Tricyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a tricyclic compound and an application of the tricyclic compound in a medicine, and particularly relates to a novel tricyclic compound and a medicine composition containing the novel tricyclic compound. The invention further relates to a preparation method of the compound and application of the compound or the pharmaceutical composition in preparation of drugs for treating GPR84 antagonist mediated diseases and / or symptoms, in particular to application of the compound or the pharmaceutical composition in preparation of drugs for treating non-alcoholic fatty liver diseases, inflammatory bowel diseases, idiopathic pulmonary fibrosis and diabetic neuralgia.

Description

Tricyclic compounds and their preparation methods and applications

[0001] This application claims priority to:

[0002] CN202211734423.7, application date December 30, 2022. Technical Field

[0003] The present invention relates to the technical field of chemical medicine, and in particular to a tricyclic compound and a preparation method and application thereof. Background Art

[0004] G protein-coupled receptor 84 (GPR84) is a fatty acid receptor that can be activated by medium-chain fatty acids and can be expressed through G αi The protein inhibits the adenylate cyclase activity of the downstream signaling pathway, thereby downregulating the level of cAMP.

[0005] GPR84 is primarily expressed in innate immune cells, and its upregulation promotes inflammation in these cells. Studies have shown that GPR84 activation leads to chemotactic responses, enhancing the release of cytokines (IL-8, IL-12) and tumor necrosis factor α (TNF-α), thereby amplifying the inflammatory response of macrophages at the site of inflammation, exacerbating inflammation and triggering a variety of inflammatory diseases (Carlota Recio et al., 2018). Studies have also shown that GPR84 plays an important role in the pathogenesis of endometriosis (Sacher F et al., 2018), inflammatory eye diseases, inflammatory kidney diseases, and inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver disease (Puengel et al., 2018; Thibodeau JF et al., 2018).

[0006] Activation of this receptor in neutrophils and macrophages triggers the release of reactive oxygen species, suggesting an immunomodulatory role for this receptor. Studies have shown that GPR84 plays a key role in the pathogenesis of diseases such as inflammatory bowel disease (Arijs et al, 2011; Planell et al, 2017; Labeguere F. et al, 2020), multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, and primary and secondary autoimmune uveitis.

[0007] GPR84's regulation of neutrophil activity and systemic inflammation is closely related to lung diseases such as asthma, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease (Nguyen et al, 2018; Saniere L. et al, 2019; Edward Jenner et al, 2020).

[0008] Normalization of GPR84 adipose tissue inflammation indicates that GPR84 is closely related to metabolic and metabolic endocrine disorders (such as metabolic syndrome, insulin resistance, type I and type II diabetes, obesity, and polycystic ovary syndrome (PCOS)). Inflammatory changes in adipose tissue enhance the expression of GPR84 in adipocytes, and regulation of GPR84 regulates the immune response capacity of adipocytes (Muredda et al, 2017; Recio et al, 2018; Simard, JC et al, 2020).

[0009] Furthermore, GPR84 signaling plays a peripherally driven role in neuropathic pain (Nicol et al, 2015). Studies have shown that GPR84 and TREM-1 signaling pathways are involved in the pathogenesis of reflux esophagitis (Abdel-Aziz, H, 2015).

[0010] Currently, researchers have conducted a number of studies in the hope of finding drugs that can prevent and / or treat diseases associated with GPR84. PCT applications WO2013092791, WO2014095798, WO2015197550, WO2016169911, WO2018161831, WO2018210822, WO2019096944, WO2020007342, WO2021122415, WO2022179940, WO2022194267, and WO2022218372 disclose numerous small molecule compounds that act as GPR84 antagonists for preventing or treating GPR84-related diseases. However, there is still an urgent need for more and better GPR84 antagonists in clinical practice.

[0011] Summary of the Invention

[0012] The present invention provides a compound, or a pharmaceutical composition thereof, that is useful as a GPR84 antagonist. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by antagonizing GPR84. The present invention further describes a method for synthesizing the compound. The compound of the present invention exhibits excellent biological activity and pharmacokinetic properties.

[0013] Specifically:

[0014] In one aspect, the present invention relates to a compound, which is a compound as represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

[0015] in:

[0016] X is N or CR 9 ;

[0017] L1 is -O-, -S-, or -CR 10 R 11 -、-O-CR 12 R 13 -or-S-CR 14 R 15 -;

[0018] L2 is a key or -CR 16 R 17 -;

[0019] R 3 is H;

[0020] R 4 and R 5 Each independently is C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R a Substituted, the R a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3- 6-membered cycloalkyl or 3-6-membered heterocyclic group;

[0021] R 1 、R 2 、R 6 and R 9 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1- 6 alkoxy and C 1-6substituted by an alkylamino substituent;

[0022] R 7 、R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

[0023] In some embodiments, R 4 and R 5 Each independently is C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R a Substituted, the R a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group.

[0024] In some embodiments, R 4 and R 5 Each is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Can be optionally replaced by 1, 2 or 3 R a Substituted, the R ais D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

[0025] In some embodiments, R 4 and R 5 are each independently an oxetane group, wherein the oxetane group, Can be optionally replaced by 1, 2 or 3 R a Substituted, the R a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

[0026] In some embodiments, R 1 、R 2 、R 6 and R 9 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino or C 3-6 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1- 3 alkoxy and C 1-3 substituted by an alkylamino substituent;

[0027] R 7 、R 8 、R 10 、R 11 、R 12 、R13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-3 Alkyl, the C 1-3 The alkyl group may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

[0028] In some embodiments, R 1 、R 2 、R 6 and R 9 Each is independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, n-propyl, isopropyl, -CHF2, -C F3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino;

[0029] R 7 、R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl or isopropyl, and the methyl, ethyl, n-propyl and isopropyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

[0030] In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

[0031] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0032] In one aspect, the present invention relates to the use of the aforementioned compound or pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating a GPR84 antagonist-mediated disease in a patient.

[0033] In some embodiments, the diseases mediated by the GPR84 antagonists of the present invention are inflammatory diseases, autoimmune diseases, pulmonary diseases, metabolic disorders and metabolic endocrine disorders.

[0034] In some embodiments, the inflammatory disease of the present invention is endometriosis, inflammatory eye disease, inflammatory kidney disease, inflammatory liver disease such as non-alcoholic or alcoholic and toxic fatty liver disease.

[0035] In some embodiments, the autoimmune disease of the present invention is inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, or primary and secondary autoimmune uveitis.

[0036] In some embodiments, the pulmonary disease of the present invention is asthma, idiopathic pulmonary fibrosis or chronic obstructive pulmonary disease.

[0037] In some embodiments, the metabolic and metabolic-endocrine disorders of the present invention are metabolic syndrome, insulin resistance, type I and type II diabetes, obesity, or polycystic ovary syndrome.

[0038] In some embodiments, the metabolic disorder and metabolic endocrine disorder of the present invention is diabetic neuropathy. In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds of formula (I).

[0039] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0040] Definitions and General Terms

[0041] The present invention will list the literature corresponding to the specific content of the invention in detail, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is intended to cover all options, variations and equivalents that may be included in the existing invention field as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0042] The following definitions apply to the present invention unless otherwise indicated. For purposes of the present invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Chemical Handbook, 75th Ed, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," by Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, all of which are incorporated herein by reference.

[0043] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0044] Compounds as described herein may optionally be substituted with one or more substituents, as described in the general formulae of the present invention, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.The substituents may be, but are not limited to, hydrogen, deuterium (D), F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxyl, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH, -alkylene-C(=O)O-alkyl, -alkylene-S(=O)2-alkyl, -alkylene-S(=O)2-amino, -S(=O)2-alkyl, -S(=O)2-amino, -S(=O)2OH, -O-alkylene-C(=O)O-alkyl, -O-alkylene-S(=O)2-alkyl, -O -alkylene-S(=O)2-amino, -O-alkylene-S(=O)2OH, -C(=O)NH2, -C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O)2-alkyl, -C(=O)NHS(=O)2-amino, -C(=O)NHS(=O)2OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O)2-alkyl, -NHS(=O)2-alkyl, -NHS(=O)2-haloalkyl, -N(alkyl)S(=O)2-haloalkyl, -N(alkyl)S(=O)2-alkylamino, -NHC(=O)-alkyl, -NHC(=O)-haloalkyl -alkyl, -N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino, -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O)O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino, -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C(=O)N(alkyl)S(=O)2-alkyl, -C(=O)N(alkyl)S(=O)2-amino, -C(=O)NH-S(=O)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -C(=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C(=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and the like.

[0045] As used herein, the term "alkyl" includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents 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), tert-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-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-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)CH2C H3), 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, etc. The term "alkyl" and its prefix "alkane" as used herein include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms. Examples of such radicals include, but are not limited to, methylene, ethylene, and isopropylene, etc.

[0046] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; and in still other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0047] The term "heteroatom" means one or more of O, S, N, P and Si, including C, N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring being substituted with a hydrogen, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl); or in the form of -CH2- in a heterocyclic ring being oxidized to form -C(=O)-.

[0048] The term "halogen" refers to F, Cl, Br or I.

[0049] The term "deuterium" refers to heavy hydrogen, D.

[0050] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0051] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C 1-4 Alkoxy groups; examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, etc., and the alkoxy groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0052] The term "alkylthio" or "alkylthio" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a sulfur atom. In some embodiments, the alkylthio group is C 1-4 Alkylthio; such examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio, etc., and the alkylthio group can be independently unsubstituted or substituted with one or more substituents described herein.

[0053] The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a nitrogen atom. In some embodiments, the alkylamino group is C1-4 Alkylamino groups; examples thereof include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino groups. The alkylamino groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0054] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbon ring system containing 3-12 carbon atoms, which may be saturated or contain one or more unsaturated bonds, but never aromatic. In one embodiment, the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0055] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, tricyclic, bridged, or spirocyclic ring containing 3 to 12 ring atoms, never aromatic, wherein at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4 to 6 ring atoms; unless otherwise specified, a heterocyclyl group may be a carbon group or a nitrogen group, and heteroatoms have the meanings as described herein. Examples of heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 1,4-dioxane, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine thiazolinone 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and 1,2,3,6-tetrahydropyridinyl. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, pyrimidinedione, and 5,6-dihydropyridin-2(1H)-onyl. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0056] The term "aryl" refers to 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 comprises 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

[0057] The term "heteroaryl" refers to 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 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.

[0058] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl, thiazolyl, pyridazinyl ... oxazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g., 5-tetrazolyl), triazolyl, thienyl (e.g., 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-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5 -thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolinyl, isoquinolyl (such as 1-isoquinolyl), quinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0059] As described herein, a substituent group is attached to a ring by a bond to form a ring system, which indicates that the substituent group can be substituted at any substitutable position on the ring. For example, formula (a) indicates that the substituent group R can be substituted at any substitutable position on the pyridine ring.

[0060] As described herein, a ring system formed by a linker attached to a ring (e.g., Formula b) represents that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.

[0061] As described herein, the group "-O-(CR m R n ) p -" has two connection sites that can be connected to the rest of the molecule, and the connection methods of the two connection sites can be interchanged. For example, formula f represents the group -O-(CR m R n )p - can be linked to the rest of the molecule via the E-terminus or the E'-terminus. For example, EO-(CR m R n ) p -E' or E'-O-(CR m R n ) p -E.

[0062] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used throughout this document, “each ... and ... are independently,” “... and ... are each independently,” and “... and ... are respectively independently,” are interchangeable and should be understood in a broad sense. They may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0063] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, geometric isomers, or conformational isomers thereof, are within the scope of the present invention.

[0064] Unless otherwise indicated, the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention are also within the scope of the present invention. Furthermore, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

[0065] "Metabolite" refers to a product obtained by metabolism in vivo of a specific compound described herein, or a pharmaceutically acceptable salt, analog, or derivative thereof, which exhibits similar activity in vivo or in vitro as the compound of formula (I). The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage. Accordingly, the present invention includes metabolites of a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0066] The definitions and conventions of stereochemistry used herein are generally those of 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 may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, 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. When describing an optically active compound, the prefix D, L or R, S is used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d, l, or (+), (-) are used to designate the sign of rotation of plane-polarized light in a compound. (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0067] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of bonding electrons.

[0068] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts formed with non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0069] The "hydrate" of the present invention refers to an association compound formed when the solvent molecule is water.

[0070] The "solvate" of the present invention refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0071] "Esters" herein refer to esters of compounds of formula (I) containing hydroxy groups that are hydrolyzable in vivo. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol. Examples of in vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups.

[0072] The "nitrogen oxide" of the present invention refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), for example, in an inert solvent (e.g., dichloromethane), by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA).

[0073] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form. Other prodrug forms include phosphates, such as these phosphate compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C. 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 SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0074] Unless otherwise indicated herein or the context clearly indicates a contrary meaning, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) may be construed to include both the singular and the plural.

[0075] As used herein, the term "GPR84 antagonist" refers to a substance that can antagonize GPR84.

[0076] General synthesis process

[0077] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0078] Generally, the compounds of the present invention can be prepared by the methods described herein, wherein the substituents are as defined herein unless otherwise specified. The following reaction schemes and examples are provided to further illustrate the present invention.

[0079] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0080] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Myrel Chemical Technology Co., Ltd., and Shanghai MacLean Biochemical Technology Co., Ltd. and used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., Hubei Xingchi Technology Co., Ltd., and Qingdao Ocean Chemical Factory.

[0081] Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile were dried over molecular sieves. Extra-dry dichloromethane was dried over calcium hydride and redistilled. Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane, and methanol were of analytical grade.

[0082] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0083] The silica gel column was purchased from Tianjin Bona Aijieer Technology Co., Ltd. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0084] 1H NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer. 1H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD, or acetone-d6 solvents (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0085] Low-resolution mass spectrometry (MS) data were collected using an 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 (H2O containing 0.1% formic acid: CH3CN = 90:10), electrospray ionization (ESI), detection at 210 nm / 254 nm, and DAD.

[0086] Compounds were purified using Cheetah Pro medium-pressure rapid purification preparative chromatography (Tianjin Bona Aijieer Technology Co., Ltd.) at 210 nm / 254 nm with UV detection.

[0087] The following abbreviations are used throughout the present invention: PE petroleum ether EtOAc / EA ethyl acetate mg milligram mmol millimole mL milliliter g gram M mole / liter DMSO-d6 deuterated dimethyl sulfoxide DMF N,N-dimethylformamide MeOH methanol DCM dichloromethane CDCl3 deuterated chloroform PdCl2(dppf) 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0088] The following reaction schemes describe the steps for preparing the compounds of the present invention. a 、R 1 、R 2 、R 4 、R 5 、R 7 、R 8 、R 18 、R 19 Has the definition as described in the present invention.

[0089] Reaction Scheme 1

[0090] The compound represented by formula (13) can be prepared by the reaction scheme 1: the compound represented by formula (1) reacts with the compound represented by formula (2) to obtain the compound represented by formula (3). The compound represented by formula (3) reacts with thionyl chloride to obtain the compound represented by formula (4). The compound represented by formula (4) reacts with the compound represented by formula (5) to obtain the compound represented by formula (6). The compound represented by formula (6) reacts with hydrazine hydrate to obtain the compound represented by formula (7). The compound represented by formula (7) reacts with the compound represented by formula (8) to obtain the compound represented by formula (9). The compound represented by formula (9) reacts with the compound represented by formula (10) and further reacts with hydrazine hydrate to obtain the compound represented by formula (11). The compound represented by formula (11) reacts with the compound represented by formula (12) to obtain the compound represented by formula (13).

[0091] Reaction Scheme 2

[0092] The compound represented by formula (20) can be prepared by reaction scheme 2: the compound represented by formula (14) and the compound represented by formula (15) are reacted to obtain the compound represented by formula (16). The compound represented by formula (16) is reacted in the presence of ammonium acetate to obtain the compound represented by formula (17). The compound represented by formula (17) is reacted in the presence of phosphorus oxychloride to obtain the compound represented by formula (18). The compound represented by formula (18) is reacted in the presence of tetrakistriphenylphosphine palladium and zinc cyanide to obtain the compound represented by formula (19). The compound represented by formula (19) is hydrolyzed to obtain the compound represented by formula (20).

[0093] Reaction Scheme 3

[0094] The compound represented by formula (13) can also be prepared by reaction scheme 3: the compound represented by formula (8) is esterified with an alcohol to obtain the compound represented by formula (21). The compound represented by formula (21) is reacted with the compound represented by formula (10) and further reacted with hydrazine hydrate to obtain the compound represented by formula (22). The compound represented by formula (22) is reacted with the compound represented by formula (12) to obtain the compound represented by formula (23). The compound represented by formula (20) is reacted under alkaline conditions to obtain the compound represented by formula (24). The compound represented by formula (24) is reacted with the compound represented by formula (7) to obtain the compound represented by formula (13). DETAILED DESCRIPTION

[0095] The present invention is described below with reference to specific examples. It should be noted that these examples are merely illustrative and do not limit the present invention in any way.

[0096] Example 1 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 1)

[0097] Step 1: Synthesis of (5-cyclopropylpyrazin-2-yl)methanol

[0098] To a reaction flask, (5-chloropyrazin-2-yl)methanol (2.0 g, 13.84 mmol), cyclopropylboronic acid (2.4 g, 27.67 mmol), PdCl2(dppf) (1.1 g, 1.52 mmol), and cesium carbonate (13.5 g, 41.51 mmol) were added in sequence. Toluene (20 mL) and water (2 mL) were then added. After addition, the mixture was stirred at 110°C for 6 hours. Saturated brine was added to the reaction system, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain 1.1 g of a yellow oily liquid in a 53.0% yield.

[0099] LC-MS(ESI):[M+H] + =151.2;

[0100] 1 H NMR (500MHz, DMSO-d6) δ8.50-8.48(m,2H),5.44-5.42(m,1H),4.57(s,2H),2.20-2.16(m,1H),1.02-1.00(m,2H),0.93-0.92(m,2H).

[0101] Step 2: Synthesis of 2-(chloromethyl)-5-cyclopropylpyrazine

[0102] Under an ice bath, (5-cyclopropylpyrazin-2-yl)methanol (2.0 g, 13.32 mmol) and ultra-dry dichloromethane (20 mL) were added to the reaction flask, followed by the slow dropwise addition of thionyl chloride (1.6 g, 13.32 mmol). After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 8:1) to afford 547 mg of a brown oil in a 24.4% yield.

[0103] LC-MS(ESI):[M+H] + =169.1.

[0104] Step 3: Synthesis of 2-((5-cyclopropylpyrazin-2-yl)methyl)isoindoline-1,3-dione

[0105] 5-(Chloromethyl)-2-cyclopropylpyrazine (500 mg, 2.97 mmol) and DMF (10 mL) were added to the reaction flask, followed by a mixed solution of ethanol (6 mL) and (1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl) potassium salt (823 mg, 4.45 mmol). After addition, the mixture was stirred at 80°C for 7 hours. The insoluble material was removed by filtration, and the mixture was concentrated under reduced pressure. The product was separated by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain 933 mg of a white solid.

[0106] LC-MS(ESI):[M+H] + =280.2.

[0107] Step 4: Synthesis of (5-cyclopropylpyrazin-2-yl)methanamine

[0108] At room temperature, 2-((5-cyclopropylpyrazin-2-yl)methyl)isoindoline-1,3-dione (828 mg, 2.96 mmol) was added to the reaction flask and dissolved in ethanol (10 mL). Hydrazine hydrate (296 mg, 5.92 mmol) was then slowly added dropwise. After addition, the mixture was stirred and refluxed at 98°C for 3.5 hours. Heating was stopped and the mixture was cooled to room temperature. A large amount of white solid was produced. The white solid was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 208 mg of the product as a yellow oil, with a yield of 47.2%.

[0109] LC-MS(ESI):[M+H] + =150.2;

[0110] 1 H NMR (500MHz, DMSO-d6) δ8.48(s,2H),3.79(s,2H),3.1(brs,2H),2.18-2.15(m,1H),1.01-0.99(m,2H),0.92-0.90(m,2H).

[0111] Step 5: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0112] To a reaction flask were added 5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (214 mg, 1.12 mmol), (5-cyclopropylpyrazin-2-yl)methanamine (200 mg, 1.34 mmol), HATU (638 mg, 1.68 mmol), diisopropylethylamine (434 mg, 3.36 mmol), and DMF (10 mL) in sequence. The mixture was stirred at room temperature for 8 hours. The mixture was washed with saturated brine and extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to afford 309 mg of a yellow oily liquid in an 85.7% yield.

[0113] LC-MS(ESI):[M+H] + =323.2;

[0114] 1 H NMR (500MHz, DMSO-d6) δ9.35(t,J=5.0Hz,1H),8.54(s,1H),8.43(s,1H),8.35(d,J=5.0Hz,1H),8.01(d,J=10.0Hz,1H) ,4.63(d,J=5.0Hz,2H),3.18-3.15(m,2H),2.71-2.69(m,2H),2.18-2.14(m,3H),1.03-1.00(m,2H),0.93-0.91(m,2H).

[0115] Step 6: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0116] To the reaction flask, add N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (500 mg, 1.55 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (351 mg, 2.02 mmol), followed by 20 mL of toluene. The mixture was stirred at 110°C for 2 hours. Heating was stopped, the mixture was cooled to room temperature, and the mixture was concentrated under reduced pressure to obtain a yellow oil. Ethanol (20 mL) was added, followed by the slow addition of hydrazine hydrate (93 mg, 1.86 mmol). After the addition, the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium bicarbonate solution was added to neutralize excess acetic acid until the mixture was alkaline. The mixture was extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:3-0:1) to obtain 178 mg of a yellow solid with a yield of 33.1%.

[0117] LC-MS(ESI):[M+H] + =347.3;

[0118] 1 H NMR(500MHz,DMSO-d6)δ12.92(s,1H),9.18-9.17(m,1H),8.54(s,1H),8.43(s,1H),8.15(d,J=5.0Hz,1H),7.93(d,J=10.0Hz,1H), 7.64(s,1H),4.62(d,J=5.0Hz,2H),3.14-3.11(m,2H),2.89-2.86(m,2H),2.20-2.16(m,1H),1.03-1.00(m,2H),0.93-0.90(m,2H).

[0119] Step 7: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0120] To a reaction flask were added N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (170 mg, 0.49 mmol), [(2R)-1,4-dioxan-2-yl]methyl 4-methylsulfonylbenzene (200 mg, 0.74 mmol), and cesium carbonate (319 mg, 0.98 mmol), followed by DMF (10 mL). The mixture was stirred at 70°C for 2 hours. The mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the solid residue, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1-15:1) to afford 33 mg of a white solid in a 15.1% yield.

[0121] LC-MS(ESI):[M+H] + =447.4;

[0122] 1H NMR(500MHz,DMSO-d6)δ9.20-9.17(m,1H),8.54(s,1H),8.43(s,1H),8.10(d,J=10.0Hz,1 H),7.92(d,J=10.0Hz,1H),7.61(s,1H),4.62-4.61(m,2H),4.20-4.18(m,2H),3.92-3.90 (m,1H),3.78-3.74(m,2H),3.65-3.63(m,1H),3.56-3.53(m,1H),3.48-3.37(m,2H),3.13 -3.10(m,2H),2.88-2.85(m,2H),2.18-2.17(m,1H),1.03-1.00(m,2H),0.92-0.91(m,2H).

[0123] Example 2 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-9-methyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 2)

[0124] Step 1: Synthesis of 4-methyl-7,8-dihydro-2H-chromene-2,5(6H)-dione

[0125] Cyclohexyl-1,3-dione (5 g, 44.6 mmol), ethyl acetoacetate (6.8 mL, 53.5 mmol), and 4-dimethylaminopyridine (1.09 g, 8.9 mmol) were added to the reaction flask in sequence. The mixture was heated to 120°C with stirring for 1.5 h. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain 2.72 g of a yellow solid in a 34.2% yield.

[0126] LC-MS(ESI):[M+H] + =179.2;

[0127] 1 H NMR (500MHz, CDCl3) δ5.98 (s, 1H), 2.87 (t, J = 6.3Hz, 2H), 2.55 (t, J = 6.7Hz, 2H), 2.48 (s, 3H), 2.11 (p, J = 6.5Hz, 2H).

[0128] Step 2: Synthesis of 4-methyl-7,8-dihydroquinoline-2,5(1H,6H)-dione

[0129] Under a nitrogen atmosphere, 4-methyl-7,8-dihydro-2H-chromene-2,5(6H)-dione (2.5 g, 14.0 mmol), ammonium acetate (3.24 g, 42.1 mmol), and dichloroethane (40 mL) were added sequentially to an autoclave. The mixture was heated to 140°C with stirring overnight. Heating was stopped, and the mixture was cooled to room temperature. The reaction mixture was filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 5:1 to 0:1) to obtain 700 mg of a yellow solid in a 28.2% yield.

[0130] LC-MS(ESI):[M+H] + =178.0;

[0131] 1 H NMR (500MHz, DMSO-d6) δ6.01(s,1H),2.79(t,J=6.2Hz,2H),2.41(t,J=6.6Hz,2H),2.38(s,3H),1.94(p,J=7.8,7.1Hz,2H).

[0132] Step 3: Synthesis of 2-chloro-4-methyl-7,8-dihydroquinolin-5(6H)-one

[0133] To the reaction flask, 4-methyl-7,8-dihydroquinoline-2,5(1H,6H)-dione (1.1 g, 6.2 mmol), acetonitrile (11 mL), and phosphorus oxychloride (2.9 mL, 31.1 mmol) were added sequentially. The mixture was heated to 75°C with stirring for 2 hours. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure, adjusted to alkalinity with saturated sodium bicarbonate solution, and extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain 760 mg of a white solid in a 62.6% yield.

[0134] LC-MS(ESI):[M+H] + =196.2;

[0135] 1 H NMR (500MHz, CDCl3) δ7.09 (s, 1H), 3.12 (t, J = 6.3Hz, 2H), 2.67 (t, J = 6.7Hz, 2H), 2.64 (s, 3H), 2.14 (p, J = 6.5Hz, 2H).

[0136] Step 4: Synthesis of 4-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile

[0137] To a reaction flask, 2-chloro-4-methyl-7,8-dihydroquinolin-5(6H)-one (911 mg, 4.7 mmol), palladium tetrakistriphenylphosphine (269 mg, 0.2 mmol), zinc cyanide (1093 mg, 9.3 mmol), and ultra-dry N,N-dimethylacetamide (8 mL) were added sequentially. Nitrogen was purged for 5 minutes, and the mixture was stirred at 120°C for 2 hours. Heating was stopped and the mixture was cooled to room temperature. Insoluble matter was removed by filtration, and saturated brine was added. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 6:1-4:1) to obtain 560 mg of a white solid in a 65.0% yield.

[0138] LC-MS(ESI):[M+H] + =187.1;

[0139] 1 H NMR (500MHz, CDCl3) δ7.43 (s, 1H), 3.16 (d, J = 6.3Hz, 2H), 2.72 (t, J = 6.5Hz, 2H), 2.69 (s, 3H), 2.16 (p, J = 6.5Hz, 2H).

[0140] Step 5: Synthesis of 4-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[0141] To the reaction flask, 4-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (560 mg, 3.0 mmol), concentrated hydrochloric acid (5 mL), and water (7 mL) were added sequentially. The mixture was heated to 100°C and refluxed with stirring overnight. The reaction solution was then concentrated under reduced pressure, and dichloromethane (15 mL) and saturated brine (15 mL) were added. The mixture was basified with sodium bicarbonate solution, and the pH was adjusted to 2-4 with 1 M HCl. The mixture was extracted with dichloromethane (25 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 580 mg of a white solid in a 93.8% yield.

[0142] LC-MS(ESI):[M+H] + =206.1.

[0143] Step 6: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0144] To the reaction flask were added 4-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (437 mg, 2.13 mmol), (5-cyclopropylpyrazin-2-yl)methanamine (381 mg, 2.56 mmol), HATU (1214 mg, 3.19 mmol), and diisopropylethylamine (826 mg, 6.39 mmol), followed by DMF (6 mL). The mixture was stirred at room temperature under nitrogen for 6 hours. Saturated brine (15 mL x 3) was added, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to afford 1.1 g of a mixture of a yellow oil and a white solid.

[0145] LC-MS(ESI):[M+H] + =337.2;

[0146] 1 H NMR(500MHz,DMSO-d6)δ9.30(s,1H),8.53(s,1H),8.42(s,1H),7.81(s,1H),4.62-4.60(m,2H),3.16-3.13(m,2 H),2.70-2.69(m,2H),2.64(s,3H),2.19-2.16(m,1H),2.09-2.07(m,2H),1.03-1.00(m,2H),0.92-0.91(m,2H).

[0147] Step 7: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-9-methyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0148] To a reaction flask, add N-((5-cyclopropylpyrazin-2-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (716 mg, 2.13 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (556 mg, 3.19 mmol), followed by toluene (20 mL). After addition, stir at 110°C for 2 hours. Discontinue heating, cool to room temperature, and concentrate under reduced pressure. Hydrazine hydrate (127 mg, 2.55 mmol), acetic acid (127 mg, 2.13 mmol), and ethanol (20 mL) are then added. Stir at room temperature for 8 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (PE:EA (v / v) = 2:1 to 0:1) to obtain 273 mg of a yellow solid in a 35.6% yield.

[0149] LC-MS(ESI):[M+H] + =361.3;

[0150] 1 H NMR (500MHz, DMSO-d6) δ12.94(s,1H),9.17-9.15(m,1H),8.54(s,1H),8.43(s,1H),7.79(s,1H),7.66(s,1H),4.62(d,J= 5.0Hz,2H),3.11-3.08(m,2H),2.84-2.81(m,2H),2.72(s,3H),2.21-2.15(m,1H),1.02-1.00(m,2H),0.93-0.91(m,2H).

[0151] Step 8: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-9-methyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0152] To the reaction flask were added N-((5-cyclopropylpyrazin-2-yl)methyl)-4-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (111 mg, 0.31 mmol), [(2R)-1,4-dioxan-2-yl]methyl-4-methylsulfonylbenzene (125 mg, 0.46 mmol), and cesium carbonate (200 mg, 0.62 mmol), followed by DMF (10 mL). After addition, the mixture was stirred at 70°C for 2 hours. Heating was stopped, the mixture was cooled to room temperature, and the excess DMF was removed under reduced pressure. The mixture was then separated on a preparative plate (DCM:MeOH (v / v) = 30:1) to afford 44 mg of a light yellow solid in a 31.0% yield.

[0153] LC-MS(ESI):[M+H] + =461.3;

[0154] 1H NMR(500MHz,DMSO-d6)δ9.17-9.15(m,1H),8.54(s,1H),8.42(s,1H),7.78(s,1H),7.63(s, 1H),4.61(d,J=10.0Hz,2H),4.21(d,J=5.0Hz,2H),3.94-3.92(m,1H),3.79-3.74(m,2H),3. 65-3.63(m,1H),3.59-3.54(m,1H),3.49-3.46(m,1H),3.34-3.30(m,1H),3.10-3.07(m,2H ),2.82-2.79(m,2H),2.70(s,3H),2.19-2.16(m,1H),1.02-1.00(m,2H),0.92-0.90(m,2H).

[0155] Example 3 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 3)

[0156] Step 1: Synthesis of 4-(trifluoromethyl)-7,8-dihydro-2H-chromene-2,5(6H)-dione

[0157] Under a nitrogen atmosphere, cyclohexyl-1,3-dione (4 g, 35.7 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (7.9 mL, 53.5 mmol), 2-(dimethylamino)pyridine (0.87 g, 7.1 mmol), and dichloroethane (50 mL) were added sequentially to an autoclave and heated to 120°C with stirring overnight. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure, saturated ammonium chloride solution (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The mixture was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain 5 g of a yellow solid with a yield of 60.4%.

[0158] LC-MS(ESI):[M+H] + =233.0

[0159] 1 H NMR (500MHz, CDCl3) δ6.68 (s, 1H), 2.93 (t, J = 6.4Hz, 2H), 2.62 (t, J = 6.7Hz, 2H), 2.16 (p, J = 6.5Hz, 2H).

[0160] Step 2: Synthesis of 4-(trifluoromethyl)-7,8-dihydroquinoline-2,5(1H,6H)-dione

[0161] Under a nitrogen atmosphere, 4-(trifluoromethyl)-7,8-dihydro-2H-chromene-2,5(6H)-dione (5 g, 21.5 mmol), ammonium acetate (4.98 g, 64.6 mmol), and dichloroethane (50 mL) were added sequentially to an autoclave, and the mixture was heated to 140°C with stirring overnight. Heating was then discontinued, and the mixture was cooled to room temperature. The reaction mixture was made alkaline with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5.5 g of a dusty gray solid, which was used directly in the next reaction.

[0162] LC-MS(ESI):[M+H] + =232.1;

[0163] 1 H NMR (500MHz, CDCl3) δ6.82 (s, 1H), 2.92 (t, J = 6.3Hz, 2H), 2.57 (t, J = 6.6Hz, 2H), 2.10 (p, J = 8.0, 7.2Hz, 2H).

[0164] Step 3: Synthesis of 2-chloro-4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one

[0165] To the reaction flask, 4-(trifluoromethyl)-7,8-dihydroquinoline-2,5(1H,6H)-dione (5.5 g, 23.8 mmol), acetonitrile (75 mL), and phosphorus oxychloride (18.3 g, 118.9 mmol) were added sequentially. The mixture was heated to 75°C with stirring for 3 hours. Heating was stopped, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The solution was adjusted to alkaline with saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain 4.4 g of a white solid with a yield of 74.1%.

[0166] LC-MS(ESI):[M+H] + =250.0;

[0167] 1 H NMR (500MHz, CDCl3) δ7.61 (s, 1H), 3.21 (t, J = 6.3Hz, 2H), 2.76 (t, J = 6.7Hz, 2H), 2.20 (p, J = 6.5Hz, 2H).

[0168] Step 4: Synthesis of 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carbonitrile

[0169] To a reaction flask, 2-chloro-4-(trifluoromethyl)-7,8-dihydroquinolin-5(6H)-one (4.3 g, 17.2 mmol), tetrakistriphenylphosphine palladium (1.0 g, 0.86 mmol), zinc cyanide (4.1 g, 34.5 mmol), and ultra-dry N,N-dimethylacetamide (40 mL) were added sequentially. Nitrogen was purged for 5 minutes, and the mixture was stirred at 120°C for 2 hours. Heating was stopped and the mixture was cooled to room temperature. Insoluble matter was removed by filtration, and saturated brine was added. The mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain 2.6 g of a white solid in a 62.8% yield.

[0170] LC-MS(ESI):[M+H] + =241.1;

[0171] 1 H NMR (500MHz, DMSO-d6) δ8.47(s,1H),3.21(t,J=6.3Hz,2H),2.79(t,J=6.7Hz,2H),2.13(p,J=6.5Hz,2H).

[0172] Step 5: Synthesis of 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[0173] To an autoclave, 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carbonitrile (2.6 g, 10.8 mmol) and concentrated hydrochloric acid (50 mL) were added sequentially. The mixture was heated to 100°C and stirred overnight. The reaction mixture was then concentrated under reduced pressure, and dichloromethane (25 mL) and saturated brine (55 mL) were added. The mixture was basified with sodium bicarbonate solution, and the pH was adjusted to 2-4 with 1 M HCl. The mixture was extracted with dichloromethane (80 mL x 3). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 2.7 g of a pale yellow solid in a 96.2% yield.

[0174] LC-MS(ESI):[M+H] + =260.0;

[0175] 1H NMR (500MHz, DMSO-d6) δ8.17(s,1H),3.23(t,J=6.2Hz,2H),2.79(t,J=6.7Hz,2H),2.14(m,J=6.4Hz,2H).

[0176] Step 6: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0177] To the reaction flask were added 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (323 mg, 1.25 mmol), (5-cyclopropylpyrazin-2-yl)methanamine (223 mg, 1.50 mmol), HATU (710 mg, 1.87 mmol), and diisopropylethylamine (483 mg, 3.74 mmol), followed by DMF (8 mL). The mixture was stirred at room temperature for 8 hours under nitrogen. Saturated brine (25 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to afford 340 mg of a light red solid in a 70.0% yield.

[0178] LC-MS(ESI):[M+H] + =391.2;

[0179] 1 H NMR(500MHz,DMSO-d6)δ9.53-9.51(m,1H),8.54(s,1H),8.45(s,1H),8.19(s,1H),4.64(d,J=5.0Hz, 2H),3.30-3.25(m,2H),2.80-2.78(m,2H),2.18-2.14(m,3H),1.03-1.01(m,2H),0.92-0.91(m,2H).

[0180] Step 7: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0181] To the reaction flask, add N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (340 mg, 0.87 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (304 mg, 1.74 mmol), followed by toluene (20 mL). After addition, stir at 110°C for 2 hours. Heating was then stopped, the mixture was cooled to room temperature, and concentrated under reduced pressure before being used in the next step. Hydrazine hydrate (52 mg, 1.05 mmol), acetic acid (10 mg, 0.17 mmol), and ethanol (20 mL) were added to the reaction mixture, followed by stirring at room temperature for 6 hours. Heating was stopped, the mixture was cooled to room temperature, and concentrated under reduced pressure. Purification was performed by silica gel column chromatography (PE:EA (v / v) = 2:1 to 0:1) to obtain 273 mg of a yellow solid in a 75.6% yield.

[0182] LC-MS(ESI):[M+H] + =415.3;

[0183] 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),9.38-9.36(m,1H),8.54(s,1H),8.45(s,1H),8.14(s,1H),7.73(s,1H),4.6 4(d,J=5.0Hz,2H),3.24-3.21(m,2H),2.85-2.85(m,2H),2.20-2.17(m,1H),1.04-1.00(m,2H),0.93-0.90(m,2H).

[0184] Step 8: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0185] To a 25 mL single-necked flask were added N-((5-cyclopropylpyrazin-2-yl)methyl)-4-(trifluoromethyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (100 mg, 0.24 mmol), [(2R)-1,4-dioxan-2-yl]methyl-4-methylsulfonylbenzene (98 mg, 0.36 mmol), and cesium carbonate (157 mg, 0.48 mmol). DMF (10 mL) was then added. The reaction was stirred at 70°C for 3 hours. The excess organic solvent was removed under reduced pressure, and the product was purified on a preparative plate (DCM:MeOH (v / v) = 30:1) to afford 33 mg of a pale yellow solid in a 26.7% yield.

[0186] LC-MS(ESI):[M+H] + =515.4;

[0187] 1 H NMR(500MHz,DMSO-d6)δ9.38-9.36(m,1H),8.54(s,1H),8.45(s,1H),8.13(s,1H),7.69 (s,1H),4.64(d,J=10.0Hz,2H),4.23-4.21(m,2H),3.92-3.90(m,1H),3.79-3.74(m,2H ),3.64-3.62(m,1H),3.57-3.52(m,1H),3.47-3.45(m,1H),3.34-3.30(m,1H),3.23-3. 20(m,2H),2.86-2.83(m,2H),2.21-2.15(m,1H),1.03-1.00(m,2H),0.92-0.91(m,2H).

[0188] Example 4 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-chloropyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 4)

[0189] Step 1: Synthesis of methyl 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylate

[0190] 5-Oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (500 mg, 2.62 mmol) and methanol (10 mL) were added sequentially to the reaction flask. Concentrated sulfuric acid (30 μL) was slowly added dropwise at room temperature, and the mixture was then stirred under reflux at 88°C for 1 hour. Saturated aqueous sodium bicarbonate was added to neutralize the mixture until slightly alkaline, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 537 mg of a yellow solid.

[0191] LC-MS(ESI):[M+H] + =274.0;

[0192] 1 H NMR (500MHz, DMSO-d6) δ8.18(s,1H),3.95(s,3H),3.25-3.23(m,2H),2.81-2.78(m,2H),2.18-2.13(m,2H).

[0193] Step 2: Synthesis of methyl 9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate

[0194] To a reaction flask, methyl 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylate (526 mg, 1.93 mmol), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (503 mg, 2.89 mmol), and toluene (20 mL) were added. The reaction mixture was stirred at 110°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethanol (10 mL) and hydrazine hydrate (116 mg, 2.31 mmol) were then added, and the reaction mixture was stirred at room temperature overnight. The product was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate (60 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to obtain 185 mg of a yellow solid in a 32.3% yield.

[0195] LC-MS(ESI):[M+H] + =298.1;

[0196] 1 H NMR (500MHz, DMSO-d6) δ13.26(s,1H),8.15(s,1H),7.74(s,1H),3.93(s,3H),3.20-3.18(m,2H),2.88-2.85(m,2H).

[0197] Step 3: Synthesis of methyl (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate

[0198] To a reaction flask, methyl 9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate (185 mg, 0.62 mmol), [(2R)-1,4-dioxan-2-yl]methyl 4-methylsulfonylbenzene (254 mg, 0.93 mmol), and cesium carbonate (405 mg, 1.24 mmol) were added sequentially. Ultra-dry DMF (8 mL) was then added. After addition, the mixture was stirred at 70°C for 3 hours. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to afford 131 mg of a pale yellow solid in a 53.3% yield.

[0199] LC-MS(ESI):[M+H] + =398.3;

[0200] 1H NMR(500MHz,DMSO-d6)δ8.14(s,1H),7.70(s,1H),4.24-4.22(m,2H),3.93(s,3H),3.94-3.90(m,1H),3.80-3.74(m,2 H),3.65-3.63(m,1H),3.58-3.53(m,1H),3.48-3.43(m,1H),3.34-3.30(m,1H),3.20-3.17(m,2H),2.86-2.83(m,2H).

[0201] Step 4: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid

[0202] To the reaction flask, methyl 2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate (131 mg, 0.33 mmol) and lithium hydroxide monohydrate (138 mg, 3.30 mmol) were added, and water (2 mL) and tetrahydrofuran (10 mL) were added to dissolve the mixture. After the addition, the mixture was stirred at 50°C for 5 hours. 2M dilute hydrochloric acid solution was added to adjust the pH to 2-4, and then ethyl acetate (25 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 121 mg of a yellow-green solid with a yield of 95.7%.

[0203] LC-MS(ESI):[M+H] + =384.2;

[0204] 1 H NMR(500MHz,DMSO-d6)δ13.44(s,1H),8.12(s,1H),7.69(s,1H),4.23-4.22(m,2H),3.92-3.90(m,1H),3.79-3.74(m,2 H),3.64-3.62(m,1H),3.57-3.52(m,1H),3.47-3.45(m,1H),3.34-3.31(m,1H),3.19-3.18(m,2H),2.85-2.82(m,2H).

[0205] Step 5: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-chloropyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0206] To a reaction flask were added (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (100 mg, 0.26 mmol), (5-chloropyrazin-2-yl)methanamine (45 mg, 0.31 mmol), HATU (149 mg, 0.39 mmol), and diisopropylethylamine (101 mg, 0.78 mmol), followed by DMF (8 mL). The mixture was stirred at room temperature for 5 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to afford 100 mg of a white solid in a 75.8% yield.

[0207] LC-MS(ESI):[M+H] + =509.3;

[0208] 1 H NMR(500MHz,DMSO-d6)δ9.46-9.44(m,1H),8.75(s,1H),8.52(s,1H),8.13(s,1H),7.69(s,1H),4.71-4.70(m,2H),4.23-4.22(m,2H),3.92-3.9 0(m,1H),3.80-3.74(m,2H),3.65-3.62(m,1H),3.58-3.53(m,1H),3.48 -3.45(m,1H),3.34-3.30(m,1H),3.23-3.20(m,2H),2.87-2.84(m,2H).

[0209] Example 5 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)-9-trifluoromethyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 5)

[0210] Step 1: Synthesis of (R)-5-oxo-N-(tetrahydrofuran-2-yl)methyl)-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0211] To the reaction flask were added 5-oxo-4-trifluoromethyl-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (350 mg, 1.35 mmol), (R)-tetrahydrofuran-2-methylamine (273 mg, 2.70 mmol), HATU (770 mg, 2.03 mmol), diisopropylethylamine (524 mg, 4.05 mmol), and DMF (8 mL) at room temperature. The reaction mixture was stirred for 3 hours. The mixture was washed with water and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to obtain 365 mg of a yellow oily liquid in a yield of 79.0%.

[0212] LC-MS(ESI):[M+H] + =343.2;

[0213] 1 H NMR (500MHz, DMSO-d6) δ8.83(t,J=6.0Hz,1H),8.19(s,1H),4.10-3.99(m,1H),3.84-.74(m,1H),3.70-3.60(m,1H),3.47-3.34( m,2H),3.26(t,J=6.3Hz,2H),2.79(t,J=6.7Hz,2H),2.21-2.11(m,2H),1.96-1.88(m,1H),1.88-1.77(m,2H),1.66-1.55(m,1H).

[0214] Step 2: Synthesis of (R)-N-(tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydropyrazolo[3,4-f]quinoline-7-carboxamide

[0215] To a reaction flask, (R)-5-oxo-N-(tetrahydrofuran-2-yl)methyl)-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (343 mg, 1.00 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (349 mg, 2.00 mmol) were added, followed by toluene (10 mL). The reaction mixture was stirred at 110°C for 2 hours. Heating was stopped, the mixture was cooled to room temperature, and concentrated under reduced pressure to yield a yellow oil. Ethanol (10 mL) was then added, followed by hydrazine hydrate (100 mg, 2.00 mmol). After addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1-1:2) to yield 256 mg of a yellow solid in a 69.7% yield.

[0216] LC-MS(ESI):[M+H] + =367.2;

[0217] 1 H NMR (500MHz, DMSO-d6) δ13.19(s,1H),8.65(t,J=6.2Hz,1H),8.13(s,1H),7.72(s,1H),4.02(q,J=6.4Hz,1H),3.85-3.76(m,1H),3.69-3.61(m,1 H),3.48-3.41(m,1H),3.39-3.34(m,1H),3.21(t,J=7.3Hz,2H),2.86(t ,J=7.3Hz,2H),1.96-1.88(m,1H),1.88-1.77(m,2H),1.64-1.56(m,1H).

[0218] Step 3: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)-9-trifluoromethyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0219] To a reaction flask were added (R)-N-(tetrahydrofuran-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydropyrazolo[3,4-f]quinoline-7-carboxamide (150 mg, 0.41 mmol), [(2R)-1,4-dioxan-2-yl]methyl-4-methylsulfonylbenzene (167 mg, 0.61 mmol), and cesium carbonate (267 mg, 0.82 mmol), followed by DMF (8 mL). The reaction mixture was stirred at 70°C for 4 hours. The mixture was washed with water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 4), dried over anhydrous sodium sulfate, and the solid residue was removed by filtration. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1-1:2) to afford 135 mg of a white solid in a 70.7% yield.

[0220] LC-MS(ESI):[M+H] + =467.3;

[0221] 1H NMR(500MHz,DMSO-d6)δ8.65(t,J=6.2Hz,1H),8.13(s,1H),7.69(s,1H),4.29-4. 15(m,2H),4.07-3.98(m,1H),3.96-3.87(m,1H),3.83-3.73(m,3H),3.68-3.61(m, 2H),3.60-3.52(m,1H),3.49-3.40(m,2H),3.39-3.31(m,2H),3.20(t,J=7.3Hz,2H ),2.84(t,J=7.4Hz,2H),1.96-1.88(m,1H),1.88-1.76(m,2H),1.65-1.55(m,1H).

[0222] Example 6 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 6)

[0223] Step 1: Synthesis of 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0224] To a polytetrafluoroethylene tube were added 6-bromo-3,4-dihydronaphthalen-1(2H)-one (1 g, 4.44 mmol), palladium acetate (99.7 mg, 0.44 mmol), Xantphos (257.1 mg, 0.44 mmol), and triethylamine (1.2 mL, 8.89 mmol), followed by dissolution with toluene (10 mL) and water (2 mL). The polytetrafluoroethylene tube was then sealed in an autoclave, filled with 15 atm of carbon monoxide, and heated to 100°C for overnight reaction. Saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH (v / v) = 10:1) to afford 225 mg of a dark brown solid in a 26.6% yield.

[0225] LC-MS(ESI):[MH] + =189.2;

[0226] 1 HNMR(500MHz,DMSO-d6)δ7.96-7.94(m,1H),7.91(s,1H),7.87-7.85(m,1H),3.03-3.00(m,2H),2.66-2.63(m,2H),2.08-2.05(m,2H).

[0227] Step 2: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0228] Under nitrogen, 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (220 mg, 1.16 mmol), (5-cyclopropylpyrazin-2-yl)methylamine (207.1 mg, 1.39 mmol), HATU (659.7 mg, 1.74 mmol), diisopropylethylamine (600.0 μL, 3.47 mmol), and N,N-dimethylformamide (10 mL) were added to the reaction flask in sequence. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 1:1-1:2) to obtain 295 mg of a white solid in a 79.0% yield.

[0229] LC-MS(ESI):[M+H] + =322.3;

[0230] 1 H NMR (500MHz, DMSO-d6) δ13.79(s,1H),9.22(t,J=5.0Hz,1H),8.44(s,1H),7.93(d,J=10.0Hz,1H),7.85(s,1H),7.80(d,J=10.0Hz,1H),4 .55(d,J=5.0Hz,2H),4.05-4.01(m,2H),3.01-2.99(m,2H),2.69-2.63(m,2H),2.19-2.17(m,1H),1.03-1.00(m,2H),0.93-0.91(m,2H).

[0231] Step 3: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0232] To a reaction flask, add N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxamide (295 mg, 0.92 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (246.4 μL, 1.19 mmol), followed by toluene (10 mL). The mixture was stirred at 110°C until the reaction was complete as monitored by TLC. The mixture was concentrated under reduced pressure, dissolved in ethanol (10 mL), and slowly added with hydrazine hydrate (53.5 μL, 1.10 mmol) and acetic acid (26.3 μL, 0.46 mmol). After addition, the mixture was stirred at room temperature. Stirring was stopped, and saturated sodium bicarbonate solution (10 mL) was added to the system for washing. The mixture was extracted with ethyl acetate (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 1:1-0:1) to obtain 72 mg of a yellow solid with a yield of 23.0%.

[0233] LC-MS(ESI):[M+H] + =346.2;

[0234] 1 H NMR(500MHz,DMSO-d6)δ12.86(s,1H),9.03(s,1H),8.55-8.53(m,1H),8.43(s,1H),7.81-7.74(m,2H),7. 54(s,2H),4.55-4.54(m,2H),2.94-2.89(m,2H),2.75-2.72(m,2H),2.19-2.17(m,1H),1.04-1.00(m,2H), 0.93-0.91(m,2H).

[0235] Step 4: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0236] To a reaction flask, nitrogen-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (72 mg, 0.21 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (85.8 mg, 0.32 mmol), cesium carbonate (136.8 mg, 0.42 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. The mixture was stirred at 70°C for 2 hours. The mixture was concentrated under reduced pressure and separated on a preparative silica gel plate (PE:THF (v / v) = 1:1) to afford 6 mg of a white solid in a 7.0% yield.

[0237] LC-MS(ESI):[M+H] + =446.3;

[0238] 1 H NMR(500MHz,DMSO-d6)δ9.04(t,J=5.0Hz,1H),8.54(s,1H),8.44(s,1H),7.80- 7.77(m,2H),7.72-7.70(m,1H),7.55(s,1H),4.55(d,J=5.0Hz,2H),4.18-4.16( m,2H),3.91-3.90(m,1H),3.77-3.74(m,2H),3.66-3.35(m,4H),2.94-2.90(m,2 H),2.74-2.71(m,2H),2.21-2.17(m,1H),1.03-1.01(m,2H),0.94-0.92(m,2H).

[0239] Example 7 Synthesis of (R)-2-((1,4-dioxane-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 7)

[0240] Step 1: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0241] To a reaction flask were added 5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (214 mg, 1.12 mmol), (5-cyclopropylpyrazin-2-yl)methanamine (200 mg, 1.34 mmol), HATU (638 mg, 1.68 mmol), diisopropylethylamine (434 mg, 3.36 mmol), and N,N-dimethylformamide (10 mL) in sequence. The mixture was stirred at room temperature until completion as monitored by TLC. The mixture was washed with saturated brine (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to afford 309 mg of a yellow oily liquid in an 86.0% yield.

[0242] LC-MS(ESI):[M+H] + =323.2;

[0243] 1H NMR (500MHz, DMSO-d6) δ9.35(t,J=5.0Hz,1H),8.54(s,1H),8.43(s,1H),8.35(d,J=5.0Hz,1H),8.01(d,J=10.0Hz,1H) ,4.63(d,J=5.0Hz,2H),3.18-3.15(m,2H),2.71-2.69(m,2H),2.18-2.14(m,3H),1.03-1.00(m,2H),0.93-0.91(m,2H).

[0244] Step 2: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0245] To a reaction flask, nitrogen-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (500 mg, 1.55 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (351 mg, 2.02 mmol) were added, followed by 20 mL of toluene. The reaction was stirred at 110°C until the reaction was complete as monitored by TLC. Concentration under reduced pressure afforded a yellow oil. Ethanol (20 mL) was added, followed by the slow dropwise addition of hydrazine hydrate (93 mg, 1.86 mmol). The reaction was stirred at room temperature for 3 hours. The product was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 1:3 to 0:1) to afford 178 mg of a yellow solid in a 33.0% yield.

[0246] LC-MS(ESI):[M+H] + =347.3;

[0247] 1 H NMR(500MHz,DMSO-d6)δ12.92(s,1H),9.18-9.17(m,1H),8.54(s,1H),8.43(s,1H),8.15(d,J=5.0Hz,1H),7.93(d,J=10.0Hz,1H), 7.64(s,1H),4.62(d,J=5.0Hz,2H),3.14-3.11(m,2H),2.89-2.86(m,2H),2.20-2.16(m,1H),1.03-1.00(m,2H),0.93-0.90(m,2H).

[0248] Step 3: Synthesis of (R)-2-((1,4-dioxan-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0249] To a reaction flask, N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (51 mg, 0.15 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (60.1 mg, 0.22 mmol), and cesium carbonate (95.9 mg, 0.29 mmol) were added sequentially. N,N-dimethylformamide (10 mL) was then added. The reaction mixture was stirred at 70°C for 2 hours. Saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to afford 10 mg of a brownish-gray solid in a 15.0% yield.

[0250] LC-MS(ESI):[M+H] + =447.3;

[0251] 1 H NMR(500MHz,DMSO-d6)δ9.20-9.18(m,1H),8.55(s,1H),8.44(s,1H),8.11(d,J=5.0Hz,1H),7. 93(d,J=10.0Hz,1H),7.61(s,1H),4.63-4.62(m,2H),4.20-4.18(m,2H),3.93-3.91(m,1H),3. 78-3.74(m,2H),3.66-3.63(m,1H),3.59-3.54(m,1H),3.49-3.44(m,1H),3.29-3.27(m,1H),3 .14-3.11(m,2H),2.88-2.85(m,2H),2.21-2.16(m,1H),1.03-1.01(m,2H),0.94-0.92(m,2H).

[0252] Example 8 Synthesis of N,2-bis((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 8)

[0253] Step 1: Synthesis of methyl (5-cyclopropylpyrazin-2-yl)methanesulfonate

[0254] To the reaction flask, (5-cyclopropylpyrazin-2-yl)methanol (243 mg, 1.62 mmol), triethylamine (270 μL, 1.94 mmol) and ultra-dry dichloromethane (10 mL) were added. Methanesulfonyl chloride (125 μL, 1.62 mmol) was slowly added under ice bath. After the addition, the ice bath was removed and stirring was continued at room temperature for 3 hours. The mixture was concentrated under reduced pressure and used directly in the next reaction.

[0255] Step 2: Synthesis of N,2-bis((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0256] To the reaction flask were added N-[(5-cyclopropylpyrazin-2-yl)methyl]-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (150 mg, 0.43 mmol), methyl (5-cyclopropylpyrazin-2-yl)methanesulfonate (148 mg, 0.65 mmol), and cesium carbonate (282 mg, 0.87 mmol), followed by N,N-dimethylformamide (6 mL). The mixture was stirred at 70°C for 3 hours. Saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed by preparative column chromatography (DCM:MeOH (v / v) = 16:1) to afford 30 mg of a white solid in a 14.5% yield.

[0257] LC-MS(ESI):[M+H] + =479.3;

[0258] 1 H NMR(500MHz,DMSO-d6)δ9.18(d,J=6.1Hz,1H),8.56(dd,J=19.2,1.5Hz,2H),8.41(dd ,J=12.3,1.5Hz,2H),8.06(d,J=7.9Hz,1H),7.90(d,J=7.9Hz,1H),7.77(s,1H),5.47( s,2H),4.61(d,J=6.1Hz,2H),3.11(t,J=7.5Hz,2H),2.87(t,J=7.5Hz,2H),2.19(dq,J =8.8,4.7,4.2Hz,2H),1.02(tt,J=8.1,2.9Hz,4H),0.92(ddd,J=7.4,4.7,2.7Hz,4H).

[0259] Example 9 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-ylmethyl)-8-methyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 9)

[0260] Step 1: Synthesis of 3-oxo-2-(iodophenyl)cyclohexyl-1-ene-1-enol

[0261] Cyclohexanedione (3.5 g, 31.2 mmol) and iodophenyldiacetic acid (6.0 mL, 31.2 mmol) were added to a reaction flask, followed by dichloromethane (200 mL). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was washed with 5% potassium hydroxide and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction residue was slurried with n-hexane to obtain 7 g of a white solid product with a yield of 71.4%.

[0262] LC-MS(ESI):[M+H] + =315.1;

[0263] 1 H NMR (500MHz, CDCl3) δ7.84 (d, J = 8.0Hz, 2H), 7.52 (t, J = 7.5Hz, 1H), 7.36 (t, J = 7.7Hz, 2H), 2.62 (t, J = 6.4Hz, 4H), 1.95 (p, J = 6.4Hz, 2H).

[0264] Step 2: Synthesis of 3-methyl-7,8-dihydro-2H-chromene-2,5(6H)-dione

[0265] Under a nitrogen atmosphere, 3-oxo-2-(iodophenyl)cyclohexyl-1-ene-1-ol (500 mg, 1.6 mmol), methacrylic acid (178 mg, 2.1 mmol), [CP*RhCl₂]₂ (49 mg, 0.08 mmol), sodium acetate (33 mg, 0.4 mmol), and hexafluoroisopropanol (10 mL) were added sequentially to an autoclave. The autoclave was then heated to 80°C with stirring overnight. Following TLC monitoring of the reaction, heating was discontinued and the mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 5:1) to afford 170 mg of a yellow solid in a 59.9% yield.

[0266] LC-MS(ESI):[M+H] + =179.1;

[0267] 1H NMR (500MHz, CDCl3) δ7.62 (s, 1H), 2.84 (t, J = 6.3Hz, 2H), 2.57-2.51 (m, 2H), 2.20-2.09 (m, 5H).

[0268] Step 3: Synthesis of 3-methyl-7,8-dihydroquinoline-2,5(1H,6H)-dione

[0269] To an autoclave were added 3-methyl-7,8-dihydro-2H-chromene-2,5(6H)-dione (170 mg, 0.95 mmol) and ammonium acetate (220 mg, 2.86 mmol), followed by dichloroethane (9 mL). After addition, the mixture was transferred to 140°C and stirred overnight. The reaction was complete as monitored by TLC. Heating was discontinued and the mixture was cooled to room temperature. The reaction mixture was made alkaline with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1-3:1) to afford 140 mg of a dark gray solid in an 82.8% yield.

[0270] LC-MS(ESI):[M+H] + =178.2;

[0271] 1 H NMR (500MHz, DMSO-d6) δ11.95(s,1H),7.63(s,1H),2.76(t,J=6.2Hz,2H),2.40(t,J=6.5Hz,2H),2.04-1.92(m,5H).

[0272] Step 4: Synthesis of 2-chloro-3-methyl-7,8-dihydroquinolin-5(6H)-one

[0273] To the reaction flask were added 3-methyl-7,8-dihydroquinoline-2,5(1H,6H)-dione (740 mg, 4.2 mmol), acetonitrile (8 mL), and phosphorus oxychloride (1.9 mL, 20.9 mmol) in sequence. The mixture was heated to 75°C with stirring for 2 hours. Following completion of the reaction as monitored by TLC, heating was discontinued and the mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure, adjusted to alkalinity with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1) to afford 580 mg of a white solid in a 70.9% yield.

[0274] LC-MS(ESI):[M+H] + =196.2;

[0275] 1 H NMR (500MHz, CDCl3) δ8.10 (s, 1H), 3.09 (t, J = 6.2Hz, 2H), 2.67 (t, J = 6.6Hz, 2H), 2.40 (s, 3H), 2.18 (p, J = 6.3Hz, 2H).

[0276] Step 5: Synthesis of 3-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile

[0277] Under a nitrogen atmosphere, 2-chloro-3-methyl-7,8-dihydroquinolin-5(6H)-one (500 mg, 2.6 mmol), tetrakistriphenylphosphine palladium (148 mg, 0.13 mmol), zinc cyanide (600 mg, 5.1 mmol), and N,N-dimethylacetamide (5 mL) were added to the reaction flask in sequence. The mixture was heated to 100°C with stirring for 2 hours and then cooled to room temperature. The insoluble material was removed by filtration, and saturated brine (40 mL) was added. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain 400 mg of a white solid in an 84.1% yield.

[0278] LC-MS(ESI):[M+H] + =187.0;

[0279] 1 H NMR (500MHz, CDCl3) δ8.22 (s, 1H), 3.15 (t, J = 6.2Hz, 2H), 2.76-2.70 (m, 2H), 2.59 (s, 3H), 2.21 (p, J = 6.4Hz, 2H).

[0280] Step 6: Synthesis of 3-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[0281] To the reaction flask, 3-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (400 mg, 2.2 mmol) and concentrated hydrochloric acid (8 mL) were added sequentially. The mixture was heated to 100°C and refluxed with stirring overnight. The reaction solution was then concentrated under reduced pressure, and dichloromethane and saturated brine were added. The solution was basified with sodium bicarbonate solution, and the pH was adjusted to 2-4 with 1 M hydrochloric acid. The solution was extracted with dichloromethane (6 x 15 mL). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 420 mg of a light brown solid in a 95.3% yield.

[0282] LC-MS(ESI):[M+H] + =206.1;

[0283] 1 H NMR (500MHz, DMSO-d6) δ8.09 (s, 1H), 3.04 (t, J = 6.2Hz, 2H), 2.66 (t, J = 6.5Hz, 2H), 2.43 (s, 3H), 2.10 (p, J = 6.3Hz, 2H).

[0284] Step 7: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-3-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0285] Under nitrogen, 3-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (400 mg, 1.9 mmol), HATU (1112 mg, 2.9 mmol), diisopropylethylamine (756 mg, 5.9 mmol), N,N-dimethylformamide (2 mL), and (5-cyclopropylpyrazin-2-yl)methanamine (349 mg, 2.3 mmol) were added to the reaction flask in sequence. The mixture was stirred at room temperature for 2 hours. TLC confirmed the reaction was complete. The mixture was washed with saturated brine (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to obtain 530 mg of a yellow solid in an 80.8% yield.

[0286] LC-MS(ESI):[M+H] + =337.3;

[0287] 1 H NMR (500MHz, DMSO-d6) δ9.22(t,J=6.0Hz,1H),8.55(s,1H),8.45(s,1H),8.08(s,1H),4.57(d,J=6.0Hz,2H),3.08( t,J=6.2Hz,2H),2.70-2.65(m,5H),2.24-2.16(m,1H),2.11(p,J=6.3Hz,2H),1.05-0.99(m,2H),0.95-0.89(m,2H).

[0288] Step 8: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-8-methyl-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0289] To the reaction flask, add N-((5-cyclopropylpyrazin-2-yl)methyl)-3-methyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (530 mg, 1.6 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (0.7 mL, 3.2 mmol), followed by toluene (20 mL). After addition, transfer the mixture to 110°C and stir for 1 hour. TLC monitoring indicates the reaction is complete. Discontinue heating, cool to room temperature, and concentrate under reduced pressure to obtain a yellow oil, which is used directly in the next step. Hydrazine hydrate (238 mg, 4.8 mmol) and ethanol (20 mL) are added to the above system, followed by stirring at room temperature for 1 hour. TLC monitoring indicates the reaction is complete. The reaction solution is concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to obtain 400 mg of a yellow solid in a 70.4% yield.

[0290] LC-MS(ESI):[M+H] + =361.3;

[0291] 1 H NMR (500MHz, DMSO-d6) δ12.89(s,1H),9.15(t,J=6.0Hz,1H),8.55(s,1H),8.45(s,1H),7.90(s,1H),7.60(s,1H),4.57(d,J=6 .0Hz,2H),3.05(t,J=7.5Hz,2H),2.85(t,J=7.5Hz,2H),2.57(s,3H),2.23-2.14(m,1H),1.07-1.00(m,2H),0.95-0.88(m,2H).

[0292] Step 9: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-ylmethyl)-8-methyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0293] To a reaction flask were added N-((5-cyclopropylpyrazin-2-yl)methyl)-8-methyl-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (200 mg, 0.55 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (227 mg, 0.83 mmol), and cesium carbonate (175 mg, 1.11 mmol). N,N-dimethylformamide (10 mL) was then added. After addition, the mixture was stirred at 70°C for 2 hours. The reaction was monitored for completion by TLC. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v:v) = 40:1-15:1) to afford 45 mg of a white solid in a 17.3% yield.

[0294] LC-MS(ESI):[M+H] + =461.3;

[0295] 1 H NMR(500MHz,DMSO-d6)δ9.18(t,J=6.1Hz,1H),8.56(s,1H),8.44(s,1H),7.86(s,1H),7.60(s ,1H),4.56(d,J=6.0Hz,2H),4.20-4.12(m,2H),3.93-3.89(m,1H),3.79-3.72(m,2H),3.64(d, J=11.3Hz,1H),3.59-3.52(m,1H),3.50-3.42(m,1H),3.31-3.25(m,1H),3.04(t,J=7.5Hz,2H) ,2.83(t,J=7.5Hz,2H),2.56(s,3H),2.21-2.14(m,1H),1.04-0.99(m,2H),0.94-0.91(m,2H).

[0296] Example 10 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-methylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 10)

[0297] Step 1: Synthesis of N-((5-methylpyrazin-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0298] Under nitrogen, 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (400 mg, 1.54 mmol), HATU (880 mg, 2.31 mmol), diisopropylethylamine (0.8 mL, 4.63 mmol), N,N-dimethylformamide (6 mL), and (5-methylpyrazin-2-yl)methanamine (228 mg, 1.85 mmol) were added to the reaction flask in sequence and stirred at room temperature for 2 hours. The reaction was monitored for completion by TLC. The mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to obtain 460 mg of a yellow solid in an 81.8% yield.

[0299] LC-MS(ESI):[M+H] + =365.2;

[0300] 1 H NMR(500MHz,DMSO-d6)δ9.59(t,J=6.1Hz,1H),8.49(d,J=16.6Hz,2H),8.20(s,1H),4.66(d, J=6.0Hz,2H),3.27(t,J=6.2Hz,2H),2.79(t,J=6.7Hz,2H),2.47(s,3H),2.19-2.13(m,2H).

[0301] Step 2: Synthesis of N-((5-methylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0302] To the reaction flask, add N-((5-methylpyrazin-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (260 mg, 0.71 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (249 mg, 1.42 mmol), followed by toluene (15 mL). After addition, transfer the mixture to 110°C and stir for 30 minutes. TLC analysis indicates that the reaction is complete. Discontinue heating, cool to room temperature, and concentrate under reduced pressure to obtain a black oil, which is used directly in the next step. Hydrazine hydrate (107 mg, 2.14 mmol) and ethanol (15 mL) are added to the reaction mixture, followed by stirring at room temperature for 1 hour. TLC analysis indicates that the reaction is complete. The reaction mixture is concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to obtain 159 mg of a yellow solid in a 57.4% yield.

[0303] LC-MS(ESI):[M+H]+ =389.3;

[0304] 1 H NMR (500MHz, DMSO-d6) δ13.21(s,1H),9.40(t,J=6.1Hz,1H),8.50(d,J=16.8Hz,2H),8.15(s,1H ),7.73(s,1H),4.67(d,J=6.0Hz,2H),3.23(t,J=7.4Hz,2H),2.88(t,J=7.3Hz,2H),2.48(s,3H).

[0305] Step 3: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-methylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0306] To a reaction flask were added N-((5-methylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (120 mg, 0.31 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (126 mg, 0.46 mmol), and cesium carbonate (97 mg, 0.62 mmol). N,N-dimethylformamide (5 mL) was then added. After addition, the mixture was stirred at 70°C for 1.5 hours. The reaction was monitored for completion by TLC. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1-15:1) to afford 40 mg of a white solid in a 25.4% yield.

[0307] LC-MS(ESI):[M+H] + =489.3;

[0308] 1H NMR(500MHz,DMSO-d6)δ9.40(t,J=6.1Hz,1H),8.50(d,J=15.5Hz,2H),8.14(s,1 H),7.70(s,1H),4.66(d,J=6.0Hz,2H),4.23(d,J=4.9Hz,2H),3.95-3.88(m,1H) ,3.82-3.73(m,2H),3.64(d,J=11.4Hz,1H),3.59-3.53(m,1H),3.51-3.41(m,1H ),3.35-3.31(m,1H),3.22(t,J=7.3Hz,2H),2.86(t,J=7.3Hz,2H),2.48(s,3H).

[0309] Example 11 Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-2-(pyridin-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 11)

[0310] To the reaction flask were added N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (70 mg, 0.17 mmol), 4-dimethylaminopyridine (1 mg, 0.01 mmol), and potassium carbonate (350 mg, 2.53 mmol). Ethyl acetate (3 mL) and 2-(bromomethyl)pyridine (44 mg, 0.25 mmol) were then added. After addition, the mixture was stirred at 70°C for 5 hours. The reaction was monitored for completion by TLC. The crude solution was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The organic phases were combined, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1-25:1) to afford 84 mg of a yellow solid in a 98.4% yield.

[0311] LC-MS(ESI):[M+H] + =506.4;

[0312] 1H NMR(500MHz,DMSO-d6)δ9.36(t,J=6.2Hz,1H),8.54(d,J=4.5Hz,2H),8.45(s,1 H),8.12(s,1H),7.83(s,1H),7.79(t,J=7.8Hz,1H),7.32(t,J=6.2Hz,1H),7.1 7(d,J=7.9Hz,1H),5.50(s,2H),4.63(d,J=6.0Hz,2H),3.22(t,J=7.4Hz,2H),2 .87(t,J=7.4Hz,2H),2.23-2.11(m,1H),1.04-0.99(m,2H),0.94-0.88(m,2H).

[0313] Example 12 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 12)

[0314] Step 1: Synthesis of 5-cyclopropylpyrazine-2-carboxaldehyde

[0315] To a reaction flask, (5-cyclopropylpyrazin-2-yl)methanol (110 mg, 0.73 mmol) was added, followed by dissolving in ethanol (5 mL), and manganese dioxide (637 mg, 7.32 mmol). After the addition, the mixture was stirred at room temperature for 2 hours. An additional manganese dioxide (637 mg, 7.32 mmol) was added, and the mixture was moved to an 85°C oil bath overnight. The reaction was monitored for completion by TLC. The mixture was filtered through celite and evaporated to dryness. The mixture was purified by silica gel column chromatography (EA:PE (v:v) = 1:10 to 1:5) to afford 101 mg of a white solid in a 93.1% yield.

[0316] LC-MS(ESI):[M+H] + =149.1;

[0317] 1 H NMR (500MHz, DMSO-d6) δ10.02(s,1H),8.93(s,1H),8.86(s,1H),2.42-2.33(m,1H),1.23-1.18(m,2H),1.12-1.07(m,2H).

[0318] Step 2: Synthesis of (E)-N-((5-cyclopropylpyrazin-2-yl)methylene)-2-methylpropane-2-sulfonamide

[0319] To a reaction flask, add 5-cyclopropylpyrazine-2-carboxaldehyde (625 mg, 4.22 mmol), dissolve in dichloromethane (20 mL), 2-methylpropane-2-sulfamide (1023 mg, 8.44 mmol), and copper sulfate (1347 mg, 8.44 mmol). After the addition, heat in a 50°C oil bath overnight. TLC monitors the reaction for completion. After evaporating the reaction solution to dryness, chromatography on a silica gel column (EA:PE (v:v) = 1:6 to 1:4) affords 1000 mg of a yellow solid in a 94.3% yield.

[0320] 1 H NMR (500MHz, DMSO-d6) δ9.06(s,1H),8.79(s,1H),8.51(s,1H),2.37-2.30(m,1H),1.20(s,9H),1.18-1.14(m,2H),1.09-1.05(m,2H).

[0321] Step 3: Synthesis of N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-2-methylpropane-2-sulfonamide

[0322] Under nitrogen, (E)-N-((5-cyclopropylpyrazin-2-yl)methylene)-2-methylpropane-2-sulfonamide (1000 mg, 3.98 mmol) was added to a reaction flask and dissolved in toluene (20 mL). Methyllithium (87.5 mg, 3.98 mmol) was then added at -78°C. Stirring was continued at -78°C for 1 hour. The reaction was stopped and quenched with saturated ammonium chloride solution (10 mL). Stirring was continued at room temperature for 10 minutes. After standing and separating the layers, the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (EA:PE (v:v) = 1:1 to 3:1) to obtain 950 mg of a yellow oily liquid in an 89.3% yield.

[0323] 1 H NMR(500MHz,DMSO-d6)δ8.58(s,1H),8.52(s,1H),5.71(d,J=7.7Hz,1H),4.54-4.42(m,1H),2.23-2.14(m,1H) ,1.51(d,J=6.9Hz,1H),1.44(d,J=6.8Hz,2H),1.12(s,6H),1.11(s,3H),1.06-0.99(m,2H),0.96-0.89(m,2H).

[0324] Step 4: Synthesis of 1-(5-cyclopropylpyrazin-2-yl)ethan-1-amine

[0325] To a reaction flask, add N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-2-methylpropane-2-sulfonamide (837 mg, 3.13 mmol) and dissolve in methanol (15 mL). Then, slowly add hydrochloric acid in ethanol (1.6 mL, 10 mol / L) dropwise. After addition, stir at room temperature for 3 hours. TLC monitors the reaction until complete. Add saturated sodium carbonate solution to adjust the pH to 8-9. Extract the mixture with dichloromethane:methanol (v:v) = 10:1 (100 mL x 3). Evaporate to dryness to obtain 710 mg of a yellow oily liquid, which is used directly in the next step.

[0326] LC-MS(ESI):[M+H] + =164.20;

[0327] 1 H NMR(500MHz,DMSO-d6)δ8.52(s,1H),8.48(s,1H),4.07-3.97(m,1H),2.20 -2.13(m,1H),1.29(d,J=6.8Hz,3H),1.03-0.97(m,2H),0.93-0.88(m,2H).

[0328] Step 5: Synthesis of N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0329] Under nitrogen, 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (323 mg, 1.25 mmol), HATU (711 mg, 1.87 mmol), and N,N-dimethylformamide (8 mL) were added sequentially to a reaction flask for dissolution. 1-(5-cyclopropylpyrazin-2-yl)ethan-1-amine (305 mg, 1.87 mmol) and diisopropylethylamine (483 mg, 3.74 mmol) were then added and stirred at room temperature for 1 hour. TLC confirmed the reaction was complete, and the mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 4). The organic phases were separated, dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE (v:v) = 1:4 to 1:1) to afford 485 mg of a yellow solid in a 96.2% yield.

[0330] LC-MS(ESI):[M+H] + =405.3;

[0331] 1H NMR(500MHz,DMSO-d6)δ9.22(d,J=8.0Hz,1H),8.57(s,1H),8.55(s,1H),8.18(s,1H),5.33-5.24(m,1H),3.28-3. 26(m,2H),2.79(t,J=6.7Hz,2H),2.24-2.11(m,3H),1.57(d,J=6.9Hz,3H),1.06-1.00(m,2H),0.95-0.91(m,2H).

[0332] Step 6: Synthesis of N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0333] To a reaction flask, add N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (438 mg, 1.08 mmol), dissolve in toluene (8 mL), and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (378 mg, 2.17 mmol). After the addition, heat in an oil bath at 110°C for 30 minutes. Monitor the reaction for completion by TLC. Evaporate the toluene, dissolve in ethanol (8 mL), and add hydrazine hydrate (108 mg, 2.17 mmol) dropwise. Continue the reaction at room temperature for 2 hours. Evaporate the reaction solution and purify it by silica gel column chromatography (EA:PE (v:v) = 1:2 to 1:1) to obtain 135 mg of a yellow solid in a yield of 29.1%.

[0334] LC-MS(ESI):[M+H] + =429.3;

[0335] 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),9.07(d,J=8.0Hz,1H),8.58(s,1H),8.56(s,1H),8.12(s,1H),7.73(s,1H),5.34-5.24(m,1 H),3.24(t,J=7.3Hz,2H),2.87(t,J=7.3Hz,2H),2.24-2.15(m,1H),1.56(d,J=6.9Hz,3H),1.06-1.00(m,2H),0.96-0.90(m,2H).

[0336] Step 7: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0337] To the reaction flask, add N-(1-(5-cyclopropylpyrazin-2-yl)ethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (135 mg, 0.32 mmol), (R)-(1,4-dioxane-2-yl)methyl p-toluenesulfonate (172 mg, 0.63 mmol), cesium carbonate (205 mg, 0.63 mmol), and dissolve in N,N-dimethylformamide (5 mL). After the addition is complete, move to 70°C oil bath and heat for 30 minutes. The reaction was complete as monitored by TLC, and water was added to quench the reaction (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 4). The organic phase was separated and dried over anhydrous sodium sulfate. The solid was removed by filtration and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (EA:PE (v:v) = 1:2 to 1:1) to give 143 mg of a light yellow solid in a yield of 84.5%.

[0338] LC-MS(ESI):[M+H] + =529.4;

[0339] 1 H NMR(500MHz,DMSO-d6)δ9.07(d,J=8.0Hz,1H),8.58(s,1H),8.56(s,1H),8.12(s,1H),7.69(s,1 H),5.34-5.24(m,1H),4.28-4.17(m,2H),3.94-3.89(m,1H),3.82-3.72(m,2H),3.64(d,J=11.4 Hz,1H),3.60-3.51(m,1H),3.49-3.41(m,1H),3.35-3.31(m,1H),3.23(t,J=7.4Hz,2H),2.85(t ,J=7.3Hz,2H),2.24-2.15(m,1H),1.56(d,J=6.9Hz,3H),1.06-1.00(m,2H),0.96-0.91(m,2H).

[0340] Example 13 Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-2-(pyridin-3-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 13)

[0341] To the reaction flask were added N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (50 mg, 0.12 mmol), 4-dimethylaminopyridine (1.5 mg, 0.01 mmol), and potassium carbonate (250 mg, 1.81 mmol). Ethyl acetate (3 mL) was then added, and finally 3-(bromomethyl)pyridine (31 mg, 0.18 mmol). After addition, the mixture was stirred at 70°C for 4 hours. The reaction was monitored for completion by TLC. The crude solution was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The organic phases were combined, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1-25:1) to afford 27 mg of a yellow solid in a 42.6% yield.

[0342] LC-MS(ESI):[M+H] + =506.4;

[0343] 1 H NMR(500MHz,DMSO-d6)δ9.36(t,J=6.1Hz,1H),8.59(d,J=2.4Hz,1H),8.55-8.4 9(m,2H),8.44(s,1H),8.12(s,1H),7.84(s,1H),7.74(d,J=7.6Hz,1H),7.39(dd ,J=7.9,4.8Hz,1H),5.45(s,2H),4.63(d,J=6.0Hz,2H),3.21(t,J=7.4Hz,2H), 2.84(t,J=7.4Hz,2H),2.20-2.15(m,1H),1.04-0.99(m,2H),0.93-0.90(m,2H).

[0344] Example 14 Synthesis of N,2-bis(((S)-1,4-dioxane-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 14)

[0345] Step 1: Synthesis of (S)-N-((1,4-dioxan-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0346] Under nitrogen, 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (350 mg, 1.35 mmol), HATU (770 mg, 2.03 mmol), diisopropylethylamine (524 mg, 4.05 mmol), N,N-dimethylformamide (10 mL), and (S)-(1,4-dioxan-2-yl)methanamine (190 mg, 1.62 mmol) were added sequentially to the reaction flask and stirred at room temperature for 1.5 hours. TLC confirmed the reaction was complete, and the mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to obtain 320 mg of a yellow solid in a 66.1% yield.

[0347] LC-MS(ESI):[M+H] + =359.2;

[0348] 1 H NMR(500MHz,DMSO-d6)δ8.91(t,J=6.2Hz,1H),8.18(s,1H),3.80-3.70(m,3H),3.65-3.60(m,1H),3.60-3.5 3(m,1H),3.50-3.44(m,1H),3.40-3.36(m,2H),3.28-3.21(m,3H),2.79(t,J=6.6Hz,2H),2.20-2.12(m,2H).

[0349] Step 2: Synthesis of (S)-N-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0350] To the reaction flask, (S)-N-((1,4-dioxan-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (300 mg, 0.84 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (292 mg, 1.67 mmol) were added, followed by toluene (10 mL). After addition, the mixture was stirred at 110°C for 30 minutes. TLC confirmed the reaction was complete. Heating was discontinued, the mixture was cooled to room temperature, and concentrated under reduced pressure to yield a black oil. Hydrazine hydrate (126 mg, 2.51 mmol) and ethanol (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. TLC confirmed the reaction was complete. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to yield 180 mg of a yellow solid in a 56.2% yield.

[0351] LC-MS(ESI):[M+H] + =383.2.

[0352] Step 3: Synthesis of N,2-bis(((S)-1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0353] To the reaction flask, add (S)-N-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (70 mg, 0.18 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (75 mg, 0.27 mmol), and cesium carbonate (119 mg, 0.37 mmol). Then, add N,N-dimethylformamide (2 mL). After the addition, transfer to 70°C and stir for 2 hours. The reaction was complete as monitored by TLC, and water (15 mL) was added for dilution. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1-15:1) to give 27 mg of a white solid in a yield of 29.9%.

[0354] LC-MS(ESI):[M+H] + =483.4;

[0355] 1 H NMR (500MHz, DMSO-d6) δ8.80(s,1H),8.12(s,1H),7.70(s,1H),4.22(d,J=5.8Hz,2H),3.93-3.88(m,1H),3.81-3.69(m,5H),3.64(d,J=1 1.4Hz,2H),3.59-3.51(m,2H),3.50-3.42(m,2H),3.37(t,J=6.1Hz,2H),3.32-3.25(m,2H),3.21(t,J=7.3Hz,2H),2.84(t,J=7.3Hz,2H).

[0356] Example 15 Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-2-((2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 15)

[0357] To the reaction flask, add N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (49 mg, 0.12 mmol), (2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl p-toluenesulfonate (58 mg, 0.18 mmol), and cesium carbonate (78 mg, 0.24 mmol). Then, add N,N-dimethylformamide (3 mL). After the addition is complete, transfer to 70°C and stir for 4 hours. The reaction was complete as monitored by TLC. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (DCM:MeOH (v / v) = 40:1-30:1) to give 25 mg of a white solid in a yield of 34.8%.

[0358] LC-MS(ESI):[M+H] + =563.4;

[0359] 1 H NMR(500MHz,DMSO-d6)δ9.44-9.40(m,1H),8.55(d,J=3.0Hz,1H),8.44(d,J=2 .9Hz,1H),8.13(d,J=3.1Hz,1H),7.77(d,J=3.1Hz,1H),6.91-6.83(m,4H),4.7 1-4.48(m,5H),4.46-4.40(m,1H),4.06-4.01(m,1H),3.23(t,J=7.1Hz,2H),2 .86(t,J=7.1Hz,2H),2.24-2.11(m,1H),1.04-0.99(m,2H),0.93-0.90(m,2H).

[0360] Example 16 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 16)

[0361] Step 1: Synthesis of (R)-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0362] Under nitrogen, 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (250 mg, 1.31 mmol), (R)-(tetrahydrofuran-2-yl)methylamine (207 mg, 1.39 mmol), HATU (749 mg, 1.97 mmol), diisopropylethylamine (652 μL, 3.94 mmol), and N,N-dimethylformamide (15 mL) were added to the reaction flask in order. The mixture was stirred at room temperature overnight. Purified water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 2:1 to 1:1) to obtain 294 mg of a yellow oily liquid in an 81.8% yield.

[0363] LC-MS(ESI):[M+H] + =274.2;

[0364] 1 H NMR (500MHz, DMSO-d6) δ8.69(t,J=5.8Hz,1H),7.91(d,J=8.1Hz,1H),7.81(d,J=1.7H z,1H),7.77(dd,J=8.2,1.7Hz,1H),3.98(p,J=6.3Hz,1H),3.85–3.71(m,1H),3.63(q, J=7.4Hz,1H),3.33–3.28(m,2H),2.99(t,J=6.1Hz,2H),2.67–2.58(m,2H),2.06(p,J= 6.2Hz,2H),1.91(ddt,J=14.5,8.1,4.1Hz,1H),1.87–1.74(m,2H),1.63–1.53(m,1H).

[0365] Step 2: Synthesis of (R)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0366] To the reaction flask, (R)-5-oxo-nitro-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (294 mg, 1.08 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (333 μL, 1.61 mmol) were added, followed by toluene (10 mL). The mixture was stirred at 110°C for 1 hour. The mixture was concentrated under reduced pressure and used directly in the next reaction. Ethanol (10 mL) was added to the above system, followed by the slow addition of hydrazine hydrate (81 mg, 1.62 mmol). After the additions were complete, the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to the system, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH (v / v) = 30:1-10:1) to obtain 264 mg of a yellow solid in an 82.5% yield.

[0367] LC-MS(ESI):[M+H] + =298.2;

[0368] 1 H NMR (500MHz, DMSO-d6) δ12.75 (s, 1H), 8.47 (t, J = 5.7Hz, 1H), 7.75 (d, J = 16. 0Hz,3H),7.58(s,1H),3.98(p,J=6.3Hz,1H),3.83–3.71(m,1H),3.63(q,J= 7.3Hz,1H),3.33–3.28(m,2H),2.91(t,J=7.3Hz,2H),2.73(t,J=7.4Hz,2H) ,1.91(ddt,J=11.8,8.4,5.8Hz,1H),1.87–1.74(m,2H),1.65–1.53(m,1H).

[0369] Step 3: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0370] To a reaction flask, (R)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (258 mg, 0.87 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (354 mg, 1.30 mmol), cesium carbonate (565 mg, 1.74 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. The mixture was stirred at 70°C for 1 hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (DCM:MeOH (v / v) = 100:1-30:1) to afford 90 mg of a white solid in a 26.1% yield.

[0371] LC-MS(ESI):[M+H] + =398.3;

[0372] 1 H NMR(500MHz,DMSO-d6)δ8.48(t,J=5.8Hz,1H),7.81–7.71(m,2H),7.69(d,J=8.0Hz,1H),7.55(s,1H),4.24–4 .09(m,2H),3.98(p,J=6.3Hz,1H),3.89(dtd,J=10.0,6.0,5.1,2.8Hz,1H),3.84–3.71(m,3H),3.71–3.60(m,2 H),3.55(td,J=11.2,2.5Hz,1H),3.46(td,J=11.0,2.6Hz,1H),3.29(td,J=12.3,11.5,8.2Hz,3H),2.91(t,J =7.3Hz,2H),2.71(t,J=7.3Hz,2H),1.90(ddd,J=17.6,9.2,4.5Hz,1H),1.86–1.73(m,2H),1.66–1.52(m,1H).

[0373] Example 17 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-9-cyclopropyl-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 17)

[0374] Step 1: Synthesis of 2,4-dichloro-7,8-dihydroquinolin-5(6H)-one

[0375] To a reaction flask, bis(2,4,6-trichlorophenyl)malonate (49800 mg, 107.58 mmol), 3-aminocyclohex-2-en-1-one (11956 mg, 107.58 mmol), and bromobenzene (120 mL) were added sequentially. The mixture was allowed to react at 155°C for 1 hour. The reaction was complete as monitored by TLC. The reaction solution was cooled to room temperature and poured into ethyl acetate (120 mL). A yellow solid precipitated. After filtration, the filter cake was dried under vacuum. Phosphorus oxychloride (87.5 mL, 939 mmol) was added and the mixture was allowed to react at 95°C for 4 hours. The reaction was complete as monitored by TLC. The mixture was evaporated to dryness and adjusted to pH 8-9 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and purified by silica gel column chromatography (EA:PE (v:v) = 1:10-1:5) to yield 2.5 g of a white solid in a 10.8% yield.

[0376] LC-MS(ESI):[M+H] + =216.6;

[0377] 1 H NMR (500MHz, CDCl3) δ7.73 (s, 1H), 3.08 (t, J = 6.2Hz, 2H), 2.66 (t, J = 6.6Hz, 2H), 2.11-2.03 (m, 2H).

[0378] Step 2: Synthesis of 4-chloro-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile

[0379] Under a nitrogen atmosphere, 2,4-dichloro-7,8-dihydroquinolin-5(6H)-one (2940 mg, 13.61 mmol), zinc cyanide (799 mg, 6.80 mmol), and tetrakistriphenylphosphine palladium (1572 mg, 1.36 mmol) were added to a reaction flask in sequence. After the addition, N,N-dimethylformamide (20 mL) was added to dissolve the mixture. The mixture was then heated in an oil bath at 120°C for 2 hours to terminate the reaction. Water (30 mL) was added to quench the mixture, followed by extraction with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 4). The organic phases were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The organic phase was purified by silica gel column chromatography (EA:PE (v:v) = 1:9-1:5) to afford 400 mg of a pale yellow solid in a 14.2% yield.

[0380] LC-MS(ESI):[M+H] + =207.1;

[0381] 1H NMR (500MHz, DMSO-d6) δ8.26 (s, 1H), 3.14 (t, J = 6.3Hz, 2H), 2.72 (t, J = 6.7Hz, 2H), 2.09 (p, J = 6.5Hz, 2H).

[0382] Step 3: Synthesis of 4-cyclopropyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile

[0383] Under nitrogen, a reaction flask was charged with 4-chloro-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (200 mg, 0.97 mmol), cyclopropylboronic acid (167 mg, 1.95 mmol), potassium carbonate (470 mg, 3.40 mmol), toluene (0.5 mL), and purified water (3 mL). Bis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) dichloride (69 mg, 0.10 mmol) was then added. The mixture was moved to a 100°C oil bath overnight. The reaction mixture was evaporated to dryness and purified by silica gel column chromatography (EA:PE (v:v) = 1:5 to 1:3) to afford 123 mg of a white solid in a 59.9% yield.

[0384] LC-MS(ESI):[M+H] + =213.1;

[0385] 1 H NMR (500MHz, DMSO-d6) δ7.48 (s, 1H), 3.24-3.17 (m, 1H), 3.06 (t, J = 6.3Hz, 2H), 2. 72(t,J=6.6Hz,2H),2.06(p,J=6.5Hz,2H),1.20-1.12(m,2H),1.02-0.95(m,2H).

[0386] Step 4: Synthesis of 4-cyclopropyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[0387] To a reaction flask, add 4-cyclopropyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (381 mg, 1.80 mmol), sodium hydroxide (718 mg, 17.95 mmol), purified water (4 mL), and ethanol (12 mL) in sequence. After addition, heat to 90°C for 3 hours. TLC monitors the reaction for completeness. Adjust the pH to 2-3 by adding 1M HCl. Extract with ethyl acetate (50 mL x 3). Combine the organic phases and dry over anhydrous sodium sulfate. A tan solid (420 mg) is obtained, which is used directly in the next step.

[0388] LC-MS(ESI):[M+H] + =232.2.

[0389] Step 5: Synthesis of 4-cyclopropyl-N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0390] Under nitrogen, a reaction flask was charged with 4-cyclopropyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (287 mg, 1.24 mmol), (5-cyclopropylpyrazin-2-yl)methanamine (222 mg, 1.49 mmol), and HATU (707 mg, 1.86 mmol). Dissolved in N,N-dimethylformamide (8 mL) was then added dropwise with diisopropylethylamine (481 mg, 3.72 mmol). The mixture was stirred at room temperature for 3 hours. Water (30 mL) was added for quenching, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 4). The organic phases were separated, dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (EA:PE (v:v) = 1:2 to 2:1) to afford 200 mg of a white solid in a 44.5% yield.

[0391] LC-MS(ESI):[M+H] + =363.3;

[0392] 1 H NMR(500MHz,DMSO-d6)δ9.28(t,J=6.1Hz,1H),8.53(s,1H),8.41(d,J=1.4H z,1H),7.38(s,1H),4.59(d,J=6.1Hz,2H),3.28-3.22(m,1H),3.13(t,J=6. 2Hz,2H),2.72(t,J=6.6Hz,2H),2.21-2.14(m,1H),2.08(p,J=6.5Hz,2H),1 .20-1.12(m,2H),1.05-0.98(m,2H),0.94-0.89(m,2H),0.88-0.82(m,2H).

[0393] Step 6: Synthesis of 9-cyclopropyl-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0394] To a reaction flask, 4-cyclopropyl-N-((5-cyclopropylpyrazin-2-yl)methyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (150 mg, 0.41 mmol) was added, dissolved in toluene (8 mL), and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (216 mg, 1.24 mmol) was added sequentially. After the addition, the mixture was heated in an oil bath at 100°C for 30 minutes. TLC confirmed the reaction completion. The toluene was evaporated to dryness, and ethanol (5 mL) was added for dissolution. Hydrazine hydrate (187 mg, 3.72 mmol) was then added. After the addition, the mixture was stirred at room temperature for 2 hours to terminate the reaction. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (EA:PE (v:v) = 1:1 to 3:1) to afford 140 mg of a yellow solid in an 87.5% yield.

[0395] LC-MS(ESI):[M+H] + =387.4;

[0396] 1 H NMR (500MHz, DMSO-d6) δ12.90(s,1H),9.15(t,J=6.1Hz,1H),8.53(s,1H),8.42(s,1H),7.68(s,1H),7.32(s,1H),4.59(d,J=6.0Hz,2H),3.08(t, J=7.3Hz,2H),2.81(t,J=7.3Hz,2H),2.21-2.14(m,1H),1.24(s,1H),1.1 6-1.12(m,2H),1.04-0.98(m,2H),0.94-0.89(m,2H),0.87-0.81(m,2H).

[0397] Step 7: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-9-cyclopropyl-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0398] 9-Cyclopropyl-N-((5-cyclopropylpyrazin-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (71 mg, 0.18 mmol), (R)-(1,4-dioxane-2-yl)methyl p-toluenesulfonate (75 mg, 0.28 mmol), cesium carbonate (119.72 mg, 0.37 mmol), and N,N-dimethylformamide (8 mL) were added sequentially to the reaction flask. After the addition, the mixture was moved to a 70°C oil bath and heated for 1 hour. Water was added to quench the reaction mixture (30 mL), and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 4). The organic phase was separated and dried over anhydrous sodium sulfate. The solid was removed by filtration and concentrated under reduced pressure. 70 mg of a white oily liquid was isolated by silica gel column chromatography (EA:PE (v:v) = 1:2 to 2:1). The yield was 79.9%.

[0399] LC-MS(ESI):[M+H] + =487.4;

[0400] 1 H NMR(500MHz,DMSO-d6)δ9.15(t,J=6.1Hz,1H),8.53(s,1H),8.42(s,1H),7.64(s,1H),7.33(s,1H),4 .59(d,J=6.0Hz,2H),4.20(d,J=5.9Hz,2H),3.95-3.88(m,1H),3.79-3.72(m,2H),3.64(d,J=11.5Hz, 1H),3.59-3.52(m,2H),3.51-3.43(m,1H),3.33-3.31(m,1H),3.07(t,J=7.3Hz,2H),2.79(t,J=7.4Hz ,2H),2.21-2.14(m,1H),1.18-1.11(m,2H),1.05-0.98(m,2H),0.94-0.88(m,2H),0.86-0.80(m,2H).

[0401] Example 18 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-9-cyclopropyl-N-(((R)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 18)

[0402] Step 1: Synthesis of (R)-4-cyclopropyl-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0403] Under nitrogen, 4-cyclopropyl-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (215 mg, 0.93 mmol), HATU (530 mg, 1.39 mmol), and N,N-dimethylformamide (5 mL) were added sequentially to a reaction flask for dissolution. (R)-(tetrahydrofuran-2-yl)methanamine (113 mg, 1.12 mmol) and diisopropylethylamine (360 mg, 2.79 mmol) were then added. The mixture was stirred at room temperature for 2 hours, quenched with water (30 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 4), and separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The organic phase was isolated by silica gel column chromatography (EA:PE (v:v) = 1:2 to 2:1) to afford 150 mg of a pale yellow solid in a 51.3% yield.

[0404] LC-MS(ESI):[M+H] + =315.3;

[0405] 1 H NMR(500MHz,DMSO-d6)δ8.58(t,J=6.2Hz,1H),7.38(s,1H),4.02-3.96(m,1H),3.82 -3.75(m,1H),3.69-3.60(m,1H),3.43-3.36(m,1H),3.35-3.31(m,1H),3.27-3.22( m,1H),3.11(t,J=6.2Hz,2H),2.72(t,J=6.6Hz,2H),2.12-2.04(m,2H),1.95-1.87( m,1H),1.86-1.75(m,2H),1.62-1.52(m,1H),1.20-1.12(m,2H),0.89-0.83(m,2H).

[0406] Step 2: Synthesis of (R)-9-cyclopropyl-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0407] To a reaction flask, add (R)-4-cyclopropyl-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (150 mg, 0.48 mmol), dissolve in toluene (8 mL), and then add 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (249 mg, 1.43 mmol). After the addition, heat in an oil bath at 100°C for 30 minutes. Add 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (300 mg, 0.96 mmol) and continue heating for 15 minutes. Monitor the reaction by TLC until complete. Evaporate the toluene, dissolve in ethanol (8 mL), and then add hydrazine hydrate (215 mg, 4.29 mmol). After the addition, stir at room temperature for 1 hour, and evaporate the reaction mixture to dryness. The product was separated by silica gel column chromatography (EA:PE (v:v) = 1:2 to 2:1) to obtain 90 mg of a light yellow solid with a yield of 55.7%.

[0408] LC-MS(ESI):[M+H] + =339.3;

[0409] 1 H NMR(500MHz,DMSO-d6)δ12.90(s,1H),8.46(t,J=6.2Hz,1H),7.68(s,1H),7.33( s,1H),4.04-3.94(m,1H),3.83-3.75(m,1H),3.71-3.60(m,2H),3.47-3.39(m,1H ),3.34-3.30(m,1H),3.06(t,J=7.3Hz,2H),2.81(t,J=7.3Hz,2H),1.95-1.87(m, 1H),1.87-1.75(m,2H),1.62-1.53(m,1H),1.18-1.11(m,2H),0.88-0.80(m,2H).

[0410] Step 3: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-9-cyclopropyl-N-(((R)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0411] To a reaction flask, (R)-9-cyclopropyl-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (90 mg, 0.27 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (109 mg, 0.40 mmol), and cesium carbonate (173 mg, 0.53 mmol) were added sequentially and dissolved in N,N-dimethylformamide (8 mL). After the addition, the mixture was heated in an oil bath at 70°C for 1 hour. Water (30 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 4), separated, dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. The mixture was separated by silica gel column chromatography (EA:PE (v:v) = 1:2 to 2:1) to give 90 mg of a light yellow solid in a yield of 77.2%.

[0412] LC-MS(ESI):[M+H] + =439.4;

[0413] 1 H NMR(500MHz,DMSO-d6)δ8.46(t,J=6.2Hz,1H),7.64(s,1H),7.33(s,1H),4.24-4.15(m,2H),4.02-3. 95(m,1H),3.95-3.89(m,1H),3.82-3.72(m,3H),3.67-3.61(m,2H),3.60-3.52(m,2H),3.50-3.45(m, 1H),3.45-3.38(m,1H),3.34-3.31(m,1H),3.28-3.26(m,1H),3.05(t,J=7.3Hz,2H),2.78(t,J=7.3Hz ,2H),1.94-1.87(m,1H),1.87-1.76(m,2H),1.62-1.53(m,1H),1.18-1.11(m,2H),0.90-0.78(m,2H).

[0414] Example 19 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 19)

[0415] Step 1: Synthesis of (S)-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0416] Under nitrogen, 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (400 mg, 1.54 mmol), HATU (880 mg, 2.31 mmol), diisopropylethylamine (598 mg, 4.63 mmol), N,N-dimethylformamide (8 mL), and (S)-(tetrahydrofuran-2-yl)methanamine (187 mg, 1.85 mmol) were added to the reaction flask in sequence. The mixture was stirred at room temperature for 1.5 hours. TLC confirmed the reaction was complete, and the mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed once with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to obtain 474 mg of the compound as a yellow oil in an 89.7% yield.

[0417] LC-MS(ESI):[M+H] + =343.2;

[0418] 1 H NMR (500MHz, DMSO-d6) δ8.84(t,J=6.1Hz,1H),8.19(s,1H),4.07-3.98(m,1H),3.83-3.75(m,1H),3.68-3.60(m,1H),3. 46-3.33(m,2H),3.26(t,J=6.3Hz,2H),2.79(t,J=6.7Hz,2H),2.20-2.11(m,2H),1.96-1.75(m,3H),1.65-1.54(m,1H).

[0419] Step 2: Synthesis of (S)-N-((tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0420] To the reaction flask, (S)-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (450 mg, 1.31 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (458 mg, 2.62 mmol) were added, followed by toluene (10 mL). After addition, the mixture was stirred at 110°C for 30 minutes. TLC monitored the reaction for completion. Heating was discontinued, the mixture was cooled to room temperature, and concentrated under reduced pressure to yield a black oil, which was used directly in the next step. Hydrazine hydrate (197 mg, 3.93 mmol) and ethanol (10 mL) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. TLC monitored the reaction for completion. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to yield 245 mg of a yellow solid in a 50.9% yield.

[0421] LC-MS(ESI):[M+H] + =367.3;

[0422] 1 H NMR(500MHz,DMSO-d6)δ13.21(s,1H),8.68(t,J=6.2Hz,1H),8.14(s,1H),7.73(s,1H),4.07-3.98(m,1H),3.84-3.76(m,1H),3.69-3 .61(m,1H),3.48-3.40(m,1H),3.40-3.32(m,1H),3.21(t,J=7.3Hz,2H),2.86(t,J=7.3Hz,2H),1.97-1.75(m,3H),1.65-1.55(m,1H).

[0423] Step 3: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0424] To a reaction flask were added (S)-N-((tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (100 mg, 0.27 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (112 mg, 0.41 mmol), and cesium carbonate (178 mg, 0.55 mmol). N,N-dimethylformamide (3 mL) was then added. After addition, the mixture was stirred at 70°C for 1.5 hours. The reaction was monitored for completion by TLC. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 0:1) to afford 94 mg of a yellow solid in a 71.5% yield.

[0425] LC-MS(ESI):[M+H] + =467.4;

[0426] 1 H NMR(500MHz,DMSO-d6)δ8.68(t,J=6.1Hz,1H),8.13(s,1H),7.69(s,1H),4.22 (d,J=5.8Hz,2H),4.06-3.98(m,1H),3.93-3.88(m,1H),3.84-3.72(m,3H),3.6 8-3.61(m,2H),3.59-3.51(m,1H),3.50-3.41(m,2H),3.39-3.33(m,2H),3.20 (t,J=7.3Hz,2H),2.84(t,J=7.4Hz,2H),1.96-1.75(m,3H),1.65-1.55(m,1H).

[0427] Example 20 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 20)

[0428] Step 1: Synthesis of 1-(4-methoxy-2-(trifluoromethyl)phenyl)cyclobutan-1-ol

[0429] To a solution of 1-bromo-4-methoxy-2-(trifluoromethyl)benzene (1.0 g, 3.92 mmol) in tetrahydrofuran (20 mL) was slowly added dropwise a 2.5 M solution of n-butyllithium in n-hexane (1.9 mL, 4.71 mmol) under nitrogen at -78°C. The reaction mixture was stirred for 0.5 hour, followed by the slow addition of cyclobutanone (0.4 mL, 4.71 mmol) and continued stirring for 2 hours. Saturated ammonium chloride was added to quench the reaction, and the insoluble material was removed by filtration. The organic solvent was removed under reduced pressure, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-2:1) to afford 622 mg of a yellow solid in a 64.4% yield.

[0430] LC-MS(ESI):[M+H] + =247.2;

[0431] 1 H NMR (500MHz, CDCl3) δ7.36(d,J=8.6Hz,1H),7.18(d,J=2.8Hz,1H),7.02(dd,J=8.7,2.7Hz ,1H),3.83(s,3H),2.62(m,2H),2.49–2.35(m,2H),2.34–2.16(m,2H),1.85–1.70(m,1H).

[0432] Step 2: Synthesis of 6-methoxy-8-(trifluoromethyl)-3,4-dihydronaphthalen-1(2H)-one

[0433] To a solution of 1-(4-methoxy-2-(trifluoromethyl)phenyl)cyclobutan-1-ol (3.5 g, 14.09 mmol) in water (70 mL) and acetonitrile (70 mL) at 0°C was added cerium ammonium nitrate (19.3 g, 35.23 mmol), and stirring was continued for 1 hour. Saturated sodium thiosulfate solution was added to the system, and most of the organic solvent was removed under reduced pressure. Ethyl acetate (20 mL x 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (PE:THF (v / v) = 8:1) to obtain 2.2 g of the product as a colorless oil in a 63.9% yield.

[0434] LC-MS(ESI):[M+H] + =245.1.

[0435] Step 3: Synthesis of 7-methoxy-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole

[0436] To the reaction flask were added 6-methoxy-8-(trifluoromethyl)-3,4-dihydronaphthalen-1(2H)-one (440 mg, 1.80 mmol), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (0.7 mL, 3.60 mmol), and toluene (15 mL). The mixture was then stirred at 110°C for 1 hour. The reaction was then concentrated under reduced pressure, and ethanol (15 mL) and hydrazine hydrate (0.2 mL, 3.60 mmol) were added. The reaction was then stirred at 60°C for 30 minutes. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 5:1 to 1:1) to obtain 200 mg of a yellow solid in a 41.4% yield.

[0437] LC-MS(ESI):[M+H] + =269.1;

[0438] 1 H NMR (500MHz, CDCl3) δ10.49(s,1H),7.45(s,1H),7.15(d,J=2.7Hz,1H),7.03(d,J= 2.7Hz,1H),3.87(s,3H),2.94(dd,J=8.5,6.1Hz,2H),2.73(dd,J=8.4,6.2Hz,2H).

[0439] Step 4: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-7-methoxy-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole

[0440] To the reaction flask were added 7-methoxy-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole (200 mg, 0.75 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (304.6 mg, 1.12 mmol), cesium carbonate (485.9 mg, 1.49 mmol), and N,N-dimethylformamide (8 mL) in sequence. The mixture was then stirred at 70°C for 2 hours. Heating was stopped, the mixture was cooled to room temperature, and extracted with purified water (8 mL) and ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (10 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to afford 330 mg of the product as a colorless oil, which was used directly in the next step.

[0441] LC-MS(ESI):[M+H] + =369.2;

[0442] 1H NMR (500MHz, CDCl3) δ7.79(d,J=8.2Hz,1H),7.35(d,J=8.0Hz,1H),7.22(s,1H),4.17–4.14(m,2H),4.04-3.94(m,2H),3.85(s,3H),3.82 –3.77(m,1H),3.77–3.71(m,1H),3.71–3.63(m,1H),3.61–3.54(m,1H),3.39–3.33(m,1H),2.88(t,J=7.0Hz,2H),2.68(t,J=7.0Hz,2H).

[0443] Step 5: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-ol

[0444] (S)-2-((1,4-dioxan-2-yl)methyl)-7-methoxy-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole (110 mg, 0.30 mmol) and hydrogen bromide solution (10 mL, 184.16 mmol) were added to the reaction flask, and the mixture was stirred at 125°C for 2.5 hours. The mixture was diluted with purified water (10 mL) and neutralized with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to yield 44 mg of a white solid in a 41.6% yield.

[0445] LC-MS(ESI):[M+H] + =355.2;

[0446] 1 H NMR (500MHz, CDCl3) δ7.21 (s, 1H), 7.07 (d, J = 2.7Hz, 1H), 6.88 (d, J = 2.7Hz, 1H), 4.15 (d, J = 5.4Hz, 2H), 4.00 (m, 1H), 3.87 (dd, J = 11.8, 2.6Hz, 1H),3.81–3.69(m,3H),3.59(dd,J=11.2,3.1Hz,1H),3.36(dd,J=11.7,9.8Hz,1H),2.83(dd,J=8.4,5.9Hz,2H),2.66(dd,J=8.3,5.8Hz,2H).

[0447] Step 6: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazol-7-yl trifluoromethanesulfonate

[0448] To a reaction flask at 0°C was added (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazol-7-ol (582 mg, 1.64 mmol), pyridine (265.7 μL, 3.29 mmol), and dichloromethane (20 mL). Trifluoromethanesulfonic anhydride (694 mg, 2.46 mmol) was then slowly added dropwise. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 5:1) to afford 732 mg of a white solid in a 91.6% yield.

[0449] LC-MS(ESI):[M+H] + =487.3;

[0450] 1 H NMR (500MHz, CDCl3) δ7.53(d,J=2.6Hz,1H),7.35(d,J=2.6Hz,1H),7.28(s,1H),4.18(d,J=5.4Hz,2H),3.99(m,1H),3.86(dd,J=11.7,2.6Hz, 1H),3.80(dd,J=11.7,2.9Hz,1H),3.77–3.67(m,2H),3.57(m,1H),3.34(dd,J=11.7,9.9Hz,1H),2.96(t,J=7.1Hz,2H),2.74(t,J=7.1Hz,2H).

[0451] Step 7: Synthesis of methyl (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylate

[0452] To an autoclave, add (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazol-7-yl trifluoromethanesulfonate (732 mg, 1.50 mmol), Pd(dppp)Cl2 (88.8 mg, 0.15 mmol), triethylamine (418.4 μL, 3.01 mmol), and methanol (10 mL). Under nitrogen, evacuate and replace CO, ultimately maintaining a carbon monoxide pressure of 20 atm. After addition, stir and react at 100°C overnight. Remove from heating, cool to room temperature, and concentrate under reduced pressure. Purify by silica gel column chromatography (PE:EA (v / v) = 8:1-2:1) to afford 476 mg of a white solid in a 79.8% yield.

[0453] LC-MS(ESI):[M+H] +=397.3;

[0454] 1 H NMR (500MHz, CDCl3) δ8.32(d,J=1.8Hz,1H),8.09(d,J=1.8Hz,1H),7.28(s,1H),4. 20(d,J=5.4Hz,2H),4.02(s,1H),3.95(s,3H),3.88(dd,J=11.7,2.6Hz,1H),3.80( d,J=2.9Hz,1H),3.78–3.74(m,1H),3.74–3.68(m,1H),3.58(d,J=3.1Hz,1H),3.36 (dd,J=11.7,9.9Hz,1H),2.98(dd,J=8.4,6.0Hz,2H),2.73(dd,J=8.3,6.1Hz,2H).

[0455] Step 8: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid

[0456] To the reaction flask, (S)-methyl 2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylate (470 mg, 1.19 mmol), 1M sodium hydroxide (10 mL, 10 mmol), and methanol (2 mL) were added. The mixture was then stirred at 80°C for 2 hours. 1M dilute hydrochloric acid was added to adjust the pH to 2-4. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 450 mg of a white solid in a 99.3% yield.

[0457] LC-MS(ESI):[M+H] + =383.2;

[0458] 1 H NMR (500MHz, DMSO-d6) δ13.26(s,1H),8.15(s,1H),8.13(s,1H),7.63(s,1H),4.27–4.13(m,2H),3.91(dtd,J=9.1,5.8,2.5Hz,1H ),3.82–3.69(m,2H),3.64(d,J=11.5Hz,1H),3.56(m,1H),3.45(m,1H),3.34(s,1H),2.99(t,J=7.1Hz,2H),2.69(t,J=7.2Hz,2H).

[0459] Step 9: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-N-(((S)-tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0460] To a 25 mL single-necked flask, (S)-2-((1,4-dioxane-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (200 mg, 0.52 mmol), [(2S)-tetrahydro-2-furyl]methylamine (64.8 μL, 0.63 mmol), HATU (298.4 mg, 0.78 mmol), diisopropylethylamine (172.9 μL, 1.05 mmol) and N,N-dimethylformamide were added in sequence. The mixture was transferred to room temperature and stirred for 2 hours under nitrogen protection. Pure water (15 mL) was added for washing, and the product was extracted with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain 197 mg of a white solid with a yield of 80.9%.

[0461] LC-MS(ESI):[M+H] + =466.3;

[0462] 1 H NMR(500MHz,DMSO-d6)δ8.75(t,J=5.8Hz,1H),8.14(d,J=1.9Hz,1H),8.09(s,1H),7.62(s,1H),4.2 6–4.11(m,2H),4.00(m,1H),3.91(m,1H),3.84–3.71(m,3H),3.65(m,2H),3.56(m,1H),3.45(m,1H), 3.34(m,3H),2.96(t,J=7.1Hz,2H),2.69(t,J=7.2Hz,2H),1.93(m,1H),1.83(m,2H),1.61(m,1H).

[0463] Example 21 Synthesis of 2-((1,4-dioxane-2-yl)methyl)-9-methyl-N-(((S)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 21)

[0464] Step 1: Synthesis of 1-(4-bromo-2-methylphenyl)cyclobutan-1-ol

[0465] To a solution of 4-bromo-1-iodo-2-toluene (5 g, 16.84 mmol) in tetrahydrofuran (50 mL) was slowly added n-butyllithium (8.4 mL, 21.05 mmol) dropwise at -78°C under a nitrogen atmosphere. The reaction mixture was stirred for half an hour, followed by the slow addition of cyclobutanone (1.3 mL, 17.68 mmol) dropwise at -78°C and continued stirring for 1.5 hours. The reaction was monitored for completion by TLC. Saturated ammonium chloride solution (100 mL) was added to quench the reaction at 0°C, followed by extraction with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 30:1-10:1) to afford 2.8 g of a white solid in a 69% yield.

[0466] 1 H NMR(500MHz,DMSO-d6)δ7.35-7.28(m,2H),7.19(d,J=8.2Hz,1H),5.28(s,1H),2.49 -2.42(m,2H),2.33(s,3H),2.29-2.19(m,2H),2.06-1.91(m,1H),1.59-1.47(m,1H).

[0467] Step 2: Synthesis of 6-bromo-8-methyl-3,4-dihydronaphthalen-1(2H)-one

[0468] To a solution of 1-(4-bromo-2-methylphenyl)cyclobutan-1-ol (2.9 g, 12.03 mmol) in water (46 mL) and acetonitrile (46 mL) at 0°C was added cerium ammonium nitrate (16.5 g, 30.07 mmol), and stirring was continued for 10 minutes. The reaction was monitored for completion by TLC. The reaction was quenched by the addition of saturated sodium thiosulfate solution (100 mL) at 0°C, and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 30:1-10:1) to afford 730 mg of the compound as a colorless oil in a 25.4% yield.

[0469] 1 H NMR (500MHz, CDCl3) δ7.26 (s, 1H), 7.24 (s, 1H), 2.91 (t, J = 6.1Hz, 2H), 2.65-2.58 (m, 5H), 2.11-2.02 (m, 2H).

[0470] Step 3: Synthesis of methyl 4-methyl-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0471] To a polytetrafluoroethylene tube, 6-bromo-8-(trifluoromethyl)-3,4-dihydronaphthalen-1(2H)-one (730 mg, 3.05 mmol), Pd(dppp)Cl2 (180 mg, 0.31 mmol), and triethylamine (618 mg, 6.11 mmol) were added sequentially, followed by dissolution in methanol (50 mL). The polytetrafluoroethylene tube was then placed in an autoclave, sealed, and replaced with low-pressure carbon monoxide three times, with a final charge of 20 atm of carbon monoxide. The reaction mixture was then transferred to 100°C and allowed to react overnight. Heating was discontinued, and the mixture was cooled to room temperature. The reaction was monitored for completion by TLC. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 20:1-10:1) to yield 440 mg of a white solid in a 66% yield.

[0472] LC-MS(ESI):[M+H] + =219.1;

[0473] 1 H NMR (500MHz, CDCl3) δ7.76 (s, 1H), 7.73 (s, 1H), 3.93 (s, 3H), 3.00 (t, J = 6.1Hz, 2H), 2.71-2.65 (m, 5H), 2.15-2.06 (m, 2H).

[0474] Step 4: Synthesis of 4-methyl-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0475] To the reaction flask, add methyl 4-methyl-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (440 mg, 2.02 mmol) and dissolve in 1N sodium hydroxide solution (10 mL) and methanol (10 mL). The mixture was then heated to 60°C with stirring for 1.5 hours. The reaction was monitored for completion by TLC, and the mixture was cooled to room temperature. 1M hydrochloric acid was added to adjust the pH to acidic. Extraction was performed with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 380 mg of a pale yellow solid (92.3% yield).

[0476] LC-MS(ESI):[MH] - =203.1;

[0477] 1 H NMR (500MHz, DMSO-d6) δ13.19(s,1H),7.73(s,1H),7.65(s,1H),2.99(t,J=6.1Hz,2H),2.62(t,J=6.6Hz,2H),2.58(s,3H),2.05-1.96(m,2H).

[0478] Step 5: Synthesis of (S)-4-methyl-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0479] Under nitrogen, 4-methyl-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (150 mg, 0.73 mmol), HATU (419 mg, 1.1 mmol), diisopropylethylamine (285 mg, 2.2 mmol), N,N-dimethylformamide (3 mL), and (S)-(tetrahydrofuran-2-yl)methanamine (111 mg, 1.1 mmol) were added sequentially to the reaction flask and stirred at room temperature for 2 hours. The reaction was monitored for completion by TLC. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to afford 200 mg of the compound as a colorless oil in a 94.8% yield.

[0480] LC-MS(ESI):[M+H] + =288.3;

[0481] 1 H NMR(500MHz,DMSO-d6)δ8.58(t,J=5.9Hz,1H),7.63(s,1H),7.57(s,1H),4.02-3.93(m,1H),3.82-3.74(m,1H),3.67-3.59(m,1H),3.3 6-3.30(m,2H),2.97(t,J=6.1Hz,2H),2.63-2.54(m,5H),2.05-1.96(m,2H),1.95-1.87(m,1H),1.86-1.76(m,2H),1.63-1.53(m,1H).

[0482] Step 6: Synthesis of (S)-9-methyl-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-1H-benzo[g]indazole-7-carboxamide

[0483] To the reaction flask, (S)-4-methyl-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (200 mg, 0.7 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (242 mg, 1.4 mmol) were added, followed by toluene (5 mL). After addition, the mixture was stirred at 110°C for 40 minutes. TLC monitored the reaction for completion. Heating was discontinued, the mixture was cooled to room temperature, and concentrated under reduced pressure to yield a black oil, which was used directly in the next step. Hydrazine hydrate (175 mg, 3.50 mmol) and ethanol (5 mL) were added to the reaction mixture, followed by stirring at room temperature for 40 minutes. TLC monitored the reaction for completion. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to yield 120 mg of a yellow solid in a 55.4% yield.

[0484] LC-MS(ESI):[M+H] + =312.2;

[0485] 1 H NMR(500MHz,DMSO-d6)δ12.73(s,1H),8.39(t,J=5.8Hz,1H),7.62-7.57(m,3H),4.01-3.94(m,1H),3.82-3.72(m,1H),3.67-3 .59(m,1H),3.36-3.25(m,2H),2.91-2.85(m,2H),2.70-2.66(m,5H),1.95-1.86(m,1H),1.86-1.76(m,2H),1.65-1.54(m,1H).

[0486] Step 7: Synthesis of 2-((1,4-dioxan-2-yl)methyl)-9-methyl-N-(((S)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0487] To a reaction flask were added (S)-9-methyl-N-(tetrahydrofuran-2-yl)methyl)-4,5-dihydro-1H-benzo[g]indazole-7-carboxamide (108 mg, 0.35 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (189 mg, 0.69 mmol), and cesium carbonate (283 mg, 0.87 mmol), followed by N,N-dimethylformamide (3 mL). The mixture was stirred at 70°C for 2 hours. The reaction was monitored for completion by TLC. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 3:1 to 0:1) to afford 70 mg of a yellow solid in a 41.7% yield.

[0488] LC-MS(ESI):[M+H] + =412.3;

[0489] 1 H NMR (500MHz, CDCl3) δ7.50(s,1H),7.49(s,1H),7.24(s,1H),6.48(t,J=5.7Hz,1H),4.22-4.12(m,2H),4.12-3.99(m,2H),3.95-3.67(m,7H ),3.63-3.55(m,1H),3.40-3.33(m,2H),2.93(t,J=7.2Hz,2H),2.75-2.68(m,5H),2.08-2.00(m,1H),1.97-1.88(m,2H),1.68-1.60(m,1H).

[0490] Example 22 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-9-methoxy-N-(((S)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 22)

[0491] Step 1: Synthesis of ((E)-4-(3-bromo-5-methoxyphenyl)but-3-enoic acid

[0492] At 0°C, under nitrogen, 3-bromo-5-methoxybenzaldehyde (6.0 g, 27.90 mmol), 2-carboxyethyltriphenylphosphonium bromide (12.2 g, 29.29 mmol), and tetrahydrofuran (60 mL) were added to the reaction flask. Potassium tert-butoxide (7.2 mL, 58.59 mmol) dissolved in tetrahydrofuran (60 mL) was then slowly added dropwise over approximately 1 hour. Stirring was continued at the same temperature for 0.5 hours. Completion of the reaction was monitored by TLC. Insoluble material was removed by filtration, and the mixture was concentrated under reduced pressure. Separation by silica gel column chromatography (PE:EA (v / v) = 1:1-1:2) afforded 6.1 g of a yellow oil in an 80.6% yield.

[0493] LC-MS(ESI):[MH] - =269.1;

[0494] 1 H NMR (500MHz, DMSO-d6) δ12.42 (s, 1H), 7.19 (t, J = 1.6Hz, 1H), 7.04-7.00 (m, 1H), 6. 98(t,J=1.9Hz,1H),6.43(s,1H),6.41(s,1H),3.78(s,3H),3.19(d,J=6.4Hz,2H).

[0495] Step 2: Synthesis of 4-(3-bromo-5-methoxyphenyl)butyric acid

[0496] Under a hydrogen atmosphere, ((E)-4-(3-bromo-5-methoxyphenyl)but-3-enoic acid (1.0 g, 3.69 mmol) and Rh(PPh3)3Cl (0.34 g, 0.37 mmol) were added to the reaction flask. After addition, the mixture was stirred at 50°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to give 1.0 g of a brown-red oily product in a yield of 99.3%.

[0497] LC-MS(ESI):[MH] - =271.1.

[0498] Step 3: Synthesis of 6-bromo-8-methoxy-3,4-dihydronaphthalen-1(2H)-one

[0499] 4-(3-Bromo-5-methoxyphenyl)butyric acid (4.2 g, 15.38 mmol) and polyphosphoric acid (5 mL, 125.63 mmol) were added to the reaction flask and heated at 100°C for 2 hours. Heating was stopped, and the mixture was diluted with purified water (15 mL). The mixture was extracted with ethyl acetate (3 × 15 mL). The organic phases were combined and washed with saturated sodium bicarbonate solution to remove excess phosphoric acid. The organic phase was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 10:1-5:1) to obtain 1.44 g of the product as a brown oil in a 36.7% yield.

[0500] LC-MS(ESI):[M+H] + =255.0;

[0501] 1 H NMR (500MHz, CDCl3) δ7.01 (s, 1H), 6.98 (s, 1H), 3.89 (s, 3H), 2.88 (t, J = 6.1Hz, 2H), 2.61 (t, J = 6.6Hz, 2H), 2.05-2.03 (m, 2H).

[0502] Step 4: Synthesis of methyl 4-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0503] To a polytetrafluoroethylene tube, 6-bromo-8-methoxy-3,4-dihydronaphthalen-1(2H)-one (400 mg, 1.57 mmol), Pd(dppp)Cl2 (92 mg, 0.16 mmol), and methanol (20 mL) were added sequentially, followed by triethylamine (436 μL, 3.14 mmol). The polytetrafluoroethylene tube was placed in an autoclave, sealed, and replaced with low-pressure carbon monoxide three times, with a final charge of 20 atm of carbon monoxide. The reaction was stirred at 100°C overnight. The organic solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography (PE:EA (v / v) = 5:1) to obtain 288 mg of a brown solid in a 78.4% yield.

[0504] LC-MS(ESI):[M+H] + =235.1;

[0505] 1 H NMR (500MHz, CDCl3) δ7.50 (s, 1H), 7.47 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 2.97 (t, J = 6.1Hz, 2H), 2.66 (t, J = 6.6Hz, 2H), 2.08-2.10 (m, 2H).

[0506] Step 5: Synthesis of 4-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0507] To the reaction flask, add methyl 4-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (288 mg, 1.23 mmol) and lithium hydroxide (516 mg, 12.29 mmol), followed by tetrahydrofuran (10 mL) and water (2 mL). After addition, transfer the mixture to 50°C and stir for 2 hours. Remove the organic solvent under reduced pressure, add ethyl acetate, extract the impurities, and discard. Then, add 1M dilute hydrochloric acid to adjust the pH to 2-4, extract with ethyl acetate (3 x 10 mL), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 270 mg of a gray solid (99.7% yield).

[0508] LC-MS(ESI):[M+H] + =221.1;

[0509] 1 H NMR (500MHz, CDCl3) δ7.58 (s, 1H), 7.54 (s, 1H), 3.97 (s, 3H), 2.99 (t, J = 6.1Hz, 2H), 2.69 (t, J = 6.6Hz, 2H), 2.08-2.10 (m, 2H).

[0510] Step 6: Synthesis of (S)-4-methoxy-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0511] To the reaction flask were added 4-methoxy-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (270 mg, 1.23 mmol), [(2S)-tetrahydro-2-furyl]methylamine (152 μL, 1.47 mmol), HATU (702 mg, 1.84 mmol), diisopropylethylamine (407 μL, 2.46 mmol), and N,N-dimethylformamide (10 mL). The mixture was then stirred at room temperature for 2 hours. Water (10 mL) and ethyl acetate (3 × 10 mL) were added to the system, and the organic phases were combined and washed with water (2 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH (v / v) = 20:1) to obtain 171 mg of a yellow solid in a 46.0% yield.

[0512] LC-MS(ESI):[M+H] + =304.3;

[0513] 1H NMR(500MHz, CDCl3)δ7.29(s,1H),7.12(s,1H),6.54-6.50(m,1H),4.15-4.03(m,1H),3.95(s,3H),3.94-3.87(m,1H),3.85-3.75 (m,2H),3.36-3.27(m,1H),2.95(t,J=6.1Hz,2H),2.65(t,J=6.6Hz,2H),2.16-2.01(m,3H),1.99-1.89(m,2H),1.67-1.56(m,1H).

[0514] Step 7: Synthesis of (S)-9-methoxy-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0515] To the reaction flask, add (S)-4-methoxy-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (170 mg, 0.56 mmol), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (231 μL, 1.12 mmol), and toluene (5 mL). After addition, transfer the mixture to 110°C and stir for 1 hour. Stirring was stopped and the mixture was cooled to room temperature. The organic solvent was removed under reduced pressure and used directly in the next step. Ethanol (5 mL) and hydrazine hydrate (41 μL, 0.84 mmol) were added to the above mixture, followed by transfer to 60°C and stirring for 3 hours. The mixture was concentrated under reduced pressure and separated by silica gel column chromatography (DCM:MeOH (v / v) = 30:1-15:1) to afford 158 mg of a yellow solid in an 86.1% yield.

[0516] LC-MS(ESI):[M+H] + =328.3;

[0517] 1 H NMR(500MHz,DMSO-d6)δ12.69(s,1H),8.50(t,J=5.9Hz,1H),7.43(s,1H),7.4 1(d,J=1.6Hz,1H),7.39(s,1H),3.98(t,J=6.3Hz,1H),3.96(s,3H),3.83-3.72 (m,1H),3.63(q,J=7.3Hz,1H),3.32(t,J=6.0Hz,2H),2.91(t,J=7.6Hz,2H),2 .71(t,J=7.6Hz,2H),1.96-1.87(m,1H),1.80-1.82(m,2H),1.64-1.54(m,1H).

[0518] Step 8: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-9-methoxy-N-(((S)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0519] To a reaction flask, (S)-9-methoxy-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (190 mg, 0.58 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (237 mg, 0.87 mmol), and cesium carbonate (378 mg, 1.16 mmol) were added, followed by N,N-dimethylformamide (4 mL). After addition, the mixture was stirred at 70°C for 2 hours. The reaction was monitored for completion by TLC, and the mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Preparative HPLC yielded 49 mg of a white solid in a 19.5% yield.

[0520] LC-MS(ESI):[M+H] + =428.3;

[0521] 1 H NMR (500MHz, CDCl3) δ7.45-7.40(m,2H),7.28(s,1H),6.57-6.48(m,1H),4.63-4.56( m,1H),4.38-4.32(m,1H),4.12-4.07(m,1H),4.02-3.84(m,5H),3.87-3.76(m,2H),3 .75-3.69(m,1H),3.68-3.51(m,4H),3.40-3.32(m,1H),3.30-3.21(m,1H),2.85-2.7 7(m,2H),2.65-2.53(m,2H),2.14-2.02(m,1H),1.99-1.91(m,2H),1.67-1.61(m,1H).

[0522] Example 23 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl))methyl)-9-(difluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 23)

[0523] Step 1: Synthesis of 4-(difluoromethyl)-7,8-dihydro-2H-chromen-2,5(6H)-dione

[0524] Under a nitrogen atmosphere, cyclohexyl-1,3-dione (3 g, 26.75 mmol), ethyl 4,4-difluoro-3-oxobutanoate (6.7 g, 40.13 mmol), 2-(dimethylamino)pyridine (0.65 g, 5.35 mmol), and dichloroethane (50 mL) were added sequentially to an autoclave and heated to 120°C with stirring for 10 hours. Heating was stopped, and the mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain 5.2 g of a yellow solid with a yield of 90.7%.

[0525] LC-MS(ESI):[M+H] + =215.0;

[0526] 1 H NMR (500MHz, CDCl3) δ7.36(t,J=54.0Hz,1H),6.61(s,1H),2.91(t,J=6.3Hz,2H),2.60(t,J=6.7Hz,2H),2.21-2.12(m,2H).

[0527] Step 2: Synthesis of 4-(difluoromethyl)-7,8-dihydroquinoline-2,5(1H,6H)-dione

[0528] Under a nitrogen atmosphere, 4-(difluoromethyl)-7,8-dihydro-2H-chromene-2,5(6H)-dione (3.3 g, 15.4 mmol), ammonium acetate (3.56 g, 46.2 mmol), and dichloroethane (33 mL) were added sequentially to an autoclave and heated to 140°C with stirring overnight. Heating was then discontinued and the mixture was cooled to room temperature. The reaction mixture was made alkaline with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3.0 g of a yellow solid, which was used directly in the next step without further purification.

[0529] LC-MS(ESI):[M+H] + =214.2;

[0530] 1 H NMR (500MHz, DMSO-d6) δ12.04(s,1H),7.48(t,J=54.6Hz,1H),6.46(s,1H),2.84(t,J=6.2Hz,2H),2.46(t,J=6.5Hz,2H),2.01-1.94(m,2H).

[0531] Step 3: Synthesis of 2-chloro-4-(difluoromethyl)-7,8-dihydroquinolin-5(6H)-one

[0532] To the reaction flask, 4-(difluoromethyl)-7,8-dihydroquinoline-2,5(1H,6H)-dione (2.3 g, 10.79 mmol), acetonitrile (25 mL), and phosphorus oxychloride (8.3 g, 53.95 mmol) were added sequentially. The mixture was heated to 75°C with stirring for 2 hours. After TLC monitoring of the reaction completion, heating was discontinued and the mixture was cooled to room temperature. The reaction solution was concentrated under reduced pressure, adjusted to alkalinity with saturated sodium bicarbonate solution, and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain 2 g of a white solid in 80% yield.

[0533] LC-MS(ESI):[M+H] + =232.1;

[0534] 1 H NMR (500MHz, CDCl3) δ7.71-7.44(m,2H),3.19(t,J=6.3Hz,2H),2.73(t,J=6.7Hz,2H),2.24-2.15(m,2H).

[0535] Step 4: Synthesis of 4-(difluoromethyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile

[0536] To a reaction flask, 2-chloro-4-(difluoromethyl)-7,8-dihydroquinolin-5(6H)-one (1 g, 4.32 mmol), palladium tetrakistriphenylphosphine (0.25 g, 0.22 mmol), zinc cyanide (1.01 g, 8.63 mmol), and ultra-dry N,N-dimethylacetamide (15 mL) were added sequentially. Nitrogen was purged for 5 minutes, and the mixture was stirred at 120°C for 2 hours. Heating was stopped and the mixture was cooled to room temperature. Insoluble matter was removed by filtration, and saturated brine was added. The mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 10:1) to obtain 560 mg of the product as a yellow oil in a 58.4% yield.

[0537] LC-MS(ESI):[M+H] + =223.1;

[0538] 1H NMR (500MHz, CDCl3) δ7.97 (s, 1H), 7.58 (t, J = 54.2Hz, 1H), 3.27 (t, J = 6.3Hz, 2H), 2.80 (t, J = 6.7Hz, 2H), 2.29-2.21 (m, 2H).

[0539] Step 5: Synthesis of 4-(difluoromethyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid

[0540] To an autoclave were added 4-(difluoromethyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (550 mg, 2.48 mmol) and concentrated hydrochloric acid (15 mL). The mixture was heated to 100°C and stirred overnight. The reaction mixture was then concentrated under reduced pressure, and dichloromethane and saturated brine were added. The mixture was basified with sodium bicarbonate solution, and the pH was adjusted to 2-4 with 1M hydrochloric acid. The mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 525 mg of a pale yellow solid in an 87.9% yield.

[0541] LC-MS(ESI):[M+H] + =242.0;

[0542] 1 H NMR (500MHz, DMSO-d6) δ13.78(s,1H),8.12(s,1H),7.59(t,J=54.3Hz,1H),3.20(t,J=6.2Hz,2H),2.75(t,J=6.6Hz,2H),2.18-2.09(m,2H).

[0543] Step 6: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-4-(difluoromethyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0544] Under nitrogen, 4-(difluoromethyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (157 mg, 0.65 mmol), HATU (371 mg, 0.98 mmol), diisopropylethylamine (252 mg, 1.95 mmol), N,N-dimethylformamide (5 mL), and (5-cyclopropylpyrazin-2-yl)methanamine (146 mg, 0.98 mmol) were added to the reaction flask in sequence. The mixture was stirred at room temperature for 2 hours. TLC confirmed the reaction was complete, and the mixture was washed with saturated brine (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. The mixture was then separated by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to afford 200 mg of a yellow solid in an 82.5% yield.

[0545] LC-MS(ESI):[M+H] + =373.3;

[0546] 1 H NMR (500MHz, DMSO-d6) δ9.47(t,J=6.1Hz,1H),8.55(s,1H),8.45(s,1H),8.17(s,1H),7.62(t,J=54.4Hz,1H),4.64(d,J=6.1Hz ,2H),3.24(t,J=6.2Hz,2H),2.77(t,J=6.6Hz,2H),2.23-2.12(m,2H),1.29-1.23(m,1H),1.05-1.00(m,2H),1.00-0.90(m,2H).

[0547] Step 7: Synthesis of N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(difluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0548] To the reaction flask, add N-((5-cyclopropylpyrazin-2-yl)methyl)-4-(difluoromethyl)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxamide (200 mg, 0.54 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (187 mg, 1.07 mmol), followed by toluene (5 mL). After addition, transfer the mixture to 110°C and stir for 20 minutes. TLC monitoring of the reaction was complete. Heating was stopped, the mixture was cooled to room temperature, and concentrated under reduced pressure to obtain a yellow oil, which was used directly in the next step. To the above system, hydrazine hydrate (134 mg, 2.69 mmol) and ethanol (5 mL) were added, followed by transfer to room temperature and stirring for 1 hour. TLC monitoring of the reaction was complete. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to obtain 101 mg of a yellow solid in a 47.4% yield.

[0549] LC-MS(ESI):[M+H] + =397.3;

[0550] 1 H NMR (500MHz, DMSO-d6) δ13.22(s,1H),9.31(s,1H),8.55(s,1H),8.45(s,1H),8.11(s,1H),7.94(t,J=54.6Hz,1H),7.76(s,1H) ,4.64(d,J=6.0Hz,2H),3.21(t,J=7.4Hz,2H),2.90(t,J=7.4Hz,2H),2.23-2.14(m,1H),1.08-0.96(m,2H),0.95-0.87(m,2H).

[0551] Step 8: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((5-cyclopropylpyrazin-2-yl))methyl)-9-(difluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0552] To a reaction flask were added N-((5-cyclopropylpyrazin-2-yl)methyl)-9-(difluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (101 mg, 0.25 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (104 mg, 0.38 mmol), and cesium carbonate (166 mg, 0.51 mmol). N,N-dimethylformamide (2 mL) was then added. After addition, the mixture was stirred at 70°C for 1.5 hours. The reaction was monitored for completion by TLC. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Preparative HPLC yielded 50 mg of a white solid in a 40.3% yield.

[0553] LC-MS(ESI):[M+H] + =497.4;

[0554] 1 H NMR(500MHz, CDCl3)δ8.70(t,J=5.9Hz,1H),8.49(s,1H),8.45-8.41(m,2H),7.84(t ,J=54.5Hz,1H),7.31(s,1H),4.78(d,J=5.9Hz,2H),4.21-4.14(m,2H),4.03-3.96( m,1H),3.87-3.78(m,2H),3.77-3.68(m,2H),3.63-3.55(m,1H),3.38-3.30(m,1H), 3.19(t,J=7.4Hz,2H),2.88(t,J=7.4Hz,2H),2.10-2.02(m,1H),1.07-1.02(m,4H).

[0555] Example 24 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-chloropyrazin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 24)

[0556] To a reaction flask, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (100 mg, 0.26 mmol), (5-chloropyrazin-2-yl)methylamine (45.1 mg, 0.31 mmol), HATU (149.2 mg, 0.39 mmol), and diisopropylethylamine (86.5 μL, 0.52 mmol) were added sequentially. The mixture was brought to room temperature and stirred under nitrogen. The mixture was washed with purified water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1) to obtain 10 mg of a white solid in a 7.5% yield.

[0557] LC-MS(ESI):[M+H] + =508.4;

[0558] 1 H NMR (500MHz, DMSO-d6) δ9.38(t,J=5.7Hz,1H),8.76(d,J=1.4Hz,1H),8.55(s,1H),8.18(d,J=1. 8Hz,1H),8.12(s,1H),7.63(s,1H),4.65(d,J=5.6Hz,2H),4.27–4.07(m,2H),3.91(dtd,J=9.2,5 .9,2.5Hz,1H),3.83–3.71(m,2H),3.64(d,J=11.4Hz,1H),3.56(td,J=11.2,2.6Hz,1H),3.46(td ,J=11.0,2.6Hz,1H),3.31(d,J=12.1Hz,1H),2.97(t,J=7.1Hz,2H),2.69(dd,J=8.6,5.8Hz,2H).

[0559] Example 25 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-methyl-N-(((S)-tetrahydrofuran-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 25)

[0560] To the reaction flask were added (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (100 mg, 0.26 mmol), (S)-N-methyl-1-(tetrahydrofuran-2-yl)methanamine (44.9 mg, 0.39 mmol), HATU (149.2 mg, 0.39 mmol), and diisopropylethylamine (85.9 μL, 0.52 mmol) in sequence. The mixture was stirred at room temperature for 2 hours under nitrogen. The mixture was washed with pure water and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain 40 mg of a white solid in a 32.1% yield.

[0561] LC-MS(ESI):[M+H] + =480.4;

[0562] 1 H NMR(500MHz,DMSO-d6)δ7.62(d,J=8.5Hz,3H),4.26–4.04(m,3H),3.90(dp,J=9.4,3.8,3.1Hz,1H),3.85–3.59(m,5H),3.51(dtd,J=53.7,10.9, 2.6Hz,3H),3.33(d,J=10.0Hz,1H),3.27–3.12(m,1H),3.02(s,3H),2.93(d,J=8.0Hz,2H),2.68(t,J=7.1Hz,2H),1.88(q,J=56.1,45.9Hz,4H).

[0563] Example 26 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-(S)-9-(methyl-d3)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 26)

[0564] Step 1: Synthesis of (5-bromo-2-iodophenyl)methane-d2-ol

[0565] To the reaction flask at 0°C, 5-bromo-2-iodobenzoic acid (500 mg, 1.53 mmol) and tetrahydrofuran (10 mL) were added, followed by the slow addition of lithium aluminum deuteride (70 mg, 1.68 mmol). Stirring continued in an ice bath until the reaction was complete as monitored by TLC. The product was concentrated under reduced pressure and purified by silica gel column chromatography (100% PE) to afford 300 mg of the product as a colorless oil, with a yield of 62.0%.

[0566] 1 H NMR (500MHz, DMSO-d6) δ7.74(d,J=8.3Hz,1H),7.59(d,J=2.5Hz,1H),7.23(dd,J=8.4,2.5Hz,1H),5.53(s,1H).

[0567] Step 2: Synthesis of (5-bromo-2-iodophenyl)methyl methanesulfonate

[0568] To a reaction flask, add (5-bromo-2-iodophenyl)methanol-d2-ol (2.4 g, 7.53 mmol), triethylamine (1.4 mL, 9.78 mmol), and dichloromethane (30 mL). Methanesulfonyl chloride (0.7 mL, 8.65 mmol) was then slowly added dropwise. The mixture was stirred at room temperature until complete, as monitored by TLC. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 6:1) to afford 1.6 g of the product as a white solid in a 53.0% yield.

[0569] 1 H NMR (500MHz, DMSO-d6) δ7.74(d,J=8.2Hz,1H),7.59(d,J=2.5Hz,1H),7.23(dd,J=8.3,2.5Hz,1H),5.53(s,3H).

[0570] Step 3: Synthesis of 4-bromo-1-iodo-2-(methyl-d3)benzene

[0571] To the reaction flask, add (5-bromo-2-iodophenyl)methyl methanesulfonate (1.6 g, 4.02 mmol) and tetrahydrofuran (10 mL), followed by the slow addition of lithium aluminum deuteride (185.6 mg, 4.42 mmol). After addition, stir at room temperature until the reaction is complete as monitored by TLC. Concentrate under reduced pressure and purify by silica gel column chromatography (100% PE) to obtain 1.2 g of the product as a colorless oil, with a yield of 95.0%.

[0572] 1 H NMR (500MHz, DMSO-d6) δ7.74(d,J=8.4Hz,1H),7.56(d,J=2.5Hz,1H),7.14(dd,J=8.4,2.4Hz,1H).

[0573] Step 4: Synthesis of 1-(4-bromo-2-(methyl-d3)phenyl)cyclobutan-1-ol

[0574] To a solution of 4-bromo-1-iodo-2-(methyl-d3)benzene (5 g, 16.84 mmol) in tetrahydrofuran (50 mL) was slowly added n-butyllithium (1.9 mL, 4.79 mmol) dropwise at -78°C under a nitrogen atmosphere. The reaction mixture was stirred for 0.5 hours, followed by the slow addition of cyclobutanone (0.3 mL, 4.60 mmol) dropwise at -78°C and continued stirring for 1.5 hours. The reaction mixture was returned to 0°C and quenched by the addition of saturated ammonium chloride. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 9:1) to afford 255 mg of the compound as a colorless oil in a 27.0% yield.

[0575] 1 H NMR (500MHz, DMSO-d6) δ7.28(d,J=1.9Hz,1H),7.21(d,J=7.5Hz,1H),7.03(dd,J=7.4,1.6Hz,1H),5.31(d,J=35.5H z,1H),2.36(tdt,J=8.0,5.2,2.7Hz,2H),2.24(ddd,J=12.3,6.2,3.7Hz,2H),1.95–1.84(m,1H),1.68–1.58(m,1H).

[0576] Step 5: Synthesis of 6-bromo-8-(methyl-d3)-3,4-dihydronaphthalen-1(2H)-one

[0577] To a mixture of 1-[4-bromo-2-(deuterated methyl)phenyl]cyclobutan-1-ol (450 mg, 1.84 mmol) in water (16 mL) and acetonitrile (16 mL) was added cerium ammonium nitrate (2.5 g, 4.61 mmol) at 0°C, and the mixture was stirred on ice for 10 minutes. The reaction was quenched by the addition of saturated sodium thiosulfate solution, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated by silica gel column chromatography (PE:EA (v / v) = 9:1) to afford 100 mg of the product in a 22.0% yield.

[0578] LC-MS(ESI):[M+H] + =242.2;

[0579] 1 H NMR (500MHz, CDCl3) δ7.28(s,1H),7.26(s,1H),2.93(q,J=6.1,5.1Hz,2H),2.63(t,J=6.8Hz,2H),2.07(dt,J=14.8,7.4Hz,2H).

[0580] Step 6: Synthesis of methyl 4-(methyl-d3)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0581] To a polytetrafluoroethylene tube, 6-bromo-8-(methyl-d3)-3,4-dihydronaphthalen-1(2H)-one (128 mg, 0.53 mmol), Pd(dppp)Cl2 (31.2 mg, 0.05 mmol), and triethylamine (0.1 mL, 1.06 mmol) were added sequentially, followed by dissolution in methanol (50 mL). The polytetrafluoroethylene tube was then placed in an autoclave, sealed, and replaced with low-pressure carbon monoxide three times, with the final charge being 20 atm of carbon monoxide gas. The reaction was then transferred to 100°C and allowed to react overnight. Heating was stopped, the mixture was cooled to room temperature, and the carbon monoxide gas was slowly released. The autoclave was then carefully opened. The product was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 20:1) to afford 85 mg of a white solid in a 73.0% yield.

[0582] LC-MS(ESI):[M+H] + =222.2;

[0583] 1 H NMR (500MHz, DMSO-d6) δ7.75(d,J=1.8Hz,1H),7.67(d,J=1.9Hz,1H),3.87(s,3H),3.00(t,J=6.1Hz,2H),2.63(t,J=6.6Hz,2H),2.01(p,J=6.5Hz,2H).

[0584] Step 7: Synthesis of 4-(methyl-d3)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0585] To a 100 mL single-necked flask, add methyl 4-(methyl-d3)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (85 mg, 0.38 mmol). Dissolve the mixture in 1N sodium hydroxide solution (5 mL, 5.0 mmol) and methanol (5 mL). After addition, stir at 50°C for 1 hour. Adjust the pH to acidic by adding 1M hydrochloric acid solution. Extract with ethyl acetate (10 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 80 mg of a yellow solid (100% yield).

[0586] LC-MS(ESI):[M+H] + =208.2.

[0587] Step 8: Synthesis of (S)-4-(methyl-d3)-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0588] Under nitrogen, 4-(methyl-d3)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (64 mg, 0.31 mmol), HATU (176.14 mg, 0.46 mmol), diisopropylethylamine (0.2 mL, 0.93 mmol), N,N-dimethylformamide (5 mL), and (S)-(tetrahydrofuran-2-yl)methylamine (46 mg, 0.46 mmol) were added to the reaction flask in sequence and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, water (5 mL) was added, and extraction with ethyl acetate (15 mL x 2) was performed. The mixture was washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and dried. The mixture was then separated and purified by silica gel column chromatography (EA:PE (v / v) = 1:2 to 1:1) to obtain 70 mg of the product as a colorless oil in a yield of 78.0%.

[0589] LC-MS(ESI):[M+H] + =291.3;

[0590] 1 H NMR (500MHz, DMSO-d6) δ8.58(t,J=5.8Hz,1H),7.63(d,J=1.8Hz,1H),7.57(d,J=1.9Hz,1H),3.97(p,J=6.3Hz,1H),3.82–3.74(m,1H),3.63 (q,J=7.3Hz,1H),3.37–3.30(m,2H),2.97(t,J=6.1Hz,2H),2.61(t,J=6.5Hz,2H),2.07–1.96(m,2H),1.96–1.75(m,3H),1.64–1.53(m,1H).

[0591] Step 9: Synthesis of (S)-9-(methyl-d3)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0592] To the reaction flask, (S)-4-(methyl-d3)-5-oxo-N-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (70 mg, 0.24 mmol), 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (0.1 mL, 0.48 mmol), and toluene (5 mL) were added. The mixture was then stirred at 110°C for 1 hour. The mixture was concentrated under reduced pressure and directly used in the next step. Ethanol (5 mL) and hydrazine hydrate (73.3 mg, 1.46 mmol) were added to the reaction flask, which was then stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to obtain 35 mg of the product as a yellow oil with a yield of 46.0%.

[0593] LC-MS(ESI):[M+H] + =315.3;

[0594] 1 H NMR (500MHz, DMSO-d6) δ12.74(s,1H),8.39(t,J=5.9Hz,1H),7.59(dd,J=6.8,4.9Hz,3H),3.98(p,J=6.3Hz,1H),3.84–3.73(m,1H) ,3.63(q,J=7.4Hz,1H),3.28(d,J=8.5Hz,2H),2.88(t,J=7.1Hz,2H),2.67(d,J=6.7Hz,2H),1.95–1.74(m,3H),1.66–1.50(m,1H).

[0595] Step 10: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-(S)-9-(methyl-d3)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0596] To the reaction flask were added (S)-9-(methyl-d3)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (920 mg, 3.43 mmol), methyl [1,4-dioxan-2-yl]-4-methanesulfonate (37.7 mg, 0.14 mmol), cesium carbonate (60.1 mg, 0.18 mmol), and N,N-dimethylformamide (5 mL). The mixture was then stirred at 70°C for 2 hours. Water (5 mL) and ethyl acetate (5 mL × 3) were added for extraction. The organic phases were combined, washed with water (5 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 81 mg of the crude product. Purification by preparative HPLC afforded 23 mg of the product as a yellow oil in a 60.0% yield.

[0597] LC-MS(ESI):[M+H] + =415.4;

[0598] 1 H NMR(500MHz,DMSO-d6)δ8.39(s,1H),7.59(d,J=2.1Hz,2H),7.56(s,1H),4.18(d,J=5.8Hz ,2H),3.98(q,J=6.3Hz,1H),3.92(dtt,J=8.6,5.7,3.2Hz,1H),3.83–3.70(m,3H),3.63(q, J=8.2,7.7Hz,2H),3.57(td,J=11.2,2.6Hz,1H),3.46(td,J=11.0,2.6Hz,1H),3.36–3.30( m,3H),2.87(t,J=7.2Hz,2H),2.66(t,J=7.2Hz,2H),1.95–1.75(m,3H),1.67–1.50(m,1H).

[0599] Example 27 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-(pyrimidin-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 27)

[0600] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.16 mmol), HATU (90 mg, 0.24 mmol), diisopropylethylamine (61 mg, 0.48 mmol), N,N-dimethylformamide (3 mL), and pyrimidin-2-ylmethanamine (26 mg, 0.24 mmol) were added to the reaction flask in sequence and stirred at room temperature for 2 hours. TLC confirmed the reaction was complete, and the mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. Preparative HPLC yielded 33 mg of a white solid in a 43.3% yield.

[0601] LC-MS(ESI):[M+H] + =474.4;

[0602] 1H NMR (500MHz, CDCl3) δ8.77 (d, J = 4.9Hz, 2H), 8.14 (s, 1H), 7.98 (s, 1H), 7.55 (t,J=4.3Hz,1H),7.27(d,J=6.6Hz,2H),4.93(d,J=4.5Hz,2H),4.20(d,J=5 .5Hz,2H),4.04-3.99(m,1H),3.91-3.86(m,1H),3.83-3.67(m,3H),3.63-3 .54(m,1H),3.41-3.33(m,1H),3.01(t,J=7.2Hz,2H),2.74(t,J=7.1Hz,2H).

[0603] Example 28 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-(pyridin-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 28)

[0604] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.16 mmol), N,N-dimethylformamide (2 mL), HATU (89.5 mg, 0.24 mmol), N,N-diisopropylethylamine (40.5 mg, 0.31 mmol), and pyridin-2-ylmethylamine (25.5 mg, 0.24 mmol) were added to a reaction flask in sequence. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water and saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 55 mg of a white solid in a 74.2% yield.

[0605] LC-MS(ESI):[M+H] + =473.4;

[0606] 1H NMR(500MHz,DMSO-d6)δ9.31(t,J=5.7Hz,1H),8.52(d,J=4.2Hz,1H),8.20(s,1H),8.15(s,1H),7.77(dd ,J=10.8,4.5Hz,1H),7.62(s,1H),7.35(d,J=7.8Hz,1H),7.29–7.24(m,1H),4.60(d,J=5.8Hz,2H),4.23 –4.16(m,2H),3.91(d,J=5.4Hz,1H),3.76(t,J=11.4Hz,2H),3.63(d,J=11.3Hz,1H),3.56(t,J=11.2Hz, 1H), 3.46 (dd, J=15.4, 6.6Hz, 1H), 3.33 (d, J=10.0Hz, 1H), 2.97 (t, J=7.1Hz, 2H), 2.69 (t, J=7.1Hz, 2H).

[0607] Example 29 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-(((S)-tetrahydrofuran-2-yl)methyl-d2)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 29)

[0608] Step 1: Synthesis of (S)-(tetrahydrofuran-2-yl)methane-d2-ol

[0609] Under an ice bath, (S)-tetrahydrofuran-2-carboxylic acid (0.8 mL, 8.61 mmol) and tetrahydrofuran (10 mL) were added to the reaction flask, followed by the slow addition of lithium deuterated tetrahydroaluminum (0.4 g, 9.47 mmol) in portions. After the addition, the mixture was stirred at reflux at 75°C for 2 hours. Stirring was stopped, and saturated aqueous ammonium chloride was added to quench the reaction. The organic solvent was removed under reduced pressure, and extraction was performed with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 363 mg of the product as a colorless oil, with a yield of 40.0%.

[0610] Step 2: Synthesis of (S)-(tetrahydrofuran-2-yl)methyl-d2-4-methylbenzenesulfonate

[0611] At room temperature, (S)-(tetrahydrofuran-2-yl)methanol-d2-ol (363 mg, 3.49 mmol), dichloromethane (10 mL), and triethylamine (1.0 mL, 6.97 mmol) were added to a reaction flask. Then, p-toluenesulfonyl chloride (1.0 mL, 5.23 mmol) was added. After addition, the mixture was brought to room temperature and stirred until the reaction was complete as monitored by TLC. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 20:1-10:1) to afford 609 mg of the product as a colorless oil in a 67.6% yield.

[0612] LC-MS(ESI):[M+H] + =259.2;

[0613] 1 H NMR (500MHz, DMSO-d6) δ7.78(d,J=8.2Hz,2H),7.48(d,J=8.0Hz,2H),3.97(t,J=7.1Hz,1H),3.68–3.53(m,2H),2.42(s ,3H),1.86(dtd,J=12.7,7.7,5.7Hz,1H),1.75(dddd,J=13.3,9.8,6.5,2.8Hz,2H),1.49(ddt,J=12.1,8.2,6.9Hz,1H).

[0614] Step 3: Synthesis of (S)-(tetrahydrofuran-2-yl)methane-d2-amine

[0615] To a reaction flask, add (S)-(tetrahydrofuran-2-yl)methyl d2-methylbenzenesulfonate (2.2 g, 8.58 mmol) and N,N-dimethylformamide (20 mL). Then, using a plastic key, weigh sodium azide (600 mg, 9.29 mmol) and add it to the reaction flask. After addition, transfer the mixture to 80°C and stir overnight. Discontinue heating, cool to room temperature, add saturated brine (20 mL), extract with ethyl acetate (20 mL x 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Add the concentrate (1.0 g, 7.74 mmol) and methanol (10 mL) to the reaction flask, followed by Pd / C (100 mg, 0.94 mmol, 10% wt). After addition, transfer the mixture to room temperature and stir overnight. Filter to remove black insoluble matter, then concentrate under reduced pressure to obtain 800 mg of the crude product in a 100% yield.

[0616] LC-MS:(ESI):[M+H] + =104.2.

[0617] Step 4: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-N-(((S)-tetrahydrofuran-2-yl)methyl-d2)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0618] To the reaction flask, (S)-2-((1,4-dioxane-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (100 mg, 0.26 mmol), (S)-(tetrahydrofuran-2-yl)methan-d2-amine (44.9 mg, 0.39 mmol), HATU (149.18 mg, 0.39 mmol) and diisopropylethylamine (85.9 μL, 0.52 mmol) were added in sequence. The mixture was transferred to room temperature under nitrogen and stirred for 2 hours. Pure water was added for washing (10 mL × 3), and ethyl acetate was used for extraction (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain 322 mg of a yellow oily crude product, which was then separated and lyophilized by preparative HPLC to obtain 11 mg of a white solid with a yield of 10.0%.

[0619] LC-MS(ESI):[M+H] + =468.4;

[0620] 1 H NMR(500MHz,DMSO-d6)δ8.72(s,1H),8.13(d,J=1.8Hz,1H),8.08(s,1H),7.61(s,1H),4.23–4.14( m,2H),3.98(t,J=6.7Hz,1H),3.91(t,J=8.0Hz,1H),3.82–3.71(m,3H),3.65–3.60(m,2H),3.55(t d,J=11.2,2.6Hz,1H),3.45(td,J=11.0,2.6Hz,1H),3.32(d,J=10.9Hz,1H),2.95(t,J=7.3Hz,2H) ,2.68(t,J=7.2Hz,2H),1.91(ddd,J=11.5,7.7,5.8Hz,1H),1.88–1.76(m,2H),1.64–1.54(m,1H).

[0621] Example 30 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-fluoropyridin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 30)

[0622] To a reaction flask were added (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.16 mmol), HATU (89.5 mg, 0.24 mmol), N,N-diisopropylethylamine (40.5 mg, 0.31 mmol), (5-fluoropyridin-2-yl)methanamine (30.3 mg, 0.24 mmol), and N,N-dimethylformamide (2 mL) in sequence. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added for dilution, followed by ethyl acetate (10 mL x 3). The organic phase was washed twice with water (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 35 mg of a white solid in a 44.6% yield.

[0623] LC-MS(ESI):[M+H] + =491.2;

[0624] 1 H NMR(500MHz,DMSO-d6)δ9.33(d,J=5.6Hz,1H),8.51(d,J=2.4Hz,1H),8.19(s,1H),8.13(s ,1H),7.73–7.66(m,1H),7.62(s,1H),7.43(dd,J=8.6,4.5Hz,1H),4.59(d,J=5.6Hz,2H), 4.18(t,J=9.2Hz,2H),3.91(s,1H),3.76(t,J=11.4Hz,2H),3.63(d,J=11.7Hz,1H),3.59– 3.51(m,1H),3.48–3.42(m,1H),3.34(s,1H),2.97(t,J=7.2Hz,2H),2.69(t,J=7.1Hz,2H).

[0625] Example 31 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-(4-fluorobenzyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 31)

[0626] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.16 mmol), HATU (89.5 mg, 0.24 mmol), N,N-diisopropylethylamine (40.5 mg, 0.31 mmol), (4-fluorophenyl)methanamine (30.0 mg, 0.24 mmol), and N,N-dimethylformamide (2 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature for 2 hours. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water and saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 50 mg of a white solid with a yield of 63.8%.

[0627] LC-MS(ESI):[M+H] + =490.1;

[0628] 1 H NMR(500MHz,DMSO-d6)δ9.23(t,J=5.6Hz,1H),8.14(d,J=26.5Hz,2H),7.61(s,1H ),7.42–7.34(m,2H),7.15(t,J=8.8Hz,2H),4.48(d,J=5.9Hz,2H),4.19(dd,J=14. 9,8.6Hz,2H),3.89(s,1H),3.76(t,J=11.4Hz,2H),3.63(d,J=11.2Hz,1H),3.60–3 .52(m,1H),3.50–3.41(m,1H),3.33(s,1H),2.99–2.92(m,2H),2.72–2.66(m,2H).

[0629] Example 32 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-(4-chloro-2-fluorobenzyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 32)

[0630] To a reaction flask, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (80 mg, 0.21 mmol), HATU (119.3 mg, 0.31 mmol), N,N-dimethylformamide (5 mL), (4-chloro-2-fluorophenyl)methanamine (50.1 mg, 0.31 mmol), and diisopropylethylamine (54.1 mg, 0.42 mmol) were added sequentially. After the addition, the mixture was brought to room temperature and stirred for 2 hours. TLC confirmed the reaction was complete. Saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (30 mL x 4), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. Preparative liquid separation afforded 50 mg of a white solid in a 45.6% yield.

[0631] LC-MS(ESI):[M+H] + =524.1;

[0632] 1 H NMR(500MHz,DMSO-d6)δ9.23(t,J=5.8Hz,1H),8.17(d,J=1.8Hz,1H),8.11(d,J=1.8H z,1H),7.62(s,1H),7.47-7.39(m,2H),7.31-7.26(m,1H),4.52(d,J=5.6Hz,2H),4.2 5-4.15(m,2H),3.95-3.88(m,1H),3.80-3.73(m,2H),3.67-3.61(m,1H),3.60-3.53( m,1H),3.49-3.42(m,1H),3.34(s,1H),2.97(t,J=7.1Hz,2H),2.69(t,J=7.2Hz,2H).

[0633] Example 33 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((3,5-difluoropyridin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 33)

[0634] To the reaction flask, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.16 mmol), (3,5-difluoropyridin-2-yl)methanamine (32.1 μL, 0.19 mmol), HATU (89.5 mg, 0.24 mmol), and diisopropylethylamine (79.3 μL, 0.48 mmol) were added sequentially. The mixture was stirred at room temperature under nitrogen overnight until the reaction was complete as monitored by TLC. The mixture was washed with purified water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Preparative HPLC yielded 36 mg of a white solid in a 45.0% yield.

[0635] LC-MS(ESI):[M+H] + =509.2;

[0636] 1 H NMR(500MHz,DMSO-d6)δ9.22(t,J=5.5Hz,1H),8.47(d,J=2.5Hz,1H),8.21–8.14(m,1H),8.11(d, J=2.0Hz,1H),7.92(td,J=9.5,2.4Hz,1H),7.62(s,1H),4.66(d,J=5.4Hz,2H),4.31–4.08(m,2H), 3.91(dtt,J=9.3,6.3,2.5Hz,1H),3.84–3.70(m,2H),3.64(d,J=11.5Hz,1H),3.56(td,J=11.3,2. 6Hz,1H),3.45(td,J=11.0,2.6Hz,1H),3.31(s,1H),2.96(t,J=7.1Hz,2H),2.69(t,J=7.2Hz,2H).

[0637] Example 34 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-chloro-3-fluoropyridin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 34)

[0638] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (50 mg, 0.13 mmol), HATU (75 mg, 0.20 mmol), diisopropylethylamine (50 mg, 0.39 mmol), N,N-dimethylformamide (3 mL), and (5-chloro-3-fluoropyridin-2-yl)methanamine (31 mg, 0.16 mmol) were added sequentially to the reaction flask and stirred at room temperature for 2 hours. The mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. Preparative HPLC yielded 35 mg of a white solid in a 50.5% yield.

[0639] LC-MS(ESI):[M+H] + =525.2;

[0640] 1 H NMR (500MHz, CDCl3) δ8.41(s,1H),8.10(s,1H),7.94(s,1H),7.52-7.47(m,2H),7.28(s,1H),4.84-4.80(m,2H),4.19(d,J=5.5H z,2H),4.04-3.98(m,1H),3.93-3.65(m,4H),3.62-3.54(m,1H),3.41-3.33(m,1H),3.00(t,J=7.1Hz,2H),2.73(t,J=7.1Hz,2H).

[0641] Example 35 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((4-chloro-2-fluorobenzyl)methyl-d2)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 35)

[0642] Step 1: Synthesis of (4-chloro-2-fluorophenyl)methane-d2-ol

[0643] At 0°C, 4-chloro-2-fluorobenzoic acid (0.7 mL, 5.73 mmol) dissolved in tetrahydrofuran (30 mL) was added to the reaction flask, and deuterated lithium aluminum tetrahydride (0.36 g, 8.60 mmol) was slowly added in batches. After the addition, the mixture was transferred to room temperature and stirred overnight until the reaction was complete as monitored by TLC. Saturated aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was separated and purified by silica gel column chromatography (PE:EA (v / v) = 8:1-5:1) to obtain 890 mg of a colorless oily product with a yield of 95.5%.

[0644] Step 2: Synthesis of (4-chloro-2-fluorophenyl)methyl methanesulfonate

[0645] To a reaction flask, (4-chloro-2-fluorophenyl)methanol-d2-ol (890 mg, 5.47 mmol), triethylamine (1.1 mL, 7.66 mmol), and dichloromethane (20 mL) were added, followed by the slow dropwise addition of methylsulfonyl chloride (0.5 mL, 6.57 mmol). The mixture was stirred at room temperature until complete, as monitored by TLC. The mixture was then concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 6:1) to afford 745 mg of the product as a white solid in a 56.5% yield.

[0646] 1 H NMR (500MHz, DMSO-d6) δ7.59 (d, J = 8.3Hz, 1H), 7.50–7.47 (m, 1H), 7.34–7.31 (m, 1H), 3.32 (s, 3H).

[0647] Step 3: Synthesis of (4-chloro-2-fluorophenyl)methane-d2-amine (1616-3)

[0648] To a reaction flask, add (4-chloro-2-fluorophenyl)methyl methanesulfonate (360 mg, 1.50 mmol) and N,N-dimethylformamide (8 mL), followed by sodium azide (126 mg, 1.94 mmol). Stir at 50°C until the reaction is complete as monitored by TLC. Discontinue heating, cool to room temperature, add saturated brine (10 mL), extract with ethyl acetate (10 mL x 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure for later use. Add the above concentrate (215 mg, 1.15 mmol) to the reaction flask, followed by tetrahydrofuran (5 mL) and water (1 mL), and then add triphenylphosphine (450.9 mg, 1.72 mmol). Transfer to reflux at 80°C until the reaction is complete as monitored by TLC. Ethyl acetate was added for extraction (10 mL×3), and the mixture was dried over anhydrous sodium sulfate. The residue was separated and purified by silica gel column chromatography (DCM:MeOH (v / v) = 20:1-10:1) to obtain 82 mg of a colorless oily product with a yield of 44.0%.

[0649] LC-MS:(ESI):[M+H] + =162.1;

[0650] 1 H NMR (500MHz, DMSO-d6) δ7.52(t,J=8.3Hz,1H),7.31(dd,J=10.1,2.1Hz,1H),7.25(dd,J=8.3,2.1Hz,1H),3.20(s,2H).

[0651] Step 4: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-((4-chloro-2-fluorobenzyl)methyl-d2)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0652] Add (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (100 mg, 0.26 mmol), (4-chloro-2-fluorophenyl)methane-d2-amine (63.4 mg, 0.39 mmol), HATU (149.2 mg, 0.39 mmol), N,N-dimethylformamide (10 mL), and diisopropylethylamine (86.5 μL, 0.52 mmol) to a reaction flask. Transfer the mixture to room temperature and stir. Monitor the reaction until complete by TLC. Pure water was added for washing (10 mL × 3), and ethyl acetate was added for extraction (10 mL × 3). The organic phase was washed with saturated brine (10 mL × 2), and the organic phase was separated and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure to obtain 312 mg of a pale yellow oily crude product, which was then separated and purified by preparative chromatography and freeze-dried to obtain 84 mg of a white solid with a yield of 61.0%.

[0653] LC-MS(ESI):[M+H] + =526.1;

[0654] 1H NMR(500MHz,DMSO-d6)δ9.26(s,1H),8.22(d,J=1.8Hz,1H),8.16(d,J=1.8Hz,1H),7.66(s,1H),7 .53–7.42(m,2H),7.32(dd,J=8.4,2.1Hz,1H),4.24(dd,J=5.8,3.8Hz,2H),3.96(dp,J=9.5,3.9,3 .3Hz,1H),3.81(td,J=10.9,10.2,2.4Hz,2H),3.68(dd,J=11.5,2.7Hz,1H),3.61(td,J=11.2,2. 6Hz,1H),3.50(td,J=11.0,2.6Hz,1H),3.39(s,1H),3.01(t,J=7.2Hz,2H),2.73(t,J=7.2Hz,2H).

[0655] Example 36 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-(oxazol-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 36)

[0656] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (50 mg, 0.13 mmol), HATU (75 mg, 0.20 mmol), diisopropylethylamine (50 mg, 0.39 mmol), N,N-dimethylformamide (3 mL), and oxazol-2-ylmethanamine (26 mg, 0.2 mmol) were added sequentially to the reaction flask and stirred at room temperature for 2 hours. TLC confirmed the reaction was complete, and the mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. Preparative HPLC yielded 45 mg of a white solid in a 73.9% yield.

[0657] LC-MS(ESI):[M+H] + =463.2;

[0658] 1H NMR (500MHz, CDCl3) δ8.07(s,1H),7.92(s,1H),7.66(s,1H),7.28(s,1H),7.11(s,1H),6.87(t,J=5.1Hz,1H),4.80(d,J=5.2Hz,2H),4.19(d,J=5. 4Hz,2H),4.04-3.98(m,1H),3.91-3.85(m,1H),3.83-3.67(m,3H),3.62- 3.54(m,1H)3.40-3.32(m,1H),2.98(t,J=7.2Hz,2H),2.76-2.69(m,2H).

[0659] Example 37 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-chloropyridin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 37)

[0660] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.16 mmol), HATU (89.5 mg, 0.24 mmol), N,N-diisopropylethylamine (40.5 mg, 0.31 mmol), (5-chloropyridin-2-yl)methanamine (30.2 mg, 0.24 mmol), and N,N-dimethylformamide (2 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (15 mL x 2) and saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 45 mg of a white solid in a 55.5% yield.

[0661] LC-MS(ESI):[M+H] + =507.2;

[0662] 1H NMR(500MHz,DMSO-d6)δ9.35(t,J=5.5Hz,1H),8.57(d,J=1.7Hz,1H),8.20(s,1H),8.14(s,1H),7 .90(dd,J=8.4,1.9Hz,1H),7.63(s,1H),7.41(d,J=8.4Hz,1H),4.59(d,J=5.7Hz,2H),4.20(d,J= 5.9Hz, 2H), 3.91 (d, J = 5.7Hz, 1H), 3.77 (t, J = 11.5Hz, 2H), 3.64 (d, J = 11.3Hz, 1H), 3.57 (t, J = 11. 2Hz,1H),3.46(dd,J=15.7,6.3Hz,1H),3.35(s,1H),2.98(t,J=7.0Hz,2H),2.70(t,J=7.0Hz,2H).

[0663] Example 38 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((6-fluoropyridin-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 38)

[0664] To a reaction flask, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.16 mmol), HATU (89.5 mg, 0.24 mmol), N,N-dimethylformamide (5 mL), (6-fluoropyridin-2-yl)methanamine (46.8 mg, 0.24 mmol), and diisopropylethylamine (81.1 mg, 0.63 mmol) were added sequentially. After the addition, the mixture was brought to room temperature and stirred for 1 hour. TLC monitored the reaction for completion. Saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine (30 mL x 4), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. Preparative liquid separation afforded 50 mg of a white solid in a 65.0% yield.

[0665] LC-MS(ESI):[M+H] + =491.1;

[0666] 1H NMR(500MHz,DMSO-d6)δ9.36(t,J=5.9Hz,1H),8.21(d,J=1.9Hz,1H),8.15(d,J=1.9Hz,1H) ,8.02-7.93(m,1H),7.63(s,1H),7.34-7.29(m,1H),7.08-7.04(m,1H),4.54(d,J=5.8Hz,2 H),4.26-4.14(m,2H),3.96-3.88(m,1H),3.81-3.74(m,2H),3.67-3.62(m,1H),3.60-3.54 (m,1H),3.50-3.43(m,1H),3.36-3.33(m,1H),2.98(t,J=7.1Hz,2H),2.70(t,J=7.1Hz,2H).

[0667] Example 39 Synthesis of 2-(((S)-1,4-dioxane-2-yl)methyl)-N-((5-oxaspiro[3.4]octan-6-yl)methyl]-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 39)

[0668] Step 1: Synthesis of 1-(but-3-en-1-yl)cyclobutan-1-ol

[0669] Under nitrogen, a solution of butan-3-en-1-yl-magnesium bromide in THF (18 mL, 18 mmol, 1 M) was slowly added to a reaction flask containing cyclobutanone (1.1 mL, 15 mmol) in tetrahydrofuran (20 mL) at 0°C. The mixture was then stirred at room temperature for 2.5 hours under nitrogen. TLC confirmed the reaction was complete. Under ice-cooling, the mixture was quenched with saturated ammonium chloride (40 mL). The mixture was extracted with diethyl ether (3 × 25 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 10:1-2:1) to afford 840 mg of a colorless oil in a 44.4% yield.

[0670] 1 H NMR (500MHz, CDCl3) δ5.88-5.77(m,1H),5.03-4.96(m,1H),4.90(d,J=10.2Hz,1 H),2.13-2.05(m,2H),2.03-1.88(m,4H),1.71-1.60(m,3H),1.53-1.40(m,1H).

[0671] Step 2: Synthesis of 6-(iodomethyl)-5-oxaspiro[3.4]octane

[0672] Under nitrogen, solid sodium bicarbonate (1.7 g, 20.21 mmol) was added to 1-(but-3-en-1-yl)cyclobutan-1-ol (850 mg, 6.74 mmol) dissolved in anhydrous acetonitrile (10 mL). The mixture was stirred for 5 minutes and then brought to 0°C. Iodine (5.1 g, 20.21 mmol) was then added. After addition, the mixture was brought to room temperature and stirred for 1.5 hours. The reaction was monitored for completion by TLC. Sodium thiosulfate solution was added for quenching. The mixture was extracted with methyl tert-butyl ether (3 × 20 mL). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 5:1-3:1) to afford 1.35 g of the product as a yellow oil in a 79.5% yield.

[0673] 1 H NMR(500MHz, CDCl3) δ4.08-4.00(m,1H),3.26(dd,J=9.8,4.5Hz,1H),3.09(dd,J=9.8,7.6Hz,1H) ,2.29-2.20(m,2H),2.18-2.08(m,1H),2.07-1.89(m,4H),1.75-1.63(m,2H),1.54-1.43(m,1H).

[0674] Step 3: Synthesis of 6-(azidomethyl)-5-oxaspiro[3.4]octane

[0675] 6-(Iodomethyl)-5-oxaspiro[3.4]octane (600 mg, 2.38 mmol), N,N-dimethylformamide (10 mL), and sodium azide (232 mg, 3.57 mmol) were added to the reaction flask in sequence, and the mixture was stirred at 85°C for 2 hours. The reaction was monitored for completion by TLC, and the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 350 mg of crude product, which was used directly in the next step without further purification.

[0676] Step 4: Synthesis of (5-oxaspiro[3.4]octan-6-yl)methanamine

[0677] To a reaction flask, 6-(azidomethyl)-5-oxaspiro[3.4]octane (350 mg, 2.09 mmol) was added, followed by tetrahydrofuran (5 mL) and water (0.5 mL), and then triphenylphosphine (824 mg, 3.14 mmol). The mixture was transferred to 50°C and allowed to react for 3 hours. TLC confirmed the reaction was complete, and the mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH (v / v) = 30:1-20:1) to obtain 180 mg of the product as a colorless oil in a 60.9% yield.

[0678] LC-MS(ESI):[M+H] + =142.2;

[0679] 1 H NMR (500MHz, CDCl3) δ4.00-3.91(m,1H),2.77(d,J=13.2Hz,1H),2.68-2.61(m,1H),2.29-2.15(m,2H),2.05-1.90(m,5H),1.73-1.44(m,3H).

[0680] Step 5: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-N-((5-oxaspiro[3.4]octan-6-yl)methyl]-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0681] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (50 mg, 0.13 mmol), HATU (75 mg, 0.20 mmol), diisopropylethylamine (50 mg, 0.39 mmol), N,N-dimethylformamide (3 mL), and (5-oxaspiro[3.4]octan-6-yl)methanamine (28 mg, 0.20 mmol) were added sequentially to the reaction flask and stirred at room temperature for 2 hours. TLC confirmed the reaction was complete, and the mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. Preparative HPLC yielded 45 mg of a white solid in a 67.0% yield.

[0682] LC-MS(ESI):[M+H] + =506.2;

[0683] 1H NMR(500MHz, CDCl3)δ8.00(s,1H),7.87(s,1H),7.27(s,1H),6.50(t,J=5.6Hz, 1H),4.21-4.13(m,3H),4.03-3.98(m,1H),3.91-3.85(m,1H),3.82-3.66(m,4H ),3.62-3.54(m,1H),3.42-3.32(m,2H),3.01-2.93(m,2H),2.72(t,J=7.1Hz,2 H),2.32-2.19(m,2H),2.09-1.90(m,5H),1.76-1.63(m,2H),1.55-1.46(m,1H).

[0684] Example 40 Synthesis of N-(4-chloro-2-fluorobenzyl)-2-((3-fluorooxetane-3-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 40)

[0685] Step 1: Synthesis of N-(4-chloro-2-fluorobenzyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0686] To the reaction flask were added 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (300 mg, 1.16 mmol), (4-chloro-2-fluorophenyl)methanamine (277 mg, 1.74 mmol), HATU (660 mg, 1.74 mmol), diisopropylethylamine (299 mg, 2.31 mmol), and N,N-dimethylformamide (4 mL) in sequence. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with water (30 mL x 2) and saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 1:3) to obtain 368 mg of a white solid in a yield of 79.1%.

[0687] LC-MS(ESI):[M+H] + =401.0;

[0688] 1H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.19(s,1H),7.40(d,J=13.7Hz,2H),7.26(d,J=8.3H z,1H),4.55(d,J=6.0Hz,2H),3.28–3.24(m,2H),2.79(t,J=6.5Hz,2H),2.20–2.12(m,2H).

[0689] Step 2: Synthesis of N-(4-chloro-2-fluorobenzyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0690] To a reaction flask, N-(4-chloro-2-fluorobenzyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (360 mg, 0.90 mmol), toluene (5 mL), and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (313 mg, 1.80 mmol) were added sequentially and stirred at 110°C for 1 hour. The solvent was removed by concentration under reduced pressure, and ethanol (5 mL) and hydrazine hydrate (90 mg, 1.80 mmol) were added to the system, followed by stirring at 60°C for 1 hour. The product was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1) to afford 293 mg of a yellow solid in a 76.8% yield.

[0691] LC-MS(ESI):[M+H] + =425.0.

[0692] Step 3: Synthesis of N-(4-chloro-2-fluorobenzyl)-2-((3-fluorooxetan-3-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0693] To a reaction flask were added N-(4-chloro-2-fluorobenzyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (50 mg, 0.12 mmol), (3-fluorooxetan-3-yl)methyl-4-methylbenzenesulfonate (43.5 mg, 0.18 mmol), cesium carbonate (76.7 mg, 0.24 mmol), and N,N-dimethylformamide (4 mL). The mixture was then stirred at 70°C for 1 hour. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with water (30 mL x 2) and saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Preparative HPLC yielded 12 mg of a white solid in a 19.9% ​​yield.

[0694] LC-MS(ESI):[M+H] + =513.1;

[0695] 1 H NMR (500MHz, DMSO-d6) δ9.37(s,1H),8.14(s,1H),7.75(s,1H),7.40(t,J=8.6Hz,2H),7.27(d,J=8.1Hz,1H),4.89(dd,J=21.2,8.1H z,2H),4.80(s,1H),4.76(s,1H),4.66(dd,J=20.4,8.1Hz,2H),4.56(d,J=5.8Hz,2H),3.22(t,J=7.1Hz,2H),2.86(t,J=7.1Hz,2H).

[0696] Example 41 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-((5-methyloxazol-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 41)

[0697] (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (100 mg, 0.29 mmol) was placed in a reaction flask at room temperature and dissolved in dichloromethane (5 mL). HATU (123.2 mg, 0.32 mmol) and diisopropylethylamine (0.1 mL, 0.74 mmol) were then added, followed by (5-methyloxazol-2-yl)methanamine (56.5 mg, 0.32 mmol). The reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated and purified by preparative HPLC to afford a light yellow solid (37.6 mg, 0.08 mmol) in a 25.6% yield.

[0698] LC-MS(ESI):[M+H] + =477.2;

[0699] 1H NMR (400MHz, CDCl3) δ8.11(s,1H),7.98(s,1H),7.29(s,1H),7.18(br s,1H),6.71(s,1H),4.77(br d,J=4.25Hz,2H),4.20(d,J=5.38Hz,2H),3.98-4.08(m,1H),3.89(dd,J=11.76,2.50Hz,1H),3.77-3.84(m,1H),3.69-3 .76(m,2H),3.54-3.64(m,1H),3.37(dd,J=11.69,9.94Hz,1H),3.00(t,J=7.07Hz,2H),2.71-2.76(m,2H),2.32(s,3H).

[0700] Example 42 Synthesis of 2-((2,3-dihydrobenzo[b][1,4]dioxane-2-yl)methyl)-N-(oxazol-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 42)

[0701] Step 1: Synthesis of 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-7-methoxy-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole

[0702] To a reaction flask, 7-methoxy-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole (600 mg, 2.24 mmol), (2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl 4-methylbenzenesulfonate (868 mg, 2.91 mmol), cesium carbonate (1458 mg, 4.47 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After addition, the mixture was heated in an oil bath at 70°C for 2 hours. TLC confirmed the reaction was complete, and the mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL × 4), dried over anhydrous sodium sulfate, and evaporated to dryness. Purified by silica gel column chromatography (EA:PE (v:v) = 1:5) to afford 1121 mg of the product as a pale yellow oil.

[0703] LC-MS(ESI):[M+H] + =417.0;

[0704] 1H NMR(500MHz,DMSO-d6)δ7.83-7.78(m,1H),7.61(s,1H),7.48(d,J=8.0Hz,1H ),7.22(d,J=2.6Hz,1H),7.14(d,J=2.6Hz,1H),6.89-6.87(m,1H),6.85-6.8 4(m,1H),4.60-4.53(m,1H),4.45(d,J=5.6Hz,2H),4.43-4.39(m,1H),4.02- 3.97(m,1H),3.84(s,3H),2.89(t,J=7.1Hz,2H),2.64(t,J=8.3,6.1Hz,2H).

[0705] Step 2: Synthesis of 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazol-7-ol

[0706] To a reaction flask, 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-7-methoxy-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole (1210 mg, 2.91 mmol) and hydrobromic acid (15 mL, 276.23 mmol) were added sequentially. After the addition, the mixture was heated in an oil bath at 120°C for 4 hours. The mixture was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL × 4), dried over anhydrous sodium sulfate, and evaporated to dryness. Purified by silica gel column chromatography (EA:PE (v:v) = 1:2) to afford 519 mg of a white solid in a 44.4% yield.

[0707] LC-MS(ESI):[M+H] + =403.1;

[0708] 1 H NMR(500MHz,DMSO-d6)δ9.99(s,1H),7.58(s,1H),7.04(d,J=2.5Hz,1H),6.98(d,J=2.5Hz,1H),6.91-6.85(m,2H),6.85-6.81(m,2H ),4.59-4.52(m,1H),4.43(d,J=5.6Hz,2H),4.42-4.38(m,1H),4.02-3.96(m,1H),2.81(t,J=7.0Hz,2H),2.62(t,J=8.3,6.0Hz,2H).

[0709] Step 3: Synthesis of 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazol-7-yl trifluoromethanesulfonate

[0710] To a reaction flask, 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazol-7-ol (519 mg, 1.29 mmol), dichloromethane (15 mL), and triethylamine (262 mg, 2.58 mmol) were added sequentially. Trifluoromethanesulfonic anhydride (546 mg, 1.93 mmol) was added at 0°C. After addition, the reaction was continued at this temperature for 1 hour. The reaction was monitored for completion by TLC. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (EA:PE (v:v) = 1:5) to afford 722 mg of a light yellow oil.

[0711] LC-MS(ESI):[M+H] + =535.1;

[0712] 1 H NMR (500MHz, DMSO-d6) δ7.85(d,J=2.6Hz,1H),7.76(d,J=2.6Hz,1H),7.71(s,1H),6.91-6.87(m,1H),6.87-6.82(m,J=3.0Hz, 3H),4.62-4.56(m,1H),4.55-4.46(m,2H),4.43-4.38(m,1H),4.02-3.97(m,1H),3.00(t,J=7.1Hz,2H),2.70(t,J=7.2Hz,2H).

[0713] Step 4: Synthesis of methyl 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylate

[0714] Under a nitrogen atmosphere, a 250 mL autoclave was charged with 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazol-7-yl trifluoromethanesulfonate (722 mg, 1.35 mmol), methanol (15 mL), Pd(dppp)Cl2 (120 mg, 0.20 mmol), and triethylamine (274 mg, 2.70 mmol). The mixture was filled with 20 atm of CO and heated in an oil bath at 100°C overnight. The reaction was monitored for completion by TLC. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (EA:PE (v:v) = 1:4) to afford 521 mg of a colorless oily liquid in an 86.8% yield.

[0715] LC-MS(ESI):[M+H] + =445.2;

[0716] 1 H NMR(500MHz,DMSO-d6)δ8.15(d,J=2.2Hz,2H),7.72(s,1H),6.92-6.88(m,1H),6.87-6.81(m,3H),4.58-4 .48(m,2H),4.48-4.41(m,1H),4.06-4.00(m,2H),3.90(s,3H),3.01(t,J=7.2Hz,2H),2.74-2.67(m,2H).

[0717] Step 5: Synthesis of 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid

[0718] To a reaction flask, add methyl 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylate (521 mg, 1.17 mmol), tetrahydrofuran (8 mL), and 1 M sodium hydroxide (10 mL). After the addition, heat in an oil bath at 50°C for 4 hours. TLC monitors the reaction for completion. Adjust the pH to 2-3 with 1 M dilute hydrochloric acid and extract with ethyl acetate (50 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness to afford 500 mg of a white solid in a 99.1% yield.

[0719] LC-MS(ESI):[M+H] + =431.1;

[0720] Step 6: Synthesis of 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-N-(oxazol-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0721] To a reaction flask, add 2-((2,3-dihydrobenzo[b][1,4]dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60 mg, 0.14 mmol), HATU (80 mg, 0.21 mmol), N,N-dimethylformamide (5 mL), oxazol-2-ylmethylamine (18 mg, 0.18 mmol), and diisopropylethylamine (54.3 mg, 0.42 mmol). After addition, bring the mixture to room temperature and continue stirring for 1.5 hours. TLC indicates the reaction is nearly complete. The mixture is quenched with water (30 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 4), and evaporated to dryness. Liquid separation is performed to obtain 35 mg of a white solid in a 49.2% yield.

[0722] LC-MS(ESI):[M+H] + =511.2;

[0723] 1 H NMR(500MHz,DMSO-d6)δ9.37(t,J=5.8Hz,1H),8.18(s,1H),8.12(s,1H), 8.05(s,1H),7.70(s,1H),7.17(s,1H),6.91-6.88(m,1H),6.88-6.82(m,3 H),4.61(d,J=5.8Hz,2H),4.60-4.57(m,1H),4.55-4.47(m,2H),4.45-4.4 0(m,1H),4.05-3.99(m,1H),2.98(t,J=7.2Hz,2H),2.71(t,J=7.2Hz,2H).

[0724] Example 43 Synthesis of (S)-2-((1,4-dioxane-2-yl)methyl)-N-(pyrimidin-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 43)

[0725] Step 1: Synthesis of methyl 9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate

[0726] To a reaction flask, methyl 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylate (261 mg, 0.96 mmol) and toluene (10 mL) were added sequentially, followed by the dropwise addition of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (355 μL, 1.72 mmol). The mixture was refluxed at 110°C for 1 hour. The reaction was concentrated under reduced pressure to afford the crude product. Ethanol (5 mL) and hydrazine hydrate (57 mg, 1.1 mmol) were added to the reaction flask, which was then stirred at room temperature overnight. The product was washed with 1 M dilute hydrochloric acid, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 1:1) to afford 80 mg of a yellow solid in a 28.0% yield.

[0727] LC-MS(ESI):[M+H] + =298.1;

[0728] 1 HNMR (500MHz, DMSO-d6) δ13.26(s,1H),8.15(s,1H),7.74(s,1H),3.93(s,3H),3.20(d,J=7.3Hz,2H),2.86(t,J=7.3Hz,2H).

[0729] Step 2: Synthesis of methyl (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate

[0730] To the reaction flask were added methyl 9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate (50 mg, 0.17 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (68.7 mg, 0.25 mmol), cesium carbonate (109.6 mg, 0.34 mmol), and N,N-dimethylformamide (10 mL) in sequence. The mixture was then heated to 60°C and reacted for 2 hours. Saturated brine (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3) and washed with pure water (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to obtain 68 mg of the product as an oil.

[0731] LC-MS(ESI):[M+H] + =398.1;

[0732] 1H NMR(500MHz,DMSO-d6)δ8.14(s,1H),7.70(s,1H),4.28–4.17(m,2H),3.93(s,3H),3.83–3.72(m,2H),3.68–3.60(m,1H) ,3.55(td,J=11.2,2.5Hz,1H),3.45(td,J=11.1,2.6Hz,1H),3.30(s,2H),3.18(t,J=7.4Hz,2H),2.84(t,J=7.3Hz,2H).

[0733] Step 3: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid

[0734] To a reaction flask, add (S)-methyl 2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate (80 mg, 0.20 mmol), sodium hydroxide (80.5 mg, 2.0 mmol), tetrahydrofuran (12 mL), and water (2 mL) in sequence. After addition, transfer to 60°C and react for 2 hours. Extract with ethyl acetate, discard the organic phase, adjust the pH to around 4, and extract with ethyl acetate (10 mL x 3). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 68 mg of a white solid (88.0% yield).

[0735] LC-MS(ESI):[M+H] + =384.1.

[0736] Step 4: Synthesis of (S)-2-((1,4-dioxan-2-yl)methyl)-N-(pyrimidin-2-ylmethyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0737] To the reaction flask were added (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (68 mg, 0.18 mmol), pyrimidine-2-methylamine (29 mg, 0.27 mmol), HATU (107.92 mg, 0.28 mmol), diisopropylethylamine (58.6 μL, 0.35 mmol), and N,N-dimethylformamide (10 mL). The mixture was stirred at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL x 3) were added, and the organic phases were combined and washed with water (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated and purified by preparative HPLC, and lyophilized to obtain 14 mg of the product as a yellow solid in a 13.0% yield.

[0738] LC-MS(ESI):[M+H] + =475.2;

[0739] 1 H NMR (500MHz, DMSO-d6) δ9.29(t,J=5.9Hz,1H),8.79(d,J=4.9Hz,2H),8.15(s,1H),7.70( s,1H),7.42(t,J=4.9Hz,1H),4.76(d,J=5.9Hz,2H),4.33–4.15(m,2H),3.92(dtd,J=8.9, 6.0,2.5Hz,1H),3.83–3.67(m,2H),3.64(d,J=11.4Hz,1H),3.55(td,J=11.2,2.5Hz,1H) ,3.45(td,J=11.1,2.7Hz,1H),3.34(s,1H),3.24(t,J=7.3Hz,2H),2.87(t,J=7.3Hz,2H).

[0740] Example 44 Synthesis of (N-(((R)-1,4-dioxan-2-yl)methyl)-2-((S)-1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 44)

[0741] Under nitrogen, (S)-2-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (50 mg, 0.13 mmol), HATU (75 mg, 0.20 mmol), diisopropylethylamine (67 mg, 0.52 mmol), N,N-dimethylformamide (3 mL), and (R)-(1,4-dioxan-2-yl)methanamine (23 mg, 0.2 mmol) were added to the reaction flask in sequence and stirred at room temperature for 2 hours. TLC confirmed the reaction was complete, and the mixture was washed with saturated brine (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. Preparative HPLC yielded 47 mg of a white solid in a 73.5% yield.

[0742] LC-MS(ESI):[M+H] + =482.2;

[0743] 1 H NMR (500MHz, DMSO-d6) δ8.74(t,J=5.9Hz,1H),8.12(s,1H),8.07(s,1H),7.61(s,1H),4.24-4.14(m,2H),3.92-3.88(m,1H),3.76(td,J= 10.7,10.1,2.7Hz,4H),3.70-3.52(m,5H),3.47(td,J=11.1,2.6Hz,2H),3.33-3.21(m,4H),2.96(t,J=7.3Hz,2H),2.68(t,J=7.1Hz,2H).

[0744] Example 45 Synthesis of N-(((R)-1,4-dioxan-2-yl)methyl)-2-(((S)-1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide (Compound 45)

[0745] Step 1: Synthesis of (R)-N-((1,4-dioxan-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide

[0746] To the reaction flask were added 5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (320 mg, 1.23 mmol), HATU (704 mg, 1.85 mmol), diisopropylethylamine (479 mg, 3.70 mmol), N,N-dimethylformamide (10 mL), and (R)-(1,4-dioxan-2-yl)methanamine (174 mg, 1.48 mmol) in sequence. The mixture was stirred at room temperature for 2 hours. TLC confirmed the reaction was complete, and the mixture was washed with saturated brine (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered to remove the solid, concentrated under reduced pressure, and separated by silica gel column chromatography (PE:EA (v / v) = 4:1 to 1:1) to afford 420 mg of a yellow solid in a 94.9% yield.

[0747] LC-MS(ESI):[M+H] + =359.1;

[0748] 1 H NMR(500MHz,DMSO-d6)δ8.91(t,J=6.2Hz,1H),8.18(s,1H),3.78-3.68(m,3H),3.65-3.61(m,1H),3.60-3.5 3(m,1H),3.51-3.43(m,1H),3.43-3.33(m,2H),3.29-3.22(m,3H),2.78(t,J=6.6Hz,2H),2.20-2.11(m,2H).

[0749] Step 2: Synthesis of (R)-N-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0750] To the reaction flask, (R)-N-((1,4-dioxan-2-yl)methyl)-5-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide (400 mg, 1.12 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (390 mg, 2.24 mmol) were added, followed by toluene (10 mL). After addition, the mixture was stirred at 110°C for 2 hours. TLC monitored the reaction for completion. Heating was discontinued, the mixture was cooled to room temperature, and concentrated under reduced pressure to afford a yellow oil, which was used directly in the next step. Hydrazine hydrate (280 mg, 5.60 mmol) and ethanol (10 mL) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (PE:EA (v / v) = 1:1 to 0:1) to afford 221 mg of a yellow solid in a 51.6% yield.

[0751] LC-MS(ESI):[M+H] + =383.1;

[0752] 1 H NMR(500MHz,DMSO-d6)δ13.20(s,1H),8.74(t,J=6.2Hz,1H),8.13(s,1H),7.72(s,1H),3.79-3.68(m,3 H),3.66-3.53(m,2H),3.50-3.43(m,1H),3.41-3.36(m,2H),3.28-3.18(m,3H),2.86(t,J=7.3Hz,2H).

[0753] Step 3: Synthesis of N-(((R)-1,4-dioxan-2-yl)methyl)-2-(((S)-1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]quinoline-7-carboxamide

[0754] To a reaction flask were added (R)-N-((1,4-dioxan-2-yl)methyl)-9-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-7-carboxamide (50 mg, 0.13 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (53 mg, 0.20 mmol), and cesium carbonate (85 mg, 0.26 mmol). N,N-dimethylformamide (2 mL) was then added, and the mixture was stirred at 70°C. The reaction was monitored for completion by TLC, and the mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Preparative HPLC yielded 49 mg of a white solid in a 77.8% yield.

[0755] LC-MS(ESI):[M+H] + =483.2;

[0756] 1 H NMR (500MHz, CDCl3) δ8.38(s,1H),8.23(t,J=6.2Hz,1H),7.31(s,1H),4.20(d,J=5.4Hz,2H),4.03 -3.97(m,1H),3.90-3.53(m,12H),3.45-3.32(m,3H),3.21(t,J=7.3Hz,2H),2.86(t,J=7.3Hz,2H).

[0757] The compounds in Table A were prepared according to the methods of Example 2 and Reaction Scheme 3.

[0758] Table A

[0759] The compounds in Table B were prepared according to Reaction Scheme 1 and the method of Example 1.

[0760] Table B

[0761] Example 152 Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-9-cyano-N-(((S)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 152)

[0762] Step 1: Synthesis of (S)-7-((tetrahydrofuran-2-yl)methyl)carbamoyl)-4,5-dihydro-2H-benzo[g]indazol-9-yl trifluoromethanesulfonate

[0763] To the reaction flask, add (S)-8-oxo-3-(((tetrahydrofuran-2-yl)methyl)carbamoyl)-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (482 mg, 1.14 mmol), toluene (8 mL), and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (598 mg, 3.43 mmol) in sequence. After the addition, heat in an oil bath at 110°C for 1 hour. Monitor the reaction for completion by TLC. Evaporate the reaction solution and proceed directly to the next step. Add ethanol (8 mL) and hydrazine hydrate (171.8 mg, 3.43 mmol) to the reaction mixture from the previous step. After the addition, bring the mixture to room temperature and continue stirring for 1 hour. The reaction was completed as monitored by TLC. Saturated brine (30 mL) was added, extracted with ethyl acetate (30 mL×3), dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:2) to obtain 100 mg of a yellow oily liquid in a yield of 19.7%.

[0764] LC-MS(ESI):[M+H] + =446.3.

[0765] Step 2: Synthesis of (S)-9-cyano-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0766] Under a nitrogen atmosphere, (S)-7-((tetrahydrofuran-2-yl)methyl)carbamoyl)-4,5-dihydro-2H-benzo[g]indazol-9-yl trifluoromethanesulfonate (100 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (38.9 mg, 0.03 mmol), zinc cyanide (52.7 mg, 0.45 mmol), and N,N-dimethylformamide (5 mL) were added sequentially to a reaction flask. The mixture was heated in an oil bath at 100°C overnight. TLC monitored the reaction completion and quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 4). The organic phases were separated, dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA (v / v) = 1:1 to 1:3) to afford 70 mg of a white solid in a 96.7% yield.

[0767] LC-MS(ESI):[M+H] + =323.3;

[0768] 1H NMR(500MHz,DMSO-d6)δ13.11(s,1H),8.70(t,J=5.8Hz,1H),8.16(d,J=1.9 Hz,1H),8.07(d,J=2.0Hz,1H),7.70(s,1H),3.99(p,J=6.4Hz,1H),3.82-3. 76(m,1H),3.68-3.61(m,1H),3.39-3.33(m,2H),2.98(t,J=7.3Hz,2H),2.7 5(t,J=7.3Hz,2H),1.97-1.90(m,1H),1.89-1.77(m,2H),1.65-1.55(m,1H).

[0769] Step 3: Synthesis of 2-(((S)-1,4-dioxan-2-yl)methyl)-9-cyano-N-(((S)-tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0770] To a reaction flask, (S)-9-cyano-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (93 mg, 0.29 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (117.8 mg, 0.43 mmol), cesium carbonate (188 mg, 0.58 mmol), and N,N-dimethylformamide (5 mL) were added sequentially. After the addition, the mixture was heated in an oil bath at 70°C for 40 minutes. TLC confirmed the reaction was complete and the mixture was quenched with water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (30 mL x 4). The organic phases were separated, dried over anhydrous sodium sulfate, filtered to remove the solid, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (PE:EA (v / v) = 1:1 to 1:3) to afford 50 mg of a white solid in a 41.0% yield.

[0771] LC-MS(ESI):[M+H] + =423.4;

[0772] 1H NMR (500MHz, DMSO-d6) δ8.69(t,J=5.8Hz,1H),8.15(d,J=1.8Hz,1H),8.06(d,J=1.8Hz,1H),7.6 6(s,1H),4.22(d,J=5.8Hz,2H),4.02-3.91(m,2H),3.86-3.80(m,1H),3.80-3.73(m,2H),3.67- 3.61(m,2H),3.60-3.53(m,1H),3.50-3.43(m,1H),3.39-3.35(m,1H),3.34-3.31(m,2H),2.96( t,J=7.3Hz,2H),2.73(t,J=7.3Hz,2H),1.97-1.89(m,1H),1.89-1.77(m,2H),1.64-1.55(m,1H).

[0773] Example 153 Synthesis of N-(((R)-1,4-dioxan-2-yl)methyl)-2-(((S)-1,4-dioxan-2-yl)methyl)-9-cyano-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 153)

[0774] Step 1: Synthesis of (E)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one O-methyloxime

[0775] To the reaction flask, add 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (8 g, 49 mmol), methylamine oxide hydrochloride (8.3 g, 98 mmol), and ethanol (160 mL). Pyridine (12.0 mL, 148 mmol) was then added. The mixture was transferred to an oil bath and refluxed with stirring for 1.5 hours. TLC confirmed the reaction was complete, and the reaction was stopped, returned to room temperature, and concentrated under reduced pressure to remove the bulk solvent. The mixture was diluted with ethyl acetate (80 mL) and washed sequentially with 2M hydrochloric acid solution and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was used directly in the next step.

[0776] Step 2: Synthesis of (E)-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate

[0777] To (E)-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one O-methyloxime (9.4 g, 49 mmol) dissolved in dichloromethane (80 mL) was added pyridine (11.9 mL, 147 mmol), followed by the slow dropwise addition of acetyl chloride (4.2 mL, 59 mmol) under ice-cooling. The mixture was stirred at 0°C for 2 hours. TLC confirmed the reaction was complete, and the reaction was quenched by addition of water. The mixture was extracted with ethyl acetate multiple times (3 × 40 mL). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE:EA (v / v) = 10:1 to 5:1) afforded 9.4 g of a white solid in 82% yield.

[0778] LC-MS(ESI):[M+H] + =234.1;

[0779] 1 H NMR (500MHz, CDCl3) δ7.99 (d, J = 8.6Hz, 1H), 6.93-6.86 (m, 2H), 3.97 (s, 3H), 2.75-2.68 (m, 4H), 2.28 (s, 3H), 1.88-1.79 (m, 2H).

[0780] Step 3: Synthesis of (E)-4-bromo-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate

[0781] To a reaction flask, add (E)-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate (9.4 g, 40 mmol), palladium acetate (0.94 g), N-bromosuccinimide (8.6 g, 48 mmol), and glacial acetic acid (90 mL). After addition, transfer the mixture to 90°C and stir for 1 hour. TLC indicates completion of the reaction. Heating is discontinued, and the mixture is cooled to room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate (3 x 40 mL). The combined organic phases are washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 10:1 to 5:1) to obtain 9.5 g of a solid with a yield of 75.5%.

[0782] LC-MS(ESI):[M+H] + =312.0;

[0783] 1H NMR (500MHz, CDCl3) δ7.30 (s, 1H), 6.89 (s, 1H), 4.02 (s, 3H), 2.75 (t, J = 6.9Hz, 2H), 2.65-2.59 (m, 2H), 2.28 (s, 3H), 1.80-1.72 (m, 2H).

[0784] Step 4: Synthesis of 8-bromo-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one

[0785] To the reaction flask, (E)-4-bromo-5-(methoxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl acetate (9.5 g, 30.4 mmol), 1,4-dioxane (50 mL), and 6M aqueous HCl (104 mL) were added sequentially. The mixture was heated to 100°C and stirred for 1 hour. TLC confirmed the reaction was complete. Heating was discontinued, and the mixture was cooled to room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with saturated brine (3 × 40 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-3:1) to obtain 5.5 g of a yellow solid in a 75% yield.

[0786] LC-MS(ESI):[M+H] + =240.9;

[0787] 1 H NMR (500MHz, DMSO-d6) δ10.63(s,1H),6.97(d,J=2.4Hz,1H),6.70(d,J=2.4Hz,1H),2.87(t,J=6.1Hz,2H),2.55-2.50(m,2H),2.00-1.89(m,2H).

[0788] Step 5: Synthesis of 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate

[0789] To a reaction flask at 0°C, 8-bromo-6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (5.5 g, 22.81 mmol), dichloromethane (100 mL), and pyridine (2.6 mL, 31.94 mmol) were added sequentially. Trifluoromethanesulfonic anhydride (4.5 mL, 27.38 mmol) dissolved in dichloromethane (5 mL) was then slowly added dropwise. The mixture was stirred at room temperature for 1 hour. TLC confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 5:1-3:1) to afford 7.2 g of the product as a colorless oil in an 84.6% yield.

[0790] LC-MS(ESI):[M+H] + =372.9;

[0791] 1 H NMR (500MHz, CDCl3) δ7.49(d,1H),7.17(d,J=2.6Hz,1H),3.03(t,J=6.1Hz,2H),2.73(t,J=6.7Hz,2H),2.19-2.10(m,2H).

[0792] Step 6: Synthesis of methyl 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

[0793] To a reaction flask, 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (4 g, 10.72 mmol), palladium acetate (0.24 g), and Pd(dppp)Cl2 (0.44 g, 1.07 mmol) were added, along with methanol (80 mL) and triethylamine (4.5 mL, 32 mmol). The atmosphere was replaced three times with a three-way CO balloon, and the mixture was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 5:1 to 3:1) to afford 1.5 g of a light yellow solid in a 49.4% yield.

[0794] LC-MS(ESI):[M+H] + =283.0;

[0795] 1 H NMR (500MHz, CDCl3) δ8.19 (s, 1H), 7.86 (s, 1H), 3.94 (s, 3H), 3.03 (t, J = 6.2Hz, 2H), 2.73 (t, J = 6.7Hz, 2H), 2.18-2.09 (m, 2H).

[0796] Step 7: Synthesis of 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0797] To the reaction flask, methyl 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (1.5 g, 5.37 mmol), 1 M sodium hydroxide solution (15 mL), and tetrahydrofuran (30 mL) were added. The mixture was then stirred at 50°C for 30 minutes. TLC confirmed the reaction was complete. 1 M dilute hydrochloric acid was added to adjust the pH to 2-4. The mixture was extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1.42 g of a yellow solid in a 98.3% yield.

[0798] LC-MS(ESI):[M+H] + =268.9;

[0799] 1 H NMR (500MHz, DMSO-d6) δ8.00(s,1H),7.89(s,1H),3.04(t,J=6.1Hz,2H),2.68(t,J=6.6Hz,2H),2.07-1.97(m,2H).

[0800] Step 8: Synthesis of (R)-N-((1,4-dioxan-2-yl)methyl)-4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxamide

[0801] To the reaction flask were added 4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (300 mg, 1.11 mmol), [(2R)-1,4-dioxan-2-yl]methanamine (169 mg, 1.44 mmol), HATU (636 mg, 1.67 mmol), diisopropylethylamine (553 μL, 3.34 mmol), and N,N-dimethylformamide (4 mL) in sequence. The mixture was stirred at room temperature for 2 hours. TLC confirmed the reaction was complete, and the mixture was diluted with water (30 mL). The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 3:1 to 1:1) to obtain 380 mg of the product as a yellow oil in a 93.0% yield.

[0802] LC-MS(ESI):[M+H] + =368.1;

[0803] 1 H NMR (500MHz, DMSO-d6) δ8.77(t,J=5.7Hz,1H),7.99(d,J=1.8Hz,1H),7.81(d,J=1.7Hz,1H),3.77-3.71(m,2H),3.70-3.60( m,2H),3.60-3.52(m,1H),3.50-3.42(m,1H),3.30(s,3H),3.02(t,J=6.1Hz,2H),2.67(t,J=6.6Hz,2H),2.07-1.97(m,2H).

[0804] Step 9: Synthesis of (R)-N-((1,4-dioxan-2-yl)methyl)-9-bromo-4,5-dihydro-1H-benzo[g]indazole-7-carboxamide

[0805] To the reaction flask, (R)-N-((1,4-dioxan-2-yl)methyl)-4-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxamide (380 mg, 1.03 mmol) and 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (246 mg, 2.06 mmol) were added, followed by toluene (10 mL). After addition, the mixture was stirred at 110°C for 1 hour. TLC indicated that the reaction was complete. Heating was discontinued, the mixture was cooled to room temperature, and concentrated under reduced pressure to yield a yellow oil, which was used directly in the next step. Hydrazine hydrate (140 mg, 2.78 mmol) and ethanol (10 mL) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA (v / v) = 3:1 to 0:1) to yield 340 mg of a yellow solid in 84.0% yield.

[0806] LC-MS(ESI):[M+H] + =392.1;

[0807] 1 H NMR(500MHz,DMSO-d6)δ12.91(s,1H),8.60(t,J=5.7Hz,1H),8.01(s,1H),7.80(s,1H),7.64(s,1H),3.77-3.71(m,2H) ,3.70-3.61(m,2H),3.61-3.52(m,2H),3.51-3.43(m,1H),3.29-3.20(m,2H),2.92(t,J=7.2Hz,2H),2.71-2.64(m,2H).

[0808] Step 10: Synthesis of (R)-N-((1,4-dioxan-2-yl)methyl)-9-cyano-4,5-dihydro-1H-benzo[g]indazole-7-carboxamide

[0809] Under nitrogen, N-((1,4-dioxan-2-ylmethyl)-9-bromo-4,5-dihydro-1H-benzo[g]indazole-7-carboxamide (50 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (30 mg, 0.03 mmol), zinc cyanide (30 mg, 0.25 mmol), and anhydrous N,N-dimethylacetamide (3 mL) were added to the reaction flask in sequence. The mixture was heated to 120°C with stirring for 2 hours. TLC confirmed the reaction was complete, and the mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v / v) = 3:1 to 0:1) to afford 26 mg of a white solid in a 60.3% yield.

[0810] LC-MS(ESI):[M+H] + =339.0.

[0811] Step 11: Synthesis of N-(((R)-1,4-dioxan-2-yl)methyl)-2-(((S)-1,4-dioxan-2-yl)methyl)-9-cyano-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0812] To a reaction flask, (R)-N-((1,4-dioxan-2-yl)methyl)-9-cyano-4,5-dihydro-1H-benzo[g]indazole-7-carboxamide (100 mg, 0.30 mmol), (R)-(1,4-dioxan-2-yl)methyl p-toluenesulfonate (121 mg, 0.44 mmol), and cesium carbonate (193 mg, 0.59 mmol) were added, followed by N,N-dimethylformamide (3 mL). After addition, the mixture was stirred at 70°C for 2 hours. The reaction was monitored for completion by TLC, and the mixture was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Preparative HPLC yielded 17 mg of a white solid in a 12.5% ​​yield.

[0813] LC-MS(ESI):[M+H] + =439.2;

[0814] 1H NMR (500MHz, CDCl3) δ7.86-7.81(m,2H),7.25(s,1H),6.43(t,J=5.7Hz,1H),4.21-4.10(m,2H),4.02-3.94(m,1H),3.84(dd ,J=11.8,2.6Hz,1H),3.80-3.61(m,9H),3.59-3.49(m,2H),3.35-3.19(m,3H),2.93(t,J=7.3Hz,2H),2.71(t,J=7.3Hz,2H).

[0815] The compounds in Table C were prepared according to the method of Example 153.

[0816] Table C

[0817] Example 166 Synthesis of 9-cyano-N-((5-cyanopyridin-2-yl)methyl)-2-((3,3-difluorocyclobutyl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide (Compound 166)

[0818] Step 1: Synthesis of methyl 9-cyano-2-((3,3-difluorocyclobutyl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylate

[0819] To the reaction flask, methyl 9-cyano-4,5-dihydro-1H-benzo[g]indazole-7-carboxylate (100 mg, 0.39 mmol), carbonic acid (192 mg, 0.59 mmol), 3-(bromomethyl)-1,1-difluorocyclobutane (80.3 mg, 0.43 mmol), and N,N-dimethylformamide (1 mL) were added sequentially. The mixture was stirred at 100°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to afford 141 mg of the crude product as a pale yellow oil in a 99.9% yield.

[0820] LC-MS(ESI):[M+H] + =358.1.

[0821] Step 2: Synthesis of 9-cyano-2-((3,3-difluorocyclobutyl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid

[0822] To the reaction flask, methyl 9-cyano-2-((3,3-difluorocyclobutyl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylate (141 mg, 0.39 mmol) and tetrahydrofuran (1 mL) were added, followed by lithium hydroxide monohydrate (18.2 mg, 0.43 mmol). The mixture was allowed to react at 25 ° C for 3 hours, the pH was adjusted to 5, and then dichloromethane was added for extraction (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 60.0 mg of a yellow solid with a yield of 44.3%.

[0823] LC-MS(ESI):[M+H] + =344.1.

[0824] Step 3: Synthesis of 9-cyano-N-((5-cyanopyridin-2-yl)methyl)-2-((3,3-difluorocyclobutyl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxamide

[0825] To a reaction flask, add 9-cyano-2-((3,3-difluorocyclobutyl)methyl)-4,5-dihydro-2H-benzo[g]indazole-7-carboxylic acid (60.0 mg, 0.17 mmol), diisopropylethylamine (33.8 mg, 0.26 mmol), 6-(aminomethyl)nicotinonitrile (27.9 mg, 0.21 mmol), HATU (99.6 mg, 0.26 mmol), and dichloromethane (1 mL) and allow to react at room temperature for 12 hours. The product was concentrated under reduced pressure and purified by preparative HPLC. After lyophilization, 17.5 mg of the product was obtained as a colorless oil in a 21.8% yield.

[0826] LC-MS(ESI):[M+H] + =459.2;

[0827] 1 H NMR (400MHz, DMSO-d6) δ9.39(t,J=5.8Hz,1H),8.99(d,J=2.1Hz,1H),8.28(dd,J=8.3,2.2Hz,1H),8.22(d,J=1.8Hz,1H),8.11(s ,1H),7.74(s,1H),7.58(d,J=8.2Hz,1H),4.66(d,J=5.8Hz,2H),4.32(d,J=5.8Hz,2H),2.98(t,J=7.4Hz,2H),2.78–2.54(m,7H).

[0828] Experimental Example 1 GPR84 antagonist activity assay

[0829] 1. Experimental Principle

[0830] GPR84 receptor protein is a G αi Protein-coupled GPCRs, which are activated by G αi The protein inhibits the adenylate cyclase activity of the downstream signaling pathway and downregulates the cAMP level. Therefore, the cAMP level detected by the cAMP quantification kit (LANCE Ultra cAMP Detection Kit) can reflect the activity of the GPR84 antagonist.

[0831] 2. Experimental Procedure

[0832] (1) HEK293-GPR84 stably transfected cells were cultured in complete medium at 37°C and 5% CO2 until they reached 70% to 90% confluency;

[0833] (2) After trypsin digestion, cells were seeded into 384-well cell culture plates, with 2000 cells per well;

[0834] (3) Prepare a series of concentrations of the positive compound and the test compound working solution;

[0835] (4) preparing a certain concentration of forskolin plus enbelin mixed working solution;

[0836] (5) Add 2.5 μL of the antagonist prepared in step 3) to the corresponding test wells of the cell plate and incubate at 37°C for 10 minutes;

[0837] (6) Add 2.5 μL of the mixed working solution of forskolin and enbelin prepared in step 4) to the corresponding test wells of the cell plate and incubate at 37°C for 30 minutes;

[0838] (7) Freeze-thaw the Europium-labeled cAMP tracer and the Uliaght-labeled cAMP antibody, dilute the labeled cAMP tracer 50-fold and dilute the Uliaght-labeled cAMP antibody 150-fold with buffer;

[0839] (8) Add 10 μL of europium-labeled cAMP tracer to all experimental wells of the cell plate;

[0840] (9) Add 10 μL of Luliaght-labeled cAMP antibody to all experimental wells of the cell plate;

[0841] (10) The cell plate was centrifuged at 200 g for 30 seconds at room temperature and then allowed to stand for 1 hour. The data were then collected using a multi-mode microplate reader (Envision 2105) and the half-maximal inhibitory concentration (IC) of the compound was calculated using GraphPad PRISM software. 50 ).

[0842] See Table 1 for the results.

[0843] Table 1 Antagonistic effect experimental results of compounds provided in some examples of the present invention

[0844] Results and Discussion: The compounds of the present invention exhibited strong GPR84 antagonistic effects.

[0845] Experimental Example 2 Human neutrophil migration assay

[0846] Experimental procedures

[0847] (1) Neutrophils were isolated from fresh human whole blood and allowed to recover in culture medium for half an hour;

[0848] (2) Resuspend neutrophils in chemotaxis buffer (complete culture medium without fetal bovine serum);

[0849] (3) 800,000 cells per well were plated in a 96-well V-bottom plate and pre-incubated with the compound for 0.5 h;

[0850] (4) Transfer cells to a 96-well multi-well cell culture plate The lower layer of the chamber was filled with chemotactic buffer containing different concentrations of chemokines, and then placed in a cell culture incubator for 1 hour;

[0851] (5) Remove the small chamber of the transwell plate and add the luminescent living cell detection system solution to the cells in the lower layer ( Luminescent Cell Viability Assay), incubate at room temperature in the dark for 30 min;

[0852] (6) The fluorescence signal value was read using an enzyme-labeled instrument, and then the half-maximal inhibitory concentration (IC) of the compound was calculated using GraphPad PRISM software. 50 ).

[0853] See Table 2 for the results.

[0854] Table 2 Neutrophil migration test results of compounds provided in some examples of the present invention

[0855] Results and discussion: The experimental results showed that the compound of the present invention exhibited a strong ability to inhibit the migration of human neutrophils.

[0856] Experimental Example 3: Pharmacokinetic Study of the Compounds of the Invention in Mice

[0857] 1. Experimental Materials

[0858] C57BL / 6 mice: male, 6-8 weeks old, weighing 20-30 g, were purchased from Weitonglihua (Beijing) Laboratory Animal Technology Co., Ltd.

[0859] Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, ultrapure water was used in the experiment, and the remaining reagents were of commercial analytical grade.

[0860] Instrument: AB LCMS-5500 tandem mass spectrometer

[0861] 2. Experimental methods

[0862] Weigh the compound and dissolve it in 10% DMSO / 5% Kolliphor-EL / 85% HP-β-CD (20%) or other appropriate system. All formulations should be clear solutions. Mice should be administered intravenously or orally. Blood samples should be collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. For each PK sampling point, 30 μL of whole blood should be collected into an EDTA-K2 anticoagulant blood collection tube and centrifuged at 4°C within 30 minutes to obtain plasma. Whole blood samples should be placed on wet ice before centrifugation. All collected plasma samples should be stored on dry ice or frozen until analysis.

[0863] Approximately 1 mg of compound was weighed and dissolved in DMSO, vortexed, and sonicated to obtain a 1 mg / mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile in water to obtain standard working solutions at concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL. Quality control working solutions at concentrations of 10, 20, 500, and 8,000 ng / mL were prepared using the same dilution method. Three μL of the standard working solutions at concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL) were added to 30 μL of blank C57BL / 6 mouse plasma to obtain a total volume of 33 μL of standard curve samples with concentrations ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng / mL). Quality control samples with concentrations of (1 ng / ml (low-1) and 2 ng / ml (low-2), 50 ng / ml (medium), 800 ng / ml (high)) were prepared separately.

[0864] Proteins were precipitated by adding 200 μL of acetonitrile containing the internal standard (dexamethasone) to 33 μL of standard sample, 33 μL of quality control sample, or 33 μL of unknown sample (30 μL of plasma and 3 μL of blank solution). The samples were then vortexed for 30 seconds and centrifuged at 4000 g at 4°C for 15 minutes. The supernatant was diluted threefold with water, and 10 μL of the supernatant was injected into the LC-MS / MS system for quantitative analysis using the following detection conditions:

[0865] Chromatographic column: Raptor Biphenyl 2.7μm 2.1×50mm

[0866] Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), gradient elution according to the table below.

[0867] 3. Data processing

[0868] Using Phoenix™ Pharmacokinetic data were analyzed using a non-compartmental model using the software.

[0869] Results and discussion: The experimental results show that the compound of the present invention is well absorbed orally in mice and has a high exposure amount.

[0870] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in: X is N or CR 9 ; L1 is -O-, -S-, -CR 10 R 11 -, -O-CR 12 R 13 - or -S-CR 14 R 15 -; L2 is a key or -CR 16 R 17 -; R 3 is H; R 4 and R 5 Each independently is C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-10 membered heteroaryl, the C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R a Substituted, the R a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; R 1 、R 2 、R 6 and R 9 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino or C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkoxy and C 1-6 substituted by an alkylamino substituent; R 7 、R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

2. The compound according to claim 1, wherein R 4 and R 5 Each independently is C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl, wherein the C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-10 membered heteroaryl may be independently optionally substituted by 1, 2 or 3 R a Substituted, the R a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group.

3. The compound according to claim 1 or 2, wherein R 4 and R 5 Each is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Can be optionally replaced by 1, 2 or 3 R a Substituted, the R a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

4. The compound according to any one of claims 1 to 3, wherein R 4 and R 5 are each independently an oxetane group, wherein the oxetane group, Can be optionally replaced by 1, 2 or 3 R a Substituted, the R a is D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

5. The compound according to any one of claims 1 to 4, wherein R 1 、R 2 、R 6 and R 9 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino or C 3-6 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino and C 3-6 The cycloalkyl group may be independently optionally substituted by 1, 2 or 3 groups selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-3 Alkoxy and C 1-3 substituted by an alkylamino substituent; R 7 、R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-3 Alkyl, the C 1-3 The alkyl group may be independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

6. The compound according to any one of claims 1 to 5, wherein R 1 、R 2 、R 6 and R 9 Each is independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, n-propyl, isopropyl, -CHF2, -C F3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are independently optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino; R 7 、R 8 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl or isopropyl, and the methyl, ethyl, n-propyl and isopropyl may be independently and optionally substituted with 1, 2 or 3 substituents selected from D, F, Cl, Br, I, CN, hydroxy, amino and nitro.

7. The compound according to any one of claims 1 to 6, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7; the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing, treating or alleviating a GPR84 antagonist-mediated disease in a patient.

10. The use according to claim 9, wherein The diseases mediated by the GPR84 antagonist are inflammatory diseases, autoimmune diseases, lung diseases, metabolic disorders and metabolic endocrine disorders.

11. The use according to claim 10, wherein The inflammatory diseases are endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver diseases; Autoimmune diseases were inflammatory bowel disease, multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, or primary and secondary autoimmune uveitis; Lung disease is asthma, idiopathic pulmonary fibrosis, or chronic obstructive pulmonary disease; Metabolic disorders and metabolic-endocrine disorders are metabolic syndrome, insulin resistance, type I and type II diabetes, obesity or polycystic ovary syndrome.

12. The use according to claim 10, wherein The metabolic disorder and metabolic endocrine disorder is diabetic neuropathy.