Macrocyclic broad spectrum antibiotics

Abstract

The present invention relates to macrocyclic broad-spectrum antibiotics. The present invention provides antibacterial compounds, some embodiments of which have broad-spectrum biological activity. In various embodiments, the compounds act through the inhibition of bacterial type 1 signal peptidase SpsB and / or LepB, which are essential proteins in bacteria. The present invention also provides pharmaceutical compositions and methods of treatment using the compounds described herein.

Description

[0001] This application is a divisional application of the application filed on May 27, 2020, with application number 202080040183.3 and invention title "Macrocyclic Broad-Spectrum Antibiotic".

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Patent Application No. 62 / 853,457, filed May 28, 2019, the contents of which are incorporated herein by reference in their entirety for all purposes. Background Technology

[0004] Antibiotic resistance is a growing and serious phenomenon in contemporary medicine and has emerged as a major public health problem in the 21st century. For example, certain antimicrobial compounds have been described in International Patent Publication No. WO 2018 / 149419, the contents of which are incorporated herein by reference in their entirety. Some of these antimicrobial compounds are shown in Table 1.

[0005] Table 1

[0006]

[0007]

[0008]

[0009]

[0010]

[0011] However, other novel types of broad-spectrum antibiotics are still needed to treat certain multidrug-resistant pathogens. Summary of the Invention

[0012] This document describes novel macrocyclic compounds for treating microbial infections, such as bacterial infections. In various embodiments, the present invention provides lipopeptide macrocyclic compounds for treating bacterial infections. In various embodiments, the present invention provides a class and subclass of compounds structurally related to arylomycin for treating bacterial infections. In various embodiments, the macrocyclic compounds function by inhibiting bacterial type 1 signal peptidase (SpsB) (an essential protein in bacteria). In some embodiments, the signal peptidase is a Gram-negative signal peptidase. In some embodiments, the signal peptidase is LepB. The compounds of the present invention are suitable for treating Gram-negative bacterial infections, and are particularly suitable for treating infections associated with non-fermenting bacteria.

[0013] In one respect, this article describes a compound of formula (I), or a pharmaceutical salt, solvate, or stereoisomer thereof:

[0014]

[0015] in:

[0016] R 1 For H or optionally via one, two or three R 1a Substituted -(C1-C6)alkyl;

[0017] Each R 1a Independent of halogen, -CN, -OR a -SR a -NR c R d -NO2, -C(=O)R b -NR a C(=O)R b -C(=O)OR a -C(=O)NR c R d -NR a C(=O)NR c R d -S(=O)2R b -S(=O)R b -S(=O)2NR c R d -S(=O)NR c R d -NR a S(=O)2R b -NR a S(=O)2NR c R d -NR a OR a -NR a C(=O)NR a OR a -O(C1-C6)alkylene-NR c R d -NR a C(=NR c )R a -C(=NR) a )NR c R d -NR a C(=NR a )NR c R d cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R on the same carbon 1a They combine to form oxygen;

[0018] R 2 H, -NR c R d Or optionally via one, two or three R 2a Substituted -(C1-C6)alkyl;

[0019] Each R 2a Independent of halogen, -CN, -OR a -SR a -NR c R d -NO2, -C(=O)R b -NR a C(=O)R b -C(=O)OR a -C(=O)NR c R d -NR a C(=O)NR c R d -S(=O)2R b -S(=O)R b -S(=O)2NR c R d -S(=O)NR c R d -NR a S(=O)2R b -NR a S(=O)2NR c R d -NR a OR a -NR a C(=O)NR a OR a -O(C1-C6)alkylene-NR c R d -NR a C(=NR c )R a -C(=NR) a )NR c R d -NR a C(=NR a )NR c R d cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R on the same carbon 2a They combine to form oxygen;

[0020] R 3 It is H, -(C3-C6)cycloalkyl, or optionally via one, two, or three R...3a Substituted -(C1-C6)alkyl;

[0021] Each R 3a Independent of halogen, -CN, -OR a -SR a -NR c R d -NO2, -C(=O)R b -NR a C(=O)R b -C(=O)OR a -C(=O)NR c R d -NR a C(=O)NR c R d -S(=O)2R b -S(=O)R b -S(=O)2NR c R d -S(=O)NR c R d -NR a S(=O)2R b -NR a S(=O)2NR c R d -NR a OR a -NR a C(=O)NR a OR a -O(C1-C6) alkylene, yl-NR c R d -NR a C(=NR c )R a -C(=NR) a )NR c R d -NR a C(=NR a )NR c R d cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R on the same carbon 3a They combine to form oxygen;

[0022] R 4 It is H or -(C1-C6) alkyl;

[0023] X is (C1-C6)alkylene, (C2-C6)enylene, (C2-C6)ynylene, (C3-C7)cycloalkylene, (C2-C7) heteroalkylene, arylene, or arylene; wherein the alkylene, enylene, ynylene, cycloalkylene, heteroalkylene, arylene, and heteroarylene are optionally derived from one, two, or three R... X replace;

[0024] Each R X Independent of halogen, -CN, -OR a -NR c R d -NO2, -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rs on the same carbon. X They combine to form oxygen;

[0025] Y is a bond, -O-, -S-, (C1-C6)alkylene, (C2-C6)enylene, (C2-C6)ynylene, (C3-C7)cycloalkylene, (C2-C7) heteroalkylene, arylene, or heteroarylene; wherein the alkylene, enylene, ynylene, cycloalkylene, heteroalkylene, arylene, and heteroarylene are optionally connected via one, two, or three R... Y replace;

[0026] Each R Y Independent of halogen, -CN, -OR a -NR c R d -NO2, -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rs on the same carbon. Y They combine to form oxygen;

[0027] Z represents H, halogen, -CN, or -OR. 10 -SR 10 -NR 12 R13 -C(=O)R 11 -C(=O)OR 2 -C(=O)NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C2-C 12 )alkenyl, -(C2-C 12 Alkynyl, -(C3-C9)cycloalkyl, -(C2-C7)heterocyclic alkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl groups are optionally derived from one, two or three R groups. Z replace;

[0028] Each R Z Independent of halogen, -CN, -OR 10 -NR l2 R 13 -NO2, -C(=O)R 11 -C(=O)OR 10 -C(=O)NR 12 R 13 -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rs on the same carbon. Z They combine to form oxygen;

[0029] Each R 10 Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7) heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally independently derived from one, two, or three R... 10a replace;

[0030] Each R 10a Independent of halogen, -CN, -OR a -NR C R d -C(=O)Rb -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 10a They combine to form oxygen;

[0031] Each R 11 Independently, it is -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7) heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally independently derived from one, two, or three R... 11a replace;

[0032] Each R 11a Independent of halogen, -CN, -OR a -NR c R d -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 11a They combine to form oxygen;

[0033] Each R 12 and R 13 Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7) heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally independently derived from one, two, or three R... 12a replace;

[0034] or R 12 and R 13 They bond together with the nitrogen atoms to form optionally one, two, or three R atoms. 12b Substituted heterocyclic alkyl groups;

[0035] Each R 12a Independent of halogen, -CN, -OR a -NRc R d -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 12a They combine to form oxygen;

[0036] Each R 12b Independent of halogen, -CN, -OR a -NR c R d -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 12b They combine to form oxygen;

[0037] Each R a Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted by one, two, or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, or -(C1-C6)alkyl;

[0038] Each R b Independently, it is -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally and independently substituted by one, two, or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, or -(C1-C6)alkyl; and

[0039] Each R c and R dIndependently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted by one, two or three halogens, -CN, -OH, -OMe, -NH3, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2 or -(C1-C6)alkyl;

[0040] or R c and R d They are bonded to nitrogen atoms to form heterocyclic alkyl groups, which are optionally substituted with one, two, or three oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, or -(C1-C6)alkyl groups.

[0041] In some embodiments of the compound of formula (I) or its pharmaceutical salt, solvate or stereoisomer, the compound has the structure of formula (Ia):

[0042]

[0043] In some embodiments of the compound of formula (I) or its pharmaceutical salt, solvate or stereoisomer, the compound has the structure of formula (Ib):

[0044]

[0045] This article also discloses a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutical salt, solvate or stereoisomer thereof, and a pharmaceutical excipient.

[0046] This article also discloses a method for treating bacterial infections in mammals, comprising administering to the mammal an effective amount of the compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof at a frequency and duration sufficient to provide a beneficial effect to the mammal.

[0047] This article also discloses a method for treating lepB-mediated infections in mammals, comprising administering to the mammal an effective amount of the compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof at a frequency and duration sufficient to provide a beneficial effect to the mammal. In some embodiments of the treatment, the bacterial infection involves the following: *Pseudomonas aeruginosa*, *Pseudomonas fluorescens*, *Pseudomonas acidovorans*, *Pseudomonas salcaligenes*, *Pseudomonas putida*, *Stenotrophomonas maltophilia*, *Burkholderia cepacia*, *Aeromonas hydrophilia*, *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhi*, *Salmonella paratyphi*, and *Salmonella enteritidis*. The following bacteria are listed: *Enteritidis*, *Shigella dysenteriae*, *Shigella flexneri*, *Shigella sonnei*, *Enterobacter cloacae*, *Enterobacter aerogenes*, *Klebsiella pneumoniae*, *Klebsiella oxytoca*, *Serratia marcescens*, *Francisella tularensis*, *Morganella morganii*, *Proteus mirabilis*, *Proteus vulgaris*, *Providencia alcalifaciens*, *Providencia rettgeri*, and *Providencia stuartii*.Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersiniapseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahemolyticus Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis. Meningitidis, Kingella, Moraxella, Gardnerella vaginalisBacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides eggerthii, Clostridium diifficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. Hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus. In some embodiments of the treatment, the bacterial infection involves Acinetobacter baumannii,Infection with Klebsiella pneumoniae or Pseudomonas aeruginosa. In some embodiments of the treatment method, the bacterial infection involves Acinetobacter baumannii. In some embodiments of the treatment method, the bacterial infection involves Gram-negative bacteria. In some embodiments of the treatment method, the method further includes administration of a second therapeutic agent. In some embodiments of the treatment method, the second therapeutic agent is not an SpsB or LepB inhibitor. In some embodiments of the treatment method, the second therapeutic agent is an aminoglycoside antibiotic, a fluoroquinolone antibiotic, a β-lactam antibiotic, a macrocyclic lactone antibiotic, a glycopeptide antibiotic, rifampicin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid. According to claim 48, the second therapeutic agent is a β-lactam antibiotic. According to the method of claim 50, the β-lactam antibiotic is selected from penicillins, monobactams, cephalosporins, cephamycins, and carbapenems. In some embodiments of the treatment method, the β-lactam antibiotic is selected from azlocillin, amoxicillin, ampicillin, doripenem, meropenem, biapenem, cefamandole, imipenem, mezlocillin, cefmetazole, cefprozil, piperacillin / tazobactam, and carbenicillin. nicillin), cefaclor, cephalothin, ertapenem, cefazolin, cefepime, cefonicid, cefoxitin, ceftazidime, oxacillin, cefdinir, cefixime, cefotaxime, cefootetan, cefpodoxime, ceftizoximeCeftriaxone, faropenem, mecillinam, methicillin, moxalactam, ticarcillin, tomopenem, ceftobiprole, ceftaroline, flomoxef, cefpirome, and cefozopran. In some embodiments of the treatment, the method further includes administration of a β-lactamase inhibitor. Detailed Implementation

[0048] definition

[0049] Unless the context clearly specifies otherwise, as used herein and in the appended claims, the singular forms “a / an” and “the” include a plurality of references. Thus, for example, a reference to “a drug” includes a plurality of such drugs, and a reference to “the cell” includes a reference to one or more cells (or a plurality of cells) and their equivalents known to those skilled in the art. When the scope used herein refers to physical properties such as molecular weight or chemical properties such as chemical formulas, it is intended to include all combinations and sub-combinations of the scope herein and specific embodiments. The term “about” when referring to a numerical value or range of values ​​means an approximation of the stated numerical value or range within experimental variability (or within experimental statistical error), and therefore in some cases, the numerical value or range may vary between 1% and 15% of the stated numerical value or range. The term “comprising” (and related terms such as “comprise / comprises” or “having” or “including”) is not intended to exclude embodiments of any subject matter composition, composition, method or process or the like described herein from being “consistent with” or “substantially composed of” the described features.

[0050] Unless otherwise stated, the following terms shall have the meanings specified below as used in the specification and the appended claims.

[0051] "alkyl" refers to a monovalent group of a straight-chain or branched saturated hydrocarbon that is optionally substituted, having one to about ten carbon atoms or one to six carbon atoms. Examples include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups, such as heptyl, octyl, and similar groups. Numerical ranges such as "C1-C6 alkyl" appearing herein whenever they mean that the alkyl group consists of 1, 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group is C1-C6. 20 Alkyl, C1-C 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the alkyl group is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted by halogen.

[0052] "Alkenyl" refers to a linear or branched monovalent hydrocarbon group that is optionally substituted, having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be cis or trans configurations with respect to the double bonds and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and similar groups. Numerical ranges such as "C2-C6 alkenyl" whenever they appear herein mean that the alkenyl group consists of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkenyl" where no numerical range is specified. In some embodiments, the alkenyl group is C2-C6. 20 alkenyl, C2-C 10 Alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted as described below, for example, by the following substitutions: oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0053] "Alynyl" refers to a selectively substituted straight-chain or selectively substituted branched-chain hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, acetylenyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and similar groups. Numerical ranges such as "C2-C6 alkynyl" whenever they appear herein mean that the alkynyl group consists of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkynyl" where no numerical range is specified. In some embodiments, the alkynyl group is C2-C 20 alkynyl group, C2-C 10The alkynyl group can be C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, or C2. Unless otherwise specified in the specification, the alkynyl group may optionally be substituted as described below, for example, by oxo, halogen, amino, nitrile, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the alkynyl group may optionally be substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group may optionally be substituted by oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkynyl group may optionally be substituted by halogen.

[0054] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, alkylene may optionally be substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0055] "Alkoxy" refers to -OR a The group, wherein R a Alkyl groups are alkyl groups as defined herein. Unless otherwise specifically stated in the specification, alkoxy groups may optionally be substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the alkoxy group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0056] "Aryl" refers to a group derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded via aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group. Aryl groups include (but are not limited to) aryl groups derived from the following hydrocarbon ring systems: anthraceneyl, ... benzene, The aryl group includes propylene, arsenyl, as-dicyclopentadienylbenzene, s-dicyclopentadienylbenzene, indane, indene, naphthalene, propylenenaphthalene, phenanthrene, pleiadene, pyrene, and terphenyl. In some embodiments, the aryl group is phenyl. Unless otherwise specified in the specification, the aryl group may optionally be substituted as described below, for example, by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group is optionally substituted with halogen or methyl. In some embodiments, the aryl group is optionally substituted with halogen.

[0057] "Cycloalkyl" refers to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaromatic ring, the cycloalkyl group is bonded via non-aromatic ring atoms) or bridged ring systems. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (C3-C5). 15 cycloalkyl groups, three to ten carbon atoms (C3-C4) 10Cycloalkyl groups are cycloalkyl groups with three to eight carbon atoms (C3-C8 cycloalkyl), three to six carbon atoms (C3-C6 cycloalkyl), three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocyclic compounds include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl compounds include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyl compounds are optionally substituted as described below, for example, by the following substitutions: oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted with a halogen or methyl group. In some embodiments, the cycloalkyl group is optionally substituted with a halogen.

[0058] "Halogen" or "halogen" refers to a bromine group, a chlorine group, a fluorine group, or an iodine group. In some embodiments, the halogen is a fluorine group or a chlorine group. In some embodiments, the halogen is a fluorine group.

[0059] "Halogenated alkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and similar groups.

[0060] "Aminoalkyl" refers to an alkyl group as defined above, which is substituted with one or more -NH2 groups, such as -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH(NH2)CH3, -CH2CH(NH2)CH3, -CH(NH2)CH2CH3 and similar groups.

[0061] "Hydroxyalkyl" refers to an alkyl group as defined above, which is substituted with one or more -OH groups, such as -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)CH3, -CH2CH(OH)CH3, -CH(OH)CH2CH3 and similar groups.

[0062] "Heterocyclic alkyl" refers to a stable 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Unless otherwise specified in this specification, a heterocyclic alkyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaromatic ring, the heterocyclic alkyl group is bonded via non-aromatic atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a (C2-C7) heterocyclic alkyl group. Examples of such heterocyclic alkyl groups include (but are not limited to) aziridine propane, aziridine butane, dioxacyclopentane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isoxazolinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolidinyl The terms pyrazolidine, quininecycloyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopenten-4-yl, and 2-oxo-1,3-dioxacyclopenten-4-yl are also included. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyl groups have 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is not the same as the total number of atoms constituting the heterocycloalkyl group (i.e., the skeletal atoms of the heterocycloalkyl ring), including heteroatoms. Unless otherwise specifically stated in the specification, heterocyclic alkyl groups are optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, and similar groups. In some embodiments, heterocyclic alkyl groups are optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocyclic alkyl groups are optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocyclic alkyl groups are optionally substituted by halogen or methyl. In some embodiments, heterocyclic alkyl groups are optionally substituted by halogen.

[0063] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In one aspect, a heteroalkyl group is a C1-C6 heteroalkyl group having one, two, or three heteroatoms selected from oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), or sulfur. In another aspect, a heteroalkyl group is a C1-C6 heteroalkyl group having one or two heteroatoms selected from oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), or sulfur. Unless otherwise specifically stated in the specification, heteroalkyl groups are optionally substituted as described below, for example, by substitution with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the heteroalkyl group is optionally substituted with the following: oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with halogen.

[0064] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. Heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl is bonded via aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include (but are not limited to) aziridine, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzom-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxane, benzonaphthuryl, benzooxazolyl, benzom-dioxacyclopentenyl, benzom-dioxacyclohexenyl, benzopiperanyl, benzopiperanone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, Linyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazoleyl, indoleyl, indazoleyl, isoindoleyl, indolinyl, isoindolelinyl, isoquinolinyl, indoleazinyl, isoxazolyl, The following are listed: pyridyl, oxadiazolyl, 2-oxoazonyl, oxazolyl, ethylene oxide, 1-oxo-pyridyl, 1-oxo-pyrimidinyl, 1-oxo-pyrazinyl, 1-oxo-pyridazinyl, 1-phenyl-1H-pyrroleyl, benzazinyl, benzathizinyl, benzoxazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in this specification, heteroaryl groups are optionally substituted as described below, for example, by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with halogen or methyl. In some embodiments, the heteroaryl group is optionally substituted with halogen.

[0065] The term "oxo" means =O.

[0066] The terms “treatment,” “prevention,” “improvement,” and “inhibition,” as used herein, and words derived therefrom, do not necessarily imply 100% or complete treatment, prevention, improvement, or inhibition. Rather, varying degrees of treatment, prevention, improvement, and inhibition that may have potential benefit or therapeutic effect can be identified by those generally skilled in the art. In this regard, the disclosed methods can provide any amount and level of treatment, prevention, improvement, or inhibition of a symptom in mammals. For example, a symptom, including its symptoms or conditions, can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, treatment, prevention, improvement, or inhibition provided by the methods disclosed herein may include treating, preventing, improving, or inhibiting one or more symptoms or conditions of a disease (e.g., cancer or inflammatory disease). Additionally, for the purposes of this document, “treatment,” “prevention,” “improvement,” or “inhibition” encompasses delaying the onset of a disease or its symptoms or conditions.

[0067] As used herein, the terms "effective amount" or "therapeutic effective amount" refer to an amount of the compound disclosed herein administered that is sufficient to alleviate one or more symptoms of the disease or condition being treated (e.g., cancer or an inflammatory disease). In some embodiments, the result is a reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising compounds as disclosed herein that is clinically necessary to achieve a significant reduction in the occurrence of disease symptoms. In some embodiments, techniques such as dose escalation studies are used to determine the appropriate "effective" amount for any individual case.

[0068] As used herein, “individual” (as in the context of therapy) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates such as apes and monkeys; and non-primates such as dogs, cats, cows, horses, sheep, and goats. Non-mammals include, for example, fish and birds.

[0069] The terms “disease” or “symptom” or “adverse condition” are used interchangeably and are used to refer to a disease or symptom in which bacterial SPases act in the biochemical mechanisms involved in the disease or adverse condition such that a therapeutic benefit can be achieved by acting on the enzyme. “Acting on” SPases may include binding to SP enzymes and / or inhibiting the biological activity of SPases.

[0070] As used herein, the term "prodrug" refers to a compound having one or more parts that can be metabolized in vivo. For example, a prodrug is metabolized in vivo by an esterase or by other mechanisms to become an active drug. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977), "Pharmaceutical Salts," J. Pharm. Sci. 66: 1-19). Prodrugs can be prepared in-situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free acid form or with a suitable esterifying agent, respectively. The hydroxyl group can be converted to an ester by treatment with formic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched low-carbon alkyl ester moieties (e.g., propionate esters), low-carbon alkenyl esters, di-low-carbon alkyl-amino low-carbon alkyl esters (e.g., dimethylaminoethyl ester), acylamino low-carbon alkyl esters (e.g., acetoxymethyl ester), acyloxy low-carbon alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl-low-carbon alkyl esters (e.g., benzyl esters), aryl and aryl-low-carbon alkyl esters substituted with (e.g., methyl, halogen or methoxy substituents), amides, low-carbon alkylamides, di-low-carbon alkylamides, and hydroxyamides.

[0071] As used herein, the term “substantially” means completely or nearly completely; for example, “substantially free” means that a composition does not have a component or contains trace amounts such that any relevant functional properties of the composition are not affected by the presence of those trace amounts, or that a compound is “substantially pure” means that only negligible trace impurities are present.

[0072] compound

[0073] In one respect, this article describes compounds of formula (I) or their pharmaceutical salts, solvates, or stereoisomers:

[0074]

[0075] in:

[0076] R 1 For H or optionally via one, two or three R 1a Substituted -(C1-C6)alkyl;

[0077] Each R 1a Independent of halogen, -CN, -OR a -SR a -NR c R d -NO2, -C(=O)R b -NR a C(=O)R b -C(=O)OR a -C(=O)NR c R d -NR a C(=O)NR c R d -S(=O)2R b -S(=O)R b -S(=O)2NR c R d -S(=O)NR c R d -NR a S(=O)2R b -NR a S(=O)2NR c R d -NR a OR a -NR a C(=O)NR a OR a -O(C1-C6) alkylene, yl-NR c R d -NR a C(=NRc )R a -C(=NR) a )NR c R d -NR a C(=NR a )NR c R d cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R on the same carbon 1a They combine to form oxygen;

[0078] R 2 H, -NR c R d Or optionally via one, two or three R 2a Substituted -(C1-C6)alkyl;

[0079] Each R 2a Independent of halogen, -CN, -OR a -SR a -NR c R d -NO2, -C(=O)R b -NR a C(=O)R b -C(=O)OR a -C(=O)NR c R d -NR a C(=O)NR c R d -S(=O)2R b -S(=O)R b -S(=O)2NR c R d -S(=O)NR c R d -NR a S(=O)2R b -NR a S(=O)2NR c R d -NR a OR a -NR a C(=O)NR a OR a -O(C1-C6)alkylene-NR c R d -NR a C(=NR c )R a -C(=NR) a )NRc R d -NR a C(=NR a )NR c R d cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R on the same carbon 2a They combine to form oxygen;

[0080] R 3 It is H, -(C3-C6)cycloalkyl, or optionally via one, two, or three R... 3a Substituted -(C1-C6)alkyl;

[0081] Each R 3a Independent of halogen, -CN, -OR a -SR a -NR c R d -NO2, -C(=O)R b -NR a C(=O)R b -C(=O)OR a -C(=O)NR c R d -NR a C(=O)NR c R d -S(=O)2R b -S(=O)R b -S(=O)2NR c R d -S(=O)NR c R d -NR a S(=O)2R b -NR a S(=O)2NR c R d -NR a OR a -NR a C(=O)NR a OR a -O(C1-C6)alkylene-NR c R d -NR a C(=NR c )R a -C(=NR) a )NR c R d -NR a C(=NR a )NRc R d cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R on the same carbon 3a They combine to form oxygen;

[0082] R 4 It is H or -(C1-C6) alkyl;

[0083] X is (C1-C6)alkylene, (C2-C6)enylene, (C2-C6)ynylene, (C3-C7)cycloalkylene, (C2-C7) heteroalkylene, arylene, or arylene; wherein the alkylene, enylene, ynylene, cycloalkylene, heteroalkylene, arylene, and heteroarylene are optionally derived from one, two, or three R... X replace;

[0084] Each R X Independent of halogen, -CN, -OR a -NR c R d -NO2, -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rs on the same carbon. X They combine to form oxygen;

[0085] Y is a bond, -O-, -S-, (C1-C6)alkylene, (C2-C6)enylene, (C2-C6)ynylene, (C3-C7)cycloalkylene, (C2-C7) heteroalkylene, arylene, or heteroarylene; wherein the alkylene, enylene, ynylene, cycloalkylene, heteroalkylene, arylene, and heteroarylene are optionally connected via one, two, or three R... Y replace;

[0086] Each R Y Independent of halogen, -CN, -OR a -NR c R d -NO2, -C(=O)R b -C(=O)OR a -C(=O)NR c R d-(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rs on the same carbon. Y They combine to form oxygen;

[0087] Z represents H, halogen, -CN, or -OR. 10 -SR 10 -NR 12 R 13 -C(=O)R 11 -C(=O)OR 2 -C(=O)NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C2-C 12 )alkenyl, -(C2-C 12 Alkynyl, -(C3-C9)cycloalkyl, -(C2-C7)heterocyclic alkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl groups are optionally derived from one, two or three R groups. Z replace;

[0088] Each R Z Independent of halogen, -CN, -OR 10 -NR 12 R 13 -NO2, -C(=O)R 11 -C(=O)OR 10 -C(=O)NR 12 R 13 -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rs on the same carbon. Z They combine to form oxygen;

[0089] Each R 10Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7) heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally independently derived from one, two, or three R... 10a replace;

[0090] Each R 10a Independent of halogen, -CN, -OR a -NR c R d -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 10a They combine to form oxygen;

[0091] Each R 11 Independently, it is -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7) heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally independently derived from one, two, or three R... 11a replace;

[0092] Each R 11a Independent of halogen, -CN, -OR a -NR c R d -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 11a They combine to form oxygen;

[0093] Each R 12 and R 13Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7) heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally independently derived from one, two, or three R... 12a replace;

[0094] or R 12 and R 13 They bond together with the nitrogen atoms to form optionally one, two, or three R atoms. 12b Substituted heterocyclic alkyl groups;

[0095] Each R 12a Independent of halogen, -CN, -OR a -NR c R d -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 12a They combine to form oxygen;

[0096] Each R 12b Independent of halogen, -CN, -OR a -NR C R d -C(=O)R b -C(=O)OR a -C(=O)NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. 12b They combine to form oxygen;

[0097] Each R aIndependently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted by one, two, or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, or -(C1-C6)alkyl;

[0098] Each R b Independently, it is -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally and independently substituted by one, two, or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, or -(C1-C6)alkyl; and

[0099] Each R c and R d Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)ynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted by one, two, or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, or -(C1-C6)alkyl;

[0100] or R c and R d They are bonded to nitrogen atoms to form heterocyclic alkyl groups, which are optionally substituted with one, two, or three oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, or -(C1-C6)alkyl groups.

[0101] In some embodiments of the compound of formula (I), R 2 To optionally pass through one, two or three R 2a Substituted H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), R 2 For any location via an R 2a Substituted H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), R 2 It is H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), R... 2 For H.

[0102] In some embodiments of the compound of formula (I), each R 2a Independent of halogen, -CN, -OR a -NR c R d -NR c C(=O)R b -NR c C(=O)NR c R d -NR c S(=O)3R b or -NR c S(=O)2NR c R d In some embodiments of the compound of formula (I), each R 2a Independently for -NR c R d or -NR c S(=O)2NR c R d .

[0103] In some embodiments of the compound of formula (I), R 3 To optionally pass through one, two or three R 3a Substituted H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), R 3 For any location via an R 3a Substituted H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), R 3 It is H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), R... 3 For H. In some embodiments of the compound of formula (I), R 3 It is a -(C1-C6)alkyl group. In some embodiments of compounds of formula (I), R 3 It is a methyl group.

[0104] In some embodiments of the compound of formula (I), each R 3aIndependent of halogen, -CN, -OR a -NR c R d -NR c C(=O)R b -NR c C(=O)NR c R d -NR c S(=O)3R b or -NR c S(=O)2NR c R d In some embodiments of the compound of formula (I), each R 3a Independently for -NR c R d or -NR c S(=O)2NR c R d .

[0105] In some embodiments of the compound of formula (I), R 4 For H. In some embodiments of the compound of formula (I), R 4 It is a -(C1-C6)alkyl group. In some embodiments of compounds of formula (I), R 4 It is a methyl group.

[0106] In some embodiments of the compound of formula (I) or its pharmaceutical salt, solvate or stereoisomer, the compound has the structure of formula (Ia):

[0107]

[0108] In some embodiments of the compound of formula (I) or its pharmaceutical salt, solvate or stereoisomer, the compound has the structure of formula (Ib):

[0109]

[0110] In some embodiments of compounds of formula (I), (Ia), or (Ib), R 1 To optionally pass through one, two or three R 1a Substituted -(C1-C6)alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 1 For optional location via one or two R 1a Substituted -(C1-C6)alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 1 For any location via an R 1a Substituted -(C1-C6)alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R1 It is -CH2CH2NH2, -CH2CH2NHSO2NH2, or -CH2NHSO2NH2. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 1 The value is -CH2CH2NH2. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 1 The form is -CH2CH2NHSO2NH2. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 1 It is -CH2NHSO2NH2.

[0111] In some embodiments of compounds of formula (I), (Ia), or (Ib), each R 1a Independent of halogen, -CN, -OR a -NR c R d -NR c C(=O)R b -NR c C(=O)NR c R d -NR c S(=O)2R b or -NR c S(=O)2NR c R d In some embodiments of compounds of formula (I), (Ia), or (Ib), each R 1a Independently for -NR c R d or -NR c S(=O)2NR c R d In some embodiments of compounds of formula (I), (Ia), or (Ib), each R 1a Independently for -NR c R d In some embodiments of compounds of formula (I), (Ia), or (Ib), each R 1a Independently for -NR c S(=O)2NR c R d .

[0112] In some embodiments of compounds of formula (I), (Ia), or (Ib), X is a (C2-C7) heterocyclic alkyl or heteroaryl group, each optionally derived from one, two, or three R groups. X Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is a (C2-C7) heterocyclic alkyl or heteroaryl group, each optionally substituted with one or two R groups. XSubstitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is a (C2-C7) heterocyclic alkyl or heteroaryl group, each optionally substituted with an R X Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally substituted via one, two, or three R... X Substituted (C2-C7) heterocyclic alkyl groups. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally substituted with one or two R groups. X Substituted (C2-C7) heterocyclic alkylene groups. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally derived from an R... X Substituted (C2-C7) heterocyclic alkyl groups. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally derived from one, two, or three R groups. X Substituted heteroaryl groups. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally substituted with one or two R groups. X Substituted heteroaryl group. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally substituted via an R X Substituted heteroaryl groups. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally substituted with one or two R groups. x Substituted pyrimidinyl group. In some embodiments of compounds of formula (I), (Ia), or (Ib), X is optionally substituted with one, two, or three R groups. X Substituted pyridinyl group.

[0113] In some embodiments of compounds of formula (I), (Ia), or (Ib), each R X Independent of halogen, -OR a -NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. X They combine to form an oxo group. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R X Independently for -NR c R d Or -(C1-C6)alkyl; or two R on the same carbon. X They combine to form an oxo group. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R X Independently for -NR c R d Or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R XIndependently, it is Cl, -CN, methyl, ethyl, -CF2H, -CF3, -CH2NH2, cyclopropyl, or 3-aminoazacyclobutane-1-yl. In some examples of compounds of formula (I), (Ia), or (Ib), each R X Independently, it is Cl, -CN, methyl, or -CH2NH2. In some examples of compounds of formula (I), (Ia), or (Ib), each R X Independently, it is Cl, methyl, or -CH2NH2. In some examples of compounds of formula (I), (Ia), or (Ib), each R X Independently methyl or -CH2NH2. In some embodiments of compounds of formula (I), (Ia), or (Ib), an R X It is 3-aminoazacyclobutane-1-yl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R X It is methyl on its own.

[0114] In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is a -(C2-C7) heterocyclic alkyl or aryl group, each optionally emanating from one, two, or three R groups. Y Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is a -(C2-C7) heterocyclic alkylene or arylene. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is a -(C2-C7) heterocyclic alkylene or arylene, each optionally substituted with one or two R... Y Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is a -(C2-C7) heterocyclic alkylene or arylene, each optionally substituted with an R Y Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is optionally substituted via one, two, or three R... Y Substituted arylene group. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is optionally substituted with one or two R groups. Y Substituted arylene. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is optionally substituted with an R Y Substituted arylene. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is arylene. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is optionally substituted with one, two, or three R groups. Y Substituted phenyl groups. In some embodiments of compounds of formula (I), (Ia), or (Ib), Y is a single bond.

[0115] In some embodiments of compounds of formula (I), (Ia), or (Ib), each R YIndependent of halogen, -OR a -NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R on the same carbon. Y They combine to form an oxo group. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R Y Independent of halogen, -OR a -NR c R d -(C1-C6)alkyl or -(C1-C6)haloalkyl. In some embodiments of compounds of formula (I), (Ia) or (Ib), each R Y Independently, it is a halogen, a -(C1-C6)alkyl, or a -(C1-C6)haloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R... Y Independently, it is F or -OH. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R... Y It is F.

[0116] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is H, halogen, -CN, -OR. 10 -SR 10 -NR 12 R 13 -C(=O)R 11 -C(=O)OR 2 -C(=O)NR 12 R 13 -(C1-C 13 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C2-C 12 )alkenyl, -(C2-C 12 Alkynyl, -(C3-C7)cycloalkyl, -(C2-C7)heterocyclic alkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, aryl and heteroaryl groups are optionally derived from one, two or three R groups. Z replace.

[0117] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C3-C9)cycloalkyl or -(C2-C7)heteroalkyl; wherein the alkyl, cycloalkyl and heteroalkyl are optionally derived from one, two or three R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C3-C9)cycloalkyl or -(C2-C7)heteroalkyl; wherein the alkyl, cycloalkyl and heteroalkyl are optionally derived from one or two R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C3-C9)cycloalkyl or -(C2-C7)heteroalkyl; wherein the alkyl, cycloalkyl and heteroalkyl are optionally derived from an R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 -Aminoalkyl, -(C3-C9)cycloalkyl or -(C2-C7)heteroalkyl.

[0118] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heteroalkyl; wherein the alkyl, cycloalkyl and heteroalkyl are optionally derived from one, two or three R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heteroalkyl; wherein the alkyl, cycloalkyl and heteroalkyl are optionally derived from one or two R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 )aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heteroalkyl; wherein the alkyl, cycloalkyl and heteroalkyl are optionally derived from an R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is a halogen, -OR 10 -NR 12 R 13 -(C1-C 12 )alkyl, -(C1-C 12 )heteroalkyl, -(C1-C 12 ) Haloalkyl, -(C1-C 12 )hydroxyalkyl, -(C1-C 12 -Aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heteroalkyl.

[0119] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 -(C1-C 12 )alkyl, -(C1-C 12 ) Haloalkyl or -(C3-C9)cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally derived from one, two or three R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 -(C1-C 12 )alkyl, -(C1-C 12 ) Haloalkyl or -(C3-C9)cycloalkyl; wherein the alkyl and cycloalkyl groups are optionally derived from one or two R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 -(C1-C 12 )alkyl, -(C1-C 12 ) Haloalkyl or -(C3-C9)cycloalkyl; wherein the alkyl and cycloalkyl groups are optionally derived from an R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 -(C1-C 12 )alkyl, -(C1-C 12 ) Haloalkyl or -(C3-C9)cycloalkyl.

[0120] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 -(C1-C 12 )alkyl, -(C1-C 12 ) Haloalkyl or -(C3-C7)cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally derived from one, two or three R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 -(C1-C 12 )alkyl, -(C1-C 12 ) Haloalkyl or -(C3-C7)cycloalkyl; wherein the alkyl and cycloalkyl groups are optionally derived from one or two R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 -(C1-C 12 )alkyl, -(C1-C 12 ) Haloalkyl or -(C3-C7)cycloalkyl; wherein the alkyl and cycloalkyl groups are optionally derived from an R Z Substitution. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR10 -(C1-C 12 )alkyl, -(C1-C 12 -Halogenated alkyl or -(C3-C7)cycloalkyl.

[0121] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -OR 10 .

[0122] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally via one, two, or three R... Z Replacement -(C1-C 12 )alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally alkylated by one or two R Z Replacement -(C1-C 12 )alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally alkylated via an R Z Replacement -(C1-C 12 )alkyl. In some embodiments of compounds of formula (I), (Ia) or (Ib), Z is -(C1-C1)alkyl. 12 )alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is 2,2-dimethylpropyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is tert-butyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is isobutyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), after being subjected to an R Z The substituted Z is cyclopropylmethyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), via an R... Z The substituted Z is cyclobutylmethyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), via an R... Z The substituted Z is 1-fluoro-2-methylpropyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), after two R... Z The substituted Z is 1,1-difluoro-2-methylpropyl.

[0123] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally via one, two, or three R... Z Replacement -(C1-C 12 ) Haloalkyl. In some embodiments of compounds of formula (I), (Ia) or (Ib), Z is optionally alkylated by one or two R Z Replacement -(C1-C 12) Haloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally alkylated via an R Z Replacement -(C1-C 12 ) Haloalkyl. In some embodiments of compounds of formula (I), (Ia) or (Ib), Z is -(C1-C2). 12 ) Haloalkyl.

[0124] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally via one, two, or three R... Z Substituted -(C3-C9)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally substituted with one or two R... Z Substituted -(C3-C9)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally via an R Z Substituted -(C3-C9)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -(C3-C9)cycloalkyl.

[0125] In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally via one, two, or three R... Z Substituted -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally substituted with one or two R... Z Substituted -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is optionally via an R Z Substituted -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), Z is 2,3-dihydro-1H-inden-5-yl.

[0126] In some embodiments of compounds of formula (I), (Ia), or (Ib), each R Z Independent of halogen, -OR 10 -NR 12 R 13 Or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R Z Independently, it is a -(C1-C6)alkyl group. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R Z Independently, it is methyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R... Z Independently, it is F.

[0127] In some embodiments of compounds of formula (I), (Ia), or (Ib), R 10 It is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 10 It is a -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 10 It is a -(C1-C6)alkyl or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 10 It is 2,2-dimethylbutyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 10 It is an isophenyl group. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 10 It is a cyclohexyl group.

[0128] In some embodiments of compounds of formula (I), (Ia), or (Ib), R 11 It is a -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 11 It is -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

[0129] In some embodiments of compounds of formula (I), (Ia), or (Ib), R 12 and R 13 Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), R 12 and R 13 It is independently H, -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

[0130] In some embodiments of compounds of formula (I), (Ia), or (Ib), -XYZ is

[0131]

[0132]

[0133] In some embodiments of compounds of formula (I), (Ia), or (Ib), -XYZ is

[0134]

[0135] In some embodiments of compounds of formula (I), (Ia), or (Ib), -XYZ is

[0136]

[0137] In some embodiments of compounds of formula (I), (Ia), or (Ib), -XYZ is

[0138]

[0139] In some embodiments of compounds of formula (I), (Ia), or (Ib), -XYZ is

[0140]

[0141] In some embodiments of compounds of formula (I), (Ia), or (Ib), each R a Independently, it is H, -(C1-C6)alkyl, (C1-C6)haloalkyl, or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R a Independently, it is H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R a For H. In some embodiments of compounds of formula (I), (Ia) or (Ib), each R a It is independently -(C1-C6)alkyl.

[0142] In some embodiments of compounds of formula (I), (Ia), or (Ib), each R a Independently, each R is a -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R a It is independently -(C1-C6)alkyl.

[0143] In some embodiments of compounds of formula (I), (Ia), or (Ib), each R c and R d Independently, it is H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C3-C7)cycloalkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R c and R d Independently, it is H or -(C1-C6)alkyl. In some embodiments of compounds of formula (I), (Ia), or (Ib), each R c and R d For H. In some embodiments of compounds of formula (I), (Ia) or (Ib), each Rc and R d It is independently -(C1-C6)alkyl.

[0144] In some embodiments, the compounds of formula (I), (Ia) or (Ib) are selected from the compounds in Table 2 or their pharmaceutical salts, solvates or stereoisomers.

[0145] Table 2

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] In some embodiments, the compound of formula (I), (Ia) or (Ib) is a compound or its pharmaceutical salt, solvate or stereoisomer, wherein the compound is (8S, 11S, 14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-2-[[4-amino-2-(4-tert-butylphenyl)-6-methyl-pyrimidin-5-carbonyl]amino]-3-(aminosulfonylamino)propionyl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

[0167] In some embodiments, the compound of formula (I), (Ia) or (Ib) is a compound or its pharmaceutical salt, solvate or stereoisomer, wherein the compound is (8S, 11S, 14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-2-[[4-methyl-2-[4-(1-methylcyclopropyl)phenyl]pyrimidin-5-carbonyl]amino]-3-(aminosulfonylamino)propionyl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

[0168] In some embodiments, the compound of formula (I), (Ia) or (Ib) is a compound or its pharmaceutical salt, solvate or stereoisomer, wherein the compound is (8S, 11S, 14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-4-amino-2-[[4-amino-2-(4-tert-butylphenyl)-6-methyl-pyrimidin-5-carbonyl]amino]butyryl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

[0169] In some embodiments, the compound of formula (I), (Ia) or (Ib) is a compound or its pharmaceutical salt, solvate or stereoisomer, wherein the compound is (8S, 11S, 14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-4-amino-2-[[4-methyl-2-[4-(1-methylcyclopropyl)phenyl]pyrimidin-5-carbonyl]amino]butyryl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

[0170] In some embodiments, the compound of formula (I), (Ia) or (Ib) is a compound or its pharmaceutical salt, solvate or stereoisomer, wherein the compound is (8S, 11S, 14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-4-amino-2-[[2-(4-tert-butylphenyl)-4-amino-6-difluoromethyl-pyrimidin-5-carbonyl]amino]butyryl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaeno-8-carboxylic acid.

[0171] In some embodiments, the compound of formula (I), (Ia) or (Ib) is a compound or its pharmaceutical salt, solvate or stereoisomer, wherein the compound is (8S, 11S, 14S)-14-[[(2S)-2-[[4-amino-2-(4-tert-butylphenyl)-6-(difluoromethyl)pyrimidin-5-carbonyl]amino]-3-(aminosulfonylamino)propionyl]-methyl-amino]-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-18-hydroxy-11-methyl-10,13-dioxo-9,12-diazatricyclo[13.3.1.12,6]eicosene-1(18),2(20),3,5,15(19),16-hexaenoic acid.

[0172] In some embodiments, compounds of formula (I), (Ia), or (Ib) are in prodrug form. Some embodiments include prodrugs of compounds of formula (I), (Ia), or (Ib) which are converted to their active form via other in vivo mechanisms. In some embodiments, the compounds of the present invention are prodrugs of any of the formulas herein.

[0173] Other forms of the compounds disclosed herein

[0174] Isomers / stereoisomers

[0175] In some embodiments, the compounds described herein exist in geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, E, and zygotic isomers and their respective mixtures. In some cases, the compounds described herein have one or more palmar centers, each center existing in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers and their respective mixtures. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion are suitable for the applications described herein. In some embodiments, the compounds described herein are prepared in their individual stereoisomer forms as follows: a racemic mixture of the compounds is reacted with an optically active resolving agent to form diastereomeric compound pairs, the diastereomers are separated, and the optically pure enantiomers are recovered. In some embodiments, a dissociable complex is preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated using these differences. In some embodiments, diastereomers are separated by diametric chromatography or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are then recovered.

[0176] Labeled compounds

[0177] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds listed herein, except that one or more atoms have undergone atomic substitutions with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein, or their solvates or stereoisomers, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P,35 S, 18 F and 36 Cl. Certain isotopically labeled compounds, such as those containing, etc. 3 H and 14 Compounds containing radioactive isotopes of C are suitable for drug and / or tissue distribution analysis. Tritiumization (i.e.,...) 3 H) and carbon-14 (i.e., H) and carbon-14 14 C) Isotopes are particularly advantageous due to their ease of preparation and detectability. Furthermore, isotopes such as deuterium (i.e., 2 Heavy isotope substitution of H) produces certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirement. In some embodiments, the isotope-labeled compound or its pharmaceutical salt, solvate, or stereoisomer is prepared by any suitable method.

[0178] In some embodiments, the compounds described herein are labeled in other ways, including (but not limited to) using chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling.

[0179] medicinal salt

[0180] In some embodiments, the compounds described herein are present in the form of their pharmaceutical salts. In some embodiments, the methods disclosed herein include methods of treating a disease by applying such pharmaceutical salts. In some embodiments, the methods disclosed herein include methods of treating a disease by applying such pharmaceutical salts in the form of a pharmaceutical composition.

[0181] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a variety of inorganic or organic bases and any of inorganic or organic acids to form pharmaceutical salts. In some embodiments, these salts are prepared on-site during the final separation and purification of the compounds disclosed herein, or by reacting the purified compound in its free form with a suitable acid or base, respectively, and separating the resulting salt.

[0182] Examples of medicinal salts include those prepared by reacting the compounds described herein with inorganic, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, disglucurons, dihydrophosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, transbutenedioates, glucoheptates, glycerophosphates, glycolic acid salts, hemisulfates, heptanoates, hexyn-1,6-dicitates, hydroxybenzoates, γ-hydroxybutyrates, and hydrochlorides. Hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, iodide, isobutyrate, lactate, maleate, malonate, methane sulfonate, amygdalinate metaphosphate, methane sulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, pyrosulfate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propane sulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluene sulfonate, undecanoate, and xylene sulfonate.

[0183] Furthermore, the compounds described herein can be prepared as pharmaceutical salts by reacting the free base form of the compounds with pharmaceutically acceptable inorganic or organic acids, including (but not limited to) inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and their analogues; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, and benzoic acid. Acids, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4′-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid.

[0184] In some embodiments, those compounds comprising free acid groups described herein react with suitable bases (such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations), ammonia, or pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts and similar salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1-4 Alkyl)4 and its analogues.

[0185] Representative organic amines suitable for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and their analogues. It should be understood that the compounds described herein also include quaternary ammoniation of any basic nitrogen-containing group they contain. In some embodiments, such quaternary ammoniation yields water- or oil-soluble or dispersible products.

[0186] solvates

[0187] In some embodiments, the compounds described herein are present in solvate form. The present invention provides a method of treating a disease by applying such solvates. The present invention further provides a method of treating a disease by applying such solvates in the form of a pharmaceutical composition. The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process using a pharmaceutical solvent (such as water, ethanol, and the like). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The solvates of the compounds described herein are preferably prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein are preferably prepared by recrystallization from an aqueous / organic solvent mixture, the organic solvent used including (but not limited to) dioxane, tetrahydrofuran, or methanol. Additionally, the compounds provided herein may exist in both solvated and non-solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0188] tautomer

[0189] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the chemical formulas described herein. Tautomers are compounds that can interconvert through the migration of hydrogen atoms, which involves the conversion of single bonds with adjacent double bonds. A chemical equilibrium of tautomers will exist in the bond arrangements in which tautomerization may occur. All tautomer forms of the compounds disclosed herein are covered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0190] Another option is a hydrate or metabolite of any of the aforementioned compounds. Yet another option is a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutical excipient.

[0191] Another aspect described herein is the use of the compounds described herein in the manufacture of medicaments for treating bacterial infections in patients.

[0192] On the other hand, a method for treating mammals requiring such treatment includes administering to the mammal any of the aforementioned compounds in an antibacterially effective amount at a frequency and duration sufficient to provide a beneficial effect to the mammal. In one embodiment, the mammal has a bacterial-associated infection resistant to arylomycin A2 treatment. In another embodiment, the pathogenic bacterial infection involves infections of the following species: *Pseudomonas aeruginosa*, *Pseudomonas fluorescens*, *Pseudomonas acidophilus*, *Pseudomonas alkaloidea*, *Pseudomonas putida*, *Stenotrophomonas maltophilia*, *Burkholderia cepacia*, *Aeromonas hydrophila*, *Escherichia coli*, *Citrobacter freundii*, *Salmonella typhimurium*, *Salmonella typhimurium*, *Salmonella paratyphimurium*, *Salmonella enteritidis*, *Shigella dysenteriae*, *Shigella freundii*, *Shigella soxella*, *Enterobacter cloacae*, *Enterobacter aerogenes*, and *Klebsiella pneumoniae*. Klebsiella pneumoniae, Serratia marcescens, Serratia tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alkaliformis, Providencia reticularis, Providencia squarrosa, Acinetobacter baumannii, Acinetobacter calcium acetate, Acinetobacter hemolyticus, Yersinia enterocolitica, Yersinia plague, Yersinia pseudotuberculosis, Yersinia intermediate, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, and others. Haemophilus influenzae, Haemophilus hemolyticus, Haemophilus parahemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella hemolyticus, Moraxella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Cladosporium chrysogenum, Moraxella catarrhalis, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides digiri, and Bacteroides 3452A homology group. Bacteria, including Bacteroides vulgaris, Bacteroides ovalis, Bacteroides polymorpha, Bacteroides monomorpha, Bacteroides escherichiae, Bacteroides viscera, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, intracellular mycobacteria, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermediate, Staphylococcus suis subsp., Staphylococcus hemolyticus, Staphylococcus aureus, or Staphylococcus glycolyticus.

[0193] In another embodiment, the bacterial infection involves Gram-negative bacteria. In such embodiments, Gram-negative bacteria may be, for example, *Escherichia coli*, *Klebsiella pneumoniae*, *Pseudomonas aeruginosa*, *Acinetobacter baumannii*, *Neisseria gonorrhoeae*, *Neisseria meningitidis*, *Chlamydia trachomatis*, *Moraxella catarrhalis*, *Haemophilus influenzae*, *Proteus mirabilis*, *Enterobacter cloacae*, *Serratia marcescens*, *Helicobacter pylori*, *Salmonella enteritidis*, *Salmonella typhi*, *Legionella pneumophila*, *Haemophilus influenzae*, *Vibrio cholerae*, *Pseudomonas stutzeri*, *Ralstonia solanacearum*, or *Xylella fastidiosa*.

[0194] In some embodiments, the bacterial infection involves non-fermenting bacteria. Such non-fermenting bacteria may be, for example, Acinetobacter baumannii, Achromobacter xylosoxidans, Bordetella pertussis, Burkholderia cepacia (also known as Pseudomonas cepacia), Burkholderia pseudomallei (also known as Pseudomonaspseudomallei), Elizabethkingia meningoseptica (also known as Chryseobacterium meningosepticum), Moraxella catarrhalis (also known as Moraxella catarrhalis), Pseudomonas aeruginosa, or Stenotrophomonas maltophilia (also known as Pseudomonas maltophilia).

[0195] In another embodiment, the bacterial infection is a lepB-mediated infection.

[0196] In another embodiment, the bacterial infection is an infection involving Gram-positive bacteria.

[0197] In another embodiment, a method for treating a mammal requiring such treatment comprises administering a second therapeutic agent to the mammal, any of the aforementioned treatment methods. In another embodiment, the second therapeutic agent is not an SpsB or LepB inhibitor. In another embodiment, the second therapeutic agent is an aminoglycoside antibiotic, a fluoroquinolone antibiotic, a β-lactam antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, rifampin, chloramphenicol, fluoromycin, colistin, mupirocin, bacitracin, daptomycin, or linezolid.

[0198] In some embodiments, this is a method of treating bacterial infections in patients, preferably humans, wherein the treatment comprises administering a therapeutic or pharmacologically effective amount of the following: 1) a β-lactam antibiotic; and 2) a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof; and 3) a pharmaceutical carrier. In embodiments where a β-lactam antibiotic is used in combination with a compound disclosed herein, the β-lactam antibiotic may be a carbapenem, cephalosporin, cephamycin, monocyclic lactam, or penicillin. Exemplary carbapenem antibiotics suitable for use in the methods of the present invention include ertapenem, imipenem, biapenem, and meropenem. Exemplary cephalosporin antibiotics suitable for use in the methods of the present invention include cefepime, cefuroxime, cefpirome, cefazolin, cefepime, cefepime, cefotaxime, and ceftriaxone. Exemplary penicillin antibiotics suitable for use in the methods of the present invention include ampicillin, amoxicillin, piperacillin, oxacillin, cloxacillin, methicillin, and nafcillin. In some embodiments of the invention, β-lactams may be administered in combination with β-lactamase inhibitors. In some embodiments of the invention, carbapenems may be administered in combination with DHP inhibitors (e.g., cilastatin).

[0199] In various embodiments of the invention, where the compounds disclosed herein are used in combination with β-lactam antibiotics, the β-lactam antibiotics and compounds disclosed herein may be administered sequentially or simultaneously. Preferably, the β-lactam antibiotics and compounds disclosed herein are administered together. When administered simultaneously, the β-lactam antibiotics and compounds disclosed herein may be administered in the same formulation or in separate formulations. When administered sequentially, the β-lactam or compound disclosed herein may be administered first. After administration of the first compound, another compound may be administered, for example, within 1 to 60 minutes, such as within 1, 2, 3, 4, 5, 10, 15, 30, or 60 minutes. In one aspect of the invention, when using a β-lactamase inhibitor, it may be administered alone or in a formulation with the compounds disclosed herein and / or β-lactam antibiotics. In one aspect of the invention, when a DHP inhibitor is used to improve the stability of carbapenems, it may be administered alone or in a formulation with the compounds disclosed herein and / or carbapenems.

[0200] This document further describes pharmaceutical compositions comprising the compounds disclosed herein, a pharmaceutical carrier, and optionally, a β-lactam antibiotic. In examples using the combination, the β-lactam antibiotic and compounds disclosed herein are present in amounts such that their combination constitutes a therapeutically effective amount. Due to the enhancing effect of the compounds disclosed herein, the amount of β-lactam antibiotic present in the combination may be lower than the amount of β-lactam antibiotic used alone. In some embodiments, the composition further comprises a β-lactamase antibiotic.

[0201] In other embodiments where the β-lactam antibiotic is a carbapenem, a pharmaceutical composition is provided comprising a carbapenem antibiotic, a DHP inhibitor, a compound disclosed herein, and a pharmaceutically acceptable carrier. In some embodiments where the β-lactam antibiotic is a carbapenem, the carbapenem antibiotic is preferably selected from the group consisting of ertapenem, imipenem, and meropenem.

[0202] In some embodiments, the compounds disclosed herein are used for treating bacterial infections. In some embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents comprising β-lactam antibiotics for treating bacterial infections. In some embodiments, the compounds disclosed herein are used as medicaments for treating bacterial infections. In some embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents comprising β-lactam antibiotics, suitable for use as medicaments for treating bacterial infections. In some embodiments, the compounds disclosed herein are used to prepare medicaments for treating bacterial infections. In some embodiments, the compounds disclosed herein are combined with one or more other therapeutic agents comprising β-lactam antibiotics, used to prepare medicaments for treating bacterial infections.

[0203] In some embodiments described herein, the compounds disclosed herein can enhance the activity of β-lactam antimicrobial agents by inducing susceptibility to antimicrobial agents in resistant strains (such as MRSA). In some embodiments, the compounds disclosed herein can enhance the activity of β-lactam antimicrobial agents by reducing the dose of antimicrobial agent required to have a therapeutic effect in drug-sensitive strains. For example, if the compounds disclosed herein reduce the minimum inhibitory concentration (MIC) of an antimicrobial agent in susceptible strains (where the MIC is the minimum concentration of an antimicrobial agent that will completely inhibit growth), such treatment can facilitate a reduction in the amount of antimicrobial agent applied (which may reduce the side effects of antibiotics) or a reduction in the frequency of application. In some embodiments, the compounds disclosed herein can enhance the activity of antimicrobial agents (such as carbapenems) to prevent the emergence of resistant subgroups in heterogeneous bacterial populations with resistant subgroups.

[0204] Synergists can be used to enhance the clinical efficacy of antimicrobial agents whose activity is limited due to the increasing prevalence of resistant strains. In some embodiments described herein, the compounds disclosed herein are used as synergists, wherein the compounds disclosed herein may be administered together with β-lactam antibiotics (simultaneously or sequentially) to allow for effective treatment of infections involving resistant bacteria, or to reduce the amount of antimicrobial agent required to treat the infection.

[0205] In one embodiment, a compound described herein exhibits antibiotic activity suitable for treating bacterial infections such as (for example only) various strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Bacillus subtilis, and Escherichia coli, including species resistant to many known antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), multidrug-resistant Enterococcus faecium, macrolide-resistant Staphylococcus aureus and Staphylococcus epidermidis, and linezolid-resistant Staphylococcus aureus and Enterococcus faecium.

[0206] Methicillin-resistant Staphylococcus aureus

[0207] Staphylococcus aureus (S. aureus) is a coccidia bacterium and the most common cause of staphylococcal infections. Staphylococcus aureus is known to cause a range of illnesses, from minor skin infections (such as papules, pustules, boils, cellulitis, folliculitis, furuncles, carbuncles, scalded skin syndrome, abscesses) to life-threatening conditions (such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome, and sepsis). In addition, Staphylococcus aureus is one of the most common causes of hospital-acquired infections, often resulting in postoperative wound infections.

[0208] Methicillin was introduced in the late 1950s to treat infections caused by penicillin-resistant Staphylococcus aureus. Acquired resistance to methicillin in Staphylococcus aureus isolates has been previously reported (methicillin-resistant Staphylococcus aureus, MRSA). The methicillin resistance gene (mecA) encodes a methicillin-resistant penicillin-binding protein not present in susceptible strains. mecA is carried on a mobile genetic element, the staphylococcal cartridge chromosome mec (SCCmec), of which four different forms with varying sizes and gene compositions have been described. The methicillin-resistant penicillin-binding protein allows for resistance to β-lactam antibiotics and prevents their clinical use during MRSA infection.

[0209] In one aspect, a method for treating an individual with resistant bacteria comprises administering to the individual a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof. In one embodiment, the bacteria are Gram-positive bacteria. In another embodiment, the Gram-positive bacteria are Staphylococcus aureus. In another embodiment, the Staphylococcus aureus is resistant to or difficult to treat with a β-lactam antibiotic. In yet another embodiment, the β-lactam antibiotic belongs to the penicillin class. In another embodiment, the β-lactam antibiotic is methicillin. In yet another embodiment, the individual has methicillin-resistant Staphylococcus aureus bacteria. In one embodiment, the β-lactam antibiotic is flucloxacillin. In another embodiment, a method for treating an individual with dicloxacillin-resistant bacteria comprises administering to the individual a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the individual is difficult to treat with dicloxacillin. This document also discloses a method for treating an individual with methicillin-resistant bacteria, comprising administering a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the individual has been identified as having methicillin-resistant bacteria. In one embodiment, the individual is screened for methicillin-resistant bacteria. In another embodiment, individual screening is performed via nasal culture. In another embodiment, methicillin-resistant bacteria are detected by swabbing the individual's nostrils and isolating bacteria. In yet another embodiment, real-time PCR and / or quantitative PCR are used to determine whether the individual has methicillin-resistant bacteria.

[0210] In one embodiment, a method for treating an individual with bacteria resistant to first-generation cephalosporins comprises administering a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the individual is difficult to treat with first-generation cephalosporins. In one embodiment, the bacteria are resistant to first-generation cephalosporins. In another embodiment, the bacteria are resistant to cefacetrile. In another embodiment, the bacteria are resistant to cefadroxil. In yet another embodiment, the bacteria are resistant to cefalexin. In one embodiment, the bacteria are resistant to cefaloglycin. In another embodiment, the bacteria are resistant to cefalonium. In another embodiment, the bacteria are resistant to cefaloridine. In yet another embodiment, the bacteria are resistant to cefalotin. In yet another embodiment, the bacteria are resistant to cefapirin. In yet another embodiment, the bacteria are resistant to cefatrizine. In one embodiment, the bacteria are resistant to cefazaflur. In another embodiment, the bacteria are resistant to cefazedone. In yet another embodiment, the bacteria are resistant to cefazolin. In another embodiment, the bacteria are resistant to cefradine. In yet another embodiment, the bacteria are resistant to cefroxadine. In one embodiment, the bacteria are resistant to ceftezole.

[0211] In one embodiment, a method for treating an individual with bacteria resistant to second-generation cephalosporins comprises administering a compound disclosed herein, or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the individual is difficult to treat with second-generation cephalosporins. In another embodiment, the bacteria are resistant to second-generation cephalosporins. In another embodiment, the bacteria are resistant to cefaclor. In another embodiment, the bacteria are resistant to cefonicid. In yet another embodiment, the bacteria are resistant to cefprozil. In one embodiment, the bacteria are resistant to cefuroxime. In another embodiment, the bacteria are resistant to cefuzonam. In another embodiment, the bacteria are resistant to cefmetazole. In yet another embodiment, the bacteria are resistant to cefotetan. In another embodiment, the bacteria are resistant to cefoxitin.

[0212] In one embodiment, a method for treating an individual with bacteria resistant to third-generation cephalosporins comprises administering a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the individual is difficult to treat with third-generation cephalosporins. In another embodiment, the bacteria are resistant to third-generation cephalosporins. In another embodiment, the bacteria are resistant to cefcapene. In another embodiment, the bacteria are resistant to cefodaloxime. In yet another embodiment, the bacteria are resistant to cefdinir. In one embodiment, the bacteria are resistant to cefditoren. In another embodiment, the bacteria are resistant to cefixime. In another embodiment, the bacteria are resistant to cefomenoxime. In yet another embodiment, the bacteria are resistant to cefodizime. In another embodiment, the bacteria are resistant to cefotaxime. In yet another embodiment, the bacteria are resistant to cefpimizole. In one embodiment, the bacteria are resistant to cefpodoxime. In another embodiment, the bacteria are resistant to cefteram. In yet another embodiment, the bacteria are resistant to ceftibuten. In another embodiment, the bacteria are resistant to ceftiofur. In yet another embodiment, the bacteria are resistant to ceftiolene. In one embodiment, the bacteria are resistant to ceftizoxime. In another embodiment, the bacteria are resistant to cefriaxone. In yet another embodiment, the bacteria are resistant to cefoperazone. In yet another embodiment, the bacteria is resistant to ceftazidime.

[0213] In one embodiment, a method for treating an individual with bacteria resistant to fourth-generation cephalosporins comprises administering a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the individual is difficult to treat with fourth-generation cephalosporins. In another embodiment, the bacteria are resistant to fourth-generation cephalosporins. In another embodiment, the bacteria are resistant to cefocilidine. In another embodiment, the bacteria are resistant to cefepime. In yet another embodiment, the bacteria are resistant to cefluprenam. In one embodiment, the bacteria are resistant to cefososelis. In another embodiment, the bacteria are resistant to cefozopran. In another embodiment, the bacteria are resistant to cefpirome. In yet another embodiment, the bacteria are resistant to cefquinome.

[0214] In one embodiment, a method of treating an individual with carbapenem-resistant bacteria comprises administering a compound disclosed herein, or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the individual is difficult to treat with carbapenems. In another embodiment, the bacteria are resistant to carbapenems. In another embodiment, the bacteria are resistant to imipenem. In another embodiment, the bacteria are resistant to meropenem. In yet another embodiment, the bacteria are resistant to ertapenem. In one embodiment, the bacteria are resistant to faropenem. In another embodiment, the bacteria are resistant to doripenem. In another embodiment, the bacteria are resistant to panipenem. In yet another embodiment, the bacteria are resistant to piappenem.

[0215] Vancomycin-intermediate Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus

[0216] Vancomycin-intermediate Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus are specific types of antimicrobial resistant Staphylococcus bacteria that are difficult to treat with vancomycin. A vancomycin MIC of 4 to 8 μg / mL is used to classify Staphylococcus aureus isolates as vancomycin-intermediate, and a vancomycin MIC ≥ 16 / mL is used to classify Staphylococcus aureus isolates as vancomycin-resistant (Clinical and Laboratory Standards Institute / NCCLS. Performance Standards for Antimicrobial Susceptibility Testing. Sixteenth informational supplement. M100-S16. Wayne, PA: CLSI, 2006).

[0217] As used herein, the term "minimum inhibitory concentration" (MIC) refers to the lowest concentration of an antibiotic required to inhibit the growth of a bacterial isolate in vitro. A common method for determining the MIC of an antibiotic is to prepare several test tubes containing serially diluted antibiotic solutions, followed by inoculation with the target bacterial isolate. The MIC of an antibiotic is determined from the lowest concentration observed in the test tubes that show no turbidity (no growth).

[0218] In one aspect, a method of treating an individual with a bacterial infection includes administering to the individual a compound disclosed herein, or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the bacterial infection comprises vancomycin-mediated Staphylococcus aureus. In one embodiment, the vancomycin-mediated Staphylococcus aureus has a MIC between about 4 and about 8 μg / mL. In another embodiment, the vancomycin-mediated Staphylococcus aureus has a MIC of about 4 μg / mL. In yet another embodiment, the vancomycin-mediated Staphylococcus aureus has a MIC of about 5 μg / mL. In another embodiment, the vancomycin-mediated Staphylococcus aureus has a MIC of about 6 μg / mL. In yet another embodiment, the vancomycin-mediated Staphylococcus aureus has a MIC of about 7 μg / mL. In one embodiment, the vancomycin-mediated Staphylococcus aureus has a MIC of about 8 μg / mL.

[0219] In another aspect, a method of treating an individual with a bacterial infection includes administering to the individual a compound disclosed herein, or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the bacterial infection comprises vancomycin-resistant Staphylococcus aureus bacteria. In one embodiment, the vancomycin-resistant Staphylococcus aureus bacteria has a MIC of about 16 μg / mL. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacteria has a MIC of about ≥16 μg / mL. In one embodiment, the vancomycin-resistant Staphylococcus aureus bacteria has a MIC of about 20 μg / mL. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacteria has a MIC of about 25 μg / mL.

[0220] In one embodiment, the conditions treated by the compounds described herein include (but are not limited to) endocarditis, osteomyelitis, meningitis, skin and skin structure infections, genitourinary tract infections, abscesses, and necrotizing infections. In another embodiment, the compounds disclosed herein are used to treat conditions such as (but not limited to) diabetic foot infections, pressure ulcers, burn infections, animal or human bite wound infections, synergistic necrotizing gangrene, necrotizing fasciitis, intra-abdominal infections associated with intestinal barrier disruption, pelvic infections associated with intestinal barrier disruption, aspiration pneumonia, and postoperative wound infections. In yet another embodiment, the conditions listed herein are caused by, contain, or result in the presence of VISA and / or VRSA.

[0221] Vancomycin-resistant Enterococci

[0222] Enterococci are bacteria commonly found in the human gut and female reproductive tract and are frequently encountered in this environment. These bacteria sometimes cause infections. In some cases, enterococci become resistant to vancomycin (also known as vancomycin-resistant enterococci or VREs). The common form of vancomycin resistance in enterococcal strains involves acquiring a set of genes encoding a guide peptidoglycan precursor incorporated into D-Ala-D-Lac in place of D-Ala-D-Ala. The six different types of vancomycin resistance exhibited by enterococci are: Van-A, Van-B, Van-C, Van-D, Van-E, and Van-F. In some cases, Van-AVREs are resistant to both vancomycin and teicoplanin, while in others, Van-B VREs are resistant to vancomycin but sensitive to teicoplanin; in still others, Van-C VREs are partially resistant to vancomycin and sensitive to teicoplanin.

[0223] In one aspect, a method of treating an individual with vancomycin-resistant enterococci includes administering to the individual a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the enterococci have developed resistance to vancomycin. In one embodiment, the individual has previously been treated with vancomycin for a prolonged period. In another embodiment, the individual has been hospitalized. In yet another embodiment, the individual has a weakened immune system, such as a patient in a intensive care unit or a cancer or transplant ward. In another embodiment, the individual has undergone surgical treatment, such as abdominal or thoracic surgery. In yet another embodiment, the individual has been colonized with a venous retinopathy (VRE). In one embodiment, the individual has a medical device that has caused the infection. In another embodiment, the medical device is a urethral catheter or an intravenous (IV) catheter.

[0224] In another embodiment, a method for treating an individual with vancomycin-resistant enterococci includes administering to the individual a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the enterococci have Van-A resistance.

[0225] In another embodiment, a method for treating an individual with vancomycin-resistant enterococci includes administering to the individual a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the enterococci are Van-B resistant.

[0226] In another embodiment, a method for treating an individual with vancomycin-resistant enterococci includes administering to the individual a compound disclosed herein or a pharmaceutical salt, solvate, or stereoisomer thereof, wherein the enterococci are Van-C resistant.

[0227] Application and pharmaceutical composition

[0228] The pharmaceutical compositions described herein comprise a therapeutically effective amount of the compound described herein (i.e., the compound disclosed herein), formulated together with one or more pharmaceutical carriers. As used herein, the term "pharmaceutical carrier" means any type of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Some examples of materials that can serve as pharmaceutical carriers are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, sodium ethyl cellulose, and sodium cellulose acetate; powdered astragalus; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic physiological saline; Ringer's solution; ethanol; and phosphate buffer solutions, as well as other non-toxic and compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweeteners, flavoring agents and aromatizers, preservatives and antioxidants, which may also be present in the composition at the discretion of the formulation user. The pharmaceutical compositions described herein may be administered to humans and other animals orally, rectally, non-intestinally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, or as oral or nasal sprays, or as inhaled liquid aerosols or dry powder formulations.

[0229] Liquid dosage forms for oral administration include pharmaceutical emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms optionally contain inert diluents commonly used in this art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0230] Optionally, injectable formulations are formulated using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. The sterile injectable formulation is optionally a sterile injectable solution, suspension, or emulsion in a non-toxic, non-enteric-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among acceptable mediators and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution are optionally used. Furthermore, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of the injectable formulation.

[0231] Injectable formulations can be sterilized, for example, by filtration via a bacterial retention filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0232] To prolong drug action, it is often necessary to slow the absorption of drugs injected subcutaneously or intramuscularly. This is optionally achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous substances. The drug absorption rate depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of non-enteral drug forms can be achieved optionally by dissolving or suspending the drug in an oil-based medium. Injectable accumulation forms are prepared by forming microcapsule matrices of the drug in biodegradable polymers, such as polylactic-co-glycolic acid. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Accumulated injectable formulations are optionally prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions.

[0233] Compositions for rectal or vaginal administration are preferably suppositories prepared by mixing the compounds described herein (i.e., the compounds disclosed herein) with suitable non-irritating excipients or carriers (such as cocoa butter, polyethylene glycol), or suppository waxes that are solid at room temperature but liquid at body temperature and thus melt in the rectal or vaginal cavity to release the active compound.

[0234] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with: at least one pharmaceutically inert excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar-agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solvent inhibitors, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as acetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form optionally includes a buffer.

[0235] Optionally, similar type of solid compositions may be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol and the like.

[0236] Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in pharmaceutical formulation techniques. They optionally contain emulsifiers and may also have compositions that optionally release the active ingredient in a delayed manner only or preferentially in a portion of the intestine; examples of usable encapsulation compositions include polymeric substances and waxes.

[0237] Optionally, similar type of solid compositions may be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol and the like.

[0238] The active compound may also be present in microencapsulation form with one or more excipients as noted above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in pharmaceutical compounding techniques. In such solid dosage forms, the active compound is optionally mixed with at least one inert diluent (such as sucrose, lactose, or starch). In normal practice, such dosage forms may optionally contain additional substances besides inert diluents, such as tablet-making lubricants and other tablet-making aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may optionally contain a buffer. It may optionally contain an emulsifier and may also have a composition that optionally releases the active ingredient in a delayed manner only or preferentially in a portion of the intestine. Examples of encapsulation compositions that may be used include polymers and waxes.

[0239] Dosage forms for topical or transdermal application of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed with a pharmaceutical carrier and any desired preservatives or buffers under sterile conditions, as optionally required. Ophthalmic formulations, ear drops, and the like are also covered.

[0240] In addition to the active compounds described herein, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragali, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0241] The compositions described herein are optionally formulated for delivery as a liquid aerosol or an inhalable dry powder. Liquid aerosol formulations are optionally primarily atomized to a particle size deliverable to the terminal and respiratory bronchioles, in which bacteria are present in patients with bronchial infections such as chronic bronchitis and pneumonia. Pathogens are typically present throughout the airway down to the bronchi, bronchioles, and lung parenchyma, particularly in the terminal and respiratory bronchioles. During exacerbations of infection, bacteria may also be present in the alveoli. Liquid aerosols and inhalable dry powder formulations are preferably delivered intrabronchially to the terminal bronchioles and ultimately to the parenchymal tissue.

[0242] The aerosol formulations described herein are optionally delivered using an aerosol forming device, such as a sprayer, vibrating perforated disc, or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles with an average diameter primarily between 1 and 5 micrometers in the presence of a mass medium. Furthermore, the formulations preferably have a balanced volumetric osmotic concentration, ionic strength, and chloride concentration, as well as a minimum aerosolizable volume, enabling the delivery of an effective dose of the compounds described herein (i.e., the compounds disclosed herein) to the site of infection. Additionally, the aerosol formulations preferably do not adversely impair airway function and do not cause undesirable side effects.

[0243] Suitable aerosol atomizing devices for administering the aerosol formulations described herein include, for example, injectors, vibrating perforated discs, ultrasonic atomizers, and powered dry powder inhalers, capable of atomizing the formulation into aerosol particles primarily ranging from 1 to 5 μm in size. Primarily, this application means that at least 70%, but preferably more than 90%, of all generated aerosol particles are in the 1 to 5 μm range. Jet atomizers function by separating a liquid solution into aerosol droplets using air pressure. Vibrating perforated disc atomizers function by using sonic vacuum generated by rapidly vibrating a perforated disc to compress solvent droplets through the disc. Ultrasonic atomizers function by shearing liquid into small aerosol droplets using piezoelectric crystals. A variety of suitable devices are available, including, for example, the AeroNeb™ and AeroDose™ vibrating perforated disc atomizers (AeroGen, Inc., Sunnyvale, California). Sprayer (Medic-Aid Ltd., West Sussex, England), Pari and Pari LC Jet sprayers (Pari Respiratory Equipment, Inc., Richmond, Virginia) and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and (Omron Healthcare, Inc., Vernon Hills, Illinois).

[0244] In some embodiments, the compounds described herein (i.e., the compounds disclosed herein) are formulated for use as topical powders and sprays, and in addition to the compounds described herein, contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Sprays optionally contain conventional propellants such as chlorofluorocarbons.

[0245] Transdermal patches offer the added advantage of controlled delivery of compounds into the body. These dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0246] According to the treatment methods described herein, a bacterial infection in a patient (such as a human or lower mammal) is treated or prevented by administering a therapeutically effective amount of the compounds described herein to the patient in the amount and for the time necessary to achieve the desired outcome. "Therapeutically effective amount" of the compounds described herein means an amount of compound sufficient to treat the bacterial infection at a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dosage of the compounds and compositions described herein will be determined by the attending physician within the bounds of reasonable medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a number of factors, including: the condition being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and elimination rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in medical technology.

[0247] The total daily dose of the compounds described herein (i.e., the compounds disclosed herein) administered to humans or other mammals in a single or multiple dose may be, for example, from 0.01 to 50 mg / kg body weight or more usually from 0.1 to 25 mg / kg body weight. A single-dose composition may contain this amount or multiples thereof constituting a daily dose. Generally, the treatment regimens described herein comprise administering, in a single or multiple dose, of about 10 mg to about 2000 mg of the compounds described herein to a patient requiring such treatment daily.

[0248] Example

[0249] The compounds disclosed herein are prepared by the methods depicted in the reaction flow shown below. In some embodiments, all compounds disclosed and claimed herein are prepared using the procedures provided herein in conjunction with the knowledge of a synthetic organic chemist with general skills in this art.

[0250] General Program A:

[0251]

[0252] Step 1: I2 (21.8 g, 86.1 mmol) was added to a solution of compound 1 (51.0 g, 78.3 mmol), Ag2SO4 (17.1 g, 54.8 mmol), and MeOH (250 mL) and THF (250 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h and filtered. The filtrate was concentrated to dryness. The residue was partitioned between ethyl acetate (300 mL) and a saturated aqueous solution of Na2S2O3 (300 mL). The organic phase was separated and washed with brine (2 × 300 mL), dried over Na2SO4, and concentrated to dryness to give crude compound 2 (60.0 g, 98.6% yield) as a yellow solid.

[0253] Step 2: SEMCl (27.1 mL, 154.0 mmol) was added to a solution of compound 2 (60.0 g, 77.2 mmol) and DIEA (38.3 mL, 231.0 mmol) in CH2Cl2 (600 mL). The reaction mixture was stirred at 25 °C for 2 h and concentrated to dryness. The residue was diluted with ethyl acetate (500 mL), washed with water (2 × 500 mL) and brine (2 × 500 mL), dried over Na2SO4, and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 100 to 200 mesh, 10 to 40% ethyl acetate in petroleum ether) to give compound 3 (65.0 g, 92.8% yield) as a yellow solid.

[0254] Step 3: Under a nitrogen atmosphere, a mixture of compound 3 (20.00 g, 22.0 mmol), bis(pinacolyl)diboron (8.39 g, 33.0 mmol), triphenylphosphine (1.16 g, 4.4 mmol), tricyclohexylphosphine (1.24 g, 4.4 mmol), Pd(OAc)2 (0.49 g, 2.2 mmol), and K2OAc (8.65 g, 88.1 mmol) in DMSO (200 mL) and water (20 mL) was stirred for 1 h at 80 °C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was washed with water (2 × 200 mL) and brine (200 mL), dried over Na2SO4, and concentrated to give crude compound 4 (20.00 g, 97% yield) as a gray solid (three parallel batches were combined at this stage).

[0255] Step 4: Add H2O2 (135 mL, 1.3 mol) to a solution of compound 4 (60.0 g, 66.0 mmol) in MeOH (600 mL). Stir the mixture at 0 °C for 2 h and dilute with ethyl acetate (700 mL). Wash the mixture with saturated aqueous solution of NaHCO3 (2 × 200 mL), saturated aqueous solution of Na2S2O3 (500 mL), and brine (2 × 200 mL), dry to Na2SO4, and concentrate under reduced pressure. Purify the residue by column chromatography (silica gel, 100 to 200 mesh, 10 to 50% ethyl acetate in petroleum ether) to give a crude product, which is further purified by preparative HPLC (water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN) to give compound 5 (37.0 g, 70.1% yield) as a white solid.

[0256] Step 5: Add 10% Pd / C (14.7 g, 13.8 mmol) and one drop of ammonia to a solution of compound 5 (50.0 g, 62.7 mmol) in ethanol (700 mL). Stir the mixture at 40 °C for 5 h under hydrogen (50 psi) and filter. Concentrate the filtrate to obtain crude compound 6 (35.0 g, 97.4% yield) as a white solid.

[0257] Step 6: DMA (20.0 mL) containing Cb2OSu (15.2 g, 60.9 mmol) was added dropwise to a solution of compound 6 (35.0 g, 61.0 mmol) in DMA (400 mL) at 0 °C. After addition, the mixture was stirred at 15 °C for 14 h and then diluted with ethyl acetate (500 mL). The separated organic phase was washed with brine (3 × 200 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 55% ethyl acetate in petroleum ether) to give compound 7 (21.0 g, 97.0% yield) as a white solid.

[0258] Step 7: Compound 8 (23.1 g, 89.0 mmol) and K₂CO₃ (24.6 g, 178.0 mmol) were added to a solution of compound 7 (21.0 g, 29.7 mmol) in DMF (84.0 mL). The mixture was stirred at 50 °C for 16 h, and another portion of compound 8 (23.1 g, 89.0 mmol) and K₂CO₃ (24.6 g, 178 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h, diluted with ethyl acetate (500 mL), and filtered. The filtrate was washed with brine (2 × 300 mL), dried over Na₂SO₄, and concentrated to dryness. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 55% ethyl acetate in petroleum ether) to give compound 9 (20.0 g, 83.3% yield) as a white solid.

[0259] Step 8: Add NaN3 (27.3 g, 420 mmol) and CeCl3 (3.6 g, 14.6 mmol) to a solution of compound 9 (24.0 g, 29.3 mmol) in MeCN (200 mL) and water (100 mL). Stir the mixture at 75 °C for 16 h. Dilute the reaction mixture with ethyl acetate (700 mL) and filter. Wash the filtrate with brine (2 × 200 mL), dry to dryness with Na2SO4, and concentrate to dryness. Dissolve the residue in DMF (200 mL), add K2CO3 (16.2 g, 117 mmol) and MeI (12.5 g, 87.8 mmol). Stir the reaction mixture at 25 °C for 1 h, dilute with ethyl acetate (600 mL), and filter. Wash the filtrate with brine (3 × 300 mL), dry to dryness with Na2SO4, and concentrate to dryness.

[0260] The residue was dissolved in THF (480 mL) and PPh3 (46.1 g, 176 mmol) and H2O (6.33 g, 351 mmol) were added. The solution was stirred at 35 °C for 16 h.

[0261] Boc₂O (14.7 g, 67.3 mmol) was added to the reaction mixture mentioned above. The reaction mixture was stirred at 30 °C for 1 h and concentrated to dryness. The residue was diluted with ethyl acetate (700 mL), washed with brine (2 × 300 mL), dried over Na₂SO₄, and concentrated. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 17% acetone in petroleum ether followed by 85% ethyl acetate in petroleum ether) to give compound 10 as a white solid (24.4 g, 79.2% yield).

[0262] General Program B:

[0263]

[0264] Step 1: A mixture of compound 10 (5.00 g, 4.74 mmol) and 10% palladium / carbon (1.51 g, 1.42 mmol) in ethanol (100 mL) was stirred for 2 h under hydrogen (50 psi) at 35 °C and filtered. The filtrate was concentrated to give crude compound 11 (4.30 g, 98.5% yield) as a white solid.

[0265] Step 2: DIEA and HATU (2.13 g, 5.61 mmol) were added to a solution of compound 11 (4.30 g, 4.67 mmol) and compound 12 (2.54 g, 6.08 mmol) in THF (43 mL) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 3 h and quenched by adding methanol (1 mL). The reaction mixture was concentrated and then diluted with ethyl acetate (100 mL). The solution was washed with saturated aqueous solution of Na₂CO₃ (150 mL) and brine (150 mL × 2), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 50% to 70% ethyl acetate in petroleum ether) to give compound 13 (6.00 g, 97.3% yield) as a white solid.

[0266] Step 3: Add 10% Pd / C (36.3 mg, 0.03 mmol) to a solution of compound 13 (150 mg, 0.11 mmol) and one drop of NH3·H2O in ethanol (15.0 mL). Stir the reaction mixture at 30 °C for 2 h under a H2 atmosphere (15 psi) and filter. Concentrate the filtrate to give compound 14 (135 mg, 63.0% yield) as a white solid.

[0267] The methods used for LCMS analysis are as follows: LCMS (Method 5-95AB, ESI): ESI was performed using a gradient dissolution of the compound from 5% AcCN / H2O to 95% AcCN / H2O over 0.7 min. This concentration was maintained for 0.4 min. The flow rate was 1.5 mL / min, using a Merck RP-18e, 2×25 mm column. TFA was present at 0.05% in all chromatographic solvents. LCMS (Method 5-100AB, 7 min): Instrument: Waters Acquity UPLC, using a 2.1×30 mm CSH 1.8 μm C18 column maintained at 40 °C and ESI ionization. A gradient dissolution of the compound was performed using a self-dissolution of the compound from 5% B to 100% B in solvent A over 5.2 min. This concentration was maintained for 1.8 min, and the total run time was 7 min. The flow rate was 0.9 mL / min, and the solvent was: (A) Milli-Q water at pH 3.8 + 10 mM ammonium formate and (B) MeCN.

[0268] Example 1:

[0269]

[0270]

[0271] Step 1: DIEA (159 μL, 0.91 mmol) and HATU (104 mg, 0.27 mmol) were added to a solution of 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (46.5 mg, 0.17 mmol) (synthesis provided in Example 17) in DMF (1.00 mL) and dichloromethane (8.00 mL) at 0 °C. After 5 min, compound 14 (135 mg, 0.11 mmol) was added. The reaction mixture was stirred at 20 °C for 2 h and quenched by adding methanol (0.50 mL). The reaction mixture was concentrated to dryness. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over Na₂SO₄, and concentrated to dryness. The crude substance was purified by preparative TLC (10% methanol in dichloromethane) to obtain compound 16 (80.0 mg, 48.8% yield) as a yellow solid.

[0272] Step 5: HCl (4N in methanol, 0.08 mL, 0.32 mmol) was added to a solution of compound 16 (80.0 mg, 0.06 mmol) in methanol (1.00 mL). The mixture was stirred at 30 °C for 0.5 h and quenched by adding NaHCO3 (70.0 mg, 0.83 mmol). The mixture was concentrated, and then THF (5 mL), water (1 mL), and Boc2O (0.01 mL, 0.06 mmol) were added. The mixture was stirred at 30 °C for 0.5 h and diluted with water (10 mL) and ethyl acetate (20 mL). The separated aqueous phase was washed with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (10% methanol in dichloromethane) to give compound 17 (50.0 mg, 68.7% yield) as a yellow solid.

[0273] Step 6: Add a solution of LiOH·H₂O (4.8 mg, 0.11 mmol) in water (1 mL) to a solution of compound 17 (50.0 mg, 0.04 mmol) in THF (4.00 mL). Stir the reaction mixture at 20 °C for 1 h and concentrate. Dilute the residue with water (20 mL) and adjust the pH to 4 by adding 5% KHSO₄ aqueous solution. Extract the mixture with ethyl acetate (3 × 30 mL). Dry the combined organic layers with Na₂SO₄ and concentrate to give crude compound 18 (49.0 mg, 99.1% yield) as a white solid.

[0274] Step 7: The mixture of compound 18 (49 mg, 0.04 mmol) in HFIP (3 mL, 2.01 mmol) containing 5% TFA was stirred for 3 h at 35 °C and concentrated. The residue was diluted with methanol (5 mL) and neutralized with NaHCO3. After filtration, the filtrate was purified by preparative HPLC (acetonitrile 19 to 29% / 0.2% formic acid aqueous solution) to give the title compound as a white solid (12.6 mg, 32.9% yield). 1 ¹H NMR (400MHz, DMSO-d6) δ (ppm) 9.39 (s, 1H), 8.47–8.30 (m, 2H), 7.57–7.50 (m, 5H), 7.05–6.73 (m, 5H), 6.36–6.22 (m, 2H), 5.13–5.01 (m, 1H), 4.64 (s, 1H), 4.22–3.99 (m, 10H), 3.25–2.67 (m, 12H), 1.32–1.06 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.789 min, [M+H] + =995.8.

[0275] Example 2:

[0276]

[0277] Step 1: A solution of diethyl malonate (8.00 g, 50.00 mmol), triethyl orthoacetate (24.30 g, 150.00 mmol), ZnCl2 (2.01 mg, 0.01 mmol), and Ac2O (1.00 mL, 4.32 mmol) was heated at 135 °C for 6 h, with additional Ac3O (1.00 mL, 4.32 mmol) added every 30 min. The reaction mixture was cooled to room temperature and partitioned between 200 mL of ethyl acetate and 200 mL of ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 10% to 20% ethyl acetate in petroleum ether) to give diethyl 2-(1-ethoxyethylidene) malonate (9.00 g, 78.3% yield) as a yellow solid.

[0278] Step 2: LHMDS (1N in THF, 50.2 mL, 50.2 mmol) was added to a solution of 4-(tert-butyl)benzonitrile (4.00 g, 25.1 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. The mixture was quenched at 0 °C by adding an aqueous solution of HCl (4 M, 20 mL), and then the pH was adjusted to >8 by adding an aqueous solution of NaOH (4 M). The separated aqueous layer was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried with Na₂SO₄ and concentrated to dryness to give crude 4-(tert-butyl)benzoamide (3.30 g, 74.5% yield) as a brown solid.

[0279] Step 3: Sodium (470 mg, 20.4 mmol) was added to ethanol (10 mL) and stirred for 30 min. This freshly prepared sodium ethoxide solution was added to a solution of 2-(1-ethoxyethylidene) diethyl malonate (4.23 g, 18.4 mmol) and 4-(tert-butyl)benzamide (1.80 g, 10.2 mmol) in ethanol (30 mL). The reaction mixture was stirred at 50 °C for 16 h and quenched with saturated aqueous NH4Cl solution (30 mL). The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30 mL) and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give ethyl 2-(4-(tert-butyl)phenyl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.00 g, 31.1% yield) as a white solid.

[0280] Step 4: A mixture of POCl3 (5.00 mL, 50.6 mmol) and ethyl 2-(4-(tert-butyl)phenyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxylate (1.00 g, 3.2 mmol) was stirred at 110 °C for 2 h. The mixture was concentrated under vacuum and diluted with ethyl acetate (100 mL). The solution was washed with saturated aqueous solution of NaHCO3 (50 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% ethyl acetate in petroleum) to give ethyl 2-(4-(tert-butyl)phenyl)-4-chloro-6-methylpyrimidin-5-carboxylate (0.90 g, 85.0% yield) as a pale yellow solid.

[0281] Step 5: A mixture of ethyl 2-(4-(tert-butyl)phenyl)-4-chloro-6-methylpyrimidin-5-carboxylate (1.00 g, 3.00 mmol) and ammonia (4 M in MeOH, 25.0 mL, 100.0 mmol) was stirred at 70 °C for 16 h. The reactants were concentrated to dryness and diluted with ethyl acetate (100 mL). The solution was washed with water (2 × 30 mL) and brine (30 mL), dried over Na₂SO₄, and concentrated to dryness. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give methyl 4-amino-2-(4-(tert-butyl)phenyl)-6-methylpyrimidin-5-carboxylate (900 mg, 95.6% yield) as a white solid.

[0282] Step 6: A mixture of methyl 4-amino-2-(4-(tert-butyl)phenyl)-6-methylpyrimidin-5-carboxylic acid (900 mg, 3.0 mmol) and NaOH (601 mg, 15.0 mmol) in water (5 mL) and MeOH (15 mL) was stirred at 80 °C for 3 h and concentrated under reduced pressure. The residue was acidified to pH < 5 by adding 1 M HCl and extracted with ethyl acetate (2 × 80 mL). The combined organic layers were concentrated under reduced pressure to give crude 4-amino-2-(4-(tert-butyl)phenyl)-6-methylpyrimidin-5-carboxylic acid (850 mg, 99.1% yield) as a white solid.

[0283] As described in Example 1, the (formate salt) was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid in the first step. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.36-8.10 (m, 3H), 7.63-7.34 (m, 2H), 7.27-6.28 (m, 6H), 5.28-5.10 (m, 1H), 4.74 -4.45 (m, 2H), 4.42-3.90 (m, 6H), 3.87-3.35 (m, 3H), 3.29-2.89 (m, 8H), 2.87-2.37 (m, 3H), 1.49-1.15 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.610 min, [M+H] + =1008.4.

[0284] Example 3:

[0285]

[0286] Step 1: A mixture of 4-hydroxybenzonitrile (5.0 g, 42.0 mmol), 1-bromo-3,3-dimethylbutane (10.4 g, 63.0 mmol), and K₂CO₃ (17.4 g, 126 mmol) in DMF (20 mL) was stirred for 2 h at 80 °C. After cooling to room temperature, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with water (2 × 300 mL) and brine (200 mL), dried over MgSO₄, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 10% ethyl acetate in petroleum ether) to obtain 4-(3,3-dimethylbutoxy)benzonitrile (8.0 g, 93.8% yield) as a colorless oil.

[0287] Step 2: LHMDS (1N in THF, 30.0 mL, 30.0 mmol) was added to 30 mL of THF containing 3.0 g (14.8 mmol) of 4-(3,3-dimethylbutoxy)benzonitrile at 0 °C. The reaction mixture was stirred at 20 °C for 16 h and quenched by adding 4 M HCl until pH = 2. The mixture was then adjusted to pH = 12 by adding 4 M NaOH and extracted with chloroform (3 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated to dryness to give crude 4-(3,3-dimethylbutoxy)benzoamide (3.0 g, 92.3% yield) as a yellow solid.

[0288] Step 3: Add 2-(1-ethoxyethylidene)malonate (3.00 g, 13.6 mmol) to a solution of 4-(3,3-dimethylbutoxy)benzamidinium (4.70 g, 20.4 mmol) and EtONa (1.85 g, 27.2 mmol) in ethanol (20 mL). Stir the reaction mixture at 50 °C for 3 h and concentrate to dryness. Partition the residue between ethyl acetate (100 mL) and water (100 mL). Wash the separated organic layer with brine (50 mL), dry with MgSO4 and concentrate to dryness. Purify the residue by column chromatography (silica gel, 100 to 200 mesh, 30% ethyl acetate in petroleum ether) to give ethyl 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.70 g, 34.8% yield) as a white solid.

[0289] Step 4: The mixture of ethyl 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (1.70 g, 4.74 mmol) in POCl3 (30.0 mL, 325 mmol) was stirred for 3 h at 110 °C and concentrated to dryness. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give ethyl 4-chloro-2-(4-(3,3-dimethylbutoxy)phenyl)-6-methylpyrimidine-5-carboxylate (1.40 g, 78.3% yield) as a white solid.

[0290] Step 5: A mixture of ethyl 4-chloro-2-(4-(3,3-dimethylbutoxy)phenyl)-6-methylpyrimidin-5-carboxylate (1.20 g, 3.18 mmol) and ammonia (4 M in MeOH, 30.0 mL, 120 mmol) was stirred at 70 °C for 16 h and concentrated to dryness. The residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The separated organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated to dryness. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 0% to 20% ethyl acetate in petroleum ether) to give ethyl 4-amino-2-(4-(3,3-dimethylbutoxy)phenyl)-6-methylpyrimidin-5-carboxylate (1.00 g, 87.9% yield) as a white solid.

[0291] Step 6: A mixture of ethyl 4-amino-2-(4-(3,3-dimethylbutoxy)phenyl)-6-methylpyrimidin-5-carboxylic acid (1.00 g, 2.80 mmol) and NaOH (560 mg, 14.0 mmol) in MeOH (15 mL) and water (10 mL) was stirred at 80 °C for 22 h and concentrated. The residue was adjusted to pH 5 by adding 1 M HCl. The solid was collected by filtration and dried to give 4-amino-2-(4-(3,3-dimethylbutoxy)phenyl)-6-methylpyrimidin-5-carboxylic acid (800 mg, 86.8% yield) as a white solid.

[0292] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(3,3-dimethylbutoxy)phenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.34 (s, 1H), 8.20 (d, J = 8.4Hz, 2H), 7.12-7.04 (m, 1H), 6.95 (d, J = 8.8Hz, 2H), 6.92-6.84 (m 1H), 6.84-6.74(m, 2H), 8.56(s, 1H), 6.44(s, 1H), 5.23-5.13(m, 1H), 4.83-4 .79(m, 2H), 4.54-4.42(m, 1H), 4.26-4.20(m, 1H), 4.18-3.97(m, 7H), 3.65-3. 56 (m. 1H), 3.40–3.33 (m, 4H), 3.28–3.13 (m, 3H), 3.12–2.94 (m, 5H), 2.45 (s, 3H), 1.80–1.68 (m, 3H), 1.34 (d, J = 6.0 Hz, 3H), 1.01 (s, 9H); LCMS (Method 5-95AB): R T = 0.823 min, [M+H] + =1052.4

[0293] Example 4:

[0294]

[0295]

[0296] Step 1: Add 1-bromo-3,3-dimethylbutane (5.00 g, 28.9 mmol) and K₂CO₃ (10.0 g, 72.2 mmol) to a solution of 4-bromophenol (7.16 g, 43.4 mmol) in DMF (30.0 mL). Stir the reaction mixture at 50 °C for 16 h and cool to room temperature. Filter the mixture and dilute the filtrate with ethyl acetate (80 mL) and water (80 mL). Wash the separated organic layer with brine (3 × 80 mL), dry with Na₂SO₄ and concentrate to dryness. Purify the residue by column chromatography (silica gel, 100 to 200 mesh, 5% methanol in dichloromethane) to give 1-bromo-4-(3,3-dimethylbutoxy)benzene (6.10 g, 82.1% yield) as a white solid.

[0297] Step 2: A mixture of 1-bromo-4-(3,3-dimethylbutoxy)benzene (6.10 g, 23.7 mmol), Pd(dppf)Cl2 (1.74 g, 2.37 mmol), bis(pinacolyl)diboron (9.04 g, 35.6 mmol), and potassium acetate (7.00 g, 71.2 mmol) in DMF (60 mL) was heated at 80 °C under a N2 atmosphere for 4 h and then filtered. The filtrate was partitioned between ethyl acetate (100 mL) and water (100 mL). The separated organic layer was washed with brine (3 × 150 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 2% ethyl acetate in petroleum ether) to give 2-(4-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron as a white solid. (6.30g, 87.3% yield).

[0298] Step 3: To 2-(4-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron Ammonium acetate (83 mL, 82.7 mmol) and NaIO4 (13.3 g, 62.0 mmol) were added to a solution of acetone (60 mL). The reaction mixture was stirred at 40 °C for 16 h and concentrated to dryness. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 2% methanol in dichloromethane) to obtain (4-(3,3-dimethylbutoxy)phenyl)boronic acid (4.50 g, 20.3 mmol, yield 98.0%) as a yellow solid.

[0299] Step 4: A mixture of (4-(3,3-dimethylbutoxy)phenyl)boronic acid (200 mg, 0.90 mmol), copper diacetate (32.7 mg, 0.18 mmol), and methyl 6-oxo-1,6-dihydropyridazine-4-carboxylate (146 mg, 0.95 mmol) in dichloromethane (6 mL) and pyridine (1 mL) was stirred for 16 h at 20 °C. The reaction mixture was diluted with ethyl acetate (80 mL) and filtered. The filtrate was washed with brine (50 mL) and concentrated to dryness. The mixture was analyzed by preparative TLC (33% ethyl acetate in petroleum ether, R...). f =0.3) The residue was purified to give methyl 1-(4-(3,3-dimethylbutoxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylate (235 mg, 79.0% yield) as a green solid.

[0300] Step 5: A mixture of methyl 1-(4-(3,3-dimethylbutoxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (235 mg, 0.71 mmol) and NaOH (71.1 mg, 1.78 mmol) in MeOH (10 mL) and water (3 mL) was stirred at 80 °C for 1 h. The reaction mixture was adjusted to pH 5 with HCl (1 M in water) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ and concentrated to dryness to give crude 1-(4-(3,3-dimethylbutoxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (220 mg, 97.8% yield) as a yellow solid.

[0301] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1-(4-(3,3-dimethylbutoxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1H NMR (400MHz, DMSO-d6): δ (ppm) 9.33 (s, IH), 8.46 (s, 1H), 8.35-8.34 (m, 2H), 8.02 (s, 1H), 7.57 (s, 1H), 7.50-7.47(m, 2H), 7.07-7.05(m, 3H), 6.90-6.66(m, 8H), 6.36(s, 1H), 6.22(s, 1H), 5.05-5.0 2 (m, 2H), 4.67-4.64 (m, 2H), 4.10-3.92 (m, 8H), 3.25-3.23 (m, 6H), 3.08-3.07 (m, 3H), 2.97-2.95 (m, 3H), 2.85-2.83 (m, 4H), 2.68 (s, 1H), 1.68 (t, J = 6.8 Hz, 2H), 1.16 (d, J = 6.4 Hz, 3H), 0.98 (s, 9H). LCMS (Method 5-95AB, ESI), R T = 0.830 min, [M+H] + =1039.3.

[0302] Example 5:

[0303]

[0304] Step 1: At 0°C under N3, apply the solution to Ph3P + n-BuLi (2.5N in hexane, 225 mL, 563 mmol) was added to a solution of MeBr (201 g, 563 mmol) in THF (500 mL). The mixture was stirred at room temperature until the solution became clear, and then 1-(4-bromophenyl)ethyl-1-one (70 g, 352 mmol) was added dropwise to a solution of THF (200 mL). After the addition, the mixture was heated at 70 °C for 20 h and quenched by adding 1000 mL of saturated aqueous NH4Cl solution. The resulting solution was extracted with ethyl acetate (2 × 1000 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, petroleum ether) to give 1-bromo-4-(prop-1-en-2-yl)benzene (50 g, 72.1% yield) as a colorless oil.

[0305] Step 2: Under a nitrogen atmosphere at 0°C, ZnEt2 (1M in toluene, 507mL, 507mmol) and CH2I2 (81.9mL, 1010mmol) were added to a solution of 1-bromo-4-(prop-1-en-2-yl)benzene (20.0g, 101mmol) in dichloromethane (100mL). The mixture was heated to 70°C for 72h and concentrated to dryness. The residue was partitioned between water (500mL) and petroleum ether (500mL). The organic layer was washed with brine (3×100mL), dried over Na2SO4, and concentrated to dryness. The residue was then purified by preparative HPLC (acetonitrile 55 to 85% / 0.225% FA aqueous solution) to give 1-bromo-4-(1-methylcyclopropyl)benzene (201g, 60.7% yield) as a colorless oil.

[0306] Step 3: Under a nitrogen atmosphere, a mixture of 1-bromo-4-(1-methylcyclopropyl)benzene (28.8 g, 136 mmol), bis(pinacolyl)diboron (36.3 g, 143 mmol), KOAc (40.1 g, 408 mmol), and Pd(dpPf)₂Cl₂ (9.97 g, 13.6 mmol) in DMF (200 mL) was heated for 6 h at 80 °C. The reaction mixture was diluted with ethyl acetate (600 mL) and filtered. The filtrate was washed with water (2 × 200 mL) and brine (3 × 200 mL), dried over Na₂SO₄, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0% to 10% ethyl acetate in petroleum ether) to give a white solid of 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxoboron. (30g, 85.2%).

[0307] Step 4: Under N2, at 100℃, 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxoboron A mixture of ethyl 2-chloro-4-methylpyrimidin-5-carboxylate (20.0 g, 77.5 mmol), Na₂CO₃ (24.6 g, 232 mmol), and Pd(dpPf)₂Cl₂ (5.67 g, 7.75 mmol) in 1,4-dioxane (400 mL) and water (20.0 mL) was heated for 16 h. The filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0% to 5% ethyl acetate in petroleum) to give ethyl 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidin-5-carboxylate (26.0 g, 56.4% yield) as a white solid.

[0308] Step 5: A mixture of ethyl 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid (26.0 g, 79.0 mmol) and NaOH (9.47 g, 237 mmol) in MeOH (260 mL) and water (26 mL) was stirred at 80 °C for 16 h and concentrated. The residue was diluted with water (100 mL) and adjusted to pH 4 with HCl (1 M). The mixture was filtered and the filtrate was concentrated to dryness to give crude 4-methyl-2-4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid (28.0 g, 100% yield) as a white solid.

[0309] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.86 (s, 1H), 8.18 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.4Hz, 2H), 6.90-6.87 (m, 2H), 6.7 8 (m, 2H), 6.39 (s, 2H), 5.29-5.26 (m, 1H), 4.80-4.75 (m, 1H), 4.60 (d, J=9.2Hz, 1H), 4.36-4.32 (m, 1H), 4.27-4.1 9 (m, 2H), 4.11-4.05 (m, 3H), 3.65-3.60 (m, 1H), 3.45-3.34 (m, 1H), 3.28-3.13 (m, 4H), 3.06 (s, 3H), 3.00-2.86 (m, 1H), 2.77-2.72 (m, 10H), 2.65 (m, 3H), 1.48 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 0.97-0.95 (m, 2H), 0.89-0.88 (m, 2H). LCMS (Method 5-95AB, ESI), R T = 0.802 min, [M+H] + =991.2.

[0310] Example 6:

[0311]

[0312] Step 1: Under a nitrogen atmosphere, a mixture of 1-bromo-4-(1-methylcyclopropyl)benzene (5.20 g, 24.6 mmol), Pd(PPh3)4 (2.80 g, 2.46 mmol), and Zn(CN)2 (6.47 g, 55.1 mmol) in DMF (50 mL) was heated for 16 h at 120 °C. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 mL) and filtered. The filtrate was washed with brine (2 × 200 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 0.5% ethyl acetate in petroleum ether) to give 4-(1-methylcyclopropyl)benzonitrile (14.0 g, 92.1% yield) as a pale yellow oil.

[0313] Step 2: A mixture of 4-(1-methylcyclopropyl)benzonitrile (5.00 g, 31.8 mmol) and LHMDS (1 N in THF, 63.6 mL, 63.6 mmol) in 50 mL of THF was stirred at 30 °C for 16 h and quenched by adding 1 M HCl (50 mL). The separated aqueous layer was adjusted to pH 8 by adding 1 M NaOH and extracted with ethyl acetate (5 × 100 mL). The combined organic layers were dried and concentrated to give crude 4-(1-methylcyclopropyl)benzoamide (4.80 g, 86.6% yield) as a yellow solid.

[0314] Step 3: A mixture of 4-(1-methylcyclopropyl)benzamidin (1.80 g, 10.3 mmol), 2-(1-ethoxyethylidene)malonate (12.0 mL, 18.6 mmol), and freshly prepared sodium ethoxide (20.7 mmol) in ethanol (40 mL) was heated at 50 °C for 16 h. After cooling to room temperature, the reaction mixture was quenched with HCl (1 M, 100 mL) and extracted with ethyl acetate (4 × 100 mL). The combined organic layers were washed with brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 30% ethyl acetate in petroleum ether) to obtain ethyl 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (2.50 g, 77.5% yield) as a yellow solid.

[0315] Step 4: The mixture of ethyl 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyrimidin-5-carboxylate (6.5 g, 20.8 mmol) in POCl3 (69.3 mL, 743 mmol) was heated at 110 °C for 2 h and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 5% ethyl acetate in petroleum ether) to obtain ethyl 4-chloro-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidin-5-carboxylate (6.1 g, 88.6% yield) as a yellow oil.

[0316] Step 5: A mixture of ethyl 4-chloro-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylate (6.10 g, 18.4 mmol) in ammonia (10 N in MeOH, 60 mL, 600 mmol) was heated at 50 °C for 16 h and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 20% ethyl acetate in petroleum ether) to give ethyl 4-amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylate (3.00 g, 52.2% yield) as a white solid.

[0317] Step 6: A mixture of ethyl 4-amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid (1.85 g, 5.94 mmol) and NaOH (0.95 g, 23.8 mmol) in MeOH (20 mL) and water (10 mL) was heated at 80 °C for 2 h. After cooling to room temperature, the mixture was filtered. The filter cake was dried to give crude 4-amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid (1.68 g, 100% yield) as a white solid.

[0318] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.12 (d, J = 8.4Hz, 2H), 7.47 (d, J = 8.4Hz, 2H), 7.21-7.15 (m, 1H), 7.02 (d, J = 8.4Hz, 1H), 6.93-6.86 (m, 1H), 6.85-6 .80(m, 1H), 6.5(s, 1H), 6.4(s, 1H), 5.25-5.17(m, 1H), 4.85-4.77(m, 2H ), 4.32-4.25(m, 1H), 4.24-4.14(m, 3H), 4.12-4.04(m, 2H), 3.66-3.59(m 1H), 3.58-3.43(m, 1H), 3.41-3.38(m.1H), 3.37-3.31(m, 2H), 3.29-3.28(m, 1H), 3.28-3.20(m, 1H), 3.19-3.14(m, 1H), 3.13-3.07 (m, 2H), 3.1 (s, 3H), 2.75 (s, 1H), 2.7 (s, 12H), 2.63 (s, 3H), 1.48 (s, 3H), 1.42-1.28 (m, 3H), 1.03-0.97 (m, 2H), 0.94-0.90 (m, 2H). LCMS (Method 10-80AB, ELSD), R T = 1.412 min, [M+H] + =1006.7.

[0319] Example 7:

[0320]

[0321] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidin-5-carboxylic acid with 2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.89 (d, J = 7.6Hz, 1H), 8.55 (d, J = 8.8Hz, 1H), 8.21 (d, J = 8.0Hz, 2 H), 7.43 (d, J=8.0Hz, 2H), 7.05-6.97 (m, 2H), 6.77 (s, 1H), 6.45 (s, 1H), 5.43-5.39 (m, 1H), 4.8 1-4.76(m, 2H), 4.27-4.21(m, 3H), 4.10-4.05(m, 3H), 3.63-3.59(m, 1H), 3.37-3.33(m, 1H), 3. 28-3.20(m, 2H), 3.12-3.07(m, 6H), 2.97-2.90(m, 1H), 2.46(s, 6H), 1.38(s, 9H), 1.37(s, 3H). LCMS (Method 10-80AB, ELSD), R T = 0.652 min, [M+H] + =1007.5.

[0322] Example 8:

[0323]

[0324] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-4-methylpyrimidine-5-carboxylic acid with 2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.84 (s, 1H), 8.381 (s, 1H), 8.34-8.25 (m, 2H), 7.55-7.4 7(m, 1H), 7.07-6.93(m, 1H), 6.89-6.74(m, 2H), 6.66-6.56(m, 1H), 6.51(s, 1H), 5.33-5 .03(m,1H),4.83-4.81(m,2H),4.47(s,1H),4.37-3.95(m,6H),3.65-3.50(m,1H),3.4 9-3.34 (m, 1H), 3.28-3.07 (m, 4H), 3.07-2.94 (m, 4H), 2.66 (s, 3H), 1.40-1.32 (m, 12H). LCMS (Method 5-95AB, ELSD), R T = 0.667 min, [M+H] + =993.4.

[0325] Example 9:

[0326]

[0327] Step 1: DIAD (17.2 mL, 86.7 mmol) was slowly added to a solution of 4-bromophenol (5.00 g, 28.9 mmol), PPh3 (22.7 g, 86.7 mmol), and cyclohexanol (8.68 g, 86.7 mmol) in THF (75.0 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h and concentrated. The residue was diluted with water (70 mL) and subsequently extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 100% petroleum ether) to give 1-bromo-4-(cyclohexyloxy)benzene (6.24 g, 85.0% yield) as a white solid. It was then converted to 1-(4-(cyclohexyloxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid using a procedure similar to that used in Example 4.

[0328] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1-(4-(cyclohexyloxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 9.33 (s, 1H), 8.44-8.34 (m, 2H), 8.06 (s, 1H), 7.55 (d, J=1 .6HZ, 1H), 7.47-7.43(m, 1H), 7.06-7.04(m, 2H), 6.89-6.67(m, 6H), 6.36(s, 1H), 6.22(s 1H), 5.02(s, 1H), 4.66(s, 1H), 4.40(s, 1H), 4.05-3.98(m, 7H), 3.25(s, 2H), 3.12- 2.97(m, 6H), 2.83(s, 3H), 1.98-1.93(m, 2H), 1.73-1.72(m, 2H), 1.53-1.15(m, 9H). LCMS (Method 5-95AB, ELSD), R T = 0.815 min, [M+H] + =1037.5.

[0329] Example 10:

[0330]

[0331]

[0332] Step 1: The mixture of compound 1 (2.50 g, 11.0 mmol) and compound 2 (4.20 g, 26.0 mmol) was stirred at 50 °C for 48 h. The reaction mixture was then heated to 70 °C and held for 1 h to complete the reaction. The mixture was then poured into ice water (100 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with water (50 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0% to 5% ethyl acetate in petroleum ether) to obtain compound 3 (177 mg, 5.8% yield) as a yellow oil.

[0333] Step 2: Under a nitrogen atmosphere, a mixture of bis(pinacolyl)diboron (177 mg, 0.70 mmol), potassium acetate (125 mg, 1.27 mmol), and compound 3 (158 mg, 0.63 mmol) in DMF (3.00 mL) was stirred for 14 h at 80 °C. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under vacuum to give crude compound 4 (138 mg, 0.47 mmol) as a brown oil.

[0334] Step 3: A mixture of compound 4 (138 mg, 0.47 mmol), compound 5 (102 mg, 0.51 mmol), sodium carbonate (98.8 mg, 0.93 mmol), and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (34.1 mg, 0.05 mmol) in water (0.5 mL) and 1,4-dioxane (5 mL) was heated at 100 °C under N2 for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL). The solution was washed with water (40 mL) and brine (40 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give compound 6 (60.0 mg, 38.5% yield) as a light-colored oil.

[0335] Step 4: The mixture of compound 6 (60.0 mg, 0.18 mmol) and sodium hydroxide (14.4 mg, 0.36 mmol) in methanol (1.5 mL) and water (1.5 mL) was stirred at 80 °C for 2 h and concentrated. The aqueous residue was adjusted to pH 5 with 5% KHSO4 and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried, and concentrated to give crude compound 7 (45.8 mg, 83.3% yield) as a white solid.

[0336] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with compound 7. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.88 (s, 1H), 8.50-8.43 (m, 2H), 8.40 (s, 1H), 7.58-7.52 (m, 2H), 7 .02(s, 1H), 6.89-6.79(m, 2H), 6.60-6.48(m, 2H), 5.29-5.16(m, 1H), 4.81-4.75(m, 3H), 4.46(s , 1H), 4.28-3.91(m, 6H), 3.69-3.53(m, 1H), 3.43-3.35(m, 1H), 3.28-3.11(m, 4H), 3.07(s, 3H), 3.01-2.98(m, 1H), 2.81-2.60(m, 4H), 2.49-2.34(m, 1H), 1.41-1.30(m, 3H), 1.04-1.00(m, 6H). LCMS (Method 5-95AB, ESI), R T = 0.771 min, [M+H] + =1029.7.

[0337] Example 11:

[0338]

[0339] Step 1: A solution of methyl 3-aminopyrazine-2-carboxylate (5.0 g, 32.7 mmol) and m-CPBA (10.6 g, 49.0 mmol) in dichloromethane (50 mL) was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (250 mL) and filtered. The filtrate was concentrated to dryness and the residue was dissolved in petroleum ether (200 mL) containing 10% ethyl acetate. The resulting mixture was stirred at 25 °C for 1 h and filtered. The solid was collected and dried to give crude 2-amino-3-(methoxycarbonyl)pyrazine 1-oxide (5.5 g, 99.6% yield) as a yellow solid.

[0340] Step 2: A mixture of 2-amino-3-(methoxycarbonyl)pyrazine 1-oxide (5.50 g, 32.5 mmol) and POCl3 (15.2 mL, 163 mmol) in DMF (30 mL) was heated at 100 °C for 16 h. After cooling to room temperature, the mixture was diluted with H2O (300 mL) and adjusted to pH 7 with solid NaHCO3. The resulting mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 10% ethyl acetate in petroleum ether) to give methyl 3-amino-5-chloropyrazine-2-carboxylate (940 mg, 15.4% yield).

[0341] Step 3: Under a nitrogen atmosphere, a mixture of (4-(tert-butyl)phenyl)boronic acid (937 mg, 5.26 mmol), methyl 3-amino-5-chloropyrazine-2-carboxylate (940 mg, 5.01 mmol), K3PO4 (2.08 g, 15.0 mmol), and Pd(dPPf)Cl2 (367 mg, 0.50 mmol) in DMF (10.0 mL) was heated for 16 h at 90 °C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with brine (2 × 100 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 15% ethyl acetate in petroleum ether) to obtain the crude substance (two isomers). The crude material was further separated by SFC to obtain methyl 3-amino-5-(4-(tert-butyl)phenyl)pyrazine-2-carboxylate (120 mg, 8.4% yield) as a yellow solid.

[0342] Step 4: A mixture of methyl 3-amino-5-(4-(tert-butyl)phenyl)pyrazine-2-carboxylic acid (120 mg, 0.42 mmol) and NaOH (42.1 mg, 1.05 mmol) in methanol (5 mL) and water (1 mL) was heated at 80 °C for 16 h. The mixture was concentrated and the aqueous residue was adjusted to pH 2 by adding 1 M HCl. The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried and concentrated to give crude 3-amino-5-(4-(tert-butyl)phenyl)pyrazine-2-carboxylic acid (110 mg, 96.4% yield) as a yellow solid.

[0343] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)pyrazin-2-carboxylic acid with 3-amino-5-(4-(tert-butyl)phenyl)pyrazin-2-carboxylic acid. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.55-8.42 (m, 1H), 8.37 (br s, 1H), 8.09-7.91 (m, 2H), 7.63-7.46 (m, 2H), 7.12-6.99 (m, 1H), 6.95-6.62 (m, 3H), 6.48-5.93 (m, 2H), 5.19-4.89 (m, 1 H), 4.70-4.51(m, 1H), 4.32-3.85(m, 5H), 3.41-3.12(m, 5H), 3.07-2.63(m, 8H), 1.39-1.25(m, 9H), 1.24-1.04(m, 3H). (Method 5-95AB, ESI): R T = 0.689 min, [M+H] + =994.4.

[0344] Example 12:

[0345]

[0346] Step 1: A mixture of 4-(tert-butyl)piperidine hydrochloride (1.00 g, 5.60 mmol), 1H-pyrazole-1-formamidinium hydrochloride (0.82 g, 5.63 mmol), and DIEA (1.45 g, 11.3 mmol) in DMF (5.00 mL) was stirred at 60 °C for 16 h and diluted with MTBE (60 mL). The resulting suspension was stirred for 10 min and filtered. The solid was collected to give crude 4-(tert-butyl)piperidine-1-formamidinium (1.00 g, 97.0% yield) as a white solid.

[0347] Step 2: A mixture of 4-(tert-butyl)piperidin-1-formamidinium (1.00 g, 5.46 mmol), NaOEt (742 mg, 10.9 mmol), and diethyl 2-(1-ethoxyethylidene)malonate (1.88 g, 8.18 mmol) in ethanol (20.0 mL) was heated at 50 °C for 20 h and concentrated to dryness. The residue was diluted with ethyl acetate (50 mL), washed with brine (2 × 30 mL), dried, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give ethyl 2-(4-(tert-butyl)piperidin-1-yl)-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate (350 mg, 20.0% yield) as a pale yellow solid.

[0348] Step 3: A mixture of ethyl 2-(4-(tert-butyl)piperidin-1-yl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-carboxylate (350 mg, 1.09 mmol) and POCl3 (10 mL, 108 mmol) was heated at 90 °C for 20 h and concentrated to dryness. The solution was then analyzed by preparative TLC (20% ethyl acetate in petroleum ether, R...). f =0.8) The residue was purified to give ethyl 2-(4-(tert-butyl)piperidin-1-yl)-4-chloro-6-methylpyrimidin-5-carboxylate (270 mg, 73.0% yield) as a light-colored oil.

[0349] Step 4: A mixture of ethyl 2-(4-(tert-butyl)piperidin-1-yl)-4-chloro-6-methylpyrimidin-5-carboxylate (170 mg, 0.50 mmol) and NH3·H2O (2.00 mL, 55.1 mmol) in MeOH (5 mL) was heated at 60 °C for 60 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 mL), washed with brine (20 mL), dried, and concentrated. The mixture was then analyzed by preparative TLC (10% ethyl acetate in petroleum ether, R...). f =0.4) The residue was purified to give ethyl 4-amino-2-(4-(tert-butyl)piperidin-1-yl)-6-methylpyrimidin-5-carboxylate (130 mg, 81.1% yield) as a light yellow solid.

[0350] Step 5: A mixture of ethyl 4-amino-2-(4-(tert-butyl)piperidin-1-yl)-6-methylpyrimidin-5-carboxylic acid (130 mg, 0.41 mmol) and NaOH (40.6 mg, 1.01 mmol) in MeOH (5 mL) and water (1 mL) was heated at 80 °C for 16 h and concentrated. The aqueous residue was adjusted to pH 2 with 1 M HCl and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were concentrated to give crude 4-amino-2-(4-(tert-butyl)piperidin-1-yl)-6-methylpyrimidin-5-carboxylic acid (100 mg, 84.3% yield) as a white solid.

[0351] Using the procedure of Example 1, the title compound, which is a white solid, was prepared by replacing l-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)piperidin-1-yl)-6-methylpyrimidin-5-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) = 8.30 (s, 1H), 7.17-7.14 (m, 1H), 6.95 (s, 1H), 6.89-6.76 (m, 2H), 6.64-6.54 (m, 1H) , 6.50 (s, 1H), 5.12-5.22 (m, 1H), 4.75-4.71 (m, 2H), 4.55 (s, 1H), 4.28-4.04 (m, 5H), 3.62-3.57 (m, 1H), 3.41-3.3 3 (m, 2H), 3.32-3.35 (m, 2H), 3.21-3.10 (m, 2H), 3.10-3.04 (m, 3H), 3.01 (s, 1H), 2.94-2.82 (m, 1H), 2.81-2.74 (m, 2H), 2.74-2.64 (m, 1H), 2.42-2.33 (m, 3H), 1.85-1.73 (m, 2H), 1.40-1.28 (m, 4H), 1.26-1.13 (m, 2H), 0.91 (s, 9H). LCMS (Method 5-95AB, ESI): R T = 0.747 min, [M / 2 + H] + =508.5.

[0352] Example 13:

[0353]

[0354] Step 1: Under a nitrogen atmosphere, a mixture of 4-isopropoxyphenylboronic acid (29.6 g, 164 mmol), methyl 2-chloro-4,6-dimethylpyrimidin-5-carboxylate (30.0 g, 150 mmol), Na₂CO₃ (31.7 g, 299 mmol), and Pd(dppf)Cl₂ (10.9 g, 15.0 mmol) in water (15 mL) and 1,4-dioxane (150 mL) was heated at 100 °C for 16 h and then filtered. The filtrate was concentrated to dryness. The residue was partitioned between ethyl acetate (500 mL) and water (500 mL). The aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were washed with brine (3 × 500 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum ether) to give methyl 2-(4-isopropoxyphenyl)-4,6-dimethylpyrimidinyl-5-carboxylate (42.0 g, 93.5% yield) as a white solid.

[0355] Step 2: A mixture of methyl 2-(4-isopropoxyphenyl)-4,6-dimethylpyrimidin-5-carboxylate (21.0 g, 69.9 mmol) and NaOH (8.39 g, 210 mmol) in MeOH (100 mL) and water (10 mL) was heated at 80 °C for 22 h and concentrated. The aqueous residue was adjusted to pH 5 by adding 1 M HCl and filtered. The collected solid was dried to give crude 2-(4-isopropoxyphenyl)-4,6-dimethylpyrimidin-5-carboxylic acid (19.0 g, 95.0% yield) as a white solid.

[0356] Using the procedure of Example 1, the title compound, which is a white solid, was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-isopropoxyphenyl)-4,6-dimethylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.47 (s, 1H), 8.30-8.28 (m, 2H), 7.02-6.94 (m, 2H), 6.82-6.70 (m, 4H), 6.57 (s, 1H), 6.43 (s, 1H), 5.33-5.3 2 (m, 1H), 4.69-4.66 (m, 2H), 4.35-4.09 (m, 6H), 3.57-3.56 (m, 1H), 3.39-3.37 (m, IH), 3.25-3.00 (m, 9H), 2.54 (s, 6H), 1.35-1.33 (m, 9H). LCMS (Method 5-95AB, ESI): R T = 0.608 min, [M+H] + =1009.5.

[0357] Example 14:

[0358]

[0359] Step 1: Under a nitrogen atmosphere, a mixture of ethyl 2-chloro-4-methylpyrimidin-5-carboxylate (30.0 g, 150 mmol), (4-isopropoxyphenyl)boronic acid (28.3 g, 157 mmol), sodium carbonate (31.7 g, 299 mmol), and Pd(dppf)Cl2 (10.9 g, 15.0 mmol) in water (30 mL) and 1,4-dioxane (300 mL) was heated for 16 h at 100 °C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (300 mL), and filtered. The filtrate was washed with brine (100 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 2% ethyl acetate in petroleum ether) to obtain ethyl 2-(4-isopropoxyphenyl)-4-methylpyrimidin-5-carboxylate (32.5 g, 72.4% yield) as a white solid.

[0360] Step 2: Ethyl 2-(4-isopropoxyphenyl)-4-methylpyrimidine-5-carboxylate (32.5 g, 108 mmol) and sodium hydroxide (21.6 g, 541 mmol) in MeOH (150 mL) and water (15 mL) were stirred at 80 °C for 3 h and concentrated. The aqueous residue was adjusted to pH 5 with 2 M HCl and filtered. The filter cake was washed with water (3 × 50 mL) and dried to give crude 2-(4-isopropoxyphenyl)-4-methylpyrimidine-5-carboxylic acid (28.0 g, 95.0% yield) as a white solid.

[0361] The title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-isopropoxyphenyl)-4-methylpyrimidine-5-carboxylic acid. 1H NMR (400MHz, MeOH-d4): δ (ppm) 8.82 (br s, 1H), 8.35 (d, J = 8.8Hz, 2H), 7.11 (d, J = 8.4Hz, 1H), 6.99 (d, J = 8.8Hz, 2H), 6.90 (d, J = 8.0Hz, 1H), 6.86-6.76 (m, 2H), 6.59 (br s, 1H), 6.45 (s, 1H), 5.27-5.16 (m, 1H), 4.75-4.66 (m, 2H), 4.65-4.45 (m, 2H), 4.37-4.19 (m, 1H), 4.17-4.00 (m, 5H), 3.71-3.54 (m, 1H), 3.50-3.44 (m, 1H), 3.42-3.35 (m, 1H), 3.29-3.09 (m, 5H), 3.06 (s, 3H), 2.69 (s, 3H), 1.33-1.38 (m, 9H). LCMS (Method 5-95AB, ESI): R T = 0.609 min, [M+H] + =996.7.

[0362] Example 15:

[0363]

[0364] Step 1: Under a nitrogen atmosphere, at 100℃, 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxoboron... A mixture of ethyl 2-chloro-4-methylpyrimidin-5-carboxylate (4.67 g, 18.1 mmol), sodium carbonate (3.49 g, 32.9 mmol), and Pd(dppf)Cl2 (1.20 g, 1.64 mmol) in water (3 mL) and 1,4-dioxane (30 mL) was heated for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (300 mL) and filtered. The filtrate was washed with water (100 mL) and brine (50 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give ethyl 4,6-dimethyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidin-5-carboxylate (2.10 g, 43.1% yield) as a white solid.

[0365] Step 2: A mixture of ethyl 4,6-dimethyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid (2.10 g, 7.09 mmol) and sodium hydroxide (567 mg, 14.2 mmol) in MeOH (30 mL) and water (3 mL) was stirred at 80 °C for 4 h and concentrated. The aqueous residue was adjusted to pH 5 with 1 M HCl and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried, and concentrated. The crude material was recrystallized from petroleum ether containing 10% ethyl acetate (10 mL) to give 4,6-dimethyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid (1.10 g, 55% yield) as a white solid.

[0366] Using the procedure of Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4,6-dimethyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.27 (d, J=8.4H, 2H), 7.34 (d, J=8.0Hz, 2H), 7.17-7.06 (m, 1H), 7.04-6.90(m, 1H), 6.87-6.70(m, 2H), 6.44(s, 1H), 6.30(m, 1H), 5.39-5.05(m, 1H), 4.75-4.58( m, 1H), 4.48-4.35 (m, 1H), 4.18-3.90 (m, 6H), 3.31-3.13 (m, 3H), 3.06-2.95 (m, 5H), 2.93-2.64 (m, 3H), 2.44 (s, 6H), 1.42 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H), 0.93-0.86 (m, 2H), 0.85-0.77 (m, 2H). LCMS (Method 5-95AB, ESI): R T = 0.631 min, [M+H] + =1006.3.

[0367] Example 16:

[0368]

[0369]

[0370] Step 1: Add 1-bromo-3,3-dimethylbutane (10.0 g, 57.8 mmol) and potassium carbonate (20.0 g, 145 mmol) to a solution of 4-bromophenol (14.3 g, 86.7 mmol) in DMF (100 mL). Stir the reaction mixture at 50 °C for 16 h. Cool the reaction mixture to room temperature and dilute it with ethyl acetate (500 mL) and filter. Wash the filtrate with brine (400 mL) and concentrate to dryness. Purify the residue by column chromatography (silica gel, 100 to 200 mesh, 0% to 2% ethyl acetate in petroleum ether) to obtain 1-bromo-4-(3,3-dimethylbutoxy)benzene (14.5 g, 97.5% yield) as a white solid.

[0371] Step 2: Under a nitrogen atmosphere, a mixture of 1-bromo-4-(3,3-dimethylbutoxy)benzene (10.0 g, 38.9 mmol), bis(pinacolyl)diboron (10.4 g, 40.8 mmol), potassium acetate (11.5 g, 116.7 mmol), and Pd(dppf)₂Cl₂ (2.85 g, 3.89 mmol) in DMF (100 mL) was heated at 80 °C for 16 h and filtered. The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 2% ethyl acetate in petroleum ether) to obtain a colorless oily substance, 2-(4-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron. (16.0g, 52.6mmol).

[0372] Step 3: Introduce 2-(4-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron at 100℃ A mixture of ethyl 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methylpyrimidin-5-carboxylate (1.00 g, 3.29 mmol), sodium carbonate (692 mg, 3.45 mmol), and Pd(dppf)Cl2 (240 mg, 0.33 mmol) in water (1 mL) and 1,4-dioxane (10 mL) was heated for 16 h and diluted with ethyl acetate (100 mL). The resulting mixture was filtered, and the filtrate was washed with water (2 × 40 mL) and brine (50 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 2% ethyl acetate in petroleum ether) to give ethyl 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methylpyrimidin-5-carboxylate (460 mg, 40.9% yield) as a colorless oil.

[0373] Step 4: A mixture of ethyl 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methylpyrimidin-5-carboxylic acid (460 mg, 1.34 mmol) and sodium hydroxide (269 mg, 6.72 mmol) in MeOH (10 mL) and water (10 mL) was stirred at 80 °C for 16 h and concentrated. The aqueous residue was adjusted to pH 5 with 1 M HCl and filtered. The filter cake was dried to give crude 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methylpyrimidin-5-carboxylic acid (400 mg, 94.7% yield) as a white solid.

[0374] Using the procedure of Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.80 (s, 1H), 8.27 (d, J=8.8Hz, 2H), 7.06-7.05 (m, 1H), 6.93 (d, J=8 .8Hz, 2H), 6.85-6.86(m, 1H), 6.69-6.66(m, 2H), 6.49(s, 1H), 6.37(s, 1H), 5.23-5.21(m, 1H), 4.55 -4.50 (m, 2H), 4.23-4.05 (m, 1H), 3.60-3.58 (m, 1H), 3.50-3.38 (m, 1H), 3.26-3.24 (m, 2H), 3.17-3.11 (m, 2H), 3.18-2.99 (m, 4H), 2.64 (s, 3H), 1.76-1.70 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H), 0.99 (s, 9H). LCMS (Method 5-95AB, ESI): R T = 0.844 min, [M+H] + =1037.4.

[0375] Example 17:

[0376]

[0377]

[0378] Step 1: Add 10% Pd / C (60.6 mg, 0.06 mmol) to a solution of compound 10 (200 mg, 0.19 mmol) and one drop of NH3·H2O in ethanol (15 mL). Stir the reaction mixture at 30 °C for 2 h under a H2 atmosphere (15 psi) and filter. Concentrate the filtrate to give crude compound 11 (174 mg, 100% yield) as a white solid.

[0379] Step 2: DIEA (0.13 mL, 0.76 mmol) and (S)-2-(((benzyloxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butyric acid (134 mg, 0.38 mmol) were added to a solution of compound 11 (174 mg, 0.19 mmol) in dichloromethane (10 mL) at 0 °C, followed by the addition of HATU (86.8 mg, 0.23 mmol) in DMF (1 mL). The mixture was stirred at 20 °C for 2 h and quenched with MeOH (0.5 mL). The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 5% MeOH in dichloromethane) to give compound 19 (200 mg, 83.8% yield) as a white solid.

[0380] Step 3: Add 10% Pd / C (76.4 mg, 0.07 mmol) to a solution of compound 19 (200 mg, 0.16 mmol) and one drop of ammonium hydroxide in ethanol (15 mL). Stir the reaction mixture at 40 °C for 6 h under a H2 atmosphere (15 psi) and filter. Concentrate the filtrate to give crude compound 20 (178 mg, 100% yield) as a white solid.

[0381]

[0382] Step 1: A mixture of 6-oxo-1,6-dihydropyridazin-4-carboxylic acid (2.00 g, 14.3 mmol) and HCl (4 M in MeOH, 15.0 mL, 60.0 mmol) was stirred for 24 h at 25 °C and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 30% to 60% ethyl acetate in petroleum ether) to give methyl 6-oxo-1,6-dihydropyridazin-4-carboxylate (1.00 g, 45.5% yield) as a white solid.

[0383] Step 2: A mixture of (4-(tert-butyl)phenyl)boronic acid (118 mg, 0.65 mmol), methyl 6-oxo-1,6-dihydropyridazine-4-carboxylate (500 mg, 3.24 mmol), copper(II) acetate (24 mg, 0.13 mmol), and pyridine (2 mL) in dichloromethane (10 mL) was stirred for 24 h and concentrated. The residue was diluted with ethyl acetate (80 mL) and washed with brine (2 × 30 mL), dried, and concentrated. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 33% ethyl acetate in petroleum ether) to give methyl 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylate (770 mg, 82.9% yield) as a white solid.

[0384] Step 3: A mixture of methyl 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (770 mg, 2.69 mmol) and lithium hydroxide hydrate (247 mg, 10.8 mmol) in THF (10 mL) and water (2 mL) was stirred for 2 h at 25 °C and concentrated. The residue was adjusted to pH 3 with 1 M HCl and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried and concentrated to give crude 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (730 mg, 99.7% yield) as a white solid.

[0385] Using the procedure of Example 1, the title compound was prepared by replacing compound 14 with compound 20. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.43 (s, 1H), 8.38-8.28 (m, 2H), 8.14-8.07 (m, 1H), 7.60-7.44 (m, 5H ), 7.10-7.04(m, 1H), 6.93-6.91(m, 1H), 6.78(s, 2H), 6.35(s, 1H), 6.24(s, 1H), 5.05-4.94(m, 1H), 4.67-4.65 (m, 3H), 4.35 (s, 1H), 4.12-3.93 (m, 11H), 3.3-3.27 (m, 2H), 3.17-3.10 (m, 3H), 2.99-2.97 (m, 4H), 2.80 (s, 4H), 2.67-2.64 (m, 1H), 2.12-2.03 (m, 2H), 1.33-1.28 (m, 9H), 1.17-1.00 (m, 3H). LCMS (Method 5-95AB, ESI): R T = 0.797 min, [M+H] + =929.4.

[0386] Example 18:

[0387]

[0388] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid with 4-amino-2-(4-(isopentoxy)phenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.41 (s, 1H), 8.23 ​​(d, J = 8.8Hz, 2H), 7.18-7.04 (m, 1H), 6 .97(d, J=8.8Hz, 2H), 6.93-6.87(m, 1H), 6.84(s, 1H), 6.81(s, 1H), 6.60(s, 1H), 6.46(s , 1H), 4.87-4.73 (m, 2H), 4.52-4.41 (m, 1H), 4.24-4.01 (m, 8H), 3.27-2.97 (m, 11H), 2.45 (s, 3H), 2.31-2.11 (m, 2H), 1.75 (t, J = 6.8 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.02 (s, 9H). LCMS (Method 5-95AB, ESI): R T = 0.767 min, [M+H] + =987.8.

[0389] Example 19:

[0390]

[0391] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidin-5-carboxylic acid with 2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.34 (s, 1H), 8.28 (d, J = 8.4Hz, 2H), 7.48 (d, J = 8.8Hz, 2H), 7.02 (d, J = 8.0Hz, 1H), 6.89 (d, J=8.8Hz, 1H), 6.81-6.80 (m, 1H), 6.66 (s, 1H), 6.55 (s, 1H), 6.56 (s, 1H), 5.21-5.18 (m, 1H), 4 .81-4.76(m, 1H), 4.41-4.39(m, 1H), 4.24-4.06(m, 6H), 3.27-3.22(m, 2H), 3.19-3.12(m, 4H), 3.10-3.07( m, 1H), 3.03 (s, 3H), 2.99-2.95 (m, 1H), 2.51 (s, 6H), 2.30-2.17 (m, 2H), 1.37 (s, 9H), 1.34 (d, J=6.8Hz, 3H). LCMS (Method 5-95AB, ESI): R T = 0.622 min, [M+H] + =942.4.

[0392] Example 20:

[0393]

[0394] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-(isopropoxyphenyl)-4-methylpyrimidine-5-carboxylic acid). 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.89 (s, 1H), 8.23 ​​(d, J=8.8Hz, 2H), 7.05-6.92 (m, 4H), 6. 87-6.82(m, 1H), 6.66(s, 1H), 6.51(s, 1H), 6.42(s, 1H), 5.20-5.11(m, 1H), 4.83-4.72(m, 2H), 4.69-4.59 (m, 1H), 4.40-4.03 (m, 6H), 3.40-3.32 (m, 1H), 3.29-3.07 (m, 6H), 2.99 (s, 3H), 2.97-2.80 (m, 1H), 2.70 (s, 12H), 2.68 (s, 3H), 2.39-2.15 (m, 2H), 1.47-1.30 (m, 9H). LCMS (Method 5-95AB, ESI): R T = 0.732 min, [M+H] + =930.7.

[0395] Example 21:

[0396]

[0397] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.36 (s, 1H), 8.18-8.15 (m, 2H), 7.33-7.31 (m, 2H), 7.1 1(s, 1H), 6.93-6.91(m, 1H), 6.86-6.81(m, 2H), 6.58-6.46(m, 3H), 5.04-5.03(m, 1H), 4.82 (s, 2H), 4.54 (s, 1H), 4.22-4.05 (m, 6H), 3.18-2.98 (m, 10H), 2.46 (s, 3H), 2.25-2.18 (m, 2H), 1.44 (s, 3H), 1.34 (d, J = 6.4 Hz, 2H), 0.93-0.91 (m, 2H), 0.82-0.80 (m, 2H). LCMS (Method 5-95AB, ESI): R T = 0.58 min, [M+H] + =941.5.

[0398] Example 22:

[0399]

[0400] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1-(4-(3,3-dimethylbutoxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1H NMR (400MHz, MeOH-d4): δ (ppm) 8.08 (s, 1H), 7.45-6.85 (m, 9H), 6.60 (s, 1H), 6 .31(s, 1H), 5.03-5.01(m, 1H), 4.74-4.71(m, 1H), 4.37(s, 1H), 4.25(s, 1H), 4. 11-4.06 (m, 4H), 3.91-3.90 (m, 1H), 3.38-3.31 (m, 3H), 3.30-3.12 (m, 3H), 2.99-2.90 (m, 7H), 2.18 (s, 2H), 1.76-1.73 (m, 2H), 1.37-1.35 (m, 3H), 1.02 (s, 2H). LCMS (Method 5-95AB, ESI): R T = 0.660 min, [M+H] + =974.6.

[0401] Example 23:

[0402]

[0403] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-(tert-butyl)phenyl)-4-methylpyrimidin-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.72 (s, 1H), 8.34 (m, 1H), 8.26-8.24 (d, J=8.0Hz, 1H), 7.47-7.45 (d, J=8.0Hz, 2H), 6.92-6.91 (d, J=4.0Hz, 1H), 6.81-6.79 (d, J=8.0Hz, 2H), 6.61 (s, 1H), 6.47 (s, 2H), 5.10-5.09 (m, 1H), 4.80-4.76 (m, 2H), 4.48-4.46 (m, 1 H), 4.29-4.27 (d, J=8.0Hz, 1H), 4.18-4.12 (m, 4H), 4.03-4.02 (d, J=4.0Hz, 1H), 3.26 (s, 1H), 3.20-3.15 (m, 4H), 3.10-3.14 (m , 1H), 2.97 (s, 3H), 2.92-2.89 (d, J=12.0Hz, 1H), 2.76-2.67 (m, 1H), 2.62-2.60 (m, 3H), 2.29-2.23 (m, 3H), 1.35-1.32 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.769 min, [M+H]+ =928.8.

[0404] Example 24:

[0405]

[0406] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.24 (s, 1H), 8.23-8.17 (m, 2H), 7.54-7.48 (m, 1H) ,7.21-7.14(m,1H),7.02-6.92(m,1H),6.88(s,1H),6.85(s,1H),6.59(s,1H),6.4 5 (s, 1H), 5.30-5.01 (m, 1H), 4.83-4.79 (m, 2H), 4.66-4.52 (m, 1H), 4.25-4.04 (m, 6H), 3.25-2.99 (m, 10H), 2.52-2.43 (m, 3H), 2.33-2.08 (m, 2H), 1.40-1.33 (s, 12H). LCMS (Method 5-95AB, ESI): R T = 0.592 min, [M+H] + =943.4.

[0407] Example 25:

[0408]

[0409] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)piperidin-1-yl)-6-methylpyrimidin-5-carboxylic acid. 1HNMR (400MHz, MeOH-d4): δ (ppm) 7.27-7.21 (m, 1H), 7.04 (d, J=8Hz, 1H), 6.92-6.87 ( m, 2H), 6.55 (m, 1H), 6.38 (s, 1H), 5.04-5.01 (m, 1H), 4.72 (m, 2H), 4.28-4.07 (m, 6H) 3.52-3.34 (m, 2H), 3.31-3.04 (m, 8H), 2.99 (s, 3H), 2.95-2.86 (m, 2H), 2.40 (s, 3H), 2.28-2.12 (m, 2H), 1.85 (m, 2H), 1.44-1.33 (m, 4H), 1.30-1.19 (m, 2H), 0.92 (s, 9H). LCMS (Method 5-95AB, ESI): R T = 0.731 min, [M / 2 + H] + =479.5.

[0410] Example 26:

[0411]

[0412] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1-(4-(cyclohexyloxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.34-8.14 (m, 1H), 7.48-7.33 (m, 1H), 7.19 -6.62(m,9H),6.35-6.30(m,1H),5.01-4.90(m,1H),4.73-4.71(m,1H),4.3 7-3.92(m, 7H), 3.36-3.30(m, 4H), 3.18-2.91(m, 9H), 2.28-2.18(m, 2H), 2 .18-1.98(m, 2H), 1.82-1.80(m, 2H), 1.55-1.43(m, 6H), 1.36-1.35(m, 3H). LCMS (Method 5-95AB, ESI): R T = 0.696 min, [M / 2 + H] + =485.9.

[0413] Example 27:

[0414]

[0415] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-(3,3-dimethylbutoxy)phenyl)-4-methylpyrimidine-5-carboxylic acid. 1 HNMR (400MHz, MeOH-d4): δ (ppm) 8.79 (s, 1H), 8.37 (d, J = 8.4Hz, 2H), 7.07-7. 00(m,3H),6.87-6.83(m,2H),6.72(s,1H),6.58(s,1H),6.47(s,1H),4.84-4 0.83 (m, 2H), 4.41 (s, 1H), 4.27-4.03 (m, 8H), 3.32-2.99 (m, 11H), 2.74-2.68 (m, 3H), 2.32-2.19 (m, 2H), 1.78-1.75 (m, 2H), 1.39-1.34 (m, 3H), 1.04 (s, 9H). LCMS (Method 5-95AB, ESI): R T = 0.825 min, [M+H] + =973.0.

[0416] Example 28:

[0417]

[0418] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid. 1H NMR (400MHz, MeOH-d4): δ (ppm) 8.79 (s, 1H), 8.20 (d, J = 8.4Hz, 2H), 7.31 (d, J = 8.4Hz, 2H), 7.00-6.80 (m, 3 H), 6.88 (s, 1H), 6.44 (s, 1H), 6.40 (s, 1H), 5.18-5.10 (m, 1H), 4.84-4.71 (m, 1H), 4.65-4.53 (m, 1H), 4.37 -4.30 (m, 1H), 4.28-4.17 (m, 2H), 4.16-3.97 (m, 3H), 3.27-3.08 (m, 6H), 3.06-2.73 (m, 5H), 2.70 (s, 12H), 2.62 (s, 3H), 2.37-2.15 (m, 2H), 1.47 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.02-0.92 (m, 2H), 0.91-0.82 (m, 2H). LCMS (Method 5-95AB, ESI): R T = 0.763 min, [M+H] + =926.3.

[0419] Example 29:

[0420]

[0421]

[0422] Step 1: At 25℃, 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxoboron A mixture of sodium periodate (8.0 g, 31.0 mmol), ammonium acetate (33.1 g, 155 mmol), and ammonium acetate (11.9 g, 155 mmol) in acetone (80 mL) and water (80 mL) was stirred for 16 h and filtered. The filtrate was concentrated and the aqueous residue was extracted with ethyl acetate (2 × 150 mL). The combined organic layers were concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 25% ethyl acetate in petroleum ether) to give (4-(1-methylcyclopropyl)phenyl)boronic acid (5.4 g, 99.0% yield) as a white solid.

[0423] Step 2: A mixture of (4-(1-methylcyclopropyl)phenyl)boronic acid (1.00 g, 5.68 mmol), copper(II) acetate (0.21 g, 1.14 mmol), and methyl 6-oxo-1,6-dihydropyridazine-4-carboxylate (0.92 g, 5.97 mmol) in dichloromethane (10 mL) and pyridine (1 mL) was stirred at 25 °C for 16 h. The mixture was diluted with 1 M HCl (50 mL) and subsequently extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 25% ethyl acetate in petroleum ether) to give methyl 1-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylate (1.00 g, 61.7%) as a yellow solid.

[0424] Step 3: A mixture of methyl 1-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (6.0 g, 21.1 mmol) and sodium hydroxide (2.1 g, 52.76 mmol) in MeOH (50 mL) and water (20 mL) was heated at 80 °C for 2 h and concentrated. The aqueous residue was adjusted to pH 5 with 1 N HCl and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried, and concentrated to give crude 1-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (5.30 g, 92.9% yield) as a pale yellow solid.

[0425] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1H NMR (400MHz, MeOH-d4): δ (ppm) 8.32 (d, J=2.0Hz, 1H), 7.53 (d, J=2.0Hz, 1H), 7.39-7.32 (m, 4H), 7.15 -7.13(m, 1H), 7.02-7.00(m, 1H), 6.90(s, 1H), 6.68(s, 1H), 6.50(s, 1H), 6.41(s, 1H), 4.87-4.78(m, 2H), 4.36-4.34(m, 1H), 4.20-4.04(m, 6H), 3.37-3.30(m, 3H), 3.21-3.05(m, 5H), 2.87(s, 3H), 2.71( s, 12H), 3.33-3.21 (m, 2H), 1.43 (s, 3H), 1.37 (d, J=6.8Hz, 3H), 0.91-0.88 (m, 2H), 0.81-0.78 (m, 2H). LCMS (Method 5-95AB, ESI): R T = 0.739 min, [M+H] + =928.4.

[0426] Example 30:

[0427]

[0428] Using the procedure of Example 22, the title compound was prepared by replacing (S)-2-(((benzoxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propionic acid with (S)-2-(((benzoxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butyric acid, and subsequently by replacing 1-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidin-5-carboxylic acid with 2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-(tert-butyl)phenyl)-4,6-dimethylpyrimidin-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.43 (s, 1H), 8.33 (d, J = 8.8Hz, 2H), 7.53 (d, J = 8.8H) z, 2H), 7.07 (d, J=8.0Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 6.61 (s, 1H), 6.39(s, 1H), 5.33-5.30(m, 1H), 4.38-4.36(m, 2H), 4.21-4.03(m, 2H), 3.49-3.44(m, 6H), 3.26-2.96(m, 10H), 2.57(s, 6H), 1.38(s, 9H), 1.34(d, J = 6.8Hz, 3H). LCMS (Method 5-95AB, ESI), R T= 0.611 min, [M+H] + =928.5.

[0429] Example 31:

[0430]

[0431] Using the procedure of Example 22, the title compound was prepared by replacing (S)-2-(((benzoxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propionic acid with (S)-2-(((benzoxy)carbonyl)amino)-4-((tert-butoxycarbonyl)amino)butyric acid, and subsequently by replacing 1-(4-(tert-butyl)phenyl)-4-methylpyrimidin-5-carboxylic acid with 2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-(tert-butyl)phenyl)-4-methylpyrimidin-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4): δ (ppm) 8.91 (s, 1H), 8.35 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.8Hz, 2H ), 7.08-7.00(m, 1H), 6.96-6.80(m, 2H), 6.71-6.60(m, 1H), 6.54(s, 1H), 6.41-6.27(m, 1 H), 5.50-5.25(m, 1H), 4.76-4.58(m, 1H), 4.54-4.41(m, 1H), 4.26-3.95(m, 6H), 3.57-3. 48(m, 1H), 3.41-3.35(m, 1H), 3.28-2.84(m, 9H), 2.71-2.66(m, 3H), 1.42-1.30(m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.770 min, [M+H] + =914.8.

[0432] Example 32:

[0433]

[0434]

[0435] The general procedure for the synthesis of 4-amino-2-(4-tert-butylphenyl)-6-(difluoromethyl)pyrimidine-5-carboxynitrile was performed using the procedure from Chem. Eur. J. 2018, 24, 1311-1316.

[0436] Step 1: Under N2, at -30°C, a solution of boron trifluoride diethyl ether (2.68 mL, 21.71 mmol, 1.05 equivalents) in acetonitrile (19.2 mL) was stirred for 15 min. Acetonitrile (27 mL) containing 1,1,2,2-tetrafluoro-N,N-dimethylethylamine (3.0 g, 20.68 mmol, 1.0 equivalents) was added and the mixture was stirred for 5 min. The reactants were allowed to return to room temperature. Under an inert atmosphere at 25°C, a solution of malononitrile (1.37 g, 20.68 mmol, 1.0 equivalents) in anhydrous acetonitrile (19.2 mL) was added to the solution, followed by the rapid addition of N,N-diisopropylethylamine (5.4 mL, 31.01 mmol, 1.5 equivalents). The mixture was stirred for 2 hours. The reactants were quenched by adding silica gel. The solution was concentrated under reduced pressure to give a yellow solid residue, which was purified by column chromatography (silica gel, 100 to 200 mesh, 10 to 50% EtOAc in heptane) to give 2-[1-(dimethylamino)-2,2-difluoro-ethylidene]malononitrile (1.68 g, 9.816 mmol, 48% yield) as a yellow solid.

[0437] Step 2: 2-[1-(dimethylamino)-2,2-difluoro-ethylidene]malononitrile (150 mg, 0.8800 mmol, 1.0 equivalent) and (4-tert-butylbenzoimino)ammonium chloride (372.87 mg, 1.75 mmol, 2.0 equivalent) were dissolved in anhydrous ethanol (2.9214 mL, 0.3 M) and the solution was capped in a microwave-safe vial. The reaction mixture was heated to 70 °C and stirred for 30 min under microwave irradiation. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 50% EtOAc in heptane) to give 4-amino-2-(4-tert-butylphenyl)-6-(difluoromethyl)pyrimidin-5-carboxylonitrile (175 mg, 0.5789 mmol, 66% yield) as a white solid.

[0438] Step 3: Dissolve 160 mg (0.5300 mmol, 1.0 equivalent) of 4-amino-2-(4-tert-butylphenyl)-6-(difluoromethyl)pyrimidin-5-carboxynitrile in anhydrous EtOH (2.6 mL). Add 0.66 mL (2.65 mmol, 5.0 equivalent) of 4M potassium hydroxide aqueous solution and heat the reaction mixture to 70 °C for 18 h. Cool the reaction mixture to room temperature, add 1 N KHSO4 solution and dilute the reaction mixture with EtOAc (20 mL). Separate the phases and extract the aqueous layer with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-amino-2-(4-(tert-butyl)phenyl)-6-(difluoromethyl)pyrimidine-5-carboxylic acid (170 mg, 0.53 mmol, 99% crude yield) as a yellow solid, which was used without further purification.

[0439] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-(difluoromethyl)pyrimidine-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.25 (d, 5.6Hz, 1H), 8.85 (d, J = 8.1Hz, 1H), 8.32 (d, J = 7.6Hz, 1H), 8.21 (d, J = 8.6 Hz, 2H), 7.52 (d, J=8.7Hz, 2H), 7.19 (dd, J=8.6, 2.2Hz, 1H), 7.01 (d, J=8.6Hz, 1H), 6.83 (s, 1H), 6.73 (s, 1H), 6 .66-6.75(m, 2H), 6.26-6.33(m, 2H), 4.80(m, 1H), 4.73-4.60(m, 2H), 4.08-3.88(m, 6H), 3.28(d, J=15.1Hz, 1H ), 3.03-2.78 (m, 11H), 2.35 (s, 3H), 2.09-1.99 (m, 1H), 1.97-1.86 (m, 1H), 1.29 (s, 9H), 1.17 (d, J=6.7Hz, 3H). LCMS (Method 5-100AB, 6min): R T = 1.66 min, [M+H] + =979.3.

[0440] Example 33

[0441]

[0442] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(2-fluoro-4-(tert-pentyl)phenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.49 (s, 1H), 7.77-7.73 (m, 1H), 7.29-7.27 ( m, 1H), 7.20-7.05 (m, 3H), 6.86-6.77 (m, 2H), 6.61-6.48 (m, 2H), 5.30-5.20 (m, 1H), 4.36-4.14 (m, 8H), 3.63-3.60 (m, 1H), 3.40-3.36 (m, 1H), 3.21-3. 01 (m, 9H), 2.48 (s, 3H), 1.74-1.71 (m, 2H), 1.33 (s, 9H), 0.74-0.70 (m, 3H). LCMS (Method 5-95AB, ESI): R T = 0.752 min, [M+H] + =1040.5.

[0443] Example 34

[0444]

[0445] As described in Example 54, 2-(4-(cyclopropylmethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron was used. Substitution of 2-(3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) 4-amino-2-(4-(cyclopropylmethyl)phenyl)-6-methylpyrimidin-5-carboxylic acid was prepared using pyridine. The title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(cyclopropylmethyl)phenyl)-6-methylpyrimidin-5-carboxylic acid, as described in Example 1. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.18 (d, J = 7.6Hz, 2H), 7.34 (d, J = 8.0Hz, 2H), 7.12-7.04 (m, 1H), 6. 90-6.74(m, 3H), 6.59(s, 1H), 6.52-6.42(m, 1H), 5.22-5.13(m, 1H), 4.82-4.80(m, 2H), 4.27-3.91 (m, 6H), 3.63-3.54 (m, 1H), 3.25-3.14 (m, 3H), 3.06 (s, 3H), 3.03-2.95 (m, 2H), 2.59 (d, J = 6.8 Hz, 2H), 2.47 (s, 3H), 1.40-1.29 (m, 3H), 1.07-0.95 (s, 1H), 0.57-0.50 (m, 2H), 0.26-0.19 (m, 2H) ppm. LCMS (Method 5-95AB, ESI): R T = 0.750 min, [M+H] + =1006.3.

[0446] Example 35

[0447]

[0448] 2-Amino-6-(4-(tert-butyl)phenyl)-4-methylnicotinic acid was produced using a method similar to that described in WO2017084630, the contents of which are incorporated herein by reference in their entirety. As described in Example 1, the title compound was prepared in formate form by substituting 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.38 (s, 2H), 7.70-7.68 (m, 1H), 7.30-7.18 (m, 2H), 7.03-6.55 (m, 6H), 5 .21 (m, 1H), 4.39-3.99 (m, 8H), 3.62-3.38 (m, 3H), 3.18-2.86 (m, 9H), 2.32-2.28 (m, 3H), 1.35 (s, 12H). LCMS (Method 5-95AB, ESI): R T = 0.783 min, [M+H] + =1025.5.

[0449] Example 36

[0450]

[0451] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid with 4-amino-2-(4-butylphenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) 8.45 (s, 1H), 8.14 (d, J = 8.4Hz 1H), 7.28 (d, J = 8.4Hz 1H), 7.12-7.10(m, 1H), 6.91-6.86(m, 2H), 6.79(s, 1H), 6.59(s, 1H), 6.44(s, 1H), 5.19-5.16(m, 1H), 4.32-4.04(m , 7H), 3.64-3.59(m, 1H), 3.23-3.07(m, 10H), 2.69-2.65(m, 3H), 2.47(s, 3H), 1.38-1.35(m, 5H), 0.97-0.93(m, 3H). LCMS (Method 5-95AB, ESI): R T = 0.781 min, [M+H] + =1008.5.

[0452] Example 37

[0453]

[0454] The general procedure for the synthesis of methyl 6-(4-(tert-butyl)phenyl)-4-chloronicotinic acid was performed using the procedure from J.Med.Chem. 2013, 56, 1023-1040.

[0455] Step 1: Methyl 4,6-dichloropyridine-3-carboxylate (3072 mg, 14.91 mmol, 1.05 equivalents) and Pd(PPh3)4 (820 mg, 0.71 mmol, 0.05 mmol) were stirred in diethylene glycol dimethyl ether (13 mL) for 15 min at room temperature. IPA (15 mL) containing 4-tert-butylphenylboronic acid (2528 mg, 14.2 mmol, 1.0 equivalents) and 2.0 M K2CO3 aqueous solution (13.14 mL, 26.27 mmol, 1.85 equivalents) were then added to this suspension. The mixture was stirred at 95 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. A saturated aqueous solution of NaHCO3 and DCM were added to the crude reaction mixture. The phases were separated, the aqueous layer was extracted with additional DCM (2 × 40 mL), and the organic layers were combined. The organic layer was then washed with brine (2 × 30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The solid was then redissolved in DCM, and silica gel (20 g) was added. The mixture was then concentrated under reduced pressure to give a packet of dry yellow solid. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 30% EtOAc in heptane) to give methyl 6-(4-tert-butylphenyl)-4-chloropyridine-3-carboxylate (2950 mg, 9.711 mmol, 68.4% yield) as a clear oil.

[0456] Step 2: Methyl 6-(4-tert-butylphenyl)-4-chloropyridine-3-carboxylate (5000 mg, 16.46 mmol, 1.0 equivalent) was dissolved in DCM (54.8 mL), and 70 wt.% of 3-chloroperbenzoic acid (m-CPBA) (8521 mg, 24.69 mmol, 1.5 equivalent) was added. The reaction mixture was stirred at rt for 36 h. The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted with DCM (3 × 40 mL). The organic phases were combined, washed with water (1 × 40 mL) and brine (1 × 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 10 to 80% EtOAc in heptane) to give methyl 6-(4-tert-butylphenyl)-4-chloro-1-oxo-pyridine-3-carboxylate as a beige solid (3100 mg, 9.6942 mmol, 59% yield).

[0457] Step 3: Methyl 6-(4-tert-butylphenyl)-4-chloro-1-oxo-pyridin-1-onthium-3-carboxylate (3100 mg, 9.69 mmol, 1.0 equivalent) was dissolved in DMSO (19.4 mL) and sodium azide (1891 mg, 29.08 mmol, 3.0 equivalent) was added. The reaction mixture was stirred at 50 °C for 30 min. The reaction mixture was cooled to rt and poured into water, and extracted with EtOAc (3 × 40 mL). The organic phases were combined, washed with water (1×40 mL) and brine (1×40 mL), dried over anhydrous Na2SO4, filtered through a sintered funnel, and concentrated under reduced pressure to give methyl 4-azido-6-(4-tert-butylphenyl)-1-oxo-pyridin-1-onthium-3-carboxylate (2052 mg, 6.29 mmol, 64.9% yield) as a light orange solid, which was used in the next step without purification.

[0458] The general procedure for the synthesis of methyl 6-(4-(tert-butyl)phenyl)-4-chloronicotinic acid was performed using the procedure from Org. Lett. 2015, 17, 2948-2951.

[0459] Step 4: Add 4.7 mL of DCM containing methyl 4-azido-6-(4-tert-butylphenyl)-1-oxo-pyridin-1-onthium-3-carboxylate (500 mg, 1.53 mmol, 1.0 equivalent) to a flame-dried nitrogen-purged flask. Cool the reaction mixture to -70 °C and add Et3N (0.43 mL, 3.06 mmol, 2.0 equivalent), followed by oxaloyl chloride (0.26 mL, 3.06 mmol, 2.0 equivalent). Stir the reaction mixture from -70 °C to rt for 3 hours. Add a saturated aqueous solution of NaHCO3 and dilute the reaction mixture with EtOAc (30 mL). Separate the phases and extract the aqueous layer with more EtOAc (2 × 10 mL). Combine the organic layers, wash with brine (2 × 20 mL), dry to Na2SO4, filter through a sintered funnel, and concentrate under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 50% EtOAc in heptane) to give methyl 4-azido-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylate as a yellow solid (280 mg, 0.812 mmol, 53% yield).

[0460] Step 5: Triphenylphosphine (197.8 mg, 0.750 mmol, 1.0 equivalent) was added to a stirred solution of methyl 4-azido-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylate (260 mg, 0.750 mmol) in THF (7.54 mL). The reaction mixture was stirred at rest for 2 hours, followed by the addition of H₂O (2 mL). The reaction mixture was stirred at rest for 12 hours. A saturated aqueous solution of NaHCO₃ and EtOAc (20 mL) were added, and the phases were separated. The aqueous layer was extracted with more EtOAc (2 × 10 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 100% EtOAc in heptane) to give methyl 4-amino-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylate as a white powder (180 mg, 0.565 mmol, 74.9% yield).

[0461] Step 6: Methyl 4-amino-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylic acid (180 mg, 0.5600 mmol) was dissolved in THF (5.65 mL), and 1.0 M lithium hydroxide aqueous solution (0.62 mL, 0.620 mmol, 1.1 equivalent) was added. The reaction mixture was stirred at rt for 24 hours. 1 N KHSO4 (40 mL) and EtOAc (40 mL) were added, and the phases were separated. The aqueous layer was extracted with EtOAc (2 × 40 mL). The organic layers were combined, washed with brine (3 × 40 mL), dried over Na2SO4, filtered through a sintered funnel, and the filtrate was concentrated under reduced pressure to give 4-amino-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylic acid (180 mg, 0.5906 mmol, 104% yield) as a white solid, which was used in the next step without purification.

[0462] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylic acid. ¹H NMR (400 MHz, DMSO-d6+D₂O) δ 8.31 (s, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.08 (s, 1H), 7.09–7.04 (m, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.74–6.64 (m, 2H), 6.34 (s, 1H), 6.2 4(s, 1H), 4.94-4.85(m, 1H), 4.60-4.58(m, 1H), 4.18-3.87(m, 7H), 3.34-3.31(m, 1H), 3.2 7-3.19 (m, 1H), 3.17-3.09 (m, 1H), 3.05-2.76 (m, 8H), 1.27 (s, 9H), 1.16 (d, J=7.0Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 1.85 min, [M+H] + =1027.5.

[0463] Example 38

[0464]

[0465] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(1,1-difluoro-2-methylpropyl)phenyl)-6-methylpyrimidine-5-carboxylic acid. 1 HNMR (400MHz, MeOH-d4) δ (ppm) 8.42-8.34 (m, 3H), 7.61-7.49 (m, 2H), 7.21 -7.03(m, 1H), 6.97-6.72(m, 3H), 6.68-6.56(m, 1H), 6.47(s, 1H), 5.20-5. 10 (m, 1H), 4.84-4.73 (m, 2H), 4.41-4.00 (m, 6H), 3.75-3.32 (m, 3H), 3.27- 2.91 (m, 8H), 2.64-2.30 (m, 4H), 1.45-1.25 (m, 3H), 1.00 (d, J=6.8Hz, 6H). LCMS (Method 5-95AB, ESI): R T = 0.645 min, [M+H] + =1045.0.

[0466] Example 39

[0467]

[0468] I3 (84.7 mg, 0.33 mmol) was added to a solution of ethyl 2-(4-(tert-butyl)-2-formylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (140 mg, 0.30 mmol) in THF (2.00 mL) and NH3·H2O (4.00 mL, 0.30 mmol). The reaction mixture was stirred at 20 °C for 2 h. The solution was concentrated to dryness. The residue was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was washed with a saturated solution of Na2S2O3 (2 × 30 mL) and brine (30 mL). The organic phase was dried over Na2SO4 and concentrated to dryness. The residue was purified by preparative TLC (ethyl acetate:petroleum ether = 1:10) to give ethyl 2-(4-(tert-butyl)-2-cyanophenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidine-5-carboxylate (135 mg, 97.1% yield) as a yellow solid.

[0469] CAN (646 mg, 1.18 mmol) was added to a solution of ethyl 2-(4-(tert-butyl)-2-cyanophenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (135 mg, 0.29 mmol) in acetonitrile (6.0 mL) and water (3.0 mL). The reaction mixture was stirred at 20 °C for 30 min. The reaction mixture was partitioned between ethyl acetate (40.0 mL) and water (40.0 mL). The organic phase was washed with brine (2 × 40 mL), dried over Na₂SO₄, and concentrated to dryness. The residue was purified by preparative TLC (ethyl acetate:petroleum ether = 2:10) to give ethyl 4-amino-2-(4-(tert-butyl)-2-cyanophenyl)-6-methylpyrimidin-5-carboxylate (80.0 mg, 80.3% yield) as a yellow solid.

[0470] Step 3: LiOH·H₂O (24.4 mg, 0.58 mmol) was added to a solution of ethyl 4-amino-2-(4-(tert-butyl)-2-cyanophenyl)-6-methylpyrimidin-5-carboxylic acid (80.0 mg, 0.23 mmol) in THF (6.0 mL) and water (2.0 mL). The reaction mixture was stirred at 80 °C for 1 h. The mixture was concentrated to remove methanol, and then water (20 mL) was added to the reaction mixture. The pH of the mixture was adjusted to 2 with 1 M HCl. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were concentrated to dryness to give 4-amino-2-(4-(tert-butyl)-2-cyanophenyl)-6-methylpyrimidin-5-carboxylic acid (50 mg, 69.2% yield) as a white solid.

[0471] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidin-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-cyanophenyl)-6-methylpyrimidin-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) 8.53 (s, 1H), 8.15-8.13 (m, 1H), 7.85-7.75 (m, 2H), 7.07 (br, 1H), 7.00-6.84 (m, 2H), 8.60 (s, 1H ), 8.48 (s, 1H), 5.20 (s, 1H), 4.38-4.01 (m, 5H), 3.63-3.60 (m, 1H), 3.38-2.94 (m, 5H), 2.50-2.45 (m, 3H), 1.38 (s, 12H). LCMS (Method 5-100AB, 1.5min): R T = 0.633 min, [M+H] + =1033.7.

[0472] Example 40

[0473]

[0474] Step 1: Methyl 2-amino-4,6-dichloropyridine-3-carboxylate (745 mg, 3.37 mmol), Pd(PPh3)4 (162 mg, 0.140 mmol), K3PO4 (894 mg, 4.21 mmol), and H2O (3 mL) were added to a mixture of 4-tert-butylphenylboronic acid (500 mg, 2.81 mmol) and 1,4-dioxane (25 mL). The reaction mixture was degassed with N2 gas and then stirred at 60 °C for 18 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (25 mL) and then extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 100% EtOAc in heptane) to give methyl 2-amino-6-(4-tert-butylphenyl)-4-chloro-pyridine-3-carboxylate (565 mg, 1.77 mmol) as a yellow solid.

[0475] Step 2: Add 1M LiOH aqueous solution (4.26 mL, 4.26 mmol) to a mixture of methyl 2-amino-6-(4-tert-butylphenyl)-4-chloropyridine-3-carboxylic acid (679 mg, 2.13 mmol) in 1,4-dioxane (5.6 mL). Stir the reaction mixture at 60 °C for 15 h, then cool to room temperature. Add diethyl ether and collect the precipitate by filtration to give 2-amino-6-(4-tert-butylphenyl)-4-chloropyridine-3-carboxylic acid (502 mg, 77.3% yield) as a pale yellow solid.

[0476] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-4-chloropyridine-3-carboxylic acid with 2-amino-6-(4-tert-butylphenyl)-4-chloropyridine-3-carboxylic acid. 1H NMR (400MHz, DMSO+D2O) δ8.35 (s, 2H), 7.93 (d, J=8.5Hz, 2H), 7.48 (d, J=8.6Hz, 2H), 7. 19 (s, 1H), 7.07 (d, J=9.7Hz, 1H), 6.89 (d, J=8.6Hz, 1H), 6.75 (s, 1H), 6.71 (s, 1H), 6.3 7(s, 1H), 6.27(s, 1H), 4.94-4.87(m, 1H), 4.67-4.58(m, 1H), 4.17-4.10(m, 1H), 4.08- 3.90 (m, 6H), 3.41-3.09 (m, 4H), 3.07-2.76 (m, 7H), 1.29 (s, 9H), 1.17 (d, J=6.7Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 1.97 min, [M+H] + =1027.5.

[0477] Example 41

[0478]

[0479] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid with 4-amino-2-(4-cyclobutylphenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) 8.48 (s, 1H), 8.15 (d, J=8.0Hz 2H), 7.35 (d, J=8.0Hz 2H), 7.18-7.16(m, 1H), 6.97-6.95(m, 2H), 6.89(s, 1H), 6.82(s, 1H), 6.61(s, 1H ), 6.43 (s, 1H), 5.23-5.19 (m, 1H), 4.47-4.44 (m, 2H), 4.33-4.08 (m, 6H), 3.67-3. 59 (m, 2H), 3.42–3.36 (m, 1H), 3.29–3.16 (m, 4H), 3.09–3.04 (m, 5H), 2.50 (s, 3H), 2.40–2.38 (m, 2H), 2.21–2.08 (m, 3H), 1.94–1.89 (m, 1H), 1.39 (d, J = 7.2 Hz, 3H). LCMS (Method 5-95AB, ESI): R T = 0.737 min, [M+H] + =1006.6.

[0480] Example 42

[0481]

[0482] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-6-methyl-2-(4-neopentylphenyl)pyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.40 (br s, 1H), 8.15 (d, J=8.0Hz, 2H), 7.24 (d, J=8.0Hz, 2H), 7.15-7.06 (m, 1H), 6.85-6.78 (m, 3H), 6.60 (br, s, 1H), 6.48 (s, 1H), 5.18 (s, 1 H), 4.50-4.22(m, 6H), 4.22-4.01(m, 6H), 3.62-3.34(m, 2H), 3.24-2.99(m, 8H), 2.58-2.34(m, 5H), 1.38-1.35(m, 3H), 0.94(s, 9H). LCMS (Method 5-95AB, ESI): R T = 0.798 min, [M+H] + =1022.3.

[0483] Example 43

[0484]

[0485] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-hydroxyphenyl)-6-methylpyrimidine-5-carboxylic acid. 1H NMR (400MHz, DMSO) δ8.87 (d, J=8.1Hz, 1H), 8.33 (d, J=7.8Hz, 1H), 8.17 (d, J=8.4Hz, 1H), 7.21 (d, J=8.7Hz, 1H ), 7.02 (d, J=8.6Hz, 1H), 6.97 (dd, J=8.5, 1.9Hz, 1H), 6.87 (d, J=1.9Hz, 1H), 6.75 (s, 1H), 6.69 (d, J=1.5Hz, 1 H), 6.33 (s, 1H), 6.30 (s, 1H), 4.84 (dd, J=9.6, 4.1Hz, 1H), 4.74-4.63 (m, 2H), 4.11-3.90 (m, 6H), 3.34-3.25 ( m, 1H), 3.12-2.79 (m, 10H), 2.37 (s, 3H), 2.36 (s, 15H), 2.10-1.89 (m, 2H), 1.27 (s, 9H), 1.18 (d, J=6.7Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 1.64 min, [M+H] + =959.7.

[0486] Example 44

[0487]

[0488] As described in Example 54, 2-(2-(benzooxy)-4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron was used. Substitution of 2-(3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) 4-amino-2-(4-(tert-butyl)-2-hydroxyphenyl)-6-methylpyrimidin-5-carboxylic acid was prepared by substituting 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-hydroxyphenyl)-6-methylpyrimidin-5-carboxylic acid. The title compound was prepared by substituting 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-hydroxyphenyl)-6-methylpyrimidin-5-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.45 (s, 1H), 8.29-8.19 (m, 1H), 7.11-7.00 ( m, 1H), 6.99-6.71 (m, 5H), 6.66-6.56 (m, 1H), 6.50 (s, 1H), 5.23-5.09 (m, 1H ), 4.83-4.52(m, 1H), 4.41(s, 1H), 4.31-3.94(m, 6H), 3.66-3.54(m, 1H), 3. 42-3.34 (m, 1H), 3.29-2.93 (m, 9H), 2.51-2.36 (m, 3H), 1.40-1.27 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.791 min, [M+H] + =1024.9.

[0489] Example 45

[0490]

[0491] Step 1: Pyridine (981 μL, 12.18 mmol, 2.0 equivalent) was added to a stirred, ice-cold DCM (50 mL) solution of 4-(1,1-dimethylpropyl)phenol (1.00 g, 6.09 mmol, 1.0 equivalent) under nitrogen atmosphere, followed by dropwise addition of trifluoromethanesulfonic anhydride (1.23 mL, 7.31 mmol, 1.2 equivalent). The mixture was stirred at 0 °C for 30 min, then allowed to warm to room temperature. The reactants were washed with 1.0 M KHSO4 aqueous solution (30 mL), followed by saturated NaHCO3 aqueous solution (2 × 30 mL) and saturated brine aqueous solution (30 mL). The solution was dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 100% EtOAc in heptane) to give [4-(1,1-dimethylpropyl)phenyl]trifluoromethane sulfonate (1800 mg, 6.075 mmol, 99.7% yield) as a clear oil.

[0492] Step 2: Bis(pinacolyl)diboron (377 mg, 1.48 mmol, 1.1 equivalence) was added to a stirred solution of [4-(1,1-dimethylpropyl)phenyl]trifluoromethanesulfonate (400 mg, 1.35 mmol, 1.0 equivalence) in anhydrous DMSO (6 mL), followed by the addition of KOAc (132 mg, 1.35 mmol, 1.0 equivalence). The mixture was stirred and purged with argon for 1 hour. Subsequently, PdCl2(dPPf)·CH2Cl2 (49 mg, 0.067 mmol, 0.05 equivalence) was added and argon purging continued for 15 min. The mixture was kept under argon and heated to 80 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (75 mL), and washed with water (50 mL) and saturated brine (4 × 25 mL). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 100% EtOAc in heptane) to give 2-[4-(1,1-dimethylpropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboron as a white solid. (310 mg, 1.13 mmol, 83.7% yield).

[0493] Step 3: Add 2-[4-(1,1-dimethylpropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboron to the flame-dried nitrogen-purging vial. (336 mg, 1.23 mmol, 1.3 equivalents), K₂CO₃ (261 mg, 1.88 mmol, 2.0 equivalents), methyl 4-amino-2-chloro-6-methylpyrimidine-5-carboxylate (190 mg, 0.9400 mmol, 1.0 equivalents), and PdCl₂·(dppf)CH₂Cl₂ (77 mg, 0.0900 mmol, 0.1 equivalents). The solids were suspended in a mixture of 1,4-dioxane (2.36 mL) and water (0.24 mL) and degassed with nitrogen for 5 min. The vials were sealed and heated to 100 °C for 2 h. The reaction mixture was cooled to rt and saturated aqueous solution of NaHCO₃ and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 10 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 60% EtOAc in heptane) to give methyl 4-amino-2-[4-(1,1-dimethylpropyl)phenyl]-6-methylpyrimidin-5-carboxylate as a white solid (80 mg, 0.255 mmol, 27% yield).

[0494] Step 4: Add methyl 4-amino-6-chloro-2-[4-(1,1-dimethylpropyl)phenyl]pyrimidinyl-5-carboxylate (70 mg, 0.21 mmol, 1.0 equivalent), THF (2.1 mL), and 1.0 M aqueous lithium hydroxide solution (0.23 mL, 0.2300 mmol, 1.1 equivalent) to a scintillation flask equipped with a magnetic stir bar. Stir the reaction mixture at rt for 12 hours. Concentrate the reaction mixture under reduced pressure to give lithium 4-amino-6-chloro-2-[4-(1,1-dimethylpropyl)phenyl]pyrimidinyl-5-carboxylate (67 mg, 0.2095 mmol, 99.9% yield) as a bright yellow solid, which was used directly without purification.

[0495] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with lithium 4-amino-6-chloro-2-[4-(1,1-dimethylpropyl)phenyl]pyrimidine-5-carboxylate. 1 H NMR (400MHz, DMSO-d6+D2O) δ8.11 (d, J=7.9Hz, 2H), 7.51 (d, J=8.0Hz, 2H), 7.19 (d, J=10.0Hz, 1H), 6. 99(d, J=8.8Hz, 1H), 6.70(s, 2H), 6.28(s, 1H), 6.20(s, 1H), 5.00-4.88(m, 1H), 4.73-4.55(m, 2H), 4. 11-3.90(m, 6H), 3.37-3.23(m, 2H), 3.16-2.90(m, 4H), 2.91-2.75(m, 4H), 2.67-2.62(m, 1H), 2.42(s , 3H), 2.36 (s, 12H), 1.63 (q, J=7.9Hz, 2H), 1.25 (s, 6H), 1.16 (d, J=6.7Hz, 3H), 0.60 (t, J=7.4Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 1.83 min, [M+H] + =1022.7.

[0496] Example 46

[0497]

[0498] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)pyrimidine-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1H NMR (400MHz, MeOH-d4) 8.81-8.72 (m, 1H), 8.47 (s, 1H), 8.17 (d, J = 6.8Hz, 2H), 7.47 (d, J = 6.8Hz, 2H), 7.06 (s, 1H), 6.78-6.67 (m, 2H), 6.48-6.40 (m, 2H), 4.77-3.48 (m, 12H), 3.13-2.69 (m, 6H), 1.49-1.22 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.778 min, [M+H] + =994.4.

[0499] Example 47

[0500]

[0501] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(1,1-dimethylindan-5-yl)-6-methylpyrimidine-5-carboxylic acid. 1 HNMR (400MHz, DMSO+D2O) δ8.32 (s, 3H), 8.07-8.05 (m, 2H), 7.22 (d, J=8.8Hz, 1H), 7.08 (d, J=9.6 Hz, 1H), 6.89 (d, J=8.5Hz, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 6.37 (s, 1H), 6.24 (s, 1H), 4.85-4.79 ( m, 1H), 4.62-4.55 (m, 1H), 4.11-4.06 (m, 1H), 4.06-3.96 (m, 4H), 3.95-3.91 (m, 2H), 3.26-3.19 ( m, 1H), 3.02-2.80 (m, 12H), 2.32 (s, 3H), 2.09-1.83 (m, 4H), 1.20 (s, 6H), 1.16 (d, J=7.0Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 1.59 min, [M+H] + =962.5.

[0502] Example 48

[0503]

[0504]

[0505] Pyridine (0.39 mL, 4.87 mmol) and Tf₂O (0.61 mL, 3.65 mmol) were added to a mixture of 4-(tert-butyl)-2-methylphenol (400 mg, 2.44 mmol) and dichloromethane (5.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with dichloromethane (30 mL). The organic layer was washed with 1 M HCl (10 mL), saturated NaHCO₃ (20 mL), and brine (2 × 50 mL). The organic layer was dried over Na₂SO₄ and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give 4-(tert-butyl)-2-methylphenyl trifluoromethanesulfonic acid (710 mg, 98.4% yield) as a colorless oil.

[0506] A mixture of 4-(tert-butyl)-2-methylphenyl trifluoromethanesulfonic acid (710.0 mg, 2.4 mmol), potassium acetate (705 mg, 7.19 mmol), Pd(dppf)Cl3 (178 mg, 0.24 mmol), and bis(pinacolyl)diboron (791 mg, 3.11 mmol) in DMF (10.0 mL) was stirred for 16 h at 80 °C under nitrogen. The mixture was diluted with ethyl acetate (80 mL), filtered, and the filtrate was washed with brine (3 × 80 mL). The organic layer was concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give 2-(4-(tert-butyl)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron as a white solid. (530 mg, 80.7% yield).

[0507] 2-(4-(tert-butyl)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron Ethyl 2-chloro-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (530 mg, 1.93 mmol), Pd(dppf)Cl2 (70.7 mg, 0.10 mmol), and Na2CO3 (615 mg, 5.80 mmol) were suspended in 1,4-dioxane (6.0 mL) and water (0.60 mL), purged with N2 (15 psi), and heated at 100 °C for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL). The reaction mixture was washed with brine (2 × 20 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give ethyl 2-(4-(tert-butyl)-2-methylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidine-5-carboxylate (500 mg, 57.8% yield) as a colorless oil.

[0508] Step 4: A solution of ethyl 2-(4-(tert-butyl)-2-methylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (200 mg, 0.45 mmol), (diacetoxyiodo)benzene (216 mg, 0.67 mmol), Cu(OTFA)₂ (12.9 mg, 0.04 mmol), and Pd(OAc)₂ (5.02 mg, 0.02 mmol) in acetic acid (0.30 mL) and acetic anhydride (4.50 mL) was stirred in air at 80 °C for 24 h. The solvent was removed under vacuum. The residue was diluted with a saturated solution of NaHCO₃ (15.0 mL) and extracted with ethyl acetate (3 × 30 mL). All organic layers were combined, washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 20% ethyl acetate in petroleum) to give ethyl 2-(2-acetoxy-4-(tert-butyl)-6-methylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidine-5-carboxylate (110 mg, 48.7% yield) as a pale yellow oil.

[0509] Step 5: The solution of ethyl 2-(2-acetoxy-4-(tert-butyl)-6-methylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (110 mg, 0.22 mmol) in trifluoroacetic acid (3.0 mL, 0.22 mmol) was stirred at 75 °C for 16 h. The mixture was concentrated to dryness and purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 20% ethyl acetate in petroleum ether) to give ethyl 4-amino-2-(4-(tert-butyl)-2-hydroxy-6-methylphenyl)-6-methylpyrimidin-5-carboxylate (74.0 mg, 99% yield) as a white solid.

[0510] Step 6: Add 1.00 mL of water containing NaOH (34.5 mg, 0.86 mmol) to a solution of ethyl 4-amino-2-(4-(tert-butyl)-2-hydroxy-6-methylphenyl)-6-methylpyrimidin-5-carboxylic acid (74.0 mg, 0.22 mmol) in methanol (5.00 mL). Stir the reaction mixture at 80 °C for 1 h. Concentrate the mixture to dryness and dilute with water (30 mL). Adjust the pH of the mixture to 5 with 1 M HCl and extract the aqueous layer with ethyl acetate (2 × 60 mL). Dry the combined organic layers over Na₂SO₄ and concentrate under vacuum to give 65.0 mg, 95.7% yield, of 4-amino-2-(4-(tert-butyl)-2-hydroxy-6-methylphenyl)-6-methylpyrimidin-5-carboxylic acid as a white solid.

[0511] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-hydroxy-6-methylphenyl)-6-methylpyrimidine-5-carboxylic acid. 1 HNMR (400MHz, MeOH-d4) 8.46 (s, 1H), 7.10-7.00 (m, 1H), 6.87-6.76 (m, 5H), 6.61 (s, 1H), 6.47 (s, 1H), 5.19-5.16 (m, 1H), 4.37-3.90 (m, 8H), 3.63-3.58 (m, 3H), 3.19-2.99 (m, 10H), 2.51 (s, 3H), 2.46 (s, 3H), 1.35 (d, J=6.8Hz, 3H), 1.30 (s, 9H). LCMS (Method 5-95AB, ESI): R T = 0.670 min, [M+H] + =1009.6.

[0512] Example 49

[0513]

[0514] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-4-methylnicotinic acid with 2-amino-6-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, DMSO+D2O) δ8.93 (d, J=9.3Hz, 1H), 8.37 (d, J=9.2Hz, 1H), 7.81 (d, J=8.5Hz , 2H), 7.60 (d, J=8.5Hz, 2H), 7.24-7.15 (m, 2H), 7.02 (d, J=8.9Hz, 1H), 6.76-6.65 (m, 2H ), 6.31 (s, 1H), 6.23 (s, 1H), 5.02-4.92 (m, 1H), 4.77-4.60 (m, 2H), 4.14-3.86 (m, 6H), 3.42-3.23 (m, 2H), 3.18-2.76 (m, 9H), 2.37 (s, 12H), 1.31 (s, 9H), 1.17 (d, J = 6.7 Hz, 3H). LCMS (Method 5-100AB, 7 min): R T = 1.77 min, [M+H] + =1007.5.

[0515] General Program C:

[0516]

[0517] Step 1: Under an inert atmosphere, at 25°C, (5S)-5-[(3-nitrophenyl)sulfonyloxymethyl]-2-oxo-oxazolidine-3-carboxylic acid tert-butyl ester (1.36 g, 3.38 mmol) (synthesized as in General Procedure A) in DMF (12 mL) was added to a solution of compound 5 (2.0 g, 2.5 mmol) (as in General Procedure D, starting with (S)-3-amino-1,2-propanediol) and potassium carbonate (1.04 g, 7.52 mmol). The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was then added dropwise to a saturated aqueous solution of water / NaHCO3 (1:1) with stirring. A beige solid precipitate formed and was recovered by filtration. The solid was purified by column chromatography (silica gel, 100 to 200 mesh, 25 to 100% EtOAc in a (1:1) DCM / heptane mixture) to give compound 6 as a white solid (1.99 g, 79.6% yield).

[0518] Step 2: Compound 6 (1.99 g, 2 mmol) was dissolved in methanol (12.7 mL), and the reaction flask was purged with nitrogen before adding the catalyst 10 wt.% palladium / carbon (159 mg, 0.15 mmol). The reaction mixture was purged with hydrogen and stirred at 25 °C for 3 h at 1 atm hydrogen. The reaction flask was purged with nitrogen for 15 min by bubbling into the solution before adding Cbz-O-succinimide (0.5 g, 2 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (2 × 100 mL) and brine (2 × 100 mL), dried over Na₂SO₄, and concentrated to dryness to give compound 7 (1.81 g, 99.8% yield) as a grayish-white solid.

[0519] Step 4: Add p-toluenesulfonic acid (29 mg, 0.155 mmol) to a solution of compound 8 (1.72 g, 1.55 mmol) in methanol (17 mL). Stir the reaction mixture at 25 °C for 16 h. Add the reaction mixture dropwise to a saturated aqueous solution of water / NaHCO3 (1:1) with stirring. A beige solid precipitate forms and is recovered by filtration. Dissolve the solid in DCM, dry with Na2SO4, filter, and concentrate under reduced pressure to give crude compound 9 (1.52 g, 100% yield) as a grayish-white solid.

[0520] Step 5: The solution of compound 9 (1.52 g, 1.55 mmol) in DMF (15 mL) and methanol (0.565 mL) was cooled to -15 °C under an inert atmosphere (N2). Cesium carbonate (1.07 g, 3.28 mmol) was added to the low-temperature solution, and the reaction mixture was stirred at -20 to -15 °C for 6 h. The filtrate was concentrated to obtain crude compound 6 (35.0 g, 97.4% yield) as a white solid. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) at -15 °C. The phases were separated and the organic phase was washed with water (2 × 30 mL) and brine (2 × 30 mL), then dried over Na2SO4 and concentrated under reduced pressure. The solid was purified by column chromatography (silica gel, 100 to 200 mesh, 2 to 10% MeOH in DCM) to give compound 10 (1.07 g, 75% yield) as a white solid.

[0521] General Program D:

[0522]

[0523] Step 1: Add (R)-3-amino-1,2-propanediol (107 mL, 1.38 mol) to a 5 L flask, along with 10 volumes of THF (1260 mL) and water (1260 mL). Stir the reaction mixture at room temperature until completely dissolved (20 min). Then, cool the solution to 0 °C and add potassium carbonate (229.4 g, 1.66 mol). Finally, add benzoyl chloroformate (237 mL, 1.66 mol) dropwise to the reaction mixture using a feeding funnel, while maintaining the internal temperature below 8 °C (over a 60 min period). After the reaction is complete (2 h), separate the layers. Concentrate the organic layer under reduced pressure (half pressure) while extracting the aqueous phase three times with EtOAc (3 × 1260 mL). Combine all organic compounds, wash with brine, dry with anhydrous sodium sulfate, filter, and concentrate to 2 to 3 volumes. Heptane (1260 mL) was added to the residue and stirred at 10°C to 20°C for 2 to 3 hours. The resulting white solid was filtered and washed with heptane. The solid was transferred to a flask and dried under high vacuum to give compound 2 as a white solid (325 g, 104% yield).

[0524] Compound 2 (175 g, 779 mmol) was dissolved in THF (2631 mL) in a 3-necked 5 L round-bottom flask equipped with a thermometer. The solution was cooled to 0 °C and potassium tert-butoxide (96.13 g, 857 mmol) was added in portions while maintaining the temperature between 0 and 10 °C. Once the reagent addition was complete, the reaction mixture was heated to 25 °C and stirred for 3 h. After completion, the reaction mixture was cooled again in an ice bath to maintain an internal temperature of approximately 10 °C, while dioxane containing 4 M HCl was added to the reaction mixture until the pH reached 5 to 6. The reaction mixture was then stirred at 25 °C for 30 min. The precipitate was filtered and washed twice with MeCN (700 mL). The wet filter cake was placed in a 2 L Erlenmeyer flask and stirred with 1.5 L MeCN for 30 min. The solid was filtered again and washed twice with MeCN (700 mL). All organic phases were combined and concentrated under reduced pressure to a concentration of 2 to 3 V at below 45 °C. MTBE (1.5 L) was added to the resulting suspension, and the suspension was concentrated again under reduced pressure until it reached 2 to 3 V at below 45 °C. 1 to 1.5 L of MTBE was added to the suspension, and it was stirred at room temperature for 30 minutes. The solid was then collected by filtration and washed with MTBE (1 L). The solid was dried under vacuum to give compound 3 (85.5 g, 93.8% yield) as a grayish-white solid.

[0525] Compound 3 (75 g, 640 mmol) was transferred to a 2 L round-bottom flask and 6 V MeCN (450 mL) was added, followed by pyridine (155 mL, 1.92 mol). The resulting solution was cooled to 0 °C. Subsequently, 149 g, 673 mmol, 3-nitrobenzenesulfonyl chloride was added in portions while maintaining the temperature at 10 °C. The reaction mixture was stirred at 0 °C for 2 h. After completion, the reaction mixture was concentrated to 2 to 3 V under reduced pressure. MTBE (10 V, 750 mL) was then added to the flask, and the resulting mixture was concentrated to 2 to 3 V under reduced pressure. 1.5 L of saturated NaHCO3 solution (20 V) was added. The mixture was stirred vigorously at 10 to 20 °C for 30 min. The resulting mixture was filtered and washed twice with water (1000 mL × 2). The wet filter cake was collected and transferred to a round-bottom flask. 1.5 L of saturated NaHCO3 solution (20 V) was added. The mixture was stirred vigorously at 10 to 20 °C for 30 min. The resulting mixture was filtered and washed twice with water (1000 mL × 2). The wet filter cake was collected and placed in a round-bottom flask. Water (10V, 750 mL) and MTBE (5V, 375 mL) were added, and the resulting two-phase suspension was stirred vigorously for 30 minutes. The solid was filtered and washed twice with MTBE (400 mL × 2). The filter cake was dried under high vacuum to give compound 4 as a grayish-white solid (178 g, 92% yield).

[0526] Compound 4 (182.7 g, 604 mmol) was added to a 5 L round-bottom flask containing 4-dimethylaminopyridine (7.38 g, 60.4 mmol) and MeCN (1.1 L) was added. The reaction mixture was cooled to 0 °C and di-tert-butyl dicarbonate (237.5 g, 1.1 mol) was added, maintaining the reaction temperature at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure. MeOH (500 mL) was added to the mixture and concentrated under reduced pressure to a thick orange gel. 700 mL of MeOH was added to the mixture. The reaction flask was placed under sonication for 3 min. A white precipitate formed and was stirred at room temperature for 30 min. The solid was recovered by filtration and washed with low-temperature MeOH to give compound 5 (191.4 g, 78.7% yield) as a white solid. 98.95%ee.1H NMR (400MHz, CDCl3) δ8.77 (t, J=1.9Hz, 1H), 8.56 (ddd, J=8.3, 2.2, 1.0Hz, 1H), 8.25 (ddd, J=7.9, 1.7, 1.1Hz, 1H), 7.85 (t, J=8.0Hz, 1H), 4.75-4 .67 (m, 1H), 4.36 (dd, J=11.5, 3.5Hz, 1H), 4.30 (dd, J=11.5, 4.2Hz, 1H), 4.05 (dd, J=10.6, 9.2Hz, 1H), 3.82 (dd, J=10.6, 6.2Hz, 1H), 1.53 (s, 9H).

[0527] Example 50

[0528]

[0529] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidin-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid and by replacing compound 14 with compound 10 as described in Procedure C. 1H NMR (400MHz, DMSO-d6+D2O) δ (ppm) δ9.28 (d, J=3.9Hz, 1H), 8.91 (d, J=6.7Hz, 1H), 8.31 (d, J=5.0Hz, 1H), 8.06 (d, J=7. 9Hz, 2H), 7.63 (d, J=8.2Hz, 2H), 7.19 (d, J=7.8Hz, 1H), 7.00 (d, J=8.7Hz, 1H), 6.69 (d, J=6.2Hz, 2H), 6.28 (s, 1H), 6.17 (s, 1H), 5.06-4.93 (m, 1H), 4.73-4.59 (m, 2H), 4.17-3.94 (m, 8H), 3.41-3.33 (m, 1H), 3.32-3.22 (m, 1H), 3.17-3.06 (m, 1H), 3.05-2.95 (m, 2H), 2.92-2.76 (m, 1H), 2.85 (s, 3H), 2.42 (s, 3H), 2.39 (s, 9H), 1.29 (s, 9H), 1.16 (d, J=6.4Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 1.62 min, [M+H] + =1008.5.

[0530] Example 51

[0531]

[0532] Using the procedure of Example 1, the title compound was prepared from compound 20 by replacing 1-(4-(tert-butyl)phenyl)-2-chloro-pyridine-3-carboxylic acid with 4-amino-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylic acid as described in Example 37. 1 H NMR (400MHz, DMSO-d6+D2O) δ8.34 (s, 3H), 7.80 (d, J = 8.5Hz, 2H), 7.48 (d, J = 8.6Hz, 2H), 7.09 (s, 1H), 7.06 (d, J=8.8Hz, 1H), 6.87 (d, J=8.6Hz, 1H), 6.74 (s, 1H), 6.67 (s, 1H), 6. 37(s, 1H), 6.24(s, 1H), 4.86-4.80(m, 1H), 4.65-4.55(m, 1H), 4.13-3.94(m, 7H), 3.26- 3.21 (m, 1H), 3.09-2.76 (m, 10H), 2.03-1.92 (m, 2H), 1.28 (s, 9H), 1.15 (d, J=6.7Hz, 3H). LCMS (Method 5-100AB, 7min): RT = 1.59 min, [M+H] + =962.5.

[0533] Example 52

[0534]

[0535]

[0536] Step 1: In a three-necked RB flask, TiCl4 (14.3 mL, 127 mmol) was added to DCM (45.0 mL), and the temperature was maintained at -78 °C under a nitrogen atmosphere. Then, toluene (127 mL, 127 mmol) containing 1 M Zn(CH3)2 was added, while maintaining the same temperature. The resulting orange-brown solution was stirred vigorously at -78 °C for one hour. A solution of 5-bromo-2,3-dihydro-1H-inden-1-one (4.50 g, 21.3 mmol) in DCM (45.0 mL) was added dropwise to the above mixture. The reaction solution was stirred at -78 °C for 2 h, then heated to -10 °C and stirred for 16 h. The reaction mixture was quenched dropwise by adding a saturated solution of ice-cold NH4Cl. The organic matter was separated, and the aqueous layer was extracted with ethyl acetate (3 × 100 mL) and washed with brine (3 × 100 mL). The organic phases were combined and dried over Na2SO4, then concentrated to dryness. The crude material was then purified by rapid column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give 5-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (4.80 g, 99.8% yield) as a yellow oil.

[0537] Step 2: Under N2, at 80 °C, a mixture of 5-bromo-1,1-dimethyl-2,3-dihydro-1H-indene (5.7 g, 25.3 mmol), Pd(dppf)Cl2 (926 mg, 1.27 mmol), KOAc (7.45 g, 75.9 mmol), and pinacol diborate (9.64 g, 37.9 mmol) in DMF (57.0 mL) was stirred for 3 h. The solvent was removed, and the residue was purified by rapid column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give a white solid 2-(1,1-dimethyl-2,3-dihydro-1H-indene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron. (6.5g, 94.3% yield).

[0538] Step 3: Add 2-(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron A mixture of ethyl 2-chloro-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (1.95 g, 7.15 mmol), Pd(dppf)Cl2 (0.22 g, 0.30 mmol), and Na2CO3 (1.89 g, 17.8 mmol) in water (2.00 mL) and 1,4-dioxane (40.0 mL) was purged with N2 (15 psi) and heated at 100 °C for 16 h. After filtration, 50.0 mL of ethyl acetate was added to the mixture. The mixture was washed with brine (2 × 50.0 mL). The organic layers were combined and dried over Na2SO4 and concentrated to dryness. The crude material was purified by column chromatography (silica gel, 100 to 200 mesh, 0% to 5% ethyl acetate in petroleum) to give ethyl 2-(6-acetoxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl))-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (2.50 g, 94.2% yield) as a colorless oil.

[0539] Step 4: 2-(6-acetoxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylic acid ethyl ester (1.00 g, 2.24 mmol), PhI(OAc)2 (1.08 g, 3.37 mmol), Cu(OTFA)2 (64.9 mg, 0.22 mmol), and Pd(OAc)2 (25.1 mg, 0.11 mmol) were stirred in a solution of HOAc (1.00 mL) and Ac2O (15 mL) for 16 h at 80 °C. The solvent was removed under vacuum. The residue was diluted with a saturated solution of NaHCO3 (30.0 mL), extracted with ethyl acetate (3 × 100 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The predetermined crude product was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give 5-(5-(ethoxycarbonyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-1,1-dimethyl-2,3-dihydro-1H-indene-4,6-diacetate diester (300 mg, 0.5957 mmol, 26.5% yield) and 2-(6-acetoxy) [unclear text - likely a typo]. Ethyl 2-(4-acetoxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (300 mg, 0.5957 mmol, 26.5% yield) and ethyl 2-(4-acetoxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (330 mg).

[0540] Step 5: The solution of 5-(5-ethoxycarbonyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-2-yl)-1,1-dimethyl-2,3-dihydro-1H-indene-4,6-diacetic acid diester (330 mg, 0.590 mmol) in TFA (5.00 mL) was stirred at 75 °C for 16 h. The mixture was concentrated. Ethyl acetate (40 mL) was added. The organic layer was washed with NaHCO3 (aqueous solution, 30.0 mL) and brine (30.0 mL), dried over Na2SO4, and concentrated. The crude material was purified by column chromatography (16% ethyl acetate in petroleum ether) to obtain ethyl 4-amino-2-(4,6-dihydroxy-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl)-6-methylpyrimidin-5-carboxylate (160 mg, 76.2% yield) as a yellow solid.

[0541] Step 6: Add NaOH (71.6 mg, 1.79 mmol) to a solution of ethyl 4-amino-2-(4,6-dihydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methylpyrimidin-5-carboxylate (160 mg, 0.450 mmol) in MeOH (5.00 mL) and water (1.00 mL). Stir the reaction mixture at 80 °C for 3 h. Adjust the pH of the mixture to 2 with 1 M HCl (aqueous solution). Partition the mixture into ethyl acetate (50.0 mL) and water (30.0 mL). Wash the organic layer with brine (40.0 mL), dry with Na₂SO₄, and filter. The filtrate was concentrated to obtain 4-amino-2-(4,6-dihydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methylpyrimidin-5-carboxylic acid (100 mg, 67.8% yield) as a yellow solid.

[0542] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4,6-dihydroxy-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl)-6-methylpyrimidin-5-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.42 (br s, 1H), 7.25-6.95 (m, 1H), 6.91-6.45 (m, 5H), 6.21 (s, 1H), 5.26-5.08 (m, 1H), 4.64-3.88 (m, 8H), 3.68-3.34 (m, 2H), 3.26-2.93(m, 9H), 2.79-2.70(m, 2H), 2.43(s, 3H), 1.95-1.83(m, 2H), 1.36(d, J=6.4Hz, 3H), 1.23(s, 6H). LCMS (Method 5-95AB, ESI): R T = 0.799 min, [M+H] + =1052.5.

[0543] Example 53

[0544]

[0545] Step 1: Sodium methoxide (25 wt.% in methanol, 16.4 mL, 71.5 mmol) was added to a solution of 4-tert-butylbenzamide (4.20 g, 23.8 mmol) in methanol (11.9 mL). The reaction mixture was stirred at room temperature for 10 min, followed by the addition of diethyl malonate (3.62 mL, 23.8 mmol). The reaction mixture was stirred at room temperature for 16 h, followed by concentration under reduced pressure. H₂O was added, followed by concentrated HCl, to obtain an acidic pH. The resulting mixture was extracted with EtOAc (3×). The organic layers were combined, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 2-(4-tert-butylphenyl)pyrimidin-4,6-diol (4.08 g, 70.1% yield) as a grayish-white solid. The crude product was used in the next step without any further purification.

[0546] Step 2: DMF (1.33 mL, 17.2 mmol) was added to POCl3 (21.5 mL, 230 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. This solution was then added to 2-(4-tert-butylphenyl)pyrimidin-4,6-diol (4.01 g, 16.4 mmol) and the reaction mixture was stirred at room temperature for 30 min, followed by stirring at 100 °C for 16 h. The mixture was then cooled to room temperature and poured onto ice / water. The resulting mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% EtOAc in heptane) to give 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidin-5-carboxaldehyde (2.94 g, 57.9% yield) as a grayish-white solid.

[0547] Step 3: A solution of sodium chlorite (1.20 g, 13.3 mmol) in water (4.2 mL) was added to a solution of 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidin-5-carboxaldehyde (2.94 g, 9.51 mmol) and ammoniasulfonic acid (1.29 g, 13.3 mmol) in tert-butanol (21 mL) and water (8.4 mL). The reaction mixture was stirred at room temperature for 5 h, followed by the addition of additional portions of ammoniasulfonic acid (260 mg, 2.68 mmol) and sodium chlorite (240 mg, 2.65 mmol). The reaction mixture was stirred again at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidin-5-carboxylic acid (3.09 g, 99.9% yield) as a grayish-white solid. The crude material was used in the next step without any further purification.

[0548] Step 4: Potassium carbonate (3.28 g, 23.8 mmol) was added to a solution of 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidin-5-carboxylic acid (3.09 g, 9.50 mmol) in DMF (47.5 mL). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of iodoethane (1.91 mL, 23.8 mmol). The reaction mixture was stirred at room temperature for 16 h, followed by dilution with EtOAc. The resulting mixture was washed with water (2×) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% EtOAc in heptane) to give ethyl 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidin-5-carboxylic acid (2.95 g, 87.9% yield) as a grayish-white solid.

[0549] Step 5: A solution of ethyl 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidin-5-carboxylate (800 mg, 2.26 mmol) and 2 M ammonia in iPrOH (24.0 mL, 48.0 mmol) was stirred for 16 h at room temperature. H₂O was then added and the mixture was extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give ethyl 4-amino-2-(4-tert-butylphenyl)-6-chloro-pyrimidin-5-carboxylate (765 mg, quantified) as a colorless oil. This crude substance was used in the next step without any further purification.

[0550] Step 6: A 1N aqueous solution of lithium hydroxide (2.40 mL, 2.40 mmol) was added to a solution of ethyl 4-amino-2-(4-tert-butylphenyl)-6-chloropyrimidine-5-carboxylic acid (200 mg, 0.599 mmol) in THF (6.0 mL). The reaction mixture was stirred at 50 °C for 16 h, then cooled to room temperature. A 1N aqueous solution of HCl was added, and the mixture was extracted with a 4:1 solution of CHCl3 / iPrOH (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 190 mg of 4-amino-2-(4-tert-butylphenyl)-6-chloropyrimidine-5-carboxylic acid as a grayish-white solid.

[0551] As described in Example 1, the title compound was prepared by replacing 1-(4-tert-butyl)phenyl)-6-chloropyrimidine-5-carboxylic acid with 4-amino-2-(4-tert-butylphenyl)-6-chloro-pyrimidine-5-carboxylic acid. 1 H NMR (400MHz, DMSO+D2O) δ8.34 (s, 1H), 8.16 (d, J=8.5Hz, 2H), 7.52 (d, J=8.6Hz, 2H), 7.07 (d, J=8. 9Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 6.72 (s, 1H), 6.70 (s, 1H), 6.35 (s, 1H), 6.25 (s, 1H), 4.94-4.88 (m , 1H), 4.66-4.56 (m, 1H), 4.19-4.11 (m, 1H), 4.08-3.99 (m, 3H), 3.99-3.93 (m, 3H), 3.40-3.29 (m, 1H), 3.25-3.10 (m, 2H), 3.07-2.98 (m, 2H), 2.97-2.79 (m, 6H), 1.28 (s, 9H), 1.17 (d, J = 6.8 Hz, 3H). LCMS (Method 5-100AB, 7 min): R T = 1.88 min, [M+H] + =1028.2.

[0552] Example 54

[0553]

[0554] Step 1: Add 1-bromo-3,3-dimethylbutane (2.85 g, 17.2 mmol) and Ag₂CO₃ (9.51 g, 34.5 mmol) to a solution of 5-bromopyridin-2-ol (2.00 g, 11.49 mmol) in DMF (10.0 mL). Stir the reaction mixture at 110 °C for 2 h. Dilute the reaction mixture with ethyl acetate (40 mL). After filtration, wash the filtrate with brine (3 × 40 mL) and dry it over Na₂SO₄. After filtration, concentrate the filtrate to dryness. Purify the residue by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% ethyl acetate in petroleum) to obtain 5-bromo-2-(3,3-dimethylbutoxy)pyridine (1.00 g, 33.7% yield) as a yellow oil.

[0555] Step 2: Under nitrogen atmosphere, a mixture of 5-bromo-2-(3,3-dimethylbutoxy)pyridine (1.20 g, 4.65 mmol), KOAc (1.37 g, 14.0 mmol), Pd(dppf)Cl2 (345 mg, 0.46 mmol), and bis(pinacolyl)diboron (1.77 g, 6.97 mmol) in DMF (10.0 mL) was stirred for 16 h at 80 °C. The reaction mixture was diluted with ethyl acetate (20 mL), filtered, and the filtrate was washed with brine (3 × 20 mL). The organic layer was concentrated under vacuum to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 50 to 100% ethyl acetate in petroleum) to give a yellow oily substance of 2-(3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron). 2-yl)pyridine (480 mg, 33.8% yield).

[0556] Step 3: Add 2-(3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) A mixture of 2-yl)pyridine (300 mg, 0.98 mmol), ethyl 2-chloro-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (347 mg, 1.03 mmol), Pd(dppf)Cl2 (36.0 mg, 0.05 mmol), and Na2CO3 (312 mg, 2.95 mmol) in a mixture of 1,4-dioxane (6.0 mL) and water (0.60 mL) was purged with N2 (15 psi) and heated at 100 °C for 16 h. After filtration, 20 mL of ethyl acetate was added to the mixture. The mixture was washed with brine (2 × 20 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The crude material was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give ethyl 2-(6-(3,3-dimethylbutoxy)pyridin-3-yl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (370 mg, 78.7% yield) as a yellow solid.

[0557] Step 4: Add cerium ammonium nitrate (802 mg, 1.46 mmol) to a solution of 2-(6-(3,3-dimethylbutoxy)pyridin-3-yl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (175.0 mg, 0.37 mmol) in acetonitrile (4.00 mL) and water (2.00 mL). Stir the reaction mixture at 20 °C for 30 min. Partition the reaction mixture between ethyl acetate (20 mL) and water (20 mL). Wash the organic layer with brine (2 × 20 mL), dry with Na₂SO₄ and concentrate to dryness. Purify the crude substance by preparative TLC (ethyl acetate:petroleum ether = 1:10, Rf = 0.3) to give ethyl 4-amino-2-(6-(3,3-dimethylbutoxy)pyridin-3-yl)-6-methylpyrimidin-5-carboxylate (100 mg, 76.3% yield) as a yellow solid.

[0558] Step 5: Add NaOH (44.6 mg, 1.12 mmol) to a solution of ethyl 4-amino-2-(6-(3,3-dimethylbutoxy)pyridin-3-yl)-6-methylpyrimidin-5-carboxylic acid (100 mg, 0.28 mmol) in methanol (5.00 mL) and water (1.00 mL). Stir the reaction mixture at 80 °C for 1 h. Concentrate the mixture to dryness. Adjust the pH of the mixture to 2 with HCl (1 M). Extract the aqueous layer with ethyl acetate (2 × 60 mL) and concentrate the combined organic layers to give 4-amino-2-(6-(3,3-dimethylbutoxy)pyridin-3-yl)-6-methylpyrimidin-5-carboxylic acid (80 mg, 86.8% yield) as a white solid.

[0559] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(6-(3,3-dimethylbutoxy)pyridin-3-yl)-6-methylpyrimidine-5-carboxylic acid. 1 HNMR (400MHz, MeOH-d4) 9.04 (s, 1H), 8.51-8.42 (m, 2H), 7.12-6.99 (m, 1H), 6.89-6.69 (m, 3H), 6.5 5(s, 1H), 5.27-5.10(m, 1H), 4.83-4.73(m, 2H), 4.53-4.29(m, 3H), 4.18-4.07(m, 3H), 4.05-3.92(m 3.67-3.52 (m, 1H), 3.44-3.37 (m, 1H), 3.36-3.33 (m, 1H), 3.29-3.19 (m, 2H), 3.18-3.09 (m, 2H), 3.07 (s, 3H), 3.00-2.91 (m, 1H), 2.45 (s, 3H), 1.79-1.67 (m, 2H), 1.41-1.28 (m, 2H), 1.00 (s, 9H). LCMS (Method 10-80AB, ESI): R T = 1.868 min, [M+H] + =1054.6.

[0560] Example 55

[0561]

[0562] The title compound was prepared by using the procedure of Example 1, replacing compound 14 with compound 20, and replacing 1-(4-(tert-butyl)phenyl)-6-chloropyrimidine-5-carboxylic acid with 4-amino-2-(4-tert-butylphenyl)-6-chloro-pyrimidine-5-carboxylic acid as described in Example 53. 1H NMR (400MHz, DMSO+D2O) δ8.87 (d, J=8.0Hz, 1H), 8.30 (d, J=7.7Hz, 1H), 8.15 (d, J=8.1Hz, 2H), 7.52 (d, J=8.2Hz, 2H), 7 .19 (d, J=8.5Hz, 1H), 7.00 (d, J=8.6Hz, 1H), 6.71 (s, 2H), 6.30 (s, 1H), 6.25 (s, 1H), 4.86-4.80 (m, 1H), 4.73-4.58 (m, 2H), 4.20-3.96 (m, 5H), 3.85-3.64 (m, 3H), 3.35-3.23 (m, 1H), 3.15-2.77 (m, 11H), 2.74-2.55 (m, 1H), 2.46-2.36 (m, 2H), 2.40 (s, 12H), 2.38-2.20 (m, 1H), 2.13-1.86 (m, 2H), 1.28 (s, 9H), 1.18 (d, J = 7.1 Hz, 3H) LCMS (Method 5-100AB, 7 min): R T = 1.63 min, [M+H] + =963.6

[0563] Example 56

[0564]

[0565] Ethanol (5.00 mL) containing ethyl 2-(4-(tert-butyl)phenyl)-4-chloro-6-methylpyrimidin-5-carboxylate (150 mg, 0.45 mmol), TEA (188 μL, 1.35 mmol), and methylamine (33.4 mg, 0.50 mmol) was stirred for 1 h at 60 °C. The reaction mixture was diluted with ethyl acetate (40 mL). The organic layer was washed with brine (2 × 30 mL), dried over Na₂SO₄, and concentrated to dryness. The mixture was analyzed by preparative TLC (10% ethyl acetate in petroleum ether, R...). f =0.4) The residue was purified to give ethyl 4-amino-2-(4-(tert-butyl)-2-methylphenyl)-6-methylpyrimidine-5-carboxylate as a white solid (125 mg, 85.0% yield).

[0566] Step 5: Ethyl 4-amino-2-(4-(tert-butyl)-2-methylphenyl)-6-methylpyrimidin-5-carboxylic acid (120 mg, 0.37 mmol) was dissolved in MeOH (10.0 mL) and water (2.0 mL). NaOH (58.6 mg, 1.47 mmol) was added, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated, and the pH was adjusted to pH 3 with 1 M HCl. The reaction mixture was partitioned between ethyl acetate (50.0 mL) and water (50.0 mL). The aqueous layer was then extracted with ethyl acetate (50.0 mL * 2). The combined organic layers were dried over Na₂SO₄ and concentrated to give 2-(4-(tert-butyl)phenyl)-4-methyl-6-(methylamino)pyrimidin-5-carboxylic acid (100 mg, 91% yield) as a white solid.

[0567] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4-(tert-butyl)phenyl)-4-methyl-6-(methylamino)pyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) 8.38 (s, 1H), 8.24 (d, J = 7.6Hz, 2H), 7.50 (d, J = 8.4Hz, 2H), 7.10-7.04 (m, 1H), 6.50-6.77 (m, 2H), 6.59 (s, 1H), 6.48 (s, 1H), 5.20-5.16 (m, 1H), 4.37-3.97 (m, 8H), 3.61-3.58 (m, 1H), 3.38-3.35 (m, 1H), 3.19-2.98 (m, 12H), 2.44 (s, 3H), 1.36-1.34 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.794 min, [M+H] + =1022.5.

[0568] Example 57

[0569]

[0570] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(6-hydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methylpyrimidin-5-carboxylic acid prepared using the procedure described in Example 52. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.47 (br s, 1H), 8.11 (s, 1H), 7.02 (br s, 1H), 6.88-6.70 (m, 3H), 6.65 (s, 1H), 6.59 (br s, 1H), 6.52 (br s, 1H), 5.18 (br d, J=8Hz 1H), 4.44-3.95(m, 8H), 3.6(br d, J=10.4Hz, 1H), 3.43-3.32(m, 1H), 3.26-2.96(m, 9H), 2.86-2.79(m, 2H), 2.44(s, 3H), 1.96-1.88(m, 2H), 1.35(br d, J = 6.4 Hz, 3H), 1.25 (br s, 6H). LCMS (Method 5-95AB, ESI): R T = 0.783 min, [M+H] + =1036.5.

[0571] Example 58

[0572]

[0573]

[0574] Step 1: Pyridine (3.89 mL, 48.3 mmol) and trifluoromethanesulfonic anhydride (6.09 mL, 36.2 mmol) were added to a mixture of 5-(tert-butyl)-2-hydroxybenzaldehyde (4.30 g, 24.1 mmol) in DCM (60 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was washed successively with 1 M HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 20% ethyl acetate in petroleum) to give 4-(tert-butyl)-2-formylphenyl trifluoromethanesulfonic acid (4.50 g, 60.1% yield) as a yellow oil.

[0575] Step 2: Under N2 (15 psi), a mixture of 4-(tert-butyl)-2-carboxyphenyl trifluoromethanesulfonate (3.90 g, 12.6 mmol), bis(pinacolyl)diboron (4.78 g, 18.85 mmol), potassium acetate (3.75 g, 37.7 mmol), and Pd(PPh3)Cl3 (882 mg, 1.26 mmol) in DMF (40.0 mL) was stirred for 16 h at 80 °C. The mixture was filtered and diluted with ethyl acetate (80 mL). The organic layer was washed with brine (2 × 100 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to obtain the crude product. The crude product was purified by preparative HPLC (using a gradient of acetonitrile and water (containing 0.225% formic acid) to give a yellow solid, 5-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron). -2-yl)benzaldehyde (1.30 g, 35.9% yield).

[0576] Step 3: Add 5-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) A mixture of 2-yl)benzaldehyde (300 mg, 1.04 mmol), ethyl 2-chloro-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (402 mg, 1.2 mmol), Pd(dppf)Cl2 (76.2 mg, 0.10 mmol), and Na2CO3 (331 mg, 3.12 mmol) in a mixed solvent of 1,4-dioxane (10.0 mL) and water (1.0 mL) was purged with N2 (15.0 psi) and heated at 100 °C for 16 h. After filtration, 20 mL of ethyl acetate was added to the reaction mixture. The mixture was washed with brine (2 × 30 mL), dried over Na2SO4, and concentrated to dryness. The crude material was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 5% ethyl acetate in petroleum) to give ethyl 2-(4-(tert-butyl)-2-formylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidine-5-carboxylate (220 mg, 45.8% yield) as a white solid.

[0577] Step 4: Add 10% Pd / C (101 mg, 0.10 mmol) to a solution of ethyl 2-(4-(tert-butyl)-2-formylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidine-5-carboxylate (220 mg, 0.48 mmol) in methanol (10.0 mL). Stir the mixture at 40 °C for 6 h under hydrogen (50 psi). Filter the mixture and concentrate the filtrate to give ethyl 2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidine-5-carboxylate (180 mg, 81.5% yield) as a white solid.

[0578] Step 5: Add cerium ammonium nitrate (851 mg, 1.55 mmol) to a solution of ethyl 2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (180 mg, 0.39 mmol) in acetonitrile (8.0 mL) and water (4.0 mL). Stir the reaction mixture at 20 °C for 30 min. Partition the reaction mixture between ethyl acetate (40 mL) and water (40 mL). Wash the organic phase with brine (2 × 40 mL), dry with Na₂SO₄ and concentrate to dryness. Analyze by preparative TLC (ethyl acetate:petroleum ether = 1:10, TLC: 15% EtOAc in petroleum, R f =0.3) The crude substance was purified to give ethyl 4-amino-2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-6-methylpyrimidine-5-carboxylate (100 mg, 75% yield) as a yellow solid.

[0579] Step 6: Add NaOH (46.59 mg, 1.16 mmol) to a solution of ethyl 4-amino-2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-6-methylpyrimidin-5-carboxylic acid (100 mg, 0.29 mmol) in methanol (10.0 mL) and water (3.0 mL). Stir the reaction mixture at 80 °C for 1 h. Concentrate the mixture to remove methanol. Add water (20 mL) to the mixture and adjust the pH to 2 with 1 M HCl. Extract the aqueous layer with ethyl acetate (2 × 20 mL). Concentrate the combined organic layers to give 4-amino-2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-6-methylpyrimidin-5-carboxylic acid (80.0 mg, 87.1% yield) as a white solid.

[0580] Step 7: As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-6-methylpyrimidine-5-carboxylic acid.1 H NMR (400MHz, MeOH-d4) 8.42 (s, 2H), 7.90 (d, J=8.4Hz, 2H), 7.55-7.48 (m, 1H), 7.46 (br, 1H), 7.09-7.82 (m, 3H), 6.63 (s, 1H), 6.50 ( s, 1H), 5.22-5.19 (m, 1H), 4.96-4.26 (m, 1H), 4.25 (br, 1H), 4.24-4.15 (m, 4H), 3.22-3.05 (m, 4H), 2.45-2.44 (m, 3H), 1.39 (s, 12H). LCMS (Method 5-95AB, ESI): R T = 0.713 min, [M+H] + =1038.5.

[0581] Example 59

[0582]

[0583] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-methylphenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) 8.41 (s, 1H), 7.49-7.39 (m, 1H), 7.36-7.26 (m, 2H), 7.18-7.01 (m, 1H), 6.94-6.73 (m, 3H), 6.67-6.57 (m, 1H), 6.49-6.28 (m, 1H), 5.23-5.10 (m, 1H), 4.74-4.50 (m, 2H), 4.45-3.91 (m, 6H), 3.66- 3.31 (m, 3H), 3.26-2.70 (m, 8H), 2.52-2.29 (m, 6H), 1.42-1.25 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.627 min, [M+H] + =1022.8.

[0584] Example 60

[0585]

[0586] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-3-fluorophenyl)-6-methylpyrimidine-5-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.42 (br s, 1H), 7.46-7.36 (m, 1H), 7.18-7.00 (m, 1H), 6.95-6.72 (m, 3H), 6.59 (s, 1H), 6.46 (s, 1H), 5.23-5.08 (m, 1H), 4.80-4.77(m, 2H), 4.50-3.94(m, 6H), 3.68-3.33(m, 3H), 3.29-2.95(m, 8H), 2.47(s, 3H), 1.45-1.31(m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.774 min, [M+H] + =1026.6.

[0587] Example 61

[0588]

[0589] Step 1: At room temperature, add DIPEA (16.4 mL, 94.17 mmol, 2.0 equivalents) to a flame-dried nitrogen-purged flask. Then add chloromethyl methyl ether (MOMCl) (5.4 mL, 70.6 mmol, 1.5 equivalents) to a solution of 5-tert-butyl-2-iodophenol (13.0 g, 47.08 mmol, 1.0 equivalents) in DCM (157 mL). Stir the reaction mixture at room temperature for 16 hours. Add a saturated aqueous solution of NaHCO3 to the reaction mixture (40 mL) at 0 °C. Extract the mixture with DCM (3 × 40 mL). Combine the organic layers, dry with Na2SO4, filter through a sintered funnel, and concentrate the filtrate under reduced pressure. The crude substance was purified by filtration through a silica gel pad (800 g) in the presence of 20% EtOAc / heptane to give 4-tert-butyl-1-iodo-2-(methoxymethoxy)benzene (13.8 g, 43.1 mmol, 91.5% yield) as a yellow oil.

[0590] Add 13.0 g (40.6 mmol, 1.0 equivalent) of 4-tert-butyl-1-iodo-2-(methoxymethoxy)benzene and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoboron to a flame-dried nitrogen-purged flask. (28.9 mL, 142.11 mmol, 3.5 equivalents) and anhydrous THF (203 mL). The solution was cooled to -78 °C, and a solution of 2.5 M n-BuLi in heptane (48.7 mL, 121.8 mmol, 3.0 equivalents) was added dropwise while stirring the reaction mixture for 3 hours. A saturated aqueous solution of NaHCO3 was added at -78 °C to raise the temperature of the flask to rt, and the mixture was diluted with EtOAc (300 mL). The phases were separated, and the aqueous layer was extracted with more EtOAc (2 × 100 mL). The organic layer was then washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 30% EtOAc in heptane) to give 2-[4-tert-butyl-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboron as a white solid. (3542 mg, 11.061 mmol, 27% yield).

[0591] As described in Example 17, 1-(4-tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid was replaced with 4-amino-6-((4-tert-butyl)-2-hydroxyphenyl)-2-chloro-pyridine-3-carboxylic acid as prepared in Example 37, and 2-[4-tert-butyl-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboron was used. The title compound was prepared by replacing 4-tert-butylphenylboronic acid. 1 H NMR (400MHz, DMSO-d6+D2O) δ88.32 (s, 2H), 7.65 (d, J=8.7Hz, 1H), 7.21 (s, 1H), 7.07 (d, J=8.0Hz, 1H), 6.95 (dd, J=8.4, 1.9Hz, 1H), 6.89 (d, J=8.3Hz, 1H), 6.85 (d, J=1.9Hz, 1H), 6.73 (s, 1H), 6.70 (s, 1H), 6.36 (s, 1H), 6.25 (s , 1H), 4.92-4.88 (m, 1H), 4.64-4.53 (m, 1H), 4.11 (dd, J=5.6, 4.7Hz, 1H), 4.05-3.91 (m, 6H), 3.37-3.30 (m, 1H), 3.26-3.18 (m, 1H), 3.19-3.09 (m, 1H), 3.02-2.88 (m, 6H), 2.86-2.75 (m, 2H), 1.24 (s, 9H), 1.16 (d, J=6.8Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 2.03 min, [M+H] +=1043.5.

[0592] Example 62

[0593]

[0594] As described in Example 54, 2-(4-(tert-butyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron was used. Substitution of 2-(3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) 4-amino-2-(4-(tert-butyl)-2-fluorophenyl)-6-methylpyrimidin-5-carboxylic acid was prepared by substituting 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-fluorophenyl)-6-methylpyrimidin-5-carboxylic acid. The title compound was prepared by substituting 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-fluorophenyl)-6-methylpyrimidin-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 7.75-7.69 (m, 1H), 7.34-7.26 (m, 1H), 7.25-7.17 (m , 1H), 7.12-7.01(m, 1H), 6.96-6.73(m, 3H), 6.63-6.54(m, 1H), 6.44(s, 1H), 5.21 -5.10 (m, 1H), 4.82-4.65 (m, 4H), 4.44 (s, 1H), 4.32-3.87 (m, 6H), 3.66-3.48 (m, 1H), 3.42-3.32 (m, 1H), 3.25-2.87 (m, 8H), 2.49-2.32 (m, 3H), 1.39-1.29 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.769 min, [M+H] + =1026.5.

[0595] Example 63

[0596]

[0597] The general procedure for the synthesis of ethyl 6-(4-(tert-butyl)phenyl)-4-chloro-2-methylnicotinate was performed using the procedure from J.Med.Chem. 2013, 56, 1023-1040.

[0598] Step 1: Ethyl 4,6-dichloro-2-methylpyridine-3-carboxylate (966 mg, 4.13 mmol, 1.05 equivalents) and Pd(PPh3)4 (227 mg, 0.2000 mmol, 0.05 equivalents) were stirred for 15 min in diethylene glycol dimethyl ether (3.6 mL) at room temperature. IPA (4.2 mL) containing 4-tert-butylphenylboronic acid (700 mg, 3.93 mmol, 1.0 equivalents) was then added to this suspension, followed by 2 M K2CO3 aqueous solution (3.64 mL, 7.27 mmol, 1.85 equivalents). The mixture was stirred at 95 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. A saturated aqueous solution of NaHCO3 and DCM were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with DCM (2 × 40 mL), and the organic layers were combined. The organic layer was then washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 6-(4-tert-butylphenyl)-4-chloro-2-methylpyridine-3-carboxylate (1.02 g, 3.0738 mmol, 78.2% yield) as a yellow solid, which was used in the next step without purification.

[0599] Step 2: Add ethyl 6-(4-tert-butylphenyl)-4-chloro-2-methylpyridine-3-carboxylate (350 mg, 1.05 mmol, 1.0 equivalent), palladium acetate (35.5 mg, 0.1600 mmol, 0.15 equivalent), and Catacxium A (113.5 mg, 0.3200 mmol, 0.3 equivalent) to a flame-dried, nitrogen-purged vial. Dissolve the powder in ethylene glycol (2.64 mL) and 1,4-dioxane (2.64 mL) (1:1) and aerate the solution with a stream of nitrogen. Add potassium (tert-butoxycarbonylamino)methyl-trifluoroborate (1000 mg, 4.22 mmol, 4.0 equivalent) and DIPEA (735 μL, 4.22 mmol, 4.0 equivalent), and heat the suspension to 100°C in an oil bath. Four hours later, the reactants were cooled to room temperature and saturated aqueous solution of NaHCO3 and EtOAc were added. The phases were separated, and the aqueous layer was extracted with more EtOAc (2 × 10 mL), and the organic layers were combined. The organic layer was then washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a black residue. The crude substance was purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 40% EtOAc in heptane) to give ethyl 4-[(tert-butoxycarbonylamino)methyl]-6-(4-tert-butylphenyl)-2-methylpyridine-3-carboxylate (175 mg, 0.3399 mmol, 32% yield) as a viscous red oil.

[0600] Step 3: Add ethyl 4-[(tert-butoxycarbonylamino)methyl]-6-(4-tert-butylphenyl)-2-methylpyridine-3-carboxylate (145 mg, 0.3400 mmol, 1.0 equivalent) to a scintillation flask equipped with a magnetic stir bar. Dissolve it in THF (1.7 mL). Then add 1.0 M aqueous lithium hydroxide solution (0.37 mL, 0.37 mmol, 1.1 equivalent). The reaction mixture is then heated to 50 °C for 1 hour. Cool the reaction mixture to room temperature and concentrate under reduced pressure to give lithium 4-[(tert-butoxycarbonylamino)methyl]-6-(4-tert-butylphenyl)-2-methylpyridine-3-carboxylate (135 mg, 0.3388 mmol, 99.7% yield) as a yellow foam / solid. This salt is used as is in the next step.

[0601] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butoxycarbonylamino)methyl]-6-(4-tert-butylphenyl)-2-methylpyridine-3-carboxylate with lithium 4-[(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, DMSO-d6+D2O) δ7.94 (d, J=8.4Hz, 2H), 7.84 (s, 1H), 7.52 (d, J=8.5Hz, 2H), 7.18 (d , J=8.9Hz, 1H), 6.99 (d, J=8.7Hz, 1H), 6.72 (s, 1H), 6.67 (s, 1H), 6.28 (s, 1H), 6.14 (s, 1H), 5.0 9-5.03(m, 1H), 4.71-4.58(m, 2H), 4.18-3.91(m, 9H), 3.90-3.75(m, 2H), 3.41-3.22(m, 1H), 3. 12-2.95 (m, 3H), 2.85-2.77 (m, 4H), 2.54 (s, 3H), 2.39 (s, 12H), 1.27 (s, 9H), 1.21-1.11 (m, 3H). LCMS (Method 5-100AB, 7min): R T = 1.48 min, [M+H] + =1021.6.

[0602] Example 64

[0603]

[0604] As described in Example 50, the title compound was prepared by replacing (5R)-5-[(3-nitrophenyl)sulfonyloxymethyl]-2-oxo-oxazolidine-3-carboxylic acid tert-butyl ester in step 3. 1 H NMR (400MHz, DMSO+D2O) δ8.98-8.90 (m, 1H), 8.40-8.31 (m, 1H), 8.12 (d, J=8.5Hz, 2H), 7.62 (d, J=8.4Hz , 2H), 7.21 (d, J=7.3Hz, 1H), 7.04 (d, J=8.6Hz, 1H), 6.76-6.67 (m, 2H), 6.30 (s, 1H), 6.21 (s, 1H), 5.00- 4.96(m, 1H), 4.74-4.62(m, 2H), 4.14-3.95(m, 5H), 3.93-3.82(m, 1H), 3.40-3.24(m, 2H), 3.18-2.93(m , 4H), 2.92-2.83(m, 4H), 2.82-2.75(m, 1H), 2.46(s, 3H), 2.37(s, 9H), 1.31(s, 9H), 1.22-1.15(m, 3H). LCMS (Method 5-100AB, 7min): R T = 1.67 min, [M+H] + =1008.6.

[0605] Example 65

[0606]

[0607] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-(aminomethyl)-6-(4-(tert-butyl)-2-hydroxyphenyl)-2-methylnicotinic acid. As described in Example 63, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-[4-tert-butyl-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxoboron. To replace 4-tert-butylphenylboronic acid in the preparation of 4-(aminomethyl)-6-(4-(tert-butyl)-2-hydroxyphenyl)-2-methylnicotinic acid. 1HNMR (400MHz, DMSO+D2O) δ8.32 (s, 2H), 8.07 (s, 1H), 7.93 (d, J = 8.5Hz, 1H), 7.08 (d, J = 8.8Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 6.94-6.87 (m, 2H), 6.74 (s, 1H), 6.71 (s, 1H), 6.37 (s, 1H), 6.25 (s, 1H), 5.08 (dd, J=8. 8, 4.6Hz, 1H), 4.66-4.58(m, 1H), 4.21-4.12(m, 1H), 4.09-3.88(m, 6H), 3.85(s, 2H), 3.39-3.29(m, 1H) , 3.27-3.19(m, 1H), 3.17-3.08(m, 1H), 3.06-2.76(m, 8H), 2.54(s, 3H), 1.27(s, 9H), 1.22-1.15(m, 3H). LCMS (Method 5-100AB, 7min): R T = 1.68 min, [M+H] + =1037.6.

[0608] Example 66

[0609]

[0610] The general procedure for the synthesis of 5-bromo-1,1-dimethyl-2,3-dihydro-1H-indene was performed using the procedure from Chem. Ber. 1985, 118, 1050.

[0611] Step 1: Add titanium chloride (IV) (1.71 mL, 15.64 mmol, 2.2 equivalents) and DCM (14.2 mL) to a flame-dried nitrogen-purged flask. Cool the solution to -30°C and stir for 5 minutes. Then, add toluene (15.64 mL, 15.64 mmol, 2.2 equivalents) containing 1 M dimethyl zinc dropwise and stir the reaction mixture for 30 minutes. Next, add 5-bromo-1-indanone (1500 mg, 7.11 mmol, 1.0 equivalent) to the slurry all at once and stir the slurry overnight from -30°C to rt. Then cool the reaction mixture to 0°C and add ice fractionally, followed by the addition of NaHCO3. Dilute the reaction mixture with EtOAc and decant the solids, separating the layers. Extract the aqueous layer with EtOAc (3 × 40 mL). Combine the organic layers, dry to Na2SO4, filter, and concentrate under reduced pressure. The crude product was diluted in DCM and filtered through a silica gel pad (200 g). The silica gel was washed with 50% EtOAc / hexane. The solution was evaporated to dryness to give crude 5-bromo-1,1-dimethyl-indane as a translucent oil (1495 mg, 6.6409 mmol, 93.4% yield), which was used in the next step without further purification.

[0612] Step 2: Add 5-bromo-1,1-dimethylindane (1500 mg, 6.66 mmol, 1.0 equivalent) and bis(pinacolyl)diboron (3384 mg, 13.33 mmol, 2.0 equivalent) to a flame-dried, nitrogen-purged vial. Dissolve the solids in anhydrous toluene (22 mL) and purge the solution with nitrogen for 15 minutes. Add KOAc (2.59 g, 19.99 mmol, 3.0 equivalent), followed by PdCl2(dppf)·CH2Cl2 (272 mg, 0.330 mmol, 0.05 equivalent). Seal the vial with a microwave-safe cap and then heat the solution to 100 °C with stirring overnight. Cool the reaction mixture to rt and dilute with EtOAc (100 mL). Wash the organic layer with a saturated aqueous solution of NaHCO3, followed by washing with brine, dry with Na2SO4, and filter through a sintered funnel. Silica gel was added and the suspension was evaporated under reduced pressure to a black solid, which was purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 20% EtOAc in heptane) to give 2-(1,1-dimethylindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron as a colloidal orange solid. (1324 mg, 4.8642 mmol, yield 73%).

[0613] Step 3: Add methyl 4-amino-2-chloro-6-methylpyrimidin-5-carboxylate (150 mg, 0.7400 mmol, 1.0 equivalent), 1,4-dioxane (3.7201 mL), and water (0.3618 mL) to a flame-dried sealed test tube. Aerate the solution with a stream of nitrogen for 10 minutes. Subsequently, add 2-(1,1-dimethylindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron to the reactants. (243 mg, 0.8900 mmol, 1.2 equivalents), PdCl2(dppf)·CH2Cl2 (60.8 mg, 0.0700 mmol, 0.1 equivalents) and K2CO3 (206 mg, 1.49 mmol, 2.0 equivalents). The test tubes were sealed with microwave-safe caps and heated in an oil bath to 95 °C for 12 hours. Afterward, the solution was cooled to rt, and saturated aqueous solution of NaHCO3 and EtOAc were added. The phases were separated, the aqueous layer was extracted with EtOAc (2 × 10 mL), and the organic layers were combined. The organic layer was then washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was then purified by rapid chromatography (silica gel, 100 to 200 mesh, 0 to 50% EtOAc in heptane) to give methyl 4-amino-2-(1,1-dimethylindan-5-yl)-6-methylpyrimidin-5-carboxylate (81 mg, 0.2601 mmol, 35% yield), which was separated as a yellow solid.

[0614] Step 4: Methyl 4-amino-2-(1,1-dimethylindan-5-yl)-6-methylpyrimidin-5-carboxylate (180 mg, 0.5800 mmol) was dissolved in THF (1.93 mL), and 1.0 M lithium hydroxide aqueous solution (2.31 mL, 2.31 mmol, 4.0 equivalent) was added. The reaction mixture was then heated at 50 °C and stirred overnight. The reaction mixture was cooled, and 1.0 M KHSO4 (40 mL) and EtOAc (40 mL) were added. The phases were separated, and the aqueous layer was extracted with EtOAc (2 × 40 mL). The organic layers were combined, washed with brine (3 × 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-amino-2-(1,1-dimethylindan-5-yl)-6-methylpyrimidine-5-carboxylic acid (165 mg, 0.5549 mmol, 96% yield) as a white solid, which was used directly in the next step without purification.

[0615] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(1,1-dimethylindan-5-yl)-6-methylpyrimidine-5-carboxylic acid. 1H NMR (400MHz, DMSO-d6+D2O) δ8.36 (s, 1H), 8.10-8.08 (m, 2H), 7.26-7.14 (m, 1H), 7.03 (d, J= 8.8Hz, 1H), 6.85 (d, J=8.2Hz, 1H), 6.73 (s, 1H), 6.69 (s, 1H), 6.35 (s, 1H), 6.24 (s, 1H), 4.98 -4.85 (m, 1H), 4.69-4.50 (m, 1H), 4.21-4.11 (m, 1H), 4.07-3.87 (m, 6H), 3.38-3.29 (m, 1H), 3.24-3.08 (m, 2H), 3.04-2.79 (m, 8H), 2.34 (s, 3H), 1.88 (t, J = 7.1 Hz, 2H), 1.27-1.11 (m, 9H). LCMS (Method 5-100AB, 7 min): R T = 1.66 min, [M+H] + =1020.5.

[0616] Example 67

[0617]

[0618] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-3-fluoro-2-hydroxyphenyl)-6-methylpyrimidine-5-carboxylic acid. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.42 (br s, 2H), 8.00 (d, J=7.6Hz, 1H), 7.12-6.51 (m, 7H), 5.26-5.16 (m, 1H), 4.83-4.80 (m, 1H), 4 .49-3.94(m, 7H), 3.69-3.32(m, 3H), 3.25-2.92(m, 8H), 2.42(s, 3H), 1.43-1.33(m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.792 min, [M+H] + =1042.6.

[0619] Example 68

[0620]

[0621] Step 1: Methyl 2-amino-4,6-dichloropyridine-3-carboxylate (1571 mg, 7.11 mmol, 1 equivalent), Pd(PPh3)4 (373 mg, 0.32 mmol, 0.05 equivalent), K3PO4 (2057 mg, 9.69 mmol, 1.5 equivalent), and H2O (5 mL) were added to a mixture of 4-tert-butylphenylboronic acid (1150 mg, 6.46 mmol, 1 equivalent) and 1,4-dioxane (58 mL), and degassed with N2 gas. After stirring at 60 °C for 18 hours, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (25 mL) and diluted, followed by extraction with EtOAc (3 × 75 mL). The organic layer was washed with brine, dried over Na2SO4, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 10 to 50% EtOAc in heptane) to give methyl 2-amino-4,6-dichloro-pyridine-3-carboxylate as a yellow solid (1510 mg, 4.74 mmol, 73% yield).

[0622] Step 2: A mixture of methyl 2-amino-6-(4-tert-butylphenyl)-4-chloro-pyridine-3-carboxylate (500 mg, 1.57 mmol, 1 equivalent), methylboronic acid (282 mg, 4.71 mmol, 3 equivalent), 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (115 mg, 0.16 mmol, 0.1 equivalent), and K3PO4 (999 mg, 4.71 mmol, 3 equivalent) in 7.8419 mL of N3-degassed 1,4-dioxane was stirred for 1 h at 110 °C. The reaction mixture was quenched with 10 mL of saturated aqueous NaHCO3 solution and diluted, followed by extraction with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 10 to 50% EtOAc in heptane) to give methyl 2-amino-6-(4-tert-butylphenyl)-4-methylpyridine-3-carboxylate (342 mg, 1.15 mmol, 73% yield) as a yellow solid.

[0623] Step 3: N-iodosuccinimide (396 mg, 1.76 mmol, 1.5 equivalents) was added to a solution of methyl 2-amino-6-(4-tert-butylphenyl)-4-methylpyridine-3-carboxylate (350 mg, 1.17 mmol, 1 equivalent) in DMF (12 mL). The reaction mixture was stirred at 65 °C for 30 h. The reaction mixture was quenched with 20 mL of saturated aqueous NaHCO3 solution and diluted, followed by extraction with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 80% EtOAc in heptane) to give methyl 2-amino-6-(4-tert-butylphenyl)-5-iodo-4-methylpyridine-3-carboxylate (279 mg, 0.66 mmol, 56% yield) as an orange solid.

[0624] Step 4: ZnCN3 (166 mg, 1.41 mmol, 3 equivalents) was added to a mixture of methyl 2-amino-6-(4-tert-butylphenyl)-5-iodo-4-methyl-pyridine-3-carboxylate (200 mg, 0.47 mmol, 1 equivalent) in N2-degassed DMA (4.7 mL), and the mixture was degassed again with N2 before the addition of XPhos Pd G3 (74 mg, 0.09 mmol, 0.2 equivalents). After stirring at 120 °C for 2 h, the reaction mixture was quenched with NaHCO3 (10 mL) and diluted, followed by extraction with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried over MgSO4, filtered through diatomaceous earth, and concentrated under reduced pressure to give methyl 2-amino-6-(4-tert-butylphenyl)-5-cyano-4-methyl-pyridine-3-carboxylate (104 mg, 0.32 mmol, 68% yield) as an orange solid. The solid was used as is in the next step without purification.

[0625] Step 5: 1 M LiOH aqueous solution (3.22 mL, 3.22 mmol, 10 equivalents) was added to a solution of methyl 2-amino-6-(4-tert-butylphenyl)-5-cyano-4-methylpyridin-3-carboxylate (104 mg, 0.32 mmol, 1 equivalent) in THF (3.2 mL), and the reaction mixture was stirred at 22 °C for 5 h. The reaction mixture was quenched with a saturated aqueous solution of NaCl (10 mL), followed by extraction with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give a yellow solid of [2-amino-6-(4-tert-butylphenyl)-5-cyano-4-methylpyridin-3-carbonyl]oxylithium (101 mg, 0.32 mmol, 99% yield). The solid was used as is in the next step without purification.

[0626] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with lithium [2-amino-6-(4-tert-butylphenyl)-5-cyano-4-methyl-pyridin-3-carbonyl]oxy. 1 HNMR (400MHz, DMSO-d6+D2O) δ8.35 (s, 1H), 7.68 (d, J = 8.4Hz, 2H), 7.52 (d, J = 8.4Hz, 2H), 7.09 (d, J = 7.8Hz, 1H) , 6.90 (d, J=8.1Hz, 1H), 6.73 (d, J=10.3Hz, 1H), 6.37 (s, 1H), 6.26 (s, 1H), 4.95-4.91 (m, 1H), 4.63-4.58 (m, 1H ), 4.14-4.07 (m, 1H), 4.06-3.91 (m, 5H), 3.38-3.34 (m, 1H), 3.26-3.22 (m, 1H), 3.15-3.11 (m, 1H), 3.01-2.90 (m, 4H), 2.87-2.76 (m, 2H), 2.70-2.66 (m, 1H), 2.36 (s, 3H), 2.34-2.32 (m, 2H), 1.30 (s, 9H), 1.22-1.14 (m, 3H). LCMS (Method 5-100AB, 7min): R T = 2.33 min, [M+H] + =1032.6.

[0627] Example 69

[0628]

[0629] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-(difluoromethyl)pyrimidine-5-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.29 (d, J = 7.6Hz, 2H), 7.48 (d, J = 8.0Hz, 2H), 7.11-6.96 (m, 1H) , 6.90-6.80(m, 2H), 6.79-6.69(m, 2H), 6.66-6.56(m, 1H), 6.53-6.41(m, 1H), 5.22-5.12(m, 1H ), 4.82-4.80 (m, 2H), 4.43-4.29 (m, 5H), 3.63-3.53 (m, 1H), 3.49-3.40 (m, 1H), 3.38-3.34 (m, 2H), 3.28-3.24 (m, 2H), 3.24-3.12 (m, 3H), 3.06 (s, 3H), 3.01-2.90 (m, 2H), 1.43-1.28 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.825 min, [M+H] + =1044.4.

[0630] Example 70

[0631]

[0632] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-hydroxy-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-6-methylpyrimidin-5-carboxylic acid prepared using the procedure described in Example 52. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.41 (br s, 1H), 8.2 (d, J = 8.4Hz, 1H), 7.05 (br s, 1H), 6.93-6.73 (m, 3H), 6.7 (d, J = 8Hz, 1H), 6.59 (s, 1H), 6.5 (br s, 1H), 5.23-5.13 (m, 1H), 4.8 (br s, 1H), 4.43 (br s, 1H), 4.27-3.97 (m, 6H), 3.66-3.54 (m, 1H), 3.41-3.32 (m, 1H), 3.28-2.98 (m, 9H), 2.89-2.81 (m, 2H), 2.45 (s, 3H), 2.00-1.91 (m, 2H), 1.36 (br d, J = 6.8 Hz, 3H), 1.26 (s, 6H). LCMS (Method 5-95AB, ESI): R T = 0.795 min, [M+H] + =1036.5.

[0633] Example 71

[0634]

[0635] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)pyrimidine-5-carboxylic acid with 2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 ¹H NMR (400MHz, MeOH-d⁴) δ (ppm) 9.21–9.13 (m, 2H), 8.47–8.25 (m, 3H), 7.55–7.49 (m, 2H), 7.10–6.35 (m, 5H), 4.30–3.37 (m, 10H), 3.25–2.74 (m, 8H), 1.39–1.36 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.814 min, [M+H] + =979.6.

[0636] Example 72

[0637]

[0638] Step 1: Copper(II) acetylacetonate (237 mg, 0.905 mmol) was added to a solution of tert-butyl acetoacetate (3.0 mL, 18.1 mmol) and ethyl cyanoacetate (1.8 mL, 18.2 mmol) in DCM (12.1 mL). The reaction mixture was stirred at room temperature for 48 h, followed by concentration under reduced pressure. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 60% EtOAc in heptane) to give (E)-2-acetyl-3-amino-but-2-eneic acid O1-tert-butyl ester O4-ethyl ester (1.73 g, 37.2% yield) as a dark gray oil (a mixture of two geometric isomers).

[0639] Step 2: 1,1,3,3-Tetramethylguanidine (1.69 mL, 13.5 mmol) was added to a solution of (E)-2-acetyl-3-amino-but-2-enediol O1-tert-butyl ester O4-ethyl ester (1.73 g, 6.72 mmol) and 4-tert-butylbenzomididine (1.30 g, 7.40 mmol) in DCM (13.4 mL). The reaction mixture was stirred at room temperature for 16 h, followed by quenching with 1 M KHSO4 aqueous solution. The mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% MeOH in DCM) to give the title compound 5-tert-butoxycarbonyl-2-(4-tert-butylphenyl)-6-methylpyrimidine-4-carboxylic acid (1.21 g, 48.6% yield) as a grayish-white solid.

[0640] Step 3: Isobutyl chloroformate (501 μL, 3.86 mmol) was added to a solution of 5-tert-butoxycarbonyl-2-(4-tert-butylphenyl)-6-methylpyrimidin-4-carboxylic acid (1.30 g, 3.51 mmol) and triethylamine (538 μL, 3.86 mmol) in 35 mL of THF at 0 °C. The reaction mixture was stirred at room temperature for 15 min, then cooled to 0 °C. Lithium borohydride (255 mg, 12.3 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h 30. MeOH (10 mL) was added at 0 °C, followed by a saturated aqueous solution of NH4Cl. The mixture was then heated to room temperature and extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 10% MeOH in DCM) to give tert-butyl 2-(4-tert-butylphenyl)-4-(hydroxymethyl)-6-methylpyrimidine-5-carboxylate (679 mg, 54.3% yield) as a yellow oil.

[0641] Step 4: Carbon tetrabromide (444 mg, 1.34 mmol), triphenylphosphine (367 mg, 1.40 mmol), and sodium azide (396 mg, 6.09 mmol) were added to a solution of tert-butyl 2-(4-tert-butylphenyl)-4-(hydroxymethyl)-6-methylpyrimidine-5-carboxylate (434 mg, 1.22 mmol) in DMF (8.1 mL). Triethylamine (373 μL, 2.68 mmol) was then added, and the reaction mixture was stirred at room temperature for 1 h. Additional portions of carbon tetrabromide (444 mg, 1.34 mmol), triphenylphosphine (367 mg, 1.40 mmol), and triethylamine (373 μL, 2.68 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc, followed by washing with saturated aqueous solution of NaHCO3, water, and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 20% EtOAc in heptane) to give tert-butyl 4-(azidomethyl)-2-(4-tert-butylphenyl)-6-methylpyrimidine-5-carboxylate (315 mg, 67.8% yield) as a yellow oil.

[0642] Step 5: Add piracetamyl methoxycarbonyl chloride (384 mg, 1.49 mmol) and sodium carbonate (182 mg, 1.71 mmol) to a solution of 4-(azidomethyl)-2-(4-tert-butylphenyl)-6-methylpyrimidine-5-carboxylic acid tert-butyl ester (436 mg, 1.14 mmol) in ethanol (8.7 mL). Purge the reaction mixture with N2 for 5 min, then add 55% moistened palladium / carbon (10% loading) (122 mg, 0.114 mmol). Purge the reaction mixture with H3 for 5 min, then stir at H3 (1 atm) for 16 h. Purge the reaction mixture with N2. Add additional portions of sodium carbonate (121 mg, 1.14 mmol) and piracetamyl methoxycarbonyl chloride (147 mg, 0.568 mmol). Stir the reaction mixture at room temperature for 5 h, then filter through diatomaceous earth. Wash the filter cake with MeOH, then concentrate the filtrate under reduced pressure. The crude substance was purified by column chromatography (silica gel, 100 to 200 mesh, 0 to 30% EtOAc in heptane) to give tert-butyl 2-(4-tert-butylphenyl)-4-[(9H-furan-9-ylmethoxycarbonylamino)methyl]-6-methylpyrimidin-5-carboxylic acid (487 mg, 73.8% yield) as a colorless oil.

[0643] Step 6: Trifluoroacetic acid (6.5 mL) was added to a solution of tert-butyl 2-(4-tert-butylphenyl)-4-[(9H-perazon-9-ylmethoxycarbonylamino)methyl]-6-methylpyrimidine-5-carboxylic acid (487 mg, 0.843 mmol) in DCM (13 mL). The reaction mixture was stirred at room temperature for 12 h, followed by concentration under reduced pressure. The crude product was purified by column chromatography (C-18, 5 to 70% acetonitrile in 10 mM NH4HCO2 aqueous solution) to give 2-(4-tert-butylphenyl)-4-[(9H-perazon-9-ylmethoxycarbonylamino)-methyl]-6-methylpyrimidine-5-carboxylic acid (303 mg, 68.9% yield) as a grayish-white solid.

[0644] As described in Example 1, the title compound was prepared by replacing 1-(4-(tert-butyl)phenyl)-4-[(9H-furo-9-ylmethoxycarbonylamino)-methyl]-6-methyl-pyrimidin-5-carboxylic acid with 2-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid. 1 H NMR (400MHz, DMSO+H2O) δ8.40 (d, J=8.4Hz, 2H), 8.34 (s, 2H), 7.55 (d, J=7.8Hz, 2H), 7.09-7 .00(m, 1H), 6.93-6.85(m, 1H), 6.77-6.71(m, 1H), 6.68(s, 1H), 6.38(s, 1H), 6.26(s, 1H), 5. 13-5.05(m, 1H), 4.62(q, J=5.6Hz, 1H), 4.18-3.85(m, 9H), 3.39-3.30(m, 2H), 3.28-3.18(m, 1H), 3.18-3.09 (m, 1H), 3.08-2.75 (m, 7H), 2.55 (s, 3H), 1.32 (s, 9H), 1.17 (d, J=6.7Hz, 3H). LCMS (Method 5-100AB, 7min): R T = 1.46 min, [M+H] + =1022.5.

[0645] Example 73

[0646]

[0647] Using the procedure of Example 1, the title compound was prepared by replacing compound 10 in Example 17 with compound 10 as described in procedure C, replacing (5R)-5-[(3-nitrophenyl)sulfonyloxymethyl]-2-oxo-oxazolidine-3-carboxylic acid tert-butyl ester in step 3 with (5S)-5-[(3-nitrophenyl)sulfonyloxymethyl]-2-oxo-oxazolidine-3-carboxylic acid tert-butyl ester, and replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid as described in Example 5. 1 H NMR (400MHz, DMSO+D2O) δ8.91 (d, J=7.1Hz, 1H), 8.79 (s, 1H), 8.30 (d, J=8.5Hz, 2H), 7.36 (d, J=8.6Hz, 2H), 7.20 (d, J=8.0Hz, 1H), 7.04 (d, J=8.5Hz, 1H), 6.74 (s, 1H), 6.72 (s, 1H), 6.31 (s, 1H), 6.25 (s, 1H), 4.95-4.88 (m, 1H), 4.74- 4.61 (m, 2H), 4.14-4.05 (m, 1H), 4.05-3.95 (m, 4H), 3.92-3.85 (m, 1H), 3.33-3.25 (m, 1H), 3.13-2.75 (m, 10H), 2.62 (s, 3H), 2.38 (s, 15H), 2.12-1.92 (m, 2H), 1.42 (s, 3H), 1.18 (d, J = 6.7 Hz, 3H), 0.96-0.89 (m, 2H), 0.88-0.82 (m, 2H). LCMS (Method 5-100AB, 7 min): R T = 1.45 min, [M+H] + =926.6.

[0648] Example 74

[0649]

[0650] The title compound was prepared using general procedure B. 1H NMR (400MHz, MeOH-d4) δ (ppm) 8.83 (s, 1H), 8.35 (d, J = 8.4Hz, 2H), 7.38 (d, J = 8.4Hz, 2H), 7.20-7. 14 (m, 1H), 7.03-6.91 (m, 2H), 6.82 (s, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 5.18-5.06 (m, 1H), 4.84-4. 76 (m, 2H), 4.61-4.50 (m, 1H), 4.35-3.92 (m, 6H), 3.60 (s, 3H), 3.26-3.00 (m, 10H), 2.77-2.67 (m, 3H), 2.38-2.12 (m, 2H), 1.47 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H), 0.97-0.91 (m, 2H), 0.89-0.81 (m, 2H). LCMS (Method 5-95AB, ESI): R T = 0.764 min, [M+H] + =940.4.

[0651] Example 75

[0652]

[0653] The title compound was prepared using general procedure B. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.46 (br s, 1H), 8.21 (d, J=8.0Hz, 2H), 7.50 (d, J=8.0Hz, 2H), 7.40-7.20 (m, 1H), 7.11 (d, J=7.6Hz, 1H), 6.91-6.83 ( m, 1H), 6.80 (s, 1H), 6.63 (s, 1H), 6.57 (s, 1H), 5.24-5.17 (m, 1H), 4.85-4.78 (m, 2H), 4.46-4.39 (m, 1H), 4.3 8-4.28 (m, 1H), 4.27-4.20 (m, 2H), 4.19-4.10 (m, 2H), 4.09-3.94 (m, 3H), 3.70-3.56 (m, 2H), 3.55-3.45 (m, 3H), 3.43-3.34 (m, 1H), 3.25-3.12 (m, 2H), 3.10 (s, 3H), 3.08-2.94 (m, 3H), 2.49 (s, 3H), 1.41-1.31 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.636 min, [M+H] + =1022.6.

[0654] Example 76

[0655]

[0656] The title compound was prepared using general procedure B. 1 H NMR (400MHz, MeOH-d4) δ (ppm) 8.34 (br s, 1H), 8.20 (d, J = 8.8Hz, 2H), 7.50 (d, J = 8.4Hz, 2H), 7.12 (d, J = 9.2Hz, 1 H), 6.94-6.79 (m, 3H), 6.60 (s, 1H), 6.50 (s, 1H), 5.15-5.03 (m, 1H), 4.83 -4.72(m, 1H), 4.52-4.42(m, 1H), 4.26-4.02(m, 6H), 3.28-3.00(m, 11H) , 2.47 (s, 3H), 2.23-2.06 (m, 1H), 2.03-1.85 (m, 1H), 1.39-1.34 (m, 12H). LCMS (Method 5-95AB, ESI): R T = 0.767 min, [M+H] + =1022.6.

[0657] Bioanalytical methods

[0658] Example B1: LepB Analysis

[0659] The in vitro antimicrobial activity of each compound was determined by measuring the minimum inhibitor concentration (MIC) using the culture medium microdilution technique approved by the Clinical and Laboratory Standards Institute (CLSI) (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - 8th Edition, CLSI Document M07-A8. Wayne, PA: Clinical and Laboratroy Standards; 2009). Antimicrobial activity was measured against *Escherichia coli* strain ATCC 25922, *Klebsiella pneumoniae* strain ATCC 700603, *Acinetobacter baumannii* strain ATCC 17978, and *Pseudomonas aeruginosa* strain PA01, each representing a clinically relevant Gram-negative species. Cells were seeded onto Mueller Hinton agar plates and incubated at 37°C for 16–18 hours. Inoculum suspensions were prepared by scraping cells into 1 mL of test medium (Mueller Hinton II cationic-adjusted medium) and diluting it to a final OD 600 nm of 0.01.

[0660] Test compounds were prepared at a concentration of 64 μg / mL in DMSO. The compounds were tested under several different dilution methods. In Scheme 1, the compound stock solution was diluted to a concentration of 64 μg / mL in the test medium in a 96-well U-shaped microtiter dish, and consecutive 2-fold dilutions were prepared in the same medium to obtain a total of 10 compound concentrations. In Scheme 2, the compound stock solution was diluted to a concentration of 4 μg / mL in the test medium in a 96-well U-shaped microtiter dish, and consecutive 2-fold dilutions were prepared in the same medium to obtain a total of 10 compound concentrations. In Scheme 3, the compound stock solution was diluted to a concentration of 0.5 μg / mL in the test medium, and consecutive 2-fold dilutions were performed as described above. In Scheme 4, the compound stock solution was diluted to a concentration of 0.13 g / mL in the test medium, and consecutive 2-fold dilutions were performed as described above. The inoculum suspension was added to a two-fold serial dilution of the test compound to achieve a final OD600 nm density of 0.0005 and incubated at 35°C for 22 hours. After incubation, each dish was visually inspected and the lowest concentration of the test compound that completely prevented bacterial growth was recorded as the MIC. To assess antimicrobial activity in the presence of plasma proteins, the MIC was also determined in growth medium supplemented with 50% serum. Bacterial inoculum and test compound dilution dishes were prepared using the same protocol as described above for standard MIC analysis, except that a mixture of 50% v / v Mueller Hinton II cationic adjusted medium and 50% v / v mouse sterile filtered serum (Equitech-Bio) was used instead of 100% Mueller Hinton II cationic adjusted medium. The results are listed in Table 3 (MIC, IC50). 50 (Value: micromoer)

[0661] Example B2: Measurement of Oxygen Consumption

[0662] Isolation of liver mitochondria

[0663] Male Sporgdolly rats (8 to 10 weeks old) were euthanized using an excess of carbon dioxide. The liver was rapidly removed and placed in ice-cold phosphate-buffered saline (PBS) prior to the dissection procedure. Mitochondria were isolated using a mitochondrial isolation kit (Cayman Chemical #701010, Ann Arbor, MI) according to the manufacturer's instructions. In short, approximately 10 to 14 grams of liver tissue was finely minced using a pair of scissors and repeatedly washed with ice-cold PBS, followed by repeated washing with Mito separation buffer. The minced tissue was homogenized in a 40 ml Durns homogenizer and a smooth glass grinder with 30 ml Mito homogenization buffer. The homogenate was divided into two clean 30 ml polycarbonate tubes and centrifuged at 1,000 × g at 4°C for 3 minutes. The supernatant was further centrifuged at 10,000 × g at 4°C for 10 minutes. The supernatant was discarded, and the mitochondrial aggregates were resuspended in Mito separation buffer using a glass stir bar and stored on ice until use. Mitochondria protein concentration was determined using a diquinoline carboxylate protein analysis kit (Thermo Scientific, Waltham, MA).

[0664] Measurement of oxygen consumption

[0665] As basically described by Will et al., “Analysis of mitochondrial function using phosphorescent oxygen-sensitive probes,” Nature Protocols Vol. 1(6)(2006) 2563, oxygen consumption was monitored. In short, isolated mitochondria (50 μg mitochondrial protein / state 3 (S3) for inhibitor identification and 100 μg / S2 for uncoupling agent identification) were cultured in 384-well culture dishes with 25 μl of measurement buffer (MB: 250 mM sucrose, 15 mM KCl, 1 mM EGTA, 5 mM MgCl2, 30 mM K2HPO4, pH 7.4) containing 1% DMSO on ice, and then mixed with 25 μl of a substrate-receiving mixture containing an oxygen-sensitive phosphorescent dye (MitoXpress Xtra, Agilent, Santa Cruz). Clara (CA), glutamate (25 mM, G1626, Sigma, St. Louis, MO), malate (25 mM, M6413, Sigma), ADP (3.3 mM, A2754, Sigma, for S3 mitochondrial respiration only), fatty acid-free BSA (0.1%, A0281, Sigma), and the complex type II specific inhibitor TTFA (2 μM, T27006, Sigma, for assessing complex type I mitochondrial respiration using glutamate / malate). The mixture was coated with HS mineral oil (Agilent) using Viaflo 384-channel pipettes (Integra, Hudson, NH). Oxygen consumption was measured at 30°C for 30 min using a spectrophotometer (FLUOstar Omega, BMG Labtech, Cary, NC). In S3, 0% and 100% inhibition were defined using DMSO as a control and antimycin A (10 M). In S2, 0% and 100% decoupling were defined using DMSO as the mediator and FCCP (0.5 to 1 μM), respectively. The area under the curve (AUC) is typically used for calculation within the range of 0 to 12 min (S3) or 0 to 24 min (S2). 50 or UC 50 (Uncoupling concentration), a concentration that induces 50% inhibition of oxygen consumption or maximal (uncoupling) activation, used to assess experimental quality. Data are presented in μM (per 50 μg (S3) or 100 μg (S2) mitochondrial protein). IC50 50 <100μM (S3) and / or UC 50Compounds with <200 μM (S2) are considered high-risk for mitochondrial toxicity. Compounds with 25 to 50% inhibition and / or uncoupling changes are classified as intermediate-risk, while compounds with >25% changes are considered reactants.

[0666] Toxicity associated with mitochondrial dysfunction has presented a promising problem for potential antibiotics and other types of therapies. Mitochondrial oxygen consumption (OCR) analysis is considered a reliable indicator of potential internal organ toxicity problems that may accompany potent antibiotics. In mitochondrial oxygen consumption (OCR) analysis, the formate compounds of the present invention showed unexpectedly low toxicity compared to prior art "glycinonitrile" erythromycin analogs (see, for example, WO 2018 / 149419). Compared to such compounds, the compounds of the present invention generally exhibited an order of magnitude better OCR IC50 values. Exemplary OCR values ​​of the compounds of the present invention are shown in Table 3.

[0667] Table 3

[0668] Example # <![CDATA[Mitochondrial oxygen consumption rate IC 50 (μM)]]> 2 261 7 ＞250 8 28 ...

Claims

1. A compound of formula (I) or a pharmaceutical salt or stereoisomer thereof: in: R 1 -(C1-C6) alkyl groups substituted with -NHSO2-NH2 or -NH2; R 2 For H; R 3 It is H or -(C1-C6) alkyl; R 4 It is H or -(C1-C6) alkyl; X is an arbitrary path passing through one, two, or three R... X Substituted pyrimidinyl, imoxypyridazinyl, pyrazinyl or pyridinyl; Each R X Independently, it is a halogen, -CN, -NH2, -NH(C1-C6)alkyl, -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C1-C6)aminoalkyl; or two Rs on the same carbon. X They combine to form oxygen; Y is an arbitrary path via one, two, or three Rs. Y Substituted 5-6 membered saturated heterocyclic alkylene groups containing one nitrogen heteroatom, 5-6 membered heteroaryl or phenylene groups containing one nitrogen heteroatom; Each R Y It can be independently a halogen, -CN, -(C1-C6)alkyl, -(C1-C6)hydroxyalkyl, or -OH; Z is -O-(C1-C6)alkyl; -O-(C3-C7)saturated cycloalkyl; or optionally -O-(C3-C7)saturated cycloalkyl substituted with -O-(C1-C6)alkyl. 12 )alkyl; -(C1-C 12 ) Haloalkyl or -(C3-C9) saturated cycloalkyl optionally substituted with -(C1-C6)alkyl; or, -XYZ is 2. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein R 3 It is an (C1-C6) alkyl group.

3. The compound according to claim 2, or its pharmaceutical salt or stereoisomer, wherein R 3 It is a methyl group.

4. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein R 4 For H.

5. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein R 4 It is a methyl group.

6. The compound according to claim 1, or a pharmaceutical salt or stereoisomer thereof, wherein the compound has the structure of formula (Ia):

7. The compound according to claim 1, or a pharmaceutical salt or stereoisomer thereof, wherein the compound has the structure of formula (Ib):

8. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein R 1 It is -CH2CH2NH2, -CH2CH2NHSO2NH2 or -CH2NHSO2NH2.

9. The compound according to claim 8, or a pharmaceutical salt or stereoisomer thereof, wherein R 1 It is -CH2CH2NH2.

10. The compound according to claim 8, or a pharmaceutical salt or stereoisomer thereof, wherein R 1 It is -CH2CH2NHSO2NH2.

11. The compound according to claim 8, or a pharmaceutical salt or stereoisomer thereof, wherein R 1 It is -CH2NHSO2NH2.

12. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein each R X Independently, it is a halogen, -NH2, -NH(C1-C6)alkyl, -(C1-C6)alkyl, or -(C1-C6)haloalkyl; or two Rs on the same carbon. X They combine to form oxygen.

13. The compound according to claim 12 or its pharmaceutical salt or stereoisomer, wherein each R X Independently -NH2, -NH(C1-C6)alkyl, or -(C1-C6)alkyl; or two Rs on the same carbon. X They combine to form oxygen.

14. The compound according to claim 1, or a pharmaceutical salt or stereoisomer thereof, wherein Y is optionally derived from one, two, or three R... Y Substituted phenylene.

15. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein each R Y It can be halogen, -OH or -(C1-C6)alkyl independently.

16. The compound of claim 1 or its pharmaceutical salt or stereoisomer, wherein Z is optionally substituted with a -(C3-C7) saturated cycloalkyl group and is a -(C1-C7) cycloalkyl group. 12 )alkyl.

17. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein Z is -(C1-C1) / (C1- ... 12 ) Haloalkyl.

18. The compound of claim 1 or its pharmaceutical salt or stereoisomer, wherein Z is a -(C3-C9) saturated cycloalkyl group optionally substituted with -(C1-C6) alkyl.

19. The compound of claim 18 or its pharmaceutical salt or stereoisomer, wherein Z is optionally a -(C3-C7) saturated cycloalkyl group substituted with -(C1-C6) alkyl.

20. The compound according to claim 1 or its pharmaceutical salt or stereoisomer, wherein Z is an -O-(C1-C6) alkyl or an -O-(C3-C7) saturated cycloalkyl.

21. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein Z is -(C1-C1) / (C1- ... 12 )alkyl.

22. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein Z is -(C1-C1) / (C1- ... 12 ) Haloalkyl.

23. The compound according to claim 1 or its pharmaceutical salt or stereoisomer, wherein Z is a -(C3-C9) saturated cycloalkyl group.

24. The compound according to claim 23 or its pharmaceutical salt or stereoisomer, wherein Z is a -(C3-C7) saturated cycloalkyl group.

25. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein -XYZ is...

26. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein -XYZ is...

27. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein -XYZ is...

28. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein -XYZ is...

29. The compound according to claim 1, or its pharmaceutical salt or stereoisomer, wherein -XYZ is...

30. A compound or its pharmaceutical salt or stereoisomer, selected from the group consisting of:

31. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutical salt or stereoisomer thereof, and a pharmaceutical excipient.

32. Use of the compound of claim 1 or its pharmaceutical salt or stereoisomer, or the pharmaceutical composition of claim 31, in the preparation of a medicament for treating a patient with a bacterial infection, wherein the bacterial infection involves Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, or Acinetobacter baumannii.

33. The use according to claim 32, wherein the compound or its pharmaceutical salt or stereoisomer is selected from the group consisting of:

34. The use according to claim 32, wherein the pharmaceutical composition comprises a compound selected from the group consisting of:

35. The use according to claim 32, wherein the compound or its pharmaceutical salt or stereoisomer is (8S,11S,14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-2-[[4-amino-2-(4-tert-butylphenyl)-6-methyl-pyrimidin-5-carbonyl]amino]-3-(aminosulfonylamino)propionyl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

36. The use according to claim 32, wherein the compound or its pharmaceutical salt or stereoisomer is (8S,11S,14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-4-amino-2-[[4-amino-2-(4-tert-butylphenyl)-6-methyl-pyrimidin-5-carbonyl]amino]butyryl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaeno-8-carboxylic acid.

37. The use according to claim 32, wherein the compound or its pharmaceutical salt or stereoisomer is (8S,11S,14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-4-amino-2-[[4-methyl-2-[4-(1-methylcyclopropyl)phenyl]pyrimidin-5-carbonyl]amino]butyryl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaeno-8-carboxylic acid.

38. The use according to claim 32, wherein the compound or its pharmaceutical salt or stereoisomer is (8S,11S,14S)-18-hydroxy-11-methyl-14-[methyl-[(2S)-4-amino-2-[[2-(4-tert-butylphenyl)-4-amino-6-difluoromethyl-pyrimidin-5-carbonyl]amino]butyryl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12-diazatricyclo[13.3.1.12,6]eicosano-1(18),2(20),3,5,15(19),16-hexaeno-8-carboxylic acid.

39. The use according to claim 32, wherein the treatment is combined with a second therapeutic agent.

40. The use according to claim 39, wherein the second therapeutic agent is not an SpsB inhibitor or a LepB inhibitor.

41. The use according to claim 40, wherein the second therapeutic agent is an aminoglycoside antibiotic, a fluoroquinolone antibiotic, a β-lactam antibiotic, a macrolide antibiotic, a glycopeptide antibiotic, rifampin, chloramphenicol, fluoromycin, colistin, mupirocin, bacitracin, daptomycin, or linezolid.

42. The use according to claim 41, wherein the second therapeutic agent is a β-lactam antibiotic.

43. The use according to claim 42, wherein the β-lactam antibiotic is selected from penicillins, monocyclic lactams, cephalosporins, cephamycins, and carbapenems.

44. The use according to claim 43, wherein the β-lactam antibiotic is selected from azlocillin, amoxicillin, ampicillin, doripenem, meropenem, biapenem, cefamandole, imipenem, meropenem, cefmetazole, cefprozil, piperacillin / tazobactam, carbenicillin, cefaclor, cephalosporin, ertapenem, cefazolin, cefepime, cefnicillin, cefoxitin, ceftazidime, oxacillin, cefdinir, cefixime, cefotaxime, cefotetan, cefpodoxime, cefazolin, ceftriaxone, faropenem, mecillin, methicillin, latamoxef, ticarcillin, tomopenem, cefepime, cefuroxime, fluoxetine, cefpirome, and cefazolin.

45. The use according to claim 32, wherein the treatment is in combination with a β-lactamase inhibitor.

46. ​​The use according to claim 32, wherein the bacterial infection involves Acinetobacter baumannii.

47. The use according to claim 32, wherein the bacterial infection is an infection involving Escherichia coli.

48. The use according to claim 32, wherein the bacterial infection is an infection involving Klebsiella pneumoniae.

49. The use according to claim 32, wherein the bacterial infection is an infection involving Pseudomonas aeruginosa.

50. The use according to claim 32, wherein the patient is a human.

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