 (s, 3H), 3.23-3.11 (m, 1H), 2.29 (s, 3H), 1.26 (d, J = 6.8Hz, 6H).

[0506] Scheme C: 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (compound 13e)

[0507]

[0508] Ethyl 2-cyano-2-(2,6-dichloro-4-nitrophenyl)acetate (13a). Ethyl 2-cyanoacetate (4.00 g, 35.33 mmol) was added dropwise to a suspension of NaH (1.41 g, 35.33 mmol, 60% purity) in DMSO (40 mL) at 0 °C and stirred at 15 °C for 30 min. Then, 1,2,3-trichloro-5-nitrobenzene (4 g, 17.66 mmol) was added, and the resulting mixture was stirred at 15 °C for 16 h. The mixture was then quenched with water (100 mL) and adjusted to pH 1 with 1 M HCl. The white precipitate was collected by filtration and dried under vacuum. The solid was washed with petroleum ether (40 mL) and dried under vacuum to produce 13a. 1 H NMR (400MHz, CDCl3) δ 8.32 (s, 2H), 5.72 (s, 1H), 4.38 (q, J = 7.1Hz, 2H), 1.37 (t, J = 7.2Hz, 3H).

[0509] 2-(2,6-Dichloro-4-nitrophenyl)acetonitrile (13b). A mixture of ethyl 2-cyano-2-(2,6-dichloro-4-nitrophenyl)acetonitrile (13a) (1.7 g, 5.61 mmol) and LiCl (285.33 mg, 6.73 mmol) in DMSO (6 mL) and H₂O (2.5 mL) was heated to 165 °C for 1 hour. After cooling, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to produce 13b. 1 H NMR (400MHz, CDCl3) δ8.21 (s, 2H), 4.03 (s, 2H).

[0510] 2-(4-amino-2,6-dichlorophenyl)acetonitrile (13c). A mixture of 2-(2,6-dichloro-4-nitrophenyl)acetonitrile (13b) (1 g, 4.33 mmol) and Fe (1.21 g, 21.64 mmol) in HOAc (10 mL) was heated to 15 °C for 1 hour. New spots were observed by TLC. The mixture was filtered, and water (100 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL). The organic phase was neutralized with saturated NaHCO3 (20 mL x 2), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to produce 13c. 1 HNMR (400MHz, CDCl3) δ6.67 (s, 2H), 3.88 (s, 4H).

[0511] 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazine-3-yl)acetonitrile (13d). t-BuOK (1M, 4.28 mL) was added dropwise to a solution of 2-(4-amino-2,6-dichlorophenyl)acetonitrile (13c) (0.43 g, 2.14 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (408.62 mg, 2.14 mmol) in THF (5 mL) at 60 °C. The resulting mixture was heated to 60 °C for 40 minutes. After cooling, the mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to produce 13d. [M+1] + (C 15 H 13 The MS quality requirement value calculated by Cl3N4 is m / z 355.0, and the measured LCMS value is m / z 355.1. 1 H NMR (400MHz, CDCl3) δ7.60 (s, 1H), 6.69 (s, 2H), 6.33 (s, 1H), 3.99 (br s, 2H), 3.33 (td, J = 6.8, 13.6Hz, 1H), 1.32 (dd, J = 4.0, 6.8Hz, 6H).

[0512] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (13e). A solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (13d) (0.15 g, 421.76 μmol) in HOAc (0.6 mL), H₂O (0.6 mL), and concentrated HCl (2.4 mL) was heated to 120 °C for 32 hours. LC-MS showed the desired MS. After cooling, the mixture was adjusted to pH ~7 with 4 M NaOH at 0 °C. The solid was filtered and dried to produce a grayish-white solid, 13e, which could be used directly in the next step. For [M+1] + (C 14 H 15 The MS quality requirement value calculated by Cl2N3O is m / z 311.0, and the measured value of LCMS is m / z 311.1.

[0513] Example 13: N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0514]

[0515] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 13). TEA (19.45 mg, 192.19 μmol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (14.27 mg, 96.09 μmol, 1.5 equivalents) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (13e) (20 mg, 64.06 μmol) in THF (3 mL) were added. The mixture was stirred at 25 °C for 0.5 h. TLC showed complete consumption of 13e. The reaction mixture was quenched by adding MeOH (1 mL) at 25 °C and then concentrated under reduced pressure to produce a residue. The residue was examined by HPLC and purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mm NH4HCO3)-ACN]; B%: 5% to 35%, 10 min) to produce Example 13. For [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 424.0, and the measured value (m / z) of LCMS is also 424.0.1 H NMR (400MHz, CD3OD) δ7.87 (s, 2H), 7.23 (s, 1H), 4.30 (s, 2H), 3.16-3.04 (m, 1H), 1.20 (d, J = 7.1Hz, 6H).

[0516] Example 14: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0517]

[0518] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (14a). H₂O (2 mL) was added to a solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazine-3-yl)acetonitrile (13d) (1.5 g, 4.22 mmol) in concentrated HCl (16 mL) and HOAc (2 mL). The mixture was stirred at 120 °C for 72 h. LCMS showed the desired mass. The pH of the mixture was adjusted to 7 by adding 6 M sodium hydroxide aqueous solution. The suspension was stirred for 15 min. The resulting solid was filtered and washed with H₂O and petroleum ether. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to produce 14a. 1 HNMR(400MHz,DMSO-d6)δ12.59(s,1H),7.12-7.10(m,1H),6.62(s,2H),5.6 0(s,2H), 3.99(s,2H), 2.96(td,J=6.9,13.5Hz,1H), 1.11(d,J=6.8Hz,6H).

[0519] 2-(3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (14b). Isobenzofuran-1,3-dione (213.50 mg, 1.44 mmol) was added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazin-3(2H)-one (14a) (450 mg, 1.44 mmol) in AcOH (5 mL). The mixture was stirred at 130 °C for 4 hours. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to remove AcOH. This mixture was extracted with water (50 mL) and ethyl acetate (50 mL), washed with NaHCO3 (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce 14b. The product was ready for use in the next step without further purification. Regarding [M+1] + (C 22 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O3 is 442.1, and the measured value (m / z) of LCMS is also 442.1.

[0520] 2-(3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (14c). A mixture of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (14b) (600 mg, 1.36 mmol) and DMF-DMA (5 mL) was heated to 105 °C for 3 hours. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to produce 14c. The product was ready for use in the next step without further purification. [M+1] + (C 23 H 19 The MS quality requirement value (m / z) calculated for Cl2N3O3 is 456.1, and the measured LCMS value (m / z) is also 456.1.

[0521] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (14d). A solution of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (14c) (600 mg, 1.31 mmol) in N-butylamine (981.11 mg, 6.57 mmol) and MeOH (3 mL) was heated to 70 °C for 3 hours. TLC showed that the reaction was complete. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1) to produce 14d. For [M+1] + (C 18 H 17 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 326.1, and the measured LCMS value (m / z) is 326.0. 1 H NMR (400MHz, CD3OD) δ7.08-7.04(m,1H), 6.72-6.69(m,2H), 4.13(s,2H), 3.70(s,3H), 3.14-3.06(m,1H), 1.15(d,J=6.8Hz,6H).

[0522] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 14). TEA (18.15 mg, 179.33 μmol, 3 equivalents) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (8.88 mg, 59.78 μmol) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (14d) (19.43 mg, 59.78 μmol) in DCM (2 mL). The mixture was degassed and washed three times with N2, and stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (NH4CO3) to produce Example 14. [M+1]+(C 18 H 17 C l2The MS quality requirement value calculated for N5O4 is 438.1 m / z, and the measured LCMS value is 438.0 m / z. The 1H NMR (400MHz, CD3OD) values ​​are 7.89 (s, 2H), 7.18 (s, 1H), 4.30 (s, 2H), 3.69-3.63 (m, 3H), 3.13 (td, J = 7.0, 13.8Hz, 1H), and 1.19 (d, J = 6.8Hz, 6H).

[0523] Example 15: 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0524]

[0525] 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazine-3(2H)-one (15a). PMB-Cl (120.39 mg, 768.75 μmol) and K₂CO₃ (106.25 mg, 768.75 μmol) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropylpyridazine-3(2H)-one (13e) (200 mg, 640.63 μmol) in DMF (5 mL). The mixture was stirred at 20 °C for 16 hours. The suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOH (5 mL x 3). The combined filtrate was concentrated to dryness to produce a residue. The residue was purified by preparative TLC to produce 15a. 1 H NMR(400MHz,DMSO-d6)δppm 7.17(d,J=8.6Hz,2H), 7.04(s,1H), 6.85-6.80(m,2H), 6.65(s,2H), 5.63(s,2H), 5.02 (s, 2H), 4.01 (s, 2H), 3.71 (s, 3H), 2.97 (td, J = 6.8, 13.5Hz, 1H), 1.07 (d, J = 7.1Hz, 6H).

[0526] 2-((3,5-Dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (15b). K₂CO₃ (57.54 mg, 416.34 μmol) and KI (28.80 mg, 173.47 μmol) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-(4-methoxybenzyl)pyridazin-3(2H)-one (15a) (150 mg, 346.95 μmol) and 2-bromoacetonitrile (416.16 mg, 3.47 mmol) in DMF (10 mL). The mixture was stirred at 100 °C for 6 hours. The reaction mixture was quenched by adding 5 mL of water and then extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1, according to TLC) to produce 15b. 1 H NMR (400MHz, DMSO-d6) δ7.15(d,J=8.6Hz,2H), 7.12(s,1H), 6.87(s,2H), 6.83(d,J=8.8Hz,2H), 6.76(t,J=6.7Hz,1H ), 5.00 (s, 2H), 4.37 (d, J = 6.6Hz, 2H), 4.08 (s, 2H), 3.71 (s, 3H), 2.99 (td, J = 6.7, 13.7Hz, 1H), 1.08 (d, J = 6.8Hz, 6H).

[0527] (Cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)tert-butyl carbamate (15c). DMAP (34.47 mg, 282.15 μmol) and Boc2O (184.74 mg, 846.45 μmol) were added to a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (15b) (133 mg, 282.15 μmol) in THF (3 mL). The mixture was stirred at 20 °C for 1 hour. The reaction was complete according to TLC. LCMS showed a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure, yielding a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, according to TLC), yielding 15c. [M+1] + (C 29 H 32The MS quality requirement value (m / z) calculated for Cl2N4O4 is 571.2, and the measured LCMS value (m / z) is 471.1 / 571.1. 1 HNMR (400MHz, CD3Cl) δ7.35-7.33(m,2H), 7.31(s,1H), 6.91(s,1H), 6.82(d,J=8.8Hz,2H), 5.13(s,2H) ), 4.49 (s, 2H), 4.24 (s, 2H), 3.78 (s, 3H), 3.16 (quintet, J = 6.9Hz, 1H), 1.51 (s, 9H), 1.15 (d, J = 6.6Hz, 6H).

[0528] (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)carbamate tert-butyl (15d). NH₂OH·HCl (97.27 mg, 1.40 mmol) and NaOAc (114.83 mg, 1.40 mmol) were added to a solution of (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)carbamate tert-butyl (15c) (100 mg, 174.98 μmol) in DMF (3 mL). The mixture was stirred at 80 °C for 6 hours. LC-MS showed a main peak with the desired MS concentration. The suspension was filtered through a diatomaceous earth pad, and the filter cake was washed with EtOAc (5 mL * 3). The combined filtrate was washed with 10 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a grayish-white gel-like substance (15d). This substance was used in the next step without further purification. [M+1] + (C 14 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O2 is 604.2, and the measured LCMS value (m / z) is 504.2 / 604.2. 1 H NMR (400MHz, DMSO-d6) δ9.15(s,1H), 7.51(s,2H), 7.18(s,1H), 7.11(d,J=8.6Hz,2H), 6.82(d,J=8.6Hz,2H), 5.40(s,2H ), 4.96 (s, 2H), 4.21 (s, 2H), 4.19 (s, 2H), 3.71 (s, 3H), 2.99 (td, J = 6.8, 13.5Hz, 1H), 1.38 (s, 9H), 1.09 (d, J = 6.8Hz, 6H).

[0529] (3,5-Dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (15e). TEA (13.39 mg, 132.34 μmol) and DSC (22.04 mg, 86.02 μmol) were added to a solution of (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)tert-butyl carbamate (15d) (40.00 mg, 66.17 μmol) in THF (3 mL) at 0 °C. The mixture was stirred at 65°C for 16 hours. LC-MS showed a main peak with the desired MS concentration. The reaction mixture was concentrated under reduced pressure, yielding a residue. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1), yielding 15e. [M+1] + (C 30 H 33 The MS quality requirement value (m / z) calculated by Cl2N5O6 is 630.1, and the measured LCMS value (m / z) is also 630.1.

[0530] (3,5-Dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (15f). CAN (47.30 mg, 86.28 μol) was added to a solution of (3,5-dichloro-4-((5-isopropyl-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (15e) (17 mg, 21.57 μmol) in ACN (2 mL) and H₂O (0.5 mL). The mixture was stirred at 20 °C for 4 hours. TLC showed 15e remaining at approximately 10% and forming a new spot. The reaction mixture was concentrated under reduced pressure to remove ACN. The residue was diluted with 5 mL of brine and extracted with 30 mL of EtOAc (10 mL * 3). The combined organic layer was washed with 10 mL of brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to produce 15f. For [M+1] + (C 22 H 25 The MS quality requirement value (m / z) calculated by Cl2N5O5 is 510.1, and the measured value (m / z) of LCMS is also 510.1.

[0531] 3-(((3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 15). A solution of (3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate tert-butyl (15f) (33 mg, 64.66 μol) in EtOAc (2 mL) and HCl / EtOAc (2 M, 161.65 μL) was stirred for 1 hour at 20 °C. TLC indicated complete consumption of the initial material and formation of a new spot. MS was determined by LCMS. The reaction mixture was concentrated under reduced pressure to remove EtOAc. The residue was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.04% HCl)-ACN]; B%: 25% to 50%, 12 min) to produce Example 15. For [M+1] + (C 17 H 17 The MS quality requirement value (m / z) calculated by Cl2N5O3 is 410.0, and the measured LCMS value (m / z) is also 410.0. 1 H NMR (400MHz, CD3OD) δ7.12 (s, 1H), 6.76 (s, 2H), 4.28 (s, 2H), 4.17 (s, 2H), 3.08 (td, J = 6.9, 13.6Hz, 1H), 1.17 (d, J = 6.8Hz, 6H).

[0532] Example 16: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0533]

[0534] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (16a). KI (38.16 mg, 229.91 μmol) and K₂CO₃ (76.26 mg, 551.77 μmol) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (14d) (150 mg, 459.81 μmol) and 2-bromoacetonitrile (551.53 mg, 4.60 mmol) in DMF (5 mL). The mixture was stirred at 100 °C for 8 hours. LCMS showed the desired mass. After cooling, the reaction mixture was partitioned between ethyl acetate (20 mL) and H₂O (20 mL). The organic phase was separated, washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to produce 16a. 1 HNMR (400MHz, DMSO-d6) δ7.10 (s, 1H), 6.85 (s, 2H), 6.75 (t, J = 6.7Hz, 1H), 4.35 (d, J = 6. 6Hz, 2H), 4.07 (s, 2H), 3.53 (s, 3H), 3.01 (td, J = 7.0, 13.7Hz, 1H), 1.10 (d, J = 6.8Hz, 6H).

[0535] (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)tert-butyl carbamate (16b). A mixture of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)acetonitrile (16a) (20 mg, 54.76 μmol), DMAP (6.69 mg, 54.76 μmol), and Boc2O (119.50 mg, 547.56 μmol) in THF (2 mL) was stirred for 0.5 h at 20 °C. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to produce 16b. 1 H NMR (400MHz, CD3OD) δ7.45 (s, 2H), 7.22-7.19 (m, 1H), 4.67-4.64 (m, 2H), 4.35-4.32 (m ,2H), 3.66-3.62(m,3H), 3.17-3.09(m,1H), 1.51-1.47(m,9H), 1.19(d,J=7.0Hz,6H).

[0536] (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)tert-butyl carbamate (16c). NH₂OH·HCl (37.33 mg, 537.20 μmol) and NaOAc (44.07 mg, 537.20 μmol) were added to a solution of (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)tert-butyl carbamate (16b) (50 mg, 107.44 μmol) in DMF (2 mL). The mixture was stirred at 80 °C for 1 hour. LCMS showed the desired mass. The reaction mixture was partitioned between ethyl acetate (20 mL) and H₂O (20 mL). The organic phase was separated, washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce 16C; no further purification was required. (For [M+1]) + (C 22 H 29 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 498.2, and the measured LCMS value (m / z) is also 498.2.

[0537] (3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (16d). DSC (17.37 mg, 67.82 μol) and TEA (10.56 mg, 104.33 μol) were added to a solution of (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)tert-butyl carbamate (16c) (26 mg, 52.17 μol) in THF (2 mL). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to produce 16d. [M+1] + (C 23 H 27 The MS quality requirement value (m / z) calculated by Cl2N5O5 is 524.1, and the measured value (m / z) of LCMS is also 524.1.

[0538] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 16). EtOAc / HCl (4M, 11.44 μL) was added to a solution of (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)carbamate tert-butyl (16d) (24 mg, 45.77 μol) in EtOAc (1 mL). The mixture was stirred at 20 °C for 2 hours. LCMS showed the desired mass. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (FA) to produce Example 16. For [M+1] + (C 18 H 19 The MS quality requirement value (m / z) calculated by Cl2N5O3 is 424.1, and the measured LCMS value (m / z) is also 424.1. 1 H NMR (400MHz, CD3OD) δ7.10-7.06(m,1H), 6.76(s,2H), 4.27(s,2H), 4.16(s,2H), 3.70-3.67(m,3H), 3.14-3.06(m,1H), 1.15(d,J=6.8Hz,6H).

[0539] Example 17: N-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0540]

[0541] (4-amino-2,6-dichlorophenyl)(6-chloro-5-isopropylpyridazin-3-yl) methyl ketone (17a). t-BuOK (1M, 2.40 mL) was added to a solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (13d) (0.9 g, 2.53 mmol) in CH3CN (20 mL) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The mixture was then cooled to 0 °C and H2O2 (573.85 mg, 5.06 mmol, 486.31 μL, 30% purity) was added dropwise. The mixture was then stirred at 0 °C for 0.5 h, followed by stirring at 20 °C for another 2 h. A saturated Na2SO3 solution (5 mL) was then added to the mixture, and the mixture was stirred at 20 °C for 1 h. The mixture was then concentrated under vacuum to remove CH3CN. The residue was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography with silica gel (petroleum ether:ethyl acetate = 30:1 to 5:1) to produce 17a. [M+1] + (C 14 H 12 The MS quality requirement value (m / z) calculated by Cl3N3O is 344.0, and the measured LCMS values ​​(m / z) are 344.0 / 346.0. 1 HNMR(400MHz, DMSO-d6)δ8.24(s,1H)6.67(s,2H)6.21(s,2H)3.18-3.31(m,1H)2.50(br s,5H)1.27-1.39(m,6H).

[0542] 2-(3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-carbonyl)phenyl)isoindoline-1,3-dione (17b). NaOAc (326.94 mg, 3.99 mmol) and isobenzofuran-1,3-dione (129.87 mg, 876.82 μmol) were added to a solution of (4-amino-2,6-dichlorophenyl)(6-chloro-5-isopropylpyridazin-3-yl) methyl ketone (17a) (260 mg, 797.11 μmol) in HOAc (10 mL). The mixture was stirred at 120 °C for 1 hour. LCMS showed the desired mass. The mixture was concentrated under vacuum, and the residue was diluted in H₂O (50 mL x 2) and NaHCO₃ (50 mL x 2). The mixture was then extracted with ethyl acetate (30 mL x 2). The assembled organic layers were concentrated in a vacuum. The residue was purified by preparative TLC to yield 17b. [M+1]+ (C 22 H 15 The MS quality requirement value (m / z) calculated by Cl2N3O4 is 456.0, and the measured value (m / z) of LCMS is also 456.0.

[0543] 2-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)isoindoline-1,3-dione (17c). 2-(3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)isoindoline-1,3-dione (17b) (250 mg, 547.91 μmol) was added to DMF-DMA (30 mL) and stirred at 110 °C for 3.5 h. LCMS showed the desired mass. The reaction mixture was partitioned between 30 mL*2 of H₂O and 30 mL*2 of EtOAc. The organic phase was concentrated under reduced pressure to produce 17c. The crude product was ready for use in the next step without further purification. For [M+1] + (C 23 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O4 is 470.1, and the measured value (m / z) of LCMS is also 470.1.

[0544] 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (17d). N-Butylamine (190.39 mg, 1.28 mmol, 204.72 μL) was added to a solution of 2-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-carbonyl)phenyl)isoindoline-1,3-dione (17c) (200 mg, 425.26 μL) in MeOH (2 mL). The mixture was stirred at 70 °C for 0.5 h. LCMS showed the desired mass. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to produce 17d. [M+1] + (C 15 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O2 is 340.1, and the measured LCMS value (m / z) is also 340.1. 1 HNMR (400MHz, CD3OD) δ7.85 (d, J = 0.9Hz, 1H), 6.64 (s, 2H), 3.76-3.72 (m, 4H), 3.22-3.14 (m, 1H), 1.29-1.26 (m, 7H).

[0545] N-(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 17). TEA (17.85 mg, 176.36 μmol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (13.10 mg, 88.18 μmol) were added to a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazine-3(2H)-one (17d) (20 mg, 58.79 μmol) in THF (5 mL). The mixture was stirred at 25 °C for 0.5 h. LC-MS analysis showed the desired MS results. The reaction mixture was quenched by adding 1 mL of MeOH at 25 °C and then concentrated under reduced pressure to produce a residue. The residue was examined by HPLC and purified by preparative HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (10 mm NH4HCO3)-ACN]; B%: 20% to 40%, 10 min) to produce Example 17. The MS quality requirement value for [M+1]+(C18H15Cl2N5O5) was 452.0, and the LCMS measured value was 452.0. 1 H NMR (400MHz, CD3OD) δ 7.94 (brs, 2H), 7.93 (br d, J = 2.9Hz, 1H), 3.73 (s, 3H), 3.26-3.11 (m, 1H), 1.30 (br d, J = 6.7Hz, 6H).

[0546] Example 18: 3-(((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0547]

[0548] 2-((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-carbonyl)phenyl)amino)acetonitrile (18a). 2-bromoacetonitrile (126.93 mg, 1.06 mmol, 70.52 μL), NaI (63.45 mg, 423.28 μL), and K₂CO₃ (58.50 mg, 423.28 μL) were added to a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-isopropyl-2-methylpyridazin-3(2H)-one (72 mg, 211.64 μL) (17d) in MeCN (2 mL). The mixture was stirred at 100 °C for 13 hours. The reaction mixture was extracted with ethyl acetate (20 mL x 2) and H₂O (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to produce 18a. [M+1] + (C 17 H 16 The MS quality requirement value (m / z) calculated for Cl2N4O2 is 379.1, and the measured LCMS value (m / z) is 379.2. 1 H NMR (400MHz, CDCl3) δ7.84 (d, J = 0.7 Hz, 1H), 6.68 (s, 2H), 4.16 (d, J = 6.8 Hz, 2H), 3.77 (s, 3H), 3.27-3.19 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H).

[0549] (Cyanomethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)tert-butyl carbamate (18b). DMAP (17.07 mg, 139.75 μol) and Boc₂O (274.51 mg, 1.26 mmol, 288.95 μL) were added to a solution of 2-((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)amino)-acetonitrile (18a) (53 mg, 139.75 μL) in THF (3 mL). The mixture was stirred at 25 °C for 5 minutes. The mixture was then partitioned between ethyl acetate (10 mL x 2) and H₂O (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to produce 18b. 1H NMR (400MHz, CDCl3) δ7.87-7.84(m,1H), 7.35(s,2H), 4.52(s,2H), 3.75(s,3H), 3.28-3.19(m,1H), 1.54(s,9H), 1.29(d,J=7.0Hz,6H).

[0550] (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)tert-butyl carbamate (18c). NH₂OH·HCl (37.11 mg, 534.05 μmol) and NaOAc (27.38 mg, 333.78 μmol) were added to a solution of (cyanomethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)tert-butyl carbamate (18b) (32 mg, 66.76 μmol) in DMF (3 mL). The mixture was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was partitioned twice between ethyl acetate (10 mL) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce 18c. The product could be used directly in the next step without further purification.

[0551] (3,5-Dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (18d). DSC (20.80 mg, 81.19 μol) and TEA (12.64 mg, 124.91 μol, 17.39 μL) were added to a solution of (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)tert-butyl carbamate (32 mg, 62.45 μol) (18c) in THF (3 mL). The mixture was stirred at 60 °C for 13 hours. LCMS showed the desired mass. The reaction mixture was extracted with 20 mL x 2 of ethyl acetate and 20 mL x 2 of H₂O. The combined organic layer was washed with 20 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce an 18d yellow solid. The crude product was ready for use in the next step without further purification. (For [M+1]) + (C 23 H 25The MS quality requirement value (m / z) calculated for Cl2N5O6 is 538.1, and the measured LCMS value (m / z) is 438.2 / 538.2.

[0552] 3-(((3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 18). A solution of tert-butyl carbamate (18d) (22 mg, 40.86 μmol) in EtOAc / HCl (2 M, 2 mL). The mixture was stirred at 25 °C for 1 hour. LCMS showed the desired mass. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (FA) to produce Example 18. For [M+1] + (C 18 H 17 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 438.1, and the measured LCMS value (m / z) is 438.2. 1 H NMR (400MHz, MeOD) δ7.86 (s, 1H), 6.78-6.71 (m, 2H), 4.32 (s, 2H), 3.72 (s, 3H), 3.18 (td, J = 6.8, 13.7Hz, 1H), 1.27 (d, J = 6.8Hz, 6H).

[0553] Scheme D: 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazine-3(2H)-one (19h)

[0554]

[0555] O-(2,6-dichloro-4-nitrophenyl) ester of dimethylthiocarbamate (19a). NaH (288.44 mg, 7.21 mmol, 60% purity) was added to a solution of 2,6-dichloro-4-nitrophenol (1 g, 4.81 mmol) in DMF (20 mL). The mixture was then stirred at 20 °C for 1 hour. N,N-dimethylthiocarbamate chloride (950.81 mg, 7.69 mmol) was then added to the mixture. The mixture was stirred at 20 °C for 16 hours. The mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography with silica gel (petroleum ether:ethyl acetate = 20:1 to 5:1) to produce 19a.1 HNMR (400MHz, CDCl3) δ8.28(s,2H)3.50(s,3H)3.44(s,3H).

[0556] S-(2,6-dichloro-4-nitrophenyl) dimethylthiocarbamate (19b). O-(2,6-dichloro-4-nitrophenyl) dimethylthiocarbamate (19a) (0.9 g, 3.05 mmol) was added to a flask and stirred at 200 °C for 4 hours. LC-MS showed the desired MS. The mixture was cooled to 20 °C to produce 19b. The crude reaction product can be used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,2H)3.13(br s,3H)2.95(br s,3H).

[0557] Dimethylthiocarbamate O-(2,6-dichloro-4-nitrophenyl) ester (19c). Fe (1.06 g, 18.97 mmol) was added to a solution of dimethylthiocarbamate S-(2,6-dichloro-4-nitrophenyl) ester (19b) (0.8 g, 2.71 mmol) in AcOH (10 mL), 2-propanol (20 mL), and H₂O (10 mL). The mixture was then stirred at 95 °C for 2 hours. The mixture was cooled to 20 °C, and a saturated NaHCO₃ solution was added until pH = 8–9 and the mixture was filtered. The filtrate was then concentrated under vacuum to remove most of the solvent. The residue was then extracted with H₂O (50 mL) and EtOAc (50 mL x 2). The combined organic layer was dried over Na₂SO₄, filtered under vacuum, and concentrated to produce 19c. The product can be used directly in the next step. 1 HNMR(400MHz, CDCl3)δ6.73(s,2H)3.98(br s,2H)2.90-3.25(m,6H).

[0558] 4-Amino-2,6-Dichlorothiophenol (19d). KOH (3M, 20mL) was added to a solution of O-(2,6-dichloro-4-nitrophenyl) ester (19c) (0.7g, 2.64mmol) in EtOH (20mL). The mixture was then refluxed at 100°C for 16 hours. LCMS showed the reaction was complete. The mixture was cooled to 20°C, and HCl solution (1M) was added until pH = 2–3. The mixture was extracted with EtOAc (50mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to produce 19d. The product was ready for use in the next step. 1H NMR (400MHz, CDCl3) δ7.27(s,2H)6.70(s,2H)4.23(s,1H)3.70(br s,2H).

[0559] 3,5-Dichloro-4-((6-chloro-5-isopropylpyridazine-3-yl)thio)aniline (19e). K₂CO₃ (1.11 g, 8.04 mmol) was added to a solution of 4-amino-2,6-dichlorothiophenol (19d) (520 mg, 2.68 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (511.90 mg, 2.68 mmol) in DMSO (15 mL). The mixture was then stirred at 95 °C for 16 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to yield 19e. 1 H NMR (400MHz, CDCl3) δppm 7.01 (s, 1H) 6.78 (s, 2H) 4.10 (brs, 2H) 3.14-3.27 (m, 1H) 1.23 (d, J = 6.84Hz, 6H).

[0560] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)isoindoline-1,3-dione (19f). NaOAc (1.18 g, 14.34 mmol) was added to a mixture of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)thio)aniline (19e) (1 g, 2.87 mmol) and isobenzofuran-1,3-dione (424.79 mg, 2.87 mmol) in HOAc (8 mL). The mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH. The solids were dissolved in water and the pH was adjusted to 9 with NaHCO3 (10 mL). The mixture was then partitioned twice with ethyl acetate (30 mL). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The solid was stirred in ethyl acetate (10 mL) and petroleum ether (50 mL), then filtered and dried to produce 19f. The product could be used directly in the next step without further purification. 1¹H NMR (400MHz, DMSO) δ 8.00-8.05 (m, 2H) 7.93-7.97 (m, 2H) 7.84 (s, 2H) 7.32 (d, J = 0.86Hz, 1H) 3.01 (quintet, J = 6.79Hz, 1H) 1.14 (d, J = 6.85Hz, 6H).

[0561] 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)isoindoline-1,3-dione (19 g). A solution of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)isoindoline-1,3-dione (19 f) (955 mg, 2.07 mmol) in DMF-DMA (8 mL) was stirred for 16 hours at 120 °C. The mixture was concentrated under vacuum to produce a residue. The residue was partitioned twice between ethyl acetate (10 mL) and H₂O (3 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce 19 g. The product was used directly in the next step without further purification. Regarding [M+1] + (C 22 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O3S is 474.0, and the measured LCMS value (m / z) is also 474.0.

[0562] 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19 h). A mixture of 2-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)isoindoline-1,3-dione (19 g) (980 mg, 2.07 mmol) and but-1-amine (453.29 mg, 6.20 mmol, 612.55 μL) in MeOH (2 mL) was stirred for 1 h at 70 °C. The mixture was concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to produce [M+1] + (C 14 H 15 The MS quality requirement value calculated by Cl2N3OS is 344.0 m / z, and the measured LCMS value is 344.1 m / z. 1H NMR (400MHz, CD3OD) δ6.85 (d, J = 0.73Hz, 1H) 6.80 (s, 2H) 3.64 (s, 3H) 3.09 (qd, J = 7.01, 6.48Hz, 1H) 1.12 (d, J = 6.97Hz, 6H).

[0563] Example 19: 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazine-3-yl)sulfonyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0564]

[0565] 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)amino)acetonitrile (19i). 2-bromoacetonitrile (731.69 mg, 6.10 mmol, 406.49 μL), K₂CO₃ (337.23 mg, 2.44 mmol), and NaI (365.75 mg, 2.44 mmol) were added to a solution of 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19h) (420 mg, 1.22 mmol) in ACN (3 mL). The mixture was stirred at 100 °C for 16 hours. The suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (10 mL * 3). The combined filtrate was concentrated and dried to produce a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to produce 19i. [M+1] + (C 16 H 16 The MS quality requirement value calculated by Cl2N4OS is 383.3 m / z, and the measured LCMS value is 383.0 m / z. 1 H NMR (400MHz, CDCl3) δ6.82 (s, 2H) 6.79 (d, J = 0.73Hz, 1H) 4.39 (d, J = 6.85Hz, 1H) 4. 12-4.24(m,2H)3.77(s,1H)3.67(s,3H)3.11-3.20(m,1H)1.16(d,J=6.85Hz,6H).

[0566] (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)tert-butyl carbamate (19j). DMAP (133.87 mg, 1.10 mmol) and Boc2O (717.45 mg, 3.29 mmol) were added to a solution of 2-((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)amino)acetonitrile (19i) (420 mg, 1.10 mmol) in 3 mL of THF at 25 °C. The mixture was stirred at 25 °C for 20 minutes. The mixture was then divided twice between 10 mL of ethyl acetate and 3 mL of H2O. The combined organic phases were washed with brine (5 mL x 3), dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 3:1) to produce 19j. 1 H NMR (400MHz, CDCl3) δ7.46 (s, 2H) 6.84 (s, 1H) 4.53 (s, 2H) 3.64 (s, 3H) 3.18 (dt, J = 13.66, 6.80Hz, 1H) 1.53 (s, 9H) 1.18 (d, J = 6.85Hz, 6H).

[0567] (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)tert-butyl carbamate (19k). At 25°C, NH₂OH·HCl (287.50 mg, 4.14 mmol, 8 equivalents) and NaOAc (339.38 mg, 4.14 mmol, 8 equivalents) were added to a solution of (cyanomethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)tert-butyl carbamate (19k) (250 mg, 517.16 μmol, 1 equivalent) in 3 mL of DMF. The mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was diluted with water (5 mL) and extracted twice with ethyl acetate (15 mL). The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce the residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1) to produce 19kJ. 1H NMR (400MHz, CDCl3) δ7.99 (s, 1H) 7.60 (s, 2H) 7.05 (d, J = 0.66Hz, 1H) 4.31 (s, 2H )3.59(s,3H)3.11(dt,J=13.67,6.84Hz,1H)1.49(s,9H)1.17(d,J=7.06Hz,6H).

[0568] (3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (19l). DSC (141.86 mg, 553.79 μol) and TEA (86.21 mg, 851.99 μol, 118.59 μL) were added to a solution of (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)tert-butyl carbamate (19k) (220 mg, 425.99 μL) in THF (4 mL). The mixture was stirred at 60°C for 16 hours. The mixture was then concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1) to yield 19 μL. [M+1] + (C 22 H 25 The MS quality requirement value (m / z) calculated by Cl2N5O5S is 542.4, and the measured LCMS value (m / z) is 542.1. 1 H NMR (400MHz, CD3OD) δ7.63 (s, 2H) 7.04 (d, J = 0.73Hz, 1H) 4.82 (s, 2H) 3.58 (s, 3H) 3.07-3.15 (m, 1H) 1.48 (s, 9H) 1.16 (d, J = 6.85Hz, 6H).

[0569] (3,5-Dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)sulfonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (19m). m-CPBA (37.43 mg, 184.35 μol, 85% purity) was added to a solution of (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (19l) (20 mg, 36.87 μmol) in DCM (2 mL). The mixture was then stirred at 60 °C for 48 hours. The reaction mixture was quenched at 20°C with the addition of Na₂SO₃ (23 mg) and stirred for 30 minutes. The mixture was then concentrated under reduced pressure to produce 19m. [M+1] + (C 22 H 25 The MS quality requirement value (m / z) calculated for Cl2N5O7S is 574.4, and the LCMS measured value is 574.1. The product can be used directly in the next step without further purification.

[0570] 3-(((3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)sulfonyl)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 19). A solution of (3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)sulfonyl)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (19m) (20 mg, 34.82 μmol) in HCl / EtOAc (4 M, 2 mL) was stirred for 2 hours at 20 °C. The mixture was then concentrated under vacuum to produce a residue. The residue was purified by preparative HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.04% HCl)-ACN]; B%: 20% to 50%, 11 min) to produce Example 19. For [M+1] + (C 17 H 17 Cl2N5O5 S The calculated MS quality requirement value m / z is 474.3, and the LCMS measured value m / z is 474.0. 1HNMR (400MHz, CD3OD) δ7.74(s,1H)6.83(s,2H)4.38(s,2H)3.72(s,3H)3.13(br d,J=1.71Hz,1H)1.24(d,J=6.85Hz,6H).

[0571] Example 20: N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)sulfonyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0572]

[0573] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (20a). TEA (29.39 mg, 290.48 μL, 40.43 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (8.63 mg, 58.10 μL) were added to a mixture of 6-((4-amino-2,6-dichlorophenyl)thio)-4-isopropyl-2-methylpyridazin-3(2H)-one (19h) (20 mg, 58.10 μL) in DCM (5 mL), and the mixture was stirred at 25 °C for 0.2 h. The reaction mixture was partitioned between H₂O (5 mL) and EtOAc (5 mL). The organic phase was separated, washed with brine (5 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The crude product was purified by reverse-phase HPLC (0.1% FA conditions) to produce 20a. [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated by Cl2N5O4S is 456.0, and the measured LCMS value (m / z) is 456.1. 1 H NMR (400MHz, CD3OD) δ7.94-8.14(m,2H)7.07(s,1H)3.52-3.64(m,3H)3.05-3.18(m,1H)1.17(d,J=6.85Hz,6H).

[0574] N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)sulfonyl)-phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 20). MCPBA (21.36 mg, 105.19 μmol, 85% purity) was added to a mixture of N-(3,5-dichloro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)thio)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (20a) (8 mg, 17.53 μmol) in DCM (1 mL), and the mixture was stirred at 50 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (acetonitrile aqueous solution w / TFA) to produce Example 20. For [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O6S is 488.0, and the measured LCMS value (m / z) is 488.1. 1 HNMR (400MHz, DMSO) δ11.40-11.66(m,1H)8.09-8.13(m,2H)7.72-7.75(m,1H)3.62-3.65(m,3H)3.08-3.11(m,1H)1.16-1.21(m,6H).

[0575] Scheme E: 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazine-3(2H)-one (21e)

[0576]

[0577] 3,6-Dichloro-4-cyclopropylpyridazine (21a). A solution of 3,6-dichloropyridazine (5 g, 33.56 mmol), cyclopropanecarboxylic acid (2.89 g, 33.56 mmol), and AgNO3 (5.70 g, 33.56 mmol) in 100 mL of H2O was added at 60 °C. Then, ammonium persulfate (22.98 g, 100.69 mmol) in 100 mL of H2O was added to the mixture at 70 °C. The resulting mixture was stirred at 70 °C for 30 minutes. The mixture was extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC (silica gel, petroleum ether:ethyl acetate = 5:1) to produce 21a. 1HNMR (400MHz, CD3Cl) δ6.94(s,1H), 2.27-2.14(m,1H), 1.37-1.23(m,2H), 0.91-0.77(m,2H).

[0578] 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-cyclopropylpyridazine-3-yl)acetonitrile (21b). t-BuOK (1M, 4.23 mL) was added dropwise to a solution of 3,6-dichloro-4-cyclopropylpyridazine (21a) (0.4 g, 2.12 mmol) and 2-(4-amino-2,6-dichlorophenyl)acetonitrile (13c) (467.96 mg, 2.33 mmol) in THF (10 mL) at 60 °C. The resulting mixture was stirred at 60 °C for 40 min. After cooling, the mixture was diluted with ethyl acetate (20 mL), washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 2:1) to produce 21b. 1 H NMR (400MHz, DMSO-d6) δ7.00(s,1H), 6.71-6.68(m,2H), 6.46(s,1H), 6.02(s,2H), 2.22-2.14(m,1H), 1.25-1.19(m,2H), 0.88-0.75(m,2H).

[0579] 6-(4-amino-2,6-dichlorobenzoyl)-4-cyclopropylpyridazin-3(2H)-one (21c). KOH (1.16 g, 20.64 mmol) was added to a solution of 2-(4-amino-2,6-dichlorophenyl)-2-(6-chloro-5-cyclopropylpyridazin-3-yl)acetonitrile (21b) (365 mg, 1.03 mmol) in dioxane (5 mL) and H₂O (10 mL). The mixture was stirred at 100 °C under O₂ for 16 h. LC-MS showed a main peak with the desired MS concentration. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with 2 M aqueous HCl to adjust pH to 5 to 7 and extracted with EtOAc (20 mL * 4). The combined organic layer was washed with 20 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce 21c. [M+1] + (C 14 H 11 The MS quality requirement value (m / z) calculated for Cl2N3O2 is 324.0, and the measured LCMS value (m / z) is 324.1.

[0580] 6-((4-amino-2,6-dichlorophenyl)(hydroxy)methyl)-4-cyclopropylpyridazine-3(2H)-one (21d). NaBH4 (116.70 mg, 3.08 mmol) was added to a solution of 6-(4-amino-2,6-dichlorobenzoyl)-4-cyclopropylpyridazine-3(2H)-one (21c) (100 mg, 308.49 μmol) in MeOH (5 mL) at 0 °C. The mixture was stirred at 15 °C for 16 h. MS was determined by LCMS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 2:1, TLC) to produce 21d. [M+1] + (C 14 H 13 The MS quality requirement value (m / z) calculated for Cl2N3O2 is 326.1, and the measured LCMS value (m / z) is also 326.1. 1 HNMR (400MHz, DMSO-d6) δ12.58(s,1H), 7.16(s,1H), 6.54(s,2H), 6.07-6.05(m,1H), 6.02-6.00(m,1H), 5.64(s,2H), 2.12-2.07(m,1H), 1.01(br dd,J=2.8,8.5Hz,2H), 0.81(br t,J=6.0Hz,2H).

[0581] 6-(4-amino-2,6-dichlorophenylmethyl)-4-cyclopropylpyridazine-3(2H)-one (21e). Et3SiH (89.12 mg, 766.46 μmol) was added to a solution of 6-((4-amino-2,6-dichlorophenyl)(hydroxy)methyl)-4-cyclopropylpyridazine-3(2H)-one (21d) (50 mg, 153.29 μmol) in TFA (1 mL) and DCE (5 mL). The mixture was stirred at 50 °C for 6 hours. LC-MS showed a main peak with the desired MS concentration. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:petroleum ether = 2:1; TLC) to produce 21e. For [M+1]+(C 14 H 13The MS quality requirement value calculated by Cl2N3O is 310.0 m / z, and the measured value by LCMS is 310.1 m / z; 1H NMR (400MHz, CDCl3) δ 10.39 (br s, 2H), 6.68 (s, 2H), 6.64 (s, 1H), 4.10 (s, 2H), 2.19-2.14 (m, 1H), 1.12-1.06 (m, 2H), 0.85-0.79 (m, 2H).

[0582] Example 21: N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0583]

[0584] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 21). TEA (15.66 mg, 154.75 μol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (11.49 mg, 77.37 μol) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazin-3(2H)-one (21e) (16 mg, 51.58 μol) in DCM (2 mL) were added. The mixture was stirred at 25 °C for 0.5 h. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Ultimate C18 150*25mm*5μm; mobile phase: [water (10mm NH4HCO3)-ACN]; B%: 20% to 40%, 10 min) to produce Example 21. For [M+1] + (C 17 H 13 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 422.0, and the measured LCMS value (m / z) is also 422.0. 1 H NMR (400MHz, CD3OD) δ7.86(s,2H), 6.88(s,1H), 4.23(s,2H), 2.15-2.06(m,1H), 1.10-1.04(m,2H), 0.85-0.79(m,2H).

[0585] Example 22: N-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0586]

[0587] 2-(3,5-Dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (22a). Isobenzofuran-1,3-dione (22.06 mg, 148.95 μmol) was added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropylpyridazin-3(2H)-one (21e) (44 mg, 141.85 μmol) in AcOH (3 mL). The mixture was stirred at 120 °C for 2 hours. TLC showed the formation of a new spot. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with 2 mL of water and saturated NaHCO3 aqueous solution was added to a modified pH of 9–10. The suspension was extracted with 20 mL (5 mL * 4) of EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to produce 22a, a pale yellow oil, which could be used in the next step without further purification. [M+1] + (C 22 H 15 The MS quality requirement value (m / z) calculated by Cl2N3O3 is 440.1, and the measured value (m / z) of LCMS is also 440.1.

[0588] 2-(3,5-Dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (22b). A solution of 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (22a) (70 mg, 158.99 μmol) in DMF-DMA (5 mL) was degassed and washed three times with N2, and then the mixture was stirred at 100 °C under N2 atmosphere for 3 h. LCMS showed complete consumption of 22a and a main peak with the desired MS. The reaction mixture was concentrated under reduced pressure to remove DMF-DMA, and then the mixture was stirred to produce a residue. The residue was diluted with 5 mL of H2O and extracted with 20 mL of EtOAc (5 mL * 4). The combined organic layer was washed with 5 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce 22b, a pale yellow gel-like substance, which could be used in the next step without further purification. [M+1] + (C23 H 17 The MS quality requirement value (m / z) calculated for Cl2N3O3 is 454.1, and the measured LCMS value (m / z) is 454.0.

[0589] 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropyl-2-methylpyridazin-3(2H)-one (22c). N-Butylamine (33.81 mg, 462.24 μmol) was added to a solution of 2-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)isoindoline-1,3-dione (22b) (100 mg, 154.08 μmol) in MeOH (3 mL). The mixture was stirred at 70 °C for 0.5 h. The desired MS was determined by LCMS. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate; TLC) to yield 22c. [M+1] + (C 15 H 15 The MS quality requirement value (m / z) calculated by Cl2N3O is 324.1, and the measured LCMS value (m / z) is 324.0. 1 HNMR (400MHz, CDCl3) δ6.70-6.65(m,2H), 6.48(s,1H), 4.07(s,2H), 3.79(br s,2H), 3.74(s,3H), 2.24-2.13(m,1H), 1.07-0.99(m,2H), 0.75-0.66(m,2H).

[0590] N-(3,5-dichloro-4-((5-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 22). TEA (9.36 mg, 92.53 μL, 12.88 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (6.87 mg, 46.27 μL) were added to a solution of 6-(4-amino-2,6-dichlorobenzyl)-4-cyclopropyl-2-methylpyridazin-3(2H)-one (22c) (10 mg, 30.84 μL) in DCM (2 mL). The mixture was stirred at 25 °C for 0.5 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was examined by HPLC and purified by preparative HPLC (column: Waters Xbridge 150*255u; mobile phase: [water (10 mm NH4HCO3)-ACN]; B%: 5% to 35%, 14 min) to produce a white solid, Example 22. For [M+1] + (C 18 H 15 The MS quality requirement value (m / z) calculated by Cl2N5O4 is 436.0, and the measured LCMS value (m / z) is also 436.0. 1 H NMR (400MHz, CD3OD) δ7.87(s,2H), 6.85(s,1H), 4.24(s,2H), 3.65(s,3H), 2.20-2.09(m,1H), 1.11-1.04(m,2H), 0.83-0.75(m,2H).

[0591] Example 23: N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0592]

[0593] N-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 23). TEA (13.24 g, 130.82 mmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (9.71 g, 65.41 mmol) were added to a solution of 3-(4-amino-2,6-dichloro-phenoxy)-5-isopropyl-1H-pyridazin-6-one (8b) (13.7 g, 43.61 mmol) in THF (140 mL). The mixture was stirred at 20 °C for 0.5 h. LC-MS showed peaks with the desired MS. The reaction mixture was concentrated under reduced pressure to produce a crude product. The crude product was ground with EtOAc (100 mL) at 80 °C for 30 min, and then cooled to 20 °C. The suspension was filtered, and the filter cake was washed with EtOAc (5 mL x 3) and concentrated to dryness to produce Example 23. For [M+1] + (C 16 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 426.0, and the measured LCMS value (m / z) is also 426.0. 1 HNMR (400MHz, CD3OD) δ7.92 (s, 2H), 7.33 (d, J = 0.9Hz, 1H), 3.21-3.13 (m, 1H), 1.29 (d, J = 6.8Hz, 6H).

[0594] Example 24: N-(6-chloro-7-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0595]

[0596] 6-Chloro-7-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-indane-4-amine (24a). 7-amino-5-chloro-indane-4-ol (0.39 g, 2.12 mmol), 3,6-dichloro-4-isopropyl-pyridazine (1a) (405.77 mg, 2.12 mmol), CuI (40.45 mg, 212.38 μmol), and K₂CO₃ (440.28 mg, 3.19 mmol) in DMA (15 mL) were degassed with N₂ and then heated to 100 °C under N₂ for 16 hours. LC-MS showed the reaction was complete, and the desired MS was detected. The mixture was filtered through a diatomaceous earth pad and washed with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to produce 24a. [M+1] + (C 16 H 17 The MS quality requirement value (m / z) calculated by Cl2N3O is 338.1, and the measured LCMS value (m / z) is also 338.1. 1 HNMR (400MHz, DMSO-d6) δ7.53 (s, 1H), 6.56 (s, 1H), 5.15 (br s, 2H), 3.14 (td, J = 6.8, 13.6Hz, 1H), 2.68 (br t, J = 7.3Hz, 2H), 2.60 (br t,J=7.4Hz,2H), 2.03-1.95(m,2H), 1.27(d,J=6.7Hz,6H).

[0597] 2-[6-chloro-7-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]indan-4-yl]isoindoline-1,3-dione (24b). AcOH (1 mL) was added to a mixture of 6-chloro-7-(6-chloro-5-isopropyl-pyridazin-3-yl)oxy-indan-4-amine (24a) (120 mg, 354.79 μmol) and isobenzofuran-1,3-dione (52.55 mg, 354.79 μmol) in NaOAc (101.87 mg, 1.24 mmol). The mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the AcOH. The solid was dissolved in water and the pH was adjusted to 9 with NaHCO3 (10 mL). The mixture was then partitioned between ethyl acetate (30 mL). This was performed twice. The combined organic phases were washed with brine (10 mL x 3), dried with anhydrous Na₂SO₄, filtered under vacuum, and concentrated to produce 24b. This product could be used directly in the next step without further purification. (For [M+1]) + (C24 H 20 The MS quality requirement value (m / z) calculated by ClN3O4 is 450.1, and the measured value (m / z) of LCMS is 450.2.

[0598] 2-[6-chloro-7-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-indan-4-yl]isoindoline-1,3-dione (24c). A solution of 2-[6-chloro-7-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]indan-4-yl]isoindoline-1,3-dione (24b) (150 mg, 333.42 μmol) in DMFDMA (2 mL) was stirred for 2 hours at 80 °C. The mixture was concentrated under vacuum. The residue was partitioned twice between 10 mL of ethyl acetate and 3 mL of H₂O. The combined filtrate was washed with brine (20 mL) and the organic phase was concentrated to produce 24c, the crude product which could be used directly in the next step. [M+1] + (C 25 H 22 The MS quality requirement value (m / z) calculated by ClN3O4 is 464.1, and the measured value (m / z) by LCMS is 464.2.

[0599] 6-(7-amino-5-chloro-indan-4-yl)oxy-4-isopropyl-2-methyl-pyridazin-3-one (24d). A mixture of 2-[6-chloro-7-(5-isopropyl-1-methyl-6-oxo-pyridazin-3-yl)oxy-indan-4-yl]isoindoline-1,3-dione (24c) (100 mg, 215.56 μmol) and N-butylamine (15.77 mg, 215.56 μmol) in MeOH (2 mL) was stirred for 1 hour at 25 °C. The mixture was concentrated under vacuum. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to produce 24d. For [M+1] + (C 17 H 20 The MS quality requirement value (m / z) calculated by ClN3O2 is 334.1, and the measured value (m / z) of LCMS is also 334.1.

[0600] N-(6-chloro-7-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-2,3-dihydro-1H-inden-4-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0601] (Example 24). TEA (9.09 mg, 89.87 μol, 12.51 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (6.67 mg, 44.94 μol) were added to a solution of 24d (10 mg, 29.96 μol, 1 equivalent) in THF (5 mL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was quenched by adding MeOH (1 mL) at 25 °C and then concentrated under reduced pressure to produce a residue. The residue was examined by HPLC and then purified by preparative HPLC (column: Luna C18 100*30 5 u; mobile phase: [water (0.04% HCl)-ACN]; B%: 35% to 60%, 12 min) to produce Example 24. For [M+1] + (C 20 H 20 The MS quality requirement value (m / z) calculated by ClN5O5 is 446.1, and the measured LCMS value (m / z) is 446.2. 1 H NMR (400MHz, CD3OD) δ7.55(s,1H), 7.27(s,1H), 3.50(s,3H), 3.20-3.12(m,1H), 2.94(br t,J=7.4Hz,2H), 2.87(br t,J=7.3Hz,2H), 2.17-2.12(m,2H), 1.27(d,J=6.8Hz,6H).

[0602] Example 25: N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0603]

[0604] 3,5-Dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline (25a).

[0605] The sample was degassed from DMA (5 mL) containing 3,6-dichloro-4-cyclopropylpyridazine (1 g, 5.29 mmol) (21a), 4-amino-2,6-dichlorophenol (941.67 mg, 5.29 mmol), K₂CO₃ (1.10 g, 7.93 mmol), and CuI (201.49 mg, 1.06 mmol) and then heated to 100 °C under N₂ for 16 hours. The solids were filtered off, and water (20 mL) was added to the filtrate, followed by extraction with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to produce 25a. [M+1] + (C 13 H 10 The MS quality requirement value (m / z) calculated by Cl3N3O is 330.0, and the measured LCMS values ​​(m / z) are 329.9 / 331.9.

[0606] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (25b). Add one drop of DMF to a solution of 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxylic acid (11.80 mg, 90.75 μO) in THF (2 mL), then add (COCl)2 (11.52 mg, 90.75 μO, 7.94 μL, 1.5 equivalents) at 0 °C, and stir the mixture at 25 °C for 1 hour. Add the solution to a mixture of 3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)aniline (25a) (20 mg, 60.50 μO) and TEA (18.37 mg, 181.50 μO, 25.26 μL) in DCM (3 mL) at 25 °C, and stir the resulting mixture at 25 °C for 30 minutes. The mixture was concentrated, and the residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to produce 25b. For [M+1] + (C 16 H 10 The MS quality requirement value (m / z) calculated by Cl3N5O4 is 442.0, and the measured value (m / z) of LCMS is also 442.0.

[0607] N-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 25). A mixture of N-(3,5-dichloro-4-((6-chloro-5-cyclopropylpyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (25b) (30 mg, 67.78 μmol) and NaOAc (33.36 mg, 406.65 μmol) in HOAc (3 mL) was heated to 110 °C for 16 hours. The mixture was concentrated. The residue was purified by preparative HPLC (neutral) to produce Example 25. For [M+1] + (C 16 H 11 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 424.2, and the measured LCMS value (m / z) is also 424.2. 1 H NMR (400MHz, MeOD) δ7.92(s,2H), 7.03(s,1H), 2.28-2.18(m,1H), 1.23-1.14(m,2H), 1.04-0.94(m,2H).

[0608] Example 26: N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0609]

[0610] 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (26a). NaHCO3 (15.36 g, 182.82 mmol) was added to a suspension of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methylpyridazin-3-one (1e) (20 g, 60.94 mmol) in CH3CN (200 mL) and THF (60 mL) under a nitrogen atmosphere. Select F (21.59 g, 60.94 mmol) was added to the resulting solution in portions over 30 min. The mixture was stirred at 20 °C for 16 h. The reaction mixture was partitioned between 200 mL of H2O and 300 mL of EtOAc. The organic phase was separated, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 4 / 1 to 1 / 1; TLC) to produce 26a. [M+1]+ (C 14 H 14 The MS quality requirement value (m / z) calculated for Cl2FN3O2 is 346.0, and the measured LCMS value (m / z) is also 346.0. 1 HNMR (400MHz, CDCl3) δ7.02 (s, 1H), 6.80 (d, J = 8.8Hz, 1H), 3.89 (br s, 2H), 3.53 (s, 3H), 3.24 (quind, J = 6.8, 13.5Hz, 1H), 1.26 (d, J = 6.8Hz, 6H).

[0611] N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 26). TEA (11.40 g, 112.66 mmol) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (8.37 g, 56.33 mmol) were added to a solution of 6-(4-amino-2,6-dichloro-3-fluoro-phenoxy)-4-isopropyl-2-methylpyridazin-3-one (26a) (13 g, 37.55 mmol) in THF (130 mL). The mixture was stirred at 20 °C for 0.5 h. LC-MS showed peaks with the desired MS. The mixture was diluted to a modified pH of 6 to 7 with 1M HCl and extracted with 300 mL (100 mL * 3) of EtOAc. The combined organic layer was washed with 150 mL of brine, dried over Na₂SO₄, and filtered to produce a pale yellow liquid. The pale yellow liquid was concentrated under reduced pressure to remove the solvent and until the solid was completely dissolved. The mixture was stirred at 20°C for 1 hour and filtered to produce Example 26. For [M+1] + (C 17 H 14 The MS quality requirement value (m / z) calculated for Cl2FN5O5 is 458.0, and the measured LCMS value (m / z) is also 458.0. 1 H NMR (400MHz, CD3OD) δ 8.30 (d, J = 7.5 Hz, 1H), 7.35 (s, 1H), 3.51 (s, 3H), 3.24-3.12 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H).

[0612] Example 27: 3-(((3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one

[0613]

[0614] 2-((3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (27a). 2-bromoacetonitrile (52.26 mg, 435.72 μL, 29.03 μL), K₂CO₃ (24.09 mg, 174.29 μL), and NaI (26.12 mg, 174.29 μL) were added to a solution of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropyl-2-methylpyridazin-3(2H)-one (26a) (20 mg, 57.77 μL) in ACN (2 mL). The mixture was stirred at 100 °C for 20 hours. The suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (5 mL * 3). The combined filtrate was concentrated and dried to produce a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:1) to produce 27a. [M+1] + (C 16 H 15 The MS quality requirement value (m / z) calculated for Cl2FN4O2 is 385.2, and the measured LCMS value (m / z) is 385.0. 1 HNMR (400MHz, CDCl3) δ7.04 (s, 1H) 6.81 (d, J = 8.16Hz, 1H) 4.38-4.50 (m, 1H) 4.21 (d,J=7.06Hz,2H)3.54(s,3H)3.24(dt,J=13.62,6.75Hz,1H)1.26-1.28(m,6H).

[0615] (Cyanomethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (27b). DMAP (6.34 mg, 51.92 μol) and Boc2O (33.99 mg, 155.76 μol, 35.78 μL) were added to a solution of 2-((3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)acetonitrile (27a) (20 mg, 51.92 μol) in THF (3 mL) at 20 °C. The mixture was stirred at 20 °C for 20 minutes. The mixture was concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 2:1) to yield 27b. [M+1] + (C 21 H 23The MS quality requirement value (m / z) calculated by Cl2FN4O4 is 485.3, and the measured LCMS value (m / z) is 485.2.

[0616] 1 H NMR (400MHz, CDCl3) δ7.43 (br s, 1H) 7.07 (s, 1H) 4.52 (br s, 2H) 3.52 (s, 3H) 3.26 (dt, J = 13.66, 6.92Hz, 1H) 1.25-1.47 (m, 15H).

[0617] (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (27c). NH₂OH·HCl (22.91 mg, 329.67 μmol) and NaOAc (27.04 mg, 329.67 μmol) were added to a solution of (cyanomethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (27b) (20 mg, 41.21 μmol) in DMF (2 mL) at 20 °C. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove DMF. The residue was partitioned twice between 10 mL of ethyl acetate and 5 mL of H₂O. The combined organic phase was washed with brine (5 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1) to produce 27c. [M+1] + (C 21 H 26 The MS quality requirement value (m / z) calculated by Cl2FN5O5 is 518.4, and the measured LCMS value (m / z) is 518.0.

[0618] (3,5-Dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (27d). DSC (12.85 mg, 50.16 μol) and TEA (7.81 mg, 77.17 μol, 10.74 μL) were added to a solution of (Z)-(2-amino-2-(hydroxyimino)ethyl)(3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)tert-butyl carbamate (27c) (20 mg, 38.58 μol) in THF (3 mL). The mixture was stirred at 60°C for 16 hours. The mixture was then concentrated under vacuum to produce a residue. The residue was analyzed by preparative TLC (SiO2, DCM:MeOH = 10:1, P1:R). f =0.3) Purification to produce 27d. For [M+1] + (C 22 H 24 The MS quality requirement value (m / z) calculated by Cl2FN5O6 is 544.4, and the measured LCMS value (m / z) is 544.0.

[0619] 3-(((3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)amino)methyl)-1,2,4-oxadiazol-5(4H)-one (Example 27). A solution of (3,5-dichloro-2-fluoro-4-((5-isopropyl-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)tert-butyl carbamate (27d) (8 mg, 14.70 μmol) in HCl / EtOAc (2 mL) was stirred for 1.5 h at 20 °C. The mixture was concentrated under vacuum to produce a residue. The residue was purified by preparative HPLC (column: Luna C18100*30 5u; mobile phase: [water (0.04% HCl)-ACN]; B%: 30% to 60%, 12 min) to produce Example 27. For [M+1] + (C 17 H 16 The MS quality requirement value (m / z) calculated by Cl2FN5O4 is 444.2, and the measured LCMS value (m / z) is 444.0. 1H NMR (400MHz, CD3OD) δ7.27 (s, 1H) 6.91 (d, J = 8.33Hz, 1H) 4.38 (s, 2H) 3.49 (s, 3H) 3.13-3.21 (m, 1H) 1.26 (d, J = 7.02Hz, 6H).

[0620] Example 28: N-(4-((5-(tert-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0621]

[0622] 4-((5-(tert-butyl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (28a). 4-amino-2,6-dichlorophenol (173.61 mg, 0.975 mmol), K₂CO₃ (404.34 mg, 2.93 mmol), and CuI (111.44 mg, 0.585 mmol) were added to a solution of 4-(tert-butyl)-3,6-dichloropyridazine (200 mg, 0.975 mmol) in DMSO (5 mL). The mixture was stirred at 90 °C under a N₂ atmosphere for 16 hours. The solvent was diluted with EtOAc (10 mL) and H₂O (10 mL), extracted with EA (10 mL x 2), the organic layer was washed with brine (20 mL x 2), dried over Na₂SO₄, and concentrated under vacuum to obtain the crude product. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate = 5:1) to produce 28a. [M+1] + (C 14 H 14 The MS quality requirement value (m / z) calculated by Cl3N3O is 346.6, and the measured LCMS value (m / z) is also 346.6. 1 H NMR (400MHz, CDCl3) δ1.51 (s, 9H), 6.67 (s, 2H), 7.24 (s, 1H).

[0623] N-(4-((5-(tert-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (28b). Under a nitrogen atmosphere, a mixture of 4-((5-(tert-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (28a) (100 mg, 288.48 mmol) in THF (2 mL) was added to DCM (2 mL) containing TEA (87.58 mg, 865.45 μmol) and 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carbonyl chloride (4e) (64.26 mg, 432.73 μmol). The mixture was stirred at 20 °C under nitrogen for 0.5 hours. The mixture was poured into H₂O (10 mL), and the resulting mixture was extracted with EtOAc (10 mL * 3). The organic layer was washed with brine (20 mL * 2), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain crude product 28c. The crude product can be used in the next step without further purification. (For [M+1]) + (C 17 H 14 The MS quality requirement value (m / z) calculated by Cl3N5O4 is 458.1, and the measured LCMS value (m / z) is also 458.1.

[0624] N-(4-((5-(tert-butyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 28). NaOAc (125.19 mg, 1.53 mmol) was added to a mixture of N-(4-((5-(tert-butyl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (140 mg, 305.2 μmmol) in HOAc (10 mL). The mixture was then stirred at 120 °C for 16 hours. The solvent was removed under vacuum to obtain the crude product. The crude product was purified by preparative HPLC (CH3CN in H2O, 40%). To obtain Example 28 (9.9 mg, 7.4% yield). For [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 440.2, and the measured LCMS value (m / z) is also 440.2. 1 H NMR (400MHz, CD3OD) δ1.44(s,9H), 7.32(s,1H), 7.92(s,2H).

[0625] Example 29 (P1 and P2): N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide)

[0626]

[0627] 1-(3,6-Dichloropyridazine-4-yl)ethanol (29a). But-3-yn-2-ol (278.59 mg, 3.97 mmol) was added to a solution of 3,6-dichloro-1,2,4,5-tetraazine (500 mg, 3.31 mmol) in toluene (3 mL). The mixture was stirred at 110 °C in a sealed tube for 16 hours. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1, TLC) to produce 29a. 1 H NMR (400MHz, CDCl3) δ7.82 (d, J = 1.0 Hz, 1H), 5.14 (dq, J = 4.2, 6.3 Hz, 1H), 2.38 (d, J = 3.4 Hz, 1H), 1.56 (d, J = 6.4 Hz, 3H).

[0628] 3,6-Dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (29b). TsOH (13.38 mg, 77.71 μol) was added to a solution of 1-(3,6-dichloropyridazine-4-yl)ethanol (29a) (300 mg, 1.55 mmol) and DHP (653.68 mg, 7.77 mmol, 710.52 μL) in DCM (10 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 5:1, according to TLC) to produce 29b. 1 H NMR (400MHz, CDCl3) δ7.77(s,1H), 7.63(s,1H), 5.10(q,J=6.5Hz,1H), 4.98(q,J=6.6Hz,1H), 4.81(br d,J=4.6Hz,1H), 4.47(br s,1H), 3.99-3.90(m,1H), 3.67-3.53(m,2H), 3.47-3.40(m,1H), 1.95-1.55(m,12H), 1.53(d,J=6.4Hz,3H), 1.46(d,J=6.4Hz,3H).

[0629] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine-3-yl)oxy)aniline (29c). K₂CO₃ (299.21 mg, 2.16 mmol) and CuI (82.46 mg, 432.98 μmol) were added to a solution of 4-amino-2,6-dichlorophenol (167.00 mg, 938.13 μmol) and 3,6-dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazine (29b) (200 mg, 721.64 μmol) in DMSO (5 mL). The solution was degassed and washed three times with N₂, and then the mixture was stirred at 90 °C under N₂ atmosphere for 2 hours. A main peak with the desired MS concentration was detected by LC-MS. The reaction mixture was diluted with 5 mL of H₂O and extracted with 30 mL of ethyl acetate (10 mL * 3). The combined organic layer was washed with 10 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1, TLC) to produce 29c. 1 H NMR (400MHz, CDCl3) δ7.55(s,1H), 7.37(s,1H), 6.68(s,4H), 5.10(q,J=6.6Hz,1H), 5.00(q,J=6 .4Hz,1H), 4.90-4.85(m,1H), 4.52(t,J=3.6Hz,1H), 3.96(ddd,J=3.8,7.5,11.2Hz,1H), 3.81(br d,J=2.4Hz,4H), 3.65(ddd,J=3.2,8.0,11.3Hz,1H), 3.61-3.54(m,1H), 3.47- 3.40(m,1H), 1.96-1.60(m,12H), 1.55(d,J=6.5Hz,3H), 1.49(d,J=6.4Hz,3H).

[0630] N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (29d). TEA (181.26 mg, 1.79 mmol, 249.32 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (133.00 mg, 895.63 μL) were added to a solution of 3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)aniline (29c) (250 mg, 597.08 μol) in DCM (5 mL). The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 10:1, according to TLC) to produce 29d. For [M+1] + (C 20 H 18 The MS quality requirement value (m / z) calculated by Cl3N5O6 is 530.0, and the measured LCMS value (m / z) is 529.9.

[0631] Ethyl 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)ethyl acetate (29e). NaOAc (37.09 mg, 452.19 μmol) was added to a solution of N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-carboxamide (29d) (60 mg, 90.44 μmol) in AcOH (3 mL). The mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH and then produce 29e, which could be used in the next step without further purification. Regarding [M+1] + (C 17 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O7 is 470.0, and the measured LCMS value (m / z) is also 470.0.

[0632] N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazin-3-carboxamide (Example 29). LiOH·H2O (18.74 mg, 446.60 μmol) was added to a solution of ethyl 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazin-3-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)acetate (29e) (105 mg, 223.30 μmol) in MeOH (3 mL) and H2O (0.5 mL). The mixture was stirred at 25 °C for 1 hour. The desired MS was determined by LCMS. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted to a modified pH of 6 to 8 with 6M HCl and extracted with EtOAc (5 mL x 4). The residue was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by preparative HPLC (column: Luna C18 100 x 30 5 u; mobile phase: [water (10 mm NH₄HCO₃)-ACN]; B%: 1% to 40%, 12 min) to produce Example 29. [M+1] + (C 15 H 11 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 428.0, and the measured LCMS value (m / z) is also 428.0. 1 HNMR (400MHz, DMSO-d6) δ12.28(s,1H), 11.31(s,1H), 7.99(s,2H), 7.40(d,J=1.1Hz,1H), 5.49(br s, 1H), 4.70 (q, J = 6.1Hz, 1H), 1.33 (d, J = 6.4Hz, 3H).

[0633] (R)-N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29-P1) and (S)-N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 29-P2). N-(3,5-dichloro-4-((5-(1-hydroxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-carboxamide (Example 29) was examined and purified by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3 * H2O MeOH]; B%: 40% to 40%, 10 min) to produce Examples 29-P1 and 29-P2.

[0634] Example 29-P1: For [M+1] + (C 15 H 11 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 428.0, and the measured LCMS value (m / z) is also 428.0. 1 H NMR (400MHz, DMSO-d6) δ12.26 (s, 1H), 10.71 (br s, 1H), 8.06 (s, 2H), 7.39 (d, J = 1.3Hz, 1H), 5.49 (br d,J=4.4Hz,1H), 4.74-4.66(m,1H), 1.33(d,J=6.6Hz,3H).

[0635] Example 29-P2: For [M+1]+(C 15 H 11 C l2 The MS quality requirement value (m / z) calculated for N5O6 is 428.0, and the measured LCMS value (m / z) is 427.9. 1 H NMR (400MHz, DMSO-d6) δ12.26 (s, 1H), 10.74 (br s, 1H), 8.05 (s, 2H), 7.39 (d, J = 1.3Hz, 1H), 5.49 (br d,J=4.4Hz,1H), 4.75-4.66(m,1H), 1.33(d,J=6.4Hz,3H).

[0636] Example 30: N-(4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0637]

[0638] 5-Bromo-2-(bromomethyl)-1,3-dimethylbenzene (30a). PPh3 (1.83 g, 6.97 mmol) was added to a solution of (4-bromo-2,6-dimethylphenyl)methanol in DCM (30 mL). The mixture was then cooled to 0 to 5 °C. CBr4 (2.31 g, 6.97 mmol) was then added to the mixture in portions. The mixture was then stirred at 15 °C under N2 for 0.5 h. The mixture was concentrated under vacuum to produce a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10:1, TLC) to produce 30a. 1 H NMR (400MHz, CDCl3) δ7.21 (s, 2H) 4.50 (s, 2H) 2.39 (s, 6H).

[0639] 2-(4-Bromo-2,6-dimethylphenyl)acetonitrile (30b). NaCN (244.35 mg, 4.99 mmol) was added to a solution of 5-bromo-2-(bromomethyl)-1,3-dimethylbenzene (30a) (1.26 g, 4.53 mmol) in DMF (30 mL) at 15 °C. The mixture was then stirred at 15 °C for 16 hours. The mixture was partitioned twice between ethyl acetate (50 mL) and an aqueous NH4Cl solution (20 mL). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to produce a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 3:1, TLC) to produce 30b. 1 H NMR (400MHz, CD3OD) δ7.28(s,2H)3.79(s,2H)2.38(s,6H).

[0640] 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyridazine-3-yl)acetonitrile (30c). t-BuOK (1M, 7.14 mL, 2 equivalents) was added dropwise to a solution of 2-(4-bromo-2,6-dimethylphenyl)acetonitrile (30b) (800 mg, 3.57 mmol) and 3,6-dichloro-4-isopropylpyridazine (1a) (682.05 mg, 3.57 mmol) in THF (10 mL) at 60 °C. The resulting mixture was heated to 60 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL, 2x). The combined organic phase was washed with brine (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 3:1, TLC) to produce 30c. [M+1] + (C 17 H 17 The MS quality requirement value (m / z) calculated by BrClN3 is 378.0, and the measured LCMS value (m / z) is 378.2. 1 HNMR(400MHz,CD3OD)δ7.34(s,3H)7.21(s,1H)6.28(s,1H)3.01(dt,J=13.5 4, 6.74Hz, 1H) 2.89 (dt, J = 13.72, 6.89Hz, 1H) 2.27 (s, 6H) 1.27-1.30 (m, 6H).

[0641] 6-(4-Bromo-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (30d). A solution of 2-(4-bromo-2,6-dimethylphenyl)-2-(6-chloro-5-isopropylpyridazin-3-yl)acetonitrile (30c) (1 g, 2.78 mmol) in AcOH (10 mL), H₂O (10 mL), and HCl (40 mL) was heated to 120 °C for 48 hours. LC-MS showed the initial material consumption and the required MS was detected. The mixture was adjusted to pH ~7 with 3M NaOH at 15 °C, the solid was filtered, and dried to produce 30d. The product could be used directly in the next step without further purification. For [M+1] + (C 16 H 19 The MS quality requirement value (m / z) calculated by BrN2O is 335.1, and the measured LCMS value (m / z) is 335.2. 1¹H NMR (400MHz, DMSO) δ 12.56 (s, 1H) 7.24 (s, 2H) 7.11 (s, 1H) 3.90 (s, 2H) 2.97 (quintet, J = 6.82Hz, 1H) 2.21 (s, 6H) 1.11 (d, J = 6.85Hz, 6H).

[0642] 6-(4-((diphenylmethylene)amino)-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one (30e). A solution of 6-(4-bromo-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one (30d) (100 mg, 298.30 μol) and benzophenone imine (54.06 mg, 298.30 μol, 50.06 μL) in dioxane (5 mL) was supplemented with t-BuONa (43.00 mg, 447.44 μol), Pd2(dba)3 (27.32 mg, 29.83 μol), and Xantphos (17.26 mg, 29.83 μol). The mixture was degassed, washed three times with N2, and stirred at 80 °C for 16 hours. The mixture was partitioned between DCM (20 mL) and a saturated NH4Cl aqueous solution (10 mL) and extracted a second time with DCM. The combined organic layer was washed with brine (10 mL x 3), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to produce 30e. For [M+1] + (C 29 H 29 The MS quality requirement value (m / z) calculated by N3O is 436.2, and the LCMS measured value is 436.4. The residue can be used directly in the next step without further purification.

[0643] 6-(4-amino-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one (30f). A solution of 6-(4-((diphenylmethylene)amino)-2,6-dimethylbenzyl)-4-isopropylpyridazine-3(2H)-one (30e) (100 mg, 229.59 μmol) in HCl / EtOAc (5 mL) was stirred for 16 hours at 15 °C. LC-MS analysis showed the desired MS results. The mixture was diluted with 5 mL of water and saturated aqueous NaHCO3 solution was added to a modified pH of 9–10. The suspension was extracted with EtOAc (15 mL x 3), the combined organic layers were dried over Na2SO4, filtered under reduced pressure, and concentrated to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to produce 30f. [M+1] + (C 16 H 21The MS quality requirement value calculated by N3O is m / z 272.2, and the measured LCMS value is m / z 272.3; 1 H NMR (400MHz, CD3OD) δ6.89 (s, 1H) 6.48 (s, 2H) 3.89 (s, 2H) 3.04 (dt, J = 13.69, 6.72Hz, 1H) 2.18 (s, 5H) 1.11 (d, J = 6.97Hz, 6H).

[0644] N-(4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-3,5-dimethylphenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 30). TEA (14.92 mg, 147.41 μol, 20.52 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (10.95 mg, 73.70 μol) were added to a mixture of 6-(4-amino-2,6-dimethylbenzyl)-4-isopropylpyridazin-3(2H)-one (30f) (10 mg, 36.85 μol) in THF (1 mL) at 15 °C. The mixture was stirred at 15 °C for 0.5 h. The mixture was concentrated under vacuum to produce a residue. The residue was purified by preparative HPLC (column: Nano-micro Kromasil C18 100*30mm 5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30% to 50%, 12 min) to produce Example 30. For [M+1] + (C 19 H 21 The MS quality requirement value (m / z) calculated for N5O4 is 384.2, and the measured LCMS value (m / z) is also 384.2. 1 H NMR (400MHz, CD3OD) δ7.41 (s, 2H) 7.02 (s, 1H) 4.86 (s, 19H) 4.02 (s, 2H) 3.07 (dt, J = 13.72, 6.77Hz, 1H) 2.30 (s, 6H) 1.15 (d, J = 6.85Hz, 6H).

[0645] Example 31: N-(4-((5-(bicyclo[1.1.1]pent-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0646]

[0647] 4-(bicyclo[1.1.1]pent-1-yl)-3,6-dichloropyridazine (31a). A mixture of 3,6-dichloropyridazine (170 mg, 1.14 mmol) and bicyclo[1.1.1]pentane-1-carboxylic acid (134.35 mg, 1.20 mmol) in H2O (5 mL) was added in portions to H2O (2.5 mL) containing AgNO3 (193.84 mg, 1.14 mmol), ammonium persulfate (286.44 mg, 1.26 mmol), and H2SO4 (335.75 mg, 3.42 mmol, 182.48 μL). The mixture was stirred at 70 °C for 20 min. After cooling, the mixture was extracted with ethyl acetate (5 mL * 2), the organic phase was washed with NaHCO3 (2 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5:1) to produce 31a. 1 H NMR (400MHz, CD3OD) δ7.62(s,1H), 2.66(s,1H), 2.34(s,6H).

[0648] 4-((5-(bicyclo[1.1.1]pent-1-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (31b). 4-(bicyclo[1.1.1]pent-1-yl)-3,6-dichloropyridazine (31a) (150 mg, 697.42 μmol) and 4-amino-2,6-dichlorophenol (124.15 mg, 697.42 μmol) were added in portions to DMSO (9 mL) at 25 °C under N2 conditions, along with K2CO3 (385.55 mg, 2.79 mmol) and CuI (79.69 mg, 418.45 μmol). The mixture was stirred at 90 °C for 16 hours. The residue was partitioned between ethyl acetate (20 mL) and H2O (5 mL x 2). The combined organic phase was washed with brine (5 mL x 3), dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The solid was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to yield 31b. [M+1] + (C 15 H 12 The MS quality requirement value calculated by Cl3N3O is 356.0 m / z, and the measured LCMS value is 355.9 m / z.

[0649] N-(4-((5-(bicyclo[1.1.1]pent-1-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichlorophenyl-)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (31c). TEA (25.54 mg, 252.36 μL, 35.13 μL) and 5-oxo-4,5-dichloroaniline (31b) (30 mg, 84.12 μL) in a mixture of 4-((5-(bicyclo[1.1.1]pent-1-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (31b) (30 mg, 84.12 μL) in DCM (5 mL) were added in a single step under N2 conditions, and the reaction was stirred at 0 °C for 30 min. The residue was diluted with water (5 mL) and extracted with DCM (10 mL, 2x). The combined organic layer was washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The solid was purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to produce 31c.

[0650] N-(4-((5-(bicyclo[1.1.1]pent-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 31). NaOAc (15.75 mg, 192.03 μmol) was added in a single batch to a mixture of N-(4-((5-(bicyclo[1.1.1]pent-1-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichlorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (31c) (18 mg, 38.41 μmol) in AcOH (3 mL). The mixture was then stirred at 120 °C under N2 for 16 hours. The mixture was then concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 45% to 75%, 10 min) to produce Example 31. For [M+1] + (C 18 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O5 is 450.0, and the measured LCMS value (m / z) is also 450.0. 1 H NMR (400MHz, CD3OD) δ7.91(s,2H), 7.19(s,1H), 2.60(s,1H), 2.25(s,6H).

[0651] Example 32: N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0652]

[0653] 1-(3,6-Dichloropyridazin-4-yl)prop-1-ol (32a). Pentyl-1-yn-3-ol (1.11 g, 13.25 mmol, 1.14 mL) was added to a solution of 3,6-dichloro-1,2,4,5-tetraazine (1 g, 6.62 mmol) in toluene (10 mL) at 20 °C. The mixture was stirred at 110 °C in a sealed tube for 16 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to produce 32a. [M+1] + The MS quality requirement value for (C7H8Cl2N2O) is 207.1 m / z, and the measured LCMS value is 207.0 m / z. 1 H NMR (400MHz, CDCl3) δ7.79 (s, 1H) 4.94 (dt, J = 7.73, 3.77Hz, 1H) 2.72 (d, J = 4.03Hz, 1H) 1. 94(dqd,J=14.52,7.39,7.39,7.39,3.55Hz,1H)1.60-1.72(m,1H)1.06(t,J=7.34Hz,3H).

[0654] 3,6-Dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazine (32b). TsOH (5.82 mg, 33.81 μol) was added to a solution of 1-(3,6-dichloropyridazine-4-yl)prop-1-ol (32a) (140 mg, 676.14 μol) and DHP (284.37 mg, 3.38 mmol, 309.10 μL) in DCM (5 mL). The mixture was stirred at 20 °C for 1 hour. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 2:1, TLC) to produce 32b. [M+1] + (C 12 H 16 The MS quality requirement value (m / z) calculated for Cl2N2O2 is 291.2, and the measured LCMS value (m / z) is 291.1. 1H NMR (400MHz, CDCl3) δ7.71 (s, 1H) 7.56 (s, 1H) 4.95-5.00 (m, 1H) 4.78 (dd, J = 7.06, 3.97Hz, 1H) 4.69 (dd, J = 5.40, 2.09Hz, 1H) 4.40 (t, J = 3.42Hz, 1H) 3.85 -4.03(m,2H)3.54-3.55(m,1H)3.45-3.62(m,2H)3.33-3.41(m,1H)2.04-2. 10(m,1H)1.47-1.94(m,24H)1.05(t,J=7.39Hz,3H)0.95(t,J=7.39Hz,3H).

[0655] 3,5-Dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)aniline (32c). K₂CO₃ (246.83 mg, 1.79 mmol) and CuI (51.02 mg, 267.88 μmol) were added to a solution of 3,6-dichloro-4-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin (32b) (130 mg, 446.47 μmol) and 4-amino-2,6-dichlorophenol (79.48 mg, 446.47 μmol) in DMSO (5 mL). The solution was degassed and washed three times with N₂, and then the mixture was stirred at 90 °C under N₂ atmosphere for 16 hours. LC-MS was performed to obtain the desired MS. The mixture was diluted in EtOAc (5 mL) and filtered, with the filtrate partitioned between ethyl acetate (5 mL) and H₂O (3 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (5 mL). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 2:1) to yield 32c. [M+1] + (C 18 H 20 The MS quality requirement value (m / z) calculated for Cl3N3O3 is 432.7, and the measured LCMS value (m / z) is 432.1. 1H NMR(400MHz, CDCl3)δ7.48(s,1H)7.29(s,1H)6.68(s,2H)4.97(dd,J=7.46,3 .79Hz,1H)4.76-4.83(m,1H)4.46(t,J=3.30Hz,1H)3.93-4.02(m,1H)3.80(br s,2H)3.54-3.62(m,1H)3.33-3.41(m,1H)1.85-1.99(m,2H)1.66-1.83(m,4H)1.06(t,J=7.34Hz,2H)0.96(t,J=7.34Hz,2H).

[0656] N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32d). TEA (77.17 mg, 762.60 μol, 106.15 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (56.63 mg, 381.30 μol) were added to a solution of 3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)aniline (32c) (110 mg, 254.20 μol) in DCM (5 mL). The mixture was stirred at 20°C for 0.5 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1) to produce 32d. [M+1] + (C 21 H 20 The MS quality requirement value (m / z) calculated for Cl3N5O6 is 544.8, and the measured LCMS value (m / z) is 544.6. 1 H NMR (400MHz, CD3OD) δ7.97 (s, 2H) 7.64 (s, 1H) 4.83 (dd, J = 8.05, 3.20Hz, 1H) 3.92 (s, 1H) 1.87-1.97 (m, 2H) 1.59-1.69 (m, 1H) 1.06 (t, J = 7.28Hz, 3H).

[0657] 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (32e). NaOAc (97.88 mg, 1.19 mmol) was added to a solution of N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-carboxamide (32d) (130 mg, 238.63 μmol, 1 equivalent) in HOAc (5 mL). The mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove AcOH to produce 32e. [M+1] + (C 18 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O7 is 484.2, and the LCMS measured value is 484.1. The crude product can be used in the next step without further purification.

[0658] N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazin-3-carboxamide (Example 32). LiOH·H2O (1M, 474.97 μL) was added to a solution of 1-(6-(2,6-dichloro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazin-3-carboxamido)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (32e) (115 mg, 237.48 μol) in MeOH (3 mL) and H2O (0.5 mL). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove AcOH. The residue was diluted with 5 mL of water. The suspension was extracted with EtOAc (30 mL * 3), the combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 μm; mobile phase: [water (0.225% FA) - ACN]; B%: 30% to 60%, 10 min) to produce Example 32. For [M+1] + (C 16 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 442.2, and the measured LCMS value (m / z) is 442.0. 1H NMR (400MHz, CD3OD) δ7.92 (s, 2H) 7.47 (s, 1H) 4.85 (s, 29H) 4.74 (br d, J = 4.77Hz, 1H) 1.88-2.02 (m, 1H) 1.51-1.64 (m, 1H) 1.02 (t, J = 7.40Hz, 3H).

[0659] Example 32: P1 and P2: N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0660]

[0661] N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32f). A solution of N-(3,5-dichloro-4-((6-chloro-5-(1-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32d) (160 mg, 293.70 μmol) in TFA (1 mL) and DCM (3 mL) was stirred for 2 hours at 20 °C. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [water (0.2% FA)-ACN]; B%: 35% to 65%, 10 min) to produce 32f. [M+1] + (C 16 H 12 The MS quality requirement value (m / z) calculated by Cl3N5O5 is 460.0, and the measured LCMS value (m / z) is 460.1.

[0662] SFC separation: N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-carboxamide (32f) (95 mg, 206.23 μol) was separated by SFC (column: DAICELCHIRALCEL OJ (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH3 * H2O MeOH]; B%: 30% to 30%, 5 min) to produce 32f-P1 and 32f-P2.

[0663] (R)-N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 32-P1). A solution of (R)-N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32f-P1) (10.00 mg, 21.71 μmol) in HOAc (2 mL) and H2O (0.1 mL) was stirred for 16 hours at 120 °C. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18200 * 40 mm * 10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20% to 50%, 12 min) to produce Example 32-P1. [M+1] + (C 16 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 442.0, and the measured LCMS value (m / z) is also 442.0. 1 H NMR (400MHz, CD3OD) δ7.92 (s, 2H) 7.47 (d, J = 0.98Hz, 1H) 4.87 (s, 40H) 4.73 (br d,J=4.03Hz,1H)1.90-1.98(m,1H)1.58(dt,J=14.15,7.29Hz,1H)1.02(t,J=7.40Hz,3H).

[0664] (S)-N-(3,5-dichloro-4-((5-(1-hydroxypropyl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 32-P2). A solution of (S)-N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (32f-P2) (10.00 mg, 21.71 μmol) in HOAc (2 mL) and H2O (0.1 mL) was stirred for 16 hours at 120 °C. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100 * 30 mm * 5 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 20% to 50%, 10 min) to produce Example 32-P2. [M+1] + (C16 H 13 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 442.0, and the measured LCMS value (m / z) is also 442.0. 1 H NMR (400MHz, CD3OD) δ7.91 (s, 2H) 7.47 (d, J = 1.10Hz, 1H) 4.87 (s, 19H) 4.73 (dd, J = 7.09, 3. 06Hz, 1H) 1.95 (ddd, J = 13.91, 7.43, 3.48Hz, 1H) 1.52-1.63 (m, 1H) 1.02 (t, J = 7.34Hz, 3H).

[0665] Example 33: N-(3,5-dichloro-4-((5-(2-hydroxypropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0666]

[0667] 2-(3,6-Dichloropyridazin-4-yl)prop-2-ol (33a). 2-Methylbut-3-yn-2-ol was added to a solution of 3,6-dichloro-1,2,4,5-tetraazine (500 mg, 3.31 mmol) in toluene (5 mL) at 20 °C. The mixture was stirred at 115 °C in a sealed tube for 16 hours. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1 to 4:1, TLC) to produce 33a. [M+1] + The MS quality requirement value (C7H8Cl2N2O) calculated is 207.0 m / z, and the LCMS measured value is also 207.0 m / z. 1 H NMR (400MHz, CDCl3) δ7.98(s,1H)2.17(s,1H)1.77(s,6H).

[0668] 3,6-Dichloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)prop-2-yl)pyridazine (33b). DHP (142.19 mg, 1.69 mmol, 154.56 μL) and PPTS (16.99 mg, 67.61 μL) were added to a solution of 2-(3,6-dichloropyridazine-4-yl)prop-2-ol (33a) (70 mg, 338.07 μL) in DCM (5 mL). The mixture was stirred at 20 °C for 16 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (15 mL, 2x). The combined organic layer was washed with brine (10 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to produce a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 5:1) to produce 33b. Regarding [M+1] + (C 12 H 16 The MS quality requirement value (m / z) calculated for Cl2N2O2 is 291.1, and the measured LCMS value (m / z) is also 291.1. 1 H NMR (400MHz, CDCl3) δ7.85 (s, 1H) 4.84 (dd, J=5.62, 2.81Hz, 1H) 4.01-4.08 (m, 1H) 3.88-3.95 (m, 1H) 3.57 (dt, J= 11.13,5.44Hz,1H)3.47(dt,J=11.37,5.69Hz,1H)1.83-1.96(m,2H)1.78(s,3H)1.75(s,3H)1.56-1.73(m,6H).

[0669] 3,5-Dichloro-4-((6-chloro-5-(2-(((tetrahydro-2H-pyran-2-yl)oxy)propyl-2-yl)pyridazin-3-yl)oxy)aniline (33c). K₂CO₃ (75.94 mg, 549.50 μmol) and CuI (15.70 mg, 82.43 μmol) were added to a solution of 3,6-dichloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)propyl-2-yl)pyridazine (33b) (40 mg, 137.38 μmol) and 4-amino-2,6-dichlorophenol (24.45 mg, 137.38 μmol) in DMSO (4 mL). The solution was degassed and washed three times with N₂, and then the mixture was stirred at 90 °C under N₂ atmosphere for 16 hours. LCMS was used to display the desired MS. The mixture was diluted in EtOAc (5 mL) and filtered. The filtrate was partitioned between ethyl acetate (5 mL) and H₂O (3 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (5 mL). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The mixture was purified by preparative TLC (petroleum ether:ethyl acetate = 3:1) to produce 33c. [M+1] + (C 18 H 20 The MS quality requirement value (m / z) calculated by Cl3N3O3 is 432.1, and the measured value (m / z) of LCMS is also 432.1.

[0670] N-(3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)prop-2-yl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (33d). TEA (17.54 mg, 173.32 μL, 24.12 μL) and 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-carbonyl chloride (4e) (12.87 mg, 86.66 μL) were added to a solution of 3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)prop-2-yl)pyridazin-3-yl)oxy)aniline (33c) (25 mg, 57.77 μL) in DCM (1.5 mL). The mixture was stirred at 20 °C for 0.5 h. LC-MS showed the desired MS. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to produce 33d. [M+1] + (C 21 H 20 The MS quality requirement value (m / z) calculated for Cl3N5O6 is 544.0, and the measured LCMS value (m / z) is 544.1.1 H NMR(400MHz,CD3OD)δ7.98(s,2H)7.76(s,1H)4.36-4.41(m,6H)3.93(s,3H)3.83-3.89(m,1H)3.62-3.65(m,2H)3.59 (t,J=6.60Hz,5H)3.48(dt,J=7.73,6.22Hz,9H)1.92(dt,J=6.14,3.10Hz,4H)1.78-1.88(m,16H)1.66-1.75(m,9H).

[0671] N-(3,5-dichloro-4-((5-(2-hydroxypropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 33). A solution of N-(3,5-dichloro-4-((6-chloro-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)propyl-2-yl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (33d) (25 mg, 45.89 μmol) in HOAc (2 mL) and H2O (0.1 mL) was stirred for 16 hours at 120 °C. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20% to 55%, 12 min) to produce Example 33. For [M+1] + (C 16 H 13 The MS quality requirement value calculated for Cl2N5O6 is 442.0 m / z, and the measured value for LCMS is 441.9 m / z; 1H NMR (400MHz, CD3OD) δ 7.91 (s, 2H) 7.58 (s, 1H) 4.85 (br s, 126H) 1.62 (s, 6H).

[0672] Example 34: N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0673]

[0674] 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropylpyridazine-3(2H)-one (34a). NaHCO3 (240.66 mg, 2.86 mmol, 111.41 μL) was added to a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazine-3(2H)-one (8b) (300 mg, 954.91 μL) in CH3CN (10 mL) and THF (10 mL). SelectF (372.11 mg, 1.05 mmol) was then added in portions to the mixture at 20 °C. The mixture was then stirred at 20 °C for 2 hours. The mixture was diluted with EtOAc (30 mL) and H2O (30 mL). The organic layer was washed with brine (10 mL) and dried under vacuum. The residue was purified by preparative TLC (petroleum ether: ethyl acetate = 1:1) to produce 34a. 1 H NMR (400MHz, CD3OD) δ7.29 (d, J = 0.86Hz, 1H) 6.89 (d, J = 8.44Hz, 1H) 3.10-3.23 (m, 1H) 1.25-1.33 (m, 6H).

[0675] N-(3,5-dichloro-2-fluoro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 34). TEA (91.39 mg, 903.19 μol, 125.71 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (4e) (67.06 mg, 451.59 μol) were added to a solution of 6-(4-amino-2,6-dichloro-3-fluorophenoxy)-4-isopropylpyridazin-3(2H)-one (34a) (100 mg, 301.06 μol) in DCM (4 mL). The mixture was stirred at 20 °C for 0.5 h. LC-MS was performed as desired. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to produce the desired material. The desired compound was further purified by preparative HPLC (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20% to 60%, 12 min) to produce Example 34. For [M+1] + (C 16 H 12 C l2 The MS quality requirement value (m / z) calculated for FN5O5 is 444.0, and the measured LCMS value (m / z) is 443.9. 1H NMR (400MHz, CD3OD) δ7.97 (br d, J = 6.72Hz, 1H) 7.37 (s, 1H) 4.87 (br s, 13H) 3.12-3.22 (m, 1H) 1.28 (br d, J = 6.60Hz, 6H).

[0676] Scheme F: 4-((5-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (compound 35c)

[0677]

[0678] 2-(3,6-Dichloropyridazine-4-yl)prop-1-ol (35a). TFA (4.97 g, 43.63 mmol, 3.23 mL) was added to H₂O (25 mL) at 50 °C, followed by 2-methylpropane-1,3-diol (6.65 g, 73.8 mmol, 6.59 mL), then 3,6-dichloropyridazine (5 g, 33.6 mmol) and AgNO₃ (7.70 g, 45.3 mmol). A solution of ammonium thiosulfate (15.3 g, 67.1 mmol, 14.6 mL) in H₂O (15 mL) was then added in portions to the mixture at 50 °C, and the resulting mixture was stirred at 50 °C for 0.5 hours. The reaction mixture was then partitioned between H₂O (45 mL) and EtOAc (50 mL). The organic phase was separated, washed with H₂O (50 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate) to produce 35a. [M+1] + The MS quality requirement value (C7H8Cl2N2O) calculated is 207.0 m / z, and the LCMS measured value is also 207.0 m / z. 1 H NMR (400MHz, CDCl3) δ7.52 (s, 1H), 3.93-3.84 (m, 2H), 3.45-3.30 (m, 1H), 1.35 (d, J = 7.2Hz, 3H).

[0679] 4-(1-((tert-butyldimethylsilyl)oxy)prop-2-yl)-3,6-dichloropyridazine (35b). Imidazole (1.34 g, 19.7 mmol) was added to a solution of 2-(3,6-dichloropyridazine-4-yl)prop-1-ol (35a) (3.4 g, 16.4 mmol) and tert-butylchloro-dimethylsilane (2.47 g, 16.4 mmol, 2.01 mL) in DMF (25 mL). The mixture was stirred at 25 °C under a N2 atmosphere for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to produce 35b. The product was used directly in the next step without further purification. For [M+1] + (C 13 H 22 The MS quality requirement value calculated by Cl2N2OSi is 321.1 m / z, and the measured LCMS value is 321.0 m / z. 1 H NMR (400MHz, CDCl3) δ7.48 (s, 1H), 3.77 (d, J = 4.4Hz, 2H), 3.38-3.29 (m, 1H), 1 .32(d,J=6.8Hz,3H), 0.88-0.79(m,9H), 0.04-0.02(m,3H), 0.02-0.08(m,3H).

[0680] 4-((5-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-6-chloropyridazine-3-yl)oxy)-3,5-dichloroaniline (35c). 4-amino-2,6-dichlorophenol (752.84 mg, 3.11 mmol), K₂CO₃ (1.29 g, 9.34 mmol), and CuI (355.63 mg, 1.87 mmol) were added to a solution of 4-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-3,6-dichloropyridazine (35b) (1 g, 3.11 mmol) in DMSO (15 mL). The mixture was stirred at 90 °C under a N₂ atmosphere for 5 hours. The suspension was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc (50 mL). The reaction mixture was quenched by adding H₂O (30 mL), then extracted with ethyl acetate (50 mL) and further extracted with EtOAc (50 mL x 5). The combined organic layers were washed with brine (50 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate) to produce 35c. [M+1] + (C 19 H 26The MS quality requirement value (m / z) calculated by Cl3N3O2Si is 462.1, and the measured value (m / z) of LCMS is also 462.1.

[0681] Example 35: N-(3,5-dichloro-4-((5-(1-hydroxypropyl-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0682]

[0683] 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindol-2-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35d). Isobenzofuran-1,3-dione (244.8 mg, 1.65 mmol) and NaOAc (271.2 mg, 3.31 mmol) were added to a solution of 4-((5-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (35c) (510 mg, 1.10 mmol) in HOAc (8 mL). The mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove HOAc. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO₂, petroleum ether:ethyl acetate) to produce 35d. [M+1] + (C 23 H 17 The MS quality requirement value (m / z) calculated for Cl2N3O6 is 502.0, and the measured LCMS value (m / z) is 502.1.

[0684] 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindol-2-yl)phenoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35e). K₂CO₃ (107.6 mg, 778.4 μol) and MeI (130.0 mg, 915.8 μol, 57.0 μL) were added to a solution of 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindol-2-yl)phenoxy)-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35d) (230 mg, 457.9 μol) in DMF (3 mL). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched by adding H₂O (15 mL) at 25 °C and then extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce 35e. The mixture was ready for use in the next step without further purification. (For [M+1]) + (C 24 H 19 The MS quality requirement value (m / z) calculated by Cl2N3O6 is 516.1, and the measured value (m / z) of LCMS is also 516.1.

[0685] 6-(4-amino-2,6-dichlorophenoxy)-4-(1-hydroxypropyl-2-yl)-2-methylpyridazin-3(2H)-one (35f). Butyl-1-amine (1.11 g, 15.2 mmol, 1.5 mL) was added to a solution of 2-(6-(2,6-dichloro-4-(1,3-dioxoisoindol-2-yl)phenoxy)-2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)propyl acetate (35e) (223 mg, 431.89 μmol) in MeOH (5 mL). The mixture was stirred at 70 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to produce 35f. [M+1] + (C 14 H 15 The MS quality requirement value (m / z) calculated for Cl2N3O3 is 344.0, and the measured LCMS value (m / z) is also 344.0.

[0686] N-(3,5-dichloro-4-((5-(1-hydroxypropyl-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (Example 35). TEA (44.1 mg, 435.8 μol, 60.7 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (32.4 mg, 217.9 μol) were added to a solution of 6-(4-amino-2,6-dichlorophenoxy)-4-(1-hydroxypropyl-2-yl)-2-methylpyridazin-3(2H)-one (35f) (50 mg, 145.3 μol) in THF (3 mL). The mixture was stirred at 25 °C for 5 minutes. TLC and LCMS showed complete consumption of 35f and the required mass +Ac was determined. The reaction mixture was quenched by adding MeOH (5 mL) at 25 °C. The pH was then adjusted to 10–12 with LiOH·H₂O, and the resulting mixture was stirred at 25 °C for 1 hour. LCMS showed the required MS in the main peak. The mixture was then concentrated under vacuum, and the residue was purified by preparative HPLC (column: Waters Xbridge preparative OBD C18 150*40mm*10μm; mobile phase: [water (10 mm NH₄HCO₃)-MeCN]) to produce Example 35. For [M+1] + (C 17 H 15 The MS quality requirement value (m / z) calculated for Cl2N5O6 is 456.0, and the measured LCMS value (m / z) is 456.1. 1 H NMR (400MHz, CD3OD) δ7.93 (s, 2H), 7.34 (s, 1H), 3.80 (dd, J = 6.0, 10.6Hz, 1H ), 3.73-3.66(m,1H), 3.51(s,3H), 3.29-3.23(m,1H), 1.29(d,J=7.0Hz,3H).

[0687] Example 36: N-(3,5-dichloro-4-((5-(1-hydroxypropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide

[0688]

[0689] N-(3,5-dichloro-4-((6-chloro-5-(1-hydroxypropyl-2-yl)pyridazin-3-yl)oxy)phenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-carboxamide (36a). TEA (32.8 mg, 324.0 μol, 45.1 μL) and 5-oxo-4H-1,2,4-oxadiazole-3-carbonyl chloride (24.1 mg, 162.0 μol) were added to a solution of 4-((5-(1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)-6-chloropyridazin-3-yl)oxy)-3,5-dichloroaniline (35c) (50 mg, 108.0 μol) in THF (2 mL). The mixture was stirred at 25 °C for 5 minutes. The reaction mixture was quenched at 25°C with the addition of 25 mL of MeOH and concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate) to yield 36a. [M+1] + (C 16 H 12 The MS quality requirement value (m / z) ...

Claims

1. A compound of formula (IIA) or (IIB), Or its pharmaceutically acceptable salt, wherein: R 1 C1-C4 alkyl, C3-C5 cycloalkyl, CON(R) groups optionally substituted with 1 to 5 halogenated or hydroxyl groups are used. 10 )2 or NR 10 COR 10 ; R 2 It is H or C1-C3 alkyl; L is O, CH2, S, SO, SO2, CO, CHF, CF2, C(R 11 CN, CHR 11 or C(R) 11 )R 11 ; R 3 and R 4 Independently, it can be Cl, Br, methyl, or ethyl; R 5 It can be H, a halogen, a C1-C4 alkyl group, or a C3-C4 cycloalkyl group; Or R 5 With R 4 Together with intercalated atoms, they form 5- to 7-membered cycloalkyl groups or 5- to 7-membered heterocycles containing 1 to 2 cyclic heteroatoms; X represents non-existent, O, or NR. 12 C(O)NR 12 NR 12 C(O), CR 12 R 12 OCR 12 R 12 CR 12 R 12 O, NR 12 CR 12 R 12 CR 12 R 12 NR 12 SO2NR 12 or NR 12 SO2; Each R 10 Independently, it is a C1-C3 alkyl group or H; Each R 11 Independently, it is a C1-C2 alkyl group optionally substituted with 1 to 5 halogen groups, or two R groups. 11 The groups, together with the carbon atoms they bond to, form cyclopropyl or cyclobutyl rings; and Each R 12 It can be H or methyl on its own.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the formula (VD): (VD) Where R 1 R 2 R 3 R 4 and R 5 As defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is a C1-C4 alkyl group or a C3-C5 cycloalkyl group optionally substituted with one or two halogen groups or hydroxyl groups.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 1 It is isopropyl, tert-butyl, HO-CH(CH3)-, HO-CH(CH2CH3)-, HO-C(CH3)2-, HO-CH2CH(CH3)-, cyclopropyl or .

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 2 It can be H or -CH3.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 3 It is chlorine or -CH3.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 4 It is chlorine or -CH3; Or R 5 With R 4 Together with intercalated atoms, they form 5- to 6-membered cycloalkyl groups.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein: R 5 With R 4 Together with intercalated atoms, they form a cyclopentyl group.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R 5 It is H or fluorine.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: X does not exist.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: X is NR 12 C(O), OCR 12 R 12 or NR 12 CR 12 R 12 ;and Each R 12 It can be H or methyl on its own.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein: X is -OCH2-, -NHCH2-, -NHC(O)-, -N(CH3)CH2-, or -N(H)CH(CH3)-.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: L represents O, CH2, SO2, CO, and CHR. 11 or C(R) 11 )R 11 ;and Each R 11 It can be methyl or ethyl on its own.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein: L can be O, CH2, SO2, or CO.

15. A compound or a pharmaceutically acceptable salt thereof, said compound having any one of the following structures:

16. A compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from one of the following compounds: 、 、 , , and .

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

18. Use of the compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 17 in the preparation of a medicament for treating a condition mediated by THR β, wherein the condition is non-alcoholic steatohepatitis (NASH).

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