S1P₁ receptor agonists and their uses

Abstract

The present invention relates to a compound of the chemical formula (1a): (1a) The invention relates to or its enantiomers, racemic mixtures, or pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition comprising a compound of formula (1a), its enantiomers, racemic mixtures, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable excipients, and a method for treating autoimmune diseases, central nervous system diseases, and leukocyte disorders, comprising the step of administering the pharmaceutical composition of the invention to an individual in need.

Description

Technology Field

[0001] The present disclosure relates to a compound of formula (1a). The present disclosure also relates to a pharmaceutical composition comprising a compound of formula (1a), and a method for treating autoimmune diseases, central nervous system diseases, and leukocyte disorders. The present disclosure also relates to a process for preparing a compound of formula (1a). Background Technology

[0002] Sphingosine-1-phosphate receptor 1 ("S1P1 receptor") is widely expressed in animals (e.g., in endothelial cells, proximal tubular epithelial cells, and immune cells) and helps regulate growth, survival, differentiation, motility, angiogenesis, calcium mobilization, lymphocyte trafficking, immune function, and cytoskeletal rearrangement. Chemical compounds that modulate S1P1 receptors are useful in the treatment of various diseases such as multiple sclerosis (MS), relapsing-remitting multiple sclerosis (RRMS), amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), psoriasis, systemic lupus erythematosus (SLE), ulcerative colitis, and Crohn's disease. See M. Guerrero et al., Expert Opinion on Therapeutic Patents (2016), 26(4), 455-70; A. Marciniak et al., Bioorg. Med. Chem Lett. (2018), 28(23-24), 3585-91; Each of these is incorporated herein by reference in its entirety.

[0003] The present disclosure relates to a compound of formula (1):

[0004] (1)

[0005] Here

[0006] Is

[0007] , , , and Selected from a group composed of;

[0008] R1 is -Q-(CR g R f ) m -U and;

[0009] R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[0010] R4, R5, R6, R7, R8, and R9 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c )2, CN, selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0011] Y is CR a or N and;

[0012] Z is CR b or N and;

[0013] Q is O, S, NH, or -(CR h R d ) p - and;

[0014] U is -COOR e , -COSR e, -CON(R e )2, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[0015] n is 0, 1, or 2, and;

[0016] m is 0, 1, 2, 3, 4, or 5;

[0017] p is 0, 1, or 2, and;

[0018] R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[0019] R c is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or a substituted C1-C6 straight-chain or branched alkyl;

[0020] R d is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0021] R e is H or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0022] R f is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0023] R g is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0024] R h is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0025] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0026] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, COOH, COSH, and CONH2;

[0027] The substituted cycloalkyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- nPr , O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, COOH, COSH, and CONH2;

[0028] The substituted heterocyclyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, COOH, COSH, and CONH2;

[0029] Here, the substituted aryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, COOH, COSH, and CONH2; and

[0030] Here, the substituted heteroaryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( iSubstituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, COOH, COSH, and CONH2; or

[0031] It relates to its enantiomers; racemic mixtures; or pharmaceutically acceptable salts.

[0032] The present disclosure also relates to a pharmaceutical composition comprising a compound of formula (1) or its enantiomer, racemic mixture, or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients.

[0033] The present disclosure also relates to a method for treating autoimmune diseases, central nervous system diseases, and leukocyte disorders, comprising the step of administering to an individual in need a pharmaceutical composition comprising a compound of formula (1) or a mirror image isomer, racemic mixture, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0034] The present disclosure also relates to a process for producing a compound of formula (1) or its enantiomer, racemic mixture, or pharmaceutically acceptable salt. Brief explanation of the drawing

[0035] To ensure a good understanding of the present disclosure, various forms provided as examples will now be described with reference to the accompanying drawings. The components of the drawings are not necessarily scaled to size. Fig. 1 Figure 1 plots the % retention rate of dextromethorphan over time with NADPH in human liver microsome samples; Fig. 2 1-(4-(2-(1 over time with NADPH in human liver microsome samples H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 HPlot the % residual rate of )-on (Compound 3 in Table 29 below); Fig. 3 Figure 1 plots the % retention rate of dextromethorphan with NADPH over time in rat liver microsome samples; Fig. 4 Figure 1 plots the % retention rate of Compound 3 with NADPH over time in rat liver microsome samples; Fig. 5 Plots of enzyme inhibition of 1A2 CYP isoforms by compound 3 at various concentrations of compound 3 are plotted; Fig. 6 Plots of enzyme inhibition of 2C9 CYP isoforms by compound 3 at various concentrations of compound 3 are plotted; Fig. 7 Plots of enzyme inhibition of 2C19 CYP isoforms by compound 3 at various concentrations of compound 3 are plotted; Fig. 8 Plots of enzyme inhibition of 2D6 CYP isoforms by compound 3 at various concentrations of compound 3 are plotted; Fig. 9 Plots of enzyme inhibition of 3A4 / 5 CYP isoforms by compound 3 at various concentrations of compound 3 are plotted; Fig. 10 Plots of enzyme inhibition of the 2B6 CYP isoform by compound 3 at various concentrations of compound 3 are plotted; Fig. 11 Plots of enzyme inhibition of 2C8 CYP isoforms by compound 3 at various concentrations of compound 3 are plotted; Fig. 12 Plots of enzyme inhibition of 1A2 CYP isoforms by the positive control at various concentrations of the positive control are plotted; Fig. 13 Plots of enzyme inhibition of 2C9 CYP isoforms by the positive control at various concentrations of the positive control are plotted; Fig. 14 Plots of enzyme inhibition of 2C19 CYP isoforms by the positive control at various concentrations of the positive control are plotted; Fig. 15Plots of enzyme inhibition of 2D6 CYP isoforms by the positive control at various concentrations of the positive control are plotted; Fig. 16 Plots of enzyme inhibition of 3A4 / 5 CYP isoforms by the positive control at various concentrations of the positive control are plotted; Fig. 17 Plots of enzyme inhibition of 2B6 CYP isoforms by the positive control at various concentrations of the positive control are plotted; Fig. 18 Plots of enzyme inhibition of 2C8 CYP isoforms by the positive control at various concentrations of the positive control are plotted; Fig. 19 Figure 1 plots the % retention rate of phenacetin over time in human hepatocyte samples; Fig. 20 Figure 1 plots the % retention rate of diclofenac over time in human hepatocyte samples; Fig. 21 Figure 1 plots the % retention rate of dextromethorphan over time in human hepatocyte samples; Fig. 22 Figure 1 plots the % retention rate of omeprazole over time in human hepatocyte samples; Fig. 23 Figure 1 plots the % retention rate of midazolam over time in human hepatocyte samples; Fig. 24 Figure 1 plots the % retention rate of 7-ethoxycoumarin over time in human hepatocyte samples; Fig. 25 Figure 1 plots the % retention rate of compound 3 over time in human hepatocyte samples; Fig. 26 Figure 1 shows a plot of the % retention rate of phenacetin over time in rat hepatocyte samples; Fig. 27 Figure 1 shows a plot of the % retention rate of diclofenac over time in rat hepatocyte samples; Fig. 28 Figure 1 plots the % retention rate of dextromethorphan over time in rat hepatocyte samples; Fig. 29 Figure 1 shows a plot of the % retention rate of omeprazole over time in rat hepatocyte samples; Fig. 30 Figure 1 plots the % retention rate of midazolam over time in rat hepatocyte samples; Fig. 31Figure 1 plots the % retention rate of 7-ethoxycoumarin over time in rat hepatocyte samples; Fig. 32 Figure 1 plots the % retention rate of compound 3 over time in rat hepatocyte samples; Fig. 33 Line plots of transient lymphopenia accompanied by complete recovery by measuring circulating lymphocytes over time following administration of the vehicle, or Compound 3 at 8 mg / kg, 60 mg / kg, and 100 mg / kg, respectively; Fig. 34 ...shows a bar-graph plot of transient lymphopenia accompanied by complete recovery by measuring circulating lymphocytes over time following administration of the vehicle, or Compound 3 at 8 mg / kg, 60 mg / kg, and 100 mg / kg, respectively; Fig. 35 It plots the number of circulating lymphocytes for vehicle administration over time; Fig. 36 Figure 1 shows the number of circulating lymphocytes for the administration of 8 mg / kg compound 3 over time; Fig. 37 Figure 1 shows the number of circulating lymphocytes for the administration of 60 mg / kg of compound 3 over time; Fig. 38 Figure 1 shows the number of circulating lymphocytes for the administration of 100 mg / kg of compound 3 over time; Fig. 39 is compound 3,2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d β-arrestin recruitment for the first experimental study of administration of ]pyrimidine-2-yl)-2,6-dimethylphenoxy)acetic acid ("Compound A"), sphingosine-1-phosphate ("S1P"), Ponesimod, and Siponimod, respectively, is illustrated; Fig. 40 Figure 1 illustrates β-arrestin recruitment for the second experimental test of administration of each of Compound 3, Compound A, S1P, Ponesimod, and Siponimod; Fig. 41 G for the first experimental test of the administration of each of Compound 3, Compound A, S1P, Ponesimod, and Siponimod αi-Plot the protein activation reaction curve; Fig. 42 is G for the second experimental test of the administration of Compound 3, Compound A, S1P, Ponesimod, and Siponimod, respectively. αi -Plot the protein activation reaction curve; Fig. 43 Figure 1 shows the mean ± standard deviation of rat plasma concentrations of Compound 3 administered orally and intravenously; Fig. 44 Figure 1 plots the individual rat plasma concentrations over time of compound 3 administered intravenously; Fig. 45 Figure 1 plots the individual rat plasma concentrations over time of orally administered compound 3; The drawings described herein are for illustrative purposes only and are not intended to limit the scope of the disclosure in any way. Specific details for implementing the invention

[0036] The following description is for illustrative purposes only and is not intended to limit the disclosure, application, or use thereof.

[0037] In the context describing this disclosure (particularly in the context of the following claims), the use of the terms “a,” “an,” “the,” and similar designations shall be interpreted as including both singular and plural forms, unless otherwise indicated herein or otherwise evidently contradictory in the context. The use of the term “plurality of” is defined by the applicant in the broadest sense, prior to any other definition or limitation prior to or subsequent, unless expressly asserted by the applicant to the contrary, and signifies a quantity greater than one. The description of a range of values ​​in this disclosure is intended to function merely as a shortened method of individually referring to each individual value within the range, unless otherwise indicated herein, and each individual value is included in the specification as individually described herein. All methods described herein may be performed in any appropriate order, unless otherwise indicated herein or otherwise evidently contradictory in the context.

[0038] As used herein, the terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variations thereof are intended as open-ended transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. This description also considers other examples of examples or elements presented herein that are “comprised,” “consisted of,” and “essentially composed of,” regardless of whether they are explicitly stated.

[0039] In describing the elements of the present disclosure, the term primary (1 st ), 2nd (2 nd ), first, second, A, B, (a), (b), etc. may be used herein. These terms are used merely to distinguish one element from another and do not restrict the corresponding elements regardless of the nature or order of the corresponding elements.

[0040] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by those skilled in the art to which this disclosure pertains. Such terms, such as those defined in commonly used dictionaries, should be interpreted as having the same meaning as their contextual meaning in the relevant technical field.

[0041] As used herein, the term “about” means a variation of ±15% or less of a numerical value when used in the context of a numerical value or a stated range. For example, values ​​differing by ±15%, ±14%, ±10%, or ±5% satisfy the definition of “about” unless more narrowly defined in a specific case.

[0042] The present disclosure relates to a compound of formula (1):

[0043] (1)

[0044] Here

[0045] Is

[0046] , , , and Selected from a group consisting of:

[0047] R1 is -Q-(CR g R f ) m -U and;

[0048] R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[0049] R4, R5, R6, R7, R8, and R9 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl groups, F, Cl, Br, I, OR c , SR c , N(R c )2, CN, selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0050] Y is CR a or N and;

[0051] Z is CR b or N and;

[0052] Q is O, S, NH, or -(CR h R d ) p - and;

[0053] U is -COOR e, -COS(O) p R e , -CONHS(O) p R e , -CONHR e , -CON(R e )2, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[0054] n is 0, 1, or 2, and;

[0055] m is 0, 1, 2, 3, 4, or 5;

[0056] p is 0, 1, or 2, and;

[0057] R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[0058] R c is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or a substituted C1-C6 straight-chain or branched alkyl;

[0059] R d is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0060] R e is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or F, Cl, Br, I, OR c , SR c , N(R c It is a C1-C6 straight-chain or branched alkyl substituted with one or more substituents selected from the group consisting of )2, and CN;

[0061] R fis H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0062] R g is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0063] R h is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0064] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0065] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2;

[0066] The substituted cycloalkyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- iPr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2;

[0067] The substituted heterocyclyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2;

[0068] Here, the substituted aryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and

[0069] Here, the substituted heteroaryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; or

[0070] It relates to its enantiomers; racemic mixtures; or pharmaceutically acceptable salts.

[0071] The term "alkyl" means a straight-chain, branched, or cyclic hydrocarbon having a specified number of carbon atoms, either itself or as part of other substituents, unless otherwise specified (i.e., "C1-C 20 " is C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 (meaning 1 to 20 carbons including ). In certain embodiments, C1-C 20may not contain C1 alkyl, and / or may not contain C2 alkyl, and / or may not contain C3 alkyl, and / or may not contain C4 alkyl, and / or may not contain C5 alkyl, and / or may not contain C6 alkyl, and / or may not contain C7 alkyl, and / or may not contain C8 alkyl, and / or may not contain C9 alkyl, and / or C 10 It may not contain alkyl groups, and / or C 11 It may not contain alkyl groups, and / or C 12 It may not contain alkyl groups, and / or C 13 It may not contain alkyl groups, and / or C 14 It may not contain alkyl groups, and / or C 15 It may not contain alkyl groups, and / or C 16 It may not contain alkyl groups, and / or C 17 It may not contain alkyl groups, and / or C 18 It may not contain alkyl groups, and / or C 19 It may not contain alkyl groups, and / or C 20 It may not contain alkyl groups. Examples include methyl, ethyl, propyl, isopropyl, and cyclopropyl. n -Butyl, isobutyl, sec -butyl, tert - It may include butyl, cyclobutyl, methylcyclopropyl, cyclopropylmethyl, pentyl, neopentyl, hexyl, and cyclohexyl.

[0072] It can be used as R4, R5, R6, R7, R8, R9, U, or R1 and R2, R1 and R3, R2 and R a , or R3 and R b Examples of cycloalkyl groups that can be formed together by any of the above may include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0073] The terms “alkene” and “olefin” each refer to a stable single-unsaturated, double-unsaturated, or polyunsaturated straight-chain, branched-chain, or cyclic hydrocarbon (“cycloalkene”), either in itself or as part of other substituents, unless otherwise specified, where “unsaturated” means a carbon-carbon double bond (-CH=CH-). The term “alkenyl” refers to a stable single-unsaturated, double-unsaturated, or polyunsaturated straight-chain, branched-chain, or cyclic hydrocarbon monovalent radical having a specified number of carbon atoms, either in itself or as part of other substituents. Examples may include vinyl, propenyl, cyclopropenyl, allyl, crotyl, isopentenyl, butadienyl, cyclobutenyl, 1,3-pentadienyl, 1,4-pentadienyl, cyclopentenyl, cyclopentadienyl, 3-hydroxy-2-methyl-1-oxo-cyclopent-2-enyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, and higher homologs and isomers.

[0074] The term “aromatic” generally refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic properties (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer). The term “aryl” means a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), either by itself or in combination with other substituents, unless otherwise specified, wherein these rings may be attached to each other in a pendant manner, as in biphenyl, or fused, as in naphthalene.

[0075] The terms “heterocycle,” “heterocyclil,” or “heterocyclic” mean an unsubstituted or substituted, stable, single- or multi-cyclic heterocyclic ring system consisting of, either as itself or as part of other substituents, a carbon atom and at least one heteroatom independently selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen atom may optionally be quaternized. Unless otherwise specified, the heterocyclic system may be attached to any heteroatom or carbon atom that provides a stable structure.

[0076] It can be used as R4, R5, R6, R7, R8, R9, U, or R1 and R2, R1 and R3, R2 and R a , or R3 and R b Examples of heterocyclic groups that can be formed together by any of the above may include, for example, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxetanil, tetrahydrofuranil, dihydrofuranil, tetrahydropyranil, dihydropyranil, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyranil, 3,5-dioxoisoxazolidinyl, and dihydrothiopyranil.

[0077] It can be used as R4, R5, R6, R7, R8, R9, U, or R1 and R2, R1 and R3, R2 and R a , or R3 and R b Examples of aryl groups that can be formed together with any of the above may include, for example, phenyl, naphthalenyl, cyclobutadienyl, cyclopentadienyl, indenyl, anthracenyl, phenanthrenyl, terphenylenyl, fluorenyl, and pyrenyl.

[0078] The terms "heteroaryl" and "heteroaromatic" refer to heterocyclic groups having aromatic properties, either by themselves or in combination with other substituents, unless otherwise specified. They may be used as R4, R5, R6, R7, R8, R9, U, or R1 and R2, R1 and R3, R2 and R a , or R3 and R b Examples of heteroaryl groups that any of the above can form together are, for example, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, 5(4 H )-oxo-1,2,4-thiadiazollil, oxazolil, 5(4 H )-oxo-1,2,4-oxadiazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinil, pyrimidinyl, pyrazinyl, tetrazolyl, 1H-indolyl, 3H-indolyl, 2H-isoindolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, furinyl, indazolyl, benzimidazolyl, benzo[ d ]Oxazole, benzo[ d ]thiazole, benzo[ c ]isooxazole, benzo[ d ]isooxazole, benzo[ c ]isothiazole, benzo[ d ]isothiazole, quinoline-2(1H)-one, isoquinoline-1(2H)-one, indoline-2-one, isoindoline-1-one, 1H-benzo[ d ]Imidazole-2(3H)-one, 1H-benzo[ d ]Imidazole-2(3H)-thion, furanyl, carbazolyl, benzofuranil, isobenzofuranil, dibenzofuranil, benzofuran-2(3H)-one, isobenzofuran-1(3H)-one, thiophenyl, benzo[ b ]thiophenyl, benzo[ c ]thiophenyl, benzo[ b ]thiophene-2(3H)-one, and benzo[ c It may contain thiophene-1(3H)-one.

[0079] In the compound of formula (1) or (1a), the cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i It can be substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2.

[0080] C1-C6 straight-chain or branched alkyl groups are F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i It can be substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2.

[0081] Another embodiment of the present invention is a compound of formula (1a):

[0082] (1a)

[0083] Here

[0084] Is

[0085] , , , and Selected from a group consisting of:

[0086] Is , , , , , , , , , , , , , and Selected from a group composed of;

[0087] R1 is (T) w -(CR g R f ) m -Q-(CR g R f ) m -U and;

[0088] R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[0089] R4, R5, R6, R7, R8, R9, and R 10 is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , S(O)2R i , S(O)2N(R c )2, N(R c )2, CN, C(O)R i , N(R c )C(O)R i , C(O)N(R c)2, selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0090] R 11 silver , , , H, OCH2C(O)2R c Selected from the group consisting of unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;

[0091] Y is CR a or N and;

[0092] Z is CR b or N and;

[0093] Q is O, S, NR i , or -(CR h R d ) p - and;

[0094] T is O, S, NR i , or -(CR h R d ) p - and;

[0095] U is -COOR e , -COS(O) p R e , -C(O)NHS(O) p R e , -CONHR e , -CON(R e )2, vinyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, , , , or B(OH)2 and;

[0096] n is 0, 1, or 2, and;

[0097] Each m is independently 0, 1, 2, 3, 4, or 5;

[0098] p is 0, 1, or 2, and;

[0099] w is 0, 1, or 2, and;

[0100] R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[0101] R c is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0102] R d is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0103] R e is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or F, Cl, Br, I, OR c , SR c , N(R c It is a C1-C6 straight-chain or branched alkyl substituted with one or more substituents selected from the group consisting of )2, and CN;

[0104] R f is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0105] R g is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0106] R his H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0107] R i is H, D, F, Cl, Br, I, an unsubstituted C1-C6 straight-chain or branched alkyl, or an unsubstituted cycloalkyl;

[0108] R j is a substituted or unsubstituted C1-C6 straight-chain or branched alkyl, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0109] Here, R1 and R2, R1 and R3, R2 and R a , R4 and R5, R6 and R7, or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0110] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OC4alkyl, OC5alkyl, OC6alkyl, unsubstituted cycloalkyl, substituted heterocyclyl, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, Substituted with one or more substituents selected from the group consisting of carbonyl, COOH, COSH, CONMe2, CONHMe, and CONH2;

[0111] The substituted cycloalkyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2;

[0112] Here, the substituted heterocyclyl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, an unsubstituted heterocyclyl group, an unsubstituted heteroaryl group, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2;

[0113] Here, the substituted aryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N(n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, CONH2, and CONHPh; and

[0114] Here, the substituted heteroaryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; or

[0115] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[0116] Another embodiment of the present disclosure is a compound of formula (1) or (1a):

[0117] Is

[0118] and Selected from a group composed of;

[0119] Is And;

[0120] R 11 silver And;

[0121] R1 is -Q-(CHR f ) m -U and;

[0122] R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[0123] R4, R5, R6, R7, R8, and R9 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl, F, Cl, Br, I, OR c Selected from the group consisting of a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0124] Y is CR a or N and;

[0125] Z is CR b or N and;

[0126] Q is O, S, or -(CHR d ) p - and;

[0127] U is -COOR e , a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[0128] n is 0 or 1 and;

[0129] m is 0, 1, 2, 3, or 4;

[0130] p is 0 or 1 and;

[0131] R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[0132] R cis H, an unsubstituted C1-C6 straight-chain or branched alkyl, or a substituted C1-C6 straight-chain or branched alkyl;

[0133] R d is H, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0134] R e is H or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0135] R f is H, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0136] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0137] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[0138] The substituted cycloalkyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( iSubstituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[0139] The substituted heterocyclyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[0140] Here, the substituted aryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; and

[0141] Here, the substituted heteroaryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; or

[0142] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[0143] Another embodiment of the present disclosure is a compound of formula (1) or (1a):

[0144] Is

[0145] and Selected from a group composed of;

[0146] Is And;

[0147] R 11 silver And;

[0148] R1 is -Q-(CHR f ) m -U and;

[0149] R2 and R3 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[0150] R4, R5, R6, R7, R8, and R9 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -Propyl, isopropyl, substituted isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, F, Cl, Br, I, OR c Selected from the group consisting of a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0151] Y is CR a or N and;

[0152] Z is CR b or N and;

[0153] Q is O or -(CHR d ) p - and;

[0154] U is -COOR e, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[0155] n is 0 or 1 and;

[0156] m is 0, 1, 2, 3, or 4;

[0157] p is 0 or 1 and;

[0158] R a and R b is independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[0159] R c is H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n - It is propyl, isopropyl, or substituted isopropyl;

[0160] R d is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[0161] R e is H, methyl, ethyl, n - It is propyl, or isopropyl;

[0162] R f is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[0163] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R bIt together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0164] The methyl, ethyl, substituted here n -Propyl, or isopropyl, is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[0165] The substituted cycloalkyl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2;

[0166] The heterocyclyl group substituted here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2;

[0167] The substituted aryl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2; and

[0168] The heteroaryl group substituted here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2; or

[0169] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[0170] Another embodiment of the present disclosure is a compound of formula (1) or (1a):

[0171] Is

[0172] and Selected from a group composed of;

[0173] Is And;

[0174] R 11 silver And;

[0175] R1 is -Q-(CHR f ) m -U and;

[0176] R2 and R3 independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[0177] R4, R5, R6, R7, R8, and R9 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -Propyl, isopropyl, substituted isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, F, Cl, Br, I, OR c Selected from the group consisting of , phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;

[0178] Y is CR a or N and;

[0179] Z is CR b or N and;

[0180] Q is O or -(CHR d ) p - and;

[0181] U is -COOR e , a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[0182] n is 0 or 1 and;

[0183] m is 0, 1, 2, 3, or 4;

[0184] p is 0 or 1 and;

[0185] R a and R b is independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[0186] R c is H, methyl, CH2F, CHF2, CF3, ethyl,n - It is propyl, or isopropyl;

[0187] R d is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[0188] R e is H, methyl, ethyl, n - It is propyl, or isopropyl;

[0189] R f is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[0190] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0191] The methyl, ethyl, substituted here n -Propyl, or isopropyl, is substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, NH2, carbonyl, and COOH;

[0192] The substituted cycloalkyl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH;

[0193] The heterocyclyl group substituted here is methyl, ethyl, n-Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH;

[0194] The substituted aryl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; and

[0195] The heteroaryl group substituted here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; or

[0196] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[0197] Another embodiment of the present disclosure is a compound of formula (1) or (1a):

[0198] Is

[0199] and Selected from a group composed of;

[0200] Is And;

[0201] R 11 silver And;

[0202] R1 is -Q-(CHR f ) m -U and;

[0203] R2 and R3 independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[0204] R4, R5, R6, R7, R8, and R9 independently H, methyl, CF3, ethyl, n -Propyl, Isopropyl, Cyclopropyl, Cyclobutyl, Cyclopentyl, F, Cl, Br, I, OR c Selected from the group consisting of , phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;

[0205] Y is CR a or N and;

[0206] Z is CR b or N and;

[0207] Q is O or -(CHR d ) p - and;

[0208] U is -COOH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[0209] n is 0 or 1 and;

[0210] m is 0 or 1 and;

[0211] p is 0 or 1 and;

[0212] R a is H or methyl;

[0213] R b is H or methyl;

[0214] R c is H, methyl, or CF3;

[0215] R d is H, F, Cl, Br, or methyl;

[0216] R f is H, F, Cl, Br, or methyl;

[0217] Herein, R1 and R2 or R1 and R3 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0218] The substituted cycloalkyl group here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[0219] The heterocyclyl group substituted here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[0220] The substituted aryl group here is methyl, ethyl, n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; and

[0221] The heteroaryl group substituted here is methyl, ethyl, n-Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; or

[0222] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[0223] Another embodiment of the present disclosure is a compound of formula (1) or (1a):

[0224] Is

[0225] and Selected from a group composed of;

[0226] Is And;

[0227] R 11 silver And;

[0228] R1 is -Q-(CHR f ) m -U and;

[0229] R2 and R3 are independently H or methyl;

[0230] R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, methyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, CF3, F, Cl, Br, OMe, and OCF3;

[0231] Y is CH or N;

[0232] Z is CH or N;

[0233] Q is O or -(CHR d ) p - and;

[0234] U is -COOH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[0235] n is 0 or 1 and;

[0236] m is 0 or 1 and;

[0237] p is 0 or 1 and;

[0238] R d is H, F, or methyl;

[0239] R f is H, F, or methyl;

[0240] Herein, R1 and R2 or R1 and R3 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[0241] The substituted cycloalkyl group here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[0242] The heterocyclyl group substituted here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[0243] The substituted aryl group here is methyl, ethyl, n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; and

[0244] The heteroaryl group substituted here is methyl, ethyl, n-Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; or

[0245] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[0246] In some embodiments, the compound of formula (1) or (1a)

[0247]

[0248]

[0249] and Selected from a group composed of;

[0250] or

[0251] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[0252] In some embodiments, the compound of formula (1) or (1a)

[0253]

[0254] and Selected from a group composed of;

[0255] Or it is a pharmaceutically acceptable salt thereof.

[0256] Pharmaceutically acceptable salts of the compound of formula (1) or (1a) are inorganic acids such as hydrochloric acid, hydrobromide, hydroiodide, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid, and, for example, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p - It can be prepared from organic acids such as toluenesulfonic acid and tartaric acid by methods known in the art.

[0257] Pharmaceutical composition

[0258] The present disclosure relates to a pharmaceutical composition comprising a compound of formula (1) or (1a) or a mirror image isomer, racemic mixture, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0259] Excipients suitable for use in the pharmaceutical compositions of the present disclosure include diluents such as lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, cellulose, microcrystalline cellulose, microcellulose, and talc; binders such as copovidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, alginate, and sodium carboxymethylcellulose; Natural starch, pregelatinized starch, sodium starch, clay, gum, sodium alginate, methylcrystalline cellulose, methylcellulose, croscarmellose, sodium croscarmellose, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch (e.g., sodium starch glycolate), cross-linked polymer (e.g., crospovidone), and disintegrants such as cross-linked polyvinylpyrrolidone; Lubricants such as stearic acid, stearate salts (e.g., magnesium stearate, calcium stearate, and zinc stearate), palmitic acid, palmitate salts (e.g., magnesium palmitate, calcium palmitate, and zinc palmitate), myristic acid, myristic salts (e.g., magnesium myristic, calcium myristic, and zinc myristic), fatty acid esters (e.g., glyceryl monostearate, sorbitan monostearate, and sucrose monopalmitate), and sodium stearyl fumarate;Fatty acids (e.g., oleic acid, palmitic acid, and stearic acid), fatty acid salts (e.g., sodium oleate, triethanolamine oleate, sodium palmitate, triethanolamine palmitate, sodium stearate, and triethanolamine stearate), glyceryl fatty acid esters (e.g., glyceryl monooleate, glyceryl monopalmitate, glyceryl monostearate), sorbitan esters (e.g., sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, and sorbitan tristearate), polyoxyethylene sorbitan esters (e.g., polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sulfate surfactants (e.g., sodium lauryl sulfate and sodium laureth sulfate), Lecithin, quaternary ammonium compounds (e.g., benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride), laurylaminopropionic acid, sodium laurylaminopropionate, alkyl polyglucosides (e.g., octyl glucoside, decyl glucoside, and lauryl glucoside), polyoxyethylene alkylphenyl ethers (e.g., nonoxynol 9, nonoxynol 10, and octoxynol 9), poloxamers (e.g., polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene alkyl ethers (e.g., polyoxyethylene (20) cetostearyl ether), polyoxyethylene fatty acid esters (e.g., polyoxyethylene (40) stearate), polyoxyethylene fatty acid glycerides and oils (e.g., polyoxyethylene (35) castor oil, and polyoxyethylene (40) hydrogenated castor oil), propylene Surfactants such as glycol fatty acid esters (e.g., propylene glycol laurate); buffers such as phosphate buffer, carbonate buffer, and citrate buffer;Antioxidants such as sulfites (e.g., sodium sulfite), ascorbic acid, ascorbates (e.g., sodium ascorbate, calcium ascorbate, and potassium ascorbate), ethylenediamine tetraacetic acid (EDTA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT), ascorbyl palmitate, fumaric acid, tocopherol, and vitamin E; quaternary ammonium compounds (e.g., benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride), benzoic acid, benzoate salts (e.g., sodium benzoate), sorbic acid, and sorbate salts (e.g., sodium sorbate); Stabilizers such as povidone, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; salts such as alkali metal salts (e.g., sodium chloride); fillers such as mannitol, sorbitol, maltodextrin, maltose, and dextrin; flavor enhancers such as sweeteners; synthetic organic food additives (e.g., food dyes, e.g., food red dyes No. 3 and 40; food yellow dyes No. 4, 5, and 6; food green dye No. 3; and food blue dyes No. 1, 2, and 3), water-insoluble lake dyes (e.g., aluminum salts of water-soluble synthetic organic food additives), and colorants such as natural pigments (e.g., beta-carotene, chlorophyll, betanin, iron oxide); and mixtures thereof may be selected from the group consisting of

[0260] The pharmaceutical compositions disclosed herein may be administered by inhalation (i.e., into the nasal cavity as an aerosol or inhalation solution or suspension); topically (i.e., in the form of an ointment, cream or lotion); orally (i.e., in solid or liquid form as a tablet, capsule, gel cap, time-release capsule, powder, solution, or suspension in an aqueous or non-aqueous liquid); intravenously by injection or injection (i.e., as a solution, suspension or emulsion in a pharmaceutically acceptable carrier); intramuscularly, intradermally, or subcutaneously by injection or injection (i.e., as a solution, suspension or emulsion in a pharmaceutically acceptable carrier) or as a depot formulation; transdermally (e.g., via a transdermal patch), rectum (e.g., as a suppository), or intraperitoneally.

[0261] There are no restrictions on the route of administration or dosage form, and the composition may be administered depending on the specific form of the formulation, the patient's age, gender and other conditions, the severity of the disease, etc. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, the composition is administered orally. In the case of injection, the composition is administered intravenously, either alone or mixed with conventional alternative fluids such as glucose and amino acids, and if necessary, the formulation alone may also be administered intramuscularly, intradermally, subcutaneously, or intraperitoneally.

[0262] The dosage of the pharmaceutical composition of the present invention is appropriately selected according to the patient's administration regimen, age, gender, and other conditions. The amount to be administered depends on the lipophilicity of the selected specific compound, as this property of the compound is expected to cause distribution to the fat deposits of the subject. The exact amount to be administered can be determined by a person skilled in the art in light of the desired dosage, side effects, and the patient's medical history. The amount is sufficient to treat or prevent the condition or disease state to be treated. That is, the amount is sufficient to treat or prevent autoimmune diseases including ulcerative colitis, Crohn's disease, psoriasis, and systemic lupus erythematosus (SLE); central nervous system diseases including multiple sclerosis (MS), relapsing-remitting multiple sclerosis (RRMS), and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease); and leukocyte disorders including lymphopenia. The dosage may be in the range of about 0.001 mg to 5,000 mg per administration. In some embodiments, the dosage is in the range of about 0.010 mg to 1,000 mg per dose. In some embodiments, the dosage is in the range of about 0.100 mg to 500 mg per dose. In some embodiments, the dosage is in the range of about 1 mg to 250 mg per dose. In certain embodiments, the dosage is from about 0.001 mg, or from 0.010 mg, or from 0.020 mg, or from 0.030 mg, or from 0.040 mg, or from 0.050 mg, or from 0.060 mg, or from 0.070 mg, or from 0.080 mg, or from 0.090 mg, or from 0.100 mg, or from 0.110 mg, or from 0.120 mg, or from 0.130 mg, or from 0.140 mg, or from 0.150 mg, or from 0.160 mg, or from 0.170 mg, or from 0.180 mg, or from 0.190 mg,or from 0.200 mg, or from 0.210 mg, or from 0.220 mg, or from 0.230 mg, or from 0.240 mg, or from 0.250 mg, or from 0.260 mg, or from 0.270 mg, or from 0.280 mg, or from 0.290 mg, or from 0.300 mg, or from 0.310 mg, or from 0.320 mg, or from 0.330 mg, or from 0.340 mg, or from 0.350 mg, or from 0.360 mg, or from 0.370 mg, or from 0.380 mg, or from 0.390 mg, or from 0.400 mg, or from 0.410 mg, or from 0.420 mg, or from 0.430 mg, or From 0.440 mg, or from 0.450 mg, or from 0.460 mg, or from 0.470 mg, or from 0.480 mg, or from 0.490 mg, or from 0.500 mg, or from 0.510 mg, or from 0.520 mg, or from 0.530 mg, or from 0.540 mg, or from 0.550 mg, or from 0.560 mg, or from 0.570 mg, or from 0.580 mg, or from 0.590 mg, or from 0.600 mg, or from 0.610 mg, or from 0.620 mg, or from 0.630 mg, or from 0.640 mg, or from 0.650 mg, or from 0.660 mg, or from 0.670 mg, or from 0.680 From mg, or from 0.690 mg, or from 0.700 mg, or from 0.710 mg, or from 0.720 mg, or from 0.730 mg, or from 0.740 mg, or from 0.750 mg, or from 0.760 mg, or from 0.770 mg,or from 0.780 mg, or from 0.790 mg, or from 0.800 mg, or from 0.810 mg, or from 0.820 mg, or from 0.830 mg, or from 0.840 mg, or from 0.850 mg, or from 0.860 mg, or from 0.870 mg, or from 0.880 mg, or from 0.890 mg, or from 0.900 mg, or from 0.910 mg, or from 0.920 mg, or from 0.930 mg, or from 0.940 mg, or from 0.950 mg, or from 0.960 mg, or from 0.970 mg, or from 0.980 mg, or from 0.990 mg, or from 1 mg, or from 5 mg, or from 10 mg, or from 15 mg, or from 20 mg, or from 25 mg, or from 30 mg, or from 35 mg, or from 40 mg, or from 45 mg, or from 50 mg, or from 55 mg, or from 60 mg, or from 65 mg, or from 70 mg, or from 75 mg, or from 80 mg, or from 85 mg, or from 90 mg, or from 95 mg, or from 100 mg, or from 105 mg, or from 110 mg, or from 115 mg, or from 120 mg, or from 125 mg, or from 130 mg, or from 135 mg, or from 140 mg, or from 145 mg, or from 150 mg, or from 155 mg, or from 160 mg, or from 165 mg, or from 170 mg, or from 175 mg, or from 180 From mg, or from 185 mg, or from 190 mg, or from 195 mg, or from 200 mg, or from 205 mg, or from 210 mg,or from 220 mg, or from 225 mg, or from 230 mg, or from 235 mg, or from 240 mg, or from 245 mg, or from 250 mg, or from 255 mg, or from 260 mg, or from 265 mg, or from 270 mg, or from 275 mg, or from 280 mg, or from 285 mg, or from 290 mg, or from 295 mg, or from 300 mg, or from 305 mg, or from 310 mg, or from 315 mg, or from 320 mg, or from 325 mg, or from 330 mg, or from 335 mg, or from 340 mg, or from 345 mg, or from 350 mg, or from 355 mg, or from 360 mg, or from 365 mg, or from 370 From mg, or from 375 mg, or from 380 mg, or from 385 mg, or from 390 mg, or from 395 mg, or from 400 mg, or from 405 mg, or from 410 mg, or from 415 mg, or from 420 mg, or from 425 mg, or from 430 mg, or from 435 mg, or from 440 mg, or from 445 mg, or from 450 mg, or from 455 mg, or from 460 mg, or from 465 mg, or from 470 mg, or from 475 mg, or from 480 mg, or from 485 mg, or from 490 mg, or from 495 mg, or from 500 mg, or from 510 mg, or from 520 mg, or from 530 mg, or from 540 mg, or From 550 mg, or from 560 mg, or from 570 mg, or from 580 mg, or from 590 mg,or from 600 mg, or from 610 mg, or from 620 mg, or from 630 mg, or from 640 mg, or from 650 mg, or from 660 mg, or from 670 mg, or from 680 mg, or from 690 mg, or from 700 mg, or from 710 mg, or from 720 mg, or from 730 mg, or from 740 mg, or from 750 mg, or from 760 mg, or from 770 mg, or from 780 mg, or from 790 mg, or from 800 mg, or from 810 mg, or from 820 mg, or from 830 mg, or from 840 mg, or from 850 mg, or from 860 mg, or from 870 mg, or from 880 mg, or from 890 mg, or from 900 From mg, or from 910 mg, or from 920 mg, or from 930 mg, or from 940 mg, or from 950 mg, or from 960 mg, or from 970 mg, or from 980 mg, or from 990 mg, or from 1000 mg, or from 1050 mg, or from 1100 mg, or from 1150 mg, or from 1200 mg, or from 1250 mg, or from 1300 mg, or from 1350 mg, or from 1400 mg, or from 1450 mg, or from 1500 mg, or from 1550 mg, or from 1600 mg, or from 1650 mg, or from 1700 mg, or from 1750 mg, or from 1800 mg, or from 1850 mg, or from 1900 mg, or from 1950 mg, or from 2000 mg, or from 2050 mg, or from 2100 mg, or from 2150 mg, or from 2200 mg,or from 2250 mg, or from 2300 mg, or from 2350 mg, or from 2400 mg, or from 2450 mg, or from 2500 mg, or from 2550 mg, or from 2600 mg, or from 2650 mg, or from 2700 mg, or from 2750 mg, or from 2800 mg, or from 2850 mg, or from 2900 mg, or from 2950 mg, or from 3000 mg, or from 3050 mg, or from 3100 mg, or from 3150 mg, or from 3200 mg, or from 3250 mg, or from 3300 mg, or from 3350 mg, or from 3400 mg, or from 3450 mg, or from 3500 mg, or from 3550 mg, or From 3600 mg, or from 3650 mg, or from 3700 mg, or from 3750 mg, or from 3800 mg, or from 3850 mg, or from 3900 mg, or from 3950 mg, or from 4000 mg, or from 4050 mg, or from 4100 mg, or from 4150 mg, or from 4200 mg, or from 4250 mg, or from 4300 mg, or from 4350 mg, or from 4400 mg, or from 4450 mg, or from 4500 mg, or from 4550 mg, or from 4600 mg, or from 4650 mg, or from 4700 mg, or from 4750 mg, or from 4800 mg, or from 4850 mg, or from 4900 mg, or It may be from 4950 mg to 5000 mg; or 0.001 mg to 0.010 mg, or 0.020 mg, or 0.030 mg, or 0.040 mg, or 0.050 mg, or 0.060 mg, or 0.070 mg,or 0.080 mg, or 0.090 mg, or 0.100 mg, or 0.110 mg, or 0.120 mg, or 0.130 mg, or 0.140 mg, or 0.150 mg, or 0.160 mg, or 0.170 mg, or 0.180 mg, or 0.190 mg, or 0.200 mg, or 0.210 mg, or 0.220 mg, or 0.230 mg, or 0.240 mg, or 0.250 mg, or 0.260 mg, or 0.270 mg, or 0.280 mg, or 0.290 mg, or 0.300 mg, or 0.310 mg, or 0.320 mg, or 0.330 mg, or 0.340 mg, or 0.350 mg, or 0.360 mg, or 0.370 mg, or 0.380 mg, or 0.390 mg, or 0.400 mg, or 0.410 mg, or 0.420 mg, or 0.430 mg, or 0.440 mg, or 0.450 mg, or 0.460 mg, or 0.470 mg, or 0.480 mg, or 0.490 mg, or 0.500 mg, or 0.510 mg, or 0.520 mg, or 0.530 mg, or 0.540 mg, or 0.550 mg, or 0.560 mg, or 0.570 mg, or 0.580 mg, or 0.590 mg, or 0.600 mg, or 0.610 mg, or 0.620 mg, or 0.630 mg, or 0.640 mg, or 0.650 mg, or 0.660 mg, or 0.670 mg, or 0.680 mg, or 0.690 mg, or 0.700 mg, or 0.710 mg, or 0.720 mg, or 0.730 mg, or 0.740 mg, or 0.750 mg, or 0.760 mg, or 0.770 mg, or 0.780 mg, or 0.790 mg, or 0.800 mg, or 0.810 mg, or 0.820 mg, or 0.830 mg, or 0.840 mg,or 0.850 mg, or 0.860 mg, or 0.870 mg, or 0.880 mg, or 0.890 mg, or 0.900 mg, or 0.910 mg, or 0.920 mg, or 0.930 mg, or 0.940 mg, or 0.950 mg, or 0.960 mg, or 0.970 mg, or 0.980 mg, or 0.990 mg, or 1 mg, or 5 mg, or 10 mg, or 15 mg, or 20 mg, or 25 mg, or 30 mg, or 35 mg, or 40 mg, or 45 mg, or 50 mg, or 55 mg, or 60 mg, or 65 mg, or 70 mg, or 75 mg, or 80 mg, or 85 mg, or 90 mg, or 95 mg, or 100 mg, or 105 mg, or 110 mg, or 115 mg, or 120 mg, or 125 mg, or 130 mg, or 135 mg, or 140 mg, or 145 mg, or 150 mg, or 155 mg, or 160 mg, or 165 mg, or 170 mg, or 175 mg, or 180 mg, or 185 mg, or 190 mg, or 195 mg, or 200 mg, or 205 mg, or 210 mg, or 215 mg, or 220 mg, or 225 mg, or 230 mg, or 235 mg, or 240 mg, or 245 mg, or 250 mg, or 255 mg, or 260 mg, or 265 mg, or 270 mg, or 275 mg, or 280 mg, or 285 mg, or 290 mg, or 295 mg, or 300 mg, or 305 mg, or 310 mg, or 315 mg, or 320 mg, or 325 mg, or 330 mg, or 335 mg, or 340 mg, or 345 mg, or 350 mg, or 355 mg, or 360 mg, or 365 mg, or 370 mg,or 375 mg, or 380 mg, or 385 mg, or 390 mg, or 395 mg, or 400 mg, or 405 mg, or 410 mg, or 415 mg, or 420 mg, or 425 mg, or 430 mg, or 435 mg, or 440 mg, or 445 mg, or 450 mg, or 455 mg, or 460 mg, or 465 mg, or 470 mg, or 475 mg, or 480 mg, or 485 mg, or 490 mg, or 495 mg, or 500 mg, or 510 mg, or 520 mg, or 530 mg, or 540 mg, or 550 mg, or 560 mg, or 570 mg, or 580 mg, or 590 mg, or 600 mg, or 610 mg, or 620 mg, or 630 mg, or 640 mg, or 650 mg, or 660 mg, or 670 mg, or 680 mg, or 690 mg, or 700 mg, or 710 mg, or 720 mg, or 730 mg, or 740 mg, or 750 mg, or 760 mg, or 770 mg, or 780 mg, or 790 mg, or 800 mg, or 810 mg, or 820 mg, or 830 mg, or 840 mg, or 850 mg, or 860 mg, or 870 mg, or 880 mg, or 890 mg, or 900 mg, or 910 mg, or 920 mg, or 930 mg, or 940 mg, or 950 mg, or 960 mg, or 970 mg, or 980 mg, or 990 mg, or 1000 mg, or 1050 mg, or 1100 mg, or 1150 mg, or 1200 mg, or 1250 mg, or 1300 mg, or 1350 mg, or 1400 mg, or 1450 mg, or 1500 mg, or 1550 mg, or 1600 mg, or 1650 mg,or 1700 mg, or 1750 mg, or 1800 mg, or 1850 mg, or 1900 mg, or 1950 mg, or 2000 mg, or 2050 mg, or 2100 mg, or 2150 mg, or 2200 mg, or 2250 mg, or 2300 mg, or 2350 mg, or 2400 mg, or 2450 mg, or 2500 mg, or 2550 mg, or 2600 mg, or 2650 mg, or 2700 mg, or 2750 mg, or 2800 mg, or 2850 mg, or 2900 mg, or 2950 mg, or 3000 mg, or 3050 mg, or 3100 mg, or 3150 mg, or 3200 mg, or 3250 mg, or 3300 mg, or 3350 mg, or 3400 mg, or 3450 mg, or 3500 mg, or 3550 mg, or 3600 mg, or 3650 mg, or 3700 mg, or 3750 mg, or 3800 mg, or 3850 mg, or 3900 mg, or 3950 mg, or 4000 mg, or 4050 mg, or 4100 mg, or 4150 mg, or 4200 mg, or 4250 mg, or 4300 mg, or 4350 mg, or 4400 mg, or 4450 mg, or 4500 mg, or 4550 mg, or 4600 mg, or 4650 mg, or 4700 mg, or It may be 4750 mg, or 4800 mg, or 4850 mg, or 4900 mg, or 4950 mg, or 5000 mg, or it may be from any one of the minimum values ​​to any one of the maximum values, or any sub-range in between.

[0263] Treatment of autoimmune diseases, central nervous system diseases, and leukocyte disorders

[0264] The present disclosure relates to a method for treating autoimmune diseases, central nervous system diseases, and leukocyte disorders, comprising the step of administering to an individual in need a pharmaceutical composition comprising a compound of formula (1) or (1a) or a mirror image isomer, racemic mixture, or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0265] Chemical compounds that modulate S1P1 receptors are useful for the treatment of various diseases such as multiple sclerosis (MS), relapsing-remitting multiple sclerosis (RRMS), amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), psoriasis, systemic lupus erythematosus (SLE), ulcerative colitis, and Crohn's disease. See M. Guerrero et al., Expert Opinion on Therapeutic Patents (2016), 26(4), 455-70; A. Marciniak et al., Bioorg. Med. Chem Lett. (2018), 28(23-24), 3585-91.

[0266] Compounds of formula (1) or (1a) regulate S1P1 receptors. Although we do not wish to be bound by theory, it is believed that compounds of formula (1) or (1a) regulate S1P1 receptors by acting as agonists of S1P1 receptors. Therefore, compounds of formula (1) or (1a) are useful for the treatment of autoimmune diseases including ulcerative colitis, Crohn's disease, psoriasis, and systemic lupus erythematosus (SLE); central nervous system diseases including multiple sclerosis (MS), relapsing-remitting multiple sclerosis (RRMS), and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease); and leukocyte disorders including lymphopenia.

[0267] A process for preparing a compound of chemical formula (1) or (1a)

[0268] The present invention relates to a process for preparing a compound of formula (1) or (1a) or its enantiomer, racemic mixture, or pharmaceutically acceptable salt. The overall process steps for preparing a compound of formula (1) or (1a) are shown in reaction schemes 1 to 6 below.

[0269] go , , A compound of formula (1) or (1a) selected from the group consisting of , or its enantiomers, racemic mixtures, or pharmaceutically acceptable salts is prepared using the process presented in reaction scheme 1.

[0270]

[0271] Here:

[0272] R2, R3, R4, R5, R6, R7, R8, Q, U, Y, Z, R f , and R g is as defined above;

[0273] X1 is F, Cl, Br, or I;

[0274] X2 is F, Cl, Br, or I;

[0275] V is N or CH and;

[0276] W is N or CH; and

[0277] R t is H or an unsubstituted C1-C6 straight-chain or branched alkyl.

[0278] Reaction Scheme 1 is a compound of chemical formula (2)

[0279] (2)

[0280] React with the compound of chemical formula (3)

[0281] (3)

[0282] Step A, which produces a compound of chemical formula (4), and

[0283] (4),

[0284] Here, R4, R5, R6, R7, R8, V, W, X1, and R t is as defined above.

[0285] Step A is presented below.

[0286]

[0287] In some embodiments, step A includes reacting the compound of formula (2) with the compound of formula (3) in the presence of a reagent selected from the group consisting of solvents, bases, and mixtures thereof.

[0288] Solvents suitable for use in Step A are amides such as dimethylformamide (DMF), dimethylacetamide (DMA), 1-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, and mixtures thereof; diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), dimethoxyethane (DME), methyl tert - Ethers such as butyl ether (MTBE), 1,4-dioxane, and mixtures thereof; methyl acetate (MeOAc), ethyl acetate (EtOAc), n -Propyl acetate ( n PrOAc), isopropyl acetate ( i PrOAc), n -Butyl acetate ( n BuOAc), sec -Butyl acetate ( sec -BuOAc), tert -Butyl acetate ( t BuOAc), and isobutyl acetate ( iIt may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as dichloromethane (DCM), chloroform (CHCl3), carbon tetrachloride (CCl4), 1,2-dichloroethane, and mixtures thereof; nitriles such as acetonitrile (MeCN), propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0289] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0290] In some embodiments, the solvent is DMF.

[0291] Bases suitable for use in Step A are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Can be selected from the group consisting of amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; and mixtures thereof.

[0292] In some embodiments, the base is ammonia, triethylamine, N , N- Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof.

[0293] In some embodiments, the base is sodium hydride.

[0294] In some embodiments, step A is performed in the presence of a solvent and a base. In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; and the base is ammonia, triethylamine, N , N - It is selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is DMF and the base is sodium hydride.

[0295] In some embodiments, step A is performed at about 0 ℃ to about 200 ℃. In some embodiments, step A is performed at about 25 ℃ to about 150 ℃. In some embodiments, step A is performed at about 50 ℃ to about 100 ℃. In some embodiments, step A is performed at about 75 ℃ to about 85 ℃.

[0296] In some embodiments, the amount of compound of formula (3) versus the amount of compound of formula (2) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0297] In some embodiments, the amount of base versus the amount of the compound of formula (2) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0298] Step A is also It may also be performed by Buchwald coupling such as.

[0299] Step A can produce 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1H)-one in 26-54% yield by a transition metal-catalyzed reaction, and can be carried out by palladium catalysis including catalysts such as, for example, Pd2(dba)3 / Xantphos, Pd(OAc)2 / Xantphos, XantPhos-Pd-G3, and BrettPhos-Pd-Ge.

[0300] Reaction Scheme 1 is a compound of chemical formula (4)

[0301] (4)

[0302] Step B further includes reacting with an acid to produce a compound of chemical formula (5).

[0303] (5),

[0304] Here, R4, R5, R6, R7, R8, V, W, and R t is as defined above.

[0305] Step B is presented below.

[0306]

[0307] In some embodiments, step B includes reacting a compound of formula (4) with an acid in the presence of a solvent.

[0308] Solvents suitable for use in Step B are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; methanol (MeOH), ethanol (EtOH), n -Propanol( n PrOH), isopropanol ( i It may be selected from the group consisting of alcohols such as PrOH), ethylene glycol, diethylene glycol, and mixtures thereof; organic acids such as formic acid and acetic acid (AcOH); water; and mixtures thereof.

[0309] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof.

[0310] In some embodiments, the solvent is AcOH.

[0311] Acids suitable for use in step B may be selected from the group consisting of organic acids such as formic acid, AcOH, trifluoroacetic acid (TFA), and mixtures thereof; inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof; and mixtures thereof.

[0312] In some embodiments, the acid is selected from the group consisting of AcOH, TFA, hydrochloric acid, hydrobromide, and mixtures thereof.

[0313] In some embodiments, the acid is hydrobromide.

[0314] In some embodiments, step B is performed in the presence of a solvent and an acid. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The solvent is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; the acid is selected from the group consisting of AcOH, TFA, hydrochloric acid, hydrobromide, and mixtures thereof. In some embodiments, the solvent is AcOH and the acid is hydrobromide.

[0315] In some embodiments, step B is performed at about 0 °C to about 200 °C. In some embodiments, step B is performed at about 5 °C to about 100 °C. In some embodiments, step B is performed at about 10 °C to about 50 °C. In some embodiments, step B is performed at about 15 °C to about 35 °C. In some embodiments, step B is performed at about room temperature (rt).

[0316] In some embodiments, the amount of acid versus the amount of the compound of formula (4) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0317] Reaction Scheme 1 is a compound of chemical formula (5)

[0318] (5)

[0319] React with the compound of chemical formula (6)

[0320] (6)

[0321] Step 1-C, which further comprises producing a compound of formula (1b),

[0322] (1b),

[0323] Here, R2, R3, R4, R5, R6, R7, R8, Q, U, V, W, X2, Y, Z, R f , R g , and R t is as defined above.

[0324] Step 1-C is presented below.

[0325]

[0326] In some embodiments, step 1-C includes reacting the compound of formula (5) with the compound of formula (6) in the presence of a reagent selected from the group consisting of a solvent, a copper salt, a base, a ligand, and mixtures thereof.

[0327] Suitable solvents for use in Step 1-C are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0328] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0329] In some embodiments, the solvent is selected from the group consisting of DMF, 1,4-dioxane, and mixtures thereof. In some embodiments, the solvent is a mixture of DMF and 1,4-dioxane, or 1,4-dioxane alone.

[0330] Copper salts suitable for use in step 1-C can be selected from the group consisting of copper(I) fluoride (CuF), copper(I) chloride (CuCl), copper(I) bromide (CuBr), copper(I) iodide (CuI), and mixtures thereof.

[0331] In some embodiments, the copper salt is CuI.

[0332] Bases suitable for use in Step 1-C are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N- Amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; Phosphates such as monosodium phosphate (NaH2PO4), disodium phosphate (Na2HPO4), trisodium phosphate (Na3PO4), monopotassium phosphate (KH2PO4), dipotassium phosphate (K2HPO4), tripotassium phosphate (K3PO4), and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0333] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof.

[0334] In some embodiments, the base is tripotassium phosphate (K3PO4).

[0335] The ligand suitable for use in Step 1-C is N , N' -Dimethylethylenediamine( N , N' -DMEDA), N , N' - Diisopropylethylenediamine, N , N'It is selected from the group consisting of diamines such as dimethyl-1,6-hexanediamine and mixtures thereof; phenanthrolines such as 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline and mixtures thereof; bipyridines such as 2,2'-bipyridine; and mixtures thereof.

[0336] In some embodiments, the ligand N , N' It is selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof.

[0337] In some embodiments, the ligand N , N' It is DMEDA.

[0338] In some embodiments, step 1-C is performed in the presence of a solvent, a copper salt, a base, and a ligand. In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; the copper salt is selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof; and the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof; the ligand is N , N' It is selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof. In some embodiments, the solvent is DMF, 1,4-dioxane, and mixtures thereof; the copper salt is CuI; the base is tripotassium phosphate; and the ligand is N , N'-DMEDA. In some embodiments, the solvent is a mixture of DMF and 1,4-dioxane, the copper salt is CuI, the base is tripotassium phosphate, and the ligand is N , N' It is DMEDA.

[0339] In some embodiments, step 1-C is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 1-C is performed at about 25 ℃ to about 150 ℃. In some embodiments, step 1-C is performed at about 50 ℃ to about 125 ℃. In some embodiments, step 1-C is performed at about 80 ℃ to about 100 ℃.

[0340] In some embodiments, the amount of compound of formula (6) versus the amount of compound of formula (5) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0341] In some embodiments, the amount of copper salt versus the amount of the compound of formula (5) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.05 to 20 molar equivalents. In some embodiments, the range is 0.1 to 15 molar equivalents. In some embodiments, the range is 0.1 to 10 molar equivalents. In some embodiments, the range is 0.5 to 5 molar equivalents.

[0342] In some embodiments, the amount of base versus the amount of the compound of formula (5) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0343] In some embodiments, the amount of ligand versus the amount of the compound of formula (5) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0344] In some embodiments, step 1-C in Scheme 1 is followed by a dealkylation step 1-D, in which U is -COOR e , -COSR e , or -CON(R e )2 and R e In a compound of formula (1b) in which α is an unsubstituted C1-C6 straight-chain or branched alkyl, by reacting the unsubstituted C1-C6 straight-chain or branched alkyl with at least one dealkylating reagent to remove it, U is -COOR e , -COSR e , or -CON(R e )2 and R e It includes the step of producing a compound of chemical formula (1c) in which is H.

[0345] In some embodiments, step 1-D is U -COOR e , -COSR e , or -CON(R e )2 and R e A compound of formula (1b) which is an unsubstituted C1-C6 straight-chain or branched alkyl, R e The method includes the step of reacting in the presence of a reagent selected from the group consisting of a solvent, a dealkylating agent, and mixtures thereof, to form a compound of formula (1c) in which H is present.

[0346] Solvents suitable for use in Step 1-D are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, iPrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; organic acids such as formic acid, AcOH; water; and mixtures thereof.

[0347] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof.

[0348] In some embodiments, the solvent is selected from the group consisting of THF, water, and mixtures thereof. In some embodiments, the solvent is a mixture of water and THF.

[0349] Dealkylation reagents suitable for use in Step 1-D are bases such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; acids such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof; Haloalkyl silanes such as trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0350] In some embodiments, the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof.

[0351] In some embodiments, the dealkylation reagent is lithium hydroxide.

[0352] In some embodiments, step 1-D is performed in the presence of a solvent and a dealkylation reagent. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, iThe solvent is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof. In some embodiments, the solvent is THF, water, and mixtures thereof; and the dealkylation reagent is lithium hydroxide. In some embodiments, the solvent is a mixture of water and THF, and the dealkylation reagent is lithium hydroxide.

[0353] In some embodiments, step 1-D is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 1-D is performed at about 5 ℃ to about 100 ℃. In some embodiments, step 1-D is performed at about 10 ℃ to about 50 ℃. In some embodiments, step 1-D is performed at about 15 ℃ to about 35 ℃. In some embodiments, step 1-D is performed at about room temperature.

[0354] In some implementations, U is -COOR e , -COSR e , or -CON(R e )2 and R e The amount of dealkylating agent relative to the amount of the compound of formula (1b), which is an unsubstituted C1-C6 straight-chain or branched alkyl, is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0355] go , , and A compound of formula (1) or (1a) selected from the group consisting of, or its enantiomer, racemic mixture, or pharmaceutically acceptable salt, is also prepared using the process presented in reaction scheme 2.

[0356]

[0357] Here:

[0358] R2, R3, R4, R5, R6, R7, R8, Q, V, W, X1, Y, Z, R f , R g , and R t is as defined above; and

[0359] X3 is F, Cl, Br, or I.

[0360] Reaction Scheme 2 includes step A as described above in Reaction Scheme 1.

[0361] Reaction Scheme 2 further includes step B as described above in Reaction Scheme 1.

[0362] Reaction Scheme 2 is a compound of chemical formula (5)

[0363] (5)

[0364] React with the compound of chemical formula (7)

[0365] (7)

[0366] Step 2-C, which further comprises producing a compound of chemical formula (8),

[0367] (8),

[0368] Here, R2, R3, R4, R5, R6, R7, R8, Q, V, W, X3, Y, Z, R f , R g , and R t is as defined above.

[0369] Step 2-C is presented below.

[0370]

[0371] In some embodiments, step 2-C includes reacting the compound of formula (5) with the compound of formula (7) in the presence of a reagent selected from the group consisting of a solvent, a copper salt, a base, a ligand, and mixtures thereof.

[0372] Suitable solvents for use in Step 2-C are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0373] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0374] In some embodiments, the solvent is selected from the group consisting of DMF, 1,4-dioxane, and mixtures thereof. In some embodiments, the solvent is a mixture of DMF and 1,4-dioxane.

[0375] Copper salts suitable for use in step 2-C can be selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof.

[0376] In some embodiments, the copper salt is CuI.

[0377] Bases suitable for use in Step 2-C are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; phosphates such as NaH2PO4, disodium phosphate Na2HPO4, Na3PO4, KH2PO4, K2HPO4, K3PO4, and mixtures thereof; It can be selected from the group consisting of and mixtures thereof.

[0378] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof.

[0379] In some embodiments, the base is tripotassium phosphate.

[0380] The ligand suitable for use in Step 2-C is N , N' -DMEDA,N , N' - Diisopropylethylenediamine, N , N' It is selected from the group consisting of diamines such as dimethyl-1,6-hexanediamine and mixtures thereof; phenanthrolines such as 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline and mixtures thereof; bipyridines such as 2,2'-bipyridine; and mixtures thereof.

[0381] In some embodiments, the ligand N , N' It is selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof.

[0382] In some embodiments, the ligand N , N' It is DMEDA.

[0383] In some embodiments, step 2-C is performed in the presence of a solvent, a copper salt, a base, and a ligand. In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; the copper salt is selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof; and the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof; the ligand is N , N' It is selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof. In some embodiments, the solvent is DMF, 1,4-dioxane, and mixtures thereof; the copper salt is CuI; the base is tripotassium phosphate; and the ligand isN , N' -DMEDA. In some embodiments, the solvent is a mixture of DMF and 1,4-dioxane, the copper salt is CuI, the base is tripotassium phosphate, and the ligand is N , N' It is DMEDA.

[0384] In some embodiments, step 2-C is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 2-C is performed at about 25 ℃ to about 150 ℃. In some embodiments, step 2-C is performed at about 50 ℃ to about 125 ℃. In some embodiments, step 2-C is performed at about 80 ℃ to about 100 ℃.

[0385] In some embodiments, the amount of compound of formula (7) versus the amount of compound of formula (5) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0386] In some embodiments, the amount of copper salt versus the amount of the compound of formula (5) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.05 to 20 molar equivalents. In some embodiments, the range is 0.1 to 15 molar equivalents. In some embodiments, the range is 0.1 to 10 molar equivalents. In some embodiments, the range is 0.5 to 5 molar equivalents.

[0387] In some embodiments, the amount of base versus the amount of the compound of formula (5) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0388] In some embodiments, the amount of ligand versus the amount of the compound of formula (5) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0389] Reaction Scheme 2 is the compound of chemical formula (8)

[0390] (8)

[0391] additionally includes step 2-D of reacting with an azide reagent to produce a compound of formula (1b-1).

[0392] (1b-1),

[0393] Here, R2, R3, R4, R5, R6, R7, R8, Q, V, W, Y, Z, R f , R g , and R t is as defined above.

[0394] Step 2-D is presented below.

[0395]

[0396] In some embodiments, step 2-D includes reacting a compound of formula (8) with an azide reagent in the presence of a solvent.

[0397] Suitable solvents for use in Step 2-D are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and iEsters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i Alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; benzene, toluene, o - Xylene, m - Xylene, p - Aromatic hydrocarbons such as xylene, mesitylene, pseudocumene (1,2,4-trimethylbenzene), hemimellitene (1,2,3-trimethylbenzene), and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0398] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p It is selected from the group consisting of xylene and mixtures thereof.

[0399] In some embodiments, the solvent is toluene.

[0400] The azide reagents suitable for use in Step 2-D are lithium azide, sodium azide, potassium azide, silver azide, barium azide, trimethyltin azide, triethyltin azide, and tripropyltin azide (tri( n -Prop)tin azide), triisopropyltin azide, tributyltin azide(tri( n -butyl)tin azide), tri( sec- Butyl)tin azide, tri(isobutyl)tin azide, tri( tert It can be selected from the group consisting of butyl tin azide and mixtures thereof.

[0401] In some embodiments, the azide reagent is selected from the group consisting of trimethyltin azide, triethyltin azide, tripropyltin azide, tributyltin azide, and mixtures thereof.

[0402] In some embodiments, the azide reagent is tributyltin azide.

[0403] In some embodiments, step 2-D is performed in the presence of a solvent and an azide reagent. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - Selected from the group consisting of xylene and mixtures thereof; the azide reagent is selected from the group consisting of trimethyltin azide, triethyltin azide, tripropyltin azide, tributyltin azide, and mixtures thereof. In some embodiments, the solvent is toluene and the azide reagent is tributyltin azide.

[0404] In some embodiments, step 2-D is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 2-D is performed at about 25 ℃ to about 175 ℃. In some embodiments, step 2-D is performed at about 50 ℃ to about 150 ℃. In some embodiments, step 2-D is performed at about 75 ℃ to about 125 ℃. In some embodiments, step 2-D is performed at about 100 ℃ to about 120 ℃.

[0405] In some embodiments, the amount of azide reagent versus the amount of the compound of formula (8) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0406] As an alternative to step 2-A, a compound of formula (30), or its enantiomer, racemic mixture, or pharmaceutically acceptable salt may be prepared using the process presented in reaction scheme 3.1.

[0407]

[0408] Here, R t , R4, R5, R6, R7, R8, and R9 are as defined above.

[0409] In one embodiment, the compound of formula (30) was prepared from the compound of formula (29) and the compound of formula (16) in the presence of a solvent and an acid.

[0410] In some embodiments, suitable solvents are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAC, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOh, i Alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; benzene, toluene, o - Xylene, m - Xylene, p - Aromatic hydrocarbons such as xylene, mesitylene, pseudocumene (1,2,4-trimethylbenzene), hemimelitene (1,2,3-trimethylbenzene), and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0411] In some embodiments, the acid suitable for preparing the compound of formula (30) may be selected from the group consisting of organic acids such as formic acid, AcOH, trifluoroacetic acid (TFA), 10-camporsulfonic acid (10-CSA), and mixtures thereof; inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof; and mixtures thereof.

[0412] In one example, 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-one was prepared from 2-chloro-3-methoxypyrazine and 2-fluoro-4-(trifluoromethyl)aniline in the presence of hydrobromide (HBr) in HOAc and 1,4-dioxane according to the reaction presented below:

[0413] .

[0414] 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H The )-one subsequently reacts with 3-(4-bromophenyl)propanenitrile to 3-(4-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-1)phenyl)propanenitrile can be prepared, which subsequently reacts with sodium azide to produce 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on (compound 3) can be prepared.

[0415]

[0416] In another embodiment, 3-chloropyrazine-2 (1 ) presented below H Pyrazinones such as )-one can be used instead of 2-chloro-3-methoxypyrazine.

[0417]

[0418] go , Compounds of formula (1) or (1a), which are enantiomers, racemic mixtures, or pharmaceutically acceptable salts thereof, are prepared using the process presented in reaction scheme 3.

[0419]

[0420] Here:

[0421] R2, R3, R4, R5, R6, R7, R8, R9, Q, Y, Z, R f , and R g is as defined above;

[0422] X4 is F, Cl, Br, or I;

[0423] X5 is a leaving group L1 that can be substituted by F, Cl, Br, I, or a nucleophile. p Selected from the group consisting of -sulfons such as toluenesulfonate (TsO-) or methanesulfonate (MsO-); perfluoroalkylsulfons such as trifluoromethanesulfonate (-OSO2CF3); nitrates (-ONO2); and phosphates (-OPO(OR2), where R may be an alkyl group);

[0424] X6 is F, Cl, Br, or I; and

[0425] X7 is F, Cl, Br, or I.

[0426] Reaction Scheme 3 is a compound of chemical formula (9)

[0427] (9)

[0428] It includes step 3-A of reacting with a cyanide reagent to produce a compound of formula (10).

[0429] (10),

[0430] Here, R2, R3, Q, X4, Y, Z, R f , and R g is as defined above.

[0431] Step 3-A is presented below.

[0432]

[0433] In some embodiments, step 3-A includes reacting a compound of formula (9) with a cyanide reagent in the presence of a solvent.

[0434] Solvents suitable for use in Step 3-A are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; organosulfur such as DMSO; and mixtures thereof.

[0435] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, DMSO, and mixtures thereof.

[0436] In some embodiments, the solvent is DMSO.

[0437] A cyanide reagent suitable for use in step 3-A may be selected from the group consisting of lithium cyanide, sodium cyanide, potassium cyanide, and mixtures thereof.

[0438] In some embodiments, the cyanide reagent is selected from the group consisting of sodium cyanide, potassium cyanide, and mixtures thereof.

[0439] In some embodiments, the cyanide reagent is sodium cyanide.

[0440] In some embodiments, step 3-A is performed in the presence of a solvent and a cyanide reagent.

[0441] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, DMSO, and mixtures thereof; and the cyanide reagent is selected from the group consisting of sodium cyanide, potassium cyanide, and mixtures thereof. In some embodiments, the solvent is DMSO and the cyanide reagent is sodium cyanide.

[0442] In some embodiments, step 3-A is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 3-A is performed at about 10 ℃ to about 150 ℃. In some embodiments, step 3-A is performed at about 20 ℃ to about 100 ℃. In some embodiments, step 3-A is performed at about 30 ℃ to about 75 ℃. In some embodiments, step 3-A is performed at about 40 ℃ to about 60 ℃.

[0443] In some embodiments, the amount of cyanide reagent versus the amount of the compound of formula (9) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0444] Reaction Scheme 3 is a compound of chemical formula (10)

[0445] (10)

[0446] additionally includes step 3-B of reacting with a hydrogenation reagent to produce a compound of formula (11).

[0447] (11),

[0448] Here, R2, R3, Q, X4, Y, Z, R f , and R g is as defined above.

[0449] Step 3-B is presented below.

[0450]

[0451] In some embodiments, step 3-B includes the step of reacting a compound of formula (10) with a hydrogenation reagent in the presence of a solvent, a catalyst, and a mixture thereof.

[0452] Suitable solvents for use in Step 3-B are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; and mixtures thereof.

[0453] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH and mixtures thereof.

[0454] In some embodiments, the solvent is selected from the group consisting of EtOH, EtOAc, and mixtures thereof. In some embodiments, the solvent is a mixture of EtOH and EtOAc.

[0455] A hydrogenation reagent suitable for use in step 3-B can be selected from the group consisting of hydrogen (H2), formic acid, isopropanol, dihydroanthracene, and mixtures thereof.

[0456] In some embodiments, the hydrogenation reagent is selected from the group consisting of hydrogen (H2), formic acid, isopropanol, and mixtures thereof.

[0457] In some embodiments, the hydrogenation agent is hydrogen (H2).

[0458] A catalyst suitable for use in step 3-B may be selected from the group consisting of homogeneous catalysts such as chloridotris(triphenylphosphine)rhodium(I) (RhCl(PPh3)3, Wilkinson's catalyst); and heterogeneous catalysts such as platinum (0), palladium (0), rhodium (0), ruthenium (0), Raney nickel, platinum on carbon (Pt / C), palladium on carbon (Pd / C), rhodium on carbon (Rh / C), ruthenium on carbon (Ru / C), and mixtures thereof; and mixtures thereof.

[0459] In some embodiments, the catalyst is selected from the group consisting of Wilkinson catalyst, platinum (0), palladium (0), Pt / C, Pd / C, and mixtures thereof.

[0460] In some embodiments, the catalyst is palladium (0).

[0461] In some embodiments, step 3-B is performed in the presence of a solvent, a hydrogenation reagent, and a catalyst.

[0462] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The solvent is selected from the group consisting of PrOH and mixtures thereof; the hydrogenation agent is selected from the group consisting of hydrogen (H2), formic acid, isopropanol, and mixtures thereof; and the catalyst is selected from the group consisting of Wilkinson catalyst, platinum (0), palladium (0), Pt / C, Pd / C, and mixtures thereof. In some embodiments, the solvent is selected from the group consisting of EtOH, EtOAc, and mixtures thereof; the hydrogenation agent is hydrogen (H2); and the catalyst is palladium (0). In some embodiments, the solvent is a mixture of EtOH and EtOAc; the hydrogenation agent is hydrogen (H2); and the catalyst is palladium (0).

[0463] In some embodiments, step 3-B is performed at about 0°C to about 200°C. In some embodiments, step 3-B is performed at about 5°C to about 100°C. In some embodiments, step 3-B is performed at about 10°C to about 50°C. In some embodiments, step 3-B is performed at about 15°C to about 35°C. In some embodiments, step 3-B is performed near room temperature.

[0464] In some embodiments, the amount of hydrogenation reagent versus the amount of the compound of formula (10) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0465] In some embodiments, the amount of catalyst versus the amount of the compound of formula (10) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0466] Reaction Scheme 3 is the compound of step formula (11)

[0467] (11)

[0468] react with the compound of chemical formula (12)

[0469] (12)

[0470] Step 3-C, which further comprises producing a compound of chemical formula (13).

[0471] (13),

[0472] Here, R2, R3, Q, X5, Y, Z, R f , and R g is as defined above.

[0473] Step 3-C is presented below.

[0474]

[0475] In some embodiments, step 3-C includes reacting a compound of formula (11) with a compound of formula (12) in the presence of a solvent, a base, and a mixture thereof.

[0476] Suitable solvents for use in Step 3-C are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and iEsters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; and mixtures thereof.

[0477] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH and mixtures thereof.

[0478] In some embodiments, the solvent is MeCN.

[0479] The bases suitable for use in Step 3-C are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N- It may be selected from the group consisting of amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; and mixtures thereof.

[0480] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof.

[0481] In some embodiments, the base is potassium carbonate.

[0482] In some embodiments, step 3-C is performed in the presence of a solvent and a base.

[0483] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The base is selected from the group consisting of PrOH and mixtures thereof; the base is ammonia, triethylamine, N , N - It is selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is MeCN and the base is potassium carbonate.

[0484] In some embodiments, step 3-C is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 3-C is performed at about 25 ℃ to about 100 ℃. In some embodiments, step 3-C is performed at about 50 ℃ to about 75 ℃. In some embodiments, step 3-C is performed at about 55 ℃ to about 65 ℃.

[0485] In some embodiments, the amount of compound of formula (12) versus the amount of compound of formula (11) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0486] In some embodiments, the amount of base versus the amount of compound of formula (11) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0487] Reaction Scheme 3 is a compound of chemical formula (13)

[0488] (13)

[0489] react with the compound of chemical formula (14)

[0490] (14)

[0491] additionally including step 3-D of producing a compound of formula (15)

[0492] (15),

[0493] Here, R2, R3, Q, X6, X7, Y, Z, R f , and R g is as defined above.

[0494] Step 3-D is presented below.

[0495]

[0496] In some embodiments, step 3-D includes the step of reacting a compound of formula (13) with a compound of formula (14) in the presence of a solvent.

[0497] Solvents suitable for use in Step 3-D are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i Alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; benzene, toluene, o - Xylene, m - Xylene, p - Aromatic hydrocarbons such as xylene, mesitylene, pseudocumene (1,2,4-trimethylbenzene), hemimelitene (1,2,3-trimethylbenzene), chlorobenzene, and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0498] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p It is selected from the group consisting of xylene, chlorobenzene, and mixtures thereof.

[0499] In some embodiments, the solvent is selected from the group consisting of DMF, chlorobenzene, and mixtures thereof. In some embodiments, the solvent is a mixture of DMF and chlorobenzene.

[0500] In some embodiments, step 3-D is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 3-D is performed at about 25 ℃ to about 175 ℃. In some embodiments, step 3-D is performed at about 50 ℃ to about 150 ℃. In some embodiments, step 3-D is performed at about 75 ℃ to about 125 ℃. In some embodiments, step 3-D is performed at about 95 ℃ to about 105 ℃.

[0501] In some embodiments, the amount of compound of formula (14) versus the amount of compound of formula (13) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0502] Reaction Scheme 3 is a compound of chemical formula (15)

[0503] (15)

[0504] React with the compound of chemical formula (16)

[0505] (16)

[0506] Step 3-E further comprises producing a compound of formula (17).

[0507] (17),

[0508] Here, R2, R3, R4, R5, R6, R7, R8, Q, X6, X7, Y, Z, R f , and R g is as defined above.

[0509] Step 3-E is presented below.

[0510]

[0511] In some embodiments, step 3-E includes reacting a compound of formula (15) with a compound of formula (16) in the presence of a solvent and a base.

[0512] Solvents suitable for use in Step 3-E are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i Alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; benzene, toluene, o - Xylene, m - Xylene, p - Aromatic hydrocarbons such as xylene, mesitylene, pseudocumene (1,2,4-trimethylbenzene), hemimelitene (1,2,3-trimethylbenzene), chlorobenzene, and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0513] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p It is selected from the group consisting of xylene, chlorobenzene, and mixtures thereof.

[0514] In some embodiments, the solvent is THF.

[0515] Bases suitable for use in Step 3-E are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Can be selected from the group consisting of amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; and mixtures thereof.

[0516] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof.

[0517] In some embodiments, the base is sodium hydride.

[0518] In some embodiments, step 3-E is performed in the presence of a solvent and a base. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o- Xylene, m - Xylene, p - Selected from the group consisting of xylene, chlorobenzene, and mixtures thereof; the base is ammonia, triethylamine, N , N - It is selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is THF and the base is sodium hydride.

[0519] In other embodiments, step 3-E is performed in the presence of an acid. In some embodiments, the acid is camphorsulfonic acid (CSA). In some embodiments, step 3-E is performed in the presence of a solvent and an acid. In some embodiments, the solvent is 1,4-dioxane.

[0520] In some embodiments, step 3-E is performed at about 0°C to about 200°C. In some embodiments, step 3-E is performed at about 5°C to about 100°C. In some embodiments, step 3-E is performed at about 10°C to about 50°C. In some embodiments, step 3-E is performed at about 15°C to about 35°C. In some embodiments, step 3-E is performed near room temperature.

[0521] In some embodiments, the amount of compound of formula (16) versus the amount of compound of formula (15) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0522] In some embodiments, the amount of base versus the amount of the compound of formula (15) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0523] Reaction Scheme 3 is a compound of chemical formula (17)

[0524] (17)

[0525] Step 3-F further includes reacting with a hydrogenation reagent to produce a compound of formula (18).

[0526] (18),

[0527] Here, R2, R3, Q, X4, Y, Z, R f , and R g is as defined above.

[0528] Step 3-F is presented below.

[0529]

[0530] In some embodiments, step 3-F includes the step of reacting a compound of formula (17) with a hydrogenation reagent in the presence of a solvent, a catalyst, a base, and a mixture thereof.

[0531] Solvents suitable for use in Step 3-F are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, iIt may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; and mixtures thereof.

[0532] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH and mixtures thereof.

[0533] In some embodiments, the solvent is MeOH.

[0534] A hydrogenation reagent suitable for use in step 3-F can be selected from the group consisting of hydrogen (H2), formic acid, isopropanol, dihydroanthracene, and mixtures thereof.

[0535] In some embodiments, the hydrogenation reagent is selected from the group consisting of hydrogen (H2), formic acid, isopropanol, and mixtures thereof.

[0536] In some embodiments, the hydrogenation agent is hydrogen (H2).

[0537] A catalyst suitable for use in step 3-F may be selected from the group consisting of: homogeneous catalysts such as chloridotris(triphenylphosphine)rhodium(I) (RhCl(PPh3)3, Wilkins catalyst); heterogeneous catalysts such as platinum (O), palladium (O), rhodium (O), ruthenium (O), Raney nickel, platinum supported on carbon (Pt / C), palladium supported on carbon (Pd / C), rhodium supported on carbon (Rh / C), ruthenium supported on carbon (Ru / C), and mixtures thereof; and mixtures thereof.

[0538] In some embodiments, the catalyst is selected from the group consisting of Wilkinson catalyst, platinum (0), palladium (0), Pt / C, Pd / C, and mixtures thereof.

[0539] In some embodiments, the catalyst is Pd / C.

[0540] Bases suitable for use in Step 3-F are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Can be selected from the group consisting of amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; and mixtures thereof.

[0541] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof.

[0542] In some embodiments, the base is potassium carbonate.

[0543] In some embodiments, step 3-F is performed in the presence of a solvent, a hydrogenation reagent, a catalyst, and a base.

[0544] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, iThe base is selected from the group consisting of PrOH and mixtures thereof; the hydrogenation reagent is selected from the group consisting of hydrogen (H2), formic acid, isopropanol, and mixtures thereof; the catalyst is selected from the group consisting of Wilkins catalyst, platinum (0), palladium (0), Pt / C, Pd / C, and mixtures thereof; and the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is MeOH; the hydrogenation reagent is hydrogen (H2); the catalyst is palladium (O); and the base is potassium carbonate.

[0545] In some embodiments, step 3-F is performed at about 0°C to about 200°C. In some embodiments, step 3-F is performed at about 5°C to about 100°C. In some embodiments, step 3-F is performed at about 10°C to about 50°C. In some embodiments, step 3-F is performed at about 15°C to about 35°C. In some embodiments, step 3-F is performed near room temperature.

[0546] In some embodiments, the amount of hydrogenation reagent versus the amount of the compound of formula (17) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0547] In some embodiments, the amount of catalyst versus the amount of the compound of formula (17) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0548] In some embodiments, the amount of base versus the amount of the compound of formula (17) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0549]

[0550] In another embodiment, step 3-F' (also presented herein as step 7-F) is a compound of formula (17) and a compound of formula (31).

[0551]

[0552] It includes the step of reacting in the presence of a palladium catalyst, a solvent, a base, and a mixture thereof.

[0553] Suitable solvents for use in step 3-F' are water; amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, i Esters such as BuOAc and mixtures thereof; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; and mixtures thereof.

[0554] In some embodiments, the solvent is water, DMF, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH and mixtures thereof.

[0555] In some embodiments, the solvent is a mixture of 1,4-dioxane and water.

[0556] Palladium catalysts suitable for use in step 3-F' include palladium(II) acetate (Pd(OAc)2), palladium(II) acetylacetonate (Pd(acac)2), tris(dibenzylideneacetone)dipalladium(O) (Pd2(dba)3), dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2), tetrakis(triphenylphosphine)palladium(O) (Pd(PPh3)4), palladium(O)(Pd), palladium(O) / carbon (Pd / C), and dichloro(1,1'-bis(di- tert It may be selected from the group consisting of butylphosphino)ferrocene)palladium(II) (Pd(dtbpf)Cl2), and mixtures thereof.

[0557] In some embodiments, the palladium catalyst is selected from the group consisting of Pd(OAc)2, Pd(acac)2, Pd2(dba)3, PdCl2(PPh3)2, Pd(PPh3)4, Pd(dtbpf)Cl2, and mixtures thereof.

[0558] In some embodiments, the palladium catalyst is Pd(dtbpf)Cl2.

[0559] The bases suitable for use in step 3-F' are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N- Amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert - Butoxide, sodium tert - Butoxide, potassium tert It may be selected from the group consisting of: alkoxide salts such as butoxide and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride and mixtures thereof; and mixtures thereof.

[0560] In some embodiments, the base is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - It is selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof.

[0561] In some embodiments, the base is potassium carbonate.

[0562] In some embodiments, step 3-F' is performed in the presence of a solvent, a compound of formula (31), a palladium catalyst, and a base.

[0563] In some embodiments, the solvent is water, DMF, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3MeCN, MeOH, EtOH, iThe palladium catalyst is selected from the group consisting of PrOH and mixtures thereof; the palladium catalyst is selected from the group consisting of Pd(OAc)2, Pd(acac)2, Pd2(dba)3, PdCl2(PPh3)2, Pd(PPh3)4, Pd(dtbpf)Cl2, and mixtures thereof; the base is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - Selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is a mixture of 1,4-dioxane and water; the palladium catalyst is Pd(dtbpf)Cl2; and the base is potassium carbonate.

[0564] In some embodiments, step 3-F' is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 3-F' is performed at about 50 ℃ to about 150 ℃. In some embodiments, step 3-F' is performed at about 75 ℃ to about 125 ℃. In some embodiments, step 3-F' is performed at about 90 ℃ to about 110 ℃.

[0565] In some embodiments, the amount of compound of formula (31) versus the amount of compound of formula (17) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0566] In some embodiments, the amount of palladium catalyst versus the amount of the compound of formula (17) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.05 to 20 molar equivalents. In some embodiments, the range is 0.1 to 15 molar equivalents. In some embodiments, the range is 0.5 to 10 molar equivalents.

[0567] In some embodiments, the amount of base versus the amount of the compound of formula (17) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0568] Reaction Scheme 3 is a compound of chemical formula (18)

[0569] (18)

[0570] additionally includes step 3-G of reacting with an azide reagent to produce a compound of formula (1b-2).

[0571] (1b-2),

[0572] Here, R2, R3, R4, R5, R6, R7, R8, Q, Y, Z, R f , and R g is as defined above.

[0573] Step 3-G is presented below.

[0574]

[0575] In some embodiments, step 3-G includes reacting a compound of formula (18) with an azide reagent in the presence of a solvent, a salt, and a mixture thereof.

[0576] Suitable solvents for use in Step 3-G are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and iEsters such as BuOAc; halogenated alkanes such as DCM, CHCl3, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i Alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; benzene, toluene, o - Xylene, m - Xylene, p - Aromatic hydrocarbons such as xylene, mesitylene, pseudocumene (1,2,4-trimethylbenzene), hemimelitene (1,2,3-trimethylbenzene), and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0577] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p It is selected from the group consisting of xylene and mixtures thereof.

[0578] In some embodiments, the solvent is DMF.

[0579] The azide reagents suitable for use in Step 3-G are lithium azide, sodium azide, potassium azide, silver azide, barium azide, trimethyltin azide, triethyltin azide, and tripropyltin azide (tri( n -Prop)tin azide), triisopropyltin azide, tributyltin azide(tri( n -butyl)tin azide), tri( sec -butyl)tin azide, tri(isobutyl)tin azide, tri( tert It can be selected from the group consisting of butyl tin azide and mixtures thereof.

[0580] In some embodiments, the azide reagent is selected from the group consisting of lithium azide, sodium azide, potassium azide, trimethyltin azide, triethyltin azide, tripropyltin azide, tributyltin azide, and mixtures thereof.

[0581] In some embodiments, the azide reagent is sodium azide.

[0582] Salts suitable for use in step 3-G may be selected from the group consisting of lithium fluoride, sodium fluoride, potassium fluoride, ammonium fluoride, lithium chloride, sodium chloride, potassium chloride, ammonium chloride, lithium bromide, sodium bromide, potassium bromide, ammonium bromide, lithium iodide, sodium iodide, potassium iodide, ammonium iodide, lithium nitrate, sodium nitrate, potassium nitrate, and mixtures thereof.

[0583] In some embodiments, the salt is selected from the group consisting of ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, and mixtures thereof.

[0584] In some embodiments, the salt is ammonium chloride.

[0585] In some embodiments, step 3-G is performed in the presence of a solvent, an azide reagent, and a salt. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p- Selected from the group consisting of xylene and mixtures thereof; the azide reagent is selected from the group consisting of lithium azide, sodium azide, potassium azide, trimethyltin azide, triethyltin azide, tripropyltin azide, tributyltin azide, and mixtures thereof; the salt is selected from the group consisting of ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, and mixtures thereof. In some embodiments, the solvent is DMF, the azide reagent is sodium azide, and the salt is ammonium chloride.

[0586] In some embodiments, step 3-G is performed at about 0 °C to about 200 °C. In some embodiments, step 3-G is performed at about 50 °C to about 175 °C. In some embodiments, step 3-G is performed at about 75 °C to about 150 °C. In some embodiments, step 3-G is performed at about 100 °C to about 140 °C. In some embodiments, step 3-G is performed at about 125 °C to about 135 °C.

[0587] In some embodiments, the amount of azide reagent versus the amount of the compound of formula (18) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0588] In some embodiments, the amount of salt versus the amount of the compound of formula (18) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0589] go Compounds of chemical formula (1) or (1a), or enantiomers, racemic mixtures, or pharmaceutically acceptable salts thereof are prepared using the process presented in reaction scheme 4.

[0590]

[0591] Here

[0592] R2, R3, R4, R5, R6, R7, R8, Q, U, X2, Y, Z, R f , R g , and n are as defined above.

[0593] Reaction Scheme 4 is a compound of chemical formula (19)

[0594] (19)

[0595] React with the compound of chemical formula (16)

[0596] (16)

[0597] including step 4-A of producing a compound of formula (20)

[0598] (20),

[0599] Here, R4, R5, R6, R7, R8, and n are as defined above.

[0600] Step 4-A is presented below.

[0601]

[0602] In some embodiments, step 4-A includes reacting a compound of formula (19) with a compound of formula (16) in the presence of a reagent selected from the group consisting of solvents, catalysts, and mixtures thereof.

[0603] Suitable solvents for use in Step 4-A are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0604] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0605] In some embodiments, the solvent is DCM.

[0606] The catalysts suitable for use in step 4-A are rhodium(II) acetate dimer (Rh2(OAc)4), rhodium(III) acetate (Rh(OAc)3), palladium(II) acetate (Pd(OAc)2), rhodium(III) acetylacetonate (Rh(acac)3), ruthenium(III) acetylacetonate (Ru(acac)3), palladium(II) acetylacetonate (Pd(acac)2), nickel(II) acetylacetonate (Ni(acac)2), platinum(II) acetylacetonate (Pt(acac)2), tris(dibenzylideneacetone)dipalladium(O)(Pd2(dba)3), and dichlorobis(triphenylphosphine)palladium(II)(PdCl2(PPh3)2). It can be selected from the group consisting of tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4), palladium(0)(Pd), palladium(0) / carbon(Pd / C), and mixtures thereof.

[0607] In some embodiments, the catalyst is selected from the group consisting of Rh2(OAc)4, Rh(OAc)3, Rh(acac)3, and mixtures thereof.

[0608] In some embodiments, the catalyst is Rh2(OAc)4.

[0609] In some embodiments, step 4-A is performed in the presence of a solvent and a catalyst.

[0610] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; and the catalyst is selected from the group consisting of Rh2(OAc)4, Rh(OAc)3, Rh(acac)3, and mixtures thereof. In some embodiments, the solvent is DCM and the catalyst is Rh2(OAc)4.

[0611] In some embodiments, step 4-A is performed at about 0°C to about 200°C. In some embodiments, step 4-A is performed at about 5°C to about 100°C. In some embodiments, step 4-A is performed at about 10°C to about 50°C. In some embodiments, step 4-A is performed at about 15°C to about 35°C. In some embodiments, step 4-A is performed near room temperature.

[0612] In some embodiments, the amount of catalyst versus the amount of the compound of formula (19) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.05 to 20 molar equivalents. In some embodiments, the range is 0.1 to 15 molar equivalents. In some embodiments, the range is 0.1 to 10 molar equivalents. In some embodiments, the range is 0.5 to 5 molar equivalents.

[0613] Reaction Scheme 4 is a compound of chemical formula (20)

[0614] (20)

[0615] React with the compound of chemical formula (6)

[0616] (6)

[0617] additionally including step 4-B of producing a compound of formula (1c)

[0618] (1d),

[0619] Here, R2, R3, R4, R5, R6, R7, R8, Q, U, X2, Y, Z, R f , R g , and n are as defined above.

[0620] Step 4-B is presented below.

[0621]

[0622] In some embodiments, step 4-B includes reacting the compound of formula (20) with the compound of formula (6) in the presence of a reagent selected from the group consisting of a solvent, a copper salt, a base, a ligand, and a mixture thereof.

[0623] Suitable solvents for use in Step 4-B are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0624] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0625] In some embodiments, the solvent is selected from the group consisting of DMF, 1,4-dioxane, and mixtures thereof. In some embodiments, the solvent is a mixture of DMF and 1,4-dioxane.

[0626] Copper salts suitable for use in step 4-B can be selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof.

[0627] In some embodiments, the copper salt is CuI.

[0628] The bases suitable for use in Step 4-B are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; phosphates such as NaH2PO4, Na2HPO4, Na3PO4, KH2PO4, K2HPO4, K3PO4, and mixtures thereof; It can be selected from the group consisting of and mixtures thereof.

[0629] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, Na3PO4, K3PO4, and mixtures thereof.

[0630] In some embodiments, the base is K3PO4.

[0631] The ligand suitable for use in Step 4-B is N , N' -Dimethylethylenediamine( N , N' -DMEDA), N ,N' - Diisopropylethylenediamine, N , N' Diamines such as -dimethyl-1,6-hexanediamine and mixtures thereof; phenanthrolines such as 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, and mixtures thereof; bipyridines such as 2,2'-bipyridine; 2,2'-Bis(diphenylphosphino)-1,1'-vinaphthyl (BINAP), 2,3-Bis(diphenylphosphino)butane (Chiraphos), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthen (Xanthphos), Bis[(2-diphenylphosphino)phenyl] ether (DPEphos), 4,4,4',4',6,6'-hexamethyl-2,2'-spirobicroman-8,8'-diylbis(diphenylphosphane) (SPANphos), 4,4'-bi-1,3-benzodioxol-5,5'-diylbis(diphenylphosphane) (SEGPhos), 1,2-Bis(2,5-dimethylphosphorano)benzene (Me-DuPhos), 1,1-Bis(diphenylphosphino)methane (dppm), Organophosphorus compounds such as 1,2-bis(dimethylphosphino)ethane (dmpe), 1,2-bis(diisopropylphosphino)ethane (dippe), 1,2-bis(diphenylphosphino)benzene (dppbz), 1,2-bis(diphenylphosphino)ethane (dppe), bis(dicyclohexylphosphino)ethane (dcpe), 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), and mixtures thereof; and mixtures thereof are selected from the group consisting of.

[0632] In some embodiments, the ligand N , N' It is selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, BINAP, Chiraphos, Xanthphos, DPEphos, SPANphos, Me-DuPhos, dppm, and mixtures thereof.

[0633] In some embodiments, the ligand N , N' It is DMEDA.

[0634] In some embodiments, step 4-B is performed in the presence of a solvent, a copper salt, a base, and a ligand. In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; the copper salt is selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof; and the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof; the ligand is N , N' It is selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof. In some embodiments, the solvent is DMF, 1,4-dioxane, and mixtures thereof; the copper salt is CuI; the base is tripotassium phosphate; and the ligand is N , N' -DMEDA. In some embodiments, the solvent is a mixture of DMF and 1,4-dioxane, the copper salt is CuI, the base is tripotassium phosphate, and the ligand is N , N' It is DMEDA.

[0635] In some embodiments, step 4-B is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 4-B is performed at about 25 ℃ to about 150 ℃. In some embodiments, step 4-B is performed at about 50 ℃ to about 125 ℃. In some embodiments, step 4-B is performed at about 80 ℃ to about 100 ℃.

[0636] In some embodiments, the amount of compound of formula (6) versus the amount of compound of formula (20) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0637] In some embodiments, the amount of copper salt versus the amount of the compound of formula (20) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.05 to 20 molar equivalents. In some embodiments, the range is 0.1 to 15 molar equivalents. In some embodiments, the range is 0.1 to 10 molar equivalents. In some embodiments, the range is 0.5 to 5 molar equivalents.

[0638] In some embodiments, the amount of base versus the amount of compound of formula (20) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0639] In some embodiments, the amount of ligand versus the amount of the compound of formula (20) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0640] In some embodiments, step 4-B of Scheme 4 is followed by a dealkylation step 4-C, which is U-COOR e , -COSR e , or -CON(R e )2 people R in the compound of chemical formula (1d) e By removing the unsubstituted C1-C6 straight-chain or branched alkyl group of by reacting with at least one dealkylating reagent, R e It includes the step of producing a compound of chemical formula (1e) in which is H.

[0641] In some embodiments, step 4-C is U -COOR e , -COSR e , or -CON(R e )2 and R e A compound of formula (1d), which is an unsubstituted C1-C6 straight-chain or branched alkyl, is reacted in the presence of a reagent selected from the group consisting of a solvent, a dealkylating reagent, and mixtures thereof, so that U becomes -COOR e , -COSR e , or -CON(R e )2 and R e It includes the step of forming a compound of chemical formula (1e) in which is H.

[0642] Suitable solvents for use in Step 4-C are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; organic acids such as formic acid, AcOH; water; and mixtures thereof.

[0643] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, iIt is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof.

[0644] In some embodiments, the solvent is selected from the group consisting of THF, water, and mixtures thereof. In some embodiments, the solvent is a mixture of water and THF.

[0645] Dealkylation reagents suitable for use in Step 4-C are bases such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; acids such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof; Haloalkyl silanes such as trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0646] In some embodiments, the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof.

[0647] In some embodiments, the dealkylation reagent is lithium hydroxide.

[0648] In some embodiments, step 4-C is performed in the presence of a solvent and a dealkylation reagent. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The solvent is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof. In some embodiments, the solvent is THF, water, and mixtures thereof; and the dealkylation reagent is lithium hydroxide. In some embodiments, the solvent is a mixture of water and THF, and the dealkylation reagent is lithium hydroxide.

[0649] In some embodiments, step 4-C is performed at about 0°C to about 200°C. In some embodiments, step 4-C is performed at about 5°C to about 100°C. In some embodiments, step 4-C is performed at about 10°C to about 50°C. In some embodiments, step 4-C is performed at about 15°C to about 35°C. In some embodiments, step 4-C is performed near room temperature.

[0650] In some implementations, U is -COOR e , -COSR e , or -CON(R e )2 and R eThe amount of dealkylating agent relative to the amount of the compound of formula (1d), which is an unsubstituted C1-C6 straight-chain or branched alkyl, is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0651] go Compounds of chemical formula (1) or (1a), or enantiomers, racemic mixtures, or pharmaceutically acceptable salts thereof are prepared using the process presented in reaction scheme 5.

[0652]

[0653] Here:

[0654] R2, R3, R4, R5, R6, R7, R8, Q, U, Y, Z, R f , R g , and n are as defined above;

[0655] R q R r , and R s is independently F, Cl, Br, I, OR h , SR h , or as a leaving group L2 that can be substituted by a nucleophile p - Can be selected from the group consisting of sulfons such as toluenesulfonate (TsO-) or methanesulfonate (MsO-); perfluoroalkylsulfonates such as trifluoromethanesulfonate (-OSO2CF3); nitrates (-ONO2); and phosphates (-OPO(OR2), where R may be an alkyl group); and

[0656] R h is H or an unsubstituted C1-C6 straight-chain or branched alkyl.

[0657] Reaction Scheme 5 is a compound of chemical formula (21)

[0658] (21)

[0659] react with the compound of chemical formula (22)

[0660] (22)

[0661] including step 5-A of producing a compound of formula (23)

[0662] (23),

[0663] Here, R2, R3, Q, U, Y, Z, R f , R g , R q R r , R s , and n are as defined above.

[0664] Step 5-A is presented below.

[0665]

[0666] In some embodiments, step 5-A includes reacting a compound of formula (21) with a compound of formula (22) in the presence of a reagent selected from the group consisting of solvents, bases, and mixtures thereof.

[0667] Solvents suitable for use in Step 5-A are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0668] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0669] In some embodiments, the solvent is MeCN.

[0670] The bases suitable for use in Step 5-A are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; phosphates such as monosodium phosphate, disodium phosphate, trisodium phosphate, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate, and mixtures thereof; It can be selected from the group consisting of and mixtures thereof.

[0671] In some embodiments, the base is ammonia, triethylamine, N , N- Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof.

[0672] In some embodiments, the base is selected from the group consisting of sodium hydride, tripotassium phosphate, and mixtures thereof. In some embodiments, the base is a mixture of sodium hydride and tripotassium phosphate.

[0673] In some embodiments, step 5-A is performed in the presence of a solvent and a base. In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; and the base is ammonia, triethylamine, N , N - It is selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is MeCN and the base is selected from the group consisting of sodium hydride, tripotassium phosphate, and mixtures thereof. In some embodiments, the solvent is MeCN and the base is a mixture of sodium hydride and tripotassium phosphate.

[0674] In some embodiments, step 5-A is performed at about 0°C to about 200°C. In some embodiments, step 5-A is performed at about 5°C to about 100°C. In some embodiments, step 5-A is performed at about 10°C to about 50°C. In some embodiments, step 5-A is performed at about 15°C to about 35°C. In some embodiments, step 5-A is performed near room temperature.

[0675] In some embodiments, the amount of compound of formula (22) versus the amount of compound of formula (21) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0676] In some embodiments, the amount of base versus the amount of the compound of formula (21) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0677] Reaction Scheme 5 is a compound of chemical formula (23)

[0678] (23)

[0679] React with the compound of chemical formula (16)

[0680] (16)

[0681] additionally including step 5-B of producing a compound of formula (1d)

[0682] (1d),

[0683] Here, R2, R3, R4, R5, R6, R7, R8, Q, U, Y, Z, R f , R g , R r , and n are as defined above.

[0684] Step 5-B is presented below.

[0685]

[0686] In some embodiments, step 5-B includes reacting the compound of formula (23) with the compound of formula (16) in the presence of a reagent selected from the group consisting of solvents, bases, and mixtures thereof.

[0687] Suitable solvents for use in Step 5-B are amides such as DMF, DMA, NMP), 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0688] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0689] In some embodiments, the solvent is DMF.

[0690] Bases suitable for use in Step 5-B are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N- Can be selected from the group consisting of amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; and mixtures thereof.

[0691] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof.

[0692] In some embodiments, the base is sodium hydride.

[0693] In some embodiments, step 5-B is performed in the presence of a solvent and a base. In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; and the base is ammonia, triethylamine, N , N - It is selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is DMF and the base is sodium hydride.

[0694] In some embodiments, step 5-B is performed at about -25 ℃ to about 100 ℃. In some embodiments, step 5-B is performed at about -20 ℃ to about 50 ℃. In some embodiments, step 5-B is performed at about -15 ℃ to about 25 ℃. In some embodiments, step 5-B is performed at about -10 ℃ to about 10 ℃. In some embodiments, step 5-B is performed at about -5 ℃ to about 5 ℃.

[0695] In some embodiments, the amount of compound of formula (16) versus the amount of compound of formula (23) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0696] In some embodiments, the amount of base versus the amount of the compound of formula (23) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0697] In some embodiments, step 5-B of Reaction Scheme 5 is followed by a dealkylation step 5-C, in which U is -COOR e , -COSR e , or -CON(R e In the compound of chemical formula (1d) where )2, R e By removing the unsubstituted C1-C6 straight-chain or branched alkyl group of by reacting with at least one dealkylating reagent, R e It includes the step of producing a compound of chemical formula (1e) in which is H.

[0698] In some embodiments, step 5-C is U -COOR e , -COSR e , or -CON(R e )2 and R eA compound of formula (1d), which is an unsubstituted C1-C6 straight-chain or branched alkyl, is reacted in the presence of a reagent selected from the group consisting of a solvent, a dealkylating reagent, and mixtures thereof, so that U becomes -COOR e , -COSR e , or -CON(R e )2 and R e It includes the step of forming a compound of chemical formula (1e) in which is H.

[0699] Suitable solvents for use in Step 5-C are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; organic acids such as formic acid, AcOH; water; and mixtures thereof.

[0700] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof.

[0701] In some embodiments, the solvent is selected from the group consisting of THF, water, and mixtures thereof. In some embodiments, the solvent is a mixture of water and THF.

[0702] Dealkylation reagents suitable for use in Step 5-C are bases such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; acids such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof; Haloalkyl silanes such as trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0703] In some embodiments, the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof.

[0704] In some embodiments, the dealkylation reagent is lithium hydroxide.

[0705] In some embodiments, step 5-C is performed in the presence of a solvent and a dealkylation reagent. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, iThe solvent is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof. In some embodiments, the solvent is THF, water, and mixtures thereof; and the dealkylation reagent is lithium hydroxide. In some embodiments, the solvent is a mixture of water and THF, and the dealkylation reagent is lithium hydroxide.

[0706] In some embodiments, step 5-C is performed at about 0°C to about 200°C. In some embodiments, step 5-C is performed at about 5°C to about 100°C. In some embodiments, step 5-C is performed at about 10°C to about 50°C. In some embodiments, step 5-C is performed at about 15°C to about 35°C. In some embodiments, step 5-C is performed near room temperature.

[0707] In some implementations, U is -COOR e , -COSR e , or -CON(R e )2 and R e The amount of dealkylating agent relative to the amount of the compound of formula (1d), which is an unsubstituted C1-C6 straight-chain or branched alkyl, is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0708] go Compounds of chemical formula (1) or (1a), or enantiomers, racemic mixtures, or pharmaceutically acceptable salts thereof are prepared using the process presented in reaction scheme 6.

[0709]

[0710] Here:

[0711] R2, R3, R4, R5, R6, R7, R8, Q, U, Y, Z, R f , R g , and n are as defined above;

[0712] X8 is F, Cl, Br, or I;

[0713] E is O or S and;

[0714] R u is F, Cl, Br, I, OR p , or SR p And;

[0715] R v is an unsubstituted C1-C6 straight-chain or branched alkyl, or a protecting group selected from various groups including but not limited to those mentioned in Greene, Chapter 7: Protection for the Amino Group;

[0716] R w is H or an unsubstituted C1-C6 straight-chain or branched alkyl;

[0717] R x is H or an unsubstituted C1-C6 straight-chain or branched alkyl; and

[0718] R p is H or an unsubstituted C1-C6 straight-chain or branched alkyl.

[0719] Suitable protecting groups Rv include benzyl (Bn) groups, (diphenyl)methylene groups, trityl (triphenylmethyl, Tr) groups, or (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) groups. N- Alkylenedaryl; an amide such as a formyl group, acetyl (Ac) group, or benzoyl (Bz) group; tert - Butyloxycarbonyl (BOC) group, carbobenzyloxy (Cbz) group, p -Carbamates such as a methoxybenzyl carbonyl (Moz) group or a 9-fluorenylmethyloxycarbonyl (Fmoc) group; and a dialkyl phosphoramidate group, a methanesulfonyl (Mesyl, Ms) group, or p - Can be selected from N-P and N-sulfonyl protecting groups such as toluenesulfonyl (tosyl, Ts) groups. R v A protector in can be introduced by a method known in the art, where R v A compound of formula (24) in which α is H is reacted with a corresponding protecting group providing reagent to provide a protected amine. Suitable reagents used to introduce the protecting group are known in the art and are commercially available. For example, D- tert -Butyl dicarbonate is tert - It can be used to introduce a butyloxycarbonyl (BOC) group.

[0720] Reaction Scheme 6 is a compound of chemical formula (21)

[0721] (21)

[0722] react with the compound of chemical formula (24)

[0723] (24)

[0724] Includes step 6-A of producing a compound of formula (25).

[0725] (25),

[0726] Here, R2, R3, R4, R5, R6, R7, R8, Q, U, Y, Z, R f , R g , R p , R u , R v , R w, E, and n are as defined above.

[0727] Step 6-A is presented below.

[0728]

[0729] In some embodiments, step 6-A includes reacting a compound of formula (21) with a compound of formula (24) in the presence of a reagent selected from the group consisting of a solvent, a peptide coupling reagent, a base, and mixtures thereof.

[0730] Suitable solvents for use in Step 6-A are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i It may be selected from the group consisting of esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; and mixtures thereof.

[0731] In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof.

[0732] In some embodiments, the solvent is DCM.

[0733] Peptide coupling reagents suitable for use in Step 6-A are carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N-cyclohexyl, N'-isopropylcarbodiimide (CIC), and mixtures thereof; Phosphonium salts such as benzotriazole-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazole-1-yloxy-tri-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (AOP), (7-azabenzotriazole-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate (PyAOP), and mixtures thereof; 2-(1 H -benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylamium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 1-[(dimethylamino)(morpholino)methylene]-1 H -[1,2,3]Triazolo[4,5- b It may be selected from the group consisting of aluminum salts such as pyridine-1-nium 3-oxide hexafluorophosphate (HDMA) and mixtures thereof; phosphonic anhydrides such as propanephosphonic anhydride (T3P); and mixtures thereof. Additional examples of suitable peptide coupling reagents are incorporated herein by reference in their entirety. Chem. Rev. It can be found in 2011, 111, 11, 6557-6602.

[0734] In some embodiments, the peptide coupling reagent is selected from the group consisting of DCC, DIC, CIC, BOP, PyBOP, AOP, PyAOP, HBTU, TBTU, HATU, HDMA, T3P, and mixtures thereof.

[0735] In some embodiments, the peptide coupling reagent is PyBOP.

[0736] The bases suitable for use in Step 6-A are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; phosphates such as NaH2PO4, disodium phosphate Na2HPO4, Na3PO4, KH2PO4, K2HPO4, K3PO4, and mixtures thereof; It can be selected from the group consisting of and mixtures thereof.

[0737] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof.

[0738] In some embodiments, the base is N , N - It is diisopropylethylamine.

[0739] In some embodiments, step 6-A is performed in the presence of a solvent, a peptide coupling reagent, and a base. In some embodiments, the solvent is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; the peptide coupling reagent is selected from the group consisting of DCC, DIC, CIC, BOP, PyBOP, AOP, PyAOP, HBTU, TBTU, HATU, HDMA, T3P, and mixtures thereof; and the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof. In some embodiments, the solvent is DCM, the peptide coupling reagent is PyBOP, and the base is N , N - It is diisopropylethylamine.

[0740] In some embodiments, step 6-A is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 6-A is performed at about 5 ℃ to about 100 ℃. In some embodiments, step 6-A is performed at about 10 ℃ to about 50 ℃. In some embodiments, step 6-A is performed at about 15 ℃ to about 35 ℃. In some embodiments, step 6-A is performed near room temperature.

[0741] In some embodiments, the amount of compound of formula (24) versus the amount of compound of formula (21) is in the range of 0.5 to 20 molar equivalents. In some embodiments, the range is 0.67 to 10 molar equivalents. In some embodiments, the range is 0.75 to 5 molar equivalents.

[0742] In some embodiments, the amount of peptide coupling reagent versus the amount of the compound of formula (21) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.05 to 20 molar equivalents. In some embodiments, the range is 0.1 to 15 molar equivalents. In some embodiments, the range is 0.1 to 10 molar equivalents. In some embodiments, the range is 0.5 to 5 molar equivalents.

[0743] In some embodiments, the amount of base versus the amount of the compound of formula (21) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0744] Reaction Scheme 6 is a compound of chemical formula (25)

[0745] (25)

[0746] additionally includes step 6-B of reacting with an alkylating agent to produce a compound of formula (26).

[0747] (26),

[0748] Here, R2, R3, Q, U, X8, Y, Z, R f , R g , R v , R w , E, and n are as defined above.

[0749] Step 6-B is presented below.

[0750]

[0751] In some embodiments, step 6-B includes reacting a compound of formula (25) with an alkylating agent in the presence of a solvent.

[0752] Suitable solvents for use in Step 6-B are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, carbon tetrachloride, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; and mixtures thereof.

[0753] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH and mixtures thereof.

[0754] In some embodiments, the solvent is DCM.

[0755] Suitable alkylating reagents for use in Step 6-B are methyl fluoride, methyl chloride, methyl bromide, methyl iodide, ethyl fluoride, ethyl chloride, ethyl bromide, and ethyl iodide. n -Propyl fluoride, n -Propyl chloride, n -Profile bromide, nIt can be selected from the group consisting of alkyl halides such as propyl iodide, isopropyl fluoride, isopropyl chloride, isopropyl bromide, isopropyl iodide, and mixtures thereof.

[0756] In some embodiments, the alkylating reagent is methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, n -Profile bromide, n - It is selected from the group consisting of propyl iodide, isopropyl bromide, isopropyl iodide, and mixtures thereof.

[0757] In some embodiments, the alkylating agent is methyl iodide.

[0758] In some embodiments, step 6-B is performed in the presence of a solvent and an alkylating reagent. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i Selected from the group consisting of PrOH and mixtures thereof; the alkylating reagent is methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, n -Profile bromide, n - It is selected from the group consisting of propyl iodide, isopropyl bromide, isopropyl iodide, and mixtures thereof. In some embodiments, the solvent is DCM and the alkylating agent is methyl iodide.

[0759] In some embodiments, step 6-B is performed at about 0°C to about 200°C. In some embodiments, step 6-B is performed at about 5°C to about 100°C. In some embodiments, step 6-B is performed at about 10°C to about 50°C. In some embodiments, step 6-B is performed at about 15°C to about 35°C. In some embodiments, step 6-B is performed near room temperature.

[0760] In some embodiments, the amount of alkylating agent versus the amount of the compound of formula (25) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0761] Reaction Scheme 6 is a compound of chemical formula (26)

[0762] (26)

[0763] Step 6-C, which further includes reacting with a non-nucleophilic base to produce a compound of formula (27).

[0764] (27),

[0765] Here, R2, R3, Q, U, X8, Y, Z, R f , R g , R v , R x , R w , E, and n are as defined above.

[0766] Step 6-C is presented below.

[0767]

[0768] In some embodiments, step 6-C includes the step of reacting a compound of formula (26) with a non-nucleophilic base in the presence of a solvent.

[0769] Suitable solvents for use in Step 6-C are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and iEsters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; and mixtures thereof.

[0770] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH and mixtures thereof.

[0771] In some embodiments, the solvent is THF.

[0772] Non-nucleophilic bases suitable for use in step 6-C are organic bases with low nucleophilicity, such as phosphazenes like cyclodiphosphazane, hexachlorophosphazene, polyphosphazene, and mixtures thereof; N,N-diisopropylethylamine, triisopropylamine, 2,6-di- tertAmines such as butylpiperidine, 1,8-diazabicycloundex-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), and mixtures thereof; alkoxide salts such as lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; amine anions such as lithium diisopropylamide (LDA), sodium diisopropylamide, potassium diisopropylamide, lithium tetramethylpiperidine (LiTMP), sodium tetramethylpiperidine (NaTMP), potassium tetramethylpiperidine (KTMP), lithium bis(trimethylsilyl)amide (LiHMDS), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and mixtures thereof; It may be selected from the group consisting of hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; and mixtures thereof.

[0773] In some embodiments, the non-nucleophilic base is N,N-diisopropylethylamine, 2,6-di- tert - Selected from the group consisting of butylpiperidine, DBU, DBN, potassium tert-butoxide, LDA, LiTMP, NaTMP, KTMP, LiHMDS, NaHMDS, KHMDS, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof.

[0774] In some embodiments, the non-nucleophilic base is LiHMDS.

[0775] In some embodiments, step 6-C is performed in the presence of a solvent and a non-nucleophilic base. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The non-nucleophilic base is selected from the group consisting of PrOH and mixtures thereof; the non-nucleophilic base is N,N-diisopropylethylamine, 2,6-di- tert- Selected from the group consisting of butylpiperidine, DBU, DBN, potassium tert-butoxide, LDA, LiTMP, NaTMP, KTMP, LiHMDS, NaHMDS, KHMDS, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. In some embodiments, the solvent is THF and the non-nucleophilic base is LiHMDS.

[0776] In some embodiments, step 6-C is performed at about -25 ℃ to about 100 ℃. In some embodiments, step 6-C is performed at about -20 ℃ to about 50 ℃. In some embodiments, step 6-C is performed at about -15 ℃ to about 25 ℃. In some embodiments, step 6-C is performed at about -10 ℃ to about 10 ℃. In some embodiments, step 6-C is performed at about -5 ℃ to about 5 ℃.

[0777] In some embodiments, the amount of non-nucleophilic base versus the amount of the compound of formula (26) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0778] Reaction Scheme 6 is a compound of chemical formula (27)

[0779] (27)

[0780] additionally includes step 6-D of reacting with a deprotection reagent to produce a compound of formula (28).

[0781] (28)

[0782] Here, R2, R3, R4, R5, R6, R7, R8, Q, U, Y, Z, R f , R g , R v , and n are as defined above.

[0783] Step 6-D is presented below.

[0784]

[0785] In some embodiments, step 6-D includes the step of reacting a compound of formula (27) with a deprotecting reagent in the presence of a solvent.

[0786] Suitable solvents for use in Step 6-D are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; organic acids such as formic acid, AcOH; water; and mixtures thereof.

[0787] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof.

[0788] In some embodiments, the solvent is 1,4-dioxane.

[0789] A deprotection reagent suitable for use in step 6-D may be selected from the group consisting of acyl halides such as acyl chloride, acyl bromide, acyl iodide, and mixtures thereof; acid anhydrides such as acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, and mixtures thereof; organic acids such as formic acid, AcOH, TFA, and mixtures thereof; inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof; and mixtures thereof.

[0790] In some embodiments, the deprotection reagent is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof.

[0791] In some embodiments, the deprotection reagent is hydrochloric acid.

[0792] In some embodiments, step 6-D is performed in the presence of a solvent and a deprotecting reagent. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The solvent is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; the deprotecting reagent is selected from the group consisting of formic acid, AcOH, TFA, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof. In some embodiments, the solvent is 1,4-dioxane, and the deprotecting reagent is hydrochloric acid.

[0793] In some embodiments, step 6-D is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 6-D is performed at about 5 ℃ to about 100 ℃. In some embodiments, step 6-D is performed at about 10 ℃ to about 50 ℃. In some embodiments, step 6-D is performed at about 15 ℃ to about 35 ℃. In some embodiments, step 6-D is performed near room temperature.

[0794] In some embodiments, the amount of deprotection reagent versus the amount of the compound of formula (27) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0795] Reaction Scheme 6 is a compound of chemical formula (28)

[0796] (28)

[0797] React with the compound of chemical formula (2)

[0798] (2)

[0799] additionally including step 6-E of producing a compound of formula (1d)

[0800] (1d),

[0801] Here, R2, R3, R4, R5, R6, R7, R8, Q, U, X1, Y, Z, R f , R g , and n are as defined above.

[0802] Step 6-E is presented below.

[0803]

[0804] In some embodiments, step 6-E includes reacting a compound of formula (28) with a compound of formula (2) in the presence of a solvent, a catalyst, a ligand, and a base.

[0805] Suitable solvents for use in Step 6-E are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i Alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; benzene, toluene, o - Xylene, m - Xylene, p - Aromatic hydrocarbons such as xylene, mesitylene, pseudocumene (1,2,4-trimethylbenzene), hemimelitene (1,2,3-trimethylbenzene), and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0806] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p It is selected from the group consisting of xylene and mixtures thereof.

[0807] In some embodiments, the solvent is toluene.

[0808] The catalysts suitable for use in step 6-E are rhodium(II) acetate dimer (Rh2(OAc)4), rhodium(III) acetate (Rh(OAc)3), palladium(II) acetate (Pd(OAc)2), rhodium(III) acetylacetonate (Rh(acac)3), ruthenium(III) acetylacetonate (Ru(acac)3), palladium(II) acetylacetonate (Pd(acac)2), nickel(II) acetylacetonate (Ni(acac)2), platinum(II) acetylacetonate (Pt(acac)2), tris(dibenzylideneacetone)dipalladium(O)(Pd2(dba)3), and dichlorobis(triphenylphosphine)palladium(II)(PdCl2(PPh3)2). It can be selected from the group consisting of tetrakis(triphenylphosphine)palladium (0)(Pd(PPh3)4), palladium (0)(Pd), palladium supported on carbon (0)(Pd / C), and mixtures thereof.

[0809] In some embodiments, the catalyst is selected from the group consisting of Pd2(dba)3, PdCl2(PPh3)2, Pd(PPh3)4, and mixtures thereof.

[0810] In some embodiments, the catalyst is Pd2(dba)3.

[0811] The ligand suitable for use in Step 6-E is N , N' -Dimethylethylenediamine( N , N' -DMEDA), N , N' - Diisopropylethylenediamine, N , N'Diamines such as -dimethyl-1,6-hexanediamine and mixtures thereof; phenanthrolines such as 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline, and mixtures thereof; bipyridines such as 2,2'-bipyridine; 2,2'-Bis(diphenylphosphino)-1,1'-vinaphthyl (BINAP), 2,3-Bis(diphenylphosphino)butane (Chiraphos), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthen (Xanthphos), Bis[(2-diphenylphosphino)phenyl] ether (DPEphos), 4,4,4',4',6,6'-hexamethyl-2,2'-spirobicroman-8,8'-diylbis(diphenylphosphane) (SPANphos), 4,4'-bi-1,3-benzodioxol-5,5'-diylbis(diphenylphosphane) (SEGPhos), 1,2-Bis(2,5-dimethylphosphorano)benzene (Me-DuPhos), 1,1-Bis(diphenylphosphino)methane (dppm), Organophosphorus compounds such as 1,2-bis(dimethylphosphino)ethane (dmpe), 1,2-bis(diisopropylphosphino)ethane (dippe), 1,2-bis(diphenylphosphino)benzene (dppbz), 1,2-bis(diphenylphosphino)ethane (dppe), bis(dicyclohexylphosphino)ethane (dcpe), 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), and mixtures thereof; and mixtures thereof are selected from the group consisting of.

[0812] In some embodiments, the ligand N , N' It is selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, BINAP, Chiraphos, Xanthphos, DPEphos, SPANphos, Me-DuPhos, dppm, and mixtures thereof.

[0813] In some embodiments, the ligand is BINAP.

[0814] The bases suitable for use in Step 6-E are ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, isopropylamine, diisopropylamine, triisopropylamine, N , N - Amine bases such as diisopropylethylamine, pyridine, imidazole, and mixtures thereof; alkoxide salts such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; hydroxide salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof; carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof; bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; hydride salts such as lithium hydride, sodium hydride, potassium hydride, and mixtures thereof; phosphates such as NaH2PO4, Na2HPO4, Na3PO4, KH2PO4, K2HPO4, K3PO4, and mixtures thereof; It can be selected from the group consisting of and mixtures thereof.

[0815] In some embodiments, the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, Na3PO4, K3PO4, and mixtures thereof.

[0816] In some embodiments, the base is cesium carbonate.

[0817] In some embodiments, step 6-E is performed in the presence of a solvent, a catalyst, a ligand, and a base. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - Selected from the group consisting of xylene and mixtures thereof; the catalyst is selected from the group consisting of Pd2(dba)3, PdCl2(PPh3)2, Pd(PPh3)4, and mixtures thereof; the ligand is selected from the group consisting of N,N'-DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, BINAP, Chiraphos, Xanthphos, DPEphos, SPANphos, Me-DuPhos, dppm, and mixtures thereof; the base is ammonia, triethylamine, N , N - Selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof. In some embodiments, the solvent is toluene, the catalyst is Pd2(dba)3, the ligand is BINAP, and the base is cesium carbonate.

[0818] In some embodiments, step 6-E is performed at about 0 °C to about 200 °C. In some embodiments, step 6-E is performed at about 25 °C to about 175 °C. In some embodiments, step 6-E is performed at about 50 °C to about 150 °C. In some embodiments, step 6-E is performed at about 75 °C to about 125 °C. In some embodiments, step 6-E is performed at about 85 °C to about 100 °C.

[0819] In some embodiments, the amount of catalyst versus the amount of the compound of formula (28) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0820] In some embodiments, the amount of ligand versus the amount of the compound of formula (28) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0821] In some embodiments, the amount of base versus the amount of the compound of formula (28) is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0822] In some embodiments, step 6-E of Scheme 5 is followed by a dealkylation step 6-F, in which U is -COOR e , -COSR e , or -CON(R e )2 and R e By reacting the unsubstituted C1-C6 straight-chain or branched alkyl in the compound of formula (1d), which is an unsubstituted C1-C6 straight-chain or branched alkyl, with at least one dealkylating agent to remove it, U is -COOR e , -COSR e , or -CON(R e )2, R e It includes the step of producing a compound of chemical formula (1e) in which is H.

[0823] In some embodiments, step 6-F is U -COOR e , -COSR e , or -CON(R e )2 and Re A compound of formula (1d), which is an unsubstituted C1-C6 straight-chain or branched alkyl, is reacted in the presence of a reagent selected from the group consisting of a solvent, a dealkylating reagent, and mixtures thereof, so that U becomes -COOR e , -COSR e , or -CON(R e )2 and R e It includes the step of forming a compound of chemical formula (1e) in which is H.

[0824] Suitable solvents for use in Step 6-F are amides such as DMF, DMA, NMP, 2-pyrrolidone, and mixtures thereof; ethers such as diethyl ether, THF, 2-MeTHF, DME, MTBE, 1,4-dioxane, and mixtures thereof; MeOAc, EtOAc, n PrOAc, i PrOAc, n BuOAc, sec -BuOAc, t BuOAc, and i Esters such as BuOAc; halogenated alkanes such as DCM, CHCl3, CCl4, 1,2-dichloroethane, and mixtures thereof; nitriles such as MeCN, propionitrile, benzonitrile, and mixtures thereof; MeOH, EtOH, n PrOH, i It may be selected from the group consisting of alcohols such as PrOH, ethylene glycol, diethylene glycol, and mixtures thereof; organic acids such as formic acid, AcOH; water; and mixtures thereof.

[0825] In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i It is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof.

[0826] In some embodiments, the solvent is selected from the group consisting of THF, water, and mixtures thereof. In some embodiments, the solvent is a mixture of water and THF.

[0827] Dealkylation reagents suitable for use in step 6-F are bases such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof; acids such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof; Haloalkyl silanes such as trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof; and mixtures thereof may be selected from the group consisting of

[0828] In some embodiments, the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof.

[0829] In some embodiments, the dealkylation reagent is lithium hydroxide.

[0830] In some embodiments, step 6-F is performed in the presence of a solvent and a dealkylation reagent. In some embodiments, the solvent is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The solvent is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; the dealkylation reagent is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, trimethylsilyl fluoride, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl fluoride, triethylsilyl chloride, triethylsilyl bromide, triethylsilyl iodide, and mixtures thereof. In some embodiments, the solvent is THF, water, and mixtures thereof; and the dealkylation reagent is lithium hydroxide. In some embodiments, the solvent is a mixture of water and THF, and the dealkylation reagent is lithium hydroxide.

[0831] In some embodiments, step 6-F is performed at about 0 ℃ to about 200 ℃. In some embodiments, step 6-F is performed at about 5 ℃ to about 100 ℃. In some embodiments, step 6-F is performed at about 10 ℃ to about 50 ℃. In some embodiments, step 6-F is performed at about 15 ℃ to about 35 ℃. In some embodiments, step 6-F is performed near room temperature.

[0832] In some implementations, U is -COOR e , -COSR e , or -CON(R e )2 and R eThe amount of dealkylating agent relative to the amount of the compound of formula (1d), which is an unsubstituted C1-C6 straight-chain or branched alkyl, is in the range of 0.01 to 25 molar equivalents. In some embodiments, the range is 0.1 to 20 molar equivalents. In some embodiments, the range is 0.5 to 15 molar equivalents. In some embodiments, the range is 1 to 10 molar equivalents.

[0833] The compositions and methods described above may be better understood in connection with the following examples. Additionally, the following non-limiting examples are illustrative. The procedures described as general methods describe those generally considered effective for preparing the indicated compositions. However, those skilled in the art will understand that it may be necessary to modify the procedures for any given example of this disclosure, for example, by changing the order or steps and / or the chemical reagents used.

[0834] Examples

[0835] A method for preparing an exemplary compound of formula (1) or (1a) using the process of the present invention is described in detail below.

[0836] Example 1

[0837] Synthesis of the 3-(4-(3-((2,4-disubstituted phenyl)amino)-2-oxopyrrolidine-1-yl)phenyl)propanoic acid compound of chemical formula (1a)

[0838]

[0839] Methyl 3-(4-aminophenyl)propanoate was reacted with 2,4-dibromobutanoyl chloride in the presence of potassium phosphate (0.5 equivalents), sodium hydroxide (2.5 equivalents), and acetonitrile. The reaction mixture was stirred at room temperature for 1 hour. The resulting intermediate, methyl 3-(4-(3-bromo-2-oxopyrrolidine-1-yl)phenyl)propanoate, was obtained in a 77% yield. Methyl 3-(4-(3-bromo-2-oxopyrrolidine-1-yl)phenyl)propanoate was reacted with 2,4-disubstituted aniline in the presence of sodium hydride (3 equivalents) and DMF. The reaction mixture was stirred at 0°C for 2 hours to obtain the product, 3-(4-(3-((2,4-disubstituted phenyl)amino)-2-oxopyrrolidine-1-yl)phenyl)propanoic acid.

[0840] Example 2

[0841] 3-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrrolidine-1-yl)phenyl)propanoic acid(compound) 11 Synthesis of )

[0842]

[0843] Methyl 3-(4-aminophenyl)propanoate first PyBOP, DCM and N , N- It was reacted with 2-((tert-butoxycarbonyl)amino)-4-(methylthio)butanoic acid in the presence of diisopropylethylamine (DIPEA). The reaction mixture was stirred at room temperature for 15 hours. After post-treatment, the residue was treated with methyl iodide to obtain (3-((tert-butoxycarbonyl)amino)-4-((4-(3-methoxy-3-oxopropyl)phenyl)amino)-4-oxobutyl)dimethylsulfonium in 80% yield, which was first reacted with LiHMDS at 0 °C for 2 hours in the presence of THF. Subsequently, hydrochloric acid and 1,4-dioxane were added to the reaction mixture, and the reaction mixture was stirred at room temperature for 48 hours. The resulting intermediate, methyl 3-(4-(3-amino-2-oxopyrrolidine-1-yl)phenyl)propanoate, was obtained in a 70% yield. Methyl 3-(4-(3-amino-2-oxopyrrolidine-1-yl)phenyl)propanoate was reacted with 2-chloro-1-iodo-4-(trifluoromethyl)benzene in the presence of 2,2'-bis(diphenylphosphino)-1,1'-vinafthyl (BINAP), tris(dibenzylideneacetone)dipalladium (O), cesium carbonate, and toluene. The reaction mixture was stirred at 95 °C for 48 hours. The resulting intermediate, methyl 3-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrrolidine-1-yl)phenyl)propanoate, was obtained in a 41% yield. Subsequently, methyl 3-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrrolidine-1-yl)phenyl)propanoate was reacted with lithium hydroxide in the presence of water and THF. The reaction mixture was stirred at room temperature for 12 hours. The resulting product, 3-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrrolidine-1-yl)phenyl)propanoic acid, was obtained in a 66% yield.

[0844] Example 3

[0845] (3 S )-3-(4-(3-((4-isopropyl-2-(trifluoromethyl)phenyl)amino)-2-oxopiperidine-1-yl)phenyl)butanoic acid(compound 14-(3S) Synthesis of )

[0846]

[0847] 3-diazopiperidin-2-one was reacted with 4-isopropyl-2-(trifluoromethyl)aniline in the presence of rhodium(II) acetate and dichloromethane. The reaction mixture was stirred at room temperature for 12 hours. The resulting intermediate, 3-((4-isopropyl-2-(trifluoromethyl)phenyl)amino)piperidin-2-one, was obtained in 50% yield. Subsequently, 3-((4-isopropyl-2-(trifluoromethyl)phenyl)amino)piperidin-2-one was reacted with K3PO4, CuI, N , N' - In the presence of DMEDA, DMF, and 1,4-dioxane ( S )-ethyl 3-(4-iodophenyl)butanoate was reacted. The reaction mixture was stirred in a sealed tube at 90 °C for 12 hours. The resulting intermediate (3 S )-ethyl 3-(4-(3-((4-isopropyl-2-(trifluoromethyl)phenyl)amino)-2-oxopiperidine-1-yl)phenyl)butanoate was obtained in a 56% yield. (3 S )-ethyl 3-(4-(3-((4-isopropyl-2-(trifluoromethyl)phenyl)amino)-2-oxopiperidine-1-yl)phenyl)butanoate was reacted with lithium hydroxide in the presence of water and THF. The reaction mixture was stirred at room temperature for 12 hours. The resulting product, (3 S )-3-(4-(3-((4-isopropyl-2-(trifluoromethyl)phenyl)amino)-2-oxopiperidine-1-yl)phenyl)butanoic acid was obtained in an 83% yield.

[0848] Reagent ( S )-ethyl 3-(4-iodophenyl)butanoate is ( S It was prepared from )-3-phenyl-butyric acid in two steps: a first iodination step and a second esterification step.

[0849] Example 4

[0850] 2-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-1)-2,6-dimethylphenoxy)acetic acid (compound) 2 Synthesis of )

[0851]

[0852] 3-methoxypyrazine-2-amine and 2-chloro-1-fluoro-4-(trifluoromethyl)benzene were reacted in the presence of sodium hydride and DMF. The reaction mixture was stirred at 80 °C for 3 hours. The resulting intermediate is N -(2-chloro-4-(trifluoromethyl)phenyl)-3-methoxypyrazine-2-amine was obtained in a 54% yield. N -(2-chloro-4-(trifluoromethyl)phenyl)-3-methoxypyrazine-2-amine was reacted with 33% hydrobromide in the presence of AcOH. The reaction mixture was stirred at room temperature for 48 hours. The resulting intermediate, 3-((2-chloro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-one was obtained in a 78% yield. 3-((2-chloro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on K3PO4, CuI, N , N' It was reacted with ethyl 2-(4-bromo-2,6-dimethylphenoxy)acetate in the presence of DMEDA, DMF, and 1,4-dioxane. The reaction mixture was stirred in a sealed tube at 90 °C for 12 hours. The resulting intermediate, ethyl 2-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-yl)-2,6-dimethylphenoxy)acetate was obtained in a 31% yield. Ethyl 2-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-yl)-2,6-dimethylphenoxy)acetate was reacted with lithium hydroxide in the presence of water and THF. The reaction mixture was stirred at room temperature for 12 hours. The resulting product, 2-(4-(3-((2-chloro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-1)-2,6-dimethylphenoxy)acetic acid was obtained in a 70% yield.

[0853] Example 5

[0854] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on(compound) 3 Synthesis of )

[0855]

[0856] 3-methoxypyrazine-2-amine was reacted with 1,2-difluoro-4-(trifluoromethyl)benzene in the presence of sodium hydride and DMF. The reaction mixture was stirred at 80 °C for 3 hours. The resulting intermediate, N-(2-fluoro-4-(trifluoromethyl)phenyl)-3-methoxypyrazine-2-amine, was obtained in 54% yield. N-(2-fluoro-4-(trifluoromethyl)phenyl)-3-methoxypyrazine-2-amine was reacted with 33% hydrobromide in the presence of AcOH. The reaction mixture was stirred at room temperature for 48 hours. The resulting intermediate, 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-one was obtained in a 78% yield. 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on K3PO4, CuI, N , N' -3-(4-bromophenyl)propanenitrile was reacted in the presence of DMEDA, DMF, and 1,4-dioxane. The reaction mixture was stirred in a sealed tube at 90 °C for 12 hours. The resulting intermediate, 3-(4-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-1)phenyl)propanenitrile was obtained in a 29% yield. 3-(4-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-yl)phenyl)propanenitrile was reacted with tributyltin azide in the presence of toluene. The reaction mixture was stirred in a sealed tube at 115 °C for 20 hours. The resulting product, 1-(4-(2-(1 H-tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on was obtained with an 82% yield.

[0857]

[0858] NaCN (980 mg, 20.00 mmol) was added to a stirred solution of 1-(2-bromoethyl)-4-nitrobenzene (4 g, 17.39 mmol) in DMSO (40 mL) at 25 °C. The reaction mixture was stirred at 50 °C for 3 hours. The resulting intermediate, 3-(4-nitrophenyl)propanenitrile, was obtained as a grayish-white solid in a 63% yield (2 g). MS (ESI): 177.1.

[0859] Pd / C (423 mg, 3.97 mmol) was added to a stirred solution of 3-(4-nitrophenyl)propanenitrile (2 g, 11.35 mmol) in MeOH (50 mL). The reaction mixture was stirred under H2 at 25 °C for 6 hours. The resulting intermediate, 3-(4-aminophenyl)propanenitrile, was obtained as a white solid in an 87% yield (1.6 g). MS (ESI): 147.1.

[0860] K2CO3 (3 g, 21.89 mmol) was added at 25 °C to a stirred solution of 3-(4-aminophenyl)propanenitrile (1.6 g, 10.94 mmol) and 2-bromoacetonitrile (3.3 g, 27.36 mmol) in MeCN (20 mL). The reaction mixture was stirred at 60 °C for 12 hours. The resulting intermediate, 3-{4-[(cyanomethyl)amino]phenyl}propanenitrile, was obtained as a white solid in a 71% yield (1.6 g). MS (ESI): 186.1.

[0861] Oxalyl dichloride (5.5 g, 43.19 mmol) was added to a stirred solution of 3-{4-[(cyanomethyl)amino]phenyl}propanenitrile (1.6 g, 8.64 mmol) in chlorobenzene (40 mL). The reaction mixture was stirred at 100 °C for 1 hour, after which DMF (126 mg, 1.73 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours. The resulting intermediate, 3-[4-(3,5-dichloro-2-oxopyrazine-1-yl)phenyl]propanenitrile, was obtained as a white solid in a 33% yield (900 mg). MS (ESI): 294.0.

[0862] NaH (544 mg, 13.60 mmol) was added at 0 °C to a stirred solution of 4-trifluoromethyl-2-fluoroaniline (398 mg, 13.60 mmol) in THF (11 mL). The reaction mixture was stirred at 25 °C for 1 hour. 3-[4-(3,5-dichloro-2-oxopyrazine-1-yl)phenyl]propanitrile (500 mg, 1.02 mmol) was added to the resulting mixture at 0 °C. The reaction mixture was stirred at 25 °C for 4 hours. The resulting intermediate, 3-(4-(5-chloro-3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-1)phenyl)propanenitrile was obtained as a grayish-white solid in a 25% yield (210 mg). MS (ESI): 437.0. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 9.27 (s, 1H), 8.30 (t, J = 8.2 Hz, 1H), 7.83 (d, J = 10.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.53 - 7.47 (m, 4H), 7.43 (s, 1H), 2.97 (t, J = 6.8 Hz, 2H), 2.88 (dd, J = 10.8, 4.0 Hz, 2H).

[0863] 3-(4-(5-chloro-3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2) in MeOH (20 mL) H Pd / C (9 mg, 0.09 mmol) was added to a stirred mixture of )-yl)phenyl)propanenitrile (110 mg, 0.25 mmol) and K2CO3 (35 mg, 0.25 mmol). The reaction mixture was stirred under H2 at 25 °C for 3 hours. The resulting intermediate, 3-(4-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-1)phenyl)propanenitrile was obtained as a white solid in a 73% yield (80 mg). MS (ESI): 403.1.

[0864] 3-(4-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 in DMF (4 mL) H Sodium azide (NaN3, 169 mg, 2.60 mmol) was added to a stirred mixture of )-yl)phenyl)propanenitrile (70 mg, 0.17 mmol) and ammonium chloride (NH4Cl, 93 mg, 1.74 mmol). The reaction mixture was stirred at 130 °C for 16 hours. The resulting product, 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on was obtained as a yellow solid in a 45% yield (37 mg). MS (ESI): 446.1. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.88 (s, 1H), 8.61 (t, J = 8.0 Hz, 1H), 7.80 (d, J = 11.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.48 - 7.41 (m, 4H), 7.18 (d, J = 4.8 Hz, 1H), 7.05 (d,J = 4.8 Hz, 1H), 3.26 - 3.24 (m, 2H), 3.17 - 3.13 (m, 2H).

[0865]

[0866] A condenser was fitted into a 300-mL flask, and 2-chloro-3-methoxypyrazine (10.99 g, 1 equivalent, 76.0 mmol), 2-fluoro-4-(trifluoromethyl)aniline (16.25 g, 1.19 equivalents, 90.7 mmol), and 1,4-dioxane (120 mL) were added. HBr in acetic acid (16.0 mL, 22.37 g, 33% by weight, 1.2 equivalents, 91.2 mmol) was added at room temperature. A white solid precipitated from the mixture. The suspension was stirred at 120 °C for 7 hours, cooled to room temperature, and then added to ice water (1 L). The resulting suspension was cooled in an ice bath while stirring. Saturated Na2CO3 (125 mL) was added to adjust the pH of the mixture to 8-9. After stirring for 30 minutes, the resulting white precipitate was collected by filtration. The solid was washed with water and dried under vacuum at 50 °C for 2 days to obtain 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on (21.47 g, 99% yield at 96% purity) was obtained as a white solid. LC-MS: 274.0. 1 ¹H NMR (400 MHz, DMSO- d 6) δ8.89 - 8.56 (m, 2H), 7.85 - 7.63 (m, 1H), 7.58 (ddt, J = 8.6, 2.0, 0.9 Hz, 1H), 7.10 - 6.81 (m, 2H).

[0867] Alternatively, the Pd-catalyzed Buchwald reaction uses various catalysts including Pd2(dba)3 / Xantphos, Pd(OAc)2 / Xantphos, XantPhos-Pd-G3, and BrettPhos-Pd-G3 to produce 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on was produced with a yield of 26-54%.

[0868] In a 500-mL flask, 3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-one (10.9 g, 1 equivalent, 39.9 mmol), 3-(4-bromophenyl)propanenitrile (10.0 g, 1.19 equivalents, 47.6 mmol), and 1,4-dioxane (160 mL) were added. CuI (8.36 g, 1.1 equivalents, 43.9 mmol) was added to the suspension. After stirring the mixture for 5 minutes, N , N' 7.7 g, 9.4 mL, 2.2 equivalents, 87.8 mmol of dimethylethane-1,2-diamine (7.7 g, 9.4 mL, 2.2 equivalents, 87.8 mmol) was added. After stirring for 5 minutes, sodium carbonate (8.46 g, 2 equivalents, 79.8 mmol) was added. The reaction mixture was heated under reflux for 10 hours and then filtered through Celite. The filtrate was evaporated. The solid pad was washed with DCM until all products were washed away. The residue and wash solution were combined, washed with brine (400 mL), and then washed with saturated aqueous NH4Cl (200 mL). The wash solution was extracted three times with DCM. The organic phase was dried over Na2SO4, filtered, and then evaporated. The residue was crystallized with EtOAc / heptane to obtain 3-(4-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-yl)phenyl)propanenitrile (11.1 g), and more product (2.0 g) was obtained from the mother liquor as a white solid in a total yield of 81.6%. LC-MS: 403.19.

[0869] In a 300-mL flask, 3-(4-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2 H )-1)phenyl)propanenitrile (13.1 g, 1 equivalent, 32.6 mmol), sodium azide (21.3 g, 10 equivalents, 326 mmol), ammonium chloride (17.4 g, 10 equivalents, 326 mmol), and N,N-dimethylacetamide (“DMAC” 110 mL) were added. The reaction mixture was heated at 120 °C for 12 hours. The mixture was cooled to room temperature, poured into saturated NH4Cl (550 mL), and stirred for 10 minutes. The resulting white solid was collected by filtration. The solid was suspended in water (400 mL), stirred, and then filtered. Filtration was slow. The solid was again suspended in water (400 mL) to form a gel-like substance and suspended in EtOAc (500 mL). The suspension was heated to aid separation. The organic phase was separated. The aqueous phase was re-extracted with EtOAc. The hot organic phase was dried with Na2SO4, filtered, and then evaporated. The residue was crystallized with EtOAc. More product was obtained from the filtrate. The two products were combined and dried under high vacuum for 3 days to obtain 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on (11.1 g, 76.5% yield, Compound 3 of Table 29) was obtained as a grayish-white solid. The remaining mother liquor was purified by flash chromatography (40 g silica gel, MeOH / DCM 0-10%). The relatively pure fractions were combined and crystallized in EtOAc to obtain an additional target product (1.42 g). The total yield was 84.8%. LC-MS: 446.1. 1 ¹H NMR (500 MHz, DMSO- d 6) δ8.86 (d, J = 2.7 Hz, 1H), 8.61 (t, J= 8.3 Hz, 1H), 7.63 (dd, J = 8.6, 2.0 Hz, 1H), 7.76 (dd, J = 11.3, 2.1 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 4.6 Hz, 1H), 7.04 (d, J = 4.6 Hz, 1H), 3.25 (t, J = 7.7 Hz, 2H), 3.14 (t, J = 7.7 Hz, 2H).

[0870] Example 6

[0871] 5-chloro-1-(4-(2-isocyanoethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H Synthesis of )-ons

[0872]

[0873] 3-(4-(3,5-dichloro-2-oxopyrazine-1(2) in 1,4-dioxane (150 mL) H To a mixture of )-yl)phenyl)propanenitrile (4.82 g, 0.02 mol), 2-methoxy-4-(trifluoromethyl)aniline (4.10 g, 0.02 mol) and 10-camporsulfonic acid (10-CSA, 4.96 g, 0.02 mol) were added at 25 °C. The semi-reaction mixture was stirred at 120 °C for 16 hours, cooled to room temperature, quenched with water (30 mL), and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine (50 mL) and concentrated under reduced pressure. The residue was purified by flash chromatography (FC) to obtain 5-chloro-1-(4-(2-isocyanoethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on (5.60 g, 58%) was obtained as a yellow solid. MS (ESI): 449.4. 1 ¹H NMR (400 MHz, DMSO- d6) δ 9.10 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.54 - 7.42 (m, 6H), 7.39 (s, 1H), 4.01 (s, 3H), 3.01 - 2.85 (m, 4H).

[0874] Example 7

[0875] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-methylpyrazine-2(1 H )-on(compound) 17 Synthesis of )

[0876]

[0877] 3-(4-(5-chloro-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxopyrazine-1(2) in 1,4-dioxane (5 mL) and H2O (1 mL) H Methylboronic acid (667 mg, 11.14 mmol), K2CO3 (185 mg, 1.34 mmol), and Pd(dtbpf)Cl2 (58 mg, 0.09 mmol) were added to a mixture of )-yl)phenyl)propanenitrile (200 mg, 0.45 mmol) at 25 °C. The reaction mixture was stirred at 105 °C under N2 for 16 hours. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (30 mL x 3), and washed with brine (20 mL x 2). The combined organic layer was concentrated under reduced pressure, and the residue was purified by FC to obtain 3-(4-(3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-methyl-2-oxopyrazine-1(2 H )-1)phenyl)propanenitrile (110 mg, 58%) was obtained as a yellow solid. MS (ESI): 429.1.

[0878] 3-(4-(3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-methyl-2-oxopyrazine-1(2 in toluene (2 mL) HAzidotribubutyltin (256 mg, 0.77 mmol) was added to a mixture of )-yl)phenyl)propanenitrile (110 mg, 0.26 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 16 hours, and then concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) to obtain 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-methylpyrazine-2(1 H )-on (53.0 mg, 44%) was obtained as a white solid. MS (ESI): 472.1. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 9.00 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H), 7.48 - 7.37 (m, 5H), 7.34 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 1.2 Hz, 1H), 4.00 (s, 3H), 3.24 - 3.20 (m, 2H), 3.15 - 3.10 (m, 2H), 2.20 (d, J = 0.8 Hz, 3H).

[0879] Example 8

[0880] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-phenylpyrazine-2(1 H )-on(compound) 21 Synthesis of )

[0881]

[0882] 5-chloro-1-(4-(2-isocyanoethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazine-2(1 in 1,4-dioxane (4 mL) and H2O (1 mL) HPhenylboronic acid (415 mg, 3.4 mmol), Pd(dtbpf)Cl2 (39 mg, 0.06 mmol), and K2CO3 (179 mg, 1.3 mmol) were added to a solution of )-one (300 mg, 0.67 mmol). The reaction mixture was refluxed under nitrogen for 12 hours. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified with FC to obtain 3-(4-(3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxo-5-phenylpyrazine-1(2 H )-yl)phenyl)propanenitrile (200 mg, 60%) was obtained as a yellow solid. MS (ESI): 491.2 [M+H] + .

[0883] 3-(4-(3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-2-oxo-5-phenylpyrazine-1(2 in toluene (2 mL) H Tributylstannanylium azide (2120 mg, 0.63 mmol) was added to a solution of )-yl)phenyl)propanenitrile (100 mg, 0.21 mmol). The reaction mixture was stirred at 120 °C for 12 hours. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-phenylpyrazine-2(1 H )-on (16.6 mg, 11%) was obtained as a yellow solid. MS (ESI): 534.2 [M+H] + . 1 ¹H NMR (400 MHz, DMSO- d 6) δ 9.08 (s, 1H), 9.03 (d,J = 8.4 Hz, 1H), 8.00 - 7.95 (m, 2H), 7.77 (s, 1H), 7.55 (d, J = 8.4 Hz, 3H), 7.45 (d, J = 8.0 Hz, 4H), 7.41 - 7.31 (m, 3H, 4.03 (s, 3H), 3.24 (d, J = 7.2 Hz, 2H), 3.15 (d, J = 8.0 Hz, 2H).

[0884] The following compounds are 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-methoxy-4-(trifluoromethyl)phenyl)amino)-5-phenylpyrazine-2(1 H Synthesized similarly to )-on:

[0885]

[0886]

[0887] The following examples include descriptions of studies conducted to evaluate the exemplary efficacy of the compound of formula (1) or (1a).

[0888] The reagents used in the following examples include the reagents listed in Table 1 below.

[0889]

[0890]

[0891] The equipment used in the following examples includes the equipment listed in Table 2 below.

[0892]

[0893] Example 9

[0894] 1-(4-(2-(1 in rat and human liver microsome fractions H In vitro metabolic kinetics of -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1H)-one (Compound 3)

[0895] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 HThe metabolic stability of )-one (Compound 3 in Table 29 below) was measured in rat and human microsomes. The liver microsome samples used in this example are listed in Table 3 below:

[0896]

[0897] Phosphate buffer was prepared by dissolving 48.709 g of K2HPO in 950 mL of water. The pH of the solution was adjusted to 7.4 using an aqueous HCl solution. The solution was adjusted to a final total volume of 1000 mL with water. The buffer was filtered through a 0.22 μm filter and stored in a refrigerator at 4 ℃ for future use.

[0898] A quenching solution was prepared by mixing a terfenadine / tolbutamide (1 mg / mL each) stock solution with DMSO, and then diluting the stock solution with acetonitrile to prepare a quenching solution containing 5 / 10 ng / mL (terfenadine / tolbutamide).

[0899] A stock solution of Compound 3 (molecular weight 445.4 g / mol) in DMSO at 10 m M It was prepared at molar concentrations. 200 μ in DMSO from the stock solution M A working solution of compound 3 at a molar concentration was prepared.

[0900] Liver microsomes were thawed in a 37°C water bath. A working solution of liver microsomes with a volume of 1669.5 μL was prepared according to Table 4 below:

[0901]

[0902] 5 m M The NADPH working solution was prepared as a phosphate buffer.

[0903] Incubation was performed by adding 1.5 μL of the working solution of the control or Compound 3 in a 1.1 mL mini tube to 238.5 μL of the working solution of liver microsomes and gently mixing. The mixture was pre-incubated in a 37 °C shaking bath for 5 minutes. The reaction was initiated by adding 60 μL of the working solution of NADPH. The solution was mixed up and down by pipetting. At each time point of 0, 5, 15, 30, and 60 minutes, 30 μL of the reaction mixture was transferred to 300 μL of quenching solution and mixed by pipetting. The samples were vigorously vortexed for 1 minute and centrifuged at 4000 rpm for 15 minutes at 4 °C. 100 μL of the supernatant from each sample was mixed with 100 μL of distilled water for LC-MS / MS analysis.

[0904] Mass spectrometry was performed on Kinetex 2.6 μm C18 100 Using a column (2.6 mm x 50 mm), for Compound 3 m / z It was performed with multiple reaction monitoring (MRM) values ​​of 446.082 and 418.000. Mobile phase A: 0.1% formic acid in H2O, mobile phase B: 0.1% formic acid in acetonitrile, run time 2 min.

[0905] The remaining percentage was calculated according to the following equation (1):

[0906] (1)

[0907] Using the first-order kinetic equation, half-life("t 1 / 2 ") and intrinsic clearance ("CL int ") was calculated. The first-order kinetic equation is Equation (2) below, from which Equation (3) providing the half-life can be derived:

[0908] (2)

[0909] (3)

[0910] The equation for the intrinsic clearance rate in the test tube is provided according to Equation (4) below. The equations for the intrinsic clearance rate and hepatic clearance rate are provided by Equations (5) and (6) below, respectively. In Equation (6), F u,B represents the unbound drug fraction in the blood, which is assumed to be 1.

[0911] (4)

[0912] (5)

[0913] (6)

[0914] The predicted values ​​of the physiological variables used to calculate intrinsic clearance and hepatic clearance are presented in Table 5 below:

[0915]

[0916] Data for human liver microsome samples are presented in Table 6 below for samples incubated with Compound 3 or dextromethorphan. A plot of the % retention rate of dextromethorphan over time in the presence of NADPH in human liver microsome samples is Fig. 1 It is illustrated in Fig. A plot of the % retention rate of Compound 3 over time in the presence of NADPH in human liver microsome samples is 2 It is depicted in.

[0917]

[0918] Data for rat liver microsome samples are presented in Table 7 below for samples incubated with Compound 3 or dextromethorphan. A plot of the % retention rate of dextromethorphan over time in rat liver microsome samples in the presence of NADPH is Fig. 3 It is illustrated in Fig. A plot of the % retention rate of Compound 3 over time in the presence of NADPH in rat liver microsome samples is 4It is depicted in.

[0919]

[0920] The intrinsic clearance and hepatic clearance data for Compound 3 and dextromethorphan in humans and rats are summarized in Table 8 below.

[0921]

[0922] Example 10

[0923] 1-(4-(2-(1 in rat heart tissue H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1H)-one(compound 3) and 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d Tissue binding determination study of pyrimidine-2-yl)-2,6-dimethylphenoxy)acetic acid (Compound A)

[0924] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H Tissue binding of )-one ("Compound 3" in Table 29 below) in rat heart tissue 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d It was measured in comparison with ]pyrimidine-2-yl)-2,6-dimethylphenoxy)acetic acid ("Compound A"), and its structure is disclosed below:

[0925]

[0926] 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d ]pyrimidine-2-yl)-2,6-dimethylphenoxy)acetic acid (compound A).

[0927] The rat heart tissue samples used in this example are listed in Table 9 below:

[0928]

[0929] The phosphate buffer is 3.12 g of NaH2PO2. 4· 2H2O, 28.64 g of Na2HPO 4·12H2O and 5.844 g of NaCl were dissolved in 950 mL of water. The pH of the solution was adjusted to 7.4 using an aqueous 12 N NaOH solution. The solution was adjusted to a final total volume of 1000 mL with water. The buffer solution was filtered through a 0.22 μm filter and stored in a refrigerator at 4 ℃ for future use.

[0930] A tissue homogenate was obtained by adding four times the weight of the phosphate buffer solution to the tissue.

[0931] The quenching solution was prepared by converting a terfenadine / tolbutamide (1 mg / mL each) stock solution into DMSO, and then diluting the stock solution with methanol / acetonitrile (1:1, v / v) to prepare a quenching solution containing 5 / 10 ng / mL of terfenadine / tolbutamide.

[0932] A stock solution of Compound 3 (molecular weight 445.4 g / mol) in DMSO at 10 m M It was prepared at molar concentration. 1 m from the stock solution M A working solution of Compound 3 at a molar concentration was prepared. Using a tissue homogenate, 5 μm from the working solution was used. M A molar concentration administration solution was prepared. 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d A stock solution of ]pyrimidine-2-yl)-2,6-dimethylphenoxy)acetic acid ("Compound A", molecular weight, 425.1 g / mol) in DMSO at 10 m M It was prepared at molar concentration. A working solution of Compound A was prepared from the stock solution. Using a tissue homogenate, 5 μm from the working solution M A molar concentration administration solution was prepared.

[0933] The control compound administration solution is 10 m M A diclofenac stock solution was prepared. 0.2 m from the diclofenac stock solution using DMSO M A working solution was prepared. Using a tissue homogenate, 1 μ from the working solution MA dosage solution was prepared.

[0934] Equilibrium dialysis was performed according to the following procedure. A dialysis plate was prepared by adding 120 μL of buffer solution to the buffer chamber and 120 μL of administration solution to the tissue side. The dialysis plate was sealed with adhesive film to prevent evaporation. The dialysis plate was incubated for 5 hours in a 37°C CO2 incubator (5% CO2) while shaking at 100 rpm. After 5 hours, the incubation plate was transferred from the incubator to a bench. For further analysis, 30 μL aliquots were taken from both the tissue side and the buffer side of the dialysis plate.

[0935] After preparing the administration solution, a 30 μL aliquot of the administration solution was taken as the T0 sample. The remaining administration solution was placed in a 37 ℃ CO2 incubator for 5 hours, and then a 30 μL aliquot was taken as the T5 sample.

[0936] To prepare the samples, a blank tissue homogenate and a blank phosphate buffer were prepared and used. 30 μL of samples from the tissue side, T0 sample, and T5 sample were each mixed with 30 μL of blank phosphate buffer. 180 μL of quenching solution was added. The samples were vortexed for 1 minute and then centrifuged at 4000 rpm for 15 minutes. 30 μL of the sample from the buffer side was mixed with 30 μL of blank tissue homogenate. 180 μL of quenching solution was added, and the samples were vortexed for 1 minute and then centrifuged at 4000 rpm for 15 minutes. A 100 μL aliquot of the supernatant was taken, thoroughly mixed with 100 μL of water, and used for LC-MS / MS analysis.

[0937] Mass spectrometry was performed on Kinetex 2.6 μm C18 100 For Compound 3 using a column (2.1 mm x 50 mm) m / z Values ​​446.082 and 418.000, and 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4-d It was performed with 426.009 and 367.000 multiple reaction monitoring (MRM) for pyrimidine-2-yl)-2,6-dimethylphenoxy)acetic acid. Mobile phase A: 0.1% formic acid in H2O, mobile phase B: 0.1% formic acid in acetonitrile, run time 2 min.

[0938] The binding rate (%), recovery rate (%), and stability (%) were calculated according to the following equations (7) - (9):

[0939] (7)

[0940] (8)

[0941] (9).

[0942] F u,100% (%) was calculated according to Equation (10):

[0943] (10).

[0944] F u,20% (%) was calculated according to Equation (11):

[0945] (11).

[0946] C in equations (7) - (11) t refers to the concentration of the test compound from the tissue side; C b represents the concentration of the test compound from the buffer side; C T5 refers to the concentration of the test compound from the T5 sample; C T0 refers to the concentration of the test compound from the T0 sample.

[0947] Compounds 3 and 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d The results of tissue binding studies for each of the pyrimidine-2-yl-2,6-dimethylphenoxyacetic acid are presented in Table 10 below.

[0948]

[0949] Example 11

[0950] 1-(4-(2-(1 in human and rat plasma proteins H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H Study on the determination of plasma protein binding of )-on (Compound 3)

[0951] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H The plasma protein binding of )-on (Compound 3 in Table 29 below) was measured in rat and human plasma proteins compared to warfarin.

[0952] The plasma protein samples used in this example are listed in Table 10 below:

[0953]

[0954] The phosphate buffer is 3.12 g of NaH2PO2. 4· 2H2O, 28.64 g of Na2HPO 4· 12H2O and 5.844 g of NaCl were dissolved in 950 mL of water. The pH of the solution was adjusted to 7.4 using an aqueous 12 N NaOH solution. The solution was adjusted to a final total volume of 1000 mL with water. The buffer solution was filtered through a 0.22 μm filter and stored in a refrigerator at 4 ℃ for future use.

[0955] The plasma was thawed in a 37°C water bath. The pH of the plasma was adjusted to 7.4.

[0956] The quenching solution was prepared by converting a terfenadine / tolbutamide (1 mg / mL each) stock solution into DMSO, and then diluting the stock solution with acetonitrile to prepare a quenching solution containing 5 / 10 ng / mL of terfenadine / tolbutamide.

[0957] A stock solution of Compound 3 (molecular weight 445.4 g / mol) in DMSO at 10 m M It was prepared at molar concentration. 1 m from the stock solution MA working solution of Compound 3 at a molar concentration was prepared. 5 μl of plasma was used from the working solution. M A molar concentration administration solution was prepared.

[0958] The control compound administration solution is 10 m M A warfarin stock solution was prepared. 1 m from the warfarin stock solution using DMSO M A working solution was prepared. 5 μl of plasma was used from the working solution. M A dosage solution was prepared.

[0959] Equilibrium dialysis was performed according to the following procedure. A dialysis plate was prepared by adding 120 μL of buffer to the buffer chamber and 120 μL of administration solution to the plasma side. The dialysis plate was sealed with adhesive film to prevent evaporation. The dialysis plate was incubated in a 37°C incubator for 5 hours while shaking at 100 rpm. After 5 hours, the incubation plate was transferred from the incubator to a bench. For further analysis, 30 μL aliquots were collected from both the plasma side and the buffer side of the dialysis plate.

[0960] After preparing the administration solution, a 30 μL aliquot of the administration solution was taken as the T0 sample. The remaining administration solution was placed in a 37°C incubator for 5 hours, and then a 30 μL aliquot was taken as the T5 sample.

[0961] To prepare the samples, blank plasma and blank phosphate buffer were prepared and used. 30 μL of samples from the plasma side, T0 sample, and T5 sample were each mixed with 30 μL of blank phosphate buffer. 180 μL of quenching solution was added. The samples were vortexed for 1 minute and then centrifuged at 4000 rpm for 15 minutes. 30 μL of the sample from the buffer side was mixed with 30 μL of blank plasma. 180 μL of quenching solution was added, and the samples were vortexed for 1 minute and then centrifuged at 4000 rpm for 15 minutes. A 100 μL aliquot of the supernatant was taken, thoroughly mixed with 100 μL of water, and used for LC-MS / MS analysis.

[0962] Mass spectrometry was performed on Kinetex 2.6 μm C18 100 Multiple reaction monitoring (MRM) was performed for Compound 3 using a column (92.1 mm x 50 mm) with m / z values ​​of 446.082 and 418.000. Mobile phase A: 0.1% formic acid in H2O, mobile phase B: 0.1% formic acid in acetonitrile, run time 2 min.

[0963] The binding rate (%) and recovery rate (%) were calculated according to the following equations (12) and (13). The stability (%) was calculated according to the above equation (9).

[0964] (12)

[0965] (13)

[0966] Glass (%) was calculated according to the following equation (14):

[0967] (14)

[0968] In equations (12) - (14) and (9), C p refers to the concentration of the test compound from the plasma side; C brepresents the concentration of the test compound from the buffer side; C T5 refers to the concentration of the test compound from the T5 sample, and C T0 refers to the concentration of the test compound from the T0 sample.

[0969] The results of a plasma protein binding study for compound 3 in human plasma are presented in Table 12 below in comparison with warfarin.

[0970]

[0971] The results of a plasma protein binding study for compound 3 in rat plasma are presented in Table 13 below in comparison with warfarin.

[0972]

[0973] Example 12

[0974] 1-(4-(2-(1 in human liver microsome fraction H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on( Compound 3 In vitro cytochrome P450 ("CYP") enzyme inhibition study

[0975] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H The metabolic stability of )-one ('Compound 3' in Table 29 below) was measured in human microsomes. The liver microsome samples used in this example are listed in Table 14 below:

[0976]

[0977] Phosphate buffer was prepared by dissolving 8.71 g of K2HPO4 in 950 mL of water. The pH of the solution was adjusted to 7.4 using an aqueous HCl solution. The solution was then adjusted to a final total volume of 1000 mL with water. The buffer was filtered through a 0.22 μm filter and stored in a refrigerator at 4 ℃ for future use.

[0978] A quenching solution was prepared by mixing a terfenadine / tolbutamide (1 mg / mL each) stock solution with DMSO, and then diluting the stock solution with acetonitrile to prepare a quenching solution containing 5 / 10 ng / mL (terfenadine / tolbutamide).

[0979] The positive working control stock solution was prepared according to Table 15:

[0980]

[0981] The control working solution (4-fold dilution, 6 non-zero concentrations) was prepared using DMSO from the above stock solution.

[0982] The substrate working control stock solution was prepared according to Table 16:

[0983]

[0984] Liver microsomes were thawed in a 37°C water bath. A working solution of liver microsomes with a volume of 8.395 mL was prepared according to Table 17 below:

[0985]

[0986] 5 m M A working solution of NADPH was prepared as a phosphate buffer.

[0987] The working solution of Compound 3 is 10 m M It was prepared by diluting the stock solution 4-fold with DMSO (6 non-zero concentrations).

[0988] Incubation was performed by adding 1.5 μL of the working solution of the control or Compound 3 to 238.5 μL of the working solution of liver microsomes in a 1.1 mL tube and mixing by pipetting multiple times. The mixture was pre-incubated in a 37 °C shaking bath for 5 minutes. The reaction was initiated by adding 60 μL of the working solution of NADPH. The solution was mixed by pipetting multiple times. Incubation was carried out in a 37 °C shaking bath for 10 minutes. Immediately after incubation, 300 μL of quenching solution was added, followed by vortexing for approximately 20 seconds. All samples were centrifuged at 4000 rpm at 4 °C for 15 minutes, and the supernatant was transferred for LC-MS / MS analysis.

[0989] Mass spectrometry was performed on Kinetex 2.6 μm C18 100 Multiple Reaction Monitoring (MRM) of the analytes was performed using a column (2.6 mm x 50 mm) according to Table 18 below. Mobile phase A: 0.1% formic acid in H2O, Mobile phase B: 0.1% formic acid in acetonitrile, run time 2.5 min.

[0990]

[0991] CYP inhibition data for Compound 3 and the positive control are presented in Table 19 below. The enzyme inhibition plots for each CYP isoform by Compound 3 at various concentrations of Compound 3 are Fig. 5 - 11 It is illustrated in Fig. 1. The enzyme inhibition plots for each CYP isoform by the positive control at various concentrations of the positive control are shown in Fig. 12 - 18 It is illustrated in [figure]. The semi-maximum inhibition concentration is [figure]. 5 - 18 Each one is marked.

[0992]

[0993]

[0994] Example 13

[0995] 1-(4-(2-(1 in rat and human hepatocyte incubation H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H Metabolic stability analysis and intrinsic clearance of )-on (Compound 3)

[0996] 1-(4-(2-(1 H The metabolic stability and intrinsic clearance of -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1H)-one ("Compound 3" in Table 29 below) were measured in rat and human hepatocyte incubations. The hepatocyte samples used in this example are listed in Table 20 below:

[0997]

[0998] A human recombinant insulin solution (4 mg / mL) was prepared by diluting acetic acid 100 times with distilled water, and then adding human recombinant insulin so that the final concentration when dissolved in the diluted acetic acid was 4 mg / mL.

[0999] 10 m M A dexamethasone solution of the concentration was prepared by dissolving dexamethasone in DMSO.

[1000] The thawing medium was prepared according to the reagents listed in Table 21 below:

[1001]

[1002] For the incubation medium, 6.122 mL of glutamine was added to 300 mL of Williams E medium to obtain a final glutamine concentration of 4.0 m M It was prepared to this extent. After thoroughly mixing the incubation medium, 15 mL of the incubation solution was dispensed into 15 mL tubes and stored at 4 ℃ for up to 30 days.

[1003] 1 mg / mL stock solutions of terfenadine and tolbutamide were prepared by dissolving an appropriate amount of terfenadine or tolbutamide in DMSO. Quenching solutions containing 5 and 10 ng / mL of terfenadine and tolbutamide, respectively, were prepared by diluting the stock solutions with acetonitrile.

[1004] Hepatocytes were prepared according to the following thawing procedure. 50 mL of cryopreserved hepatocyte recovery medium ("CHRM") was preheated in a 37 °C water bath incubator for at least 25 minutes prior to use. The rat or human hepatocyte vials were removed from the liquid nitrogen tank. The vials were immediately placed in a 37 °C water bath incubator. The vials were gently shaken until completely thawed. The preheated CHRM was dispensed into EP tubes for future use (1 mL per hepatocyte vial). The thawed hepatocytes were immediately added to the preheated CHRM. 1 mL of CHRM was added to the emptied vial to resuspend the remaining cells. The suspension was combined with the hepatocyte / CHRM solution. The hepatocyte / CHRM solution was gently inverted several times to mix and resuspend the hepatocytes. The hepatocytes were centrifuged at room temperature (100 xg for 10 minutes). The supernatant was discarded. 1.5 mL of preheated incubation medium was added to the pellet in each vial and mixed by gently swirling.

[1005] Cell counting was performed under a microscope after diluting 50 μL of cells with 400 μL of incubation medium and 50 μL of trypan blue. 12 μL of the diluted cell suspension was taken for counting. Cells were used only when the cell viability exceeded 70%. Cells were diluted to 2 million viable cells / mL in the incubation medium. Cell counting data are presented in Table 22 below.

[1006]

[1007] A stock solution of Compound 3 (molecular weight, 445.4 g / mol) in DMSO is 10 m MIt is a molar concentration. 2 μm as incubation medium M A working solution of compound 3 at a molar concentration was prepared.

[1008] Incubation was performed according to the following procedure. The hepatocyte suspension was pre-incubated in a 37°C CO2 incubator for 20 minutes. 400 μL of positive control or Compound 3 solution was added to the wells of a 24-well plate. The reaction was initiated by adding 400 μL of hepatocytes (2 million cells / mL) to the wells containing the control or Compound 3 solution. The plate was mixed by gently shaking it on an orbital shaker at 100 rpm. The plate was incubated in a CO2 incubator. At each time point (0, 15, 30, 60, 90, and 120 minutes), 30 μL of the reaction mixture was taken from the plate, added to 300 μL of quenching solution, and mixed by vortexing for 1 minute. The sample was centrifuged at 4000 rpm at 4°C for 15 minutes. 100 μL of the supernatant was transferred to a 96-well plate and mixed with 100 μL of distilled water for LC-MS / MS analysis.

[1009] Mass spectrometry was performed on Kinetex 2.6 μm C18 100 Multiple Reaction Monitoring (MRM) of the analytes was performed using a column (3.0 mm x 30 mm) according to Table 23 below. Mobile phase A: 0.1% formic acid in H2O, Mobile phase B: 0.1% formic acid in acetonitrile, run time 2 min.

[1010] The remaining percentage was calculated according to Equation (1). Using the first-order kinetic equation (Equation (2)), the half-life ("t 1 / 2 ") and intrinsic clearance ("CL int ") was calculated, and from this, equation (3) providing the half-life can be derived.

[1011] The equation for the intrinsic clearance rate in the test tube is provided according to Equation (15) below. The equations for the intrinsic clearance rate and hepatic clearance rate are provided by Equations (16) and (17) below, respectively. In Equation (17), F u represents the unbound drug fraction in plasma, which is assumed to be 1.

[1012] (15)

[1013] (16)

[1014] (17)

[1015] The predicted values ​​of the physiological variables used to calculate intrinsic clearance and hepatic clearance are presented in Table 23 below.

[1016]

[1017] Data for human hepatocyte samples are presented in Table 24 below for samples incubated with Compound 3, phenacetin, diclofenac, dextromethorphan, omeprazole, midazolam, and 7-ethoxycoumarin. Plots of the % retention rates of phenacetin, diclofenac, dextromethorphan, omeprazole, midazolam, 7-ethoxycoumarin, and Compound 3, respectively, in human hepatocyte samples are shown in Fig. 19 - 25 It is depicted in.

[1018]

[1019]

[1020]

[1021] Data for rat hepatocyte samples are presented in Table 25 below for samples incubated with Compound 3, phenacetin, diclofenac, dextromethorphan, omeprazole, midazolam, and 7-ethoxycoumarin. A plot of the % retention rates of phenacetin, diclofenac, dextromethorphan, omeprazole, midazolam, 7-ethoxycoumarin, and Compound 3, respectively, in rat hepatocyte samples is Fig. 26 - 32 It is depicted in.

[1022]

[1023]

[1024] Example 14

[1025] In rats 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H Study of transient lymphopenia induced by administration of )-on (compound 3)

[1026] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H The ability of )-on (Compound 3 in Table 29 below) to induce transient lymphopenia in rats was evaluated.

[1027] Male Sprag Dooli rats (300 g) were divided into four groups and administered by oral gavage (1) vehicle (solutol 20% in water); (2) compound 3 8 mg / kg in vehicle (pH 7.4); (3) compound 3 60 mg / kg in vehicle (pH 7.4); and (4) 100 mg / kg in vehicle (pH 7.4). Blood was collected in EDTA tubes at 0, 2, 6, 24, and 48 hours. Samples were taken from all rats. Samples were analyzed for lymphocyte percentage, change from baseline, and total lymphocyte count.

[1028] The maximum reduction in circulating lymphocytes was obtained 6 hours after administration of compound 4, which is 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- dIt was the same as the administration of ]pyrimidine-2-yl)-2,6-dimethylphenoxy)acetic acid, and at low doses, 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d Consistent with pyrimidine-2-yl-2,6-dimethylphenoxyacetic acid, levels returned to normal by 24 hours after administration. Additionally, there was no difference in the observed decrease between the 8 mg / kg and 60 mg / kg administrations at all evaluated time points.

[1029] In addition, a dose of 100 mg / kg of compound 3 showed a maximum transient decrease in lymphocytes and a delayed recovery to normal values, which is 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- d It was consistent with the kinetics of pyrimidine-2-yl-2,6-dimethylphenoxyacetic acid administration. 33 and also 34 Figure 1 illustrates transient lymphopenia accompanied by complete recovery as measured by circulating lymphocytes. Figure 1 35 Figure plots the number of circulating lymphocytes for vehicle administration over time. 36 - 38 is plotted for the administration of compound 3 at 8 mg / kg, 60 mg / kg, and 100 mg / kg over time, respectively.

[1030] Example 15

[1031] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H Cell analysis upon administration of )-on (Compound 3) and comparison with administration of other compounds

[1032] PathHunter CHO-K1 EDG1(S1P1R) cell lines were submitted to a cell assay measuring β-arrestin recruitment and cyclic adenosine monophosphate (cAMP) accumulation, 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H )-on("Compound 3" in Table 29 below), 2-(4-(5-(3-chlorophenoxy)oxazolo[5,4- dThe relative S1P1 agonist activities of pyrimidine-2-yl-2,6-dimethylphenoxyacetic acid, sphingosine-1-phosphate ("S1P"), ponesimod, and siponimod were tested.

[1033] β-arrestin recruitment is a luminescence-based assay, where the S1P1 receptor and β-arrestin can be tagged as complementary fragments of the β-galactosidase ("β-gal") enzyme, respectively. Recruitment of β-arrestin to the S1P1 receptor can generate an active β-gal enzyme, which produces light in the presence of a substrate.

[1034] A diagram summarizing β-arrestin recruitment for each of the two experimental trials 39 and also 40 As shown in Figure 26, Compound 3 and Compound A exhibited very similar reaction curves, which can be clearly distinguished from the functional antagonists S1P, ponesimod, and siponimod. Additionally, Table 26 shows similar ECs for β-arrestin recruitment for Compound A and Compound 3. 50 Represents the value.

[1035]

[1036] cAMP recruitment is a homogeneous time-resolved fluorescence ("HTRF")-based assay. G αi Protein-coupled receptors ("GPCRs") can inhibit the activity of the adenylyl cyclase ("AC") enzyme responsible for cAMP production. This analysis measures the total intracellular accumulation of cAMP after the S1P1 receptor is activated in the presence of the AC activator Forskolin and the non-selective phosphodiesterase ("PDE") inhibitor 3-isobutyl-1-methylxanthine ("IBMX").

[1037] G of each of the two experimental tests αi - A diagram summarizing the protein activation response curve 41 and also 42As shown in [Figure], Compound 3 and Compound A exhibited very similar reaction curves, which can be clearly distinguished from the functional antagonists S1P, ponesimod, and siponimod. Additionally, Table 27 shows the G of Compound A and Compound 3. αi - Similar EC for protein activation 50 Represents the value.

[1038]

[1039] β-arrestin vs. G αi - The protein activation rate is G for the S1P1 receptor αi - It may exhibit protein-biased activity. As shown in Table 28, β-arrestin versus G αi - The protein activation rate is G for the S1P1 receptor, where compound 3 is nearly identical to compound A. αi - Indicates that it has protein-biased activity.

[1040]

[1041] S1P1 regulatory activity was further tested for exemplary compounds 1-13. The results of these tests are listed in Table 29.

[1042]

[1043]

[1044] Example 16

[1045] In rats 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H Pharmacokinetic study of oral and intravenous administration of )-on

[1046] 1-(4-(2-(1 H -tetrazole-5-yl)ethyl)phenyl)-3-((2-fluoro-4-trifluoromethyl)phenyl)amino)pyrazine-2(1 H The plasma concentration of )-on (compound 3) was measured over time after oral or intravenous administration to rats.

[1047] For intravenous administration, the dose of compound 3 at a concentration of 0.20 mg / mL in a 90% PEG400 / 10% EtOH vehicle was 1.00 mg / kg, and the administration volume was 5.00 mL / kg.

[1048] The formulations of Compound 3 for intravenous administration are in accordance with Table 30 below:

[1049]

[1050] The intravenous formulation was prepared by weighing a known amount of Compound 3 into a 12 mL glass vial on the day of administration. 6.216 mL of PEG400 was added, and the mixture was dissolved by vortexing and sonication. 0.691 mL of EtOH was added, and the mixture was dissolved by vortexing and sonication. The administration solution was filtered using a 0.22 μm filter (Millipore, Durapore®, PVDF). 50 μL of the administration solution was pipetted into a 20 mL glass vial, and 10 mL of MeOH was added to verify the dose concentration.

[1051] For oral administration, the dose of compound 3 at a concentration of 0.50 mg / mL in a 90% PEG400 / 10% EtOH vehicle was 5.0 mg / kg, and the administration volume was 10.0 mL / kg.

[1052] The formulations of compound 3 for oral administration are in accordance with Table 31 below:

[1053]

[1054] The oral formulation was prepared by weighing a known amount of compound 3 into a 12 mL glass vial on the day of administration. 9.809 mL of PEG400 was added, and the mixture was dissolved by vortexing and sonication. 1.090 mL of EtOH was added, and the mixture was dissolved by vortexing and sonication. 50 μL of the administration solution was pipetted into a 20 mL glass vial, and 10 mL of MeOH was added to confirm the dose concentration.

[1055] The dosage was tested to be within the standard by ultra-high performance liquid chromatography-MS / MS ("UPLC-MS / MS") (for oral administration, it was retested and confirmed).

[1056] The dosage was tested by preparing a dosage solution based on the designed formulation. For the dosage formulation, (1) 50 μL of the intravenous and oral dosage formulation was pipetted into 10 mL of MeOH (200-fold dilution) to verify the concentration, and (2) 5 μL of the intravenous and oral dosage from (1) was added to 50 μL of blank plasma (10-fold dilution) to test (a total of 2000-fold dilution for both intravenous and oral dosages from the original dosage formulation). The calculated concentrations of compound 3 during intravenous and oral administration are presented in Table 32 below.

[1057]

[1058] The calculated concentration of intravenous administration was within the reference range (±20%) compared to the nominal administration concentration (0.200 mg / mL). Since the calculated concentration of oral administration was not within the reference range (±20%) compared to the nominal administration concentration (0.500 mg / mL), oral administration was retested using a pure solvent.

[1059] Oral administration was retested by preparing administration solutions based on the designed formulation. The rat pharmacokinetic administration formulation was tested by (1) pipetting 100 μL of the oral administration formulation into 900 μL of MeOH (10-fold dilution) for concentration verification, (2) pipetting 10 μL of the oral administration from (1) into 990 μL of MeOH (100-fold dilution) for concentration verification, and (3) adding 5 μL of the oral administration from (2) into 100 μL of MeOH / H2O (1:1, v / v) containing 100 μL of IS and 0.1% FA (a total of 1000-fold dilution of the oral administration from the original administration formulation). The calculated concentrations of compound 3 during oral administration are presented in Table 33 below.

[1060]

[1061] The calculated oral concentration was within the reference range (±20%) compared to the nominal dosage (0.200 mg / mL). Since the calculated oral concentration did not match the initial test, the oral administration was retested.

[1062] Retesting of oral administration was confirmed by preparing a dosing solution based on the designed formulation. The rat pharmacokinetic dosing formulation was retested by (1) pipetting 100 μL of the oral administration formulation into 900 μL of MeOH (10-fold dilution) for concentration verification, (2) pipetting 10 μL of the oral administration from (1) into 990 μL of MeOH (100-fold dilution) for concentration verification, and (3) adding 5 μL of the oral administration from (2) into 100 μL of MeOH / H2O (1:1, v / v) containing 100 μL of IS and 0.1% FA (total 1000-fold dilution from the original dosing formulation for oral administration). The calculated concentrations of compound 3 during oral administration are presented in Table 34 below.

[1063]

[1064] The calculated oral dosage was within the reference range (±20%) compared to the nominal dosage.

[1065] The LC / MS / MS conditions used in this embodiment are as follows:

[1066] LC / MS / MS Instrument Type: AB Sciex APi 5500+ (JS #2)

[1067] LC / MS / MS Quantitative Software and Version Number: Analyst Software 1.7.2.

[1068] Ionization mode: Electrospray, Cation

[1069] Scan Mode: Multi-Reaction Monitoring (MRM)

[1070] Analyst MRM: 446.08 / 418.00 (MW: 445.38)

[1071] Internal standard MRM: 472.40 / 436.40 (Terfenadine)

[1072] LC Method Pump: Shimadzu LC-40D XS

[1073] LC Column: Kinetex® C18 2.6 μm 100 (50 mm * 2.10 mm) column

[1074] LC Mobile Phase A: 2m in water M NH4OAc (including 0.1% FA)

[1075] LC Mobile Phase B: Acetonitrile (containing 0.1% FA)

[1076] Column temperature: Room temperature

[1077] Injection volume: 1 μL

[1078] UPLC Gradient:

[1079]

[1080] Plasma samples were prepared according to the following procedure. The sample volume was 50 μL for plasma. Protein precipitation (PPT) by internal standard (ISTD) was performed in MeOH:acetonitrile (1:1, v / v): (1) 5 μL of MeOH was added to the sample; (2) 200 μL of 5 ng / mL ISTD (terfenadine) in MeOH:acetonitrile (1:1, v / v) was added to the sample; (3) the sample was vortexed for 1 minute and centrifuged at 4000 rpm for 15 minutes; and (4) the supernatant was diluted three-fold with MeOH:H2O (1:1, v / v, containing 0.1% FA) for infusion. The sample matrix and blank matrix were male Sprag-Dowley rat plasma:

[1081]

[1082] Pharmacokinetic data for intravenous administration of Compound 3 at a dose of 1 mg / kg in 90% PEG400 / 10% EtOH are presented in Table 35:

[1083]

[1084] Pharmacokinetic data for oral administration of Compound 3 at a dose of 5 mg / kg in 90% PEG400 / 10% EtOH are presented in Table 36:

[1085]

[1086] The mean ± standard deviation concentrations of rat plasma concentrations of Compound 3 administered orally and intravenously are Fig. 43 It is illustrated in [figure]. Individual rat plasma concentrations over time of intravenously administered compound 3 are Fig. 44 It is illustrated in [figure]. Individual and average plasma concentrations over time for intravenous administration are presented in Table 37 below. Rat #8 chewed the tape at the injection site, causing it to detach and resulting in excessive bleeding, which caused an aberration in the measurement data. The drug was re-administered to another rat, and the re-test data was used to calculate pharmacokinetic parameters.

[1087]

[1088] The individual rat plasma concentrations of orally administered compound 3 over time are Fig. 45 It is illustrated in [figure]. Individual and average plasma concentrations over time for intravenous administration are presented in Table 38 below.

[1089]

[1090] In addition, pharmacokinetic profiles of exemplary compounds 1-3 and 6 were obtained. The pharmacokinetic profiles are listed in Table 39.

[1091]

[1092] The pharmacokinetic profiles of additional exemplary compounds are listed in Table 40 below.

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133] The foregoing description and examples are merely illustrative of the invention and are not intended to limit it. Since variations of the described embodiments containing the spirit and essence of the invention may occur to those skilled in the art, the invention should be interpreted broadly to include all variations within the scope of the claims and their equivalents.

[1134] The subject matter of the present disclosure may also be related, among other things, to the following aspects.

[1135] The first aspect relates to a compound of formula (1a):

[1136] (1a)

[1137] Here

[1138] silver

[1139] , , and Selected from a group composed of;

[1140] Is , , , , , , , , , , , , , and Selected from a group composed of;

[1141] R1 is (T) w -(CR g R f ) m -Q-(CR g R f ) m -U and;

[1142] R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[1143] R4, R5, R6, R7, R8, R9, and R 10 is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , S(O)2R j , S(O)2N(R c )2, N(R c )2, CN, C(O)R j , N(R c )C(O)R j , C(O)N(R c)2, selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1144] R 11 silver , , , H, OCH2C(O)2R c Selected from the group consisting of unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;

[1145] Y is CR a or N and;

[1146] Z is CR b or N and;

[1147] Q is O, S, NR i , or -(CR h R d ) p - and;

[1148] T is O, S, NR i , or -(CR h R d ) p - and;

[1149] U is -COOR e , -COS(O) p R e , -CONHS(O) p R e , -CONHR e , -CON(R e )2, vinyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, , , , or B(OH)2 and;

[1150] n is 0, 1, or 2, and;

[1151] Each m is independently 0, 1, 2, 3, 4, or 5;

[1152] p is 0, 1, or 2, and;

[1153] w is 0, 1, or 2, and;

[1154] R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;

[1155] R c is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or a substituted C1-C6 straight-chain or branched alkyl;

[1156] R d is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[1157] R e is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or F, Cl, Br, I, OR c , SR c , N(R c It is a C1-C6 straight-chain or branched alkyl substituted with one or more substituents selected from the group consisting of )2, and CN;

[1158] R f is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[1159] R g is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[1160] R his H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[1161] R i is H, D, F, Cl, Br, I, an unsubstituted C1-C6 straight-chain or branched alkyl, or an unsubstituted cycloalkyl;

[1162] R j is a substituted or unsubstituted C1-C6 straight-chain or branched alkyl, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[1163] Here, R1 and R2, R1 and R3, R2 and R a , R4 and R5, R6 and R7, or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1164] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OC4alkyl, OC5alkyl, OC6alkyl, unsubstituted cycloalkyl, substituted heterocyclyl, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, CONMe2, CONHMe, and CONH2;

[1165] The substituted cycloalkyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2;

[1166] Here, the substituted heterocyclyl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, an unsubstituted heterocyclyl group, an unsubstituted heteroaryl group, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2;

[1167] Here, the substituted aryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N(n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, CONH2, and CONHPh;

[1168] Here, the substituted heteroaryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; or

[1169] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[1170] The second aspect is my 1 Regarding the compound of the side, here:

[1171] Is and Selected from a group composed of;

[1172] Is And;

[1173] R 11 silver And;

[1174] R1 is -Q-(CHR f ) m -U and;

[1175] R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[1176] R4, R5, R6, R7, R8, and R9 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , CN, selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1177] Y is CR a or N and;

[1178] Z is CR b or N and;

[1179] Q is O, S, or -(CHR d ) p - and;

[1180] U is -COOR e , a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[1181] n is 0 or 1 and;

[1182] m is 0, 1, 2, 3, or 4;

[1183] p is 0 or 1 and;

[1184] R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[1185] R cis H, an unsubstituted C1-C6 straight-chain or branched alkyl, or a substituted C1-C6 straight-chain or branched alkyl;

[1186] R d is H, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[1187] R e is H or an unsubstituted C1-C6 straight-chain or branched alkyl;

[1188] R f is H, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl;

[1189] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1190] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[1191] The substituted cycloalkyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( iSubstituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[1192] The substituted heterocyclyl group here is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, CF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[1193] Here, the substituted aryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[1194] Here, the substituted heteroaryl group is an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; or

[1195] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[1196] The third aspect relates to a compound of any aforementioned aspect, wherein:

[1197] Is and Selected from a group composed of;

[1198] R1 is -Q-(CHR f ) m -U and;

[1199] R2 and R3 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[1200] R4, R5, R6, R7, R8, and R9 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -Propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, OR c Selected from the group consisting of , CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1201] Y is CR a or N and;

[1202] Z is CR b or N and;

[1203] Q is O or -(CHR d ) p - and;

[1204] U is -COOR e , a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[1205] n is 0 or 1 and;

[1206] m is 0, 1, 2, 3, or 4;

[1207] p is 0 or 1 and;

[1208] R a and R b is independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[1209] R c is H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n - It is propyl, isopropyl, or substituted isopropyl;

[1210] R d is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[1211] R e is H, methyl, ethyl, n - It is propyl, or isopropyl;

[1212] R f is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[1213] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R b It together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1214] The methyl, ethyl, substituted here n -Propyl, or isopropyl, is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( nPr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2;

[1215] The substituted cycloalkyl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2;

[1216] The heterocyclyl group substituted here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2;

[1217] The substituted aryl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2; and

[1218] The heteroaryl group substituted here is methyl, ethyl,n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2; or

[1219] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[1220] The fourth aspect relates to a compound of any aforementioned aspect, wherein:

[1221] Is and Selected from a group composed of;

[1222] R1 is -Q-(CHR f ) m -U and;

[1223] R2 and R3 independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[1224] R4, R5, R6, R7, R8, and R9 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -Propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, OR c Selected from the group consisting of , CN, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;

[1225] Y is CR a or N and;

[1226] Z is CR b or N and;

[1227] Q is O or -(CHR d ) p - and;

[1228] U is -COOR e , a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[1229] n is 0 or 1 and;

[1230] m is 0, 1, 2, 3, or 4;

[1231] p is 0 or 1 and;

[1232] R a and R b is independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[1233] R c is H, methyl, CH2F, CHF2, CF3, ethyl, n - It is propyl, or isopropyl;

[1234] R d is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[1235] R e is H, methyl, ethyl, n - It is propyl, or isopropyl;

[1236] R f is H, F, Cl, Br, I, methyl, ethyl, n - It is propyl, or isopropyl;

[1237] Here, R1 and R2, R1 and R3, R2 and R a , or R3 and R bIt together forms a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1238] The methyl, ethyl, substituted here n -Propyl, or isopropyl, is substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, NH2, and COOH;

[1239] The substituted cycloalkyl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH;

[1240] The heterocyclyl group substituted here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH;

[1241] The substituted aryl group here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( iSubstituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; and

[1242] The heteroaryl group substituted here is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; or

[1243] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[1244] The fifth aspect relates to a compound of any aforementioned aspect, wherein:

[1245] Is and Selected from a group composed of;

[1246] R1 is -Q-(CHR f ) m -U and;

[1247] R2 and R3 independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from a group composed of;

[1248] R4, R5, R6, R7, R8, and R9 independently H, methyl, CF3, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OR c Selected from the group consisting of , CN, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl;

[1249] Y is CR a or N and;

[1250] Z is CR b or N and;

[1251] Q is O or -(CHR d ) p - and;

[1252] U is -COOH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[1253] n is 0 or 1 and;

[1254] m is 0 or 1 and;

[1255] p is 0 or 1 and;

[1256] R a is H or methyl;

[1257] R b is H or methyl;

[1258] R c is H, methyl, or CF3;

[1259] R d is H, F, Cl, Br, or methyl;

[1260] R f is H, F, Cl, Br, or methyl;

[1261] Herein, R1 and R2 or R1 and R3 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1262] The substituted cycloalkyl group here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[1263] The heterocyclyl group substituted here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[1264] The substituted aryl group here is methyl, ethyl, n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; and

[1265] The heteroaryl group substituted here is methyl, ethyl, n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; or

[1266] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[1267] The sixth aspect relates to a compound of any aforementioned aspect, wherein:

[1268] Is and Selected from a group composed of;

[1269] R1 is -Q-(CHR f ) m -U and;

[1270] R2 and R3 are independently H or methyl;

[1271] R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, methyl, isopropyl, CF3, F, Cl, Br, OMe, OCF3, CN, cyclopropyl, cyclopentyl, and phenyl;

[1272] Y is CH or N;

[1273] Z is CH or N;

[1274] Q is O or -(CHR d ) p - and;

[1275] U is -COOH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2;

[1276] n is 0 or 1 and;

[1277] m is 0 or 1 and;

[1278] p is 0 or 1 and;

[1279] R d is H, F, or methyl;

[1280] R f is H, F, or methyl;

[1281] Herein, R1 and R2 or R1 and R3 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group;

[1282] The substituted cycloalkyl group here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[1283] The heterocyclyl group substituted here is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH;

[1284] The substituted aryl group here is methyl, ethyl,n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; and

[1285] The heteroaryl group substituted here is methyl, ethyl, n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; or

[1286] It is its enantiomer; racemic mixture; or pharmaceutically acceptable salt.

[1287] The seventh aspect relates to a compound of any of the aforementioned aspects, wherein U is a cycloalkyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropphenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl, and cyclooctatrienyl;

[1288] Here, the cycloalkyl group is unsubstituted, or an unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and

[1289] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i It is substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2.

[1290] The 8th side is the side 1 inside 6 The present invention relates to a compound of which U is a heterocyclyl group selected from the group consisting of azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxetanil, tetrahydrofuranil, dihydrofuranil, tetrahydropyranil, dihydropyranil, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyranil, and dihydrothiopyranil;

[1291] Here, the heterocyclyl group is unsubstituted, or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and

[1292] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i It is substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2.

[1293] The ninth side is the side 1 inside 6 The invention relates to a compound of which U is an aryl group selected from the group consisting of phenyl, naphthalenyl, cyclobutadienyl, cyclopentadienyl, indenyl, anthracenyl, phenanthrenyl, terphenylenyl, fluorenyl, and pyrenyl;

[1294] Here, the aryl group is unsubstituted, or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, CF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and

[1295] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O-n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i It is substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2.

[1296] The 10th side is the side 1 inside 6 It relates to a compound of, where U is pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, 5(4 H )-oxo-1,2,4-thiadiazollil, oxazolil, 5(4 H )-oxo-1,2,4-oxadiazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinil, pyrimidinyl, pyrazinyl, tetrazolyl, 1H-indolyl, 3H-indolyl, 2H-isoindolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, furinyl, indazolyl, benzimidazolyl, benzo[ d ]Oxazole, benzo[ d ]thiazole, benzo[ c ]isooxazole, benzo[ d ]isooxazole, benzo[ c ]isothiazole, benzo[ d ]isothiazole, quinoline-2(1H)-one, isoquinoline-1(2H)-one, indoline-2-one, isoindoline-1-one, 1H-benzo[ d ]Imidazole-2(3H)-one, 1H-benzo[ d ]Imidazole-2(3H)-thion, furanyl, carbazolyl, benzofuranil, isobenzofuranil, dibenzofuranil, benzofuran-2(3H)-one, isobenzofuran-1(3H)-one, thiophenyl, benzo[ b ]thiophenyl, benzo[ c ]thiophenyl, benzo[ b]thiophene-2(3H)-one, and benzo[ c ] A heteroaryl group selected from the group consisting of thiophene-1(3H)-one;

[1297] Here, the heteroaryl group is unsubstituted, or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and

[1298] The C1-C6 straight-chain or branched alkyl substituted here is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i It is substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2.

[1299] The eleventh aspect relates to a compound of any aforementioned aspect, wherein R1 and R2, R1 and R3, R2 and R a , or R3 and R bIt forms a cycloalkyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropphenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl,...

Claims

Claim 1 A compound of formula (1a), or a mirror image isomer thereof; a racemic mixture; or a pharmaceutically acceptable salt, (1a) Here, Is , , , and Selected from a group consisting of: Is: , , , , , , , , , , , , , and Selected from the group consisting of: R1 is (T) w -(CR g R f ) m -Q-(CR g R f ) m -U and; R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN; R4, R5, R6, R7, R8, R9, and R 10 is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , S(O)2R j , S(O)2N(R c )2, N(R c )2, CN, C(O)R j , N(R c )C(O)R j , C(O)N(R c )2, selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; R 11 silver , , , H, OCH2C(O)2R c , selected from the group consisting of unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group; Y is CR a or N and; Z is CR b or N and; Q is O, S, NR i , or -(CR h R d ) p - and;T is O, S, NR i , or -(CR h R d ) p -igo;U is -COOR e , -COS(O) p R e , -CONHS(O) p R e , -CONHR e , -CON(R e )2, vinyl, substituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, , , or B(OH)2; n is 0, 1, or 2; each m is independently 0, 1, 2, 3, 4, or 5; p is 0, 1, or 2; w is 0, 1, or 2; and R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , N(R c Selected from the group consisting of )2, and CN;R c is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or a substituted C1-C6 straight-chain or branched alkyl; R d is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl; R e is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or F, Cl, Br, I, OR c , SR c , N(R c It is a C1-C6 straight-chain or branched alkyl substituted with one or more substituents selected from the group consisting of )2, and CN; R f is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl; R g is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl; R h is H, D, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl; R i is H, D, F, Cl, Br, I, an unsubstituted C1-C6 straight-chain or branched alkyl, or an unsubstituted cycloalkyl; R j is a substituted or unsubstituted C1-C6 straight-chain or branched alkyl, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; where R1 and R2, R1 and R3, R2 and R a , R4 and R5, R6 and R7, or R3 and R b is formed together with a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OC4alkyl, OC5alkyl, OC6alkyl, unsubstituted cycloalkyl, substituted heterocyclyl, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, CONMe2, CONHMe, and CONH2; wherein the substituted cycloalkyl group is substituted with unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; wherein the substituted heterocyclyl group is unsubstituted or substituted C1-C6 straight-chain or branched alkyl, unsubstituted heterocyclyl group, unsubstituted heteroaryl group, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i The substituted aryl group is substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; wherein the substituted aryl group is unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i The substituted group is substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, CONH2, and CONHPh; and wherein the substituted heteroaryl group is substituted with unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i It is substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 2 my 1 In the clause, Is and Selected from a group consisting of: Is Igo;R 11 silver And;R1 is -Q-(CHR f ) m -U and; R2 and R3 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, and OR c Selected from the group consisting of; R4, R5, R6, R7, R8, and R9 are independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OR c , SR c , CN, selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; Y is CR a or N and; Z is CR b or N and;Q is O, S, or -(CHR d ) p -igo;U is -COOR e , substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or B(OH)2; n is 0 or 1; m is 0, 1, 2, 3, or 4; p is 0 or 1; R a and R b is independently H, unsubstituted C1-C6 straight-chain or branched alkyl, substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, and OR c Selected from a group consisting of;R c is H, an unsubstituted C1-C6 straight-chain or branched alkyl, or a substituted C1-C6 straight-chain or branched alkyl; R d is H, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl; R e is H or an unsubstituted C1-C6 straight-chain or branched alkyl; R f is H, F, Cl, Br, I, or an unsubstituted C1-C6 straight-chain or branched alkyl; where R1 and R2, R1 and R3, R2 and R a , or R3 and R b is formed together with a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; wherein the substituted cycloalkyl group is unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i The substituted heterocyclyl group is substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; wherein the substituted heterocyclyl group is unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i The substituted aryl group is substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; wherein the substituted aryl group is unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; and wherein the substituted heteroaryl group is substituted with unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; or its enantiomers; a racemic mixture; or a pharmaceutically acceptable salt. Claim 3 my 1 In the clause, Is and Selected from a group consisting of: Is Igo;R 11 silver And;R1 is -Q-(CHR f ) m -U and; R2 and R3 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, and OR c Selected from the group consisting of; R4, R5, R6, R7, R8, and R9 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -Propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, OR c , selected from the group consisting of CN, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; Y is CR a or N and; Z is CR b or N and;Q is O or -(CHR d ) p -igo;U is -COOR e , substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or B(OH)2; n is 0 or 1; m is 0, 1, 2, 3, or 4; p is 0 or 1; R a and R b is independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, and OR c Selected from a group consisting of;R c is H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -propyl, isopropyl, or substituted isopropyl;R d is H, F, Cl, Br, I, methyl, ethyl, n -Propyl, or isopropyl, and;R e is H, methyl, ethyl, n -Propyl, or isopropyl, and;R f is H, F, Cl, Br, I, methyl, ethyl, n -propyl, or isopropyl; where R1 and R2, R1 and R3, R2 and R a , or R3 and R b is formed together with a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; wherein the substituted methyl, ethyl, n -Propyl, or isopropyl, is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, carbonyl, COOH, and CONH2; wherein the substituted cycloalkyl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2; wherein the substituted heterocyclyl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2; wherein the substituted aryl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, COOH, CH2CONH2, and CONH2; and wherein the substituted heteroaryl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, COOH, CH2CONH2, and CONH2; or its enantiomers; a racemic mixture; or a pharmaceutically acceptable salt. Claim 4 my 1 In the clause, Is and Selected from a group consisting of: Is Igo;R 11 silver And;R1 is -Q-(CHR f ) m -U and; R2 and R3 are independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from the group consisting of; R4, R5, R6, R7, R8, and R9 are independently H, methyl, substituted methyl, ethyl, substituted ethyl, n -Profile, replaced n -Propyl, isopropyl, substituted isopropyl, F, Cl, Br, I, OR c , selected from the group consisting of CN, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; Y is CR a or N and; Z is CR b or N and;Q is O or -(CHR d ) p -igo;U is -COOR e , substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or B(OH)2; n is 0 or 1; m is 0, 1, 2, 3, or 4; p is 0 or 1; R a and R b is independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from a group consisting of;R c is H, methyl, CH2F, CHF2, CF3, ethyl, n -Propyl, or isopropyl, and;R d is H, F, Cl, Br, I, methyl, ethyl, n -Propyl, or isopropyl, and;R e is H, methyl, ethyl, n -Propyl, or isopropyl, and;R f is H, F, Cl, Br, I, methyl, ethyl, n -propyl, or isopropyl; where R1 and R2, R1 and R3, R2 and R a , or R3 and R b is formed together with a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; wherein the substituted methyl, ethyl, n -Propyl, or isopropyl, is substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, NH2, and COOH; wherein the substituted cycloalkyl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; wherein the substituted heterocyclyl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; wherein the substituted aryl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; and wherein the substituted heteroaryl group is methyl, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, CH2COOH, carbonyl, and COOH; or an enantiomer thereof; a racemic mixture; or a pharmaceutically acceptable salt. Claim 5 my 1 In the clause, Is and Selected from a group consisting of: Is Igo;R 11 silver And;R1 is -Q-(CHR f ) m -U and; R2 and R3 are independently H, methyl, ethyl, n -Propyl, isopropyl, F, Cl, Br, I, and OR c Selected from the group consisting of; R4, R5, R6, R7, R8, and R9 are independently H, methyl, CF3, ethyl, n -Propyl, Isopropyl, F, Cl, Br, I, OR c , selected from the group consisting of CN, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl; Y is CR a or N and; Z is CR b or N and;Q is O or -(CHR d ) p - and; U is -COOH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2 and; n is 0 or 1 and; m is 0 or 1 and; p is 0 or 1 and; R a is H or methyl;R b is H or methyl;R c is H, methyl, or CF3 and;R d is H, F, Cl, Br, or methyl;R f is H, F, Cl, Br, or methyl; where R1 and R2 or R1 and R3 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; where the substituted cycloalkyl group is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; wherein the substituted heterocyclyl group is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; wherein the substituted aryl group is methyl, ethyl, n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; and wherein the substituted heteroaryl group is methyl, ethyl, n - A compound substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; or an enantiomer thereof; a racemic mixture; or a pharmaceutically acceptable salt. Claim 6 my 1 In the clause, Is and Selected from a group consisting of: Is Igo;R 11 silver And;R1 is -Q-(CHR f ) m -U is; R2 and R3 are independently H or methyl; R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, methyl, isopropyl, CF3, F, Cl, Br, OMe, OCF3, CN, cyclopropyl, cyclopentyl, and phenyl; Y is CH or N; Z is CH or N; Q is O or -(CHR d ) p - and; U is -COOH, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or B(OH)2 and; n is 0 or 1 and; m is 0 or 1 and; p is 0 or 1 and; R d is H, F, or methyl;R f is H, F, or methyl; where R1 and R2 or R1 and R3 together form a cyclic structure selected from the group consisting of a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; where the substituted cycloalkyl group is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; wherein the substituted heterocyclyl group is methyl, ethyl, n - Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; wherein the substituted aryl group is methyl, ethyl, n -Substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; and wherein the substituted heteroaryl group is methyl, ethyl, n - A compound substituted with one or more substituents selected from the group consisting of propyl, isopropyl, F, Cl, Br, I, OH, OMe, OCF3, NH2, NMe2, CH2COOH, carbonyl, and COOH; or an enantiomer thereof; a racemic mixture; or a pharmaceutically acceptable salt. Claim 7 my 1 In the claim, U is a cycloalkyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropphenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl, and cyclooctatrienyl; wherein the cycloalkyl group is unsubstituted or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 8 my 1 In the claim, U is a heterocyclyl group selected from the group consisting of azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxetanil, tetrahydrofuranil, dihydrofuranil, tetrahydropyranil, dihydropyranil, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyranil, and dihydrothiopyranil; wherein the heterocyclyl group is unsubstituted or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 9 my 1 In the claim, U is an aryl group selected from the group consisting of phenyl, naphthalenyl, cyclobutadienyl, cyclopentadienyl, indenyl, anthracenyl, phenanthrenyl, terphenylenyl, fluorenyl, and pyrenyl; wherein the aryl group is unsubstituted or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 10 my 1 In the clause, U is pyrrolyl, imidazolyl, pyrazolil, thiazolil, 5(4 H )-oxo-1,2,4-thiadiazollil, oxazolil, 5(4 H )-oxo-1,2,4-oxadiazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, 1 H -Indolil, 3 H -Indolil, 2 H -Isoindolyl, Indoliginil, Quinolinil, Isoquinolinil, Quinoxalinil, Cinnolinil, Quinazolinil, Phthalaginil, Purinyl, Indazollil, Benzimidazolil, Benzo[ d ]Oxazole, benzo[ d ]thiazole, benzo[ d ]isooxazole, benzo[ d ]isooxazole, benzo[ c ]isothiazole, benzo[ d ]Isothiazole, Quinoline-2(1 H )-on, isoquinoline-1(2 H )-one, indolin-2-one, isoindolin-1-one, 1 H -Benzo[ d ]Imidazole-2(3 H )-on, 1 H -Benzo[ d ]Imidazole-2(3 H )-Thion, furanyl, carbazolyl, benzofuranil, isobenzofuranil, dibenzofuranil, benzofuran-2(3 H )-on, isobenzofuran-1(3 H )-one, thiophenyl, benzo[ b ]thiophenyl, benzo[ c ]thiophenyl, benzo[ b ]Thiophen-2(3 H )-on, and benzo[ c ] A heteroaryl group selected from the group consisting of thiophene-1(3H)-one; wherein the heteroaryl group is unsubstituted, or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 11 my 1 In the clause, R1 and R2, R1 and R3, R2 and R a , or R3 and R b It forms a cycloalkyl group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropphenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl, and cyclooctatrienyl; wherein the cycloalkyl group is unsubstituted or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 12 my 1 In the clause, R1 and R2, R1 and R3, R2 and R a , or R3 and R b Together, they form a heterocyclyl group selected from the group consisting of azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, imidazolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxetanil, tetrahydrofuranil, dihydrofuranil, tetrahydropyranil, dihydropyranil, tetrahydrothiophene, dihydrothiophene, tetrahydrothiopyranil, 3,5-dioxoisooxazolidinyl, and dihydrothiopyranil; wherein the heterocyclyl group is unsubstituted, or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 13 my 1 In the clause, R1 and R2, R1 and R3, R2 and R a , or R3 and R b together form an aryl group selected from the group consisting of phenyl, naphthalenyl, cyclobutadienyl, cyclopentadienyl, indenyl, anthracenyl, phenanthrenyl, terphenylenyl, fluorenyl, and pyrenyl; wherein the aryl group is unsubstituted, or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 14 my 1 In the clause, R1 and R2, R1 and R3, R2 and R a , or R3 and R b together with pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, 5(4 H )-oxo-1,2,4-thiadiazollil, oxazolil, 5(4 H )-oxo-1,2,4-oxadiazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, 1 H -Indolil, 3 H -Indolil, 2 H -Isoindolyl, Indoliginil, Quinolinil, Isoquinolinil, Quinoxalinil, Cinnolinil, Quinazolinil, Phthalaginil, Purinyl, Indazollil, Benzimidazolil, Benzo[ d ]Oxazole, benzo[ d ]thiazole, benzo[ c ]isooxazole, benzo[ d ]isooxazole, benzo[ c ]isothiazole, benzo[ d ]Isothiazole, Quinoline-2(1 H )-on, isoquinoline-1(2 H )-one, indolin-2-one, isoindolin-1-one, 1 H -Benzo[ d ]Imidazole-2(3 H )-on, 1H-benzo[d]imidazole-2(3 H )-Thion, furanyl, carbazolyl, benzofuranil, isobenzofuranil, dibenzofuranil, benzofuran-2(3 H )-on, isobenzofuran-1(3 H )-one, thiophenyl, benzo[ b ]thiophenyl, benzo[ c ]thiophenyl, benzo[b]thiophene-2(3 H )-on, and benzo[ c ]Thiophen-1(3 H Forming a heteroaryl group selected from the group consisting of )-ones; wherein the heteroaryl group is unsubstituted, or unsubstituted or substituted C1-C6 straight-chain or branched alkyl, F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i Substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2; and wherein the substituted C1-C6 straight-chain or branched alkyl is F, Cl, Br, I, OH, OMe, OEt, O- n Pr, O- i Pr, OCH2F, OCHF2, OCF3, SH, SMe, SEt, S- n Pr, S- i Pr, SCH2F, SCHF2, SCF3, NH2, NMe2, NEt2, N( n Pr)2, N( i A compound substituted with one or more substituents selected from the group consisting of Pr)2, N(CH2F)2, N(CHF2)2, N(CF3)2, carbonyl, COOH, COSH, and CONH2. Claim 15 my 1 In the clause, and A compound selected from the group consisting of; or its enantiomer; a racemic mixture; or a pharmaceutically acceptable salt. Claim 16 my 15 In the clause, and A compound selected from the group consisting of; or a pharmaceutically acceptable salt thereof. Claim 17 my 1 A pharmaceutical composition comprising a compound of the same and one or more pharmaceutically acceptable excipients. Claim 18 my 17 In the clause, and A compound selected from the group consisting of; or its enantiomer; a racemic mixture; or a pharmaceutically acceptable salt. Claim 19 my 18 In the clause, and A compound selected from the group consisting of; or a pharmaceutically acceptable salt thereof. Claim 20 As a method for treating multiple sclerosis, relapsing-remitting multiple sclerosis, amyotrophic lateral sclerosis, psoriasis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, and lymphopenia, for individuals in need 17 A method comprising the step of administering a pharmaceutical composition of the object. Claim 21 my 20 In the clause, and A compound selected from the group consisting of; or its enantiomer; a racemic mixture; or a pharmaceutically acceptable salt. Claim 22 my 21 In the clause, and A compound selected from the group consisting of; or a pharmaceutically acceptable salt thereof. Claim 23 my 22 A method wherein the pharmaceutical composition is administered to an individual into the nasal cavity; into the lungs; topically; orally; intravenously as an infusion or injection; intramuscularly as an infusion or injection; subcutaneously as an infusion, injection, or depot formulation; transdermally; into the abdominal cavity; or rectum. Claim 24 my 1 As a process for manufacturing a compound of the protest, here Is , , and A process selected from the group consisting of, comprising: Step A, a compound of formula (2) React with the compound of chemical formula (3) Step of producing the compound of chemical formula (4) As step B, the compound of formula (4) Step of reacting with acid to produce a compound of chemical formula (5). ; and as step 1-C, the compound of formula (5) React with the compound of chemical formula (6) Step of producing a compound of chemical formula (1b) ,where X1 is F, Cl, Br, or I; X2 is F, Cl, Br, or I; V is N or CH; W is N or CH; and R t is H or an unsubstituted C1-C6 straight-chain or branched alkyl. Claim 25 my 24 A process wherein, in claim 1, step A is performed at about 50 ℃ to about 100 ℃; step B is performed at about 50 ℃ to about 100 ℃; and step 1-C is performed at about 50 ℃ to about 125 ℃. Claim 26 my 24 In the process, step A is performed in the presence of a solvent and a base; step B is performed in the presence of a solvent and an acid; and steps 1-C are performed in the presence of a solvent, a copper salt, a base, and a ligand. Claim 27 my 26 In the clause, the solvent in step A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the base in step A is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - A process selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 28 my 26 In the clause, the solvent in step B is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The process is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; wherein the acid in step B is selected from the group consisting of AcOH, TFA, hydrochloric acid, hydrobromide, and mixtures thereof. Claim 29 my 26 In the clause, the solvent in step 1-C is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the copper salt in step 1-C is selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof; wherein the base in step 1-C is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - Selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof; wherein the ligand in step 1-C is N , N A process selected from the group consisting of '-DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof. Claim 30 my 1 As a process for manufacturing a compound of the protest, here Is , , and A process selected from the group consisting of, comprising: Step A, a compound of formula (2) React with the compound of chemical formula (3) Step of producing the compound of chemical formula (4) ; As step B, the compound of formula (4) Step of reacting with acid to produce a compound of chemical formula (5). ; and as step 2-C, the compound of formula (5) React with the compound of chemical formula (7) Step of producing the compound of chemical formula (8) ,where X3 is F, Cl, Br, or I; V is N or CH; W is N or CH; and R t is H or an unsubstituted C1-C6 straight-chain or branched alkyl. Claim 31 my 30 A process wherein, in claim 1, step A is performed at about 50 ℃ to about 100 ℃; step B is performed at about 50 ℃ to about 100 ℃; and step 2-C is performed at about 50 ℃ to about 125 ℃. Claim 32 my 30 In the process, step A is performed in the presence of a solvent and a base; step B is performed in the presence of a solvent and an acid; and steps 2-C are performed in the presence of a solvent, a copper salt, a base, and a ligand. Claim 33 my 32 In the clause, the solvent in step A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the base in step A is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - A process selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 34 my 32 In the clause, the solvent in step B is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The process is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; wherein the acid in step B is selected from the group consisting of AcOH, TFA, hydrochloric acid, hydrobromide, and mixtures thereof. Claim 35 my 32 In the clause, the solvent in step 2-C is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the copper salt in step 2-C is selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof; wherein the base in step 2-C is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - Selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof; wherein the ligand in step 2-C is N , N' A process selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof. Claim 36 my 1 As a process for manufacturing a compound of the protest, here Is And, comprising the following, process: as step 3-A, a compound of formula (9) Step of reacting with a cyanide reagent to produce a compound of chemical formula (10). ; As step 3-B, the compound of formula (10) Step of reacting with a hydrogenation agent to produce a compound of chemical formula (11). ; As step 3-C, the compound of formula (10) react with the compound of chemical formula (12) Step of producing a compound of chemical formula (13) ; As step 3-D, the compound of formula (13) react with the compound of chemical formula (14) Step of producing a compound of chemical formula (15) ; As step 3-E, the compound of formula (15) React with the compound of chemical formula (16) Step of producing a compound of chemical formula (17) ; As step 3-F, the compound of formula (17) Step of reacting with a hydrogenation agent to produce a compound of chemical formula (18). ; and as step 3-G, the compound of formula (18) Step of reacting with an azide reagent to produce a compound of formula (1b-2). ,where X4 is F, Cl, Br, or I; X5 is F, Cl, Br, I, or a leaving group L1 selected from the group consisting of p-toluenesulfonate (-OTs), methanesulfonate (-OMs), trifluoromethanesulfonate (-SO3CF3), nitrate (-ONO2), and phosphate (-OPO(OR)2), where R is an alkyl group; X6 is F, Cl, Br, or I; and X7 is F, Cl, Br, or I, process. Claim 37 my 36 A process wherein, in claim 3-A, step 3-A is performed at about 30 ℃ to about 75 ℃; step 3-B is performed at about 15 ℃ to about 35 ℃; step 3-C is performed at about 50 ℃ to about 75 ℃; step 3-D is performed at about 75 ℃ to about 125 ℃; step 3-E is performed at about 15 ℃ to about 35 ℃; step 3-F is performed at about 15 ℃ to about 35 ℃; and step 3-G is performed at about 100 ℃ to about 140 ℃. Claim 38 my 36 In the process, step 3-A is performed in the presence of a solvent and a cyanide reagent; step 3-B is performed in the presence of a solvent, a hydrogenation reagent, and a catalyst; step 3-C is performed in the presence of a solvent and a base; step 3-D is performed in the presence of a solvent; step 3-E is performed in the presence of a solvent and a base; step 3-F is performed in the presence of a solvent, a hydrogenation reagent, a catalyst, and a base; and step 3-G is performed in the presence of a solvent, an azide reagent, and a salt. Claim 39 my 38 In the process, the solvent in step 3-A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, DMSO, and mixtures thereof; wherein the cyanide reagent in step 3-A is selected from the group consisting of sodium cyanide, potassium cyanide, and mixtures thereof. Claim 40 my 38 In the clause, the solvent in step 3-B is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The process is selected from the group consisting of PrOH and mixtures thereof; wherein the hydrogenation reagent in step 3-B is selected from the group consisting of hydrogen (H2), formic acid, isopropanol, and mixtures thereof; and wherein the catalyst is selected from the group consisting of Wilkinson's catalyst, platinum (0), palladium (0), Pt / C, Pd / C, and mixtures thereof. Claim 41 my 38 In the clause, the solvent in step 3-C is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i Selected from the group consisting of PrOH and mixtures thereof; the base in step 3-C is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - A process selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 42 my 38 In the clause, the solvent in step 3-D is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - A process selected from the group consisting of xylene, chlorobenzene, and mixtures thereof. Claim 43 my 38 In the clause, the solvent in step 3-E is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - Selected from the group consisting of xylene, chlorobenzene, and mixtures thereof; wherein the base in step 3-E is ammonia, triethylamine, N , N - A process selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 44 my 38 In the clause, the solvent in step 3-F is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i Selected from the group consisting of PrOH and mixtures thereof; wherein the hydrogenation reagent in step 3-F is selected from the group consisting of hydrogen (H2), formic acid, isopropanol, and mixtures thereof; wherein the catalyst in step 3-F is selected from the group consisting of Wilkinson catalyst, platinum (0), palladium (0), Pt / C, Pd / C, and mixtures thereof; wherein the base in step 3-F is ammonia, triethylamine, N , N - A process selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 45 my 38 In the clause, the solvent in step 3-G is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - Selected from the group consisting of xylene and mixtures thereof; wherein the azide reagent in step 3-G is selected from the group consisting of lithium azide, sodium azide, potassium azide, trimethyltin azide, triethyltin azide, tripropyltin azide, tributyltin azide, and mixtures thereof; wherein the salt in step 3-G is selected from the group consisting of ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, and mixtures thereof, process. Claim 46 my 1 As a process for manufacturing a compound of the protest, here Is And, comprising the following, process: as step 4-A, a compound of formula (19) React with the compound of chemical formula (16) Step of producing a compound of chemical formula (20) ; and as step 4-B, the compound of formula (20) React with the compound of chemical formula (6) Step of producing a compound of chemical formula (1d) . Claim 47 my 46 A process wherein, in the claim, step 4-A is performed at about 15 ℃ to about 35 ℃; and step 4-B is performed at about 50 ℃ to about 125 ℃. Claim 48 my 46 In the above, step 4-A is performed in the presence of a solvent and a catalyst; step 4-B is performed in the presence of a solvent, a copper salt, a base, and a ligand, process. Claim 49 my 48 In the process, the solvent in step 4-A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the catalyst in step 4-A is selected from the group consisting of Rh2(OAc)4, Rh(OAc)3, Rh(acac)3, and mixtures thereof. Claim 50 my 48 In the clause, the solvent in step 4-B is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the copper salt in step 4-B is selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof; wherein the base in step 4-B is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - Selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof; wherein the ligand in step 4-B is N , N' A process selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof. Claim 51 my 1 As a process for manufacturing a compound of the protest, here Is And, as a process comprising the following: step 5-A, a compound of formula (21) react with the compound of chemical formula (22) Step of producing a compound of chemical formula (23) ; and as step 5-B, the compound of formula (23) React with the compound of chemical formula (16) Step of producing a compound of chemical formula (1d) ,here R q R r , and R s is independently F, Cl, Br, I, OR h , SR h , or p - A leaving group L2 selected from the group consisting of toluenesulfonate (-OTs), methanesulfonate (-OMs), trifluoromethanesulfonate (-OSO2CF3), nitrate (-ONO2), and phosphate (-OPO(OR)2), wherein R is an alkyl group; R h is H or an unsubstituted C1-C6 straight-chain or branched alkyl. Claim 52 my 51 A process wherein, in the claim, step 5-A is performed at about 15 ℃ to about 35 ℃; and step 5-B is performed at about -10 ℃ to about 10 ℃. Claim 53 my 51 In the above, step 5-A is performed in the presence of a solvent and a base; and step 5-B is performed in the presence of a solvent and a catalyst, process. Claim 54 my 53 In the clause, the solvent in step 5-A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; and the base in step 5-A is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - A process selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 55 my 53 In the clause, the solvent in step 5-B is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the base in step 5-B is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - A process selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 56 my 1 As a process for manufacturing a compound of the protest, here Is And, comprising the following, process: as step 6-A, a compound of formula (21) react with the compound of chemical formula (24) Step of producing a compound of chemical formula (25) ; As step 6-B, the compound of formula (25) Step of reacting with an alkylating agent to produce a compound of formula (26). ; As step 6-C, the compound of formula (26) Step of reacting with a non-nucleophilic base to produce a compound of formula (27). ; As step 6-D, the compound of formula (27) Step of reacting with a deprotective agent to produce a compound of chemical formula (28). ; and as step 6-E, the compound of formula (28) React with the compound of chemical formula (2) Step of producing a compound of chemical formula (1d) ,where X8 is F, Cl, Br, or I; E is O or S; R u is F, Cl, Br, I, OR p , or SR p and; R v is an unsubstituted C1-C6 straight-chain or branched alkyl group, or a benzyl (Bn) group, (diphenyl)methylene group, trityl (triphenylmethyl, Tr) group, (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, formyl group, acetyl (Ac) group, benzoyl (Bz) group, tert - Butyloxycarbonyl (BOC) group, carbobenzyloxy (Cbz) group, p -Methoxybenzylcarbonyl (Moz) group, 9-fluorenyl-methyloxycarbonyl (Fmoc) group, dialkyl phosphoramidate group, methanesulfonyl (Mesyl, Ms) group, and p - A protecting group selected from the group consisting of toluenesulfonyl (tosyl, Ts) groups; R w is H or an unsubstituted C1-C6 straight-chain or branched alkyl; R x is H or an unsubstituted C1-C6 straight-chain or branched alkyl; R p is H or an unsubstituted C1-C6 straight-chain or branched alkyl. Claim 57 A process according to claim 56, wherein step 6-A is performed at about 15 ℃ to about 35 ℃; step 6-B is performed at about 15 ℃ to about 35 ℃; step 6-C is performed at about -10 ℃ to about 10 ℃; step 6-D is performed at about 15 ℃ to about 35 ℃; and step 6-E is performed at about 75 ℃ to about 125 ℃. Claim 58 In paragraph 56, step 6-A is performed in the presence of a solvent, a peptide coupling reagent, and a base; step 6-B is performed in the presence of a solvent and an alkylating reagent; step 6-C is performed in the presence of a solvent and a non-nucleophilic base; step 6-D is performed in the presence of a solvent and a deprotecting reagent; and step 6-E is performed in the presence of a solvent, a catalyst, a ligand, and a base, process. Claim 59 In claim 58, the solvent in step 6-A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; wherein the peptide coupling reagent in step 6-A is selected from the group consisting of DCC, DIC, CIC, BOP, PyBOP, AOP, PyAOP, HBTU, TBTU, HATU, HDMA, T3P, and mixtures thereof; wherein the base in step 6-A is ammonia, triethylamine, N , N - A process selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof. Claim 60 In paragraph 58, the solvent in step 6-B is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH is selected from the group consisting of mixtures thereof; wherein the alkylating reagent in step 6-B is methyl bromide, methyl iodide, ethyl bromide, ethyl iodide, n -Profile bromide, n - A process selected from the group consisting of propyl iodide, isopropyl bromide, isopropyl iodide, and mixtures thereof. Claim 61 In paragraph 58, the solvent in step 6-C is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, and mixtures thereof are selected from the group consisting of mixtures thereof; and the non-nucleophilic base in step 6-C is N,N-diisopropylethylamine, 2,6-di- tert - A process selected from the group consisting of butylpiperidine, DBU, DBN, potassium tert-butoxide, LDA, LiTMP, NaTMP, KTMP, LiHMDS, NaHMDS, KHMDS, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 62 In paragraph 58, the solvent in step 6-D is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The process is selected from the group consisting of PrOH, AcOH, water, and mixtures thereof; wherein the deprotecting reagent in step 6-D is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof. Claim 63 In paragraph 58, the solvent in step 6-E is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - Selected from the group consisting of xylene and mixtures thereof; wherein the catalyst in step 6-E is selected from the group consisting of Pd2(dba)3, PdCl2(PPh3)2, Pd(PPh3)4, and mixtures thereof; wherein the ligand in step 6-E is selected from the group consisting of N,N'-DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, BINAP, Chiraphos, Xanthphos, DPEphos, SPANphos, Me-DuPhos, dppm, and mixtures thereof; wherein the base in step 6-E is ammonia, triethylamine, N , N - A process selected from the group consisting of diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof. Claim 64 my 1 As a process for manufacturing a compound of the protest, here Is and, as a process comprising the following: Step 7-A, a compound of formula (9) Step of reacting with a cyanide reagent to produce a compound of chemical formula (10). ; As step 7-B, the compound of formula (10) Step of reacting with a hydrogenation agent to produce a compound of chemical formula (11). ; As step 7-C, the compound of formula (11) react with the compound of chemical formula (12) Step of producing a compound of chemical formula (13) ; As step 7-D, the compound of formula (13) react with the compound of chemical formula (14) Step of producing a compound of chemical formula (15) ; As step 7-E, the compound of formula (15) react with the compound of chemical formula (16) Step of producing a compound of chemical formula (17) ; As step 7-F, the compound of formula (17) react with a palladium catalyst and a compound of chemical formula (31). Step of producing a compound of chemical formula (18') ; As step 7-G, the compound of formula (18') Step of reacting with an azide reagent to produce a compound of chemical formula (1a-2'). ,where X4 is F, Cl, Br, or I; X5 is F, Cl, Br, I, or p - A leaving group L1 selected from the group consisting of toluenesulfonate (-OTs), methanesulfonate (-OMs), trifluoromethanesulfonate (-OSO2CF3), nitrate (-ONO2), and phosphate (-OPO(OR)2), where R is an alkyl group; X6 is F, Cl, Br, or I; and X7 is F, Cl, Br, or I. Claim 65 my 64 A process wherein, in claim 7-A, step 7-A is performed at about 30°C to about 75°C; step 7-B is performed at about 15°C to about 35°C; step 7-C is performed at about 50°C to about 75°C; step 7-D is performed at about 75°C to about 125°C; step 7-E is performed at about 15°C to about 35°C; step 7-F is performed at about 50°C to about 140°C; and step 7-G is performed at about 100°C to about 140°C. Claim 66 my 64 In the paragraph, step 7-A is performed in the presence of a solvent and a cyanide agent; step 7-B is performed in the presence of a solvent, a hydrogenation reagent, and a catalyst; step 7-C is performed in the presence of a solvent and a base; step 7-D is performed in the presence of a solvent; step 7-E is performed in the presence of a solvent and a base; step 7-F is performed in the presence of a solvent; and step 7-G is performed in the presence of a solvent, an azide reagent, and a salt, process. Claim 67 my 66 In the process, the solvent in step 7-A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, DMSO, and mixtures thereof; wherein the cyanide reagent in step 7-A is selected from the group consisting of sodium cyanide, potassium cyanide, and mixtures thereof. Claim 68 my 66 In the clause, the solvent in step 7-B is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i The process is selected from the group consisting of PrOH and mixtures thereof; wherein the hydrogenation reagent in step 7-B is selected from the group consisting of hydrogen (H2), formic acid, isopropanol, and mixtures thereof; and wherein the catalyst is selected from the group consisting of Wilkinson catalyst, platinum (0), palladium (0), Pt / C, Pd / C, and mixtures thereof. Claim 69 my 66 In the clause, the solvent in step 7-C is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i Selected from the group consisting of PrOH and mixtures thereof; wherein the base in step 7-C is ammonia, triethylamine, N , N - Diisopropiethylamine, potassium tert - A process selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 70 my 66 In the clause, the solvent in step 7-D is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - A process selected from the group consisting of xylene, chlorobenzene, and mixtures thereof. Claim 71 my 66 In the clause, the solvent in step 7-E is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - Selected from the group consisting of xylene, chlorobenzene, and mixtures thereof; wherein the base in step 7-E is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - A process selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydride, sodium hydride, potassium hydride, and mixtures thereof. Claim 72 my 66 In the clause, the solvent in step 7-F is DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i A process selected from the group consisting of PrOH, water, and mixtures thereof. Claim 73 my 64 In the paragraph, the palladium catalyst in step 7-F is palladium acetate (II) (Pd(OAc)2), palladium (II) acetylacetonate (Pd(acac)2), tris(dibenzylideneacetone)dipalladium (O) (Pd2(dba)3), dichlorobis(triphenylphosphine)palladium (II) (PdCl2(PPh3)2), tetrakis(triphenylphosphine)palladium (O) (Pd(PPh3)4), palladium (O) (Pd), palladium (O) supported on carbon (Pd / C), dichloro(1,1'-bis(di- tert A process selected from the group consisting of butylphosphino)ferrocene)palladium(II)(Pd(dtbpf)Cl2), and mixtures thereof. Claim 74 my 66 In the clause, the solvent in step 7-G is DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, DCM, CHCl3, MeCN, MeOH, EtOH, i PrOH, benzene, toluene, o - Xylene, m - Xylene, p - Selected from the group consisting of xylene and mixtures thereof; wherein the azide reagent in step 7-G is selected from the group consisting of lithium azide, sodium azide, potassium azide, trimethyltin azide, triethyltin azide, tripropyltin azide, tributyltin azide, and mixtures thereof; wherein the salt in step 7-G is selected from the group consisting of ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, and mixtures thereof, process. Claim 75 my 1 As a process for manufacturing a compound of the protest, here Is and, a process comprising the following: as step 8-A, a compound of formula (16) react with the compound of chemical formula (29) Step of producing a compound of chemical formula (30) ; As step 8-B, the compound of formula (30) react with the compound of chemical formula (7) Step of producing a compound of chemical formula (18') ,where X3 is F, Cl, Br, or I; and R t is H or an unsubstituted C1-C6 straight-chain or branched alkyl. Claim 76 my 75 A process wherein, in the claim, step 8-A is performed at about 50°C to about 125°C; and step 8-B is performed at about 50°C to about 125°C. Claim 77 my 75 In the above, step 8-A is performed in the presence of a solvent and an acid; step 8-B is performed in the presence of a solvent, a copper salt, a base, and a ligand, process. Claim 78 my 77 In the claim, the solvent in step 8-A is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, EtOAc, 1,4-dioxane, DCM, CHCl3, MeCN, AcOH, and mixtures thereof; and the acid in step 8-A is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromide, hydroiodide, and mixtures thereof, process. Claim 79 my 77 In the clause, the solvent in step 8-B is selected from the group consisting of DMF, DMA, NMP, THF, 2-MeTHF, 1,4-dioxane, EtOAc, DCM, CHCl3, MeCN, and mixtures thereof; the copper salt in step 8-B is selected from the group consisting of CuF, CuCl, CuBr, CuI, and mixtures thereof; and the base in step 8-B is ammonia, triethylamine, N , N - Diisopropylethylamine, potassium tert - Selected from the group consisting of butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, trisodium phosphate, tripotassium phosphate, and mixtures thereof; and wherein the ligand in step 8-B is N , N' A process selected from the group consisting of -DMEDA, 1,10-phenanthroline, 2,2'-bipyridine, and mixtures thereof.

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