Compound as xanthine oxidase inhibitor and use thereof

Abstract

The present invention relates to a class of xanthine oxidase inhibitors and the use thereof in the preparation of a related drug. The drug is used for treating and / or preventing hyperuricemia and diseases caused by hyperuricemia, such as gout, arthritis, or heart failure. Specifically, the present invention relates to a compound as shown in (Xa) or (Xb), and a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, deuterated compound, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

Description

Compounds as inhibitors of xanthine oxidase and uses thereof

[0001] This application claims priority to:

[0002] CN202410599150.2, filed on May 14, 2024;

[0003] CN202411203520.2, filed on August 29, 2024. TECHNICAL FIELD

[0004] The present application relates to the field of chemical medicine, in particular to a compound as an inhibitor of xanthine oxidase and uses thereof. BACKGROUND

[0005] Hyperuricemia (HUA) is caused by excessive uric acid production and / or excretion in the body under normal dietary conditions. Male and female patients are diagnosed as hyperuricemia if their fasting blood uric acid levels are higher than 420 μmol / L and 360 μmol / L, respectively, on two different days. Hyperuricemia is the second most common metabolic disease worldwide and is a major risk factor for gout, kidney damage, and metabolic syndrome.

[0006] Hyperuricemia is treated mainly by increasing uric acid excretion and inhibiting uric acid production. Purine metabolism is the main source of uric acid in the human body. Purine undergoes a series of metabolic changes to form uric acid as the final product. There are two sources of purine, about 80% of which comes from endogenous nucleotide metabolism, and the other 20% of which comes from exogenous purine food metabolism in the intestinal tract. Endogenous nucleotides (adenine nucleotides and guanine nucleotides) undergo a series of biochemical reactions to ultimately generate uric acid. Adenine nucleotides are catalyzed by nucleotidases, nucleoside deaminases, and nucleoside phosphorylases to generate hypoxanthine, which is then catalyzed by xanthine oxidase twice to ultimately generate uric acid. Guanine is catalyzed by guanine deaminase to generate xanthine, which is then catalyzed by xanthine oxidase to generate uric acid. Xanthine oxidase is considered an important inhibitory target in the uric acid production pathway.

[0007] Xanthine oxidase inhibitors are first-line drugs for the treatment of hyperuricemia. Currently marketed drugs mainly include allopurinol and febuxostat. Allopurinol is the first xanthine oxidase inhibitor used in the treatment of gout and hyperuricemia in clinical practice and has been widely used in clinical practice. The marketing of febuxostat largely makes up for the clinical defects of allopurinol: the uric acid-lowering effect is better than that of allopurinol, but such drugs cannot meet the clinical needs of all patients and have obvious side effects. Allopurinol can cause severe drug-induced skin rash. Febuxostat can cause abnormal liver function, renal tubular nephritis, and increased cardiovascular adverse reactions.

[0008] Therefore, it is still of great significance to develop xanthine oxidase inhibitor drugs with better safety and excellent efficacy in clinic. SUMMARY

[0009] The present application provides a compound, or a pharmaceutical composition thereof, which can be used as a xanthine oxidase inhibitor. The present application further relates to the use of the compound, or a pharmaceutical composition thereof, for the preparation of a medicament for the treatment of a disease and / or a disorder by inhibiting xanthine oxidase with the compound. The present application still further describes a method for synthesizing the compound. The compound of the present application shows excellent biological activity and pharmacokinetic properties.

[0010] In particular:

[0011] A compound is a compound as shown in formula (Xa) or (Xb), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a deuterated compound, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in formula (Xa) or (Xb),

[0012] Wherein:

[0013] A ring is a five-membered heteroaromatic ring, which can be optionally substituted by 1, 2 or 3 R a ;

[0014] Each R a is independently H, D, F, Cl, Br, I, CN, hydroxyl, carboxyl, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, which C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can be optionally substituted by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro and carboxyl;

[0015] X1is NR 1 or CR 1 ; X2is NR 2 or CR 2 , R 1 and R 2 , together with the atoms to which they are respectively attached, form a C 5-8 cycloalkyl or 5-8 membered heterocycle, which C 5-8 cycloalkyl and 5-8 membered heterocycle can be optionally substituted by 1, 2, 3, 4, 5 or 6 R bsubstituted, provided that when X1is NR 1 , X2is not NR 2 ;

[0016] X3is NH, N, S, O, or CR 3 ;

[0017] X4is N or CR 4 ;

[0018] X5is N or CR 5 ;

[0019] X6is N or CR 6 ;

[0020] X7is N or C;

[0021] X8is N or C;

[0022] each R b is independently H, D, F, Cl, Br, I, hydroxyl, carboxyl, amino, nitro, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino, said C 3- 6cycloalkyl and 3-6 membered heterocyclyl being optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxyl, amino, nitro, oxo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino;

[0023] or two R b on the same atom form oxo, or two R b together with the atom to which they are both attached form a C 3-6 cycloalkyl or 3-5 membered heterocycle; said C 3-6 cycloalkyl and 3-5 membered heterocycle being optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxyl, amino, nitro, oxo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino;

[0024] or two Rb with the attached atom(s) to form a C 3-6 cycloalkyl or 3-5 membered heterocycle; said C 3-6 cycloalkyl and 3-5 membered heterocycle can be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, hydroxyl, amino, nitro, oxo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino;

[0025] R 3 , R 4 , R 5 , and R 6 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, carboxyl, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, or C 3-6 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, and C 3-6 cycloalkyl can be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino, and R 3 , R 4 , R 5 , and R 6 are at least one CN.

[0026] In some embodiments, it is a compound as shown in Formula (Xc), (Xd), (I), or (I’), or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, deuterated compound, metabolite, pharmaceutically acceptable salt, or prodrug of a compound shown in Formula (Xc), (Xd), (I), or (I’),

[0027] In some embodiments, wherein is Formula (Ia), (Ib), (Ic), (Id), or (Ie):

[0028] wherein:

[0029] Y1is S, O, Se, or NH;

[0030] each Y2is independently N or CR a .

[0031] In some embodiments, wherein is

[0032] In some embodiments, wherein each R a is independently H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl.

[0033] In some embodiments, wherein each R b is independently H, D, F, Cl, Br, I, hydroxyl, carboxyl, amino, nitro, CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, CH2CN, cyclopropyl, cyclobutyl, or azetidinyl; or two R b on the same atom form an oxo, or two R b on adjacent atoms, together with the atoms to which they are both attached, form a cyclopropyl or cyclobutyl; or two R b on adjacent atoms, together with the atoms to which they are each attached, form a cyclopropyl or cyclobutyl.

[0034] In some embodiments, wherein R 3 , R 4 , R 5 , and R 6 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, cyclopropyl, or cyclobutyl, and R 3 , R 4 , R 5 , and R 6 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, cyclopropyl, or cyclobutyl.

[0035] In some embodiments, wherein R 3 , R 4 , R 5 , and R 6 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, cyclopropyl, or cyclobutyl.

[0036] In some embodiments, the compounds of the present application have the structure of Formula (IIa), (IIb), (IIc), or (IId):

[0037] wherein:

[0038] X3is N or CR 3 ;

[0039] each Z is independently -O-, -S-, -S(=O)-, -S(O)2-, -NH-, or -CH2-;

[0040] n is 1, 2, or 3;

[0041] m is 1, 2, 3, or 4.

[0042] In some embodiments, the compounds of the present application have the structure of (IIe):

[0043] wherein:

[0044] X3is S, O, or NH;

[0045] each Z is independently -O-, -S-, -S(=O)-, -S(O)2-, -NH-, or -CH2-;

[0046] n is 1, 2, or 3;

[0047] m is 1, 2, 3, or 4.

[0048] In some embodiments, the compounds of the present application have the structure of Formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh):

[0049] wherein:

[0050] X3is NH, O, or S;

[0051] Z is -O-, -S-, -S(=O)-, -S(O)2-, -NH-, or -CH2-;

[0052] m is 1, 2, 3, or 4.

[0053] In some embodiments, the compounds of the present application are compounds having one of the following structures or stereoisomers, geometric isomers, tautomers, nitroso forms, hydrates, solvates, deuterated forms, metabolites, pharmaceutically acceptable salts, or prodrugs of the compounds having one of the following structures:

[0054] In one aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I) as described herein, or a stereoisomer, geometric isomer, tautomer, nitroso, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

[0055] In one aspect, the present application relates to the use of the above-mentioned compound for the preparation of a xanthine oxidase inhibitor-related medicament. The xanthine oxidase inhibitor-related medicament is used for the treatment and / or prevention of hyperuricemia, and diseases caused by hyperuricemia, such as gout, arthritis, or heart failure.

[0056] The foregoing merely illustrates some aspects and embodiments of the present application and does not limit the present application thereto. These and other aspects and embodiments will become more fully understood from the following detailed description.

[0057] The compounds of the present application have excellent inhibitory effects on xanthine oxidase activity as XO inhibitors, and have very low clearance rate and long half-life in vivo, and have little toxic side effects on the liver.

[0058] Definitions and General Terminology

[0059] The present application will be described in greater detail by making specific written detailed descriptions of the contents of the present application, and the examples are accompanied by structural formulas and chemical formulas. The present application is intended to cover all alternatives, modifications, and equivalents that can be included within the scope of the present application as defined by the claims. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The present application is not intended to be limited to the embodiments described. Many documents and similar materials are distinguished from, or contrary to, the present application, including but not limited to the definitions of terms, the use of terms, the described techniques, or the scope controlled by the present application.

[0060] The following definitions will apply throughout this application unless otherwise indicated. For purposes of this application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., 1994. Additionally, general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5thEd., Ed.: Smith, Michael B., and Jerry March, John Wiley & Sons, New York: 2007, the disclosures of which are incorporated herein by reference.

[0061] The term "comprising" is used in the inclusive sense, i.e., to mean including, but not limited to.

[0062] Compounds as described herein can optionally be substituted with one or more substituents, such as described herein for the compounds of the application, or as exemplified in the Examples, subgroups, and classes of compounds encompassed by the application. It will be appreciated that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally" means that any given structure can be substituted or unsubstituted. Unless otherwise indicated, an optionally substituted group can have a substitution at each substitutable position of the group. When a given structure is substituted with more than one non-hydrogen substituent it will be appreciated that the substituents can be the same or different.wherein the substituents can be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=0), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C(=0)0-alkyl, -alkylene-S(=0)2-alkyl, -alkylene-S(=0)2-amino, -S(=0)2-alkyl, -S(=0)2-amino, -S(=0)2OH, -0-alkylene-C(=0)0-alkyl, -0-alkylene-S(=0)2-alkyl, -0-alkylene-S(=0)2-amino, -0-alkylene-S(=0)2OH, -C(=0)NH2, -C(=0)NH-alkyl, -C(=0)N(alkyl)-alkyl, -C(=0)NHS(=0)2-alkyl, -C(=0)NHS(=0)2-amino, -C(=0)NHS(=0)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=0)2-alkyl, -NHS(=0)2-alkyl, -NHS(=0)2-haloalkyl, -N(alkyl)S(=0)2-haloalkyl, -N(alkyl)S(=0)2-alkylamino, -NHC(=0)-alkyl, -NHC(=0)-haloalkyl, -N(alkyl)C(=0)-haloalkyl, -N(alkyl)C(=0)-alkylamino, -N(alkyl)C(=0)0-alkyl, -NHC(=0)0-alkyl, -NHC(=0)0-haloalkyl, -N(alkyl)C(=0)0-haloalkyl, -N(alkyl)C(=0)0-aminoalkyl, -NHC(=0)-NH2, -NHC(=0)NH-(alkyl), -NHC(=0)NH(haloalkyl), -NHC(=0)N(alkyl)-alkyl, -OC(=0)-alkyl, -OC(=0)-amino, -OC(=0)-alkylamino, -OC(=0)-aminoalkyl, -OC(=0)-alkoxy, -C(=0)N(alkyl)S(=0)2-alkyl, -C(=0)N(alkyl)S(=0)2-amino, -C(=0)NH-S(=0)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=0)NH-alkylene-S(=0)2OH, -C(=0)NHC(=0)OH, -C(=0)NHC(=0)0-alkyl, -C(=0)N(alkyl)C(=0)0-alkyl, -C(=0)NH-alkylene-C(=0)OH, and -C(=0)NH-alkylene-C(=0)0-alkyl, and the like.

[0063] The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon radicals of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 to 2 carbon atoms, wherein the alkyl group can be independently optionally substituted with one or more substituents as described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, and n-octyl, and the like. The term "alkyl" and its prefix "alk" as used herein includes both straight chain and branched saturated carbon chains.

[0064] The term "alkenyl" denotes a straight chain or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is sp 2"anti", "syn" or "E", "Z" orientation, wherein examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0065] The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is a sp-triple bond, wherein the alkynyl group can be independently and optionally substituted with one or more substituents described herein, wherein examples of alkynyl groups include, but are not limited to, ethynyl (-CºCH), propargyl (-CH2CºCH), and the like.

[0066] The term "heteroatom" denotes one or more O, S, N, P, Si, and Se, including any oxidation state of C, N, S, and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or forms in which the hydrogen on a nitrogen atom in a heterocycle is replaced by substitution, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl); or forms in which a -CH2- in a heterocycle is oxidized to form -C(=O)-.

[0067] The term "halogen" means F, Cl, Br, or I.

[0068] The term "deuterium" means heavy hydrogen, D.

[0069] The term "unsaturated" as used herein denotes a moiety containing one or more degrees of unsaturation.

[0070] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen atom. In some embodiments, the alkoxy group is a C 1-4 alkoxy group; examples include, but are not limited to, methoxy, ethoxy, propyloxy, and butyloxy, and the like. Also, the alkoxy group can be independently unsubstituted or substituted with one or more substituents described herein.

[0071] The term "alkylthio" or "alkylsulfanyl" as used herein refers to an alkyl group, as defined herein, attached to the remainder of the molecule through a sulfur atom. In some embodiments, the alkylthio group is a C 1-4 alkylthio group; examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio, and the like. Also, the alkylthio group can be independently unsubstituted or substituted with one or more substituents described herein.

[0072] The term "alkylamino" or "alkylamino group" as used herein refers to an alkyl group, as defined herein, attached through a N atom to the remainder of the molecule. In some embodiments, the alkylamino group is a C 1-4 alkylamino; examples of which include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, and the like. Also, the alkylamino groups can be independently unsubstituted or substituted with one or more substituents described herein.

[0073] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or multivalent monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3 to 12 carbon atoms, which is either a saturated ring or a ring containing one or more unsaturated linkages, but never an aromatic ring. In one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl, and the like. The cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.

[0074] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, which never contains an aromatic ring, wherein at least one ring atom is a heteroatom. In one embodiment, the "heterocyclyl" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, the "heterocyclyl" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, the "heterocyclyl" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, the "heterocyclyl" or "heterocycle" contains 3 to 6 ring atoms; in yet another embodiment, the "heterocyclyl" or "heterocycle" contains 3 to 5 ring atoms; in yet another embodiment, the "heterocyclyl" or "heterocycle" contains 5 to 6 ring atoms; in yet another embodiment, the "heterocyclyl" or "heterocycle" contains 4 to 6 ring atoms; the heterocyclyl can be carbon-based or nitrogen-based, the heteroatoms having the meaning as described herein, unless otherwise indicated. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, aziridinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxoanyl, homopiperazinyl, homopiperidinyl, oxazepinyl, thiazepinyl, oxazinanyl, thiazinanyl, diazepinyl, oxazolidinonyl, dioxolanyonyl, and the like. The heterocyclyl groups can be independently unsubstituted or substituted with one or more substituents described herein. oxazepinyl, thiazepinyl, oxazinanyl, thiazinanyl, diazepinyl, oxazolidinonyl, dioxolanyonyl, and the like. The heterocyclyl groups can be independently unsubstituted or substituted with one or more substituents described herein. oxazepinyl, thiazepinyl, oxazinanyl, thiazinanyl, diazepinyl, oxazolidinonyl, dioxolanyonyl, and the like. The heterocyclyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples of -CH2- groups in a heterocyclyl group that are replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-l,3-thiazolidinyl, 2-piperidonyl, 3,5- dioxopiperidinyl, pyrimidinedionyl, and 5,6-dihydropyridin-2(lH)-onyl. Examples of sulfur atoms in a heterocyclyl group that are oxidized include, but are not limited to, a sulfolanyl group and a l,l-dioxothiomorpholinyl group. The heterocyclyl groups described can be optionally substituted with one or more substituents described herein.

[0075] The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring contains 3-7 atoms in a ring, and has one or more attachment points to the remainder of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring." Examples of aryl groups can include phenyl, naphthyl, and anthryl. The aryl groups described can be independently optionally substituted with one or more substituents described herein.

[0076] The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 atoms in a ring, and has one or more attachment points to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound." The heteroaryl groups described are optionally substituted with one or more substituents described herein. In one embodiment, a 5-10 atom containing heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.

[0077] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (such as 5-tetrazolyl), triazolyl, thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; also included are bicyclic rings such as, but not limited to, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolanyl, indolinyl, isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo[l,2-a]pyridinyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5-a]pyrimidinyl, imidazo[l,2-b]pyridazinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, and [l,2,4]triazolo[l,5-a]pyridinyl, and the like.

[0078] The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0079] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

[0080] The term "aminoalkyl" means an alkyl group substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, aminoethyl, and the like.

[0081] Also, it is to be understood that the description and examples in this document employ use of the phrases "each of... and... is independently," "each of... and... is respectively independently," and "each of... and... is individually independently" interchangeably and broadly, and can mean that the specific options expressed by the same symbols between different groups do not affect each other, or that the specific options expressed by the same symbols between the same groups do not affect each other.

[0082] Unless otherwise stated, the structural formulae depicted and the compounds described herein encompass all tautomeric forms (e.g., enantiomeric, diastereomeric, geometric isomers or conformers) thereof: for example, the R, S configuration of asymmetric centers, the (Z), (E) isomers of double bonds, and the (Z), (E) conformers. Accordingly, individual stereochemically isomeric or enantiomeric, diastereomeric, geometric or conformer mixtures of the compounds of the present application are within the scope of the present application.

[0083] Unless otherwise stated, the structural formulae depicted and the compounds described herein encompass all tautomeric forms (e.g., enantiomeric, diastereomeric, geometric isomers or conformers), nitroso, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof. Accordingly, individual stereochemically isomeric, enantiomeric, diastereomeric, geometric or conformer mixtures, nitroso, hydrates, solvates, deuterated, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present application are within the scope of the present application. In addition, unless otherwise stated, the structural formulae depicted and the compounds described herein encompass one or more isotopically enriched atoms.

[0084] "Metabolite" refers to a product produced through metabolism of a specified compound of the present application or a pharmaceutically acceptable salt, analog or derivative thereof in the body of a mammal, which exhibits the same or substantially the same activity as the compound of formula (I) in vivo or in vitro. Metabolites of a compound can be identified using techniques well known in the art and their activity can be determined using assays described herein or otherwise. Such products can be oxidized, reduced, hydrolyzed, amidated, deamidated, esterified, deesterified, or enzymatically cleaved, for example. Accordingly, the present application includes metabolites of compounds of the present application, including those produced by the action of mammalian enzyme(s) on the compounds of the present application.

[0085] The definitions and conventions used in the present invention for stereochemistry are generally in accord with those found in S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomers. All stereoisomers of the compounds of the present invention, including but not limited to, diastereomeric, enantiomeric, atropisomeric, and their mixtures, such as racemates, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D, L or R, S are used to denote the absolute configuration of the molecule. The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, (-) or 1 meaning that the compound is levorotatory, and the prefix (+) or d meaning that the compound is dextrorotatory. The chemical structures of these stereoisomers are identical but their orientations in the solid or solution are mirror images of each other. A specific stereoisomer can be referred to as an enantiomer if its mirror image is not superimposable. A mixture of enantiomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can result from racemic synthesis or from resolution of an enantiomeric mixture. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric forms lacking optical activity.

[0086] The term "tautomer" or "tautomeric forms" refers to isomers of different energy which interconvert by a low energy barrier. For example, prototropic tautomers (i.e., prototropically shifting tautomers) include tautomeric isomerization by proton migration, such as keto-enol and imine-enamine isomerization. Atomic valence (bonding) tautomers include isomerization by reorganization of bonding electrons.

[0087] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the application. Pharmaceutically acceptable salts are well known in the art, e.g., S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, salts of inorganic acids such as hydrochloride, hydrobromic, phosphoric, sulfuric, perchloric acid; salts of organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, malonic, salicylic acid; or by other methods well within the purview of this art such as ion exchange. Other pharmaceutically acceptable salts include adipate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 alkyl)4 salts. The present application also contemplates the quaternization of any basic nitrogen-containing groups of the compounds of the application by such methods as those described herein. Water or oil-soluble or dispersable products can be obtained by quaternization. Salts of the bases which are included in the salts of the application include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include, where appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by the inclusion of an appropriate counterion, such as halogen, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate, and aromatic sulfonate.

[0088] As used herein, "hydrates" refer to the association of solvent molecules, water, with the compounds of the application.

[0089] As used herein, "solvates" refer to the association of one or more solvent molecules with the compounds of the application. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

[0090] The "deuterated compounds" of the present application refer to compounds of the present application wherein one or more hydrogens are replaced by deuterium to improve the metabolic cycle of the drug, to reduce the production of toxic metabolites or the interaction between drugs, thus reducing the dose of administration, increasing safety and obtaining better efficacy, among others.

[0091] The "esters" of the present application refer to in vivo hydrolysable esters of the compounds of formula (I) containing a hydroxy group. Such esters are, for example, pharmaceutically acceptable esters of the parent alcohol produced by hydrolysis in the human or animal body. Groups of the in vivo hydrolysable esters of the compounds of formula (I) containing a hydroxy group include, but are not limited to, phosphonate, acetyloxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups, among others.

[0092] The "nitroxides" of the present application refer to the oxidation of one or more than one nitrogen atom to form N-oxides when the compound contains several amine functions. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen heterocycle ring nitrogen atoms. N-oxides can be formed by treatment of the corresponding amines with oxidizing agents such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) (see Advanced Organic Chemistry, Wiley Interscience, 4thedition, Jerry March, pages 350-351). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), for example by reacting the amine compound with meta-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0093] The term "prodrugs" as used herein denotes a compound which is converted into a compound of formula (I) in vivo. Such conversion is achieved by the hydrolysis of the prodrug in the blood or by enzymatic conversion in the blood or in the tissues to the parent structure. The prodrug class of compounds of the present application can be esters, among which the following can be mentioned as prodrugs: phenyl esters, aliphatic (C 1-24esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present application containing a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphates, such as those compounds which are phosphorylated on a hydroxyl group of the parent. A complete discussion of prodrugs is found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0094] As used herein, the terms "a," "an," "the," and like terms used in the context of the present application, particularly in the claims, are to be construed to cover both the singular and the plural, unless otherwise indicated by the context.

[0095] General Synthetic Procedures

[0096] To describe the present application, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not meant to limit the present application in any manner.

[0097] Generally, the compounds of the present application can be prepared by the methods illustrated herein, unless otherwise indicated by the context of the description, wherein the definitions of substituents are as described herein. The following reaction schemes and examples are intended to further illustrate the present application.

[0098] Those skilled in the art will recognize that the chemical reactions described in this invention can be suitably used to prepare other compounds of this invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention. For example, the synthesis of those non-illustrative compounds according to this invention can be successfully accomplished by those skilled in the art through modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents besides those described in this invention, or by making some conventional modifications to the reaction conditions. Furthermore, the reactions disclosed in this invention or the known reaction conditions are also generally accepted to be applicable to the preparation of other compounds of this invention.

[0099] Unless otherwise specified, the raw materials and reagents used in the following examples are all derived from commercially available or known synthetic routes.

[0100] The equipment and detection conditions are described below: ¹H NMR spectra were recorded using a Bruker 500MHz NMR spectrometer. ¹H NMR spectra were recorded using CDCl₃, DMSO-d₆, CD₃OD, or acetone-d₆ as solvents (in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant J is expressed in Hertz (Hz).

[0101] The determination conditions for low-resolution mass spectrometry (MS) data were as follows: Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate: 1 mL / min; mobile phase: 0%-95% (CH3CN) in a ratio of H2O containing 0.1% formic acid:CH3CN = 90:10), electrospray ionization (ESI) at 210 nm / 254 nm, and detection by DAD.

[0102] The following abbreviations are used throughout the application: mg milligram mmol millimole mL milliliter g gram μM micromole per liter h hour

[0103] Compounds are named according to the principles of nomenclature in the art or using software, and commercially available compounds are named using the supplier's catalog name. DETAILED DESCRIPTION

[0104] The application is described below with reference to specific examples, which are intended to be illustrative only and not limiting of the application in any way.

[0105] Example 1: Synthesis of 2-(6-cyano-4-methyl-3,4-dihydro-lH- [l,4]oxazino[4,3-a]indol-8-yl)thiazole-4-carboxylic acid (Compound 1)

[0106] Step 1: Synthesis of 2-amino-5-bromo-3-iodobenzonitrile

[0107] 2-amino-5-bromobenzonitrile (7 g, 35.53 mmol), iodine (17 g, 38.32 mmol), silver sulfate (12 g, 38.49 mmol) were dissolved in methanol (150 mL) and stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 10 g.

[0108] LC-MS (ESI): [M+H] + = 323.0.

[0109] Step 2: Synthesis of 2-amino-5-bromo-3-(3-(2-hydroxypropoxy)prop-l-yn-l- yl)benzonitrile

[0110] 2-amino-5-bromo-3-iodobenzonitrile (10 g, 30.97 mmol), 1-(prop-2-yn-1-yloxy)propan-2-ol (4 g, 35.04 mmol), cuprous iodide (1.5 g, 7.88 mmol), bis(triphenylphosphine)palladium dichloride (2 g, 2.85 mmol), triethylamine (21.5 mL, 154.83 mmol) were dissolved in acetonitrile (200 mL), replaced with nitrogen for three times, stirred at 50 °C for 12 hours. After natural cooling to room temperature, water (300 mL) was added to the reaction solution, then extracted with ethyl acetate (500 mL), the separated organic phase was washed twice with saturated sodium chloride solution (100 mL x 2), then the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 6 g.

[0111] LC-MS (ESI): [M+H] + = 309.0.

[0112] Step 3: Synthesis of 5-bromo-2-(((2-hydroxypropoxy)methyl)-1H-indazole-7- carbonitrile

[0113] 2-amino-5-bromo-3-(3-(2-hydroxypropoxy)prop-1-yn-1-yl)benzonitrile (5.5 g, 17.79 mmol) was dissolved in N,N-dimethylformamide (200 mL), cuprous iodide (4.5 g, 23.63 mmol) was added, replaced with nitrogen for three times, stirred at 100 °C for 12 hours. After natural cooling to room temperature, water (200 mL) was added to the reaction solution, then extracted with ethyl acetate (300 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column, concentrated to obtain the product 1.5 g.

[0114] LC-MS (ESI): [M+H] + = 309.9.

[0115] Step 4: Synthesis of 1-((5-bromo-7-cyano-1H-indol-2-yl)methoxy)propan-2-yl methanesulfonate

[0116] 5-bromo-2-(((2-hydroxypropoxy)methyl)-1H-indazole-7-carbonitrile (1.4 g, 4.53 mmol), methanesulfonic anhydride (946 mg, 5.43 mmol) were dissolved in dichloromethane (15 mL), triethylamine (916 mg, 9.06 mmol) was added, stirred at 20 °C for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction solution, then extracted with ethyl acetate (100 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column, concentrated to obtain the product 2 g.

[0117] LC-MS (ESI): [M+Na] = 411.0. +

[0118] Step 5: Synthesis of 8-bromo-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-6- carbonitrile

[0119] 1-((5-bromo-7-cyano-1H-indol-2-yl)methoxy)propan-2-yl methanesulfonate (2 g, 5.16 mmol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (1427 mg, 10.33 mmol) was added, and stirring was performed at 80°C for 2 hours. Water (100 mL) was added to the reaction solution, which was then extracted with ethyl acetate (100 mL). The separated organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column chromatography and concentrated to obtain 800 mg of the product.

[0120] LC-MS (ESI): [M+H] = 291.0. +

[0121] Step 6: Synthesis of 4-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydro-1H-[1,4]oxazino[4,3-a]indole-6-carbonitrile

[0122] 8-bromo-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-6-carbonitrile (500 mg, 1.72 mmol), pinacol diboronic acid (500 mg, 1.97 mmol), potassium acetate (400 mg, 4.08 mmol), and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (120 mg, 0.16 mmol) were dissolved in dioxane (15 mL), and nitrogen was replaced three times. After stirring at 100°C for 2 hours, the reaction solution was naturally cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column chromatography and concentrated to obtain 500 mg of the product.

[0123] LC-MS (ESI): [M+H] = 339.2. +

[0124] Step 7: Synthesis of methyl 2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-8- yl)thiazole-4-carboxylate

[0125] ​​​Methyl 2-(6-cyano-4-methyl-3,4-dihydro-lH-[l,4]oxazino[4,3-a]indol-8-yl)thiazole-4- carboxylate (150 mg, 0.42 mmol) was dissolved in acetonitrile (3 mL), saturated lithium bromide aqueous solution (3 mL), triethylamine (3 mL) was added, and stirred at 50 °C for 12 hours. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (50 mL) was added, and then extracted with ethyl acetate (50 mL), the organic phase was washed twice with saturated sodium chloride (25 mL x 2), then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain the product 60 mg.

[0126] LC-MS (ESI): [M+H] = 340.1. + = 354.1.

[0127] Step 8: Synthesis of 2-(6-cyano-4-methyl-3,4-dihydro-lH-[l,4]oxazino[4,3-a]indol-8-yl)thiazole- 4-carboxylic acid

[0128] Methyl 2-(6-cyano-4-methyl-3,4-dihydro-lH-[l,4]oxazino[4,3-a]indol-8-yl)thiazole-4- carboxylate (150 mg, 0.42 mmol) was dissolved in acetonitrile (3 mL), saturated lithium bromide aqueous solution (3 mL), triethylamine (3 mL) was added, and stirred at 50 °C for 12 hours. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (50 mL) was added, and then extracted with ethyl acetate (50 mL), the organic phase was washed twice with saturated sodium chloride (25 mL x 2), then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain the product 60 mg.

[0129] LC-MS (ESI): [M+H] = 340.1. + = 354.1.

[0130] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 6.58 (s, 1H), 5.30-4.81 (m, 3H), 4.19-3.98 (m, 2H), 1.50 (d, J = 6.4 Hz, 3H).

[0131] Example 2: 2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-8-yl)-4- methylthiazole-5-carboxylic acid (Compound 2)

[0132] Step 1: Synthesis of 2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-8- yl)-5-methylthiazole-4-carboxylic acid ethyl ester

[0133] 4-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H- [1,4]oxazino[4,3-a]indole-6-carbonitrile (300 mg, 0.89 mmol), 2-bromo-4-methylthiazole- 5-carboxylic acid ethyl ester (266 mg, 1.06 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium chloride (65 mg, 0.09 mmol), potassium carbonate (245 mg, 1.77 mmol) were dissolved in dioxane (10 mL) and water (1 mL), replaced with nitrogen for three times, stirred at 100 °C for 12 hours. After natural cooling to room temperature, the reaction solution was added to water (50 mL), then extracted with ethyl acetate (50 mL), the organic phase was washed twice with saturated sodium chloride (25 mL x 2), then the separated organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column, concentrated to obtain the product 250 mg.

[0134] LC-MS (ESI): [M+H] + = 382.2.

[0135] Step 2: Synthesis of 2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-8- yl)-4-methylthiazole-5-carboxylic acid

[0136] 2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-8-yl)-5-methylthiazole- 4-carboxylic acid ethyl ester (250 mg, 0.66 mmol) was dissolved in acetonitrile (5 mL), saturated lithium bromide aqueous solution (5 mL) and triethylamine (5 mL) were added, stirred at 50 °C for 12 hours. After natural cooling to room temperature, the reaction solution was transferred to a 250 mL round-bottom flask with water (10 mL), after removing acetonitrile under reduced pressure, saturated sodium bicarbonate (30 mL) and ethyl acetate (50 mL) were added, the separated aqueous phase was adjusted to pH = 3 or so with 1 mol hydrochloric acid, extracted with ethyl acetate (50 mL), the separated organic phase was washed twice with saturated sodium chloride (25 mL x 2), then dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the product 130 mg.

[0137] LC-MS (ESI): [M+H] @ 354.1. + = 354.1.

[0138] 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 6.64 - 6.38 (m, 1H), 5.19 - 4.82 (m, 3H), 4.15 - 4.02 (m, 2H), 2.67 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H).

[0139] Example 3: Synthesis of (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid (Compound 3)

[0140] Step 1: Synthesis of (R)-7-(trimethylsilyl)hept-6-yn-2-ol

[0141] Magnesium chips (20 g, 823.05 mmol), lithium chloride (34 g, 802.08 mmol) were dissolved in tetrahydrofuran (500 mL), and nitrogen was replaced for 3 times, (4-bromo-l-alkyn-l-yl)trimethylsilane (150 g, 731.10 mmol) was slowly added at 0 °C with constant pressure dropping funnel. After the addition was completed (the temperature was controlled not more than 5 °C during the addition), the reaction was initiated by heat, and stirred at 0 °C until the temperature rose to room temperature, and then continued to stir for 2 hours, and stand for one hour. The prepared Grignard reagent was drawn into a constant pressure dropping funnel with double row needle, and slowly added to tetrahydrofuran (500 mL) containing cuprous iodide (14 g, 73.51 mmol) and (R)-2-methyloxirane (47 g, 809.23 mmol) at 0 °C, and stirred at 0 °C for 12 hours. The reaction solution was poured into a mixture of saturated ammonium chloride (1000 mL) and ethyl acetate (1000 mL) to extract, and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column, and concentrated under reduced pressure to obtain the product 90 g.

[0142] 1H NMR (400 MHz, DMSO-d6) δ = 4.29 (d, J = 4.8 Hz, 1H), 3.54 - 3.41 (m, 1H), 2.13 - 2.04 (m, 2H), 1.46 - 1.21 (m, 4H), 0.92 (d, J = 6.4 Hz, 3H), 0.02 - 0.03 (m, 9H).

[0143] Step 2: Synthesis of (R)-2-amino-5-bromo-3-(6-hydroxyhept-l-yn-l- yl)benzonitrile

[0144] (R)-7-(trimethylsilyl)hept-6-yn-2-ol (45 g, 244.10 mmol), 2-amino-5-bromo-3- iodobenzonitrile (55 g, 170.32 mmol), cuprous iodide (5 g, 26.25 mmol), bis(triphenylphosphine)palladium dichloride (13 g, 16.71 mmol) and cesium fluoride (39 g, 256.75 mmol) were dissolved in acetonitrile (550 mL), triethylamine (150 mL, 1079.16 mmol) was added, replaced with nitrogen for three times, stirred at 50 °C for 12 hours. Cooled to room temperature, the reaction was filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, purified by normal phase silica gel column, concentrated under reduced pressure to obtain the product 35 g.

[0145] LC-MS (ESI): [M+H] + = 307.1.

[0146] Step 3: Synthesis of (R)-5-bromo-2-(4-hydroxypentyl)-lH-indole-7-carbonitrile

[0147] (R)-2-amino-5-bromo-3-(6-hydroxyhept-l-yn-l-yl)benzonitrile (35 g, 113.94 mmol) was dissolved in N,N-dimethylformamide (1 L), cuprous iodide (44 g, 231.03 mmol) was added, replaced with nitrogen for three times, stirred at 100 °C for 12 hours. The crude product was monitored by nuclear magnetic resonance, the raw material reaction was completed, cooled to room temperature, the reaction was filtered, the filtrate was extracted with water (1000 mL) and ethyl acetate (1000 mL), the organic phase was washed with saturated calcium chloride and sodium chloride, then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 25 g.

[0148] LC-MS (ESI): [M+H] + = 307.1;

[0149] 1H NMR (400 MHz, DMSO-d6) δ = 12.01 (s, 1H), 7.99-7.94 (m, 2H), 7.67 (d, J = 1.6 Hz, 1H), 6.33 (s, 1H), 4.40 (d, J = 4.4 Hz, 1H), 3.62 (d, J = 11.2 Hz, 1H), 1.84-1.59 (m, 2H), 1.45-1.29 (m, 2H), 1.05 (d, J = 6.0 Hz, 3H).

[0150] Step 4: Synthesis of (S)-2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indole-4-carbonitrile

[0151] (R)-5-bromo-2-(4-hydroxypentyl)-lH-indole-7-carbonitrile (25 g, 81.38 mmol) was dissolved in toluene (750 mL), cyanomethylidene tributylphosphonium bromide (70 g, 289.16 mmol) was added, and the reaction was stirred at 80 °C for 12 h after being replaced with nitrogen three times. The reaction was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain 18 g of the product.

[0152] LC-MS (ESI): [M+H] + = 289.0.

[0153] Step 5: Synthesis of (S)-6-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile

[0154] (S)-2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (18 g, 62.24 mmol), bis(pinacolato)diboron (21 g, 82.70 mmol), 1,1'-bis(diphenylphosphino) ferrocene palladium chloride (5 g, 6.83 mmol), and potassium acetate (16 g, 163.03 mmol) were dissolved in dioxane (500 mL), replaced with nitrogen three times, and stirred at 100 °C for 12 h. After cooling to room temperature, the reaction was extracted with water (500 mL) and ethyl acetate (500 mL), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain 19 g of the product.

[0155] LC-MS (ESI): [M+H] + = 337.1.

[0156] Step 6: Synthesis of (S)-methyl 2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylate

[0157] (S)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydropyrido[1,2- a]indole-4-carbonitrile (19 g, 56.51 mmol), methyl 2-bromothiazole-5-carboxylate (29 g, 130.60 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (4 g, 5.47 mmol) and potassium carbonate (22 g, 159.19 mmol) were dissolved in dioxane (500 mL) and water (50 mL), replaced with nitrogen for three times, stirred at 120 °C for 12 hours. Cooled to room temperature, the reaction solution was added to water (500 mL) and ethyl acetate (500 mL) to extract, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 13 g.

[0158] LC-MS (ESI): [M+H] + = 352.1.

[0159] Step 7: Synthesis of (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazole-5- carboxylic acid

[0160] Methyl (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazole-5-carboxylate (13 g, 36.99 mmol) was dissolved in tetrahydrofuran (140 mL), and a solution of lithium hydroxide monohydrate (2 g, 48.09 mmol) in water (30 mL) was added, and stirred at 20 °C for 12 hours. The reaction solution was added to water (200 mL) and ethyl acetate (200 mL) to extract, and the aqueous phase was adjusted to pH = 3 with 1 mol hydrochloric acid, and the solid was precipitated and filtered, and the filter cake was slurried with ethyl acetate; then filtered, and finally the filter cake was concentrated under reduced pressure to obtain the product 10.2 g.

[0161] LC-MS (ESI): [M+H] + = 338.0;

[0162] 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 6.50 (s, 1H), 5.25-5.14 (m, 1H), 3.13-3.06 (m, 1H), 2.94-2.81 (m, 1H), 2.23-2.11 (m, 1H), 2.04-1.81 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H).

[0163] Example 4: Synthesis of (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)-4-methylthiazole-5-carboxylic acid (Compound 4)

[0164] Step 1: Synthesis of ethyl (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)-4-methylthiazole-5-carboxylate

[0165] (S)-6-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7,8,9- tetrahydropyrido[l,2-a]indole-4-carbonitrile (250 mg, 0.74 mmol), ethyl 2-bromo-4- methylthiazole-5-carboxylate (204 mg, 0.82 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium chloride (54 mg, 0.07 mmol) and potassium carbonate (205 mg, 1.49 mmol) were dissolved in dioxane (10 mL) and water (1 mL), replaced with nitrogen for three times, then stirred at 100 °C for 12 hours. After natural cooling to room temperature, the reaction solution was added to water (50 mL) and ethyl acetate (50 mL x 2) for extraction, the organic phase was washed twice with saturated sodium chloride (50 mL x 2), then the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column, concentrated under reduced pressure to obtain the product 220 mg.

[0166] LC-MS (ESI): [M+H] + = 380.2.

[0167] Step 2: Synthesis of (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)-4-methylthiazole-5-carboxylic acid

[0168] Ethyl (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)-4- methylthiazole-5-carboxylate (220 mg, 0.58 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL), lithium bromide (503 mg, 5.80 mmol) and triethylamine (587 mg, 5.80 mmol) were added, and stirred at 60 °C overnight. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1M hydrochloric acid, added to water (20 mL) and ethyl acetate (20 mL x 2) for extraction, the organic phase was washed twice with saturated sodium chloride (25 mL x 2), then the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reversed phase C 18 column, and freeze-dried to obtain Compound 4 (80 mg).

[0169] LC-MS (ESI): [M+H] + = 352.1;

[0170] 1 H NMR (400 MHz, DMSO-d6) d = 8.32 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 6.48 (s, 1H), 5.18 (br t, J = 5.2 Hz, 1H), 3.09 (br d, J = 17.2 Hz, 1H), 2.94 - 2.83 (m, 1H), 2.62 (s, 3H), 2.15 (br d, J = 13.8 Hz, 1H), 2.04 - 1.92 (m, 2H), 1.86 (br s, 1H), 1.41 (d, J = 6.4 Hz, 3H).

[0171] Example 5: (S)-2-(5-cyano-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)thiazole-5- carboxylic acid and (R)-2-(5-cyano-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)thiazole-5- carboxylic acid (Compound 5A and Compound 5B)

[0172] Step 1: Synthesis of pent-4-ynal

[0173] Dimethyl sulfoxide (92.9 g, 1188 mmol) was dissolved in dichloromethane (300 mL), triethylamine (99.1 mL, 713.27 mmol) was added, pent-4-yn-1-ol (10 g, 118.9 mmol), sulfur trioxide pyridine (75.7 g, 475.5 mmol) was added at 0 °C, after stirring for 30 minutes, it was naturally raised to room temperature and continued to stir for 30 minutes. The reaction solution was added to saturated copper sulfate, the organic phase was separated and washed with saturated ammonium chloride, concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 5.0 g.

[0174] Step 2: Synthesis of hex-5-yn-2-ol

[0175] Pent-4-ynal (4.0 g, 48.72 mmol) was dissolved in tetrahydrofuran (40 mL), methyl magnesium bromide solution (25 mL) was added at 0 °C, after stirring for 1 hour, it was naturally raised to room temperature and continued to stir for 1 hour. The reaction solution was slowly added to saturated ammonium chloride solution for quenching, water and ethyl acetate were added for extraction, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 2.0 g.

[0176] Step 3: Synthesis of 2-amino-5-bromo-3-(5-hydroxyhex-1-yn-1-yl)benzonitrile

[0177] 2-amino-5-bromo-3-iodobenzonitrile (4.0 g, 12.39 mmol), hex-5-yn-2-ol (1.82 g, 18.58 mmol), cuprous iodide (350 mg, 1.84 mmol), bis(triphenylphosphine)palladium dichloride (0.30 g, 0.39 mmol) were dissolved in acetonitrile (10 mL), triethylamine (17.2 mL, 123.87 mmol) was added, and the mixture was stirred at 50 °C for 2 h under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to give the product 1.2 g.

[0178] Step 4: Synthesis of 5-bromo-2-(3-hydroxybutyl)-1H-indole-7-carbonitrile

[0179] 2-amino-5-bromo-3-(5-hydroxyhex-1-yn-1-yl)benzonitrile (1.0 g, 3.41 mmol) was dissolved in N,N-dimethylformamide (150 mL), and cuprous iodide (1.3 g, 6.83 mmol) was added. The mixture was stirred at 100 °C for 12 h under nitrogen. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added to the reaction mixture. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to give the product 800 mg.

[0180] LC-MS (ESI): [M+H] + = 293.0.

[0181] Step 5: Synthesis of 4-(5-bromo-7-cyano-1H-indol-2-yl)butan-2-yl methanesulfonate

[0182] 5-bromo-2-(3-hydroxybutyl)-1H-indole-7-carbonitrile (800 mg, 2.73 mmol) and triethylamine (0.8 mL, 5.46 mmol) were dissolved in dichloromethane (15 mL), and methanesulfonic anhydride (569.8 mg, 3.27 mmol) was added at room temperature. The mixture was stirred at 20 °C for 2 h. Water and ethyl acetate were added to the reaction mixture. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product 1.0 g.

[0183] Step 6: Synthesis of 7-bromo-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-5- carbonitrile

[0184] Dissolve 4-(5-bromo-7-cyano-lH-indol-2-yl)butan-2-yl methanesulfonate (1.0 g, 2.69 mmol) in N,N-dimethylformamide (10 mL), add potassium carbonate (372 mg, 2.69 mmol), stir at 80 °C for 2 hours, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated calcium chloride and saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, purify the crude product on a normal phase silica gel column, and concentrate under reduced pressure to obtain the product 600 mg.

[0185] Step 7: Synthesis of 3-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydro-lH-pyrrolo[l,2-a]indole-5-carbonitrile

[0186] Dissolve 7-bromo-3-methyl-2,3-dihydro-lH-pyrrolo[l,2-a]indole-5-carbonitrile (360 mg, 1.31 mmol), pinacol diboronic acid (420 mg, 1.65 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium chloride (100 mg, 0.14 mmol), potassium acetate (260 mg, 2.65 mmol) in dioxane (10 mL), replace with nitrogen three times, stir at 100 °C for 2 hours, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, purify the crude product on a normal phase silica gel column, and concentrate under reduced pressure to obtain the product 400 mg.

[0187] Step 8: Synthesis of methyl 2-(5-cyano-3-methyl-2,3-dihydro-lH-pyrrolo[l,2-a]indol-7- yl)thiazole-5-carboxylate

[0188] Dissolve 3-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro-lH- pyrrolo[l,2-a]indole-5-carbonitrile (240 mg, 0.74 mmol), methyl 2-bromothiazole-5- carboxylate (380 mg, 1.71 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (55 mg, 0.08 mmol), potassium carbonate (210 mg, 1.52 mmol) in dioxane (5 mL) and water (0.5 mL), replace with nitrogen three times, stir at 120 °C for 12 hours, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, purify the crude product on a normal phase silica gel column, and concentrate under reduced pressure to obtain the product 120 mg.

[0189] LC-MS (ESI): [M+H]+ = 338.0.

[0190] Step 9: Synthesis of 2-(5-cyano-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7- yl)thiazole-5-carboxylic acid

[0191] Methyl 2-(5-cyano-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)thiazole-5- carboxylate (100 mg, 0.30 mmol) was dissolved in acetonitrile (2 mL), saturated aqueous lithium bromide (2 mL), triethylamine (2 mL) was added, stirred at 50 °C for 12 h, cooled to room temperature naturally, the reaction solution was adjusted to pH = 3 with 1 mol / L hydrochloric acid, water and ethyl acetate were added for extraction, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by a reversed-phase C18 column and freeze-dried to obtain the product 80 mg.

[0192] LC-MS (ESI): [M+H] + = 324.0;

[0193] 1H NMR (400 MHz, DMSO-d6) d = 8.48 (d, J = 1.6 Hz, 1H), 8.36 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 6.48 (s, 1H), 5.06-4.94 (m, 1H), 3.16 (d, J = 8.4 Hz, 1H), 3.02 (d, J = 8.8 Hz, 1H), 2.86-2.74 (m, 1H), 2.35-2.25 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H).

[0194] Step 10: Synthesis of (S)-2-(5-cyano-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7- yl)thiazole-5-carboxylic acid, (R)-2-(5-cyano-3-methyl-2,3-dihydro-1H-pyrrolo[1,2- a]indol-7-yl)thiazole-5-carboxylic acid (Compound 5A or Compound 5B)

[0195] Racemic 2-(5-cyano-3-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)thiazole-5- carboxylic acid (80 mg, 0.25 mmol) was resolved by SFC to obtain Compound 5A 20 mg and Compound 5B 30 mg, respectively.

[0196] Compound 5A: LC-MS (ESI): [M+H] + = 324.1;

[0197] 1H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 6.48 (s, 1H), 5.06 - 4.94 (m, 1H), 3.16 (d, J = 8.4 Hz, 1H), 3.02 (d, J = 8.8 Hz, 1H), 2.86 - 2.72 (m, 1H), 2.33 - 2.25 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H).

[0198] Compound 5B: LC-MS (ESI): [M+H] + = 324.1;

[0199] 1 H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 6.48 (s, 1H), 5.06 - 4.94 (m, 1H), 3.16 (d, J = 8.4 Hz, 1H), 3.02 (d, J = 8.8 Hz, 1H), 2.86 - 2.72 (m, 1H), 2.33 - 2.25 (m, 1H), 1.45 (d, J = 6.4 Hz, 3H).

[0200] Example 6: (S)-2-(5-cyano-3-methyl-2,3-dihydro-lH-pyrrolo[l,2-a]indol-7-yl)-4- methylthiazole-5-carboxylic acid and (R)-2-(5-cyano-3-methyl-2,3-dihydro-lH- pyrrolo[l,2-a]indol-7-yl)-4-methylthiazole-5-carboxylic acid (Compounds 6A and 6B)

[0201] Compounds 6A and 6B were synthesized by the method of Reference Example 5

[0202] SFC separation purification conditions: Column: Chiralpak AD-3 50x4.6mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 5% to 25%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar.

[0203] 4. 100 min eluting compound 6A: LC-MS (ESI): [M+H] + = 338.0;

[0204] 1 H NMR (400 MHz, DMSO-d6) δ = 8.32 (s, 1H), 7.98 (s, 1H), 6.44 (s, 1H), 4.97 (t, J = 6.4 Hz, 1H), 3.18 - 3.09 (m, 1H), 3.03 - 2.94 (m, 1H), 2.85 - 2.73 (m, 1H), 2.60 (s, 3H), 2.25 (dd, J = 7.2, 12.4 Hz, 1H), 1.44 (d, J = 6.4 Hz, 3H).

[0205] 4. 451 min eluting compound 6B: LC-MS (ESI): [M+H] + = 338.0;

[0206] 1 H NMR (400 MHz, DMSO-d6) δ = 8.30 (s, 1H), 7.96 (s, 1H), 6.40 (s, 1H), 4.97 (t, J = 6.4 Hz, 1H), 3.16 - 3.07 (m, 1H), 3.05 - 2.90 (m, 1H), 2.82 - 2.70 (m, 1H), 2.40 (s, 3H), 2.27 (dd, J = 7.2, 12.4 Hz, 1H), 1.42 (d, J = 6.4 Hz, 3H).

[0207] Example 7: (S)-2-(4-cyano-6-methyl-7,8,9,10-tetrahydro-6H-azepino[1,2- a]indol-2-yl)thiazole-5-carboxylic acid and (R)-2-(4-cyano-6-methyl-7,8,9,10- tetrahydro-6H-azepino[1,2-a]indol-2-yl)thiazole-5-carboxylic acid (Compounds 7A and 7B)

[0208] Step 1: Synthesis of hept-6-ynal

[0209] Dimethyl sulfoxide (200 mL, 2815.82 mmol) was dissolved in dichloromethane (400 mL), triethylamine (31 mL, 223.03 mmol) was added, hept-6-yn-1-ol (5.0 g, 44.58 mmol), sulfur trioxide pyridine (28.4 g, 118.88 mmol) was added at 0 °C, after stirring for 30 min, it was naturally raised to room temperature and continued to stir for 30 min. The reaction solution was added to saturated copper sulfate and stirred, the organic phase was separated, the organic phase was washed with saturated ammonium chloride, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 4.0 g.

[0210] Step 2: Synthesis of oct-7-yn-2-ol

[0211] Hept-6-ynal (10.0 g, 90.78 mmol) was dissolved in tetrahydrofuran (120 mL), methyl magnesium bromide solution (45 mL, 135.00 mmol) was added at 0 °C, and stirring was continued for 1 h, and then it was naturally raised to room temperature and continued to stir for 1 h. The reaction solution was slowly added to saturated ammonium chloride solution and quenched, water and ethyl acetate were added for extraction, the organic phase was washed with saturated sodium chloride and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 6.0 g.

[0212] Step 3: Synthesis of 2-amino-5-bromo-3-(7-hydroxyoct-1-yn-1-yl)benzonitrile

[0213] 2-Amino-5-bromo-3-iodobenzonitrile (8.8 g, 27.25 mmol), oct-7-yn-2-ol (5.5 g, 43.58 mmol), cuprous iodide (4 g, 12.6 mmol), bis-triphenylphosphine palladium dichloride (2 g, 2.57 mmol) were dissolved in acetonitrile (100 mL), triethylamine (40 mL, 287.78 mmol) was added, and nitrogen was replaced for 3 times, and stirred at 50 °C for 2 h, and then it was naturally cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 7.0 g.

[0214] Step 4: Synthesis of 5-bromo-2-(5-hydroxyhexyl)-1H-indole-7-carbonitrile

[0215] To a solution of 2-amino-5-bromo-3-(7-hydroxyoct-1-yn-1-yl)benzonitrile (8.5 g, 26.46 mmol) in N,N-dimethylformamide (150 mL) was added cuprous iodide (10 g, 52.51 mmol) and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel to obtain the product (7.0 g).

[0216] Step 5: Synthesis of 6-(5-bromo-7-cyano-1H-indol-2-yl)hexan-2-yl methanesulfonate

[0217] To a solution of 5-bromo-2-(5-hydroxyhexyl)-1H-indole-7-carbonitrile (8.0 g, 24.91 mmol) in dichloromethane (200 mL) was added methylsulfonic anhydride (5.2 g, 29.89 mmol), triethylamine (6.9 mL, 49.81 mmol) at room temperature and stirred at 20 °C for 2 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the product (9.0 g).

[0218] Step 6: Synthesis of 2-bromo-6-methyl-7,8,9,10-tetrahydro-6H-azepino[1,2- a]indole-4-carbonitrile

[0219] To a solution of 6-(5-bromo-7-cyano-1H-indol-2-yl)hexan-2-yl methanesulfonate (8000 mg, 20.04 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (2768.8 mg, 20.04 mmol) and stirred at 80 °C for 2 h. The reaction mixture was allowed to cool to room temperature and was diluted with water and ethyl acetate. The organic layer was washed with saturated calcium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel to obtain the product (8.0 g).

[0220] Step 7: Synthesis of 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10- tetrahydro-6H-azepino[1,2-a]indole-4-carbonitrile

[0221] Dissolve 2-bromo-6-methyl-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-4- carbonitrile (550 mg, 1.81 mmol), bis(pinacolato)diboron (590 mg, 2.32 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium chloride (130 mg, 0.18 mmol), potassium acetate (360 mg, 3.67 mmol) in dioxane (10 mL), replace with nitrogen for three times, stir at 100 °C for 2 hours, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to get the crude product, purify with normal phase silica gel column, concentrate under reduced pressure to get the product 600 mg.

[0222] LC-MS (ESI): [M+H] + = 351.0.

[0223] Step 8: Synthesis of methyl 2-(4-cyano-6-methyl-7,8,9,10-tetrahydro-6H- azepino[1,2-a]indol-2-yl)thiazole-5-carboxylate

[0224] Dissolve 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10- tetrahydro-6H-azepino[1,2-a]indole-4-carbonitrile (300 mg, 0.86 mmol), methyl 2- bromothiazole-5-carboxylate (420 mg, 1.89 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium chloride (65 mg, 0.09 mmol), potassium carbonate (250 mg, 1.81 mmol) in dioxane (5 mL) and water (0.5 mL), replace with nitrogen for three times, stir at 120 °C for 12 hours, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to get the crude product, purify with normal phase silica gel column, concentrate under reduced pressure to get the product 120 mg.

[0225] LC-MS (ESI): [M+H] + = 366.1.

[0226] Step 9: Synthesis of 2-(4-cyano-6-methyl-7,8,9,10-tetrahydro-6H-azepino[1,2- a]indol-2-yl)thiazole-5-carboxylic acid

[0227] Methyl 2-(4-cyano-6-methyl-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-2-yl)thiazole-5- carboxylate (100 mg, 0.27 mmol) was dissolved in acetonitrile (2 mL), added saturated aqueous lithium bromide (2 mL), triethylamine (2 mL), stirred at 50 °C for 12 hours, cooled to room temperature naturally, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, added water and ethyl acetate to extract, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain the product 80 mg

[0228] LC-MS (ESI): [M+H] + = 352.0;

[0229] 1H NMR (400 MHz, DMSO-d6) d = 8.45 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 6.60 (s, 1H), 5.71 (t, J = 7.2 Hz, 1H), 3.16 (dd, J = 5.2, 15.2 Hz, 1H), 2.89 (t, J = 14.4 Hz, 1H), 2.23 - 2.13 (m, 1H), 2.11 - 2.02 (m, 1H), 1.98 - 1.88 (m, 1H), 1.88 - 1.76 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H), 1.45 - 1.31 (m, 1H).

[0230] Step 10: Synthesis of (S)-2-(4-cyano-6-methyl-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indol-2- yl)thiazole-5-carboxylic acid and (R)-2-(4-cyano-6-methyl-7,8,9,10-tetrahydro-6H-azepino[1,2- a]indol-2-yl)thiazole-5-carboxylic acid (Compounds 7A and 7B)

[0231] Racemic 2-(5-cyano-3-methyl-2,3-dihydro-lH-pyrrolo[l,2-a]indol-7-yl)thiazole-5- carboxylic acid (80 mg, 0.25 mmol) was resolved by SFC (Column: Chiralpak IG-3 50*4.6 mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 20% to 60%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar) to give the compound 7A with 1.689 min out peak and compound 7B with 1.873 min out peak.

[0232] LC-MS (ESI): [M+H] + = 352.1.

[0233] Compound 7A: 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 6.60 (s, 1H), 5.71 (t, J = 7.2 Hz, 1H), 3.16 (dd, J = 5.2, 15.2 Hz, 1H), 2.89 (t, J = 14.4 Hz, 1H), 2.23 - 2.13 (m, 1H), 2.11 - 2.02 (m, 1H), 1.96 - 1.89 (m, 1H), 1.88 - 1.76 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H), 1.45 - 1.31 (m, 1H).

[0234] Compound 7B: 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 6.60 (s, 1H), 5.71 (t, J = 7.2 Hz, 1H), 3.16 (dd, J = 5.2, 15.2 Hz, 1H), 2.89 (t, J = 14.4 Hz, 1H), 2.23 - 2.13 (m, 1H), 2.11 - 2.02 (m, 1H), 1.96 - 1.89 (m, 1H), 1.88 - 1.76 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H), 1.45 - 1.31 (m, 1H).

[0235] Example 8: Synthesis of (S)-2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)-4-fluorothiazole-5-carboxylic acid (Compound 8)

[0236] (S)-6-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7,8,9- tetrahydropyrido[l,2-a]indole-4-carbonitrile (446.3 mg, 1.33 mmol), 2-bromo-4- fluorothiazole-5-carboxylic acid (300 mg, 1.33 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium chloride (100 mg, 0.14 mmol), potassium carbonate (400 mg, 2.89 mmol) were dissolved in dioxane (10 mL) and water (1 mL), replaced with nitrogen for three times, stirred at 100 °C for 2 hours, cooled to room temperature naturally, the reaction solution was added with water and extracted with ethyl acetate, the water phase was adjusted to pH = 3 with 1 mol hydrochloric acid, then extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by a reversed-phase C18 column and freeze-dried to obtain the product 50 mg.

[0237] LC-MS (ESI): [M+H] + = 356.0;

[0238] 1 H NMR (400 MHz, DMSO-d6) d = 8.44 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 6.53 (s, 1H), 5.29-5.12 (m, 1H), 3.16-3.07 (m, 1H), 2.95-2.82 (m, 1H), 2.23-2.12 (m, 1H), 2.05-1.82 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H).

[0239] Example 9: 2-(4-cyano-6,7,8,9-tetrahydropyrido[l,2]indol-2-yl)thiazole-5- carboxylic acid (Compound 9)

[0240] Step 1: Synthesis of 2-amino-5-bromo-3-iodobenzene-l-carbonitrile

[0241] To a solution of 2-amino-5-bromo-benzene-1-carbonitrile (30.00 g, 152.26 mmol) in methanol (300 mL) was added iodine (42.51 g, 167.49 mmol), silver sulfate (18.99 g, 60.90 mmol) at room temperature under stirring. The reaction mixture was stirred at room temperature overnight. After concentration under reduced pressure, the residue was directly applied to a silica gel column and purified (PE:EA = 40%) to give 2-amino-5-bromo-3-iodo-benzene-1-carbonitrile as a solid.

[0242] Step 2: Synthesis of 2-amino-5-bromo-3-(6-hydroxyhex-1-ynyl)benzene-1- carbonitrile

[0243] To a solution of 2-amino-5-bromo-3-iodo-benzene-1-carbonitrile (6.00 g, 18.58 mmol) in hex-5-yn-1-ol (2.7 mL, 24.15 mmol), bis(triphenylphosphine)palladium dichloride (1.45 g, 1.86 mmol), CuI (1.06 g, 5.57 mmol), acetonitrile (15 mL), triethylamine (15 mL) was added. After nitrogen substitution, the reaction mixture was stirred at 50 °C overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL) for three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 50%) to give the title product 4.60 g.

[0244] Step 3: Synthesis of 5-bromo-2-(4-hydroxybutyl)-indole-7-carbonitrile

[0245] To a solution of 2-amino-5-bromo-3-(6-hydroxyhex-1-ynyl)benzene-1-carbonitrile (4.60 g, 15.69 mmol) in N,N-dimethylformamide (80 mL) was added cuprous iodide (3.59 g, 18.83 mmol). After nitrogen substitution for 1 min, the reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with water and ethyl acetate and extracted twice. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by normal phase silica gel column (PE:EA = 60%) to give the title product 3.80 g.

[0246] Step 4: Synthesis of Methanesulfonic acid-4-(5-bromo-7-cyano-indol-2-yl)butyl ester

[0247] Dissolve 5-bromo-2-(4-hydroxybutyl)-indole-7-carbonitrile (3.80 g, 17.06 mmol), methanesulfonic anhydride (4.46 g, 25.58 mmol) in dichloromethane (100 mL), add triethylamine (7.2 mL, 51.17 mmol) at 0 °C, stir at 20 °C for 2 hours. Add water to the reaction mixture and extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title product 5.40 g.

[0248] Step 5: Synthesis of 2-bromo-6,7,8,9-tetrahydropyrido[l,2]indole-4-carbonitrile

[0249] Dissolve methane sulfonic acid-4-(5-bromo-7-cyano-indol-2-yl)butyl ester (5.40 g, 16.97 mmol) in N,N-dimethylformamide (100 mL), then add potassium carbonate (4.69 g, 33.94 mmol), and replace with nitrogen for one minute after addition is complete. Stir at 80 °C for 2 hours. Add water to the reaction mixture and extract with ethyl acetate twice, combine the organic phases, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain the crude product, which is purified by normal silica gel column (PE:EA = 10%) to obtain the title product 3.31 g.

[0250] Step 6: Synthesis of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7,8,9- tetrahydropyrido[l,2]indole-4-carbonitrile

[0251] Dissolve 2-bromo-6,7,8,9-tetrahydropyrido[l,2]indole-4-carbonitrile (400 mg, 0.73 mmol) and pinacol diboronic acid (732.8 mg, 1.45 mmol) in 1,4 dioxane (8 mL), then add potassium acetate (285.2 mg, 1.45 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (118.6 mg, 0.07 mmol), and replace with nitrogen for one minute after addition is complete. Stir at 100 °C for 1 hour. Add water to the reaction mixture and extract with ethyl acetate twice, combine the organic phases, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the title product 404 mg.

[0252] Step 7: Synthesis of methyl 2-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2]indol-2- yl)thiazole-5-carboxylate

[0253] Methyl 2-(4-cyano-6,7,8,9-tetrahydropyrido[l,2]indol-2-yl)thiazole-5- carboxylate (60.0 mg, 0.18 mmol) was dissolved in tetrahydrofuran (6 mL), methanol (1.5 mL) in a 50 mL single neck flask at room temperature, then lithium hydroxide monohydrate (122.9 mg, 2.93 mmol) in water (3 mL) was added dropwise, the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water (50 mL), the pH was adjusted to 5 with 0.5 M trifluoroacetic acid, extracted with ethyl acetate (30 mL) three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The title product was isolated and purified by silica gel column chromatography (PE:EA = 80%) to give 28.6 mg.

[0254] Step 8: Synthesis of 2-(4-cyano-6,7,8,9-tetrahydropyrido[l,2]indol-2-yl)thiazole-5- carboxylic acid

[0255] Methyl 2-(4-cyano-6,7,8,9-tetrahydropyrido[l,2]indol-2-yl)thiazole-5- carboxylate (60.0 mg, 0.18 mmol) was dissolved in tetrahydrofuran (6 mL), methanol (1.5 mL) in a 50 mL single neck flask at room temperature, then lithium hydroxide monohydrate (122.9 mg, 2.93 mmol) in water (3 mL) was added dropwise, the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water (50 mL), the pH was adjusted to 5 with 0.5 M trifluoroacetic acid, extracted with ethyl acetate (30 mL) three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The title product was isolated and purified by silica gel column chromatography (PE:EA = 80%) to give 28.6 mg.

[0256] LCMS: [M+H] + = 324.2;

[0257] 1 H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 6.51 (s, 1H), 4.50 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 6.1 Hz, 2H), 2.08 - 2.23 (m, 2H), 1.87 - 1.83 (m, 2H).

[0258] Example 10: Synthesis of 2-(4-cyano-6,7,8,9-tetrahydropyrido[l,2]indol-2-yl)-4- methylthiazole-5-carboxylic acid (Compound 10)

[0259] Reference compound 9 was synthesized according to the method of compound 10:

[0260] LCMS: [M+H] = 338.1. +

[0261] 1 H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.06 (s, 1H), 6.50 (s, 1H), 4.49 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.67 (s, 3H), 2.07 - 2.24 (m, 2H), 1.86 - 1.81 (m, 2H).

[0262] Example 11: Synthesis of 2-(4-cyano-6-oxo-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid (compound 11)

[0263] Step 1: Synthesis of methyl 6-(2-amino-5-bromo-3-cyanophenyl)hex-5-enoate

[0264] Methyl 5-heptanoate (2.6 g, 20.61 mmol), bis(triphenylphosphine)palladium dichloride (1.0 g, 1.42 mmol), cuprous iodide (1.0 g, 5.25 mmol) were dissolved in acetonitrile (50 mL), triethylamine (50 mL, 359.72 mmol) was added, and the mixture was stirred at 50 °C for 2 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column chromatography to give the product 4.1 g.

[0265] LC-MS (ESI): [M+H] = 321.1. +

[0266] Step 2: Synthesis of methyl 4-(5-bromo-7-cyano-lH-indol-2-yl)butanoate

[0267] Methyl 6-(2-amino-5-bromo-3-cyanophenyl)hex-5-enoate (5.40 g, 16.81 mmol) was dissolved in N,N-dimethylformamide (200 mL), and cuprous iodide (6.50 g, 34.13 mmol) was added. The mixture was stirred at 100 °C for 12 h. The reaction was cooled to room temperature, and water and ethyl acetate were added to the reaction mixture. The organic phase was washed with saturated calcium chloride and sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column chromatography to give the product 3.2 g. ​​

[0268] Step 3: Synthesis of 4-(5-bromo-7-cyano-lH-indol-2-yl)butanoic acid

[0269] Methyl 4-(5-bromo-7-cyano-lH-indol-2-yl)butanoate (1.6 g, 4.98 mmol) was dissolved in tetrahydrofuran (20 mL), a solution of lithium hydroxide monohydrate (320 mg, 7.62 mmol) in water (2 mL) was added, and the mixture was stirred at 20 °C for 2 h. The reaction solution was added to water and extracted with ethyl acetate, the aqueous phase was added to 1 mol / L hydrochloric acid to adjust pH = 3, and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to obtain 1.2 g of the crude product.

[0270] LC-MS (ESI): [M+H] + = 307.0.

[0271] Step 4: Synthesis of 2-bromo-6-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indole-4- carbonitrile

[0272] 4-(5-Bromo-7-cyano-lH-indol-2-yl)butanoic acid (0.76 g, 2.47 mmol) was dissolved in N,N-dimethylformamide (100 mL), O-(7-azabenzotriazol-l-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (1.03 g, 2.72 mmol), and diisopropylethylamine (0.64 g, 4.95 mmol) were added, and the mixture was stirred at 20 °C for 12 h. The reaction solution was added to water and extracted with ethyl acetate. The organic phase was washed with saturated calcium chloride and sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The product 510 mg was obtained by normal silica gel column purification and concentration under reduced pressure.

[0273] LC-MS (ESI): [M+H] + = 289.0.

[0274] Step 5: Synthesis of methyl 2-(4-cyano-6-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)thiazole-5-carboxylate

[0275] Dissolve 2-bromo-6-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (250 mg, 0.86 mmol), methyl thiazole-5-carboxylate (247.6 mg, 1.73 mmol), palladium acetate (150 mg, 0.67 mmol), tricyclohexylphosphonium (150 mg, 0.53 mmol), potassium carbonate (500 mg, 3.62 mmol) in toluene (5 mL), replace with nitrogen for three times, stir at 100 °C for 12 hours. Cool to room temperature naturally, add water and ethyl acetate to extract, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to get the crude product, purify with normal phase silica gel column, concentrate under reduced pressure to get the product 123 mg.

[0276] LC-MS (ESI): [M+H] + = 352.0.

[0277] Step 6: Synthesis of 2-(2-(3-carboxypropyl)-7-cyano-lH-indol-5-yl)thiazole-5- carboxylic acid

[0278] Dissolve 2-(4-cyano-6-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylic acid methyl ester (120 mg, 0.34 mmol) in acetonitrile (4 mL), add saturated aqueous lithium bromide solution (2 mL) and triethylamine (0.5 mL, 3.42 mmol), stir at 50 °C for 12 hours. Cool to room temperature naturally, add water and ethyl acetate to extract, adjust the pH of the aqueous phase to 3 with 1 mol hydrochloric acid, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to get the crude product, purify with reverse phase C18 column, freeze-dry to get the product 82 mg.

[0279] LC-MS (ESI): [M+H] + = 356.0.

[0280] Step 7: Synthesis of 2-(4-cyano-6-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylic acid

[0281] Dissolve 2-(2-(3-carboxypropyl)-7-cyano-lH-indol-5-yl)thiazole-5-carboxylic acid (80 mg, 0.23 mmol) in N,N-dimethylformamide (20 mL), add O-(7-azabenzotriazol-l-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (105 mg, 0.28 mmol), diisopropylethylamine (0.1 mL, 0.46 mmol), stir at 20 °C for 2 hours. Add water to quench the reaction, purify with reverse phase C18 column, freeze-dry to get the product 12 mg.

[0282] LC-MS (ESI): [M+H] + = 338.1.

[0283] 1H NMR (400 MHz, DMSO-d6) δ = 8.53 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 6.75 (s, 1H), 3.06 (t, J = 5.6 Hz, 2H), 2.89 (t, J = 6.4 Hz, 2H), 2.23 - 1.98 (m, 2H).

[0284] Example 12: Synthesis of 2-(9-cyano-l-methyl-l,2,3,4-tetrahydrodipyridazino[l,6- a]indol-7-yl)thiazole-5-carboxylic acid (Compound 12)

[0285] Step 1: Synthesis of methyl 5-(2-amino-5-bromo-3-cyanophenyl)pent-4-ynoate

[0286] Methyl 5-(2-amino-5-bromo-3-cyanophenyl)pent-4-ynoate (4.0 g, 12.48 mmol) was dissolved in methanol (100 mL) and then added with 2-mercaptoacetic acid (1.0 g, 12.48 mmol) and stirred at room temperature for 2 hours. LCMS monitoring showed that the starting material was completely reacted. Then cooled to room temperature, the reaction solution was added with water (100 mL) and extracted with ethyl acetate (100 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 3.0 g.

[0287] LC-MS (ESI): [M+H] + = 307.1.

[0288] Step 2: Synthesis of methyl 3-(5-bromo-7-cyano-lH-indol-2-yl)propanoate

[0289] Methyl 5-(2-amino-5-bromo-3-cyanophenyl)pent-4-ynoate (4.0 g, 13.02 mmol) was dissolved in N,N-dimethylformamide (250 mL), then cuprous iodide (6.2 g, 32.56 mmol) was added, after the addition, nitrogen was replaced for one minute, and the reaction was carried out at 100 °C overnight. LCMS monitoring showed that the raw material was completely reacted. Then after cooling to room temperature, water (300 mL) and ethyl acetate (500 mL) were added to the reaction solution, and the organic phase was washed with saturated sodium chloride (250 mL x 2) twice, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 2.3 g.

[0290] LC-MS (ESI): [M+H] + = 307.0.

[0291] Step 3: Synthesis of methyl 3-(1-amino-5-bromo-7-cyanoindol-2-yl)propanoate

[0292] Methyl 3-(5-bromo-7-cyano-1H-indol-2-yl)propanoate (2.0 g, 6.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), then potassium tert-butoxide (1.1 g, 9.8 mmol) was added, then O-p-nitrobenzoylhydroxylamine (1.8 g, 9.8 mmol) was added at zero degrees, after the addition, the reaction was carried out at room temperature overnight. LCMS monitoring showed that the raw material was completely reacted. The reaction solution was extracted with ammonium chloride (50 mL) and ethyl acetate (50 mL x 2), and the organic phase was combined after extraction, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 860 mg.

[0293] LC-MS (ESI): [M+H] + = 322.0.

[0294] Step 4: Synthesis of 7-bromo-3,4-dihydropyrido[1,6-a]indole-9-carbonitrile

[0295] Methyl 3-(1-amino-5-bromo-7-cyanoindol-2-yl)propanoate (860 mg, 2.67 mmol) was dissolved in tetrahydrofuran (50 mL), and diisobutylaluminum hydride (8.0 mL, 8.01 mmol) was added at -78 °C, after the addition, the reaction was carried out at -78 °C for two hours, then at room temperature overnight. LCMS monitoring showed that the raw material was completely reacted. Water (20 mL) and ethyl acetate (30 mL) were added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 600 mg.

[0296] LC-MS (ESI): [M+H] + = 274.0.

[0297] Step 5: Synthesis of 7-bromo-l,2,3,4-tetrahydropyridazino[l,6-a]indole-9- carbonitrile

[0298] 7-bromo-3,4-dihydropyrido[ 1,6-a]indole-9-carbonitrile (600 mg, 2.19 mmol) was dissolved in tetrahydrofuran (20 mL), sodium borohydride (248 mg, 6.57 mmol) was added at zero degree, after addition, reaction at room temperature for two hours. LCMS monitoring showed that the starting material was completely reacted. Water (20 mL) and ethyl acetate (25 mL x 2) were added to extract, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 180 mg.

[0299] LC-MS (ESI): [M+H] + = 276.0.

[0300] Step 6: Synthesis of 7-bromo-l-methyl-l,2,3,4-tetrahydropyridazino[l,6-a]indole-9- carbonitrile

[0301] 7-bromo-l,2,3,4-tetrahydropyridazino[l,6-a]indole-9-carbonitrile (170 mg, 0.62 mmol) was dissolved in N,N-dimethylformamide (10 mL), sodium hydride (49 mg, 1.23 mmol) was added, stirred at room temperature for 30 minutes, then iodomethane (131 mg, 0.92 mmol) was added, after addition, reaction at room temperature for three hours. LCMS monitoring showed that the starting material was completely reacted. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (25 mL x 2), the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 55 mg.

[0302] LC-MS (ESI): [M+H] + = 290.0.

[0303] Step 7: Synthesis of l-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,4-tetrahydropyrido[l,6-a]indole-9-carbonitrile

[0304] Dissolve 7-bromo-l-methyl-l,2,3,4-tetrahydropyridino[l,6-a]indole-9-carbonitrile (45 mg, 0.16 mmol) and bis(pinacolato)diboron (90 mg, 0.31 mmol) in dioxane (5 mL), then add potassium acetate (30.4 mg, 0.31 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium chloride (11.4 mg, 0.02 mmol), and then replace with nitrogen for one minute. React at 100 °C for one hour. LCMS monitoring shows that the starting material is completely reacted. Add water and ethyl acetate to the reaction solution, extract twice, combine the organic phase, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the title product 46 mg.

[0305] LC-MS (ESI): [M+H] + = 338.2.

[0306] Step 8: Synthesis of methyl 2-(9-cyano-l-methyl-l,2,3,4-tetrahydropyridino[l,6- a]indol-7-yl)thiazole-5-carboxylate

[0307] Dissolve l-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,4- tetrahydropyridino[l,6-a]indole-9-carbonitrile (30 mg, 0.09 mmol) and methyl 2- bromothiazole-5-carboxylate (39.5 mg, 0.18 mmol) in dioxane (10 mL) and water (1 mL), add l,l'-bis(diphenylphosphino)ferrocene palladium chloride (13 mg, 0.02 mmol) and potassium carbonate (36.9 mg, 0.27 mmol), and then replace with nitrogen for one minute. React at 120 °C for two hours. LCMS detection shows that the starting material is completely reacted. Then cool to room temperature, add water (20 mL) and ethyl acetate (30 mL) to the reaction solution, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the title product 20 mg.

[0308] LC-MS (ESI): [M+H] + = 353.1.

[0309] Step 9: Synthesis of 2-(9-cyano-l-methyl-l,2,3,4-tetrahydropyridino[l,6-a]indol-7- yl)thiazole-5-carboxylic acid

[0310] Methyl 2-(9-cyano-l-methyl-l,2,3,4-tetrahydropyridazino[l,6-a]indol-7-yl)thiazole-5- carboxylate (20 mg, 0.06 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL), then lithium bromide (49.3 mg, 0.57 mmol) and triethylamine (57.4 mg, 0.57 mmol) were added, and the reaction was carried out at 60 °C overnight. LCMS detection showed that the starting material was completely reacted. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added for extraction, the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain the product 4.1 mg.

[0311] LC-MS (ESI): [M+H] + = 346.9;

[0312] 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 3.23-3.16 (m, 4H), 2.89 (s, 3H), 2.57-2.51 (m, 2H).

[0313] Example 13: (S)-2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylic acid and (R)-2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylic acid (Compounds 13A and 13B)

[0314] Step 1: Synthesis of 2-((trimethylsilyl)oxy)hex-6-ynenitrile

[0315] Hex-5-ynal (4.5 mL, 41.61 mmol) and trimethylsilyl cyanide (11.0 mL, 82.65 mmol) were dissolved in dichloromethane (50 mL), then triethylamine (5.8 mL, 41.61 mmol) was added, and the reaction was carried out at room temperature for two hours. TLC monitoring showed that the starting material was completely reacted, and the main spot was the product. Water (30 mL) and dichloromethane (50 mL) were added to the reaction solution for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain the title product 4.2 g.

[0316] Step 2: Synthesis of 2-amino-5-bromo-3-(6-cyano-6-((trimethylsilyl)oxy)hex-1-yn-1- yl)benzonitrile

[0317] Dissolve 2-amino-5-bromo-3-iodobenzonitrile (5.0 g, 15.48 mmol) and 2-[(trimethylsilyl)oxy]hept-6-ynenitrile (3.93 g, 20.13 mmol) in acetonitrile (200 mL), then add cuprous iodide (1.47 g, 7.74 mmol), dichlorobis(triphenylphosphine)palladium (1.20 g, 1.55 mmol) and triethylamine (100 mL), after adding, replace with nitrogen for one minute, after replacement, react at 50 °C for 6 hours. LCMS monitoring shows that the raw material is completely reacted. The reaction solution is directly filtered, concentrated under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the title product 1.50 g.

[0318] LC-MS (ESI): [M+H] + = 390.1.

[0319] Step 3: Synthesis of 5-bromo-2-(4-cyano-4-hydroxybutyl)-1H-indazole-7- carbonitrile

[0320] Dissolve 2-amino-5-bromo-3-(6-cyano-6-((trimethylsilyl)oxy)hex-1-yn-1-yl)benzonitrile (1.40 g, 4.40 mmol) in N,N-dimethylformamide (100 mL), then add cuprous iodide (1.676 g, 8.80 mmol), after adding, react at 100 °C for five hours. LCMS monitoring shows that the raw material is completely reacted. After cooling to room temperature, add water (200 mL) and ethyl acetate (150 mL x 2) to the reaction solution to extract twice, combine the organic phase, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the title product 650 mg.

[0321] LC-MS (ESI): [M+H] + = 318.0.

[0322] Step 4: Synthesis of 4-(5-bromo-7-cyano-1H-indazol-2-yl)-1-cyanobutyl methanesulfonate

[0323] Dissolve 5-bromo-2-(4-cyano-4-hydroxybutyl)-1H-indazole-7-carbonitrile (600 mg, 1.89 mmol) in dichloromethane (25 mL), then add methanesulfonic anhydride (492.7 mg, 2.83 mmol) and triethylamine (0.8 mL, 5.66 mmol), after adding, react at room temperature for two hours. LCMS monitoring shows that the raw material is completely reacted. Add water (20 mL) and ethyl acetate (50 mL) to the reaction solution to extract, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title product crude product 600 mg.

[0324] LC-MS (ESI): [M+H] + = 396.0.

[0325] Step 5: Synthesis of 2-bromo-6,7,8,9-tetrahydropyrido[l,2-a]indole-4,6- dicarbonitrile

[0326] 4-(5-bromo-7-cyano-lH-indol-2-yl)-l-cyanobutyl methanesulfonate (500 mg, 1.28 mmol) was dissolved in N,N-dimethylformamide (10 mL), then potassium carbonate (177 mg, 1.28 mmol) was added, after adding, it was reacted at 60 °C overnight. LCMS monitoring showed that the raw material was completely reacted. After cooling to room temperature, water (20 mL) and ethyl acetate (25 mL x 2) were added to extract, the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain 120 mg of the title product.

[0327] LC-MS (ESI): [M+H] + = 300.0.

[0328] Step 6: Synthesis of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7,8,9- tetrahydropyrido[l,2-a]indole-4,6-dicarbonitrile

[0329] 2-bromo-6,7,8,9-tetrahydropyrido[l,2-a]indole-4,6-dicarbonitrile (100 mg, 0.33 mmol) and pinacol diboronic acid (169.2 mg, 0.67 mmol) were dissolved in dioxane (10 mL), then potassium acetate (65.4 mg, 0.67 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (24.4 mg, 0.03 mmol) were added, after adding, it was replaced with nitrogen for one minute, and reacted at 100 °C for two hours. LCMS monitoring showed that the raw material was completely reacted. After cooling to room temperature, water (20 mL) and ethyl acetate (25 mL x 2) were added to extract twice, the organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain 120 mg of the title product.

[0330] LC-MS (ESI): [M+H] + = 448.2.

[0331] Step 7: Synthesis of methyl 2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)thiazole-5-carboxylate

[0332] Dissolve 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydropyrido[1,2- a]indole-4,6-dicarbonitrile (120 mg, 0.35 mmol) and methyl 2-bromothiazole-5-carboxylate (153.5 mg, 0.69 mmol) in dioxane (20 mL) and water (2 mL), add 1,1-bis(diphenylphosphino)ferrocene palladium chloride (50.6 mg, 0.07 mmol) and potassium carbonate (143.3 mg, 1.04 mmol), after addition, replace with nitrogen for one minute, react at 120 °C overnight. LCMS detection, the raw material is completely reacted. Then cool to room temperature, add water (50 mL) and ethyl acetate (30 x 2 mL) to the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain a crude product, purify by normal silica gel column to obtain 105 mg of the title product.

[0333] LC-MS (ESI): [M+H] + = 363.1.

[0334] Step 8: Synthesis of 2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazole-5- carboxylic acid

[0335] Dissolve methyl 2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazole-5- carboxylate (100 mg, 0.28 mmol) in acetonitrile (5 mL) and water (1 mL), then add lithium bromide (239.7 mg, 2.76 mmol) and triethylamine (279.2 mg, 2.76 mmol), react at 60 °C overnight. LCMS detection, the raw material is completely reacted. After natural cooling to room temperature, adjust the pH of the reaction solution to about 3 with 1 mol hydrochloric acid, add water (20 mL) and ethyl acetate (25 mL x 2) to extract, wash the organic phase with saturated sodium chloride (25 mL x 2) twice, then dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a crude product, purify by reverse phase C18 column, and freeze-dry to obtain 30 mg of the title product.

[0336] LC-MS (ESI): [M+H] + = 349.1.

[0337] Step 9: Synthesis of (S)-2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazole-5- carboxylic acid, (R)-2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazole-5- carboxylic acid (Compound 13A or 13B)

[0338] SFC resolution of 2-(4,6-dicyano-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylic acid (30 mg, 0.09 mmol) gave fraction A and fraction B, which were concentrated under reduced pressure to give solids, and the product 13A 11 mg and the product 13B 10 mg were obtained after re-lyophilization with acetonitrile (5 mL) and water (30 mL).

[0339] LC-MS (ESI): [M+H] + = 349.1;

[0340] Compound 13A:

[0341] 1 H NMR (400 MHz, DMSO-d6) d = 8.51 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.24 (s, 1H), 6.66 (s, 1H), 6.29 (d, J = 3.6 Hz, 1H), 3.24-3.17 (m, 1H), 2.97-2.87 (m, 1H), 2.57-2.51 (m, 1H), 2.40-2.31 (m, 1H), 2.15-2.08 (m, 1H), 1.86-1.83 (m, 1H).

[0342] Compound 13B:

[0343] 1 H NMR (400 MHz, DMSO-d6) d = 8.51 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.24 (s, 1H), 6.66 (s, 1H), 6.29 (d, J = 3.6 Hz, 1H), 3.24-3.17 (m, 1H), 2.97-2.87 (m, 1H), 2.57-2.51 (m, 1H), 2.40-2.31 (m, 1H), 2.15-2.08 (m, 1H), 1.86-1.83 (m, 1H).

[0344] Example 14: Synthesis of 2-(9-cyano-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-7-yl)thiazole-5-carboxylic acid (Compound 14)

[0345] Step 1: Synthesis of methyl 5-bromo-2-(2-methylpiperidin-l-yl)-3-nitrobenzoate

[0346] Methyl 5-bromo-2-fluoro-3-nitrobenzoate (5.0 g, 17.98 mmol) and 2- methylpiperidine (4.2 mL, 35.97 mmol) were dissolved in N,N-dimethylformamide (20 mL), then N,N-diisopropylethylamine (8.9 mL, 53.95 mmol) was added, after the addition, it was reacted at 90 °C overnight. LCMS monitoring showed that the raw material was completely reacted. After cooling to room temperature, water (30 mL) and ethyl acetate (50 mL) were added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 4.0 g.

[0347] LC-MS (ESI): [M+H] + = 357.0.

[0348] Step 2: Synthesis of methyl 3-amino-5-bromo-2-(2-methylpiperidin-1- yl)benzoate

[0349] Methyl 5-bromo-2-(2-methylpiperidin-1-yl)-3-nitrobenzoate (4.0 g, 11.20 mmol) was dissolved in ethanol (50 mL) and water (10 mL), then iron powder (3.12 g, 55.99 mmol) and ammonium chloride (2.99 g, 55.99 mmol) were added, after the addition, it was reacted at 90 °C for two hours. LCMS monitoring showed that the raw material was completely reacted. After cooling to room temperature, the reaction solution was directly filtered, water (50 mL) and ethyl acetate (50 mL x 2) were added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 3.6 g.

[0350] LC-MS (ESI): [M+H] + = 327.0.

[0351] Step 3: Synthesis of methyl 7-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyridine-9-carboxylate

[0352] Methyl 3-amino-5-bromo-2-(2-methylpiperidin-1-yl)benzoate (3000 mg, 9.17 mmol) was dissolved in ethyl acetate (20 mL), then hydrogen peroxide (9 mL, 299.03 mmol) was added, after the addition, it was reacted at 80 °C overnight. LCMS monitoring showed that the raw material was completely reacted. After cooling to room temperature, water (30 mL) and ethyl acetate (50 mL) were added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 1.6 g.

[0353] LC-MS (ESI): [M+H]+ = 323.0.

[0354] Step 4: Synthesis of 7-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyridine-9-carboxylic acid

[0355] Methyl 7-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9- carboxylate (1.5 g, 4.64 mmol) was dissolved in methanol (20 mL) and water (10 mL), then lithium hydroxide hydrate (292.4 mg, 6.96 mmol) was added, after the addition, the reaction was carried out at room temperature overnight. LCMS monitoring showed that the raw material was completely reacted. The reaction solution was adjusted to pH = 2 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (30 mL x 2) were added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 1.0 g.

[0356] LC-MS (ESI): [M+H] + = 323.0.

[0357] Step 5: Synthesis of 7-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyridine-9-carboxamide

[0358] 7-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-9-carboxylic acid (1.0 g, 3.23 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (2.46 g, 6.47 mmol) were dissolved in N,N-dimethylformamide (50 mL), then ammonium chloride (519 mg, 9.70 mmol) and N,N-diisopropylethylamine (1.25 g, 9.70 mmol) were added, after the addition, the reaction was carried out at room temperature overnight. LCMS monitoring showed that the raw material was completely reacted. Water (50 mL) and ethyl acetate (50 mL x 2) were added for extraction, the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal silica gel column to obtain the title product 750 mg.

[0359] LC-MS (ESI): [M+H] + = 323.0.

[0360] Step 6: Synthesis of 7-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2- a]pyridine-9-carbonitrile

[0361] Dissolve 7-bromo-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridine-9-carboxamide (800 mg, 2.60 mmol) in dichloromethane (20 mL), add Burgess reagent (2.28 g, 7.79 mmol) at zero degree, after addition, react at room temperature overnight. LCMS monitoring shows that the starting material is reacted completely. Add water (50 mL) and ethyl acetate (50 mL x 2) to the reaction solution, extract the organic phase with saturated sodium chloride (25 mL x 2) twice, then dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by normal silica gel column to obtain 500 mg of the title product.

[0362] LC-MS (ESI): [M+H] + = 290.0.

[0363] Step 7: Synthesis of l-methyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridine-9-carbonitrile

[0364] Dissolve 7-bromo-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridine-9-carbonitrile (450 mg, 1.55 mmol) and pinacol diboronic acid (787.0 mg, 3.10 mmol) in dioxane (30 mL), then add potassium acetate (304.4 mg, 3.10 mmol) and 1,1-bis(diphenylphosphino)ferrocene palladium chloride (113.5 mg, 0.16 mmol), replace with nitrogen for one minute after addition, react at 100 °C for two hours. LCMS monitoring shows that the starting material is reacted completely. After cooling to room temperature, add water (20 mL) and ethyl acetate (30 x 2 mL) to the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is purified by normal silica gel column to obtain 300 mg of the title product.

[0365] LC-MS (ESI): [M+H] + = 338.2.

[0366] Step 8: Synthesis of methyl 2-(9-cyano-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2-a]pyridin-7-yl)thiazole-5-carboxylate

[0367] Methyl 2-(9-cyano-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-7-yl)thiazole-5-carboxylate (100 mg, 0.28 mmol) was dissolved in acetonitrile (15 mL) and water (5 mL), then lithium bromide (246.4 mg, 2.84 mmol) and triethylamine (287.14 mg, 2.84 mmol) were added, and the reaction was carried out at 60 °C overnight. LCMS detection showed that the raw material was completely reacted. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, and water (20 mL) and ethyl acetate (25 mL x 2) were added for extraction. The organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain 70 mg of the title product.

[0368] LC-MS (ESI): [M+H] + = 353.1.

[0369] Step 9: Synthesis of 2-(9-cyano-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-7-yl)thiazole-5-carboxylic acid

[0370] Methyl 2-(9-cyano-l-methyl-l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyridin-7-yl)thiazole-5-carboxylate (100 mg, 0.28 mmol) was dissolved in acetonitrile (15 mL) and water (5 mL), then lithium bromide (246.4 mg, 2.84 mmol) and triethylamine (287.14 mg, 2.84 mmol) were added, and the reaction was carried out at 60 °C overnight. LCMS detection showed that the raw material was completely reacted. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, and water (20 mL) and ethyl acetate (25 mL x 2) were added for extraction. The organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain 70 mg of the title product.

[0371] LC-MS (ESI): [M+H] + = 339.1;

[0372] 1H NMR (400 MHz, DMSO-d6) δ = 8.47 (s, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 5.10 (t, J = 5.6 Hz, 1H), 3.18-3.12 (m, 1H), 3.04-2.95 (m, 1H), 2.21-1.94 (m, 4H), 1.52 (d, J = 6.4 Hz, 3H).

[0373] Example 15: (S)-2-(4-cyano-10-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid and (R)-2-(4-cyano-10-fluoro-6-methyl- 6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5-carboxylic acid (Compounds 15A and 15B)

[0374] Step 1: Synthesis of 10-fluoro-6-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile

[0375] Step 2: Synthesis of methyl 2-(4-cyano-10-fluoro-6-methyl-6,7,8,9- tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5-carboxylate

[0376] LC-MS (ESI): [M+H] + = 355.1.

[0377] Step 2: Synthesis of methyl 2-(4-cyano-10-fluoro-6-methyl-6,7,8,9- tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5-carboxylate

[0378] Methyl 2-(4-cyano-10-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)thiazole-5-carboxylate (25 mg, 0.07 mmol) was dissolved in acetonitrile (1 mL), saturated aqueous lithium bromide (1 mL) and triethylamine (1 mL, 6.8 mmol) were added, stirred at 50 °C for 12 h, cooled to room temperature naturally, the reaction solution was adjusted to pH = 3 by 1 mol hydrochloric acid, water and ethyl acetate were added for extraction, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, purified by reverse phase column, freeze-dried to obtain the product 16 mg.

[0379] LC-MS (ESI): [M+H] + = 370.2.

[0380] Step 3: Synthesis of 2-(4-cyano-10-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid

[0381] Methyl 2-(4-cyano-10-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)thiazole-5-carboxylate (25 mg, 0.07 mmol) was dissolved in acetonitrile (1 mL), saturated aqueous lithium bromide (1 mL) and triethylamine (1 mL, 6.8 mmol) were added, stirred at 50 °C for 12 h, cooled to room temperature naturally, the reaction solution was adjusted to pH = 3 by 1 mol hydrochloric acid, water and ethyl acetate were added for extraction, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, purified by reverse phase column, freeze-dried to obtain the product 16 mg.

[0382] LC-MS (ESI): [M+H] + = 356.0;

[0383] 1H NMR (400 MHz, DMSO-d6) d = 8.38 (d, J = 1.6 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 5.26-5.16 (m, 1H), 3.13-3.10 (m, 1H), 2.84-2.76 (m, 1H), 2.19-2.09 (m, 1H), 2.00 (d, J = 13.6 Hz, 1H), 1.91-1.87 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.29-1.22 (m, 1H).

[0384] Step 4: Synthesis of (S)-2-(4-cyano-10-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid, (R)-2-(4-cyano-10-fluoro-6-methyl-6,7,8,9- tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5-carboxylic acid

[0385] Racemic 2-(4-cyano-10-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole- 5-carboxylic acid (15 mg, 0.04 mmol) was resolved by SFC to give two peaks of A and B, which were concentrated under reduced pressure and then freeze-dried with water to give compound 15A 3 mg, 15B 5 mg.

[0386] Compound 15A: LC-MS (ESI): [M+H] + = 356.1;

[0387] 1H NMR (400 MHz, DMSO-d6) d = 8.38 (d, J = 1.6 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 5.26-5.16 (m, 1H), 3.13-3.10 (m, 1H), 2.84-2.76 (m, 1H), 2.19-2.09 (m, 1H), 2.00 (d, J = 13.6 Hz, 1H), 1.91-1.87 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.29-1.22 (m, 1H).

[0388] Compound 15B: 1H NMR (400 MHz, DMSO-d6) d = 8.40 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 5.28-5.13 (m, 1H), 3.15-3.12 (m, 1H), 2.79-2.73 (m, 1H), 2.17-2.07 (m, 1H), 2.00 (d, J = 13.6 Hz, 1H), 1.87-1.84 (m, 1H), 1.44 (d, J = 6.4 Hz, 3H), 1.27-1.20 (m, 1H).

[0389] Example 16: 2-((laS,9bS)-5-cyano-la,2,3,9b-tetrahydro-lH-cyclopropyl[3,4]pyrido[l,2- a]indol-7-yl)thiazole-5-carboxylic acid and 2-((laR,9bR)-5-cyano-la,2,3,9b-tetrahydro- lH-cyclopropyl[3,4]pyrido[l,2-a]indol-7-yl)thiazole-5-carboxylic acid (compounds 16A and 16B)

[0390] Step 1: Synthesis of 2-amino-5-bromo-3-(3,3-diethoxyprop-1-yn-1-yl)benzonitrile

[0391] 2-amino-5-bromo-3-iodobenzonitrile (5.0 g, 15.48 mmol), 3,3-diethoxyprop-1-yn (2.97 g, 23.22 mmol), dichlorobispalladium(II)triphenylphosphine (1.2 g, 1.55 mmol), cuprous iodide (1.47 g, 4.64 mmol) and triethylamine (100 mL) were dissolved in acetonitrile (250 mL), and after addition, nitrogen was replaced for three times, and stirred at 50 °C overnight. LCMS monitoring showed that the raw material was completely reacted, and the main peak was the product. After natural cooling to room temperature, water (300 mL) and ethyl acetate (500 mL) were added to the reaction solution, and the organic phase was washed twice with saturated sodium chloride solution (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column to obtain the title product 4.8 g.

[0392] LC-MS (ESI): [M+H] + = 323.0.

[0393] Step 2: Synthesis of 5-bromo-2-(diethoxymethyl)-1H-indole-7-carbonitrile

[0394] 2-amino-5-bromo-3-(3,3-diethoxyprop-1-yn-1-yl)benzonitrile (4.5 g, 13.92 mmol) was dissolved in N-methylpyrrolidone (500 mL), and then 1M tert-butoxide potassium (27.8 mL, 27.85 mmol) in tetrahydrofuran was added, and after addition, nitrogen was replaced for 1 minute, and the reaction was carried out at zero to room temperature overnight. LCMS monitoring showed that the raw material was completely reacted, water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column to obtain the title product 3.0 g.

[0395] LC-MS (ESI): [M+H] + = 323.0.

[0396] Step 3: Synthesis of 5-bromo-2-formyl-1H-indole-7-carbonitrile

[0397] Dissolve 5-bromo-2-(diethoxymethyl)-lH-indole-7-carbonitrile (3000 mg, 9.28 mmol) in tetrahydrofuran (100 mL) and water (10 mL), then add acetic acid (30 mL). After adding, react at room temperature overnight. LCMS monitoring shows that the raw material is completely reacted. The reaction solution is added to water (100 mL) and ethyl acetate (100 mL x 2) and extracted, and the organic phase is combined after extraction, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain 2.3 g.

[0398] LC-MS (ESI): [M+H] + = 249.0.

[0399] Step 4: Synthesis of 5-bromo-l-(but-3-en-l-yl)-2-formyl-lH-indole-7-carbonitrile

[0400] Dissolve 5-bromo-2-formyl-lH-indole-7-carbonitrile (2.3 g, 9.23 mmol) and 4- bromobut-l-ene (2.49 g, 18.47 mmol) in N,N-dimethylformamide (30 mL), then add potassium carbonate (3.83 g, 27.70 mmol) and react at 60°C overnight. LCMS monitoring shows that the main peak is the product. Add water (200 mL) and ethyl acetate (150 mL) to the reaction solution and extract, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the title product 2.1 g.

[0401] LC-MS (ESI): [M+H] + = 303.0.

[0402] Step 5: Synthesis of 5-bromo-l-(but-3-en-l-yl)-2-vinyl-lH-indole-7-carbonitrile

[0403] Dissolve methyltriphenylphosphonium bromide (2.47 g, 6.93 mmol) in tetrahydrofuran (200 mL), add 2.5M n-butyllithium n-hexane solution (2.8 mL, 6.93 mmol) at 0°C, then add 5-bromo-l-(but-3-en-l-yl)-2-formyl-lH-indole-7-carbonitrile (1400 mg, 4.62 mmol) after adding at room temperature for 0.5 hours, then stir at room temperature for 2 hours. LCMS monitoring shows that the raw material is completely reacted, and the main peak is the product. Add water (20 mL) and ethyl acetate (25 mL x 2) to the reaction solution and extract twice, combine the organic phase, dry with anhydrous sodium sulfate, and distill under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the title product 1.3 g.

[0404] LC-MS (ESI): [M+H]+ = 301.0.

[0405] Step 6: Synthesis of 2-bromo-6,7-dihydropyrido[l,2-a]indole-4-carbonitrile

[0406] Dissolve 5-bromo-l-(but-3-en-l-yl)-2-ethenyl-lH-indole-7-carbonitrile (625 mg, 2.0 mmol) in dichloromethane (50 mL), then add (l,3-dimethylimidazolidin-2-ylidene)(2- isopropoxybenzylidene)ruthenium chloro ruthenium(VI) (130 mg, 0.2 mmol), react at room temperature for 3 hours. LCMS monitoring shows that the raw material is completely reacted, and the main peak is the product. Distill the reaction solution under reduced pressure to obtain the crude product, and purify it by normal silica gel column to obtain 500 mg of the title product.

[0407] LC-MS (ESI): [M+H]+ = 287.0. + = 301.0.

[0408] Step 7: Synthesis of 7-bromo-la,2,3,9b-tetrahydro-lH-cyclopropane[3,4]pyrido[l,2- a]indole-5-carbonitrile

[0409] Dissolve 2,6-di[l-(2-tert-butylphenylimino)ethyl]pyridine (155.8 mg, 0.37 mmol) and cobalt bromide (400.4 mg, 1.83 mmol) in tetrahydrofuran (25 mL), then add 2-bromo-6,7-dihydropyrido[l,2-a]indole-4-carbonitrile (500 mg, 1.83 mmol), dibromomethane (477.4 mg, 2.75 mmol), zinc bromide (412.2 mg, 1.83 mmol), and zinc powder (239.37 mg, 3.66 mmol), and react at room temperature overnight after addition. LCMS monitoring shows that the raw material is completely reacted, and the main peak is the product. Add water (20 mL) and ethyl acetate (30 mL x 2) to the reaction solution, extract twice, combine the organic phases, dry over anhydrous sodium sulfate, distill the crude product under reduced pressure, and purify it by normal silica gel column to obtain 390 mg of the title product.

[0410] LC-MS (ESI): [M+H]+ = 287.0.

[0411] Step 8: Synthesis of 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-la,2,3,9b-tetrahydro- lH-cyclopropane[3,4]pyrido[l,2-a]indole-5-carbonitrile

[0412] Dissolve 7-bromo-1a,2,3,9b-tetrahydro-1H-cyclopropane[3,4]pyrrolo[1,2-a]indole-5- carbonitrile (250 mg, 0.87 mmol) and bis(pinacolato)diboron (442 mg, 1.74 mmol) in dioxane (15 mL), then add potassium acetate (171 mg, 1.74 mmol) and 1,1'- bis(diphenylphosphino)ferrocene palladium chloride (63 mg, 0.09 mmol), and replace with nitrogen for 1 min, and react at 100 °C for 1 h. LCMS monitoring shows that the raw material is completely reacted, and the main peak is the product. After natural cooling to room temperature, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by normal silica gel column to obtain the product 290 mg.

[0413] LC-MS (ESI): [M+H] + = 335.3;

[0414] Step 9: Synthesis of methyl 2-(5-cyano-1a,2,3,9b-tetrahydro-1H-cyclopropane[3,4]pyrrolo[1,2- a]indol-7-yl)thiazole-5-carboxylate

[0415] Dissolve 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1a,2,3,9b-tetrahydro-1H- cyclopropane[3,4]pyrrolo[1,2-a]indole-5-carbonitrile (400 mg, 1.20 mmol) and methyl 2- bromothiazole-5-carboxylate (531.5 mg, 2.39 mmol) in dioxane (15 mL) and water (5 mL), add 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (175.1 mg, 0.24 mmol) and potassium carbonate (330.79 mg, 2.39 mmol), and replace with nitrogen for 1 min, and react at 120 °C for 2 h. LCMS detection shows that the raw material is completely reacted, and the main peak is the product. Then cool to room temperature, add water (50 mL) and ethyl acetate (50 mL) to the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product, which is purified by normal silica gel column to obtain the title product 256 mg.

[0416] LC-MS (ESI): [M+H] + = 350.1.

[0417] Step 10: Synthesis of 2-(5-cyano-1a,2,3,9b-tetrahydro-1H-cyclopropane[3,4]pyrrolo[1,2-a]indol-7- yl)thiazole-5-carboxylic acid

[0418] Methyl 2-(5-cyano-1a,2,3,9b-tetrahydro-1H-cyclopropane[3,4]pyrrolo[1,2- a]indol-7-yl)thiazole-5-carboxylate (256 mg, 0.73 mmol) was dissolved in acetonitrile (20 mL) and water (5 mL), then lithium bromide (636.3 mg, 7.33 mmol) and triethylamine (741.4 mg, 7.33 mmol) were added, and the reaction was allowed to react at 60 °C overnight. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1M hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added and extracted, and the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain 70 mg of the title compound, respectively.

[0419] LC-MS (ESI): [M+H] + = 336.1;

[0420] Step 11: Synthesis of 2-((1aS,9bS)-5-cyano-1a,2,3,9b-tetrahydro-1H- cyclopropyl[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole-5-carboxylic acid, 2-((1aR,9bR)-5- cyano-1a,2,3,9b-tetrahydro-1H-cyclopropyl[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole-5- carboxylic acid

[0421] 2-(5-cyano-1a,2,3,9b-tetrahydro-1H-cyclopropane[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole- 5-carboxylic acid (70 mg, 0.23 mmol) was SFC resolved (Column: Chiralpak AD-3 50 x 4.6 mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 20% to 60%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar) to give compound 16A 31 mg with 1.497 min out peak and compound 16B 27 mg with 1.807 min out peak.

[0422] Compound 16A: LC-MS (ESI): [M+H] + = 336.1;

[0423] 1H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 6.66 (s, 1H), 4.90-4.85 (m, 1H), 3.97-3.89 (m, 1H), 2.37-2.29 (m, 2H), 2.17-2.10 (m, 1H), 1.77-1.74 (m, 1H), 1.19-1.08 (m, 2H).

[0424] Compound 16B: LC-MS (ESI): [M+H] + = 336.1;

[0425] 1 H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 6.66 (s, 1H), 4.90-4.85 (m, 1H), 3.97-3.89 (m, 1H), 2.37-2.29 (m, 2H), 2.17-2.10 (m, 1H), 1.77-1.74 (m, 1H), 1.19-1.08 (m, 2H).

[0426] Example 17: 2-(4-cyano-6,7-dihydropyrido[l,2-a]indol-2-yl)thiazole-5-carboxylic acid (Compound 17)

[0427] Compound 17 was obtained by the synthetic method of Reference Example 9.

[0428] LC-MS (ESI): [M+H] + = 322.1;

[0429] 1 H NMR (400 MHz, DMSO-d6) δ = 8.41 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 6.66 (s, 1H), 4.90-4.85 (m, 1H), 3.97-3.89 (m, 1H), 2.37-2.29 (m, 2H), 2.17-2.10 (m, 1H), 1.77-1.74 (m, 1H), 1.19-1.08 (m, 2H).

[0430] Example 18: 2-((laS,9bS)-5-cyano-la,2,3,9b-tetrahydro-lH- cyclopropyl[3,4]pyrrolo[l,2-a]indol-7-yl)-4-methylthiazole-5-carboxylic acid and 2- ((laR,9bR)-5-cyano-la,2,3,9b-tetrahydro-lH-cyclopropyl[3,4]pyrrolo[l,2-a]indol-7- yl)-4-methylthiazole-5-carboxylic acid (Compounds 18A and 18B)

[0431] Compounds 18A, 18B were obtained following the synthetic procedure of Reference Example 16.

[0432] Compound 18B: LC-MS (ESI): [M+H] + = 350.1;

[0433] 1 H NMR (400 MHz, DMSO-d6) δ = 8.38 (s, 1H), 8.04 (s, 1H), 6.66 (s, 1H), 4.89-4.85 (m, 1H), 3.96-3.89 (m, 1H), 2.68 (s, 3H), 2.36-2.29 (m, 2H), 2.15-2.12 (m, 1H), 1.77-1.75 (m, 1H), 1.17-1.09 (m, 2H).

[0434] Example 19: 2-((laS,3S,9bS)-5-cyano-3-methyl-la,2,3,9b-tetrahydro-lH- cyclopropyl[3,4]pyrrolo[l,2-a]indol-7-yl)thiazole-5-carboxylic acid and 2-((laR,3S,9bR)-5-cyano-3-methyl-la,2,3,9b-tetrahydro-lH-cyclopropyl[3,4]pyrrolo[l,2-a]indol-7- yl)thiazole-5-carboxylic acid (Compounds 19A and 19B)

[0435] Step 1: Synthesis of 2-amino-5-bromo-3-(3,3-diethoxyprop-l-yne-l-yl)benzonitrile

[0436] To a solution of 2-amino-5-bromo-3-iodobenzonitrile (30 g, 92.90 mmol), 3,3- diethoxyprop-1-yne (18 g, 140.44 mmol), copper iodide (5 g, 26.25 mmol), bis(triphenylphosphine)palladium dichloride (6.5 g, 9.26 mmol) in acetonitrile (500 mL) was added triethylamine (129.1 mL, 928.99 mmol) and the reaction mixture was purged with nitrogen three times. The reaction mixture was stirred at 50 °C for 12 h. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a crude product which was purified by normal silica gel column to give the product 25.2 g.

[0437] LC-MS (ESI): [M+H] + = 323.1.

[0438] Step 2: Synthesis of 5-bromo-2-(diethoxymethyl)-1H-indazole-7-carbonitrile

[0439] To a solution of 2-amino-5-bromo-3-(3,3-diethoxyprop-1-yn-1-yl)benzonitrile (25 g, 77.35 mmol) in N-methylpyrrolidone (900 mL) was added potassium tert-butoxide (17.36 g, 154.71 mmol) and the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated calcium chloride and sodium chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by normal silica gel column to give the product 20.5 g.

[0440] Step 3: Synthesis of 5-bromo-2-formyl-1H-indazole-7-carbonitrile

[0441] To a solution of 5-bromo-2-(diethoxymethyl)-1H-indazole-7-carbonitrile (20 g, 61.88 mmol) in tetrahydrofuran (200 mL) and water (50 mL) was added acetic acid (100 mL, 1775.07 mmol) and the reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product which was triturated with petroleum ether: ethyl acetate = 10:1, filtered and the filter cake was concentrated under reduced pressure to give the product 15.1 g.

[0442] Step 4: Synthesis of 5-bromo-2-vinyl-1H-indazole-7-carbonitrile

[0443] Methyltriphenylphosphonium bromide (8.61 g, 24.09 mmol) was dissolved in tetrahydrofuran (300 mL), potassium tert-butoxide (36 mL, 36.00 mmol) was added at 0 °C, after stirring for 1 hour, 5-bromo-2-formyl-1H-indole-7-carbonitrile (3 g, 12.04 mmol) was added in tetrahydrofuran (100 mL), stirring was continued for 1 hour. The reaction solution was added to water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was washed with dichloromethane to obtain the product 2.6 g.

[0444] Step 5: Synthesis of (S)-5-bromo-1-(pent-4-en-2-yl)-2-vinyl-1H-indole-7-carbonitrile

[0445] 5-bromo-2-vinyl-1H-indole-7-carbonitrile (2.6 g, 10.52 mmol), (R)-pent-4-en-2-ol (0.91 g, 10.52 mmol) was dissolved in toluene (150 mL), cyanomethylphosphonic acid tributyl ester (10 g, 28.92 mmol) was added, nitrogen was replaced for three times, stirring was continued at 100 °C for 12 hours, and the reaction solution was naturally cooled to room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column, and concentrated under reduced pressure to obtain the product 502 mg.

[0446] LC-MS (ESI): [M+H] + = 315.0.

[0447] Step 6: Synthesis of (S)-2-bromo-6-methyl-6,7-dihydropyrido[1,2-a]indole-4-carbonitrile

[0448] (S)-5-bromo-1-(pent-4-en-2-yl)-2-vinyl-1H-indole-7-carbonitrile (500 mg, 1.59 mmol) was dissolved in dichloromethane (150 mL), [1,3-bis(2,4,6-trimethylphenyl)tetrahydro-1H-imidazol-2-ylidene]dichloro{[2-(propan-2-yloxy)phenyl]methylene}-λ6-ruthenium (130 mg, 0.21 mmol) was added, and stirring was continued at 20 °C for 1 hour. The reaction solution was added to water and extracted with dichloromethane, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column, and concentrated under reduced pressure to obtain the product 406 mg.

[0449] LC-MS (ESI): [M+H] + = 287.0.

[0450] Step 7: Synthesis of (3S)-7-bromo-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile

[0451] To a solution of (3S)-7-bromo-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile (360 mg, 1.20 mmol), bis(pinacolato)diboron (400 mg, 1.58 mmol), 1,1'-bis(diphenylphosphino) ferrocene palladium chloride (100 mg, 0.14 mmol), potassium acetate (250 mg, 2.55 mmol) in dioxane (10 mL) was purged with nitrogen for three times, stirred at 100 °C for 2 hours, cooled to room temperature naturally, the reaction solution was added water and ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, purified by normal phase silica gel column, concentrated under reduced pressure to give the product 205 mg.

[0452] LC-MS (ESI): [M+H] + = 302.0.

[0453] Step 8: Synthesis of (3S)-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile

[0454] To a solution of (3S)-7-bromo-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile (360 mg, 1.20 mmol), bis(pinacolato)diboron (400 mg, 1.58 mmol), 1,1'-bis(diphenylphosphino) ferrocene palladium chloride (100 mg, 0.14 mmol), potassium acetate (250 mg, 2.55 mmol) in dioxane (10 mL) was purged with nitrogen for three times, stirred at 100 °C for 2 hours, cooled to room temperature naturally, the reaction solution was added water and ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, purified by normal phase silica gel column, concentrated under reduced pressure to give the product 205 mg.

[0455] LC-MS (ESI): [M+H] + = 349.1.

[0456] Step 9: Synthesis of methyl 2-(((3S)-5-cyano-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole-5-carboxylate

[0457] (3S)-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile (200 mg, 0.57 mmol), methyl 2- bromothiazole-5-carboxylate (200 mg, 0.90 mmol), palladium acetate (55 mg, 0.24 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylheptane (135 mg, 0.23 mmol), potassium phosphate (243.80 mg, 1.15 mmol) were dissolved in dioxane (5 mL) and water (0.5 mL), replaced with nitrogen for three times, stirred at 100 °C for 2 hours, cooled to room temperature naturally, the reaction solution was added with water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain 102 mg of the product.

[0458] LC-MS (ESI): [M+H] + = 364.1.

[0459] Step 10: Synthesis of 2-(((3S)-5-cyano-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole-5-carboxylic acid

[0460] Methyl 2-(((3S)-5-cyano-3-methyl-1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2- a]indol-7-yl)thiazole-5-carboxylate (100 mg, 0.28 mmol) was dissolved in acetonitrile (2 mL), saturated aqueous lithium bromide solution (1 mL) and triethylamine (1 mL) were added, stirred at 50 °C for 2 hours, cooled to room temperature naturally, the reaction solution was added with water and extracted with ethyl acetate, the aqueous phase was added with 1 mol / L hydrochloric acid to adjust pH = 3, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 and freeze-dried to obtain 81 mg of the product.

[0461] LC-MS (ESI): [M+H] + = 350.1.

[0462] Step 11: Synthesis of 2-((laS,3S,9bS)-5-cyano-3-methyl-la,2,3,9b-tetrahydro-lH- cyclopropyl[3,4]pyrrolo[l,2-a]indol-7-yl)thiazole-5-carboxylic acid, 2-((laR,3S,9bR)-5- cyano-3-methyl-la,2,3,9b-tetrahydro-lH-cyclopropyl[3,4]pyrrolo[l,2-a]indol-7-yl)thiazole-5- carboxylic acid

[0463] Racemic 2-(((3S)-5-cyano-3-methyl-la,2,3,9b-tetrahydro-lH-cyclopropan[3,4]pyrrolo[l,2- a]indol-7-yl)thiazole-5-carboxylic acid (40 mg, 0.11 mmol) was resolved by SFC (Column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 um; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 20% to 60%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 C; Back Pressure: 100 Bar) to give two peaks before (A, 1.358 min) and after (B, 1.705 min) the peak. After concentration under reduced pressure, 5 mg of compound 19A and 6 mg of compound 19B were obtained by lyophilization with pure water.

[0464] LC-MS (ESI): [M+H] + = 350.1.

[0465] Compound 19A: 1 H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 8.25-8.14 (m, 1H), 8.08 (s, 1H), 6.70 (s, 1H), 5.22 (m, 1H, 1H), 2.27 (s, 1H), 2.07-1.95 (m, 1H), 1.77-1.68 (m, 1H), 1.53 (d, J = 7.2 Hz, 3H), 1.24 (s, 2H), 1.06 (d, J = 4.4 Hz, 1H), 0.92-0.85 (m, 1H).

[0466] Compound 19B: 1H NMR (400 MHz, DMSO-d6) δ = 8.32 (s, 1H, 1H), 8.02 (m, 1H, 1H), 7.76 (s, 1H), 6.74 (s, 1H), 5.19-4.95 (m, 1H), 2.24-2.13 (m, 1H), 1.82-1.70 (m, 1H), 1.60-1.52 (m, 1H), 1.46 (d, J = 6.4 Hz, 3H), 1.28-1.24 (m, 2H), 0.91-0.86 (m, 1H), 0.44 (q, J = 4.4 Hz, 1H).

[0467] Example 20: Synthesis of (S)-2-(4-cyano-6-methyl-6,7-dihydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid (Compound 20)

[0468] Compound 20 was synthesized according to Reference Example 9.

[0469] LC-MS (ESI): [M+H] + = 336.1;

[0470] 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 6.74 (dd, J = 2.8, 10.4 Hz, 1H), 6.70 (s, 1H), 6.25-6.15 (m, 1H), 5.40 (t, J = 6.8 Hz, 1H), 3.02-2.89 (m, 1H), 2.54 (s, 1H), 2.49-2.47 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H).

[0471] Example 21: 2-((laR,9aR)-4-cyano-la,2,9,9a-tetrahydro-lH-cyclopropyl[4,5]pyrido[l,2- a]indol-6-yl)thiazole-5-carboxylic acid and 2-((laS,9aS)-4-cyano-la,2,9,9a-tetrahydro- lH-cyclopropyl[4,5]pyrido[l,2-a]indol-6-yl)thiazole-5-carboxylic acid (Compounds 21A and 21B)

[0472] Step 1: Synthesis of 2-(l-hydroxyprop-2-yn-l-yl)cyclopropane-l-carboxylate

[0473] Ethyl 2-formylcyclopropane-1-carboxylate (4650 mg, 32.71 mmol) was dissolved in tetrahydrofuran (50 mL), then ethynylmagnesium bromide (5.0 mL) was added at -78 °C, and after the addition was complete, the reaction was allowed to react at -78 °C for 1.5 hours. After being allowed to naturally rise to room temperature, water (100 L) and ethyl acetate (100 mL) were added to the reaction solution, and the organic phase was washed twice with saturated sodium chloride solution (100 mL x 2), then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 4.71 g.

[0474] Step 2: Synthesis of ethyl 2-(3-(2-amino-5-bromo-3-cyanophenyl)-1- hydroxyprop-2-yn-1-yl)cyclopropane-1-carboxylate

[0475] Ethyl 2-(3-(2-amino-5-bromo-3-cyanophenyl)-1-hydroxyprop-2-yn-1-yl)cyclopropane-1-carboxylate (7010 mg, 23.47 mmol) was dissolved in N,N-dimethylformamide (300 L), then cuprous iodide (7970 mg, 41.85 mmol) was added, and after the addition was complete, the reaction was allowed to react at 100 °C overnight. Water (1000 mL) and ethyl acetate (1000 mL) were added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 3.1 g.

[0476] LC-MS (ESI): [M+H] + = 363.0.

[0477] Step 3: Synthesis of ethyl 2-((5-bromo-7-cyano-1H-indol-2-yl)(hydroxy)methyl)cyclopropane-1-carboxylate

[0478] Ethyl 2-(3-(2-amino-5-bromo-3-cyanophenyl)-1-hydroxyprop-2-yn-1-yl)cyclopropane-1-carboxylate (7010 mg, 23.47 mmol) was dissolved in N,N-dimethylformamide (300 L), then cuprous iodide (7970 mg, 41.85 mmol) was added, and after the addition was complete, the reaction was allowed to react at 100 °C overnight. Water (1000 mL) and ethyl acetate (1000 mL) were added to the reaction solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 3.1 g.

[0479] LC-MS (ESI): [M+H] + = 363.0.

[0480] Step 4: Synthesis of 2-((5-bromo-7-cyano-lH-indol-2-yl)methyl)cyclopropane-l- carboxylic acid ethyl ester

[0481] Dichlorodimethylsilane (2.1 mL, 21.48 mmol) and sodium iodide (6437 mg, 42.95 mmol) were dissolved in dichloromethane (25 mL) and acetonitrile (25 mL), then 2-((5-bromo-7-cyano-lH-indol-2-yl)(hydroxy)methyl)cyclopropane-l- carboxylic acid ethyl ester (2600 mg, 7.16 mmol) was added, after addition, the reaction was carried out at room temperature for one hour. Water (200 mL) and ethyl acetate (150 mL) were added to the reaction solution, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain the product 1.8 g.

[0482] LC-MS (ESI): [M+H] + = 347.0.

[0483] Step 5: Synthesis of 5-bromo-2-((2-(hydroxymethyl)cyclopropyl)methyl)-lH-indole-7- carbonitrile

[0484] 2-((5-bromo-7-cyano-lH-indol-2-yl)methyl)cyclopropane-l-carboxylic acid ethyl ester (1800 mg, 5.18 mmol) was dissolved in tetrahydrofuran (30 mL), diisobutylaluminum hydride 1M toluene solution (11.4 mL, 11.41 mmol) was added at zero degrees, then the reaction was carried out at zero degrees for one hour. Ammonium chloride (50 mL) and ethyl acetate (55 mL x 2) were added to the reaction solution, the organic phase was combined, dried with anhydrous sodium sulfate, and distilled under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain the product 1.05 g.

[0485] LC-MS (ESI): [M+H] + = 305.0.

[0486] Step 6: Synthesis of methyl (2-(((5-bromo-7-cyano-lH-indol-2-yl)methyl)cyclopropyl)methyl) methanesulfonate

[0487] Dissolve 5-bromo-2-((2-(hydroxymethyl)cyclopropyl)methyl)-lH-indole-7- carbonitrile (740 mg, 2.42 mmol) and methanesulfonic anhydride (844 mg, 4.85 mmol) in dichloromethane (20 mL), then add triethylamine (1.0 mL, 7.27 mmol), after adding, react for three hours at room temperature. Add water (20 mL) to the reaction solution and extract twice with ethyl acetate (30 mL x 2), combine the organic phase, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain 750 mg of crude product.

[0488] LC-MS (ESI): [M+H] + = 383.0.

[0489] Step 7: Synthesis of 6-bromo-l a,2,9,9a-tetrahydro-lH-cyclopropane[4,5]pyrido[l,2- a]indole-4-carbonitrile

[0490] Dissolve (2-(((5-bromo-7-cyano-lH-indol-2-yl)methyl)cyclopropyl)methyl methanesulfonate (750 mg, 1.96 mmol) in N,N-dimethylformamide (20 mL), then add potassium carbonate (270 mg, 1.96 mmol), after adding, react overnight at 60°C. Add water (50 mL) to the reaction solution and extract twice with ethyl acetate (50 mL x 2), combine the organic phase, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain crude product, purify the product 200.1 mg by normal silica gel column.

[0491] LC-MS (ESI): [M+H] + = 287.0.

[0492] Step 8: Synthesis of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l a,2,9,9a- tetrahydro-lH-cyclopropane[4,5]pyrido[l,2-a]indole-4-carbonitrile

[0493] Dissolve 6-bromo-l a,2,9,9a-tetrahydro-lH-cyclopropane[4,5]pyrido[l,2-a]indole-4- carbonitrile (130 mg, 0.45 mmol) and pinacol diboronic acid (149.45 mg, 0.59 mmol) in dioxane (15 mL), then add potassium acetate (88.9 mg, 0.91 mmol) and 1,1- bis(diphenylphosphino)ferrocene palladium chloride (66.3 mg, 0.09 mmol), after adding, replace with nitrogen for one minute, react for one hour at 100°C. After natural cooling to room temperature, filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain crude product, purify the product 170.1 mg by normal silica gel column.

[0494] LC-MS (ESI): [M+H] + = 335.2.

[0495] Step 9: Synthesis of methyl 2-(4-cyano-1a,2,9,9a-tetrahydro-1H- cyclopropano[4,5]pyrrolo[1,2-a]indol-6-yl)thiazole-5-carboxylate

[0496] Methyl 2-(4-cyano-1a,2,9,9a-tetrahydro-1H-cyclopropano[4,5]pyrrolo[1,2- a]indol-6-yl)thiazole-5-carboxylate (60 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and water (5 mL), then lithium bromide (149.2 mg, 1.72 mmol) and triethylamine (173.7 mg, 1.72 mmol) were added, and the reaction was carried out at 60°C overnight. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added for extraction, and the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reversed phase C18 column, and the product was obtained after freeze-drying, 43 mg.

[0497] LC-MS (ESI): [M+H] + = 350.1.

[0498] Step 10: Synthesis of 2-(4-cyano-1a,2,9,9a-tetrahydro-1H-cyclopropano[4,5]pyrrolo[1,2-a]indol-6-yl)thiazole-5-carboxylic acid

[0499] Methyl 2-(4-cyano-1a,2,9,9a-tetrahydro-1H-cyclopropano[4,5]pyrrolo[1,2- a]indol-6-yl)thiazole-5-carboxylate (60 mg, 0.17 mmol) was dissolved in acetonitrile (20 mL) and water (5 mL), then lithium bromide (149.2 mg, 1.72 mmol) and triethylamine (173.7 mg, 1.72 mmol) were added, and the reaction was carried out at 60°C overnight. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added for extraction, and the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reversed phase C18 column, and the product was obtained after freeze-drying, 43 mg.

[0500] LC-MS (ESI): [M+H] += 322.1.

[0501] Step 11: Synthesis of 2-((laR,9aR)-4-cyano-la,2,9,9a-tetrahydro-lH- cyclopropyl[4,5]pyrrolo[l,2-a]indol-6-yl)thiazole-5-carboxylic acid, 2-((laS,9aS)-4- cyano-la,2,9,9a-tetrahydro-lH-cyclopropyl[4,5]pyrrolo[l,2-a]indol-6-yl)thiazole-5- carboxylic acid

[0502] SFC resolution of 2-(4-cyano-la,2,9,9a-tetrahydro-lH-cyclopropano[4,5]pyrrolo[l,2- a]indol-6-yl)thiazole-5-carboxylic acid (43 mg, 0.23 mmol) (Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um; Mobile phase: Phase A for CO2, and Phase B for IPA+ACN (0.05% DEA); Gradient elution: 5% to 40% IPA+ACN (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35C; Back Pressure: 100 Bar) gave fraction 3.243 min out peak product compound 21A 11 mg and 3.389 out peak product compound 21B 15 mg.

[0503] LC-MS (ESI): [M+H]+= 322.1;

[0504] Compound 21A: 1 H NMR (400 MHz, DMSO-d6) d = 8.50 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 6.55 (s, 1H), 5.12 (t, J = 6.0 Hz, 1H), 3.76 (t, J = 7.2 Hz, 1H), 3.19-3.13 (m, 1H), 2.95-2.91 (m, 1H), 2.68-2.54 (m, 1H), 2.38-2.34 (m, 1H), 2.12-2.05 (m, 1H), 1.86-1.81 (m, 1H).

[0505] Compound 21B: 1H NMR (400 MHz, DMSO-d6) δ = 8.50 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 6.55 (s, 1H), 5.12 (t, J = 6.0 Hz, 1H), 3.76 (t, J = 8.0 Hz, 1H), 3.19-3.13 (m, 1H), 2.95-2.91 (m, 1H), 2.68-2.58 (m, 1H), 2.38-2.33 (m, 1H), 2.11-2.06 (m, 1H), 1.86-1.82 (m, 1H).

[0506] Example 22: Synthesis of 2-(((3R)-5-cyano-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole-5-carboxylic acid (Compound 22)

[0507] Step 1: Synthesis of (R)-5-bromo-1-(pent-4-en-2-yl)-2-vinyl-1H-indazole-7- carbonitrile

[0508] Dissolve 5-bromo-2-vinyl-1H-indazole-7-carbonitrile (3 g, 12.14 mmol), (S)-pent-4-en-2-ol (2.09 g, 24.28 mmol) in toluene (30 mL), add cyanomethylidene phosphonic acid tributyl ester (16.80 g, 48.57 mmol), replace with nitrogen for three times, stir at 80 °C for 12 hours. Cool to room temperature naturally, concentrate the reaction solution directly under reduced pressure to get the crude product, purify by normal phase silica gel column, concentrate under reduced pressure to get the product 1.05 g.

[0509] LC-MS (ESI): [M+H] + = 315.1.

[0510] Step 2: Synthesis of (R)-2-bromo-6-methyl-6,7-dihydropyrido[1,2-a]indazole-4- carbonitrile

[0511] Dissolve (R)-5-bromo-1-(pent-4-en-2-yl)-2-vinyl-1H-indazole-7-carbonitrile (1000 mg, 3.17 mmol) in dichloromethane (50 mL), add [1,3-bis(2,4,6-trimethylphenyl)tetrahydro-1H-imidazol-2- ylidene]dichloro{[2-(propan-2-yloxy)phenyl]methylene}-lambda6-ruthenium (400 mg, 0.64 mmol), stir at 20 °C for 3 hours. Add water to the reaction solution, extract with dichloromethane, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to get the crude product, purify by normal phase silica gel column, concentrate under reduced pressure to get the product 720 mg.

[0512] LC-MS (ESI): [M+H] = 287.2. +

[0513] Step 3: Synthesis of (3R)-7-bromo-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile

[0514] Dissolve 2,6-bis{1-[(E)-[2,6-di(propan-2-yl)phenyl]hydrazono}ethyl]pyridine (270 mg, 0.56 mmol) and cobalt bromide (660 mg, 2.79 mmol) in tetrahydrofuran (15 mL), replace with nitrogen for three times, add (R)-2-bromo-6-methyl-6,7-dihydropyrido[1,2-a]indole-4- carbonitrile (700 mg, 2.44 mmol), dibromomethane (0.3 mL, 4.20 mmol), zinc (400 mg, 6.12 mmol), zinc bromide (620 mg, 2.79 mmol) at room temperature, stir for 12 hours at 40 °C. Cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a crude product, purify with normal phase silica gel column, concentrate under reduced pressure to obtain the product 306 mg.

[0515] LC-MS (ESI): [M+H] = 301.0. +

[0516] Step 4: Synthesis of (3R)-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile

[0517] Dissolve (3R)-7-bromo-3-methyl-1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2- a]indole-5-carbonitrile (300 mg, 1.00 mmol), pinacol diboronic acid (328.8 mg, 1.29 mmol), potassium acetate (195.5 mg, 1.99 mmol), 1,1-bis(diphenylphosphino) ferrocene palladium chloride (72.9 mg, 0.10 mmol) in dioxane (10 mL), replace with nitrogen for three times, stir for 1 hour at 100 °C. Cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a crude product, purify with normal phase silica gel column, concentrate under reduced pressure to obtain the product 310 mg.

[0518] LC-MS (ESI): [M+H] = 287.2.​​+ = 349.0.

[0519] Step 5: Synthesis of methyl 2-((3R)-5-cyano-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole-5-carboxylate

[0520] (3R)-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1a,2,3,9b-tetrahydro- 1H-cyclopropa[3,4]pyrrolo[1,2-a]indole-5-carbonitrile (300 mg, 0.86 mmol), methyl 2- bromothiazole-5-carboxylate (478.2 mg, 2.15 mmol), palladium acetate (38.7 mg, 0.17 mmol), 4,5-bis(diphenylphosphanyl)-9,9-dimethylheptane (99.7 mg, 0.17 mmol), potassium phosphate (365.7 mg, 1.72 mmol) were dissolved in dioxane (10 mL) and water (2 mL), replaced with nitrogen for three times, stirred at 100 °C for 2 hours. Naturally cooled to room temperature, the reaction solution was added with water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 206 mg.

[0521] LC-MS (ESI): [M+H] + = 364.0.

[0522] Step 6: Synthesis of 2-(((3R)-5-cyano-3-methyl-1a,2,3,9b-tetrahydro-1H- cyclopropa[3,4]pyrrolo[1,2-a]indol-7-yl)thiazole-5-carboxylic acid

[0523] Methyl 2-((3R)-5-cyano-3-methyl-1a,2,3,9b-tetrahydro-1H-cyclopropa[3,4]pyrrolo[1,2- a]indol-7-yl)thiazole-5-carboxylate (200 mg, 0.55 mmol) was dissolved in acetonitrile (5 mL), saturated aqueous lithium bromide solution (5 mL) and triethylamine (5 mL, 35.97 mmol) were added, and stirred at 50 °C for 12 hours. Naturally cooled to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, added with water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain the product 20 mg.

[0524] LC-MS (ESI): [M+H] + = 350.1;

[0525] LC-MS (ESI): [M+H]1 H NMR (400 MHz, DMSO-d6) δ = 8.34 (d, J = 1.2 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.92 (s, 1H), 6.74 (s, 1H), 5.21-5.01 (m, 1H), 2.57 (d, J = 9.6 Hz, 1H), 2.19 (t, J = 4.8, 8.4 Hz, 1H), 1.81-1.68 (m, 1H), 1.57-1.50 (m, 1H), 1.49-1.40 (m, 3H), 1.31 (t, J = 4.4, 8.4 Hz, 1H), 0.43 (q, J = 4.4 Hz, 1H).

[0526] Example 23: Synthesis of 2-(8-cyano-1a,2,3,9a-tetrahydro-1H- cyclopropa[5,6]pyrido[1,2-a]indol-6-yl)thiazole-5-carboxylic acid (Compound 23)

[0527] Step 1: Synthesis of 2-bromo-6-hydroxy-6,7,8,9-tetrahydropyrido[1,2- a]indole-4-carboxylic acid methyl ester

[0528] 2-bromo-6-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-4-carboxylic acid methyl ester (3200 mg, 11.07 mmol) was dissolved in tetrahydrofuran (300 mL), diisobutylaluminum hydride solution in toluene (22.1 mL, 22.14 mmol) was added at 0 °C, and stirring was continued for 2 hours. To the reaction solution was added saturated ammonium chloride solution and ethyl acetate solution at 0 °C for quenching, and extraction was performed. The organic phase was washed with 1 molar hydrochloric acid, and the organic phase was concentrated under reduced pressure to obtain a crude product. Purification was performed by normal phase silica gel column chromatography, and the product was obtained by concentration under reduced pressure. Yield: 3.01 g.

[0529] LC-MS (ESI): [M+H] + = 291.1.

[0530] Step 2: Synthesis of 2-bromo-8,9-dihydropyrido[1,2-a]indole-4-carbonitrile

[0531] 2-bromo-6-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-4-carbonitrile (3000 mg, 10.30 mmol) was dissolved in dichloromethane (100 mL), methylsulfonic anhydride (3500 mg, 20.11 mmol), and triethylamine (6 mL, 43.17 mmol) were added, and stirring was performed at 20 °C for 2 hours. Water was added, and extraction was performed with dichloromethane. The organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification was performed by normal phase silica gel column chromatography, and the product was obtained by concentration under reduced pressure. Yield: 2.3 g.

[0532] LC-MS (ESI): [M+H] + = 273.1.

[0533] Step 3: Synthesis of 6-bromo-1a,2,3,9a-tetrahydro-1H-cyclopropane[5,6]pyrido[1,2- a]indole-8-carbonitrile

[0534] In a flow chemistry lab, 2-bromo-8,9-dihydropyrido[1,2-a]indole-4-carbonitrile (1000 mg, 3.66 mmol) was dissolved in dichloromethane (50 mL), and the above solution, a solution of diazomethane (769 mg, 18.31 mmol) in dimethyltetrahydrofuran, and a solution of palladium acetate (82.20 mg, 0.37 mmol) in dichloromethane were pumped into a fluidic reaction channel at -20 °C and flowed out, respectively, using a peristaltic pump. The whole process lasted for 10 minutes. After the reaction mixture was allowed to warm to room temperature and stirred for another 10 minutes, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the product 1.03 g.

[0535] LC-MS (ESI): [M+H] + = 287.1.

[0536] Step 4: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1a,2,3,9a- tetrahydro-1H-cyclopropane[5,6]pyrido[1,2-a]indole-8-carbonitrile

[0537] 6-bromo-1a,2,3,9a-tetrahydro-1H-cyclopropane[5,6]pyrido[1,2-a]indole-8- carbonitrile (1000 mg, 3.48 mmol), bis(pinacolato)diboron (1000 mg, 4.53 mmol), 1,1'- bis(diphenylphosphino)ferrocene palladium chloride (255 mg, 0.35 mmol), potassium acetate (685 mg, 6.98 mmol) were dissolved in dioxane (20 mL), and the reaction mixture was stirred at 100 °C for 12 hours after being replaced with nitrogen three times. The reaction mixture was allowed to cool to room temperature, and the reaction mixture was extracted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to give the product 610 mg.

[0538] LC-MS (ESI): [M+H] + = 335.1.

[0539] Step 5: Synthesis of methyl 2-(8-cyano-1a,2,3,9a-tetrahydro-1H-cyclopropane[5,6]pyrido[1,2- a]indol-6-yl)thiazole-5-carboxylate

[0540] To a solution of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-la,2,3,9a- tetrahydro-lH-cyclopropa[5,6]pyrido[l,2-a]indole-8-carbonitrile (600 mg, 1.80 mmol), methyl 2-bromothiazole-5-carboxylate (800 mg, 3.60 mmol), palladium acetate (100 mg, 0.45 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylheptane (210 mg, 0.36 mmol), potassium phosphate (850 mg, 3.69 mmol) in dioxane (15 mL) and water (2 mL) was purged with nitrogen for 3 times, stirred at 100 °C for 12 h, cooled to room temperature naturally, the reaction solution was added to water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column and reversed phase C18 column, and then lyophilized to give the product 53 mg.

[0541] LC-MS (ESI): [M+H] + = 350.1;

[0542] Step 6: Synthesis of 2-(8-cyano-la,2,3,9a-tetrahydro-lH-cyclopropa[5,6]pyrido[l,2- a]indol-6-yl)thiazole-5-carboxylic acid

[0543] To a solution of methyl 2-(8-cyano-la,2,3,9a-tetrahydro-lH-cyclopropa[5,6]pyrido[l,2- a]indol-6-yl)thiazole-5-carboxylate (30 mg, 0.09 mmol) in acetonitrile (1 mL) was added saturated aqueous lithium bromide (1 mL) and triethylamine (1 mL, 7.19 mmol), stirred at 50 °C for 12 h, cooled to room temperature naturally, the reaction solution was added to water and extracted with ethyl acetate, the aqueous phase was adjusted to pH = 3 by adding 1 mol / L hydrochloric acid, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure to give a crude product, which was purified by reversed phase C18 column and lyophilized to give the product 11.2 mg.

[0544] LC-MS (ESI): [M+H] + = 336.1;

[0545] 1 H NMR (400 MHz, DMSO-d6) δ = 8.31 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 6.45 (s, 1H), 2.84-2.77 (m, 2H), 2.05-1.89 (m, 1H), 1.82-1.74 (m, 1H), 1.48-1.41 (m, 1H), 1.13 (t, J = 6.8 Hz, 2H), 0.75-0.63 (m, 1H).

[0546] Example 24: Synthesis of 2-(4-cyano-7,7-difluoro-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid (Compound 24)

[0547] Step 1: Synthesis of 5-(2-amino-5-bromo-3-cyanophenyl)pent-4-enoic acid ethyl ester

[0548] Dissolve 2-amino-5-bromo-3-iodobenzene-l-carbonitrile (10.0 g, 30.97 mmol) and pent-4-ynoic acid ethyl ester (4.7 g, 37.16 mmol) in acetonitrile (240 mL), then add cuprous iodide (2.9 g, 15.48 mmol), dichlorobis(triphenylphosphine)palladium (2.4 g, 3.10 mmol) and triethylamine (80 mL), replace with nitrogen for three times after adding, stir at 50 °C overnight. After natural cooling to room temperature, add water (300 mL) and ethyl acetate (500 mL) to the reaction solution, extract the organic phase, wash the organic phase twice with saturated sodium chloride solution (100 mL x 2), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by normal phase silica gel column to obtain 8.5 g of the product.

[0549] LC-MS (ESI): [M+H] + = 322.0.

[0550] Step 2: Synthesis of 3-(5-bromo-7-cyano-lH-indol-2-yl)propanoic acid ethyl ester

[0551] Dissolve 5-(2-amino-5-bromo-3-cyanophenyl)pent-4-enoic acid ethyl ester (8.5 g, 26.47 mmol) in N,N-dimethylformamide (300 mL), then add cuprous iodide (10.1 g, 52.93 mmol), replace with nitrogen for one minute after adding, and react at 100 °C overnight. Add water (1000 mL) and ethyl acetate (1000 mL) to the reaction solution, extract the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is purified by normal phase silica gel column to obtain 3.1 g of the product.

[0552] LC-MS (ESI): [M+H] + = 322.0.

[0553] Step 3: Synthesis of 3-(5-bromo-l-(2-(tert-butoxy)-2-oxoethyl)-7-cyano-lH-indol-2- yl)propanoic acid ethyl ester

[0554] Ethyl 3-(5-bromo-7-cyano-lH-indol-2-yl)propanoate (2.0 g, 6.23 mmol) and tert-butyl 2-bromoacetate (1.8 mL, 12.45 mmol) were dissolved in N,N-dimethylformamide (30 mL), then cesium carbonate (4.1 g, 12.45 mmol) was added, and the reaction was allowed to proceed at 60 °C overnight. The reaction solution was added to water (100 mL) and extracted with ethyl acetate (100 mL x 2), and the organic phase was combined after extraction, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain the product 2.7 g.

[0555] LC-MS (ESI): [M+H] + = 434.1.

[0556] Step 4: Synthesis of tert-butyl 2-bromo-4-cyano-7-oxo-6,7,8,9-tetrahydropyrido[l,2- a]indole-6-carboxylate

[0557] Ethyl 3-(5-bromo-l-(2-(tert-butoxy)-2-oxoethyl)-7-cyano-lH-indol-2-yl)propanoate (2.2 g, 5.05 mmol) was dissolved in tetrahydrofuran (50 mL), then potassium tert-butoxide (10 mL, 10.00 mmol, 1 M) was added, and the reaction was allowed to proceed at 0 °C for two hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain the product 2.3 g.

[0558] LC-MS (ESI): [M+H] + = 390.0.

[0559] Step 5: Synthesis of 2-bromo-7-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile

[0560] Tert-butyl 2-bromo-4-cyano-7-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indole-6-carboxylate (2.1 g, 5.39 mmol) was dissolved in toluene (50 mL), then silica gel (2.2 g) was added, and the reaction was allowed to proceed at 120 °C for three hours. The reaction solution was directly distilled under reduced pressure to obtain a crude product, which was purified by normal silica gel column to obtain the product 1.4 g.

[0561] LC-MS (ESI): [M+H] + = 290.0.

[0562] Step 6: Synthesis of 2-bromo-7,7-difluoro-6,7,8,9-tetrahydropyrido[l,2-a]indole-4- carbonitrile

[0563] Dissolve 2-bromo-7-oxo-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (690 mg, 2.39 mmol) in dichloromethane (10 mL), then add diethylaminosulfur trifluoride (1.6 mL, 11.93 mmol) at -78 °C, slowly return to room temperature after adding, react for two hours. Add water (50 mL) and dichloromethane (50 mL) to the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the product 551 mg.

[0564] LC-MS (ESI): [M+H] + = 312.0.

[0565] Step 7: Synthesis of methyl 2-(4-cyano-7,7-difluoro-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylate

[0566] Dissolve 2-bromo-7,7-difluoro-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (250 mg, 0.80 mmol) and methyl thiazole-5-carboxylate (345 mg, 2.41 mmol) in toluene (15 mL), then add palladium acetate (36 mg, 0.16 mmol), potassium carbonate (333 mg, 2.41 mmol) and tricyclohexylphosphine (45 mg, 0.16 mmol), add at 100 °C overnight after adding. After cooling to room temperature, add water (50 mL) and ethyl acetate (50 mL) to the reaction solution, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product, which is purified by normal silica gel column to obtain the product 41 mg.

[0567] LC-MS (ESI): [M+H] + = 374.1.

[0568] Step 8: Synthesis of 2-(4-cyano-7,7-difluoro-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)thiazole-5-carboxylic acid

[0569] Methyl 2-(4-cyano-7,7-difluoro-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylate (40 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL) and water (2 mL), lithium bromide (92 mg, 1.07 mmol), triethylamine (108 mg, 1.07 mmol) were added, and the reaction was allowed to react at 50 °C for 12 hours. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added and extracted, the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reversed-phase C18 column and freeze-dried to obtain the product 3.5 mg, respectively.

[0570] LC-MS (ESI): [M+H] + = 360.1;

[0571] Compound 24: 1 H NMR (400 MHz, DMSO-d6) d = 8.45 (d, J = 1.6 Hz, 1H), 8.16-8.13 (m, 1H), 8.12-8.07 (m, 1H), 6.66-6.62 (m, 1H), 5.01-4.84 (m, 2H), 3.20 (br t, J = 6.8 Hz, 2H), 2.48-2.40 (m, 2H).

[0572] Example 25: Synthesis of 2-(4-cyano-6-isopropyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)thiazole-5-carboxylic acid (Compound 25)

[0573] Step 1: Synthesis of hex-5-ynal

[0574] Dimethyl sulfoxide (8.4 g, 107 mmol) was dissolved in dichloromethane (100 mL), cooled to -78 °C, and oxalyl chloride (9.7 g, 76.42 mmol) was added dropwise and reacted for 30 min. Hex-5-yn-l-ol (5 g, 50.95 mmol) was added dropwise, and stirred at -78 °C for 1 h. Triethylamine (20.6 g, 203.79 mmol) was added, and water (50 mL) and dichloromethane (50 mL) were added to extract the organic phase, which was washed with saturated sodium chloride (25 mL) twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 2 g.

[0575] Step 2: Synthesis of 2-methyloct-7-yn-3-ol

[0576] Hex-5-ynal (1.8 g, 18.72 mmol) was dissolved in tetrahydrofuran (10 mL) and isopropylmagnesium chloride 2.0 M in tetrahydrofuran (14.0 mL, 28.09 mmol) was added dropwise at 0 °C and the reaction was stirred at 25 °C for 12 h. Saturated ammonium chloride aqueous (50 mL) was added and the organic phase was extracted with dichloromethane (50 mL) and washed with saturated sodium chloride (25 mL) twice. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude product which was purified by normal phase silica gel column to obtain the product 2.2 g.

[0577] Step 3: Synthesis of 2-amino-5-bromo-3-(6-hydroxy-7-methyloct-1-yn-1- yl)benzonitrile

[0578] 2-amino-5-bromo-3-iodobenzonitrile (4.6 g, 14.26 mmol) and 2-methyloct-7-yn-3- ol (2 g, 14.26 mmol) were dissolved in acetonitrile (50 mL) and cuprous iodide (1.4 g, 7.13 mmol), dichlorobis(triphenylphosphine)palladium (1.1 g, 1.43 mmol) and triethylamine (25 mL, 179.86 mmol) were added and stirred at 50 °C for 12 h. Water (50 mL) was added and the organic phase was extracted with ethyl acetate (50 mL) and washed with saturated sodium chloride (25 mL) twice. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude product which was purified by normal phase silica gel column to obtain the product 1.5 g.

[0579] LC-MS (ESI): [M+H] + = 337.0;

[0580] Step 4: Synthesis of 5-bromo-2-(4-hydroxy-5-methylhexyl)-1H-indazole-7- carbonitrile

[0581] 2-amino-5-bromo-3-(6-hydroxy-7-methyloct-1-yn-1-yl)benzonitrile (1.3 g, 3.88 mmol) was dissolved in 1-methyl-2-pyrrolidinone (30 mL) and potassium tert-butoxide (870 mg, 7.76 mmol) was added at 0 °C and stirred at 25 °C for 12 h. Water (50 mL) was added and the organic phase was extracted with ethyl acetate (50 mL) and washed with saturated sodium chloride (50 mL) twice. The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude product which was purified by normal phase silica gel column to obtain the product 800 mg.

[0582] Step 5: Synthesis of 2-bromo-6-isopropyl-6,7,8,9-tetrahydropyrido[1,2- a]indazole-4-carbonitrile

[0583] Dissolve 5-bromo-2-(4-hydroxy-5-methylhexyl)-lH-indole-7-carbonitrile (800 mg, 2.39 mmol) in toluene (10 mL), add cyanomethylidene phosphonic acid tributyl ester (1.2 g, 4.77 mmol), heat to 80 °C for 12 h. Concentrate the filtrate under reduced pressure to give a crude product, purify the crude product by normal phase silica gel column to give the product 410 mg.

[0584] LC-MS (ESI): [M+H] + = 319.1;

[0585] Step 6: Synthesis of 26-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile

[0586] Dissolve the starting material 2-bromo-6-isopropyl-6,7,8,9-tetrahydropyrido[l,2- a]indole-4-carbonitrile (350 mg, 1.1 mmol), bis(pinacolato)diboron (331 mg, 1.32 mmol) in dioxane (10 mL), add potassium acetate (324 mg, 3.31 mmol) and 1,1- bis(diphenylphosphino)ferrocene palladium chloride (178 mg, 0.24 mmol), stir at 100 °C for 1 h. Add water (50 mL) and ethyl acetate (50 mL) to extract, wash the organic phase with saturated sodium chloride (50 mL) twice, then dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to give a crude product, purify the crude product by normal phase silica gel column to give the product 300 mg.

[0587] LC-MS (ESI): [M+H] + = 365.2;

[0588] Step 7: Synthesis of methyl 2-(4-cyano-6-isopropyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylate

[0589] The starting materials 26-isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole-4-carboxynitrile (300 mg, 0.82 mmol) and methyl 2-bromothiazolium-5-carboxylate (366 mg, 1.65 mmol) were dissolved in dioxane (5 mL) and water (0.5 mL). Potassium carbonate (341 mg, 2.47 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (120 mg, 0.16 mmol) were added, and the reaction was carried out at 100 °C for 18 h. After extraction with water (50 mL) and ethyl acetate (50 mL), the organic phase was washed twice with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by normal-phase silica gel column chromatography to obtain 200 mg of the product.

[0590] LC-MS(ESI):[M+H] + =380.1;

[0591] Step 8: Synthesis of 2-(4-cyano-6-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazolyl-5-carboxylic acid

[0592] Methyl 2-(4-cyano-6-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazolyl-5-carboxylic acid (200 mg, 0.53 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL). Triethylamine (533 mg, 5.27 mmol) and lithium bromide (453 mg, 5.27 mmol) were added, and the mixture was heated at 50 °C for 12 h. The pH of the reaction solution was adjusted to approximately 3 with 1 mol of hydrochloric acid. The solution was extracted with water (50 mL) and ethyl acetate (50 mL). The organic phase was washed twice with saturated sodium chloride (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase C18 column chromatography and lyophilized to obtain 140 mg of the product.

[0593] LC-MS(ESI):[M+H] + =366.1;

[0594] 1H NMR (400 MHz, DMSO-d6) δ = 8.47 (d, J = 1.8 Hz, 1H), 8.39 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 6.55 (s, 1H), 4.98 - 4.92 (m, 1H), 3.08 - 2.87 (m, 2H), 2.32 - 2.27 (m, 1H), 2.15 - 1.99 (m, 3H), 1.81 - 1.57 (m, 1H), 0.90 (d, J = 6.9 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H).

[0595] Example 26: Synthesis of 2-(4-cyano-6-ethyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid (Compound 26)

[0596] Referring to Example 25, replace isopropyl magnesium bromide with ethyl magnesium bromide to synthesize Compound 26 by a similar method.

[0597] LC-MS (ESI): [M+H] + = 352.2;

[0598] 1 H NMR (400 MHz, DMSO-d6) δ = 13.57 (br s, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 6.50 (s, 1H), 4.93 - 4.88 (m, 1H), 3.40 - 3.34 (m, 2H), 3.13 - 3.05 (m, 1H), 2.96 - 2.86 (m, 1H), 2.21 - 2.14 (m, 1H), 2.09 - 1.99 (m, 1H), 1.92 - 1.72 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H).

[0599] Example 27: Synthesis of 2-(4-cyano-6-cyclopropyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid (Compound 27)

[0600] Referring to Example 25, replace isopropyl magnesium bromide (2A) with cyclopropyl magnesium bromide to synthesize Compound 27 by a similar method.

[0601] LC-MS (ESI): [M+H] + = 364.1;

[0602] 1H NMR (400 MHz, DMSO-d6) δ = 13.57 (br s, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 6.56 (s, 1H), 4.87 - 4.84 (m, 1H), 3.17 - 3.10 (m, 1H), 3.03 - 2.91 (m, 1H), 2.21 - 2.10 (m, 3H), 1.90 - 1.81 (m, 1H), 1.17 - 1.08 (m, 1H), 0.63 - 0.56 (m, 1H), 0.54 - 0.39 (m, 2H), 0.21 - 0.15 (m, 1H).

[0603] Example 28: Compounds 28A, 28B, 28C and 28D

[0604] Step 1: Synthesis of tert-butyldimethyl((4-methyl-6-(trimethylsilyl)hex-5-yn-1- yl)oxy)silane

[0605] The starting material ethynyltrimethylsilane (7.7 g, 60.98 mmol) was dissolved in tetrahydrofuran (70 mL), at -78 °C, lithium diisopropylamide 2M tetrahydrofuran n-heptane mixed solution (39.6 mL, 79.27 mmol) was added, the reaction was carried out for 1 hour, (3-bromopropoxy)(tert-butyl)dimethylsilane (17.0 g, 10.18 mmol) was added dropwise, and stirred at room temperature for 1 hour. Water (200 mL) and ethyl acetate (200 mL) were added to extract, and the organic phase was washed with saturated sodium chloride (250 mL) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product 18 g.

[0606] Step 2: Synthesis of 2-amino-5-bromo-3-(6-((tert-butyldimethylsilyl)oxy)-3- methylhex-1-yn-1-yl)benzonitrile

[0607] To a solution of 2-amino-5-bromo-3-iodobenzonitrile (10 g, 30.97 mmol) and tert-butyldimethyl((4-methyl-6-(trimethylsilyl)hex-5-yn-1-yl)oxy)silane (12.7 g, 34.06 mmol) in acetonitrile (50 mL) was added copper iodide (2.95 g, 15.48 mmol) and bis(triphenylphosphine)palladium dichloride (2.4 g, 3.10 mmol) and triethylamine (43.0 mL, 309.66 mmol). The reaction mixture was stirred at 50 °C for 12 h under nitrogen atmosphere. The reaction mixture was filtered, the filtrate was added to water (200 mL) and ethyl acetate (300 mL), the aqueous layer was extracted with ethyl acetate (200 mL), the organic layers were combined and washed with brine, the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain a crude product which was purified on a silica gel column to obtain 6.5 g.

[0608] LC-MS (ESI): [M+H+2] = 423.1. + = 423.1.

[0609] Step 3: Synthesis of 5-bromo-2-(5-(((tert-butyldimethylsilyl)oxy)pentan-2-yl)-1H- indol-7-carbonitrile

[0610] To a solution of 2-amino-5-bromo-3-(6-((tert-butyldimethylsilyl)oxy)-3- methylhex-1-yn-1-yl)benzonitrile (6.5 g, 15.42 mmol) in N,N-dimethylformamide (180 mL) was added copper iodide (9.8 g, 30.84 mmol). The reaction mixture was stirred at 100 °C for 12 h, cooled to room temperature, filtered and the filtrate was added to water (200 mL) and ethyl acetate (300 mL), the aqueous layer was extracted with ethyl acetate (200 mL), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain a crude product which was purified on a silica gel column to obtain 5.7 g.

[0611] Step 4: Synthesis of tert-butyl 5-bromo-2-(5-(((tert-butyldimethylsilyl)oxy)pentan-2-yl)- 7-cyano-1H-indole-1-carboxylate

[0612] Step 1 : Synthesis of tert-butyl 5-bromo-2-(5-(((tert-butyldimethylsilyl)oxy)pentan-2-yl)- 1 H-indole-7-carboxylate tert-Butyl 5-bromo-2-(5-(((tert-butyldimethylsilyl)oxy)pentan-2-yl)-1 H-indole-7- carboxylate (6.2 g, 11.89 mmol) was dissolved in tetrahydrofuran (120 mL), tetrabutylammonium fluoride (1 M in tetrahydrofuran) (11.9 mL, 11.89 mmol) was added and the reaction was stirred at 25 °C for 12 h. The reaction was diluted with water (200 mL) and ethyl acetate (300 mL), the aqueous phase was extracted with ethyl acetate (200 mL), the organic phases were combined and washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column to give 3.2 g.

[0613] LC-MS (ESI): [M+H+2] = 407.0. + = 523.1.

[0614] Step 5: Synthesis of tert-butyl 5-bromo-7-cyano-2-(5-hydroxypentan-2-yl)-1 H-indole-1- carboxylate

[0615] tert-Butyl 5-bromo-2-(5-(((tert-butyldimethylsilyl)oxy)pentan-2-yl)-1 H-indole-7- carboxylate (6.2 g, 11.89 mmol) was dissolved in tetrahydrofuran (120 mL), tetrabutylammonium fluoride (1 M in tetrahydrofuran) (11.9 mL, 11.89 mmol) was added and the reaction was stirred at 25 °C for 12 h. The reaction was diluted with water (200 mL) and ethyl acetate (300 mL), the aqueous phase was extracted with ethyl acetate (200 mL), the organic phases were combined and washed with brine, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by silica gel column to give 3.2 g.

[0616] LC-MS (ESI): [M+H] = 407.0. + = 523.1.

[0617] Step 6: Synthesis of tert-butyl 5-bromo-7-cyano-2-(5-oxopentan-2-yl)-1 H-indole-1- carboxylate

[0618] The starting material tert-butyl 5-bromo-7-cyano-2-(5-hydroxypentan-2-yl)- lH-indole-l-carboxylate (3.2 g, 7.86 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (5 g, 11.78 mmol) was added. The reaction was carried out at 25 °C for 12 h. The reaction solution was added to water (200 mL) and ethyl acetate (300 mL), and the aqueous phase was extracted with ethyl acetate (200 mL). The organic phase was combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel to obtain 1.7 g.

[0619] LC-MS (ESI): [M+H] + = 405.0.

[0620] Step 7: Synthesis of tert-butyl 5-bromo-7-cyano-2-(5-hydroxyhexan-2-yl)-lH- indole-l-carboxylate

[0621] The starting material tert-butyl 5-bromo-7-cyano-2-(5-hydroxypentan-2-yl)- lH-indole-l-carboxylate (3.2 g, 7.86 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (5 g, 11.78 mmol) was added. The reaction was carried out at 25 °C for 12 h. The reaction solution was added to water (200 mL) and ethyl acetate (300 mL), and the aqueous phase was extracted with ethyl acetate (200 mL). The organic phase was combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel to obtain 1.7 g.

[0622] LC-MS (ESI): [M+H] + = 421.1.

[0623] Step 8: Synthesis of 5-bromo-2-(5-hydroxyhexan-2-yl)-lH-indole-7-carbonitrile

[0624] Tert-butyl 5-bromo-7-cyano-2-(5-hydroxyhexan-2-yl)-lH-indole-l-carboxylate (1 g, 2.37 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL, 26.93 mmol) was added. The reaction was stirred at 25 °C for 1 h. The reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate solution, and the reaction solution was added to water (200 mL) and ethyl acetate (300 mL). The aqueous phase was extracted with ethyl acetate (200 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel to obtain 500 mg.

[0625] LC-MS (ESI): [M+H] + = 321.0.

[0626] Step 9: Synthesis of 2-bromo-6,9-dimethyl-6,7,8,9-tetrahydropyrido[l,2- a]indole-4-carbonitrile

[0627] 5-bromo-2-(5-hydroxyhexan-2-yl)-lH-indole-7-carbonitrile (500 mg, 1.56 mmol) was dissolved in toluene (5 mL), and cyanomethylphosphonic acid tributyl ester (563 mg, 2.33 mmol) was added, and heated to 80 °C for 12 hours. The reaction was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column to give the product 400 mg.

[0628] LC-MS (ESI): [M+H] + = 305.1.

[0629] Step 10: Synthesis of 6,9-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile

[0630] 2-bromo-6,9-dimethyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (360 mg, 1.19 mmol), and pinacol diboron (445 mg, 1.78 mmol) were dissolved in dioxane (5 mL), and potassium acetate (350 mg, 3.57 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium chloride (173 mg, 0.24 mmol) were added, and stirred at 100 °C for 1 hour. Water (100 mL) and ethyl acetate (100 mL) were added and extracted, and the organic phase was washed with saturated sodium chloride (100 mL) twice, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column to give the product 400 mg.

[0631] LC-MS (ESI): [M+H] + = 351.1.

[0632] Step 11: Synthesis of methyl 2-(4-cyano-6,9-dimethyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylate

[0633] The starting material 6,9-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 6,7,8,9-tetrahydropyrido[1,2-a]indole-4-carbonitrile (400 mg, 1.14 mmol) was dissolved in dioxane (10 mL) and water (1 mL), 45-bisdiphenylphosphino-99-dimethyl- oxazone (66 mg, 0.11 mmol), palladium acetate (51 mg, 0.23 mmol), potassium phosphate (789 mg, 3.43 mmol) were added. The reaction was heated to 100 °C under nitrogen for 1 h. Water (100 mL) and ethyl acetate (100 mL) were added and the organic phase was washed twice with saturated sodium chloride (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by normal phase silica gel column to give the product 360 mg.

[0634] LC-MS (ESI): [M+H] = 366.1. +

[0635] Step 12: Synthesis of 2-(4-cyano-6,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2- a]indol-2-yl)thiazole-5-carboxylic acid

[0636] Methyl 2-(4-cyano-6,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)thiazole-5- carboxylate (360 mg, 0.99 mmol) was dissolved in water (20 mL) and acetonitrile (20 mL), lithium bromide (847 mg, 9.85 mmol) and triethylamine (997 mg, 9.85 mmol) were added. The reaction was carried out at 50 °C for 12 h. The reaction was adjusted to pH = 3 with 1 M hydrochloric acid and water (100 mL) and ethyl acetate (100 mL) were added. The organic phase was washed twice with saturated sodium chloride (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by reverse phase C18 column and lyophilized to give the product 220 mg.

[0637] LC-MS (ESI): [M+H] = 352.1. +

[0638] Step 13: Synthesis of compounds 28A, 28B, 28C and 28D

[0639] ​​SFC resolution of 2-(4-cyano-6,9-dimethyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid (220 mg, 0.63 mmol) (Column: Chiralpak IG-3 50*4.6 mm I.D., 3 um; Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 10% to 60%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 C; Back Pressure: 100 Bar) gave compound 28A 45 mg, 1.945 min out peak, compound 28B 47 mg, 2.225 min out peak, compound 28C 35 mg, 2.577 min out peak and compound 28D 35 mg, 2.677 min out peak.

[0640] LC-MS (ESI): [M+H] + = 352.1;

[0641] Compound 28A: 1 H NMR (400 MHz, DMSO-d6) δ = 8.44 (d, J = 1.6 Hz, 1H), 8.33-8.24 (m, 1H), 8.17-8.09 (m, 1H), 6.56 (s, 1H), 5.17 (br s, 1H), 3.46-3.38 (m, 1H), 2.42-2.31 (m, 1H), 2.23-2.11 (m, 1H), 1.90-1.73 (m, 1H), 1.58-1.48 (m, 1H), 1.46-1.41 (m, 3H), 1.35-1.28 (m, 3H).

[0642] Compound 28B: 1 H NMR (400 MHz, DMSO-d6) δ = 8.46-8.43 (m, 1H), 8.31 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 6.62 (s, 1H), 5.20 (br t, J = 5.6 Hz, 1H), 3.08-2.92 (m, 1H), 2.30-2.16 (m, 1H), 2.01 (br d, J = 13.6 Hz, 1H), 1.94-1.83 (m, 1H), 1.73-1.60 (m, 1H), 1.40 (d, J = 6.0 Hz, 6H).

[0643] Compound 28C:1 H NMR (400 MHz, DMSO-d6) d = 8.44 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 5.20 (quin, J = 6.0 Hz, 1H), 3.40 (br s, 1H), 2.31 - 2.17 (m, 1H), 2.01 (br d, J = 13.6 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.76 - 1.58 (m, 1H), 1.41 (dd, J = 1.2, 6.8 Hz, 6H).

[0644] Compound 28D: 1 H NMR (400 MHz, DMSO-d6) d = 8.44 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 6.63 (d, J = 1.6 Hz, 1H), 5.20 (quin, J = 6.0 Hz, 1H), 3.40 (br s, 1H), 2.31 - 2.17 (m, 1H), 2.01 (br d, J = 13.6 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.76 - 1.58 (m, 1H), 1.41 (dd, J = 1.2, 6.8 Hz, 6H).

[0645] Example 29: (S)-2-(6-cyano-4-methyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid and (R)-2-(6-cyano-4-methyl-l,2,3,4- tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5-carboxylic acid (Compounds 29A and 29B)

[0646] Step 1 : Synthesis of 2-amino-5-bromo-3-(3,3-diethoxyprop-l-yne-l-yl)benzonitrile

[0647] To a solution of 2-amino-5-bromo-3-iodobenzonitrile (10 g, 30.97 mmol) and 3,3-diethoxyprop-1-yne (6 g, 46.81 mmol) in acetonitrile (250 mL) was added copper iodide (2.9 g, 15.48 mmol), dichlorobis(triphenylphosphine)palladium (2.41 g, 3.10 mmol) and triethylamine (18.2 g, 179.86 mmol) and stirred at 50 °C for 12 h. Water (500 mL) and ethyl acetate (500 mL) was added and the organic phase was washed with saturated sodium chloride (250 mL) twice. The organic phase was then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product which was purified by normal phase silica gel column and concentrated under reduced pressure to give the product 8 g.

[0648] Step 2: Synthesis of 5-bromo-2-(diethoxymethyl)-lH-indole-7-carbonitrile

[0649] 2-amino-5-bromo-3-(3,3-diethoxyprop-l-yne-l-yl)benzonitrile (7.5 g, 23.21 mmol) was dissolved in 1-methyl-2-pyrrolidinone (70 mL), potassium tert-butoxide (5.21 g, 46.41 mmol) was added dropwise, and the reaction was allowed to proceed at 25 °C for 12 h. Water (200 mL) and ethyl acetate (300 mL) were added to the reaction mixture, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to obtain the product (6.2 g).

[0650] Step 3: Synthesis of 5-bromo-2-formyl-lH-indole-7-carbonitrile

[0651] 5-bromo-2-(diethoxymethyl)-lH-indole-7-carbonitrile (6.2 g, 19.18 mmol) was dissolved in tetrahydrofuran (80 mL), and acetic acid (10.8 mL, 191.84 mmol) and water (8 mL, 443.95 mmol) were added. The reaction was allowed to proceed at 50 °C for 12 h. The reaction mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, and water (50 mL) and ethyl acetate (300 mL) were added to the reaction mixture. The organic phase was washed with saturated sodium chloride solution (100 mL) twice, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to obtain the product (4.5 g).

[0652] Step 4: Synthesis of 5-bromo-2-(((2-hydroxypropyl)amino)methyl)-lH-indole-7- carbonitrile

[0653] 5-bromo-2-formyl-lH-indole-7-carbonitrile (1 g, 4.01 mmol) was dissolved in 1-methyl-2-pyrrolidinone (10 mL), and acetic acid (2 mL, 35.50 mmol) and 1-aminopropanol (1.9 mL, 24.09 mmol) were added. The reaction was allowed to proceed at 25 °C for 1 h, and then sodium triacetoxyborohydride (8.5 g, 40.15 mmol) was added. The reaction was allowed to proceed at 25 °C for 12 h. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to obtain the product (700 mg).

[0654] LC-MS (ESI): [M+H] + = 308.1.

[0655] Step 5: Synthesis of tert-butyl ((5-bromo-7-cyano-lH-indol-2- yl)methyl)(2-hydroxypropyl)carbamate

[0656] Dissolve 5-bromo-2-(((2-hydroxypropyl)amino)methyl)-lH-indole-7- carbonitrile (700 mg, 2.27 mmol) in water (5 mL) and tetrahydrofuran (5 mL), add sodium bicarbonate (1.9 g, 22.71 mmol) and di-tert-butyl dicarbonate (743 mg, 3.41 mmol), stir at 25 °C for 2 h, add water (50 mL) and ethyl acetate (50 mL) and extract the organic phase with saturated sodium chloride (25 mL) twice, then dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to give a crude product, which is purified by normal phase silica gel column and concentrated under reduced pressure to give the product 650 mg.

[0657] LC-MS (ESI): [M+H] + = 313.0;

[0658] Step 6: Synthesis of tert-butyl 8-bromo-6-cyano-4-methyl-3,4- dihydropyrazino[l,2-a]indole-2(lH)-carboxylate

[0659] Dissolve tert-butyl ((5-bromo-7-cyano-lH-indol-2-yl)methyl)(2- hydroxypropyl)carbamate (600 mg, 1.47 mmol) in toluene (10 mL), add cyanomethylidene phosphonic acid tributyl ester (709 mg, 2.94 mmol), and heat to 80 °C under nitrogen protection for 12 h. Concentrate under reduced pressure to give a crude product, which is purified by normal phase silica gel column and concentrated under reduced pressure to give the product 550 mg.

[0660] LC-MS (ESI): [M+H] + = 334.0;

[0661] Step 7: Synthesis of methyl 2-(2-(tert-butoxycarbonyl)-6-cyano-4- methyl-l,2,3,4-tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5-carboxylate

[0662] tert-Butyl 8-bromo-6-cyano-4-methyl-3,4-dihydropyrazino[l,2-a]indole-2(lH)- carboxylate (600 mg, 1.54 mmol) was dissolved in toluene (4 mL), added methyl thiazole-5-carboxylate (592 mg, 3.46 mmol), palladium acetate (103.55 mg, 0.46 mmol), potassium carbonate (424 mg, 3.07 mmol), tricyclohexylphosphine (129 mg, 0.46 mmol), reacted at 120 °C for 12 h. Added water (50 mL) and ethyl acetate (50 mL) to extract, the organic phase was washed with saturated sodium chloride (25 mL) twice, then the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain 650 mg of the product.

[0663] LC-MS (ESI): [M+H] + = 453.2;

[0664] Step 8: Synthesis of methyl 2-(6-cyano-4-methyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylate

[0665] Methyl 2-(2-(tert-butoxycarbonyl)-6-cyano-4-methyl-l,2,3,4- tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5-carboxylate (400 mg, 0.88 mmol) was dissolved in dichloromethane (3 mL) and added into trifluoroacetic acid (3 mL, 40.39 mmol), stirred at 25 °C for 0.5 h. Concentrated under reduced pressure to obtain a crude product, which was freeze-dried with water to obtain 300 mg of the product.

[0666] LC-MS (ESI): [M+H] + = 353.2;

[0667] Step 9: Synthesis of 2-(6-cyano-4-methyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid

[0668] Methyl 2-(6-cyano-4-methyl-l,2,3,4-tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5- carboxylate (80 mg, 0.23 mmol) was dissolved in acetonitrile (5 mL), added water (5 mL), triethylamine (229 mg, 2.27 mmol), lithium bromide (195 mg, 2.27 mmol), stirred at 50 °C for 12 h. The reaction solution was adjusted to pH = 7 with 1 mol hydrochloric acid, added water (50 mL) and ethyl acetate (50 mL) to extract, the organic phase was washed with saturated sodium chloride (25 mL) twice, then the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain 15 mg of the product.

[0669] LC-MS (ESI): [M+H] + = 339.1;

[0670] 1H NMR (400 MHz, DMSO-d6) d = 8.60 (d, J = 1.6 Hz, 1H), 8.44-8.40 (m, 1H), 8.27 (d, J = 1.6 Hz, 1H), 6.74 (s, 1H), 5.31-5.21 (m, 1H), 4.59 (d, J = 16.4 Hz, 1H), 4.41 (br d, J = 16.6 Hz, 1H), 3.63 (br d, J = 2.3 Hz, 1H), 3.20-2.99 (m, 2H), 1.57 (d, J = 6.6 Hz, 3H).

[0671] Step 10: Synthesis of (S)-2-(6-cyano-4-methyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid and (R)-2-(6-cyano-4-methyl-l,2,3,4- tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5-carboxylic acid (Compound 29A and 29B)

[0672] The racemic product (R)-2-(6-cyano-4-methyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid (35 mg, 0.10 mmol) was purified by SFC (Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um; Mobile phase: Phase A for CO2, and Phase B for MeOH (0.05% DEA); Gradient elution: MeOH (0.05% DEA) in CO2 from 20% to 60%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 C; Back Pressure: 100 Bar) to give the product 29A 3 mg at 1.457 min peak and the product 29B 1.3 mg at 1.647 min peak.

[0673] LC-MS (ESI): [M+H] + = 339.1;

[0674] Compound 29A: 1H NMR (400 MHz, DMSO-d6) δ = 8.48 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.15 (d, J = 1.6 Hz, 1H), 6.51 (s, 1H), 4.96 (br d, J = 4.4 Hz, 1H), 4.25 (br d, J = 16.8 Hz, 1H), 4.04 (br d, J = 16.4 Hz, 1H), 3.27 (br d, J = 9.2 Hz, 1H), 3.18 - 3.14 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H).

[0675] Compound 29B: 1 H NMR (400 MHz, DMSO-d6) δ = 8.53 (s, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 6.57 (s, 1H), 5.12 - 4.93 (m, 1H), 4.36 (br s, 2H), 3.92 - 3.75 (m, 1H), 3.50 - 3.49 (m, 1H), 1.51 (d, J = 6.4 Hz, 3H).

[0676] Example 30: (S)-2-(6-cyano-2,4-dimethyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid and (R)-2-(6-cyano-2,4-dimethyl-l,2,3,4- tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5-carboxylic acid (Compounds 30A and 30B)

[0677] Step 1: Synthesis of methyl 2-(6-cyano-2,4-dimethyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylate

[0678] Methyl 2-(6-cyano-4-methyl-l,2,3,4-tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5- carboxylate (200 mg, 0.57 mmol) was dissolved in dichloroethane (10 mL), and paraformaldehyde (34 mg, 1.14 mmol), sodium triacetoxyborohydride (359 mg, 1.70 mmol), acetic acid (20 mg, 0.28 mmol) were added, and stirred at 25 °C for 12 h. Water (50 mL) and ethyl acetate (50 mL) were added to extract, and the organic phase was washed with saturated sodium chloride (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 120 mg.

[0679] LC-MS (ESI): [M+H] + = 367.1.

[0680] Step 2: Synthesis of 2-(6-cyano-2,4-dimethyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid

[0681] Methyl 2-(6-cyano-2,4-dimethyl-l,2,3,4-tetrahydropyrazino[l,2-a]indol-8-yl)thiazole- 5-carboxylate (120 mg, 0.33 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL), triethylamine (331 mg, 3.27 mmol), lithium bromide (281 mg, 3.27 mmol) were added, heated at 50 °C for 12 h. The reaction was adjusted to pH = 3 with 1 mol / L hydrochloric acid, water (50 mL) and ethyl acetate (50 mL) were added and extracted, the organic phase was washed with saturated sodium chloride (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase C18 column and lyophilized to give the product 68 mg.

[0682] LC-MS (ESI): [M+H] + = 353.0;

[0683] 1 H NMR (400 MHz, DMSO-d6) d = 8.45-8.42 (m, 1H), 8.23 (s, 1H), 8.11 (d, J = 1.2 Hz, 1H), 6.52 (s, 1H), 5.05-4.98 (m, 1H), 4.16 (br d, J = 15.2 Hz, 1H), 3.30 (d, J = 15.6 Hz, 1H), 3.00 (br d, J = 11.6 Hz, 1H), 2.75-2.69 (m, 1H), 2.40 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H).

[0684] Step 3: Synthesis of (S)-2-(6-cyano-2,4-dimethyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid, (R)-2-(6-cyano-2,4-dimethyl-l,2,3,4- tetrahydropyrazino[l,2-a]indol-8-yl)thiazole-5-carboxylic acid (Compound 30A or 30B)

[0685] The racemic product 2-(6-cyano-2,4-dimethyl-l,2,3,4-tetrahydropyrazino[l,2- a]indol-8-yl)thiazole-5-carboxylic acid (70 mg, 0.20 mmol) was subjected to SFC resolution (Column: Chiralpak AD-3 100 x 4.6 mm I.D., 3 um; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: B in A from 5% to 40%; Flow rate: 2.5 mL / min; Detector: DAD; Column Temp: 35 C; Back Pressure: 100 Bar) to give product 30A 10 mg at 4.492 min and product 30B 10 mg at 4.706 min.

[0686] LC-MS (ESI): [M+H] + = 353.1;

[0687] Compound 30A: 1 H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 1.6 Hz, 1H), 8.23 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 6.52 (s, 1H), 5.02 (br s, 1H), 4.17 (d, J = 14.8 Hz, 1H), 3.31 (d, J = 15.2 Hz, 1H), 3.00 (br d, J = 12.0 Hz, 1H), 2.75 - 2.70 (m, 1H), 2.43 - 2.37 (m, 3H), 1.49 (d, J = 6.4 Hz, 3H).

[0688] Compound 30B: 1 H NMR (400 MHz, DMSO-d6) δ = 8.42 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 6.51 (s, 1H), 5.05 - 4.98 (m, 1H), 4.15 (d, J = 15.2 Hz, 1H), 3.30 (d, J = 16.4 Hz, 1H), 3.00 (br d, J = 12.0 Hz, 1H), 2.72 (dd, J = 3.6, 12.0 Hz, 1H), 2.39 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H).

[0689] Example 31: (R)-2-(6-cyano-4-methyl-3,4-dihydro-1H- [1,4]thiazino[4,3-a]indol-8-yl)thiazole-5-carboxylic acid and (S)-2-(6-cyano-4-methyl- 3,4-dihydro-1H-[1,4]thiazino[4,3-a]indol-8-yl)thiazole-5-carboxylic acid (Compounds 31A and 31B)

[0690] Step 1: Synthesis of 2-(prop-2-yn-1-ylthio)ethan-1-ol

[0691] 2-Mercaptoethan-1-ol (6.6 g, 84.47 mmol) was dissolved in ethanol (200 mL), sodium ethoxide (40 mL, 102.04 mmol) was added at 0 °C, after stirring for 1 hour, 3-bromoprop-1-yne (10 g, 84.06 mmol) was added, after continuing to stir for 30 minutes, after natural rising to room temperature, stirring for 2 hours. The reaction solution was added to saturated ammonium chloride and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal silica gel column and concentrated under reduced pressure to obtain the product 6.0 g.

[0692] Step 2: Synthesis of 2-amino-5-bromo-3-(3-((2-hydroxyethyl)thio)prop-1-yn-1-yl)benzonitrile

[0693] 2-Amino-5-bromo-3-iodobenzonitrile (10 g, 30.97 mmol), 2-(prop-2-yn-1-ylthio)ethan-1-ol (4.5 g, 38.73 mmol), cuprous iodide (0.45 g, 1.42 mmol), bis(triphenylphosphine)palladium dichloride (0.45 g, 0.64 mmol) were dissolved in acetonitrile (30 mL) and triethylamine (150 mL), replaced with nitrogen for 3 times, stirred at 50 °C for 2 hours, naturally cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 6.3 g.

[0694] Step 3: Synthesis of 5-bromo-2-(((2-hydroxyethyl)thio)methyl)-1H-indole-7-carbonitrile

[0695] To a solution of 5-bromo-2-(((2-hydroxyethyl)thio)methyl)-lH-indole-7-carbonitrile (8000 mg, 25.71 mmol) and chlorodimethyl(2-methylpropan-2-yl)silane (4300 mg, 28.53 mmol) in dichloromethane (150 mL) was added imidazole (3.5 g, 51.41 mmol) and stirred at 20 °C for 12 h. The reaction mixture was diluted with water and dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by normal phase silica gel column to give the product 10.3 g.

[0696] Step 4: Synthesis of 5-bromo-2-(((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)methyl)-lH- indole-7-carbonitrile

[0697] To a solution of 5-bromo-2-(((2-hydroxyethyl)thio)methyl)-lH-indole-7-carbonitrile (8000 mg, 25.71 mmol) and chlorodimethyl(2-methylpropan-2-yl)silane (4300 mg, 28.53 mmol) in dichloromethane (150 mL) was added imidazole (3.5 g, 51.41 mmol) and stirred at 20 °C for 12 h. The reaction mixture was diluted with water and dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by normal phase silica gel column to give the product 10.3 g.

[0698] LC-MS (ESI): [M+H] + = 425.2.

[0699] Step 5: Synthesis of tert-butyl 5-bromo-2-(((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)methyl)- 7-cyano-lH-indole-l-carboxylate

[0700] To a solution of 5-bromo-2-(((2-hydroxyethyl)thio)methyl)-lH-indole-7-carbonitrile (8000 mg, 25.71 mmol) and chlorodimethyl(2-methylpropan-2-yl)silane (4300 mg, 28.53 mmol) in dichloromethane (150 mL) was added imidazole (3.5 g, 51.41 mmol) and stirred at 20 °C for 12 h. The reaction mixture was diluted with water and dichloromethane, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by normal phase silica gel column to give the product 10.3 g.

[0701] LC-MS (ESI): [M+H] + = 525.2.

[0702] Step 6: Synthesis of tert-butyl 5-bromo-7-cyano-2-(((2-hydroxyethyl)thio)methyl)- 1H-indole-1-carboxylate

[0703] Tert-butyl 5-bromo-2-(((2-((tert-butyldimethylsilyl)oxy)ethyl)thio)methyl)-7- cyano-1H-indole-1-carboxylate (11.0 g, 20.93 mmol) was dissolved in tetrahydrofuran (120 mL), at 0 °C, added tetrahydrofuran solution of tetrabutylammonium fluoride (25.1 mL, 25.12 mmol), after natural rising to room temperature, continued to stir for 1 hour. The reaction liquid was added water and ethyl acetate extraction, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, purified by normal phase silica gel column, concentrated under reduced pressure to obtain the product 8.03 g.

[0704] LC-MS (ESI): [M+H] + = 411.3.

[0705] Step 7: Synthesis of tert-butyl 5-bromo-7-cyano-2-(((2-oxoethyl)thio)methyl)-1H- indole-1-carboxylate

[0706] 5-Bromo-7-cyano-2-{[(2-hydroxyethyl)thio]methyl}indole-1-carboxylic acid-2- methylpropan-2-yl ester (8.0 g, 19.45 mmol) was dissolved in dichloromethane (200 mL), at 0 °C, added Dess-Martin oxidant (10 g, 23.58 mmol), after natural rising to room temperature, continued to stir for 12 hours. The reaction liquid was added water and dichloromethane, filtered, extracted, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, purified by normal phase silica gel column, concentrated under reduced pressure to obtain the product 6.3 g.

[0707] LC-MS (ESI): [M+H] + = 409.1.

[0708] Step 8: Synthesis of tert-butyl 5-bromo-7-cyano-2-(((2-hydroxypropyl)thio)methyl)- 1H-indole-1-carboxylate

[0709] Tert-butyl 5-bromo-7-cyano-2-(((2-hydroxypropyl)thio)methyl)-lH-indole- 1 -carboxylate (3000 mg, 7.05 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (0.5 mL, 7.05 mmol) was added dropwise slowly, stirred at 20 °C for 2 hours. The reaction was concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column, and concentrated under reduced pressure to obtain the product 2.05 g.

[0710] LC-MS (ESI): [M+H] + = 425.2.

[0711] Step 9: Synthesis of 5-bromo-2-(((2-hydroxypropyl)thio)methyl)-lH-indole-7- carbonitrile

[0712] Tert-butyl 5-bromo-7-cyano-2-(((2-hydroxypropyl)thio)methyl)-lH-indole- 1 -carboxylate (3000 mg, 7.05 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (0.5 mL, 7.05 mmol) was added dropwise slowly, stirred at 20 °C for 2 hours. The reaction was concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column, and concentrated under reduced pressure to obtain the product 2.05 g.

[0713] LC-MS (ESI): [M+H] + = 325.2.

[0714] Step 10: Synthesis of 8-bromo-4-methyl-3,4-dihydro-lH-[l,4]thiazino[4,3- a]indole-6-carbonitrile

[0715] 5-Bromo-2-(((2-hydroxypropyl)thio)methyl)-lH-indole-7-carbonitrile (1200 mg, 3.69 mmol) was dissolved in toluene (60 mL), cyanomethylidene phosphonic acid tributyl ester (2500 mg, 7.23 mmol) was added, replaced with nitrogen for three times, stirred at 80 °C for 12 hours, cooled to room temperature naturally, the reaction was directly concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column, and concentrated under reduced pressure to obtain the product 810 mg.

[0716] LC-MS (ESI): [M+H] + = 309.1.

[0717] Step 11: Synthesis of 4-methyl-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,4-dihydro-lH-[l,4]thiazino[4,3-a]indole-6-carbonitrile

[0718] Dissolve 8-bromo-4-methyl-3,4-dihydro-1H-[1,4]thiazino[4,3-a]indole-6- carbonitrile (600 mg, 1.95 mmol), bis(pinacolato)diboron (740 mg, 2.91 mmol), 1,1- bis(diphenylphosphino)ferrocene palladium chloride (140 mg, 0.19 mmol), potassium acetate (385 mg, 3.92 mmol) in dioxane (15 mL), replace with nitrogen for three times, stir at 100 °C for 1 hour, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a crude product, purify with normal phase silica gel column, concentrate under reduced pressure to obtain the product 620 mg.

[0719] LC-MS (ESI): [M+H] + = 355.2.

[0720] Step 12: Synthesis of methyl 2-(6-cyano-4-methyl-3,4-dihydro-1H- [1,4]thiazino[4,3-a]indol-8-yl)thiazole-5-carboxylate

[0721] Dissolve 4-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4- dihydro-1H-[1,4]thiazino[4,3-a]indole-6-carbonitrile (600 mg, 1.69 mmol), methyl 2- bromothiazole-5-carboxylate (940.22 mg, 4.23 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylheptane (196.00 mg, 0.34 mmol), palladium acetate (76.05 mg, 0.34 mmol), potassium phosphate (718.98 mg, 3.39 mmol) in dioxane (15 mL) and water (1 mL), replace with nitrogen for three times, stir at 100 °C for 12 hours, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain a crude product, purify with normal phase silica gel column, concentrate under reduced pressure to obtain the product 304 mg.

[0722] LC-MS (ESI): [M+H] + = 370.1.

[0723] Step 13: Synthesis of 2-(6-cyano-4-methyl-3,4-dihydro-1H- [1,4]thiazino[4,3-a]indol-8-yl)thiazole-5-carboxylic acid

[0724] Methyl 2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]thiazino[4,3-a]indol-8-yl)thiazole-5- carboxylate (150 mg, 0.41 mmol) was dissolved in acetonitrile (2 mL), saturated aqueous lithium bromide (2 mL), triethylamine (2 mL) was added, stirred at 50 °C for 12 hours, cooled to room temperature naturally, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water and ethyl acetate were added and extracted, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain the product 90 mg

[0725] LC-MS (ESI): [M+H] + = 356.1;

[0726] 1H NMR (400 MHz, DMSO-d6) d = 8.54 (d, J = 1.6 Hz, 1H), 8.42 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 6.63 (s, 1H), 5.41 (dd, J = 3.2, 5.6 Hz, 1H), 4.24-4.14 (m, 1H), 4.09-3.96 (m, 1H), 3.55 (s, 1H), 3.16-3.05 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H).

[0727] Step 14: Synthesis of (R)-2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]thiazino[4,3-a]indol-8- yl)thiazole-5-carboxylic acid, (S)-2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]thiazino[4,3-a]indol- 8-yl)thiazole-5-carboxylic acid (Compound 31A and 31B)

[0728] Racemic 2-(6-cyano-4-methyl-3,4-dihydro-1H-[1,4]thiazino[4,3-a]indol-8-yl)thiazole-5- carboxylic acid (90 mg, 0.25 mmol) was resolved by SFC, concentrated under reduced pressure, and then freeze-dried to obtain the products 31A and 31B after adding water.

[0729] LC-MS (ESI): [M+H] + = 356.1;

[0730] Compound 31A: 1H NMR (400 MHz, DMSO-d6) δ = 8.44 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 3.2 Hz, 1H), 6.63 (s, 1H), 5.52 - 5.32 (m, 1H), 4.29 - 4.13 (m, 1H), 4.10 - 3.97 (m, 1H), 3.63 - 3.52 (m, 1H), 3.20 - 3.07 (m, 1H), 1.63 - 1.55 (m, 3H).

[0731] Compound 31B: 1H NMR (400 MHz, DMSO-d6) δ = 8.47 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 1.6 Hz, 2H), 6.61 (s, 1H), 5.45 - 5.32 (m, 1H), 4.18 (d, J = 17.2 Hz, 1H), 4.07 - 3.94 (m, 1H), 3.53 (dd, J = 3.6, 14.0 Hz, 1H), 3.10 (d, J = 13.6 Hz, 1H), 1.59 - 1.53 (m, 3H).

[0732] Example 32: (S)-2-(6-cyano-4-methyl-2,2-dioxido-3,4-dihydro-lH- [l,4]thiazino[4,3-a]indol-8-yl)thiazole-5-carboxylic acid (Compound 32)

[0733] Compound 31B (20 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL), and m-chloroperoxybenzoic acid (40 mg, 0.23 mmol) was added, and stirred at 20 °C for 1 hour. The reaction solution was added with water and extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by a reversed-phase C18 column and freeze-dried to obtain the product 3 mg.

[0734] LC-MS (ESI): [M+H] + = 388.1;

[0735] 1 1H NMR (400 MHz, DMSO-d6) δ = 8.51 (d, J = 1.6 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 6.81 (s, 1H), 5.71 (d, J = 2.4, 6.4 Hz, 1H), 5.09 - 4.88 (m, 2H), 4.11 (dd, J = 5.6, 14.4 Hz, 1H), 3.82 (d, J = 14.8 Hz, 1H), 1.67 (d, J = 6.8 Hz, 3H).

[0736] Examples 33-39, 43 and 44: Synthesis method according to Example 3

[0737] Example 40: Synthesis of (S)-3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)isoxazole-5-carboxylic acid (Compound 40)

[0738] Step 1: Synthesis of (S)-2-formyl-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-4- carbonitrile

[0739] (S)-2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (2000 mg, 6.92 mmol) was dissolved in tetrahydrofuran (50 mL), n-butyllithium, 2.5 M n-hexane solution (3.3 mL, 8.30 mmol) was added at -78 °C, after adding, it was reacted for half an hour at -78 °C, then N,N-dimethylformamide (0.5 mL, 6.92 mmol) was added, and then it was slowly raised to room temperature and reacted for two hours. The reaction solution was added to ammonium chloride (50 mL) and ethyl acetate (30 mL x 2) was extracted, after extraction, the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 1.65 g.

[0740] LC-MS (ESI): [M+H] + = 239.2;

[0741] Step 2: Synthesis of (S,E)-2-((hydroxyimino)methyl)-6-methyl-6,7,8,9- tetrahydropyrido[l,2-a]indole-4-carbonitrile

[0742] (6S)-2-formyl-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (650 mg, 2.73 mmol) was dissolved in ethanol (10 mL), hydroxylamine hydrochloride (379.11 mg, 5.46 mmol) and triethylamine (1.1 mL, 8.18 mmol) were added, after adding, it was reacted at room temperature overnight. Water (20 mL) was added to the reaction solution and extracted with ethyl acetate (30 mL x 2), the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 485 mg.

[0743] LC-MS (ESI): [M+H] + = 254.3;

[0744] Step 3: Synthesis of (S)-3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)isoxazole-5-carboxylic acid methyl ester

[0745] (S,E)-2-((hydroxyimino)methyl)-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indole-4-carbonitrile (400 mg, 1.58 mmol) and methyl prop-2-ynoate (146.0 mg, 1.74 mmol) were dissolved in acetonitrile (15 mL) and water (5 mL), then iodine benzene diacetate (511.8 mg, 1.58 mmol) was added at zero degree. After the addition, the reaction was carried out at zero degree for one hour. After the reaction was completed, water (20 mL) was added to the reaction solution and extracted with ethyl acetate (25 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain 125 mg of the product.

[0746] LC-MS (ESI): [M+H] = 336.1; +

[0747] Step 4: Synthesis of (S)-3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)isoxazole-5-carboxylic acid

[0748] (S)-3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)isoxazole-5- carboxylic acid methyl ester (100 mg, 0.30 mmol) was dissolved in acetonitrile (10 mL) and water (2 mL), then lithium bromide (259 mg, 2.98 mmol) and triethylamine (301 mg, 2.98 mmol) were added, and the reaction was carried out at 50°C overnight. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added and extracted, and the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and lyophilized to obtain 21 mg of the product.

[0749] LC-MS (ESI): [M+H] = 322.0; +

[0750] 1 ​​H NMR (400 MHz, DMSO-d6) δ = 8.27 (s, 1H), 7.96 (s, 1H), 7.18 (s, 1H), 6.45 (s, 1H), 5.16 (t, J = 4.8 Hz, 1H), 3.08-3.03 (m, 1H), 2.88-2.81 (m, 1H), 2.15-2.07 (m, 1H), 1.98-1.80 (m, 3H), 1.37 (d, J = 6.4 Hz, 3H).

[0751] Example 41: Synthesis of 3-((S)-4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)adamantane-l-carboxylic acid (Compound 41)

[0752] (S)-2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (500 mg, 1.73 mmol) was dissolved in N,N-dimethylformamide (3 mL), pyridine-2,6-dimethylformamidine dihydrochloride (Ligand 2) (85 mg, 0.52 mmol), 3-bromo-adamantane-l-carboxylic acid (4.5 g, 17.29 mmol), sodium iodide (78 mg, 0.52 mmol), zinc powder (226 mg, 3.46 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (76 mg, 0.35 mmol), trifluoroacetic acid (39 mg, 0.35 mmol) were added. The reaction was carried out at 50 °C for 12 h. Water (50 mL) and ethyl acetate (50 mL) were added and the organic phase was washed with saturated sodium chloride (25 mL) twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase preparation to obtain 15 mg of the product.

[0753] LC-MS (ESI): [M+H] + = 389.1;

[0754] 1 H NMR (400 MHz, DMSO-d6) δ = 7.47 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 5.15 (br s, 1H), 3.09-3.02 (m, 1H), 2.83 (br s, 1H), 2.19-2.11 (m, 3H), 2.09-2.01 (m, 4H), 1.99-1.86 (m, 4H), 1.85-1.75 (m, 5H), 1.73-1.66 (m, 2H), 1.34 (br d, J = 6.4 Hz, 3H).

[0755] Example 42: Synthesis of (S)-3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)bicyclo[l. l. l]pentane- 1 -carboxylic acid (Compound 42)

[0756] Step 1: Synthesis of (S)-methyl 3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)bicyclo[l. l. l]pentane- 1 -carboxylate

[0757] (S)-2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-4-carbonitrile (200 mg, 0.69 mmol), methyl 1-iodobicyclo[l. l. l]pentane-3-carboxylate (174 mg, 0.69 mmol), pyridine-2,6-dimethylidinamide dihydrochloride (34 mg, 0.21 mmol), sodium iodide (31 mg, 0.21 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (31 mg, 0.14 mmol) and zinc powder (136 mg, 2.07 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of trifluoroacetic acid (16 mg, 0.14 mmol). The reaction was heated to 70 °C under a nitrogen atmosphere for 18 h. Water (50 mL) and ethyl acetate (50 mL) were added and the organic phase was washed twice with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to give the product 50 mg.

[0758] LC-MS (ESI): [M+H] + = 335.2.

[0759] Step 2: Synthesis of (S)-3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)bicyclo[l. l. l]pentane- 1 -carboxylic acid

[0760] (S)-methyl 3-(4-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)bicyclo[l. l. l]pentane- 1 -carboxylate (50 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL) and water (1 mL), and triethylamine (151 mg, 1.50 mmol), lithium bromide (128 mg, 1.50 mmol) were added, and the reaction was heated at 50 °C for 12 h. The reaction was adjusted to pH = 3 with 1 M hydrochloric acid, and water (50 mL) and ethyl acetate (50 mL) were added and the organic phase was washed twice with saturated sodium chloride (25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse phase C18 column chromatography and lyophilized to give the product 20 mg.

[0761] LC-MS (ESI): [M+H] + = 321.1;

[0762] 1 H NMR (400 MHz, DMSO-d6) d = 12.45 (br s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 1.2 Hz, 1H), 6.31 (s, 1H), 5.18 - 5.10 (m, 1H), 3.11 - 3.01 (m, 1H), 2.92 - 2.79 (m, 1H), 2.29 - 2.08 (m, 7H), 2.01 - 1.79 (m, 3H), 1.36 (d, J = 6.4 Hz, 3H).

[0763] Example 45: (S)-2-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid and (R)-2-(10-cyano-6-methyl-6,7,8,9- tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5-carboxylic acid (Compounds 45A and 45B)

[0764] Step 1: Synthesis of N-methoxy-N-methylhex-5-ynoic amide

[0765] hex-5-ynoic acid (20 g, 178.37 mmol), N, O-dimethylhydroxylamine hydrochloride (21 g, 215.29 mmol) were dissolved in dichloromethane (500 mL), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.45 g, 231.88 mmol), 4- dimethylaminopyridine (2.2 g, 18.01 mmol) were added, triethylamine (74.2 mL, 533.65 mmol) was added under stirring at 0 °C, after 30 minutes, it was naturally raised to room temperature and stirred for 12 hours. The reaction solution was slowly added to water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column and concentrated under reduced pressure to obtain the product 24.6 g.

[0766] Step 2: Synthesis of hept-6-yn-2-one

[0767] N-methoxy-N-methylhex-5-ynoic amide (24.00 g, 154.64 mmol) was dissolved in tetrahydrofuran (300 mL), methyl magnesium bromide (77.3 mL, 231.96 mmol) was added at 0 °C, after stirring for 30 minutes, it was naturally raised to room temperature and stirring was continued for 1 hour. The reaction solution was quenched by slowly adding saturated ammonium chloride solution, saturated ammonium chloride and ethyl acetate were added for extraction, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 15.3 g.

[0768] Step 3: Synthesis of heptan-6-yn-2-ol

[0769] Heptan-6-yn-2-one (15000 mg, 136.17 mmol) was dissolved in methanol (300 mL), sodium borohydride (9 g, 237.91 mmol) was added in batches under nitrogen flow at 0 °C, after stirring for 30 minutes, it was naturally raised to room temperature and stirring was continued for 2 hours. The reaction solution was extracted with saturated ammonium chloride and ethyl acetate, the organic phase was washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 6500 mg.

[0770] Step 4: Synthesis of 7-(2-amino-5-bromophenyl)heptan-6-yn-2-ol

[0771] 4-Bromo-2-iodoaniline (10.00 g, 33.57 mmol), heptan-6-yn-2-ol (5.6 g, 49.92 mmol), cuprous iodide (1.3 g, 6.83 mmol), triethylamine (50 mL, 359.72 mmol), bis(triphenylphosphine)palladium dichloride (2.6 g, 3.34 mmol) were dissolved in acetonitrile (150 mL), replaced with nitrogen three times, stirred at 50 °C for 2 hours, naturally cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 9200 mg.

[0772] LC-MS (ESI): [M+H] + = 282.1.

[0773] Step 5: Synthesis of 5-(5-bromo-1H-indol-2-yl)pentan-2-ol

[0774] To a solution of 7-(2-amino-5-bromophenyl)hept-6-yn-2-ol (9.00 g, 31.89 mmol) in N,N-dimethylformamide (300 mL) was added cuprous iodide (20 g, 63.02 mmol). After three nitrogen purges, the reaction was stirred at 100 °C for 12 h. The reaction was allowed to cool to room temperature and filtered. The filtrate was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The product was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to give 8100 mg of the product.

[0775] Step 6: Synthesis of 2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indole

[0776] To a solution of 5-(5-bromo-lH-indol-2-yl)pentan-2-ol (8.00 g, 28.35 mmol) in toluene (250 mL) was added tributyl cyanomethyl phosphonium chloride (14.00 g, 58.01 mmol). After three nitrogen purges, the reaction was stirred at 80 °C for 12 h. The reaction was allowed to cool to room temperature and concentrated directly under reduced pressure to give a crude product. The product was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to give 6500 mg of the product.

[0777] LC-MS (ESI): [M+H] + = 264.1.

[0778] Step 7: Synthesis of 2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indole-10-carbonitrile

[0779] To a solution of 2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole (6.50 g, 24.61 mmol) in N,N-dimethylformamide (100 mL) was added (oxy methylene) azoniunm sulfonyl chloride (4.88 g, 34.47 mmol) at 0 °C. The reaction was stirred for 30 min and allowed to warm to room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The product was purified by normal phase silica gel column chromatography and concentrated under reduced pressure to give 4.0 g of the product.

[0780] LC-MS (ESI): [M+H] + = 289.0.

[0781] Step 8: Synthesis of 6-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6,7,8,9-tetrahydropyrido[l,2-a]indole-10-carbonitrile

[0782] Dissolve 2-bromo-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indole-10-carbonitrile (1.5 g, 5.19 mmol), bis(pinacolato)diboron (1.7 g, 6.69 mmol), l,l'-bis(diphenylphosphino)ferrocene palladium chloride (380 mg, 0.52 mmol), potassium acetate (1.10 g, 11.21 mmol) in dioxane (20 mL), replace with nitrogen for three times, stir at 100 °C for 2 hours, cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, purify with normal phase silica gel column, concentrate under reduced pressure to obtain the product 1.4 g.

[0783] LC-MS (ESI): [M+H] + = 337.1.

[0784] Step 9: Synthesis of methyl 2-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylate

[0785] Dissolve 6-methyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7,8,9- tetrahydropyrido[l,2-a]indole-10-carbonitrile (700 mg, 2.08 mmol), methyl 2- bromothiazole-5-carboxylate (925 mg, 4.16 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (Xantphos) (65 mg, 0.09 mmol), palladium acetate (94 mg, 0.42 mmol), potassium phosphate (884 mg, 4.16 mmol) in dioxane (15 mL) and water (1.5 mL), replace with nitrogen for three times, stir at 100 °C for 12 hours. Cool to room temperature naturally, add water to the reaction solution and extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, purify with normal phase silica gel column, concentrate under reduced pressure to obtain the product 200 mg.

[0786] LC-MS (ESI): [M+H] + = 352.1.

[0787] Step 10: Synthesis of 2-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2- yl)thiazole-5-carboxylic acid

[0788] Methyl 2-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylate (200 mg, 0.57 mmol) was dissolved in acetonitrile (3 mL), saturated aqueous lithium bromide (3 mL) and triethylamine (3 mL, 21.58 mmol) were added and stirred at 50 °C for 12 h, cooled to room temperature naturally, the reaction solution was adjusted to pH = 3 with 1 mol / L hydrochloric acid, water and ethyl acetate were added and extracted, the organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase C18 column and freeze-dried to obtain the product 160 mg.

[0789] LC-MS (ESI): [M+H] + = 338.1.

[0790] Step 11: Synthesis of (S)-2-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)thiazole-5-carboxylic acid, (R)-2-(10-cyano-6-methyl-6,7,8,9- tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5-carboxylic acid (Compound 45A, 45B)

[0791] Racemic 2-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)thiazole-5- carboxylic acid (160 mg, 0.47 mmol) was resolved by SFC (Column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 um; Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05% DEA); Gradient elution: EtOH (0.05% DEA) in CO2 from 10% to 60%; Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 C; Back Pressure: 100 Bar) to obtain Compound 45A 40 mg with 1.536 min peak and Compound 45B 30 mg with 1.859 min peak.

[0792] LC-MS (ESI): [M+H] + = 338.1;

[0793] Compound 45A: 1H NMR (400 MHz, DMSO-d6) δ = 8.08 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.84 (dd, J = 1.6, 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 4.90 - 4.68 (m, 1H), 3.21 - 3.11 (m, 1H), 3.08 - 2.95 (m, 2H), 2.19 - 2.07 (m, 1H), 2.03 - 1.82 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H).

[0794] Compound 45B: 1 H NMR (400 MHz, DMSO-d6) δ = 8.08 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.84 (dd, J = 1.6, 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 4.90 - 4.68 (m, 1H), 3.21 - 3.11 (m, 1H), 3.08 - 2.95 (m, 2H), 2.19 - 2.07 (m, 1H), 2.03 - 1.82 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H).

[0795] Example 46: (S)-2-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)-4-methylthiazole-5-carboxylic acid and (R)-2-(10-cyano-6-methyl- 6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)-4-methylthiazole-5-carboxylic acid (Compounds 46A and 46B)

[0796] Synthetic Method Refer to Example 45:

[0797] LC-MS (ESI): [M+H] + = 352.0;

[0798] 1.758 min for Compound 46A: 1 H NMR (400 MHz, DMSO-d6) δ = 8.08 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.84 (dd, J = 1.6, 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 4.90 - 4.68 (m, 1H), 3.21 - 3.11 (m, 1H), 3.08 - 2.95 (m, 2H), 2.19 - 2.07 (m, 1H), 2.03 - 1.82 (m, 3H), 1.43 (d, J = 6.4 Hz, 3H).

[0799] 1.958 min for Compound 46B: 1H NMR (400 MHz, DMSO-d6) d = 8.08 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.75-7.64 (m, 1H), 4.87-4.74 (m, 1H), 3.19-3.12 (m, 1H), 3.09-2.97 (m, 1H), 2.65 (s, 3H), 2.21-2.08 (m, 1H), 2.04-1.83 (m, 3H), 1.43 (br d, J = 6.4 Hz, 3H).

[0800] Example 47: (S)-1-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[1,2- a]indol-2-yl)-1H-pyrazole-4-carboxylic acid and (R)-1-(10-cyano-6-methyl-6,7,8,9- tetrahydropyrido[1,2-a]indol-2-yl)-1H-pyrazole-4-carboxylic acid (Compounds 47A and 47B)

[0801] Step 1: Synthesis of ethyl 1-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[1,2- a]indol-2-yl)-1H-pyrazole-4-carboxylate

[0802] Ethyl 1H-pyrazole-4-carboxylate (370 mg, 2.64 mmol) and 2-bromo-6-methyl-6,7,8,9- tetrahydropyrido[1,2-a]indole-10-carbonitrile (500 mg, 1.73 mmol) were dissolved in N,N- dimethylformamide (20 mL), then cuprous iodide (35 mg, 0.18 mmol), methyl [(1R,2R)-2- (methylamino)cyclohexyl]amine (50 mg, 0.35 mmol) and potassium carbonate (480 mg, 3.47 mmol) were added, and the mixture was heated at 100 °C for three hours under nitrogen. After natural cooling to room temperature, water (100 mL) was added to the reaction solution, and the organic phase was extracted with ethyl acetate (50 x 2 mL). After the organic phase was washed twice with saturated sodium chloride solution (50 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by normal phase silica gel column to obtain the product 350.5 mg.

[0803] LC-MS (ESI): [M+H] + = 349.2.

[0804] Step 2: Synthesis of 1-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-2-yl)- 1H-pyrazole-4-carboxylic acid

[0805] Ethyl 1-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)-lH- pyrazole-4-carboxylate (350.5 mg, 1.00 mmol) was dissolved in acetonitrile (20 mL) and water (5 mL), then lithium bromide (872.4 mg, 10.05 mmol) and triethylamine (1016.5 mg, 10.05 mmol) were added and reacted at 60 °C overnight. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added and extracted, the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reversed-phase C18 column and freeze-dried to obtain 161 mg of the product, respectively.

[0806] LC-MS (ESI): [M+H] + = 321.1;

[0807] Step 3: Synthesis of (S)-l-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2- a]indol-2-yl)-lH-pyrazole-4-carboxylic acid and (R)-l-(10-cyano-6-methyl-6,7,8,9- tetrahydropyrido[l,2-a]indol-2-yl)-lH-pyrazole-4-carboxylic acid (Compound 47A and 47B)

[0808] Ethyl 1-(10-cyano-6-methyl-6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl)-lH- pyrazole-4-carboxylate (350.5 mg, 1.00 mmol) was dissolved in acetonitrile (20 mL) and water (5 mL), then lithium bromide (872.4 mg, 10.05 mmol) and triethylamine (1016.5 mg, 10.05 mmol) were added and reacted at 60 °C overnight. After natural cooling to room temperature, the reaction solution was adjusted to pH = 3 with 1 mol hydrochloric acid, water (20 mL) and ethyl acetate (25 mL x 2) were added and extracted, the organic phase was washed with saturated sodium chloride (25 mL x 2) twice, then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reversed-phase C18 column and freeze-dried to obtain 161 mg of the product, respectively.

[0809] LC-MS (ESI): [M+H] + = 321.1;

[0810] Compound 47A: 1H NMR (400 MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.79-7.76 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 4.79 (t, J = 5.2 Hz, 1H), 3.16-3.12 (m, 1H), 3.02-2.95 (m, 1H), 2.13-2.08 (m, 1H), 1.99-1.86 (m, 3H), 1.42 (d, J = 6.4 Hz, 1H).

[0811] LC-MS (ESI): [M+H] + = 336.1;

[0812] Compound 47B: 1 H NMR (400 MHz, DMSO-d6) δ = 8.84 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.79-7.76 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 4.79 (t, J = 5.2 Hz, 1H), 3.16-3.12 (m, 1H), 3.02-2.95 (m, 1H), 2.13-2.08 (m, 1H), 1.99-1.86 (m, 3H), 1.42 (d, J = 6.4 Hz, 1H).

[0813] Experimental Example 1 Test for xanthine oxidase inhibitory activity of the compound of the present application

[0814] The Amplex® Red Xanthine / Xanthine Oxidase Assay Kit (Thermo #A22182) was used to test the inhibitory activity of the compounds on xanthine oxidase. TM The Amplex® Red Xanthine / Xanthine Oxidase Assay Kit (Thermo #A22182) was used to test the inhibitory activity of the compounds on xanthine oxidase.

[0815] An appropriate amount of the test compound was accurately weighed and dissolved in dimethyl sulfoxide to prepare a 10 mM stock solution; the test compound was diluted with the kit reaction buffer (0.5 M Tris-HCl, pH 7.5) to a series of concentration dilutions with a 4-fold gradient, with a final concentration of 1000 nM, 250 nM, 62.5 nM, 15.63 nM, 3.91 nM, 0.977 nM, 0.244 nM, 0.061 nM, 0.015 nM, 0.004 nM; 0.1 μL of the test compound series concentration dilution was taken to a 384-well plate, then 10 μL of bovine milk-derived xanthine oxidase was added to incubate at 37°C for 5 minutes; 10 μL of fluorescent red dye was added to incubate at 37°C for 30 minutes, and the absorbance value at 540 / 590 was read by an enzyme marker, and the IC 50 was calculated. The results are shown in Table 1.

[0816] Table 1 Inhibition activity of compounds of the present application on xanthine oxidase

[0817] The experimental results show that the compounds of the present application have excellent inhibitory effect on xanthine oxidase activity.

[0818] Experimental Example 2: Pharmacokinetic study of the compounds of the present application in rats

[0819] A certain amount of each test compound was weighed and prepared into a 0.3 mg / mL colorless and clear solution with 5% DMSO + 10% solutol HS15 + 85% physiological saline. 6 male rats weighing 250 ± 50 g were divided into two groups, one group was orally administered a single dose of 3 mg / kg, and the other group was administered a single dose of 1 mg / kg via tail vein. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration. The plasma samples were pretreated and detected by LC / MS / MS in MRM mode, and a suitable standard curve was established to quantify the target compound in the plasma sample to obtain the drug concentration-time curve. The pharmacokinetic parameters were calculated by non-compartment model using WinNonlin software, and the results are shown in Table 2.

[0820] Table 2 Pharmacokinetic data of the compounds of the present application in rats

[0821] The experimental results show that the compounds of the present application have good oral absorption in rats, and have high exposure and bioavailability.

[0822] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. Furthermore, the skilled person in the art can combine and combine the different embodiments or examples described in the present specification and the features of the different embodiments or examples, without contradiction.

Claims

A compound that is a compound of Formula (Xa) or (Xb), or a stereoisomer, geometric isomer, tautomer, N-oxide, hydrate, solvate, deuterated derivative, metabolite, pharmaceutically acceptable salt or prodrug of a compound of Formula (Xa) or (Xb), wherein: A ring is a five-membered heteroaromatic ring, which can be optionally substituted by 1, 2 or 3 R a substituents; Each R a Independently, H, D, F, Cl, Br, I, CN, hydroxyl, carboxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl and 3-6 membered heterocyclic groups may optionally be replaced by 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxyl, amino, nitro and carboxyl groups; X1is NR 1 or CR 1 ; X2is NR 2 or CR 2 , R 1 and R 2 , together with the atoms to which they are each attached, form a C 5-8 cycloalkyl or 5-8 membered heterocycle, said C 5-8 cycloalkyl and 5-8 membered heterocycle optionally substituted with 1, 2, 3, 4, 5 or 6 R b , provided that when X1is NR 1 , X2is not NR 2 ; X3is NH, N, S, O or CR 3 ; X4is N or CR 4 ; X5is N or CR 5 ; X6is N or CR 6 ; X7 is N or C; X8 is N or C; Each R b Independently, it can be H, D, F, Cl, Br, I, hydroxyl, carboxyl, amino, nitro, CN, or C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3- The 6-cycloalkyl group and the 3-6-membered heterocyclic group may optionally be replaced by 1, 2, 3, 4, 5 or 6 groups selected from D, F, Cl, Br, I, hydroxyl, amino, nitro, oxo, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio and C 1-6 Substituents of alkylamino groups; or two R connected to the same atom b form an oxo, or two R b form a C 3-6 cycloalkyl or 3-5 membered heterocycle; said C 3-6 cycloalkyl and 3-5 membered heterocycle can optionally be substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, CI, Br, I, hydroxy, amino, nitro, oxo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and C 1-6 alkylamino; or two R connected to adjacent atoms b with the atoms to which they are each attached to form C 3-6 cycloalkyl or 3-5 membered heterocycle; said C 3-6 cycloalkyl and 3-5 membered heterocycle are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of D, F, CI, Br, I, hydroxyl, amino, nitro, oxo, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, and C 1-6 alkylamino; R 3 , R 4 , R 5 and R 6 are each independently H, D, F, Cl, Br, I, CN, hydroxyl, carboxyl, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 3-6 cycloalkyl, which C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino and C 3-6 cycloalkyl can optionally be substituted with 1, 2 or 3 substituents selected from the group consisting of D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio and C 1-6 alkylamino and R 3 , R 4 , R 5 and R 6 are at least one CN. The compound according to claim 1 is a compound as shown in formula (Xc), (Xd), (I) or (I’), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a deuterated derivative, a metabolite, a pharmaceutically acceptable salt or a prodrug of a compound shown in formula (Xc), (Xd), (I) or (I’), The compound according to claim 1 or 2, wherein (Ia), (Ib), (Ic), (Id), or (Ie): wherein: Y1 is S, O, Se or NH; each Y2is independently N or CR a . The compound according to any one of claims 1 to 3, wherein For The compound according to any one of claims 1-4, wherein each R a is independently H, D, F, CI, Br, I, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl. The compound according to any one of claims 1-5, wherein each R b is independently H, D, F, CI, Br, I, hydroxyl, carboxyl, amino, nitro, CN, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, CH2CN, cyclopropyl, cyclobutyl, or azetidinyl; or two R connected to the same atom b form an oxo, or two R b form a cyclopropyl or cyclobutyl group together with the atom to which they are both attached; or two R connected to adjacent atoms b with the atoms to which they are each attached to form a cyclopropyl or cyclobutyl. The compound according to any one of claims 1 to 6, wherein R 3 , R 4 , R 5 and R 6 are each independently H, D, F, CI, Br, I, CN, hydroxyl, carboxyl, amino, nitro, methyl, ethyl, n-propyl, i-propyl, t-butyl, methoxy, ethoxy, CH2F, CHF2, CF3, OCH2F, OCHF2, OCF3, cyclopropyl or cyclobutyl, and R 3 , R 4 , R 5 and R 6 are at least one CN. The compound according to any one of claims 1 to 7, wherein R 3 , R 4 , R 5 and R 6 is CN and the others are H. A compound according to any one of claims 1 to 8 having the structure of formula (IIa), (IIb), (IIc) or (IId): wherein: X3is N or CR 3 ; each Z is independently -O-, -S-, -S(=O)-, -S(O)2-, -NH- or -CH2-; n is 1, 2 or 3; m is 1, 2, 3 or 4. A compound according to any one of claims 1 to 8 having the structure (lie): wherein: X3 is S, O or NH; each Z is independently -O-, -S-, -S(=O)-, -S(O)2-, -NH- or -CH2-; n is 1, 2 or 3; m is 1, 2, 3 or 4. A compound according to any one of claims 1-10 having the structure of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IIIg), or (IIIh): wherein: X3 is NH, O or S; Z is -O-, -S-, -S(=O)-, -S(O)2-, -NH- or -CH2-; m is 1, 2, 3 or 4. A compound is a compound having one of the following structures or a stereoisomer, a geometric isomer, a tautomer, a nitroso, a hydrate, a solvate, a deuterated compound, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound having one of the following structures: A pharmaceutical composition comprising a compound according to any one of claims 1 to 12; said pharmaceutical composition optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof. Use of a compound according to any one of claims 1 to 12 or of a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment and / or prevention of hyperuricemia. Use of a compound according to any one of claims 1 to 12 or of a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment and / or prevention of gout, arthritis or heart failure diseases caused by hyperuricemia.

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