Piperidinylindole derivatives, their preparation method and medicinal use

Abstract

The compounds of formula (I) are piperidinylindole derivatives, their preparation, pharmaceutical compositions containing said compounds, and their medical use for treating diseases or conditions mediated by complement activation. [Formula 1] TIFF2024541929000282.tif39160

Description

[Technical field]

[0001] The present invention belongs to the pharmaceutical field, and relates to piperidinylindole derivatives, their preparation methods, pharmaceutical compositions containing said compounds and their medical uses. [Background technology]

[0002] The complement system is a part of innate immune surveillance and plays a key role in eliminating pathogens and tissue homeostasis. The complement cascade can be activated by three different pathways, including the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP). The CP and LP are initiated on the target surface by the binding of immune complexes and mannan-binding lectins or ficolin, respectively, to specific microbial glycomoiety patterns. However, the AP does not require specific initiation. The AP cascade is initiated by the spontaneous hydrolysis (tick-over) of C3 and the subsequent deposition of C3b on the activated surface. The three complement activation pathways are centered on two main events: C3 cleavage and C5 cleavage. C3 convertase cleaves C3 into C3a and C3b. C3b forms another AP C3 convertase (amplification) and C5 convertase. C5 convertase cleaves C5 into C5a and C5b. The resulting C5b initiates the formation of the C5b-9 membrane attack complex (MAC) and C6-C9, which causes bacterial and cellular division by inserting into the membrane. The division products C3a and C5a play roles as allergenic toxins and promote pro-inflammatory responses by leukocyte activation and chemotaxis. C3b further promotes phagocytosis by opsonization and plays an important role in the removal of bacteria and cellular waste (e.g. immune complexes and apoptotic cells) (Front Immunol.2015 Jun 2;6:262.doi: 10.3389 / fimmu.2015.00262.eCollection 2015.Complement System Part I-Molecular Mechanisms of Activation and Regulation.Nicolas S Merle,Sarah Elizabeth Church,Veronique Fremeaux-Bacchi,Lubka T Roumenina). The AP maintains basal complement activity by the "tick-over process".Even if initiated via other CPs or LPs, APs contributed more than 80% of terminal cleavage pathway activation (MAC formation) through amplification loops (Harboe, M., Garred, P., Karlstrom, E., Lindstad, JK, Stahl, GL, Mollnes, TE, 2009. The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification. Mol. Immunol. 47, 373-380. https: / / doi.org / 10.1016 / j.molimm.2009.09.005). Spontaneously activated C3 forms C3 convertase by binding with factor B (FB). After factor D cleaves FB to Bb, C3b and Bb generate AP C3 convertase (C3bBb). The newly formed C3bBb splits more C3 to generate more AP C3 convertase, leading to the amplification of the complement cascade. AP can exert its full complement activity in seconds, which can cause normal tissue damage if not properly controlled (J Clin Invest. 2020 May 1; 130(5): 2152-2163. doi: 10.1172 / JCI136094. Complementopathies and precision medicine. Eleni Gavriilaki, Robert A Brodsky). Unbalanced complement activation has already been shown to be associated with diseases in various organs, including paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, rheumatoid arthritis, hemolytic uremic syndrome, myasthenia gravis and C3 glomerulonephritis (J Clin Invest.2020 May 1;130(5):2152-2163.doi:10.1172 / JCI136094). Therefore, controlling AP by FB inhibition may be a promising strategy to limit excessive activation of the complement pathway.

[0003] Currently, no small molecules have been approved for modulating the complement pathway. The following disclosures describe examples of factor B inhibitors: Advanced Vision Therapies Inc. patent publication WO2008 / 106644, entitled "Treatment of diseases characterized by inflammation," Wellstate Immunotherapeutics patent publication WO2012 / 151468, entitled "Complement Factor B analogs and their uses," William Marsh Rice University patent publication WO2014 / 035876, entitled "Heat-inactivated Complement Factor B compositions and methods," Muse.Foundation for Research Development patent publication US1999 / 023485, entitled "Blocking factor b to treat complement-mediated immune disease," and Novartis patent publications WO2013 / 192345 and US2015 / 126592, entitled "Complement pathway modulators and uses thereof." Other factor B inhibitors are described in Novartis patent publications WO2015 / 066241, US2016 / 311779, WO2015 / 009616, US2016 / 152605, WO2014 / 143638, and US2016 / 024079. Another example of a factor B inhibitor is IONIS Pharmaceuticals Inc. patent publication WO2015 / 038939, entitled "Modulators of Complement Factor B." Examples of allowed patents covering factor B inhibitors include US 9,452,990, US 9,676,728, US 9,682,968, and US 9,475,806.

[0004] Considering the large number of diseases caused by an overactive complement pathway, there is a large unmet need for patients with complement disorders. The present invention aims to provide compounds that regulate factor B and treat diseases associated with complement pathway imbalance. Summary of the Invention

[0005] In one aspect, the present invention provides a compound of formula (I) or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] Where: [ka] is a saturated or unsaturated ring, A is a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; L is a bond, (CR a R b ) p or not present, R a and R b are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, and hydroxyalkyl; R3 and R4 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, halogenated alkenyl, hydroxyalkyl, deuterated alkoxy, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy, and optionally the hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, deuterated alkoxy, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy groups are substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, deuterated alkoxy, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy groups; R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and optionally the amino, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl and hydroxyalkyl; or two of R5 together with the C atom to which they are attached form a cycloalkyl or heterocyclyl group, optionally the cycloalkyl or heterocyclyl group being substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, halogenated alkyl and hydroxyalkyl, R6 is hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, alkyl group, alkoxy group, alkylthio group, halogenated alkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) r OR8, -(CH2) r C(O)R8, -S(O)NH alkyl group, -SO2 alkyl group, -C(O)NHSO2 alkyl group and -SO2NHC(O) alkyl group; Or R6 is [ka] together with the C atom in the formula (I) form a cycloalkyl or heterocyclyl group, and optionally the cycloalkyl or heterocyclyl group is substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, halogenated alkyl and hydroxyalkyl groups, R7 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl and hydroxyalkyl; R8 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl and hydroxyalkyl; p is 1, 2 or 3; r is 0, 1, 2 or 3; t is 1, 2 or 3; m is 1, 2 or 3; n is 0, 1, 2 or 3; The conditions are as follows: When R1 and R2 are hydrogen, R3 is a cyclopropyl group or a methoxy group, R4 is a methyl group, L is a bond, R6 is -COOH or -COOCH3, R7 is hydrogen or a trifluoromethyl group, A is a phenyl group, and n is 1, 2, or 3, R5 is hydrogen or [ka] Instead, When R1 and R2 are hydrogen, R4 is a methyl group, L is a bond, R7 is hydrogen, A is a phenyl group, a pyridine group or a thiazolyl group, m is 1 and n is 2, R5 is not a hydrogen, an amino group, a hydroxy group, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a propoxy group, a hydroxymethyl group, an ethoxy group, a cyanomethyl group or a methylamino group; When R1 and R2 are hydrogen, R4 is a methyl group, L is a bond, R7 is hydrogen, A is a phenyl group, m is 2 or 3, and n is 2, then R5 is not hydrogen or a methyl group.

[0006] In one embodiment, A is C 6-10 It is an aryl group or a 5- to 10-membered heteroaryl group.

[0007] In one preferred embodiment, A is a phenyl group, a naphthyl group, or a 5-8 membered heteroaryl group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S.

[0008] In one preferred embodiment, A is a phenyl group, a benzocycloalkyl group or a 5-8 membered heteroaryl group containing 1, 2 or 3 N heteroatoms.

[0009] In one more preferred embodiment, A is [ka] It is.

[0010] In one preferred embodiment, L is a bond, CH2, or absent.

[0011] In one preferred embodiment, L is a bond.

[0012] In one preferred embodiment, R1 and R2 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups and C 1-6 The radical is selected from hydroxyalkyl radicals.

[0013] In one more preferred embodiment, R1 and R2 are hydrogen.

[0014] In one preferred embodiment, R3 and R4 are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkenyl groups, C 1-6 Hydroxyalkyl groups, deuterated C 1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, 4-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-10 membered heteroaryl groups, C 3-6 Cycloalkyloxy group, 4-10 membered heterocyclyloxy group, C 6-10 aryloxy group and 5-10 membered heteroaryloxy group, 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl groups, deuterated C1-6 Alkoxy group, C 1-6 Halogenated alkoxy groups are deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 4-10 membered heterocyclyl groups, C 6-10 It is substituted with one or more substituents selected from an aryl group and a 5- to 10-membered heteroaryl group.

[0015] In one more preferred embodiment, R3 and R4 are independently C 1-3 Alkyl group, C 1-3 Alkoxy groups, deuterium, halogens, deuterated C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl Groups and C 3-6 cycloalkyloxy group, optionally selected from the group consisting of C 1-3 Alkyl group, C 1-3 Alkoxy group, deuterated C 1-3 Alkoxy group, C 1-3 The halogenated alkoxy group is C 3-6 Cycloalkyl groups, 4-6 membered heterocyclyl groups, C 6-10 It is substituted with one or more substituents selected from an aryl group and a 5- to 10-membered heteroaryl group.

[0016] In one more preferred embodiment, R and R are independently selected from deuterium, halogen, C 1-3 Alkyl group, C 1-3 Alkoxy group, deuterated C 1-3 Alkoxy groups and C 1-3 halogenated alkoxy groups.

[0017] In one preferred embodiment, R6 is hydrogen, deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-6 Alkyl group, C 1-6Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 4-10 membered heterocyclyl groups, C 5-10 Aryl groups, 5-10 membered heteroaryl groups, -(CH2) r C 1-6 Alkoxy group, -(CH2) r C(O)OH, -S(O)NHC 1-6 Alkyl group, -SO2C 1-6 Alkyl group, -C(O)NHSO2C 1-6 Alkyl groups and -SO2NHC(O)C 1-6 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0018] In one preferred embodiment, R6 is hydrogen, deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 5-6 membered heterocyclyl groups containing 1-3 heteroatoms selected from N, O and S, C 5-10 an aryl group, and a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S; -(CH2) r C 1-6 Alkoxy group, -(CH2) r C(O)OH, -S(O)NHC 1-6 Alkyl group, -SO2C 1-6 Alkyl group, -C(O)NHSO2C 1-6 Alkyl groups and -SO2NHC(O)C 1-6 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0019] In one more preferred embodiment, R6 is -COOH, a 5- to 6-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O, and S.

[0020] In one more preferred embodiment, R6 is -F, -OMe, -CH2OH, -CH2OCH3, -CH2F, -CF2H, -CF3, -COOH, -C(O)NHSO2CH3 or -S(O)NHCH3.

[0021] In one more preferred embodiment, R6 is -COOH or -S(O)NHCH3.

[0022] In one more preferred embodiment, R6 is -COOH, [ka] It is.

[0023] In one more preferred embodiment, R6 is [ka] It is.

[0024] In one more preferred embodiment, R6 is -COOH.

[0025] In one preferred embodiment, R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups, C 1-6 Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 4-10 membered heterocyclyl groups, C 5-10 aryl group and 5-10 membered heteroaryl group, 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups, C 1-6Hydroxyalkyl group, C 3-8 Cycloalkyl groups, 4-10 membered heterocyclyl groups, C 5-10 Aryl groups and 5- to 10-membered heteroaryl groups are free of deuterium, halogens, amino groups, cyano groups, hydroxy groups, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups and C 1-6 hydroxyalkyl groups; Or, two of R5 together with the C atom to which they are attached are C 3-6 A cycloalkyl group or a 4-6 membered heterocyclyl group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S, which optionally contain deuterium, halogen, amino, cyano, hydroxyl, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy group, C 1-6 Alkyl group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups and C 1-6 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0026] In one preferred embodiment, R7 is hydrogen, deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups and C 1-6 The radical is selected from hydroxyalkyl radicals.

[0027] In one preferred embodiment, R7 is hydrogen or C 1-3 It is an alkyl group.

[0028] In one preferred embodiment, R8 is hydrogen, deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkylthio group, C 1-6 Halogenated alkyl groups and C 1-6 The radical is selected from hydroxyalkyl radicals.

[0029] In one preferred embodiment, R5 is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 3-6 a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S; 5-10 aryl groups and 5-6 membered heteroaryl groups containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S, and optionally 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclyl groups, C 5-10 Aryl groups and 5- to 6-membered heteroaryl groups can be substituted with deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; Or, two of R5 together with the C atom to which they are attached are C 3-6A cycloalkyl group or a 4-6 membered heterocyclyl group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S, which optionally contain deuterium, halogen, amino, cyano, hydroxyl, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0030] In one preferred embodiment, the compound of formula (I) may be a compound of formula (II-a)-(II-e) or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] Where: [ka] is a single bond or a double bond, R5 is independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups, C 1-3 Hydroxyalkyl group, C 3-6 a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S; 5-10 aryl groups and 5-6 membered heteroaryl groups containing 1, 2 or 3 ring heteroatoms independently selected from N, O and S, and optionally 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups, C 1-3Hydroxyalkyl group, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclyl groups, C 5-10 Aryl groups and 5- to 6-membered heteroaryl groups can be substituted with deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; B is, [ka] and optionally B is deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; C is [ka] and optionally C is deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0031] In one preferred embodiment, a compound of formula (II-a)-(II-e) or a tautomer or a pharma- ceutically acceptable salt thereof is provided, B is, [ka] and optionally B is deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; C is [ka] and optionally C is deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0032] In one preferred embodiment, C is [ka] and optionally C is deuterium, a halogen, an amino group, a cyano group, a hydroxy group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0033] In one more preferred embodiment, the compound of formula (II-a)-(II-e) may be a compound of formula (III-a)-(III-e) or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] .

[0034] In one more preferred embodiment, [ka] teeth, [ka] and optionally [ka] is a deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; [ka] teeth, [ka] and optionally [ka] is a deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0035] In one more preferred embodiment, [ka] teeth, [ka] and optionally [ka] is a deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0036] In one more preferred embodiment, [ka] teeth, [ka] and [ka] teeth, [ka] and optionally [ka] is a deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; [ka] teeth, [ka] and optionally [ka] is a deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0037] In one more preferred embodiment, [ka] teeth, [ka] and optionally [ka] is a deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; Or, [ka] teeth, [ka] and optionally [ka] is a deuterium, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 It is substituted with one or more substituents selected from hydroxyalkyl groups.

[0038] In one more preferred embodiment, the compound of formula (I) may be a compound of formula (IV) or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] R9 is hydrogen, halogen, amino group, cyano group, hydroxyl group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups, which are optionally substituted with halogens, amino groups, hydroxy groups, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkylamino group, C 3-6 Substituted by one or more substituents selected from a cycloalkyl group and a 5- to 6-membered heterocyclyl group containing 1 or 2 ring heteroatoms independently selected from N and O; Or, two of R9 together with the C atom to which they are attached are C 3-6 Forming a cycloalkyl group, which is optionally substituted with deuterium, halogen, amino group, cyano group, hydroxy group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkylamino group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 1-3 Alkylthio group, C 1-3 Halogenated alkyl groups and C 1-3 hydroxyalkyl groups; n is 1 or 2; q is 1, 2 or 3; s is 0, 1 or 2.

[0039] In one more preferred embodiment, [ka] teeth, [ka] It is.

[0040] In one more preferred embodiment, A is, [ka] and or R3 and R4 are each a methyl group or a methoxy group; Or, R5 is hydrogen, halogen, cyano group, C 1-3 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-3 Alkoxy group, C 1-3 Halogenated alkyl groups, C 1-3 Alkyl group, C1-3 Alkoxy group, C 1-3 Alkoxy group, C 1-3 Alkyl group, C 3-6 a 5-membered heteroaryl group containing 1 or 2 ring heteroatoms independently selected from cycloalkyl, N and O; Or, R6 is -COOH or -S(O)NHCH3.

[0041] In one more preferred embodiment, the compound of formula (I) is of formula (Va)-(Vc), which may be a compound or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] is a single bond or a double bond, M is O or CR c R d and R c and R d are independently hydrogen, halogen and C 1-3 alkyl groups, R3 and R4 are independently C 1-3 Alkyl group, C 1-3 Alkoxy groups and C 3-6 cycloalkyl groups, R5 is hydrogen, halogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, R6 is -COOH, -C(O)NHSO2CH3 or -S(O)NHCH3; R7 is hydrogen, C 1-3 Alkyl group or C 1-3 is a hydroxyalkyl group, R9 is hydrogen, halogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, Or, two of R9 together with the C atom to which they are attached are C 3-6 Forming a cycloalkyl group, R 10 is hydrogen, C 1-3 Alkyl group or C 1-3is a halogenated alkyl group, n is 1 or 2; q is 1, 2 or 3; s is 0, 1 or 2; t is 1 or 2.

[0042] In one more preferred embodiment, the compound of formula (I) is of formula (Va)-(Vc), which may be a compound or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] is a single bond or a double bond, M is O or CR c R d and R c and R d are independently hydrogen, halogen and C 1-3 alkyl groups, R3 and R4 are independently deuterium, halogen, or C 1-3 Alkyl group, C 1-3 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkoxy group, deuterated C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups and C 3-6 Cycloalkyl groups, C 1-3 alkoxy groups, R5 is hydrogen, halogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, R6 is -COOH, -C(O)NHSO2CH3 or -S(O)NHCH3; R7 is hydrogen, C 1-3 Alkyl group or C 1-3 is a hydroxyalkyl group, R9 is hydrogen, halogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, Or, two of R9 together with the C atom to which they are attached are C 3-6Forming a cycloalkyl group, R 10 is hydrogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, n is 1 or 2; q is 1, 2 or 3; s is 0, 1 or 2; t is 1 or 2.

[0043] In one more preferred embodiment, the compound of formula (I) is of formula (VI), which may be a compound or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] R3 and R4 are independently deuterium, halogen, or C 1-3 Alkyl group, C 1-3 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, deuterated C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups and C 3-6 Cycloalkyl groups, C 1-3 alkoxy groups, R6 is -COOH, -C(O)NHSO2CH3, -S(O)NHCH3, [ka] and R7 is hydrogen, C 1-3 Alkyl group or C 1-3 is a hydroxyalkyl group, R 10 is hydrogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, R c and R d are independently hydrogen, halogen, or C 1-3 Alkyl groups and C 1-3 The halogenated alkyl groups are selected from halogenated alkyl groups.

[0044] In one preferred embodiment, for formula (VI) or a tautomer or a pharma- ceutically acceptable salt thereof, wherein: R3 and R4 are independently deuterium, halogen, or C 1-3 Alkyl group, C 1-3 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, deuterated C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups and C 3-6 Cycloalkyl groups, C 1-3 alkoxy groups, R6 is -COOH, -C(O)NHSO2CH3, -S(O)NHCH3, [ka] and R7 is hydrogen, C 1-3 Alkyl group or C 1-3 is a hydroxyalkyl group, R 10 is hydrogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, R c and R d are F, respectively.

[0045] In one preferred embodiment, for formula (VI), R3 and R4 are independently deuterium, halogen, or C 1-3 Alkyl group, C 1-3 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 Cycloalkyloxy group, deuterated C 1-3 Alkoxy group, C 1-3 Halogenated alkoxy groups and C 3-6 Cycloalkyl groups, C 1-3 alkoxy groups, R6 is, [ka] and R7 is hydrogen, C1-3 Alkyl group or C 1-3 is a hydroxyalkyl group, R 10 is hydrogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, R c and R d are F, respectively.

[0046] In one preferred embodiment, the compound of formula (VI) may be a compound of formula (VI-a) or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] In one preferred embodiment, for formula (VI-a), R3 and R4 are independently deuterium, halogen, or C 1-3 Alkyl group, C 1-3 Alkoxy group, C 3-6 cycloalkyl groups, R6 is -COOH, -C(O)NHSO2CH3, -S(O)NHCH3; R7 is hydrogen, C 1-3 Alkyl group or C 1-3 is a hydroxyalkyl group, R 10 is hydrogen, C 1-3 Alkyl group or C 1-3 is a halogenated alkyl group, R c and R d are independently hydrogen, halogen, or C 1-3 Alkyl groups and C 1-3 The halogenated alkyl groups are selected from halogenated alkyl groups.

[0047] In one preferred embodiment, the compound of formula (VI-a) may be a compound of formula (VI-b) or a tautomer or a pharma- ceutically acceptable salt thereof: [ka] Where: R3 and R4 are independently deuterium, halogen, or C 1-3 Alkyl group, C 1-3 is selected from an alkoxy group, a cyclopropyl group, and a cyclobutyl group; R6 is -COOH, -C(O)NHSO2CH3, -S(O)NHCH3; R7 is hydrogen, C 1-3 Alkyl group or C 1-3 is a hydroxyalkyl group, R 10 is hydrogen, C 1-3 Alkyl group or C 1-3 a halogenated alkyl group, wherein said halogenated alkyl group contains at least two halogen atoms selected from F; R c and R d are independently hydrogen, halogen, or C 1-3 Alkyl groups and C 1-3 The halogenated alkyl groups are selected from halogenated alkyl groups.

[0048] The present invention further provides pharmaceutical compositions, which comprise a therapeutically effective amount of any of the compounds of Formula (I)-(VI-b) or a tautomer or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0049] In another aspect, the present invention relates to a method for modulating the alternative complement pathway activity, comprising administering to a subject in need thereof an effective amount of any of the compounds of Formulae (I)-(VI-b) or a pharmaceutical composition comprising said compound.

[0050] In one embodiment, the amount of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharma- ceutically acceptable salt thereof, is about 0.1-99%, 0.2-98.5%, 0.3-98%, 0.4-97.5%, 0.5-97%, 0.6-96.5%, 0.7-96%, 0.8-95.5%, 0.9-95%, 1-94.5%, 1.1-94%, 1.2-93.5%, 1.3-93%, 1.4-92.5%, 1.5-92%, 1.6-91.5%, 1.7-91%, or 1.8-1.9% by weight of the free base. ,1.8~90.5%,1.9~90%,2~89.5%,2.1~89%,2.2~88.5%,2.3~88%,2.4~87.5%,2.5~87%,2.6~86.5%,2.7~86%,2.8~85.5%,2.9~85%,3~84.5%,3.1~84%,3. 2~83.5%, 3.3~83%, 3.4~82.5%, 3.5~82%, 3.6~81.5%, 3.7~81%, 3.8~80.5%, 3.9~80%, 4~79.5%, 4.1~79%, 4.2~78.5%, 4.3~78%, 4.4~77.5%, 4.5~77%, 4.6 ~76.5%, 4.7~76%, 4.8~75.5%, 4.9~75%, 5~74.5%, 5.1~74%, 5.2~73.5%, 5.3~73%, 5.4~72.5%, 5.5~72%, 5.6~71.5%, 5.7~71%, 5.8~70.5%, 5.9~70%, 6~6 9.5%, 6.1-69%, 6.2-68.5%, 6.3-68%, 6.4-67.5%, 6.5-67%, 6.6-66.5%, 6.7-66%, 6.8-65.5%, 6.9-65%, 7-64.5%, 7.1-64%, 7.2-63.5%, 7.3-63%, 7.4-62% .5%, 7.5-62%, 7.6-61.5%, 7.7-61%, 7.8-60.5%, 7.9-60%, 8-59.5%, 8.1-59%, 8.2-58.5%, 8.3-58%, 8.4-57.5%, 8.5-57%, 8.6-56.5%, 8.7-56%, 8.8-55. 5%, 8.9-55%, 9-54.5%, 9.1-54%, 9.2-53.5%, 9.3-53%, 9.4-52.5%, 9.5-52%, 9.6-51.5%, 9.7-51%, 9.8-50.5%, 9.9-50%, 10-49.5%, 10.1-49%, 10.2-48.5%, 10.3-48%, 10.4-47.5%, 10.5-47%, 10.6-46.5%, 10.7-46%, 10.8-45.5%, 10.9-45%, 11-44.5%, 11.1-44%, 11.2-43.5%, 11.3-43%, 11.4-42.5%, 11.5-42%, 11.6-41.5%, 11.7-41%, 11.8-44.5%, 11.9 ... 0.5%, 11.9-40%, 12-39.5%, 12.1-39%, 12.2-38.5%, 12.3-38%, 12.4-37.5%, 12.5-37%, 12.6-36.5%, 12.7-36%, 12.8-35.5%, 12.9-35%, 13-34.5%, 13.1-34%, 13.2-33.5%, 13.3-33%, 13.4-33. 2.5%, 13.5-32%, 13.6-31.5%, 13.7-31%, 13.8-30.5%, 13.9-30%, 14-29.5%, 14.1-29%, 14.2-28.5%, 14.3-28%, 14.4-27.5%, 14.5-27%, 14.6-26.5%, 14.7-26%, 14.8-25.5%, 14.9-25%, 15-2 4.5%, 15.1-24%, 15.2-23.5%, 15.3-23%, 15.4-22.5%, 15.5-22%, 15.6-21.5%, 15.7-21%, 15.8-20.5%, 15.9-20%, 16-19.5%, 16.1-19%, 16.2-18.5%, 16.3-18%, 16.4-17.5% or 16.5-17%.

[0051] In one embodiment, the amount of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharma- ceutically acceptable salt thereof, is about 15-30%, 15.1-29.9%, 15.2-29.8%, 15.3-29.7%, 15.4-29.6%, 15.5-29.5%, 15.6-29.4%, 15.7-29.3%, 15.8-29.2%, 15.9-29.1%, 16-29%, 16.1-28.9%, 17.5-29.8%, 17.5-29 ... 16.2-28.8%, 16.3-28.7%, 16.4-28.6%, 16.5-28.5%, 16.6-28.4%, 16.7-28.3%, 16.8-28.2%, 16.9-28.1%, 17-28%, 17.1-27.9%, 17.2-27.8%, 17.3-27.7%, 17.4-27.6%, 17.5-27.5%, 17.6-27.4%, 17.7-27.3%, 17.8-27.2%, 17.9-27.1%, 18-27%, 18.1-26.9%, 18.2-26.8%, 1 8.3-26.7%, 18.4-26.6%, 18.5-26.5%, 18.6-26.4%, 18.7-26.3%, 18.8-26.2%, 18.9-26.1%, 19-26%, 19.1-25.9%, 19.2-25.8%, 19.3-25.7%, 19.4-25.6%, 19.5-25.5%, 19.6-25.4%, 19.7-25.3%, 19.8-25.2%, 19.9-25.1%, 20-25%, 20.1-24.9%, 20.2-24.8%, 20.3-24.7%, 20 .4-24.6%, 20.5-24.5%, 20.6-24.4%, 20.7-24.3%, 20.8-24.2%, 20.9-24.1%, 21-24%, 21.1-23.9%, 21.2-23.8%, 21.3-23.7%, 21.4-23.6%, 21.5-23.5%, 21.6-23.4%, 21.7-23.3%, 21.8-23.2%, 21.9-23.1%, 22-23%, 22.1-22.9%, 22.2-22.8%, 22.3-22.7% or 22.4-22.6%.

[0052] In one embodiment, the unit dose of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharma- ceutically acceptable salt thereof, is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, based on the weight of the free base. , 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg , 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg.

[0053] In one embodiment, the compound, its tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, can be administered by any suitable route of administration, such as oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal, or transdermal, and the drug composition is adjusted accordingly. In one embodiment, the compound, its tautomer, cis or trans isomer, meso form, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, is formulated in a solid or liquid form, such as a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, granule.

[0054] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The structure is selected from the following:

[0055] In another aspect, the present invention relates to a method for treating a condition or disease mediated by complement activation, in particular by complement alternative pathway activation, in a subject, comprising administering to a subject in need thereof an effective amount of any of the compounds of Formulae (I)-(VI-b) or a pharmaceutical composition comprising said compound.

[0056] In one preferred embodiment, the disease or condition is age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retinochoroiditis, retino-chorioditis), sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system diseases, multiple sclerosis, stroke, Guillain-Barre syndrome, traumatic brain injury, Parkinson's disease, diseases of inappropriate or unwanted complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, postischemic reperfusion disease, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary or renal bypass, atherosclerosis, blood The disease is selected from dialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, hepatic fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitosis, Goodpasture's syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, membranous nephropathy, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, glomerulonephritis and obesity. [Brief description of the drawings]

[0057] [Figure 1] Ex vivo assessment of plasma PD inhibition in mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] Various publications, articles, and patents have been cited or described in the specification, and each of these references is incorporated herein by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like that have been previously included in this specification is for the purpose of providing a context for the disclosure. Such discussion is not an admission that any or all of these items form part of the prior art with respect to the present disclosure.

[0059] The following provides definitions of terms used in this application. Any term not defined herein will adopt the ordinary meaning as one of ordinary skill in the art understands that term.

[0060] "Alkyl group" means C1-C 20It is a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups. Preferably, the alkyl group is an alkyl group having 1 to 12, optionally preferably 1 to 6, optionally more preferably 1 to 4 carbon atoms. Representative examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 2,3-dimethylbutyl group, an n-heptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl More preferably, the alkyl group is a lower alkyl group having from 1 to 6 carbon atoms.Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment, and preferably the substituents are one or more substituents independently selected from alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylthio groups, alkylamino groups, mercapto groups, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups.

[0061] The term "alkenyl group" refers to an alkyl group having at least two carbon atoms and at least one carbon-carbon double bond, as defined above, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-, 2- or 3-butenyl group, etc., and preferably a C 2-20 alkenyl group, more preferably C 2-12 alkenyl group, most preferably C 2-6It is an alkenyl group. The alkenyl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, optionally more preferably one to three groups, said groups being independently selected from alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylthio groups, alkylamino groups, mercapto groups, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups and oxo groups.

[0062] An "alkynyl group" is an alkyl group having at least two carbon atoms and at least one carbon-carbon triple bond as defined above, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-, 2- or 3-butynyl group, etc., and preferably a C 2-20 Alkynyl groups, more preferably C 2-12 Alkynyl groups, most preferably C 2-6 Alkynyl groups. The alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, optionally more preferably one to three groups, said groups being independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio groups.

[0063] An "alkylene group" is a saturated straight or branched chain aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. A straight or branched chain group containing 1 to 20 carbon atoms preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH-), 1,1-ethylene (-CH(CH)-), 1,2-ethylene (-CHCH-), 1,1-propylene (-CH(CHCH)-), 1,2-propylene (-CHCH(CH)-), 1,3-propylene (-CHCHCH-), 1,4-butylene (-CHCHCHCH-), and the like. An alkylene group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, and optionally more preferably one to three groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio groups.

[0064] An "alkenylene group" is an alkylene group, as defined above, having at least two carbon atoms and at least one carbon-carbon double bond, preferably C 2-20 alkenylene group, more preferably C 2-12 alkenylene group, most preferably C 2-6Alkenylene groups. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, and the like. Alkenylene groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, optionally more preferably one to three groups, said groups being independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0065] An "alkynylene group" is an alkynyl group, as defined above, having at least two carbon atoms and at least one carbon-carbon triple bond, preferably C 2-20 Alkynylene group, more preferably C 2-12 Alkynylene group, most preferably C 2-6 Alkynylene groups. Non-limiting examples of alkynylene groups include, but are not limited to, -CH≡CH-, -CH≡CHCH2-, -CH≡CHCH2CH2-, -CH2CH≡CHCH2-, and the like. Alkynylene groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, optionally more preferably one to three groups, said groups being independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0066] A "cycloalkyl group" is a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, and most preferably from 3 to 8 carbon atoms or from 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include cycloalkyl groups having spiro, fused, or bridged rings.

[0067] A "spirocycloalkyl group" is a 5- to 20-membered polycyclic group, in which the rings are linked by one common carbon atom (called a spiro atom), where one or more rings may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably, the spirocycloalkyl group has 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of common spiro atoms, the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bisspirocycloalkyl group, or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group or a bisspirocycloalkyl group, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl group. Representative examples of spirocycloalkyl groups are: [ka] The substituents include, but are not limited to,

[0068] A "fused cycloalkyl group" is a 5- to 20-membered polycyclic hydrocarbon group, in which each ring in the system shares an adjacent pair of carbon atoms with another ring, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system. Preferably, the fused cycloalkyl group has 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. Depending on the number of rings, the fused cycloalkyl group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic fused cycloalkyl group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl group. Representative examples of fused cycloalkyl groups are: [ka] The substituents include, but are not limited to,

[0069] A "bridged cycloalkyl group" is a 5- to 20-membered polycyclic hydrocarbon group in which every two rings in the system share two unlinked carbon atoms. The rings may have one or more double bonds, but do not have a completely conjugated pi-electron system. Preferably, the bridged cycloalkyl group is 6- to 14-membered, more preferably 7- to 10-membered, and most preferably 7- to 8-membered. Depending on the number of rings, the bridged cycloalkyl group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl group, more preferably a bicyclic or tricyclic bridged cycloalkyl group. Representative examples of bridged cycloalkyl groups include, but are not limited to, the following substituents: [ka]

[0070] Cycloalkyl groups may be fused to the ring of an aryl group, a heteroaryl group, or a heterocycloalkyl group, where the ring attached to the parent structure is a cycloalkyl group. Representative examples include, but are not limited to, indanylacetic acid, tetrahydronaphthalene, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, and in some cases preferably one to five, and in some cases more preferably one to three, said substituents being independently selected from alkyl groups, halogens, alkoxy groups, alkenyl groups, alkynyl groups, alkylthio groups, alkylamino groups, mercapto groups, hydroxy groups, nitro groups, cyano groups, amino groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocyclyl groups, cycloalkylthio groups, heterocycloalkylthio groups, and oxo groups. Representative examples are: [ka] The substituents include, but are not limited to,

[0071] A "heterocyclyl group" is a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group, which has one or more, optionally preferably one to five, and optionally more preferably N, O and S(O) m(where m is 0, 1 or 2), the ring atoms are one to three heteroatoms selected from, but the ring does not include -OO-, -OS- or -SS-, and the remaining ring atoms are C. Preferably, the heterocyclyl group is a 3- to 12-membered heterocyclyl group having 1 to 4 heteroatoms, more preferably a 3- to 10-membered heterocyclyl group having 1 to 3 heteroatoms, and most preferably a 5- to 6-membered heterocyclyl group having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidine, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include heterocyclyl groups having spiro rings, fused rings, or bridged rings.

[0072] A "spiroheterocyclyl group" is a 5- to 20-membered polycyclic heterocyclyl group in which the rings are joined by one common carbon atom (called a spiro atom), and in which the rings have one or more, optionally preferably one to five, and optionally more preferably N, O, and S(O). m (where m is 0, 1 or 2) and the remaining ring atoms are C, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spiroheterocyclyl group is 6 to 14 membered, more preferably 7 to 10 membered, and most preferably 7 to 8 membered. Depending on the common number of spiro atoms, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group, a bisspiroheterocyclyl group or a polyspiroheterocyclyl group, preferably a monospiroheterocyclyl group or a bisspiroheterocyclyl group, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl group. Representative examples of spiroheterocyclyl groups are: [ka] The substituents include, but are not limited to,

[0073] A "fused heterocyclyl group" is a 5- to 20-membered polycyclic heterocyclyl group, in which each ring in the system shares an adjacent pair of carbon atoms with another ring, and in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which said rings have one or more, optionally preferably one to five, and optionally more preferably N, O and S(O) p (wherein p is 0, 1 or 2), with the remaining ring atoms being C. Preferably, the fused heterocyclyl group is 6 to 14 membered, more preferably 7 to 10 membered, most preferably 7 to 8 membered. Depending on the number of rings, the fused heterocyclyl group is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic fused heterocyclyl groups, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl groups. Representative examples of fused heterocyclyl groups are: [ka] The substituents include, but are not limited to,

[0074] A "bridged heterocyclyl group" is a 5- to 14-membered polycyclic heterocycloalkyl group, where every two rings in the system share two non-linking atoms, the rings may have one or more double bonds, but do not have a completely conjugated pi-electron system, and the rings are preferably selected from the group consisting of N, O and S(O) m (where m is 0, 1 or 2) as ring atoms, the remaining ring atoms being C. Preferably, the bridged heterocyclyl group is 6 to 14 membered, more preferably 7 to 10 membered, most preferably 7 to 8 membered. Depending on the number of rings, the bridged heterocyclyl group is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl groups, more preferably bicyclic or tricyclic bridged heterocyclyl groups. Representative examples of bridged heterocyclyl groups are: [ka] The substituents include, but are not limited to,

[0075] A ring of the heterocyclyl group may be fused to a ring of an aryl group, a heteroaryl group, or a cycloalkyl group, where the ring attached to the parent structure is the heterocyclyl group. Representative examples are: [ka] The substituents include, but are not limited to, the following:

[0076] Heterocyclyl groups are optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, and optionally more preferably one to three, groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio groups.

[0077] An "aryl group" is a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group and has a completely conjugated pi-electron system. Preferably, the aryl group is 6 to 10 membered, such as phenyl and naphthyl groups, most preferably phenyl groups. An aryl group may be fused to a ring of a heteroaryl group, heterocyclyl group, or cycloalkyl group, where the ring attached to the parent structure is an aryl group. Representative examples are: [ka] The substituents include, but are not limited to,

[0078] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, optionally more preferably one to three, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio groups.

[0079] A "heteroaryl group" is an aryl system having 1 to 4 heteroatoms selected from O, S and N as ring atoms and having 5 to 14 ring atoms. Preferably, the heteroaryl group is 5 to 10 membered, more preferably 5 or 6 membered, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, isoxazolyl, etc. Heteroaryl groups may be fused to the ring of an aryl, heterocyclyl or cycloalkyl group, where the ring attached to the parent structure is the heteroaryl group. Representative examples are: [ka] The substituents include, but are not limited to,

[0080] Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, optionally preferably one to five, optionally more preferably one to three, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio groups.

[0081] "Alkoxy group" refers to -O-(alkylyl) and -O-(unsubstituted cycloalkylyl) groups, where the alkyl group is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, and in some cases preferably one to five, and in some cases more preferably one to three, and the substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0082] A "halogenated alkoxy group" is an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0083] The hydrogen atoms of the present invention may be replaced with their isotopes, deuterium. Any hydrogen atom in the compounds of the embodiments of the present invention may be replaced with a deuterium atom.

[0084] A "bond" is a covalent bond and is designated by the symbol "-".

[0085] A "hydroxyalkyl group" is an alkyl group substituted with a hydroxy group, where alkyl is as defined above.

[0086] A "hydroxyl" or "hydroxy group" is an --OH group.

[0087] "Halogen" or "halogenated" refers to a fluorine, chlorine, bromine, or iodine atom.

[0088] An "amino group" is an -NH2 group.

[0089] A "cyano group" is a -CN group.

[0090] A "nitro group" is a -NO2 group.

[0091] An "oxo group" is a =O group.

[0092] A "carboxyl group" is a -C(O)OH group.

[0093] An "alkoxycarbonyl group" is a -C(O)O(alkylyl) or -C(O)O(cycloalkylyl) group, where the alkyl and cycloalkyl groups are defined above.

[0094] When groups or substituents are stated to be "independently selected from a list of choices" (and variations thereof), this means that the selection of any one such group or substituent does not determine the selection of any other one such group or substituent. By way of illustration, but not limitation, the terms "A and B are independently selected from a and b" or "A and B are each independently selected from a and b" are intended to cover the choices where A is a and B is a, A is b and B is b, A is a and B is b, and A is b and B is a.

[0095] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but does not necessarily, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group and instances where the heterocyclyl group is not substituted with an alkyl group.

[0096] "Substituted" means that one or more hydrogens of a group are independently replaced with the corresponding number of substituents. In some embodiments, the number of such hydrogens is up to 5. In other embodiments, it is 1 to 3. Needless to say, the substituents are only present at their possible chemical positions. Those skilled in the art can determine whether substitution is possible without excessive effort by experiment or theory. For example, the combination of an amino group or a hydroxy group having free hydrogen and a carbon atom having an unsaturated bond (e.g., an olefin) may be unstable.

[0097] A "pharmaceutical composition" is a mixture of one or more compounds according to the present invention or their physiologically / pharmaceutical acceptable salts or prodrugs, together with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism and favor the absorption of the active ingredient, thereby exerting its biological activity.

[0098] A "pharmaceutically acceptable salt" is a salt of a compound of the present invention, which is safe and effective when used in mammals, and which possesses the relevant biological activity.

[0099] Working Example The following examples are provided to illustrate the present invention, but should not be construed as limiting the scope of the present invention. The examples of the present invention generally follow the usual conditions or the recommended conditions of the manufacturers of materials and products, unless otherwise specified for the specific conditions of the experimental procedures. All reagents not specified by specific origin are common reagents available commercially.

[0100] The structure of each compound is identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR chemical displacements (δ) are within 10 -6 The spectra are given in ppm. NMR was measured on a Varian Mercury 300 MHz and a Bruker Avance III 400 MHz instrument. The solvents used were deuterated dimethylsulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD).

[0101] High performance liquid chromatography (HPLC) is performed on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150x4.6mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150x4.6mm chromatographic column). Liquid chromatography mass spectrometry (LCMS) is performed on an Agilent 1200 high pressure liquid chromatograph-mass spectrometer (Sunfire C18 4.6*50mm 3.5um chromatographic column) and an Agilent 19091S-433 HP-5 high pressure liquid chromatograph-mass spectrometer (XBridge C18 4.6*50mm 3.5um chromatographic column).

[0102] Chiral high performance liquid chromatography (HPLC) was performed on a SFC Thar 80 & 150 & 200 (Waters).

[0103] Mean rate of ATPase inhibition and IC 50 Values ​​are measured with a Victor Nivo multimodal reader (PerkinElmer, USA).

[0104] The thin-layer silica gel plate used in thin-layer chromatography is Yantai Xinnuo silica gel plate. The size of the plate used in TLC is 0.15 to 0.2 mm, and the size of the plate used in thin-layer chromatography for product purification is 0.4 to 0.5 mm.

[0105] Column chromatography generally uses Qingdao Ocean 200 to 300 mesh silica gel as the carrier.

[0106] The known starting materials of the present invention can be prepared by common synthetic methods in the prior art or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.

[0107] Unless otherwise stated in the examples, all of the reactions below are carried out under an argon or nitrogen atmosphere.

[0108] The term "argon atmosphere" or "nitrogen atmosphere" means that the reaction flask is equipped with a balloon containing 1 L of argon gas or nitrogen gas.

[0109] The term "hydrogen atmosphere" means that the reaction flask is equipped with a balloon containing 1 L of hydrogen gas.

[0110] MS is mass spectrometry, where (+) is the positive pattern, usually giving M+1 (or M+H) absorbance, where M=molecular mass.

[0111] synthesis process Synthesis of intermediate A8: [ka]

[0112] Step 1: Synthesis of 4-bromo-5,7-dimethyl-1H-indole (A1) [ka]

[0113] A solution of 1-bromo-2,4-dimethyl-5-nitrobenzene (60.0 g, 0.260 mol) in THF (800 mL) was cooled to -78 °C and vinylmagnesium bromide (880 mL, 1.0 M in THF, 0.880 mol) was added dropwise. The reaction mixture was slowly warmed to -40 °C and stirred at this temperature for 4 h. Water was added and the reaction mixture was warmed to room temperature. The aqueous layer was extracted with ethyl acetate (3 x 600 mL) and the combined organic layers were washed with brine (2 x 600 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by high-performance column chromatography (SiO2, 20:1 petroleum ether / ethyl acetate) to give the title compound 4-bromo-5,7-dimethyl-1H-indole (18.0 g), a brown solid. LCMS (m / z): [M+H] + C 10 H 11 BrN calculation, 224 / 226; actual measurement, 224 / 226.

[0114] [Table 1]

[0115] Step 2: Synthesis of 4-bromo-5,7-dimethyl-1-toluenesulfonyl-1H-indole (A2) [ka]

[0116] A solution of 4-bromo-5,7-dimethyl-1H-indole (18.0 g, 80.0 mmol) in DMF (200 mL) was cooled to 0° C. and NaH (4.8 g, 0.12 mol, 60%) was added in a batch. The mixture was warmed to room temperature, stirred at this temperature for 30 min, and recooled to 0° C. TsCl (22.8 g, 0.120 mol) was added in a batch and warmed to room temperature and stirred at this temperature overnight. The reaction mixture was quenched with water (200 mL) and the aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by high performance column chromatography (SiO2, 30:1 petroleum ether / ethyl acetate) to give the title compound 4-bromo-5,7-dimethyl-1-toluenesulfonyl-1H-indole (12.4 g, 13% over two steps) as a brown solid. LCMS (m / z): [M+H] + C 17 H 17 N2OS calculation: 378 / 380, actual measurement: 378 / 380.

[0117] [Table 2]

[0118] Step 3: Synthesis of 5,7-dimethyl-1-toluenesulfonyl-4-vinyl-1H-indole (A3) [ka]

[0119] To a solution of 4-bromo-5,7-dimethyl-1-toluenesulfonyl-1H-indole (12.4 g, 32.8 mmol) in dioxane (120 mL) and H2O (30 mL) was added potassium vinyltrifluoroborate (8.8 g, 66 mmol), Et3N (20.8 g, 206 mmol) and Pd(dppf)Cl2 (1.2 g, 1.6 mmol) and the reaction mixture was stirred at 80 °C overnight. The reaction was quenched by adding H2O (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by high performance column chromatography (SiO2, 20:1 petroleum ether / ethyl acetate) to give the title compound 5,7-dimethyl-1-toluenesulfonyl-4-vinyl-1H-indole (7.0 g, 65%) as a colorless oil. LCMS (m / z): [M+H] + C 19 H 20 NO2S calculation, 326; actual measurement, 326.

[0120] [Table 3]

[0121] Step 4: Synthesis of 5,7-dimethyl-1-toluenesulfonyl-1H-indole-4-carbaldehyde (A4) [ka]

[0122] To a solution of 5,7-dimethyl-1-toluenesulfonyl-4-vinyl-1H-indole (7.0 g, 22 mmol) in acetone (150 mL) and H2O (30 mL) was added OsO4 (173 mg, 0.680 mmol) and NaIO4 (23.0 g, 108 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove volatiles and the remaining aqueous layer was extracted with CHCl2 (3 x 60 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by high performance column chromatography (SiO2, 5:1 petroleum ether / ethyl acetate) to give 5,7-dimethyl-1-toluenesulfonyl-1H-indole-4-carbaldehyde (3.8 g, 54%) as a white solid. LCMS (m / z): [M+H] + C 18 H 18 NO3S calculation: 328, actual measurement: 328.

[0123] Step 5: Synthesis of 5,7-dimethyl-1H-indole-4-carbaldehyde (A5) [ka]

[0124] To a solution of 5,7-dimethyl-1-toluenesulfonyl-1H-indole-4-carbaldehyde (2.3 g, 7.0 mmol) in THF (25 mL) was added TBAF (10.5 mL, 10.5 mmol, 1.0 M in THF) and the mixture was stirred at 65 °C for 4 h. The reaction was quenched by addition of H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude 5,7-dimethyl-1H-indole-4-carbaldehyde (1.4 g) as a brown oil. LCMS (m / z): [M+H] + C 11 H 12 NO calculation: 174, actual measurement: 174.

[0125] [Table 4]

[0126] Step 6: Synthesis of t-butyl 4-formyl-5,7-dimethyl-1H-indole-1-carboxylate (A6) [ka]

[0127] To a solution of 5,7-dimethyl-1H-indole-4-carbaldehyde (1.4 g, 8.1 mmol) and DMAP (1.1 g, 8.9 mmol) in CHCl (15 mL) was added BocO (3.8 g, 12 mmol) and the mixture was stirred at room temperature for 16 h. The reaction was quenched by adding HO (30 mL) and extracted with CHCl (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered and concentrated. The crude product was purified by high-performance column chromatography (SiO, 10:1 petroleum ether / ethyl acetate) to give tert-butyl 4-formyl-5,7-dimethyl-1H-indole-1-carboxylate (1.5 g, 68%) as a colorless oil. LCMS (m / z): [M+H] + C 16 H 20 NO3 calculated, 274, actual measurement, 274.

[0128] [Table 5]

[0129] Step 7: Synthesis of tert-butyl 4-(hydroxymethyl)-5,7-dimethyl-1H-indole-1-carboxylate (A7) [ka]

[0130] To a solution of tert-butyl 4-formyl-5,7-dimethyl-1H-indole-1-carboxylate (1.00 g, 3.66 mmol) in MeOH (10 mL) at 0° C. was added NaBH4 (318 mg, 8.41 mmol) in a batch and the mixture was stirred at room temperature for 1 h. The reaction was quenched with half-saturated aqueous KHSO4, diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give crude tert-butyl [4-(hydroxymethyl)-5,7-dimethylindol-1-yl]carboxylate (950 mg) as a yellow oil. LCMS (m / z): [M-OH] + C 16 H 20 NO2 calculation: 258, actual measurement: 258.

[0131] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 7 above.

[0132] [Table 6]

[0133] Step 8: Synthesis of tert-butyl 4-(chloromethyl)-5,7-dimethyl-1H-indole-1-carboxylate (A8) [ka]

[0134] At room temperature under nitrogen gas, a batch of (chloromethylene)dimethylammonium chloride (711 mg, 5.56 mmol) was added to a solution of tert-butyl 4-(hydroxymethyl)-5,7-dimethyl-1H-indole-1-carboxylate (950 mg, 3.45 mmol) in CHCl (10 mL), and the mixture was stirred at this temperature for 2 h. The reaction mixture was cooled to 0° C. and quenched with 5% aqueous NaHCO3. The mixture was extracted with CHCl (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO4, filtered and concentrated. The crude product tert-butyl 4-(chloromethyl)-5,7-dimethyl-1H-indole-1-carboxylate (900 mg) was obtained as a yellow oil. LCMS (m / z): [M-Cl] + C 16 H 20 NO2 calculation: 258, actual measurement: 258.

[0135] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 8 above.

[0136] [Table 7]

[0137] Synthesis of tert-butyl 4-(1-chloroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (A12) [ka]

[0138] Step 1: Synthesis of tert-butyl 4-(1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (A11) [ka]

[0139] At 0° C., CH3MgBr (240 mL, 138.4 mmol) was added to a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (20 g, 69.20 mmol) in THF (200 mL). The mixture was warmed to room temperature and stirred for 3 h at the same time. The organic layer was separated and the aqueous layer was extracted twice with CHCl2 (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The filtrate was concentrated in vacuum and the residue was purified by high-performance column chromatography (3:1 petroleum ether / ethyl acetate) to give product A11 (18 g, 59.02 mmol, 85% yield), a white solid. LCMS (m / z): [M-Boc-OH] + C 17 H 24 N2O4 calculated, 306; measured, 186.

[0140] Synthesis of 3-azabicyclo[3.1.0]hexane (B1) [ka]

[0141] A 50 mL round bottom flask was charged with diethanolamine (7.92 g, 75.3 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (3.00 g, 25.1 mmol). Small batches of CaH2 were added until no gas evolution was observed. The flask was equipped with a stir bar and a short distillation head, and a 25 mL round bottom flask was used as a receiver. The mixture was heated to 50 °C in an oil bath under reduced pressure. The receiver was cooled with a dry ice / EtOH bath. The vaporized amine was transferred to the receiver by gentle heating with a heat gun. The title product (1.0 g, 45%) was obtained as a colorless liquid. 1 H NMR (300MHz, CDCl3): δ 2.87(q,J=11.5Hz,4H),1.44-1.25(m,2H),0.44(dd,J=12.9,7.7Hz,1H),0.11(dd,J=8.7,4.2Hz,1H).

[0142] Synthesis of 1-oxa-8-azaspiro[4.5]decane (B2) [ka]

[0143] 1-Oxa-8-azaspiro[4.5]decane hydrochloride (5.00 g, 28.0 mmol) was added to a solution of NaOH (aq., 1 M). The mixture was extracted with CH2Cl2 (4 x 30 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated in vacuo to give the product (3.30 g, 83%) as a yellow oil. LCMS (m / z): [M+H] + C8H 16 Calculated NO: 142.1, actual measured: 142.1.

[0144] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0145] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0146] [Table 8]

[0147] Synthesis of (((t-butyldimethylsilyl)oxy)methyl)pyrrolidine (B4) [ka]

[0148] A 50 mL round bottom flask charged with a solution of pyrrolidin-3-ylmethanol (3 g, 30 mmol) and imidazole (6.06 g, 90 mmol) in DCM (20 mL) was stirred at 0 °C for 20 min. Then, a solution of TBSCl (6.7 g, 45 mmol) in DCM (10 mL) was added dropwise. The resulting solution was stirred at room temperature for 4 h. The mixture was concentrated, and the residue was diluted with 1N NaOH (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic extracts were washed with water (3 x 10 mL) and concentrated. The crude product was purified by high performance column chromatography (dichloromethane:methanol = 10:1) to give 3-(((t-butyldimethylsilyl)oxy)methyl)pyrrolidine (3.44 g, 51%) as a pale yellow liquid. LCMS (m / z): [M+H] + C 11 H 26 NOSi calculated: 216.1, measured: 216. 1 H NMR(400MHz,CDCl3)δ 3.50(ddd,J=16.9,9.9,6.5Hz,2H),3.04-2.87(m,2H),2.83(dt,J=10.9,7.3Hz,1H),2.68(dd,J=11.2,5.7Hz,1 H),2.41(br,1H),2.25(dt,J=14.4,7.3Hz,1H),1.91-1.71(m,1H),1.48-1.32(m,1H),0.87(s,9H),0.03(s,6H).

[0149] Synthesis of t-butyl 2-(4-cyanophenyl)-4-formylpyrrolidine-1-carboxylate (B5) [ka]

[0150] To a solution of tert-butyl 2-(4-cyanophenyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (120 mg, 0.4 mmol) in anhydrous DCM (5 mL) under N2 atmosphere was added DMP (252 mg, 0.6 mmol) and the reaction was stirred at room temperature for 2 h. The mixture was concentrated and the crude product was directly purified by silica gel column chromatography (0-60% ethyl acetate in petroleum ether) to give tert-butyl 2-(4-cyanophenyl)-4-formylpyrrolidine-1-carboxylate (68 mg, 53%). LCMS (m / z): [M-tBu] + C 13 H 13 N2O3 calculation: 245.1, actual measurement: 245.

[0151] Synthesis of t-butyl 2-(4-(methoxycarbonyl)phenyl)-3-azabicyclo[3.2.0]heptane-3-carboxylate (B6) [ka]

[0152] To a solution of t-butyl 3-azabicyclo[3.2.0]heptane-3-carboxylate (200 mg, 1 mmol) and TMEDA (603 mg, 5.20 mmol) in Et2O (5 mL) at -78 °C, sec-BuLi solution (1.3 N in hexane, 4 mL) was added dropwise at a rate that kept the temperature below -78 °C. The resulting solution was aged at -78 °C for 3 h. ZnCl2 solution (2.8 mL, 2.8 mmol, 1 M in Et2O) was added dropwise to the reaction under rapid stirring, keeping the temperature below -78 °C. The resulting light suspension was aged at -78 °C for 30 min and then warmed to 20 °C. The resulting homogeneous solution was aged at 20° C. for 30 min and then methyl 4-bromobenzoate (428 mg, 2.00 mmol) was added and Pd(OAc) 2 (135 mg, 0.6 mmol) and tBu3P-HBF4 (348 mg, 1.2 mmol) was added in one portion. The mixture of zinc salts that precipitated during the reaction was aged overnight in a 20 °C water bath. The reaction mixture was quenched with water (5 mL), concentrated, and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were concentrated, and the crude product was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give t-butyl 2-(4-(methoxycarbonyl)phenyl)-3-azabicyclo[3.2.0]heptane-3-carboxylate (28 mg, 8%). LCMS (m / z): [M-tBu] + C 15 H 18 NO4 calculation: 276.1, actual measurement: 276.

[0153] Synthesis of (3aR,6aS)-2-benzyl-5-(2,2-difluoroethyl)octahydropyrrolo[3,4-c]pyrrole (B7) [ka]

[0154] To a solution of (3aS,6aR)-2-benzyl-octahydropyrrolo[3,4-c]pyrrole (1 g, 5 mmol) in anhydrous acetonitrile (40 mL) was added K2CO3 (1 g, 10 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.3 g, 6.0 mmol). The mixture was stirred at room temperature for 4 h. The reaction was then concentrated and the residue was dissolved in ethyl acetate (50 mL), washed with water (2 x 20 mL), dried over Na2SO4, and concentrated in vacuo to give (3aR,6aS)-2-benzyl-5-(2,2-difluoroethyl)octahydropyrrolo[3,4-c]pyrrole (1.62 g, 93%) as a colorless oil. LCMS (m / z): [M+H] + C 15 H 21 F2N2 calculated: 267.2, actual measurement: 267.2.

[0155] Synthesis of (3aR,6aS)-2-(2,2-difluoroethyl)-octahydropyrrolo[3,4-c]pyrrole (B8) [ka]

[0156] To a solution of (3aR,6aS)-2-benzyl-5-(2,2-difluoroethyl)-octahydropyrrolo[3,4-c]pyrrole (1.2 g, 4.5 mmol) in MeOH (50 mL) was added Pd / C (120 mg, 1.12 mmol, 10% on carbon). The reaction mixture was stirred at room temperature under H2 atmosphere for 3 h. After filtering the solid, the filtrate was concentrated in vacuo to give (3aR,6aS)-2-(2,2-difluoroethyl)-octahydropyrrolo[3,4-c]pyrrole (660 mg, 83%) as a yellow oil. LCMS (m / z): [M+H] + C8H 15 F2N2 calculated: 177.1, actual measurement: 177.2.

[0157] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0158] [Table 9]

[0159] Synthesis of 6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (B14) [ka]

[0160] Step 1: Synthesis of 2-(4-(methoxycarbonyl)phenyl)-4-methylenepiperidine-1-carboxylic acid benzyl ester (B14-i) [ka]

[0161] LiHMDS (4.74 ml, 7.62 mol) was added to a solution of methylated Julia reagent (1.716 g, 8.16 mmol) in THF (50 mL) at -78 °C under N2 atmosphere (balloon). The mixture was stirred at -78 °C for 30 min, and then a solution of (S)-2-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (1 g, 2.72 mmol) [obtained by chiral separation of the commercially available racemate (CAS: 2238811-87-3), retention time on IG-H column (0.46 cm ID x 15 cm L) = 4.85 min, at 2.5 mL / min] in THF (10 ml) was added dropwise to the mixture. The mixture was stirred at room temperature for 16 h. The mixture was then quenched with water and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with brine (3×20 mL), dried over Na2SO4 and concentrated. The crude product was purified by silica gel high-speed column chromatography (petroleum ether / ethyl acetate=16 / 1) to give 2-(4-(methoxycarbonyl)phenyl)-4-methylenepiperidine-1-carboxylic acid benzyl ester (600 mg, 60%) as a colorless oil. LCMS (m / z): [M+H] + C 22 H 24 NO4 calculation: 366.2, actual measurement: 366.

[0162] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0163] [Table 10]

[0164] Step 2: Synthesis of 1,1-dichloro-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (B14-ii) [ka]

[0165] At room temperature under nitrogen atmosphere, a solution of trichloroacetyl chloride (1.5 g, 8.1 mmol) in Et2O (5 mL) was added dropwise to a suspension of Cu-Zn (1.08 g, 16.2 mmol) and 2-(4-(methoxycarbonyl)phenyl)-4-methylenepiperidine-1-carboxylic acid benzyl ester (300 mg, 0.81 mmol) in Et2O (35 mL). After stirring the mixture at 40 °C for 2 h, the reaction mixture was poured into aqueous NaHCO3 at 0 °C and filtered. The filtrate was extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine (3 × 10 mL) and concentrated to give crude 1,1-dichloro-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (400 mg), which was an oil and used in the next step without further purification. LCMS(m / z):[M+H] + C 24 H 24 Calculated Cl2NO5: 476.1; measured: 476.

[0166] Step 3: Synthesis of 6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (B14) [ka]

[0167] At room temperature, NH4Cl (800 mg, 16.8 mmol) and zinc (760 mg, 12 mmol) were added in batches to a solution of crude 1,1-dichloro-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (800 mg, 1.7 mmol) in MeOH (24 mL). The reaction mixture was stirred at 60° C. for 2 h and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by silica gel high-performance column chromatography (EA / PE=4 / 1) to give 6-(4-(methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (133 mg, 40% for two steps). LCMS (m / z): [M+H]+ C 24 H 26 NO5 calculation: 408.2, actual measurement: 408.

[0168] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0169] [Table 11]

[0170] Synthesis of 1-bromo-1-fluoro-5-(4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (B17) [ka]

[0171] A solution of 2-(4-(methoxycarbonyl)phenyl)-4-methylenepiperidine-1-carboxylic acid benzyl ester (600 mg, 1.64 mmol), CBr3F (1.33 g, 4.92 mmol) and NaOH (196 mg, 4.92 mmol) in a mixture of HO (3 mL) and dichloromethane (3 mL) was stirred at room temperature for 16 h. The mixture was diluted with additional HO (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were concentrated and the crude residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give 1-bromo-1-fluoro-5-(4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (545 mg, 70%). LCMS (m / z): [M+H] + C 23 H 24 BrFNO4 calculated: 476.1, measured: 476.

[0172] Synthesis of methyl 4-(2-hydroxy-7-azaspiro[3.5]nonan-6-yl)benzoate (B19) [ka]

[0173] Step 1: Synthesis of 2-hydroxy-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (B18) To a solution of B14 (300 mg, 0.74 mmol) in THF (5 mL) was added NaBH4 (56 mg) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with ice water (3 mL), extracted twice with CH2Cl2 (2 x 5 mL) and washed with brine (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the product B18 (170 mg, 0.42 mmol, 57% yield), a yellow oil. LCMS (m / z): [M+H] + C 24 H 28 NO5 calculation: 410.2, actual measurement: 410.

[0174] Synthesis of ethyl 4-(3-azabicyclo[3.1.0]hexan-2-yl)benzoate (C2) [ka]

[0175] Step 1: Synthesis of 4-(3-azabicyclo[3.1.0]hexan-2-yl)benzonitrile (C1) [ka]

[0176] Under nitrogen gas, i-PrMgCl LiCl (6.9 mL, 9.0 mmol, 1.3 M hexane solution) was cooled to 0 °C, and a solution of 4-bromobenzonitrile (2.19 g, 12.0 mmol) in THF (6.9 mL) was added dropwise. The resulting solution was stirred at 0 °C for 2 h.

[0177] A solution of 3-azabicyclo[3.1.0]hexane (500 mg, 6.02 mmol) in anhydrous ether (12 mL) was cooled to -78 °C under nitrogen atmosphere, and n-BuLi (2.5 mL, 6.0 mmol, 2.4 M in hexane) was added dropwise. The resulting solution was stirred at this temperature for 10 min, and a solution of PhCOCF3 (1.26 g, 7.22 mmol) in anhydrous ether (6 mL) was added. The resulting mixture was stirred at -78 °C for 10 min, and the previously prepared organometallic nucleophile (13.8 mL, 9.02 mmol) was added in one portion, followed immediately by boron trifluoride etherate (1.02 g, 7.22 mmol). The reaction vessel was then removed from the cold bath and stirred at room temperature for 2 h. The reaction mixture was then cooled to 0 °C and quenched by the addition of methanol (10 mL). The mixture was diluted with 2M sodium hydroxide (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude residue. The residue was purified by silica gel high performance column chromatography to give the product (180 mg, 9%) as a colorless oil.

[0178] 1 H NMR(300MHz,CDCl3):δ 7.62(d,J=8.3Hz,2H),7.46(d,J=8.4Hz,2H),4.25(br s,1H),3.07(dt,J=17.9,7.2Hz,2H),1.62-1.51(m,2H),0.71(td,J=7.9,5.6Hz,1H),0.37(dd,J=8.9,4.2Hz,1H).

[0179] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 1 above.

[0180] [Table 12-1] [Table 12-2] [Table 12-3]

[0181] Step 2: Synthesis of ethyl 4-(3-azabicyclo[3.1.0]hexan-2-yl)benzoate (C2) [ka]

[0182] To a solution of 4-(3-azabicyclo[3.1.0]hexan-2-yl)benzonitrile (160 mg, 0.870 mmol) in ethanol (5 mL) was added sulfuric acid (2 mL, 9 M), and the reaction mixture was heated to 90° C. and stirred at this temperature for 48 h. The reaction was quenched by adding saturated sodium carbonate solution (50 mL) and extracted with CHCl (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude residue. The residue was purified by high-performance column chromatography (SiO, 10:1 CHCl / MeOH) to give the product (90 mg, 40%) as a colorless oil. LCMS (m / z): [M+H] + C 14 H 18 N2O calculated: 232.1, actual measured: 232.1.

[0183] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 2 above.

[0184] [Table 13-1] [Table 13-2] [Table 13-3]

[0185] Synthesis of 4-(2-oxa-8-azaspiro[4.5]decan-7-yl)benzonitrile (C38) [ka]

[0186] Step 1: Synthesis of t-butyl 7-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (C38-i) [ka]

[0187] To a solution of NaIO4 (2.93 g, 13.7 mmol) in water (75 mL) was added RuCl3·3H2O (715 mg, 2.74 mmol). To the resulting yellow solution was added a solution of tert-butyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate (3.30 g, 13.7 mmol) in ethyl acetate (120 mL), and the mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether=1 / 1) to give tert-butyl 7-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.0 g, 29%) as a yellow oil. LCMS (m / z): [M-tBu] + C9H 14 NO4 calculation: 200.1, actual measurement: 200.

[0188] Step 2: Synthesis of t-butyl (2-(3-(2-(4-cyanophenyl)-2-oxoethyl)tetrahydrofuran-3-yl)ethyl)carbamate (C38-ii) [ka]

[0189] A solution of 4-BrPhCN (5.26 g, 28.9 mmol) in THF (25 mL) was added to the i-PrMgCl·LiCl solution (19.3 mL, 25.0 mmol, 1.3 M in THF) at 0 °C. The mixture was then stirred at 0 °C for 2 h and carefully added to a solution of tert-butyl 7-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (983 mg, 3.85 mmol) in THF (15 mL) at -78 °C (within 15 min). The resulting mixture was stirred at -78 °C for 15 min, warmed to 0 °C and stirred for 1 h. The reaction was quenched with ice water (30 mL), extracted with ethyl acetate (3 x 50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE=1 / 2) to give t-butyl (2-(3-(2-(4-cyanophenyl)-2-oxoethyl)tetrahydrofuran-3-yl)ethyl)carbamate (255 mg, 18%) as a yellow oil. LCMS (m / z): [M-Boc] + C 15 H 19 N2O2 calculated: 259.1; measured: 259.

[0190] Step 3: Synthesis of 4-(2-oxa-8-azaspiro[4.5]decan-7-yl)benzonitrile (C38) [ka]

[0191] To a solution of t-butyl (2-(3-(2-(4-cyanophenyl)-2-oxoethyl)tetrahydrofuran-3-yl)ethyl)carbamate (100 mg, 0.28 mmol) in DCM (10 mL) was added TFA (50 μL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated under N2. The residue was dissolved in MeOH (10 mL) and NaBH4 (106 mg, 2.8 mmol) was added at 0 °C. The resulting solution was stirred for 1 h, quenched with water (10 mL), extracted with DCM (3 x 15 mL), dried over Na2SO4 and concentrated to give 4-(2-oxa-8-azaspiro[4.5]decan-7-yl)benzonitrile (64 mg, crude), a yellow solid. LCMS (m / z): [M+H]+ C 15 H 19 N2O calculation, 243.1; actual measurement, 243.

[0192] Synthesis of (5S)-1,1-difluoro-5-(4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (D2) [ka]

[0193] Step 1: Synthesis of (S)-2-(4-(methoxycarbonyl)phenyl)-4-methylenepiperidine-1-carboxylic acid benzyl ester (D1) [ka]

[0194] (S)-2-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (racemic, CAS: 2238811-87-3, 200 mg, 0.550 mmol, which is separated on a chiral column (retention time = 4.855 min on an IG-H column (0.46 cm ID x 15 cm L) at 2.5 mL / min)), methyltriphenylphosphorus bromide (207 mg, 0.980 mmol) and t-BuOK (122 mg, 1.10 mol) were dissolved in DMF (10 mL) and stirred at room temperature for 1 h. The mixture was diluted with H2O and extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by high-performance column chromatography (SiO2, 5:1 petroleum ether / ethyl acetate) to give the pure desired product (90 mg, 45%), as a colorless oil. LCMS(m / z):[M+H] + C 22 H 24 NO2 calculation: 366.2, actual measurement: 366.

[0195] [Table 14]

[0196] Step 2: Synthesis of (5S)-1,1-difluoro-5-(4-(methoxycarbonyl)phenyl)-6-azaspiro[2.5]octane-6-carboxylic acid benzyl ester (D2) [ka]

[0197] In a microwave tube, (S)-2-(4-(methoxycarbonyl)phenyl)-4-methylenepiperidine-1-carboxylic acid benzyl ester (90 mg, 0.24 mmol), TMSCF3 (140 mg, 0.980 mmol) and NaI (36 mg, 0.24 mmol) were dissolved in THF (2 mL) and stirred at 110 °C for 8 h. The mixture was diluted with H2O and extracted with ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by high-performance column chromatography (SiO2, 8:1 petroleum ether / ethyl acetate) to give the desired product (80 mg, 80%) as a yellow oil. LCMS (m / z): [M+H] + C 23 H 24 F2NO4 calculation: 416.2, actual measurement: 416.

[0198] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0199] [Table 15]

[0200] Synthesis of methyl 4-(1-oxa-7-azaspiro[3.5]nonan-6-yl)benzoate (D7) [ka]

[0201] Step 1: Synthesis of 4-(7-((benzyloxy)carbonyl)-1-oxa-7-azaspiro[3.5]nonan-6-yl)benzoic acid (D5) [ka]

[0202] Trimethyl iodide sulfoxide (12 g, 54.5 mmol) and t-BuOK (6.1 g, 54.5 mmol) were dissolved in THF (50 mL) and the mixture was stirred at 50° C. for 1 h. Then, 2-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (5 g, 13.6 mmol) was added and stirred overnight. The mixture was evaporated to give the crude product D5 (7 g).

[0203] Step 2: Synthesis of 6-(4-(methoxycarbonyl)phenyl)-1-oxa-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (D6) [ka]

[0204] At 0°C, 2-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylic acid benzyl ester (7 g, 18.3 mmol) and NaH (3.67 g, 91.8 mmol) were dissolved in THF (50 mL) and the mixture was stirred for 30 min. Iodine (26 g, 1 mol) was added and the mixture was warmed to room temperature and stirred at this temperature for 8 h. The mixture was diluted with H2O and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and evaporated in vacuum, and the resulting residue was purified by high-performance column chromatography (silica gel, 8:1 petroleum ether / ethyl acetate) to give pure D6 (2 g, 37% yield for two steps).

[0205] Synthesis of methyl 4-((2R,3S)-3-hydroxyazetidin-2-yl)benzoate (E2) [ka]

[0206] Step 1: Synthesis of (2R,3S)-3-hydroxy-2-(4-(methoxycarbonyl)phenyl)azetidine-1-carboxylate t-butyl ester (E1) [ka]

[0207] To a solution of methyl 4-bromobenzoate (2.16 g, 10.0 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (2.60 g, 15.0 mmol) in DMSO (22 mL) and HO (9.03 g, 502 mmol) was added Ir[dF(CF3)ppy]2(dtbbpy)PF6 (112 mg, 0.100 mmol), 3-acetoxyquinine (1.86 g, 11.0 mmol), 4,7-dimethoxy-1,10-phenanthroline (24 mg, 0.10 mmol) and NiBr2·3HO (27 mg, 0.10 mmol). The mixture was stirred at room temperature under a 34 W blue LED for 16 h, then diluted with HO (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4 and concentrated to give the crude desired product. The crude residue was purified by preparative HPLC (MeCN / H2O+0.1% FA) to give the pure desired compound (380 mg, 12%) as a white solid. LCMS (m / z): [M+H] + C 16 H 22 N2O5 calculated: 308.1, actual measurement: 308.

[0208] Step 2: Synthesis of methyl 4-(3-hydroxyazetidin-2-yl)benzoate (E2) [ka]

[0209] At 0° C. under nitrogen gas, TFA (1 mL) was added to a solution of tert-butyl 3-hydroxy-2-(4-(methoxycarbonyl)phenyl)azetidine-1-carboxylate (300 mg, 0.240 mmol) in CHCl (5 mL). The mixture was stirred for 3 h, and the mixture was diluted with CHCl (20 mL), washed with saturated aqueous NaHCO (10 mL), and washed with brine (10 mL), dried over anhydrous NaSO, and concentrated in vacuo to give a crude residue. The crude material was purified by high-performance column chromatography (SiO, 0-10% CHCl in ethyl acetate) to give the pure desired compound (45 mg, 75%) as a yellow oil. LCMS (m / z): [M+H] + C 11 H 14 NO3 calculation: 208.1, actual measurement: 208.0.

[0210] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 2 above.

[0211] [Table 16]

[0212] Synthesis of (3aR,6aS)-Tetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,1'-cyclopropane]-2(3H)-carboxylic acid benzyl ester (E6) [ka]

[0213] Step 1: Synthesis of (3aR,6aS)-5-methylenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid benzyl ester (E6-i) [ka]

[0214] To a solution of (3aR,6aS)-5-methyleneoctahydrocyclopenta[c]pyrrole (750 mg, 6.10 mmol) and triethylamine (1.85 g, 18.3 mmol) in DCM (20 mL) was added CbzCl (1.04 g, 6.10 mmol). The resulting solution was stirred at room temperature for 3 h. The residue was then purified by column chromatography to give (3aR,6aS)-5-methylenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid benzyl ester (1.3 g, 95%) as a yellow liquid. LCMS (m / z): [M+H] + C 16 H 20 NO2 calculation: 258.1, actual measurement: 258.3.

[0215] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 1 above.

[0216] [Table 17]

[0217] Synthesis of (3aR,6aS)-Tetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,1'-cyclopropane]-2(3H)-carboxylic acid benzyl ester (E6) [ka]

[0218] Diiodomethane (10.2 g, 58.0 mmol) was slowly added to a solution of diethylzinc (3.6 g, 29 mmol) in dichloromethane (20 mL) cooled to -60 °C. The resulting solution was stirred at -60 °C for 1 h, and then a solution of (3aR,6aS)-5-methylenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid benzyl ester (1.3 g, 5.80 mmol) in dichloromethane (20 mL) was added. The resulting mixture was stirred at room temperature for 5 h. Water (50 mL) was then added, and the aqueous solution was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were evaporated and purified by column chromatography to give (3aR,6aS)-tetrahydro-1H-spiro[cyclopenta[c]pyrrole-5,1'-cyclopropane]-2(3H)-carboxylic acid benzyl ester (1.15 g, 88%) as a white solid. LCMS (m / z): [M+H] + C 17 H 22 NO2 calculation: 272.2, actual measurement: 272.1.

[0219] Synthesis of 5-(difluoromethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid benzyl ester (E10) [ka]

[0220] Step 1: Synthesis of t-butyl 5-(difluoromethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (E7) [ka]

[0221] A mixture of t-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (225 mg, 1 mmol), 2-((difluoromethyl)sulfonyl)pyridine (193 mg, 1 mmol), and KOtBu (112 mg, 1 mmol) in DMF (5 mL) was stirred at -40°C for 2 h. The reaction mixture was poured into water and the residue was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by high-performance chromatography (SiO2, 1:9 ethyl acetate / petroleum ether) to give pure E7 (130 mg, 50% yield), as a colorless oil. LCMS (m / z): [M-55] + C9H 12 F2NO2 calculation: 204.1, actual measurement: 204.0.

[0222] Step 2: Synthesis of t-butyl 5-(difluoromethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (E8) [ka]

[0223] A mixture of E7 (259 mg, 1 mmol) and Pd / C (10 mg) in ethyl acetate (5 mL) was stirred at room temperature under H2 for 2 h. The reaction mixture was filtered and concentrated to give the product E8 (248 mg, 95% yield), a yellow oil. LCMS (m / z): [M-55] + C9H 14 F2NO2 calculation: 206.1, actual measurement: 206.0.

[0224] Synthesis of 5-(difluoromethyl)octahydrocyclopenta[c]pyrrole-2-ammonium chloride (E9) [ka]

[0225] A mixture of E8 (261 mg, 1 mmol) in 4M HCl in ethyl acetate (5 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the product E9 (153 mg, 95% yield), a yellow oil. LCMS (m / z): [M+H] + C8H 14 F2N calculation: 162.1, actual measurement: 162.0.

[0226] Synthesis of 5-(difluoromethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid benzyl ester (E10) [ka]

[0227] A mixture of E9 (161 mg, 1 mmol), CbzCl (170 mg, 1 mmol) and TEA (202 mg, 2 mmol) in CH2Cl2 (5 mL) was stirred at 0 °C for 2 h at room temperature. The reaction mixture was poured into water and the residue was extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by high-performance chromatography (SiO2, 1:9 ethyl acetate / petroleum ether) to give the product mixture E10 (264 mg, 90% yield), a colorless oil. LCMS (m / z): [M+H] + C 16 H 20 F2NO2 calculation: 296.1, actual measurement: 296.0.

[0228] The purified racemic E10 (26 g, 88 mmol) was separated by SFC (instrument: SFC-150 (Waters), column: AD-H 4.6 x 100 mm, 5 μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / MeOH (0.2% ammonia), flow rate: 4 mL / min, back pressure: 120 bar, detection wavelength: 214 nm, period: 4.0 min, injection volume: 5 μl) to give E10 isomer 1 (11 g, 42% yield) at a retention time of 1.38 min, a colorless oil, and E10 isomer 2 (8 g, 31% yield) at a retention time of 1.68 min, a colorless oil. LCMS (LCMS) (m / z): [M+H] + C16 H 20 F2NO2 calculated: 296.1, measured: 296.0 (E10 isomer 1) and m / z = 296.0 (E10 isomer 2).

[0229] Synthesis of methyl 4-(4-(difluoromethyl)piperidin-2-yl)benzoate (F3) and methyl 4-(4-(fluoromethyl)piperidin-2-yl)benzoate (F4) [ka]

[0230] Step 1: Synthesis of 2-bromo-4-(difluoromethyl)pyridine (F1) [ka]

[0231] DAST (13.0 g, 80.6 mmol) was added to a solution of 2-bromopyridine-4-carbaldehyde (5.00 g, 26.9 mmol) in CH2Cl2 (50 mL) at -78 °C. The reaction mixture was warmed to room temperature, stirred at this temperature for 1 h, and quenched with saturated aqueous NH4Cl (30 mL). The mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the desired crude product. The crude product was purified by high-performance column chromatography (SiO2, 10:1 petroleum ether / ethyl acetate) to give the pure desired compound (3.8 g, 67%) as a yellow oil. LCMS (m / z): [M+H] + C6H5BrF2N calculated: 208.0, measured: 208.7.

[0232] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 1 above.

[0233] [Table 18-1] [Table 18-2]

[0234] Step 2: Synthesis of methyl 4-(4-(difluoromethyl)pyridin-2-yl)benzoate (F2) [ka]

[0235] To a solution of 2-bromo-4-(difluoromethyl)pyridine (3.80 g, 18.4 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (6.59 g, 36.7 mmol) in dioxane (40 mL) and H2O (10 mL) was added Na2CO3 (3.88 g, 36.7 mmol) and Pd(PPh3)4 (2.11 g, 1.84 mmol), and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with H2O (50 mL), and extracted with CHCl2 (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by high-performance column chromatography (SiO2, 10:1 petroleum ether / ethyl acetate) to give the pure desired compound (3.1 g, 47%) as a yellow oil. LCMS(m / z):[M+H] + C 14 H 12 F2NO2 calculation: 264.1, actual measurement: 264.0.

[0236] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 2 above.

[0237] [Table 19]

[0238] Step 3: Synthesis of methyl 4-(4-(difluoromethyl)piperidin-2-yl)benzoate (F3) and methyl 4-(4-(fluoromethyl)piperidin-2-yl)benzoate (F4) [ka]

[0239] To a solution of methyl 4-(4-(difluoromethyl)pyridin-2-yl)benzoate (1.2 g, 4.6 mmol) in MeOH (10 mL) was added HCl / MeOH solution (0.5 mL) and PtO2 (310 mg, 1.37 mmol). The reaction mixture was stirred at room temperature under hydrogen gas for 4 h. The suspension was filtered and evaporated to give the crude product, which was purified by high-performance column chromatography (SiO2, 80:1 CHCl / MeOH) to give pure methyl 4-(4-(difluoromethyl)piperidin-2-yl)benzoate (F3, 240 mg, 20%) as a yellow oil. LCMS (m / z): [M+H] + C 14 H 18 F2NO2 calcd. 270.1, found 269.9) and methyl 4-(4-(fluoromethyl)piperidin-2-yl)benzoate (F4, 30 mg, 3%), yellow oil. LCMS (m / z): [M+H] + C 14 H 19 FNO2 calculation: 252.1, actual measurement: 251.9).

[0240] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0241] [Table 20]

[0242] Synthesis of ethyl 2-(difluoromethyl)-4-(piperidin-2-yl)benzoate (F13) [ka]

[0243] To a solution of ethyl 2-(difluoromethyl)-4-(pyridin-2-yl)benzoate (139 mg, 0.50 mmol) in toluene (5 mL) was added Ph2NH (338 mg, 2.00 mmol), Ph2SiH2 (460 mg, 2.50 mmol) and TPFPB (51 mg, 0.10 mmol). The mixture was stirred at 110 °C under N2 for 0.5 h. LCMS showed that most of the product was formed and the mixture was concentrated. The residue was purified by high performance column chromatography (EA / PE=1 / 1) to give ethyl 2-(difluoromethyl)-4-(piperidin-2-yl)benzoate (81 mg, 58%) as a yellow oil. LCMS (m / z): [M+H] + C 15 H 20 F2NO2 calculation, 284.1; actual measurement, 284.

[0244] The following intermediates were synthesized using similar conditions as above and the appropriate starting materials.

[0245] [Table 21]

[0246] Synthesis of (S)-2,2-difluoro-6-(4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (F9') [ka]

[0247] Step 1: (S)-2,2-Difluoro-6-(4-(hydradibonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester To a solution of (S)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester F9 (240 mg, 0.559 mmol) in MeOH (2 mL) was added NH2NH2·H2O (4 mL) at room temperature, and the mixture was stirred at 100 °C for 1 h. LCMS of a small sample showed that the product was formed. The solution was concentrated to give the crude product (260 mg), which was used in the next step without further purification. MS: m / z = 430 (M+1, ESI+).

[0248] Step 2: (S)-2,2-Difluoro-6-(4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester Crude (S)-2,2-difluoro-6-(4-(hydrazone-3-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester (260 mg), triphosgene (309 mg, 1.05 mmol) and DIEPA (406 mg, 3.15 mmol) were dissolved in DCM (10 mL) and stirred at room temperature for 2 h. The mixture was diluted with H2O and extracted with EA (20 mL x 3). The combined organic phase was dried over Na2SO4, filtered and evaporated in vacuo, and the residue was purified by silica gel to give (S)-2,2-difluoro-6-(4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid benzyl ester F9' (240 mg). MS: m / z=456 (M+1, ESI+).

[0249] Synthesis of 4-((7-(4-cyanophenyl)-2,2-difluoro-8-azaspiro[4.5]decan-8-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate t-butyl ester (compound 41) [ka]

[0250] Step 1: Synthesis of t-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (F17) N,4-Dimethyl-N-nitrosobenzenesulfonamide (13 g, 63 mmol), F16 (10 g, 42 mmol) and t-BuOK (7 g, 126 mmol) were dissolved in a 10:1 THF / H2O solution (200 mL) and stirred at room temperature overnight. The mixture was diluted with H2O and extracted with ethyl acetate (3 x 500 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo, and the residue was purified by high-performance column chromatography (silica gel) to give the product (8 g, 74% yield). LCMS (m / z): [M+H] + C 14 H 24 F2NO3 calculation: 254, actual measurement: 254.

[0251] Synthesis of 4-(3-((5,7-dimethyl-1H-indol-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-2-yl)benzoic acid (Example 1) [ka]

[0252] Step 1: Synthesis of tert-butyl 4-((2-(4-(ethoxycarbonyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (C3) [ka]

[0253] To a solution of ethyl 4-(3-azabicyclo[3.1.0]hexan-2-yl)benzoate (70 mg, 0.30 mmol) in MeCN was added tert-butyl 4-(chloromethyl)-5,7-dimethyl-1H-indole-1-carboxylate (93 mg, 0.33 mmol) and DIPEA (296 mg, 0.910 mmol). The reaction mixture was stirred under reflux for 16 h. The reaction was concentrated and purified by high performance column chromatography (SiO2, 10:1 ethyl acetate / petroleum ether) to give the desired product (70 mg, 42%) as a white solid. LCMS (m / z): [M+H] + C 30 H 37 N2O4 calculation: 489.3, actual measurement: 489.0.

[0254] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 1 above.

[0255] [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5] [Table 22-6] [Table 22-7] [Table 22-8] [Table 22-9]

[0256] Step 2: Synthesis of 4-(3-((5,7-dimethyl-1H-indol-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-2-yl)benzoic acid (Example 1) [ka]

[0257] To a solution of tert-butyl 4-((2-(4-(ethoxycarbonyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (70 mg, 0.14 mmol) in MeOH (3 mL) was added a solution of NaOH (28 mg, 0.70 mmol) in water (0.3 mL) and the mixture was stirred at 60 °C for 4 h, then cooled to room temperature and concentrated in vacuo. A solution of citric acid (1 M in H2O) was added to adjust the pH to 6.4-6.7 and the mixture was extracted with CHCl2 (3 x 20 mL). The combined organic layers were washed with brine (10 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters (商標) Purification was performed using an XBridge 2.1 x 50mm 3.5μm column, mobile phase A [water (0.05% trifluoroacetic acid v / v)] and B [acetonitrile (0.05% trifluoroacetic acid)], gradient B: 10-100% within 7 min.

[0258] Example 1: 4-(3-((5,7-dimethyl-1H-indol-4-yl)methyl)-3-azabicyclo[3.1.0]hexan-2-yl)benzoic acid (11.9 mg, 23%) was obtained as a white solid. LCMS (LCMS) (m / z): [M+H] + C 23 H 25 N2O2 calculation: 361.2, actual measurement: 361.9. 1H NMR(400MHz,CD3OD)δ 8.29(br s,0.8H),8.09(d,J=8.1Hz,2H),7.55(d,J=7.9Hz,2H),7.19(d,J=3.0Hz,1H),6.71(s,1H),6.17(d,J=0.6Hz,1H),4.27(m,1H),4.18(d,J= 12.5Hz,1H), 3.94(d,J=13.0Hz,1H),3.48(m,1H),3.03(d,J=11.0Hz,1H),2.42(s,3H),2.05(s,3H),1.89(d,J=18.3Hz,2H),1.09(m,2H).

[0259] Using the appropriate starting materials, the following examples were synthesized using the ester hydrolysis procedure described above.

[0260] [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] [Table 23-7] [Table 23-8] [Table 23-9] [Table 23-10] [Table 23-11] [Table 23-12] [Table 23-13] [Table 23-14]

[0261] Synthesis of 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzoic acid (Example 11) and 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzamide (Example 12) [ka]

[0262] Step 1: Synthesis of tert-butyl 4-((3-(4-cyanophenyl)-2-azabicyclo[2.2.1]hept-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (G2) [ka]

[0263] To a solution of 4-(2-azabicyclo[2.2.1]hept-3-yl)benzonitrile (85 mg, 0.43 mmol) in CH3CN (1.50 mL) was added K2CO3 (178 mg, 1.29 mmol) and the resulting mixture was stirred for 10 min. 4-(chloromethyl)-5,7-dimethyl-1H-indole-1-carboxylate tert-butyl (152 mg, 0.51 mmol) was added and the reaction mixture was heated to 80 °C and kept at this temperature for 4 h. The resulting mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude residue, which was purified by high-performance column chromatography (SiO2, 10:1 petroleum ether / ethyl acetate) to give the pure desired compound (110 mg, 56%) as a colorless gel. LCMS(m / z):[M+H] + C 29 H 34 N3O2 calculation: 456.2, actual measurement: 455.8.

[0264] Step 2: Synthesis of 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzoic acid (Example 11) and 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzamide (Example 12) [ka]

[0265] To a solution of tert-butyl 4-((3-(4-cyanophenyl)-2-azabicyclo[2.2.1]hept-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (50 mg, 0.11 mmol) in water (0.5 mL) was added KOH (123 mg, 2.19 mmol). The reaction mixture was heated to 100° C. and stirred at this temperature for 36 h. After cooling to room temperature, the pH was adjusted to 6.4-6.7 with citric acid (1 M) and extracted with CHCl (3×20 mL). The combined organic layers were washed with brine (10 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters (商標) Purification was performed using an XBridge 2.1 x 50mm 3.5μm column, mobile phase A [water (0.05% trifluoroacetic acid v / v)] and B [acetonitrile (0.05% trifluoroacetic acid)], gradient B: 0-60% within 7 min.

[0266] Example 11: 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzoic acid (5 mg) was obtained as a white solid. LCMS (m / z): [M+H] + C 24 H 27 N2O2 calculation: 375.2, actual measurement: 374.9. 1 H NMR(400MHz,CD3OD):δ 8.43(br s,1H),7.92(d,J=6.0Hz,2H),7.36(d,J=7.5Hz,2H),7.26(d,J=1.9Hz,1H),6.72(s,1H),6.43(d,J=1.1Hz,1H),4.5 6(brs,2H),4.08-3.71(m,2H),2.75-2.53(m,2H),2.43(s,3H),2.36-2.33(m,1H),2.20(s,3H),2.00-1.66(m,4H).

[0267] The isomers of Example 11 were separated by SFC. Isomer 1 and Isomer 2 were purified on a CHIRALPAK OJ-H column. Mobile phase A [CO2] and B [ethanol (0.2% NH4OH)], flow rate 12.5 mL / min, column temperature 39 °C (35% B in A). Retention time of Isomer 1 is 3.64 min. Retention time of Isomer 2 is 4.51 min.

[0268] Isomer 1: 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzoic acid (14 mg). LCMS (m / z): [M+H] + C 24 H 27 N2O2 calculated: 375.2, actual measured: 375.2. 1 H NMR(400MHz,CD3OD):δ 7.77(d,J=7.3Hz,2H),7.22(d,J=8.0Hz,2H),7.12(d,J=2.5Hz,1H),6.59(s,1H),6.32(d,J=1.5Hz,1H),4.37(br s, 2H), 3.83-3.63 (m, 2H), 2.56-2.37 (m, 2H), 2.30 (s, 3H), 2.10 (s, 3H), 1.87-1.40 (m, 5H).

[0269] Isomer 2: 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzoic acid. LCMS (m / z): [M+H] + C 24 H 27 N2O2 calculated: 375.2, actual measured: 375.2. 1 H NMR(400MHz,CD3OD):δ 7.89(d,J=7.2Hz,2H),7.34(d,J=7.1Hz,2H),7.24(d,J=2.7Hz,1H),6.71(s,1H),6.44(d,J=1.8Hz,1H),4.45(br s, 2H), 3.99-3.71 (m, 2H), 2.68-2.51 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 1.94-1.59 (m, 5H).

[0270] Example 12: 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azabicyclo[2.2.1]hept-3-yl)benzamide is obtained as a white solid. LCMS (m / z): [M+H] + C 24 H 28 N3O calculated: 374.5, actual measurement: 373.8. 1 H NMR(400MHz,CD3OD):δ 8.41(s,0.47H),7.70(d,J=7.1Hz,2H),7.33(d,J=8.0Hz,2H),7.17(d,J=2.6Hz,1H),6.63(s,1H),6.45(d,J=2.8Hz,1H),4.25(br s,2H),3.75-3.45(m,2H),2.51-2.40(m,2H),2.36(s,3H),2.25(s,3H),2.10-1.98(m,1H),1.86-1.36(m,4H).

[0271] Using the appropriate starting materials, the following examples were synthesized using the ester hydrolysis procedure described above.

[0272] [Table 24-1] [Table 24-2] [Table 24-3] [Table 24-4] [Table 24-5] [Table 24-6] [Table 24-7] [Table 24-8]

[0273] Synthesis of 4-(2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (Example 13) [ka]

[0274] Step 1: Synthesis of tert-butyl 4-((1-(4-(ethoxycarbonyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (H1) [ka]

[0275] To a solution of 4-(octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (154 mg, 0.590 mmol) in THF (60 mL) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (170 mg, 0.590 mmol), the mixture was stirred at room temperature for 3 h, and NaBH(OAc)3 (382 mg, 1.80 mmol) was added. The resulting reaction mixture was stirred at room temperature for an additional 16 h. The reaction was quenched by addition of aqueous NH4Cl and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by high-performance column chromatography (SiO2, 4:1 petroleum ether / ethyl acetate) to give the pure desired product (80 mg, 25%) as a yellow solid. LCMS (m / z): [M+H] + C 32 H 41 N2O5 calculated: 533.3, actual measurement: 533.

[0276] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 1 above.

[0277] [Table 25]

[0278] Step 2: Synthesis of 4-(2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (Example 13) [ka]

[0279] To a stirred solution of tert-butyl 4-((1-(4-(ethoxycarbonyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (80 mg, 0.15 mmol) in EtOH (3 mL) was added a solution of NaOH (24 mg, 0.60 mmol) in HO (0.3 mL). The mixture was stirred at 60 °C for 16 h, then cooled to room temperature, concentrated in vacuo, and the pH was adjusted (pH ~ 6.4-6.7) with citric acid solution (1 M, aq). The mixture was then concentrated in vacuo. The crude residue was purified by SFC (column: Gemini-C18 150 x 21.2 mm 5 μm, mobile phase A [H2O (0.1% formic acid)] and B [acetonitrile (0.1% trifluoroacetic acid)], gradient B: 20-40% within 7 min).

[0280] Example 13: 4-(2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (34 mg, 65%) was obtained as a white solid. LCMS (m / z): [M+H] + C 25 H 29 N2O3 calculation: 405.2, actual measurement: 405.5. 1H NMR(400MHz,CD3OD):δ 8.11-8.09(d,J=8.0Hz,2H),7.61(d,J=8.0Hz,2H),7.27(d,J=3.2Hz,1H),6.71(s,1H),6.25(d,J=3.2Hz,1H),4.25 (m,2H),4.06(br,1H),3.73(m,3H),3.67(m,1H),2.90(m,3H),2.84(s,3H),1.91(m,1H),1.82(m,1H),1.65(m,4H).

[0281] The two isomers of Example 13 were separated by chiral SFC on a CHIRALPAK OJ-H 250 x 20 mm, 5 μm column. Mobile phase A [CO2] and 35% B [ethanol (0.2% NH4OH)], flow rate 12.5 mL / min, column temperature 39°C. Retention time of isomer 1 is 3.64 min. Retention time of isomer 2 is 4.51 min.

[0282] Isomer 1: 4-(2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (11 mg). 1 H NMR(400MHz,CD3OD):δ 8.10-8.08(d,J=8.0Hz,2H),7.57-7.55(d,J=8.0Hz,2H),7.27(d,J=2.8Hz,1H),6.72(s,1H),6.22-6.21(d,J=2.8Hz,1H) ,4.23(m,2H),3.99(br,1H),3.74(m,3H),3.64(m,1H),2.87(m,3H),2.48(s,3H),1.92(m,1H),1.82(m,1H),1.66(m,4H).

[0283] Isomer 2: 4-(2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (12 mg). 1H NMR(400MHz,CD3OD):δ 8.10-8.09(d,J=8.0Hz,2H),7.57-7.55(d,J=8.0Hz,2H),7.27(d,J=2.8Hz,1H),6.72(s,1H),6.22-6.21(d,J=2.8Hz,1H) ,4.22(m,2H),4.02(br,1H),3.74(m,3H),3.64(m,1H),2.87(m,3H),2.48(s,3H),1.91(m,1H),1.81(m,1H),1.66(m,4H).

[0284] Using the appropriate starting materials, the following examples were synthesized using the ester hydrolysis procedure described above.

[0285] [Table 26]

[0286] Synthesis of 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azaspiro[3.5]nonan-1-yl)benzoic acid (Example 16) [ka]

[0287] Step 1: Synthesis of 1-(4-bromophenyl)-N-(trimethylsilyl)azomethine (I1) [ka]

[0288] A solution of LiHMDS (1M, 89.2 mL, 89.2 mmol) in THF (50 mL) was cooled to 0° C. and a solution of 4-bromobenzaldehyde (15 g, 81 mmol) in THF (50 mL) was added. The mixture was warmed to 20° C. and stirred at this temperature for 16 h. The resulting solution was concentrated in vacuo and hexane was added. The resulting solid was filtered and the filtrate was concentrated. The process was repeated twice to give a pale yellow oil (21 g) which was used in the next step without further purification.

[0289] Step 2: Synthesis of 3-(4-bromophenyl)-2-azaspiro[3.5]nonan-1-one (I2) [ka]

[0290] A solution of LDA (46.8 mL, 2 M) in THF (50 mL) was cooled to -78 °C under N2 and a solution of methyl cyclohexanecarboxylate (13.3 g, 93.7 mmol) in THF (20 mL) was added. The mixture was continued to stir at -78 °C for 40 min and then at 20 °C for 10 min. The resulting mixture was recooled to -78 °C and a solution of 1-(4-bromophenyl)-N-(trimethylsilyl)azomethine (6.00 g, 23.4 mmol) in THF (50 mL) was added dropwise. The mixture was warmed to 20 °C and stirred at this temperature for 15 h. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by high performance column chromatography (SiO2, 4:1 petroleum ether / ethyl acetate) to give the pure desired product (3.4 g, 44%) as a yellow oil. LCMS (m / z): [M+H]+C 14 H 17 Calculated BrNO: 294.0, measured: 293.9.

[0291] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 2 above.

[0292] [Table 27]

[0293] Step 3: Synthesis of tert-butyl 4-((1-(4-bromophenyl)-3-oxo-2-azaspiro[3.5]nonan-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (I3) [ka]

[0294] A solution of 3-(4-bromophenyl)-2-azaspiro[3.5]nonan-1-one (300 mg, 1.02 mmol), tert-butyl 4-(chloromethyl)-5,7-dimethyl-1H-indole-1-carboxylate (300 mg, 1.02 mmol) and Cs2CO3 (997 mg, 3.06 mmol) in MeCN (10 mL) was heated to 80 °C and stirred at this temperature for 2 h. The resulting reaction mixture was concentrated and the residue was purified by high-performance column chromatography (SiO2, 20:1 petroleum ether / ethyl acetate) to give the pure desired product (320 mg, 53%) as a white solid. LCMS (m / z): [M-Boc] + C 25 H 27 BrN2O calculated: 450.1; measured: 450.7.

[0295] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 3 above.

[0296] [Table 28]

[0297] Step 4: Synthesis of tert-butyl 4-((1-(4-bromophenyl)-2-azaspiro[3.5]nonan-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (I4) [ka]

[0298] A solution of tert-butyl 4-((1-(4-bromophenyl)-3-oxo-2-azaspiro[3.5]nonan-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (220 mg, 0.400 mmol), phenylsilane (172 mg, 1.59 mmol), Dppp (33 mg, 0.080 mmol) and [Rh(COD)2]BF4 (16 mg, 0.040 mmol) in THF (1 mL) was stirred at 50 °C for 3 h. The reaction solution was cooled to 20 °C, and aqueous NHF (0.1 mL) was added, and the mixture was stirred at 20 °C for 20 h. The resulting mixture was concentrated and purified by high-performance column chromatography (SiO2, 12:1 petroleum ether / ethyl acetate) to give the pure desired product (140 mg, 55%) as a colorless oil. LCMS (m / z): [M+H] + C 30 H 38 BrN2O2 calculated: 537.2, measured: 537.0.

[0299] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 4 above.

[0300] [Table 29]

[0301] Step 5: Synthesis of tert-butyl 4-((1-(4-(butoxycarbonyl)phenyl)-2-azaspiro[3.5]nonan-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (I5) [ka]

[0302] A solution of tert-butyl 4-((1-(4-bromophenyl)-2-azaspiro[3.5]nonan-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (140 mg, 0.260 mmol), Et3N (1.32 g, 13.0 mmol), dppp (22 mg, 0.050 mmol) and Pd(OAc)2 (5.6 mg, 0.026 mmol) in n-BuOH (10 mL) was stirred at 100 °C for 16 h under CO atmosphere. The mixture was concentrated in vacuo and the residue was purified by high-performance column chromatography (SiO2, 15:1 petroleum ether / ethyl acetate) to give the pure desired product (100 mg, 68%) as a yellow oil. LCMS (m / z): [M+H] + C 35 H 47 N2O4 calculated: 559.4, actual measurement: 558.9.

[0303] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 5 above.

[0304] [Table 30]

[0305] Step 6: Synthesis of 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azaspiro[3.5]nonan-1-yl)benzoic acid (Example 16) [ka]

[0306] To a solution of tert-butyl 4-((1-(4-(butoxycarbonyl)phenyl)-2-azaspiro[3.5]non-2-yl)methyl)-5,7-dimethyl-1H-indole-1-carboxylate (100 mg, 0.180 mmol) in MeOH (5 mL) was added aqueous NaOH (3 M, 2 mL), the mixture was heated to 70° C. and stirred at this temperature for 6 h, then cooled to room temperature and concentrated in vacuo. The crude residue was purified by preparative HPLC (column: Waters (商標)Purification was performed using an XBridge 2.1 x 50mm 3.5μm column, mobile phase A [water (0.05% trifluoroacetic acid v / v)] and B [acetonitrile (0.05% trifluoroacetic acid)], gradient B: 0-60% within 7 min.

[0307] Example 16: 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azaspiro[3.5]nonan-1-yl)benzoic acid (50 mg, 69%) was obtained as a white solid. LCMS (m / z): [M+H] + C 26 H 31 N2O2 calculation: 403.2, actual measurement: 403.0. 1 H NMR(400MHz,CD3OD):δ 8.40(br s,0.6H),7.95(d,J=8.0Hz,2H),7.37-7.22(m,3H),6.79(s,1H),6.55( d,J=3.0Hz,1H),4.90-4.88(m,1H),4.67-4.47(m,2H),3.85-3.66(m,2H) ),2.44(s,3H),2.40(s,3H),1.85-1.70(m,2H),1.65-1.54(m,2H),1.54 -1.45(m,1H),1.38-1.20(m,3H),1.16-1.04(m,1H),1.02-0.89(m,1H).

[0308] The isomers of Example 16 were separated from 45 mg material by SFC. Isomer 1 and Isomer 2 were purified on a CHIRALPAK AD-H column. Mobile phase A [CO2] and B [i-PrOH (0.2% NH4OH)], flow rate 12.5 mL / min, column temperature 40.7 °C. Retention time of Isomer 1 is 4.03 min. Retention time of Isomer 2 is 6.22 min.

[0309] Isomer 1: 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azaspiro[3.5]nonan-1-yl)benzoic acid (15 mg, 37%) was obtained. LCMS (m / z): [M+H] + C 26 H 31 N2O2 calculation: 403.2, actual measurement: 403.1. 1H NMR(400MHz,CD3OD):δ 7.93(d,J=8.2Hz,2H),7.35-7.23(m,3H),6.78(s,1H),6.54(d,J=3.2Hz ,1H),4.73-4.61(s,1H),4.38(s,2H),3.61-3.41(m,2H),2.44(s,3H),2. 41(s,3H),1.84-1.74(m,1H),1.73-1.65(m,1H),1.64-1.54(m,2H),1.5 2-1.44(m,1H),1.32-1.20(m,3H),1.15-1.04(m,1H),0.96-0.88(m,1H).

[0310] Isomer 2: 4-(2-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-azaspiro[3.5]nonan-1-yl)benzoic acid (16 mg, 39%) was obtained. LCMS (m / z): [M+H] + C 26 H 31 N2O2 calculation: 403.2, actual measurement: 403.0. 1 H NMR(400MHz,CD3OD):δ 7.93(d,J=8.0Hz,2H),7.33-7.25(m,3H),6.78(s,1H),6.54(d,J=3.2Hz ,1H),4.79-4.65(s,1H),4.42(s,2H),3.65-3.49(m,2H),2.44(s,3H),2. 41(s,3H),1.83-1.75(m,1H),1.74-1.66(m,1H),1.64-1.54(m,2H),1.5 3-1.45(m,1H),1.31-1.18(m,3H),1.15-1.06(m,1H),0.97-0.89(m,1H).

[0311] Using the appropriate starting materials, the following examples were synthesized using the ester hydrolysis procedure described above.

[0312] [Table 31-1] [Table 31-2]

[0313] Synthesis of 4-(5-(difluoromethyl)-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (Example 39) [ka]

[0314] Step 1: Synthesis of 5-(difluoromethyl)octahydrocyclopenta[c]pyrrole (E11) [ka]

[0315] A mixture of E10 isomer 1 (11 g, 37.3 mmol) and Pd / C (1 g) in ethyl acetate (50 mL) was stirred at room temperature for 2 h under H2. The reaction mixture was filtered and concentrated to give the product E11 isomer mixture 1 (4.5 g, 75% yield), a yellow oil. LCMS (m / z): [M+H]+C8H 14 F2N calculation: 162.1, actual measurement: 162.1.

[0316] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 1 above.

[0317] [Table 32]

[0318] Step 2: Synthesis of 4-(5-(difluoromethyl)octahydrocyclopenta[c]pyrrol-1-yl)benzonitrile (E12) [ka]

[0319] Under an argon atmosphere, a solution of 4-bromoxynil (2.54 g, 14 mmol) in THF (10 mL) was slowly added to a solution of i-PrMgCl·LiCl (8.1 mL, 10.5 mmol, 1.3 M) in THF cooled to 0 °C, and the resulting solution was stirred at the same temperature for 2 h.

[0320] Under argon atmosphere, n-BuLi (3.36 mL, 8.4 mmol, 2.5 M) was slowly added to a solution of E11 isomer mixture 1 (1.12 g, 7 mmol) in anhydrous ether (20 mL) cooled to -78 °C, and the resulting solution was stirred at the same temperature for 10 min. Then, a solution of PhCOCF3 (1.46 g, 8.4 mmol) in anhydrous ether (8 mL) was added thereto. The resulting mixture was stirred at -78 °C for 60 min, and the organometallic nucleophile prepared previously was added in one portion, followed by boron trifluoride etherate (0.99 ml, 7 mmol) immediately. Then, the reaction vessel was removed from the cold bath and stirred at room temperature for 2 h. Then, the reaction mixture was cooled to 0 °C and quenched by adding methanol (2 mL). The reaction was diluted with 2 M sodium hydroxide solution (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by high-performance column chromatography (silica gel, 1-3% MeOH in CH2Cl2) to give product E12 isomeric mixture 1 (488 mg, 27% yield), as a colorless oil. LCMS (m / z): [M+H]+C 15 H 17 F2N2 calculation: 263.1, actual measurement: 263.3.

[0321] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 2 above.

[0322] [Table 33]

[0323] Step 3: Synthesis of tert-butyl 4-((1-(4-cyanophenyl)-5-(difluoromethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (E13) [ka]

[0324] At 0°C, Ti(EtO)4 (748 mg, 3.28 mmol) was added to a solution of E12 isomeric mixture 1 (430 mg, 1.64 mmol) and tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (570 mg, 1.97 mmol) in THF (10 mL), and the mixture was stirred at 50°C for 16 h. At 0°C, NaBH3CN (516 mg, 8.2 mmol) was added to the reaction solution. The mixture was allowed to warm to room temperature and was allowed to continue for 16 h. The mixture was quenched with 10 mL of H2O, diluted with EtOAc (50 mL x 3), and washed with brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by high-performance column chromatography (silica gel, 4:1 petroleum ether / ethyl acetate) to give pure E13 isomeric mixture 1 (470 mg, 53% yield), a white solid. LCMS(m / z):[M+H]+C 31 H 36 F2N3O3 calculated: 536.3, actual measurement: 536.2.

[0325] The following intermediates were synthesized using similar conditions and appropriate starting materials as described in Step 3 above.

[0326] [Table 34]

[0327] Step 4: Synthesis of 4-(5-(difluoromethyl)-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (Example 39) [ka]

[0328] To a solution of E13 (470 mg, 0.879 mmol) in EtOH (4 ml) was added a solution of KOH (984 mg, 17.58 mmol) in HO (0.8 ml). The mixture was stirred at 80° C. for 48 h under N2 atmosphere (using a balloon). The reaction mixture was adjusted to pH=6.4-6.7 with citric acid solution (1 mol / L) and concentrated in vacuum. The residue was dissolved in MeOH and water and purified by preparative HPLC (Waters SunFire 10 μm C18 column, 100 Å, 250 x 19 mm, solvent A is water / 0.01% trifluoroacetic acid, solvent B is acetonitrile, elution conditions are 5% linear gradient to 100% increase of solvent B within 20 min, flow rate is 30 mL / min) to give the racemic mixture of product Example 39 (370 mg, 93% yield), a white solid.

[0329] Example 39: 4-(5-(difluoromethyl)-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (370 mg, 93% yield) was obtained as a white solid. LCMS (m / z): [M+H]+C 26 H 29 F2N2O3 calculated: 455.2, actual measurement: 455.1.

[0330] The isomers of Example 39 were separated by SFC from a solution of 370 mg material in 50 mL MeOH. Isomer 1 and Isomer 2 were purified on an OZ 20*250 mm, 10 um (Daicel). Mobile phase CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 55 / 45, flow rate 100 g / min, back pressure 100 bar, column temperature 35 °C, period 4 min, injection volume 2 mL, detection wavelength 214 nm. Retention time of Isomer 1 is 1.69 min, retention time of Isomer 2 is 2.8 min.

[0331] Isomer 1: 4-(5-(difluoromethyl)-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (143.9 mg, 39% yield), a white solid. LCMS (m / z): [M+H]+C26H29F2N2O3 calcd, 455.2, found, 455.1. 1H NMR (400 MHz, MeOD) δ 8.10(d,J=7.9Hz,2H),7.56(d,J=7.8Hz,2H),7.29(d,J=3.0Hz,1H),6.72(s,1H),6.2 4(d,J=2.9Hz,1H),5.89(td,J=56.8,4.6Hz,1H),4.35(s,1H),4.30(s,2H),3.74(s,3 H),3.73-3.62(m,1H),3.26(d,J=10.3Hz,1H),3.00(d,J=37.8Hz,2H),2.63(s,1H),2 .48(s,3H),2.22-2.11(m,1H),2.01(d,J=7.6Hz,1H),1.62(dt,J=19.0,12.3Hz,2H).

[0332] Isomer 2: 4-(5-(difluoromethyl)-2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)octahydrocyclopenta[c]pyrrol-1-yl)benzoic acid (155.7 mg, 42% yield), a white solid. LCMS (m / z): [M+H]+C26H29F2N2O3 calcd, 455.2, found, 455.1. 1H NMR (400 MHz, MeOD) δ 8.39(s,1H),8.12(d,J=7.9Hz,2H),7.59(d,J=7.9Hz,2H),7.30(d,J=2.9Hz,1H),6.72(s,1 H),6.26(d,J=2.8Hz,1H),5.90(td,J=56.6,4.5Hz,1H),4.44(d,J=10.4Hz,1H),4.35(q,J= 12.7Hz,2H),3.74(s,3H),3.73-3.66(m,1H),3.34(d,J=4.9Hz,1H),3.02(d,J=38.8Hz,2H) ,2.64(s,1H),2.48(s,3H),2.23-2.11(m,1H),2.01(s,1H),1.64(dt,J=19.3,12.3Hz,2H).

[0333] Using the appropriate starting materials, the following examples were synthesized using the ester hydrolysis procedure described above.

[0334] [Table 35-1] [Table 35-2]

[0335] Synthesis of compound 43 [ka]

[0336] Step 1 DAST (33.99 g, 210.9 mmol) was added to a solution of methyl 4-bromo-3-formylbenzoate (10.2 g, 42.2 mmol) in dichloroethane (153 ml, 15V) at -80 °C under N2 atmosphere (using a balloon) and allowed to warm to room temperature for 4 h. The reaction mixture was quenched with NH4Cl solution and concentrated in vacuo to give product 43-1, a yellow oil (7.70 g, 69% yield). LCMS (m / z): [M+H] + Calculated for C9H8BrF2O2: 265.0; measured: 265.0.

[0337] Step 2 At room temperature, under N2 atmosphere (using a balloon), a solution of 43-1 (7.70 g, 29.1 mmol) in dioxane (116 mL, 15 V) was added with B2Pin2 (10.3 g, 40.7 mmol), Pd(dppf)Cl2·CH2Cl2 (2.38 g, 2.91 mmol) and KOAc (8.28 g, 84.4 mmol), and the mixture was heated to 90 °C for 4 h and filtered. The filtrate was concentrated in vacuum, and the residue was purified by silica gel high-performance column chromatography (ethyl acetate:petroleum ether = 10 / 1) to give product 43-2, a yellow oil (5.10 g, 56% yield). LCMS (m / z): [M+H] + C 15 H20 BF2O4 calculated: 313.1, actual measurement: 313.0.

[0338] Step 3 In a glove box at room temperature, purified water (5 mL, 2 V) was added to a solution of 43-2 (5.06 g, 16.2 mmol, 1.5 equiv) and 4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (2.50 g, 10.8 mmol, 1.0 equiv) in t-amyl alcohol (50 mL, 20 V). Rh(Acac)(C2H4)2 (84 mg, 0.32 mmol) and (R,R)-Ph-PBE (164 mg, 0.324 mmol) were added. The mixture was stirred at 50 °C for 12 h and filtered. The filtrate was concentrated in vacuum, and the residue was purified by silica gel high-performance column chromatography (ethyl acetate:petroleum ether = 4 / 1) to give product 43-3, a yellow oil (2.08 g, 46% yield, 100% ee). LCMS (m / z): [M+H] + C 22 H 22 F2NO5 calculation: 418.15, actual measurement: 418.19.

[0339] Test method: Column: CHIRALPAK IA 4.6*250mm, 5μm Mobile phase: 60% hexane, 40% EtOH, 0.1% methanesulfonic acid Flow rate: 1.0mL / min Column temperature: 30℃ Retention time = 7.9 minutes The following intermediates were synthesized using similar conditions and appropriate starting materials as described in the steps above.

[0340] [Table 36]

[0341] Step 4 A solution of PPh3CH3Br (2.668 g, 7.47 mmol, 1.5 equiv.) in toluene (21.6 mL, 20 V) was dissolved in NaO tBu (684 mg, 7.12 mmol, 1.43 equiv) was added. The mixture was stirred at room temperature for 2 h. At room temperature, a solution of 43-3 (2.080 g, 4.94 mmol, 1.0 equiv) in toluene (10.8 mL, 10V) was added to the mixture and stirred for 1 h. The reaction mixture was quenched with 108 mL (50V) saturated NH4Cl solution, extracted with ethyl acetate (156 mL X 2,75V), washed with brine (52 mL, 25V), dried over Na2SO4, concentrated in vacuum, and purified by silica gel high-performance column chromatography (ethyl acetate:petroleum ether = 1 / 16 to 1 / 8) to give colorless oil 43-4 (1.16 g, 56% yield). LCMS (m / z): [M+H] + C 23 H 24 F2NO4 calculation: 416.2, actual measurement: 416.3.

[0342] Step 5 Trichloroacetyl chloride (4.4 g, 24 mmol, 10 equiv) was added to a suspension of Cu-Zn (3.5 g, 3% Cu) and 43-4 (1.0 g, 2.4 mmol, 1.0 equiv) in dioxane (70 mL, 70 V) at 20 °C under nitrogen atmosphere within 30 min. The mixture was heated to 35 °C and maintained for 3 h. The reaction mixture was quenched with NH4Cl solution. The solid was filtered and the filtrate was extracted with ethyl acetate (30 mL x 3, 30 V) and washed with brine (40 mL, 40 V). The combined filtrate was dried over Na2SO4 and concentrated in vacuum to give oily crude product 43-5 (1.17 g), which was used in the next step without further purification. LCMS (m / z): [M+H] + C 25 H 23 Calculated for Cl2F2NO5: 526.1; measured: 526.3.

[0343] Step 6 To a solution of 43-5 (1.17 g, crude) in MeOH (50 mL) was added NH4Cl (2.6 g, 48 mmol) and zinc (1.6 g, 24 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 2 h and filtered. The filtrate was concentrated in vacuum, and the residue was purified by silica gel high-performance column chromatography (ethyl acetate:petroleum ether = 4 / 1) to give product 43-6 as an oil (830 mg, 2-step yield 75%). LCMS (m / z): [M+H] + C 25 H 26 F2NO5 calculation: 458.2, actual measurement: 458.3.

[0344] Step 7 At 0°C, 43-6 (830 mg, 1.82 mmol) was dissolved in BAST (1.5 mL). The reaction mixture was stirred at 60°C for 12 h. The reaction was cooled to room temperature and 15 mL of ethyl acetate was added. Carefully, the reaction mixture was poured into ice (10 g). The residue was extracted with ethyl acetate (30 mL X 3), washed with brine (30 mL), and dried over Na2SO4. The filtrate was concentrated in vacuum and purified by silica gel high performance column chromatography (ethyl acetate:petroleum ether = 4 / 1) to give the product 43-7 as an oil (569 mg, 65% yield). LCMS (m / z): [M+H] + C 25 H 26 F4NO4 calculation: 480.2, actual measurement: 480.1.

[0345] Step 8 To a solution of 43-7 (569 mg, 1.19 mmol) in MeOH (17 mL) was added activated charcoal (569 mg). The reaction was heated to reflux for 0.5 h. The activated charcoal was filtered and to the filtrate was added Pd / C (57 mg, Pd 10%). The reaction mixture was stirred at room temperature for 2 h with a H2 balloon. The Pd / C was removed and the filtrate was concentrated under reduced pressure to give the product 43-8 as an oil (328 mg, 80% yield). LCMS (m / z): [M+H] + C 17 H 20 F4NO2 calculation: 346.1, actual measurement: 346.2.

[0346] Step 9 To a solution of 43-8 (330 mg, 0.95 mmol) in DCE (1.5 mL) was added aldehyde (316 mg, 1.09 mmol) and NaBH(OAc)3 (632 mg, 2.98 mmol). The mixture was stirred at room temperature for 15 h. The reaction mixture was quenched with 1.0 mL of water, and the solvent was evaporated and concentrated to give the crude product. The crude product was purified by silica gel high-performance column chromatography (ethyl acetate:petroleum ether=10 / 1) to give product 43-9, a white solid (270 mg, 46% yield). LCMS (m / z): [M+H] + C 33 H 39 F4N2O5 calculated: 619.3, actual measurement: 619.2.

[0347] Step 10 To a solution of 43-9 (270 mg, 0.44 mmol) in EtOH (8 mL) was added 30% KOH solution (0.8 mL) and the mixture was stirred at 80° C. for 4 h. The reaction mixture was adjusted to pH=6 and concentrated in vacuo to give 120 mL of solution. The solution was purified by preparative HPLC. The preparative solution was concentrated to remove CH3CN, extracted with ethyl acetate (20 mL X 5), dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to give Example 43 (32 mg, 15% yield) as a white solid. LCMS (m / z): [M+H] + C 27 H 29 F4N2O3 calculated, 505.21, measured, 505.29; 1 H NMR(400MHz,CD3OD):δ 8.34(d,J=7.8Hz,1H),8.26(s,1H),7.95(d,J=7.6Hz,1H),7.33(d,J=3.0 Hz,1H),7.17(br,1H),7.04(br,1H),6.77(s,1H),6.46(d,J=3.2Hz,1H),4 .56(s,1H),4.19(d,J=12.0Hz,1H),4.05-3.87(m,1H),3.79(s,3H),3.50- 3.39(m,1H),3.27-3.05(m,1H),2.80-2.55(m,2H),2.52(s,3H),2.42(t,J =12.4Hz,2H),2.25-1.95(m,3H),1.92-1.80(m,1H).

[0348] The preparation of Examples 43-77 is as follows:

[0349] [Table 37-1] [Table 37-2] [Table 37-3] [Table 37-4] [Table 37-5] [Table 37-6] [Table 37-7] [Table 37-8] [Table 37-9] [Table 37-10] [Table 37-11] [Table 37-12]

[0350] Biological Testing Biological Example 1. Factor B Binding Measurements by TR-FRET Materials and Reagents 1. Recombinant human factor B catalytic domain (aa470-764, C-terminal histidine tagged, produced in-house) 2. 5X Kinase Buffer A (Thermo Fisher, CAT# PV3189) 3. LANCE Eu-W1024 anti-6xHis antibody (PerkinElmer, CAT#AD0401) 4. Probes (TRFRET_tool 2, reported in WO 2015 / 009616) [ka] 5. DMSO (Thermo Fisher Scientific) 6. Compound - 10 mM stock solution in DMSO 7. Victor Nivo Multimode Enzyme Marker (PerkinElmer) 8. OptiPlate-384, white opaque 384-well microplate (PerkinElmer, CAT#6007290)

[0351] Experimental process The factor B binding affinity of each test compound was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) technology. 10 nM recombinant histidine-tagged factor B catalytic domain, different concentrations of inhibitor, 4 nM LANCE Eu-W1024 anti-6xHis antibody and 100 nM TR-FRET_tool2 tracer were incubated for 1 h in 1X kinase buffer A. Measurements were performed in a reaction volume of 15 μL by adding 5 μL test compound, 5 μL factor B / antibody mixture and 5 μL tracer to a white opaque 384-well measurement plate. The TR-FRET signal was read on a plate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 nm and 665 nm. The TR-FRET signal was measured at different concentrations of compound and the relative fluorescence emission ratio (665 nm / 615 nm) versus inhibitor concentration was plotted using a four-parameter dose-response inhibition curve with variable slope model in GraphPad Prism to obtain the IC for the emission ratio from [compound]. 50 The binding affinity of each compound was determined by estimating

[0352] The binding affinity of the compound of the present invention to the recombinant factor B catalytic domain was measured by the above-mentioned measurement method, and IC 50 The values ​​(nM) are as shown in Table 1 below.

[0353] [Table 38-1] [Table 38-2] [Table 38-3]

[0354] Biological Example 2. Target Retention Times of Factor B Inhibitors Measured by Surface Plasmon Resonance (SPR) Materials and Reagents 1. Recombinant human factor B catalytic domain (aa470-764, C-terminal histidine tagged, produced in-house) 2. PBS-P+Buffer 10X (Cytiva, CAT#28995084) 3. Series S Sensor Chip NTA(Cytiva, CAT#BR100532) 4. Amine Coupling Kit (Cytiva, CAT#BR100050) 5. DMSO (Millipore Sigma, CAT#34869-1L) 6. Greiner 96 orifice plate, polypropylene (Sigma-Aldrich, CAT#M7310-100EA) 7. Microplate foil, 96 orifice (Cytiva, CAT# 28975816) 8. Biacore 8k (Cytiva)

[0355] Experimental process The Biacore 8k instrument was started with 1X PBS-P+ buffer and docked to the Cytiva NTA chip. Recombinant human factor B catalytic domain was immobilized to the NTA chip using 1X PBS-P+ buffer [containing 20 mM phosphate buffer, 2.7 mM KCl, 137 mM NaCl and 0.05% (v / v) Tween-20], reaching a level of approximately 5000 resonance units (RU). The protein ligand was further crosslinked to the sensor chip surface by an amine coupling kit. Immobilization and binding experiments were performed at room temperature.

[0356] After buffer exchange with 1X PBS-P+ buffer containing 2% (v / v) DMSO, a pre-run was performed for at least 30 min at a flow rate of 30 μl / min to obtain a stable surface. Kinetic constants of compounds were measured by single cycle kinetics of six consecutive injections (or multi-cycle kinetics of eight consecutive injections) of increasing concentrations of compounds at 0.8-200 nM, 12.5-400 nM, 4.1-1,000 nM or 41-10,000 nM (depending on potency). Single cycle kinetic experiments were performed with an association time of 60 s for each concentration and a dissociation time of 300 s (or a dissociation time of 120 s for multi-cycle kinetic experiments). A flow rate of 30 μl / min was used. A blank run was performed under the same conditions before compound injection.

[0357] The SPR sensorgrams were analyzed using the Biacore Insight Evaluation Software using the double referencing method. The resulting curves were fitted using a 1:1 binding model. The bound compounds were fitted with a two-state reaction model based on the induced fitting model. The kinetic constants of the repeats (k on , k off , K D ) was averaged. The dissociation constant k off Based on the formula t 1 / 2 =ln2 / k off The binding half-life (t 1 / 2 ) was calculated. 1 / 2 ) and retention time (1 / k off ) are as shown in Table 2 below.

[0358] [Table 39]

[0359] Conclusion: Examples of the present invention had significant binding affinity.

[0360] Biological Example 3. Rat Ocular Pharmacokinetic Studies Three-month-old brown Norway rats were administered the example compounds in the form of a suspension in 2 volumes of 1N HCl+30% PEG300+50% (20% Cremophor EL aqueous solution) by oral gavage. Ocular tissues and plasma from both eyes were collected from the rats at 0.25, 0.5, 1, 6 and 24 hours after administration. The collected ocular tissues were the retina and posterior eyecup (RPE / choroid and posterior sclera). Before analysis, the tissues were diluted in phosphate buffered saline containing 10% acetonitrile, homogenized and centrifuged. At each time point, the concentrations of the test articles in the plasma and ocular homogenate supernatants were measured in four separate retina, four separate posterior eyecup and two separate plasma specimens by HPLC-MS / MS. Chromatography was performed on a Waters BEH C18 Column (2.1 × 50 mm, 1.7 μm) (MAC-MOD Analytical, Chadds Ford, PA) using a gradient elution method of water and acetonitrile, both of which contained 0.025% formic acid-1 mM NH4OAc. Mass spectrometry measurements under positive electrospray ionization were performed on an API6500 triple quadrupole mass spectrometer (Sciex, Framingham, MA) using the parent ion [M+H] + The aim was to quantify mass transition. Relevant pharmacokinetic parameters were estimated using non-atrial ventricular methods using WinNonlin (Enterprise, version 8.2).

[0361] [Table 40]

[0362] Conclusion: The compounds of the present invention had better exposure in the retina.

[0363] Biological Example 4. In vivo evaluation of mouse AP complement function activity Female C57BL / 6 mice were administered Example 57 formulation (20 mg / kg in 0.5% (w / v) methylcellulose, 0.5% (v / v) Tween 80) by oral gavage 20 hours prior to the end of the study. To activate the complement pathway, lipopolysaccharide (LPS) from Salmonella typhimurium (Sigma) (2.5 mg / kg) was injected intraperitoneally 7.5 hours prior to the end of the study. Control mice were injected intraperitoneally with saline solution and administered carrier by oral gavage. Plasma specimens were collected from the mice at the end of the study. AP complement activation was assessed by measuring plasma C3 split products C3b / iC3b / C3c by ELISA using rat anti-mouse C3b / iC3b / C3c monoclonal antibody (clone 2 / 11, Hycult biotech, 0.1ug / well) and goat anti-rat IgG (whole molecule)-peroxidase (Sigma) diluted in TBST (TBS / 0.05% Tween 20). Plasma C3b / iC3b / C3c is as shown in Table 4 below.

[0364] [Table 41]

[0365] Conclusion: The results show that Example 57 exhibited sustained inhibition for 20 hours in mouse in vivo PD assays. (*: p<0.05; **: p<0.01; ****: p<0.0001; ns: no significant difference)

[0366] Biological Example 5. Ex vivo evaluation of plasma PD inhibition Male Sprague Dawley rats (n=3) were dosed orally at 2 mg / kg with carrier (0.5% (w / v) methylcellulose, 0.5% (v / v) Tween 80), compound Iptacopan or example compound formulation (in 0.5% (w / v) methylcellulose, 0.5% (v / v) Tween 80). Serum samples from rats were collected 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after dosing and stored at -80°C. 96-well microtiter plates (Black Maxisorp, Invitrogen) were coated overnight at 4°C with 3 μg / ml LPS from Salmonella strains and used for alternative complement pathway (AP) ELISA (TLRGRADE, Enzo Life Sciences, in PBS / 10 mM MgCl2). The coated plates were washed with GVB buffer (Complement tech) containing 5 mM MgCl2 and 10 mM EGTA (blocks classical and lectin pathways). Collected serum samples were diluted by adding an equal volume of GVB buffer containing 10 mM MgCl2 and 20 mM EGTA. For negative controls, serum was diluted in GVB buffer containing 40 mM EDTA (blocks all complement pathways). Aliquots (50ul) of 50% serum samples were placed in the LPS-coated wells. The reaction plates were left at 37°C for 20 minutes (rat serum). The wells were punched by inverting the plate and blocking buffer (50μL, SuperBlock (商標) The reaction was terminated by adding T20 (TBS) Blocking Buffer (Thermo #37536). For detection of rat MAC deposition on LPS, anti-rat C5b-9 novel epitope was used with mAb 2A1 (HM3033-IA, Hycult Biotech, 0.1ug / well) and goat anti-mouse IgG (Fc specific)-peroxidase (Sigma, #A2554). Baseline (EDTA-treated serum) and maximum signal (EGTA-treated serum from carrier-treated mice) were used to generate percent inhibition values ​​for each well.

[0367] Rats (3 rats / group) were orally administered compound Iptacopan or Example 57 (2 mg / kg), and the AP deposition inhibitory activity of the compound in 50% serum was evaluated after 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours of dosing. Each data point represents the average AP activity in rat serum in Figure 1. The results showed that Example 57 showed sustained inhibition for 24 hours in rat ex vivo PD assay.

[0368] [Table 42]

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a tautomer or a pharmaceutically acceptable salt thereof, A is a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; L is a bond, (CR ａ R ｂ ) ｐ or not present, R ａ and R ｂ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; R １ and R ２ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, and hydroxyalkyl; R ３ and R ４ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, halogenated alkenyl, hydroxyalkyl, deuterated alkoxy, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy and heteroaryloxy groups, optionally said hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, deuterated alkoxy, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy and heteroaryloxy groups are substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy and heteroaryloxy groups; R ５ are independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally the amino, alkyl, alkoxy, alkylthio, halogenated alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylthio, halogenated alkyl and hydroxyalkyl groups; Or, R ５ two of which together with the C atom to which they are attached form a cycloalkyl or heterocyclyl group, optionally said cycloalkyl or heterocyclyl group being substituted with one or more substituents selected from deuterium, halogen, amino, cyano, hydroxy, alkyl, alkoxy, alkylalkoxy, alkoxyalkyl, alkylthio, halogenated alkyl and hydroxyalkyl groups, R ６ represents hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, alkyl group, alkoxy group, alkylthio group, halogenated alkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH ２ ) ｒ OR ８ , -(CH ２ ) ｒ C(O)R ８ , —S(O)NH alkyl group, —SO ２ Alkyl group, —C(O)NHSO ２ Alkyl group and -SO ２ NHC(O)alkyl groups; Or, R ６ teeth, 【Chemistry 2】 together with the C atom in R ７ is selected from hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, alkyl group, alkoxy group, alkylthio group, halogenated alkyl group and hydroxyalkyl group; R ８ is selected from hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, alkyl group, alkoxy group, alkylthio group, halogenated alkyl group and hydroxyalkyl group; p is 1, 2 or 3; r is 0, 1, 2 or 3; t is 1, 2, or 3; m is 1, 2 or 3; n is 0, 1, 2 or 3; The conditions are as follows: R １ and R ２ is hydrogen, and R ３ is a cyclopropyl group or a methoxy group, and R ４ is a methyl group, L is a bond, and R ６ is -COOH or -COOCH ３ and R ７ is hydrogen or a trifluoromethyl group, A is a phenyl group, and n is 1, 2, or 3, then R ５ is hydrogen or 【Transformation 3】 Instead, R １ and R ２ is hydrogen, and R ４ is a methyl group, L is a bond, and R ７ is hydrogen, A is a phenyl group, pyridine or thiazolyl group, m is 1 and n is 2, then R ５ is not hydrogen, amino, hydroxy, methyl, ethyl, methoxy, ethoxy, propoxy, hydroxymethyl, ethoxy, cyanomethyl and methylamino groups, R １ and R ２ is hydrogen, and R ４ is a methyl group, L is a bond, and R ７ is hydrogen, A is a phenyl group, m is 2 or 3, and n is 2, then R ５ is not hydrogen or a methyl group, or a tautomer or a pharmaceutically acceptable salt thereof.

2. A is C ６－１０ 2. The compound according to claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein R is an aryl group or a 5- to 10-membered heteroaryl group.

3. A is a phenyl group, a benzocycloalkyl group, or a 5-8 membered heteroaryl group containing 1, 2 or 3 N heteroatoms; Preferably, A is 【Chemistry 4】 3. The compound of claim 2, wherein:

4. L is a bond, CH ２ 2. The compound of claim 1, wherein:

5. R １ and R ２ 2. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, wherein: is hydrogen.

6. R ３ and R ４ are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group, C １－６ Halogenated alkenyl group, C １－６ Hydroxyalkyl group, deuterated C １－６ Alkoxy group, C １－６ Halogenated alkoxy group, C ３－６ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 10-membered heteroaryl group, C ３－６ cycloalkyloxy group, 4- to 10-membered heterocyclyloxy group, C ６－１０ aryloxy group and 5- to 10-membered heteroaryloxy group, and optionally １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, deuterated C １－６ Alkoxy group, C １－６ The halogenated alkoxy group is a group containing deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ６－１０ substituted with one or more substituents selected from aryl groups and 5- to 10-membered heteroaryl groups; Preferably, R ３ and R ４ are independently deuterium, halogen, C １－３ Alkyl group, C １－３ Alkoxy group, deuterated C １－３ Alkoxy group, C １－３ Halogenated alkoxy group, C ３－６ Cycloalkyl groups and C ３－６ cycloalkyloxy groups, optionally selected from the C １－３ Alkyl group, C １－３ Alkoxy group, deuterated C １－３ Alkoxy group, C １－３ The halogenated alkoxy group is C ３－６ Cycloalkyl group, 4- to 6-membered heterocyclyl group, C ６－１０ 2. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, substituted with one or more substituents selected from an aryl group and a 5- to 10-membered heteroaryl group.

7. R ６ represents hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ５－１０ an aryl group, a 5- to 10-membered heteroaryl group, —(CH ２ ) ｒ C １－６ Alkoxy group, -(CH ２ ) ｒ C(O)OH, -S(O)NHC １－６ Alkyl group, —SO ２ C １－６ Alkyl group, —C(O)NHSO ２ C １－６ Alkyl group and -SO ２ NHC(O)C １－６ alkyl groups, preferably R ６ is -F, -OMe, -CH ２ OH, -CH ２ OCH ３ , -CH ２ F, -CF ２ H, -CF ３ , -COOH, -C(O)NHSO ２ CH ３ , -S(O)NHCH ３ or a 5- to 6-membered heterocyclyl group containing 1 to 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S, or a tautomer or a pharmaceutically acceptable salt thereof.

8. R ５ are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ５－１０ aryl group and 5- to 10-membered heteroaryl group, and optionally １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group, C １－６ Hydroxyalkyl group, C ３－８ Cycloalkyl group, 4- to 10-membered heterocyclyl group, C ５－１０ The aryl group and the 5- to 10-membered heteroaryl group may be substituted with deuterium, halogen, amino group, cyano group, hydroxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group and C １－６ substituted with one or more substituents selected from hydroxyalkyl groups; Or, R ５ Two of them, together with the C atoms to which they are connected, are C ３－６ Form a cycloalkyl group or a 4-6 membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O and S, which may optionally be deuterium, halogen, amino, cyano, hydroxy, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy group, C １－６ Alkyl group, C １－６ Alkylthio group, C １－６ Halogenated alkyl group and C １－６ 10. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, substituted with one or more substituents selected from hydroxyalkyl groups.

9. R ７ is hydrogen or C １－３ 2. The compound of claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group.

10. The compounds have the formula (II-a)-(II-e): 【Transformation 5】 and where: 【Transformation 6】 is a single or double bond, R ５ are independently hydrogen, deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C ３－６ a cycloalkyl group, a 4- to 6-membered heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O and S; C ５－１０ aryl groups, and 5-6 membered heteroaryl groups containing 1, 2 or 3 heteroatoms selected from N, O and S, and optionally １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group, C １－３ Hydroxyalkyl group, C ３－６ Cycloalkyl group, 4- to 6-membered heterocyclyl group, C ５－１０ The aryl group and the 5- to 6-membered heteroaryl group may be substituted with deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ substituted with one or more substituents selected from hydroxyalkyl groups; 【Transformation 7】 teeth, 【Transformation 8】 and B is, 【Chemistry 9】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ substituted with one or more substituents selected from hydroxyalkyl groups; C is 【Chemistry 10】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ 10. The compound of any one of claims 1 to 9, or a tautomer or pharmaceutically acceptable salt thereof, substituted with one or more substituents selected from hydroxyalkyl groups.

11. The compounds have the formula (III-a)-(III-e): 【Chemistry 11】 and where: 【Chemistry 12】 teeth, 【Chemistry 13】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ substituted with one or more substituents selected from hydroxyalkyl groups; 【Chemistry 14】 teeth, 【Chemistry 15】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ 11. The compound of claim 10, or a tautomer or pharmaceutically acceptable salt thereof, substituted with one or more substituents selected from hydroxyalkyl groups. 【Request Item 12】 【Chemistry 16】 teeth, 【Chemistry 17】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ substituted with one or more substituents selected from hydroxyalkyl groups; [Chemistry 18] teeth, 【Chemistry 19】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ 12. The compound of claim 11, or a tautomer or pharmaceutically acceptable salt thereof, substituted with one or more substituents selected from hydroxyalkyl groups.

13. A is, 【Chemistry 20】 and 【Chemistry 21】 teeth, 【Chemistry 22】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ substituted with one or more substituents selected from hydroxyalkyl groups; 【Chemistry 23】 teeth, 【Chemistry 24】 which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ substituted with one or more substituents selected from hydroxyalkyl groups; R ３ and R ４ are each independently deuterium, halogen, or C １－３ Alkyl group, C １－３ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkyloxy group, deuterated C １－３ Alkoxy group, C １－３ Halogenated alkoxy group and C ３－６ Cycloalkyl group, C １－３ alkoxy groups, R ５ is hydrogen, halogen, cyano group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Halogenated alkyl group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C ３－６ a 5-membered heteroaryl group containing 1 or 2 ring heteroatoms independently selected from cycloalkyl, N, and O; R ６ is —COOH or —S(O)NHCH ３ 12. The compound of claim 11, wherein:

14. The compound has formula (IV): 【Chemistry 25】 and R ９ represents hydrogen, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkoxy group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ hydroxyalkyl groups, which may optionally be halogen, amino groups, hydroxy groups, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkylamino group, C ３－６ substituted with one or more substituents selected from cycloalkyl groups and 5- to 6-membered heterocyclyl groups containing 1 or 2 ring heteroatoms independently selected from N and O; Or, R ９ Two of them, together with the C atoms to which they are connected, are C ３－６ Forms a cycloalkyl group, which optionally contains deuterium, halogen, amino group, cyano group, hydroxy group, C １－３ Alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, C １－３ Alkylamino group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkoxy group, C １－３ Alkoxy group, C １－３ Alkyl group, C １－３ Alkylthio group, C １－３ Halogenated alkyl group and C １－３ substituted with one or more substituents selected from hydroxyalkyl groups; n is 1 or 2; q is 1, 2 or 3; 10. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, wherein s is 0, 1 or 2.

15. The compound has the formula (V-a)-(V-c): 【Chemistry 26】 and M is O or CR ｃ R ｄ and R ｃ and R ｄ are independently hydrogen, halogen and C １－３ alkyl groups, R ３ and R ４ is independently C １－３ Alkyl group, C １－３ Alkoxy group and C ３－６ cycloalkyl groups, R ５ is hydrogen, halogen, C １－３ Alkyl group or C １－３ is a halogenated alkyl group, R ６ is -COOH, -C(O)NHSO ２ CH ３ or -S(O)NHCH ３ and R ７ is hydrogen, C １－３ Alkyl group or C １－３ is a hydroxyalkyl group, R ９ is hydrogen, halogen, C １－３ Alkyl group or C １－３ is a halogenated alkyl group, Or, R ９ Two of them, together with the C atoms to which they are connected, are C ３－６ forming a cycloalkyl group, R １０ is hydrogen, C １－３ Alkyl group or C １－３ is a halogenated alkyl group, n is 1 or 2; q is 1, 2 or 3; s is 0, 1 or 2; 10. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, wherein t is 1 or 2.

16. The compound has the formula (VI): 【Chemistry 27】 and R ３ and R ４ are independently deuterium, halogen, C １－３ Alkyl group, C １－３ Alkoxy group, C ３－６ Cycloalkyl group, C ３－６ Cycloalkyloxy group, deuterated C １－３ Alkoxy group, C １－３ Halogenated alkoxy group and C ３－６ Cycloalkyl group, C １－３ alkoxy groups, R ６ は、-COOH、-C(O)NHSO ２ CH ３ 、-S(O)NHCH ３ 、 【Chemistry 28】 and R ７ is hydrogen, C １－３ Alkyl group or C １－３ is a hydroxyalkyl group, R １０ is hydrogen, C １－３ Alkyl group or C １－３ is a halogenated alkyl group, R ｃ and R ｄ are each independently hydrogen, halogen, or C １－３ Alkyl group and C １－３ 10. The compound of any one of claims 1 to 9, or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from halogenated alkyl groups.

17. The compound has the formula (VI-a): 【Chemistry 29】 17. The compound of claim 16, wherein:

18. R ３ and R ４ are independently deuterium, halogen, C １－３ Alkyl group, C １－３ Alkoxy group, C ３－６ cycloalkyl groups, R ６ is -COOH, -C(O)NHSO ２ CH ３ , -S(O)NHCH ３ and R ７ is hydrogen, C １－３ Alkyl group or C １－３ is a hydroxyalkyl group, R １０ is hydrogen, C １－３ Alkyl group or C １－３ is a halogenated alkyl group, R ｃ and R ｄ are each independently hydrogen, halogen, or C １－３ Alkyl group and C １－３ 18. The compound of claim 17, or a tautomer or pharmaceutically acceptable salt thereof, wherein: R is selected from halogenated alkyl groups.

19. The compound has the formula (VI-b): 【Transformation 30】 and R ３ and R ４ are independently deuterium, halogen, C １－３ Alkyl group, C １－３ selected from an alkoxy group, a cyclopropyl group, and a cyclobutyl group; R ６ is -COOH, -C(O)NHSO ２ CH ３ , -S(O)NHCH ３ and R ７ is hydrogen, C １－３ Alkyl group or C １－３ is a hydroxyalkyl group, R １０ is hydrogen, C １－３ Alkyl group or C １－３ a halogenated alkyl group, wherein the halogenated alkyl group contains at least two halogen atoms selected from F; R ｃ and R ｄ are each independently hydrogen, halogen, or C １－３ Alkyl group and C １－３ 18. The compound of claim 17, or a tautomer or pharmaceutically acceptable salt thereof, wherein: R is selected from halogenated alkyl groups.

20. The compound has the following structure: 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 2. The compound of claim 1, or a tautomer or a pharmaceutically acceptable salt thereof, selected from:

21. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

22. the amount of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is about 0.1% to 95% by weight of the free base, preferably about 0.5% to 85% by weight of the free base; More preferably, about 1% to 60% by weight of the free base; More preferably, about 10% to 50% by weight of the free base; More preferably, about 15% to 40% by weight of the free base; More preferably, about 20% to 30% by weight of the free base; More preferably, the pharmaceutical composition of claim 21 is about 20% to 25% by weight of the free base.

23. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is in the form of a tablet, capsule, liquid, or injectable.

24. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is an immediate release dosage form or a sustained release dosage form.

25. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient, carrier, or carrier selected from a filler, disintegrant, glidant, lubricant, and diluent.

26. the unit dose of the compound, its tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof is about 1 to 1000 mg based on the weight of the free base; Preferably, about 1 to 500 mg based on the weight of the free base; More preferably, about 3 to 300 mg based on the weight of the free base; More preferably, about 5 to 200 mg based on the weight of the free base; 22. The pharmaceutical composition of claim 21, more preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg based on the weight of the free base.

27. A method for modulating alternative complement pathway activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 9 or a pharmaceutical composition described in any one of claims 21 to 26.

28. A method for treating a condition or disease in a subject mediated by complement activation, particularly by alternative complement pathway activation, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 9 or a pharmaceutical composition described in any one of claims 21 to 26.

29. The diseases or conditions include age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot chorioretinitis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, nervous system diseases, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, diseases of inappropriate or unwanted complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, inflammatory diseases, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disease, myocardial infarction, balloon hemorrhage, and the like.

29. The method of claim 28, wherein the treatment is selected from angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infection or sepsis, immune complex diseases and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrosing dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpature syndrome, pulmonary vasculitis, microimmune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, membranous nephropathy, paroxysmal nocturnal hemoglobinuria, IgA nephropathy, glomerulonephritis and obesity.

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