Tricyclic compounds, their preparation, and therapeutic use as ERK5 inhibitors

Abstract

A compound capable of inhibiting ERK5 is provided. Additionally, a pharmaceutical composition and its medical uses are provided, including use in the treatment or prevention of pathological conditions such as cancer. [Chemical Formula I]

Description

Technology Field

[0001] A compound capable of inhibiting ERK5 is provided. Additionally, a pharmaceutical composition and its medical uses are provided, including use in the treatment or prevention of pathological conditions such as cancer.

[0002] The mitogen-activated protein kinase (MAPK) cascade is a highly conserved cellular pathway that transmits signals from the cell surface to the nucleus. This pathway plays a crucial role in cell proliferation, differentiation, and migration, and is well known to be associated with cancer development. Proteins within the pathway include extracellular signal-regulating kinase (ERK) proteins; among them, ERK5 ( MAPK7 Expression from genes plays an important role in cell proliferation as well as epithelial development and neural differentiation (e.g., literature [Nishimoto] et al. [See , EMBO Reports (2006) 7(8):782-786]). ERK5 is unique among ERK proteins in that it possesses a transcriptional activation domain (TAD) and a large C-terminal domain containing nuclear localization signals and two proline-rich regions (e.g., the literature [Guo et al. See [Exp Ther Med. (2020) 19:1997-2007]). Autophosphorylation of TAD is required for transcriptional activation (e.g., see literature [Morimoto et al. , see J Biol Chem. (2007) 282(49):35449-35456).

[0003] ERK5 plays an important role in controlling cell proliferation and cell cycle progression through direct or indirect phosphorylation of, for example, MEF2C, cMYC, SGK1, RSK, FOS, and FRA1 (e.g., literature [Paudel et al. , Int J Mol Sci. (2021) 22:7594-7614; Terasawa et al.[Refer to Genes to Cells (2003) 8(3):263-273]). The fact that ERK5 is involved in multiple biological pathways implies that its activity is associated with various aspects of cancer progression, including tumor angiogenesis, metastasis, inflammation, sustained proliferation, and evasion of growth inhibition. Therefore, this presents an attractive target for regulating disease pathology and treatment across a wide range of conditions. Previous studies have shown that ERK5 inhibition or downregulation blocks tumorigenesis in murine leukemia cells, reduces the growth of chronic myeloid leukemia cells, inhibits the growth of breast cancer and multiple myeloma cells, suppresses colon cancer cell proliferation, and affects cell growth or survival including in renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma (e.g., the literature [Stecca et al. , see Int J Mol Sci. (2019) 20:1426-1446]).

[0004] Therefore, ERK5 inhibition represents a promising approach to addressing a wide range of cancers. Several ERK5 inhibitors have been developed, and some are currently under clinical review. For example, WO 2019 / 170543 (Bayer AG and Bayer Pharma AG) discloses a compound known to have activity as an ERK5 inhibitor in the concentration range of μM to nM.

[0005] Despite recent advancements in cancer treatment due to the development of targeted therapies and immunotherapy, effective treatment solutions cannot be provided for all cancer patients. Therefore, the discovery and development of new drugs are necessary. This disclosure aims to address this need by providing novel compounds for use as ERK5 inhibitors in the treatment of ERK5-related diseases and pathologies.

[0006] Therefore, the first embodiment is a compound of formula I.

[0007] [Chemical Formula I]

[0008]

[0009] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula,

[0010] Ring A is a (C5-C8)cycloalkane, a (C6-C8)cycloalkene, or a 5 to 8-membered heterocycloalkane, where ring A is R in one or more cases. A Optionally replaced with,

[0011] Here, each case R A Is

[0012] (a) independently selected from -D, halo, -OH, oxo, =N-OH, -NHR', -CN, -C(O)-R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3 to 6 heterocycloalkyl, wherein in each case the -(C1-C3)alkyl is optionally substituted with one or more groups selected from halo and -OH, and

[0013] Here, each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl optionally substituted with one or more halos, and

[0014] Here, each R'' is selected from -OH, -O(C1-C3)alkyl, and -(C1-C3)alkyl (e.g., -CH3);

[0015] (b) R in another case A and taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring and the cycloalkyl ring are optionally substituted with one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl;

[0016] R 1 is selected from -H and halo (e.g., -F);

[0017] R 2 -(C6-C 10 )aryl, and here R 2 is R in one or two cases B It is replaced with

[0018] (Here, each R B is independently selected from halo, -OH, -NH2, -SF5, -(C1-C3)alkyl, and -O(C1-C3)alkyl, wherein in each case -(C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted with one or more halos;

[0019] n is 0, 1, or 2, and

[0020] However, R 2 ga is 4-(pentafluorosulfanyl)phenyl, and R 1 If this is -H and n is 1, ring A is not unsubstituted cyclopentane.

[0021] In an embodiment, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxephane, azephane, 1,4-oxasephane, and thiephane, wherein ring A is R in one or more cases as previously defined. A It is optionally replaced with.

[0022] In an embodiment, ring A is

[0023]

[0024] Selected from, where the dotted bond indicates the fusion point with the pyrrole ring, and ring A is R in one or more cases as previously defined. A It is optionally replaced with.

[0025] In the implementation example, R 2 Is

[0026]

[0027] Selected from.

[0028] Another aspect is a compound of chemical formula II.

[0029] [Chemical Formula II]

[0030]

[0031] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula,

[0032] Ring A is a (C5-C8)cycloalkane or a 6- to 7-membered heterocycloalkane, where ring A is R in one or more cases. A Optionally replaced with,

[0033] Here, each case R A Is

[0034] (a) independently selected from -OH, oxo, -NHR', -C(O)CH3, -(C1-C3)alkyl, and -O(C1-C3)alkyl, and

[0035] Here, each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl selectively substituted with one or more halos;

[0036] (b) R in another case A and taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo;

[0037] R 1 is selected from -H and -F;

[0038] R B1 It is selected from -H and -NH2, and

[0039] R B2 is selected from -OCF3 and -SF5, and

[0040] However, R B1 This is -H and R B2 g is -SF5, and R 1 In the case of -H, ring A is not unsubstituted cyclopentane.

[0041] In an embodiment, ring A is

[0042]

[0043] Selected from, where the dotted bond indicates the fusion point with the pyrrole ring, and ring A is R in one or more cases as previously defined. A It is optionally replaced with.

[0044] In the implementation example, R B2 is -OCF3.

[0045] In the implementation example, R 1 is -F.

[0046] Another aspect is a compound of formula III, formula IV, formula V, or formula VI:

[0047] [Chemical Formula III]

[0048]

[0049] [Chemical Formula IV]

[0050]

[0051] [Chemical Formula V]

[0052]

[0053] [Chemical Formula VI]

[0054]

[0055] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula, ring A and R 1 is as previously defined, provided that the compound is a compound of chemical formula V and R 1 In the case of -H, ring A is not unsubstituted cyclopentane.

[0056] Further embodiments provide a compound selected from the group consisting of the following and a pharmaceutically acceptable salt thereof:

[0057] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0058] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0059] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0060] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene-13-yl)-1-piperidyl]methanone;

[0061] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-oxetane]-4-yl)-1-piperidyl]methanone;

[0062] - [4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0063] - [4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0064] - (rac)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0065] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indole-6-one;

[0066] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0067] - (6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;

[0068] - (6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0069] - [4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0070] - [4-[(3S,8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0071] - [4-((2S, 7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0072] - [4-((2R, 7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0073] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0074] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-13-methyl-6,8,13-triaztricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0075] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0076] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0077] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0078] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0079] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0080] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0081] - (7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0082] - (7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0083] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-azetidine]-4-yl)-1-piperidyl]methanone;

[0084] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0085] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0086] - [4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0087] - [4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0088] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0089] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0090] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0091] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0092] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0093] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0094] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0095] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0096] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0097] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0098] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0099] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0100] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0101] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0102] - [4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0103] - [4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0104] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0105] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0106] - [4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0107] - [4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0108] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0109] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0110] - 1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-13-yl]ethanone;

[0111] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0112] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0113] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0114] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0115] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0116] - [4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0117] - [4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0118] - 4-fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0119] - [4-[(6R)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0120] - [4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0121] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0122] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0123] - [4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0124] - [4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0125] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0126] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0127] - (6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;

[0128] - (6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0129] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0130] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0131] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone; and

[0132] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone.

[0133] Further embodiments provide a pharmaceutical composition comprising the compound defined above and at least one pharmaceutically acceptable excipient or carrier.

[0134] Additional embodiments provide a compound or pharmaceutical composition as previously defined for use in treatment.

[0135] Additional embodiments provide a compound or pharmaceutical composition as previously defined for use in the treatment or prevention of cancer.

[0136] In an embodiment, the cancer is increased MAPK7 It is characterized by expression and / or increased ERK5 activity.

[0137] In an embodiment, the cancer is selected from leukemia, breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma. Specific details for implementing the invention

[0138] Specific embodiments of the present disclosure will now be described with reference to the description and examples, but it should be understood that such embodiments are merely examples and are only illustrative of a few of the many possible specific embodiments that may demonstrate the application of the principles of the present disclosure. Various modifications and variations will be obvious to those skilled in the art in light of the advantages of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0139] definition

[0140] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. Any method and material similar or equivalent to those described herein may be used to practice or test this disclosure, but exemplary methods, apparatus, and materials are described below. All technical and patent publications cited herein are incorporated herein by reference in their entirety.

[0141] Unless otherwise indicated, the practice of the present disclosure will utilize conventional techniques within the scope of the art, such as chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA. For example, the literature [Michael R. Green and Joseph Sambrook, Molecular Cloning (4 th ed., Cold Spring Harbor Laboratory Press 2012); Series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; series Methods in Enzymology (Academic Press, Inc., NY); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5 thedition; Gait ed. (1984) Oligonucleotide Synthesis; 미국 특허 제4,683,195호; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3 rd edition (Cold Spring Harbor Laboratory Press (2002)); Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press)]을 참조한다.

[0142] All numerical designations, including ranges, e.g., pH, temperature, time, concentration, molecular weight, etc., are approximations that vary by (+) or (-) in increments of, for example, 0.1 or 1.0, where appropriate. It should be understood that, although not always explicitly stated, the term "approximately" is used to precede all numerical designations to indicate a normal level of variability. For example, a numerical designation that is "approximately" a specified value may vary by ± 10% of the said value; alternatively, the variation may be ± 5%, ± 2%, or ± 1% of the said value. It should also be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents are known in the art.

[0143] As used in the specification and claims, the singular form includes plural subjects unless the context clearly indicates otherwise. For example, the term “cell” includes plural cells, including a mixture of cells. Unless specifically stated or evident from the context, the term “or” is understood as inclusive as used herein. The term “including” is used herein to mean the phrase “including but not limited to” and is used interchangeably with it.

[0144] As used herein, the terms “consisting of” or “consist of” are intended to mean that the composition and method include the mentioned elements without excluding other elements. When used to define the composition and method, “consisting of” means excluding other elements of any essential significance for the mentioned purpose. Accordingly, a composition essentially composed of elements as defined herein will not exclude trace amounts of contaminants from isolation and purification methods, and pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, etc. “consisting of” means excluding elements exceeding trace amounts of process steps for producing the composition or achieving the intended result, or substantial method steps for administering the composition of this disclosure. Embodiments defined by each of these conjunctions are within the scope of this disclosure. The use of the term “consisting of” herein is intended to encompass and disclose corresponding descriptions in which the term “consisting of” is replaced by “consisting of” or “consisting of”.

[0145] "Subject," "Individual," or "Patient" are used interchangeably herein and refer to vertebrates such as mammals. Mammals include, but are not limited to, rodents, farm animals, sports animals, pets, and primates; e.g., murine, rat, rabbit, monkey, cattle, sheep, pig, dog, cat, horse, and human. In certain embodiments, mammals are human.

[0146] "Administration" is defined herein as a means of providing a formulation, or a composition containing a formulation, to a subject in such a manner that the formulation comes into contact with the subject's body (e.g., within the subject's body). Such administration may be made by any route, including, without limitation, oral administration, transdermal administration (e.g., administration via vaginal, rectal, or oral mucosal membranes), administration by injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or central nervous system administration), or administration by inhalation (e.g., oral or nasal administration). Administration may also include providing a substance or composition to a portion of the subject's body surface, e.g., by administering it topically to the skin. Of course, pharmaceutical formulations are provided in a form suitable for each respective route of administration.

[0147] Treatment of a disease ("treating" or "treatment") includes the following: (1) prevention of the disease, i.e., preventing the occurrence of clinical symptoms of the disease in patients who may be susceptible to the disease but have not yet experienced or exhibited symptoms of the disease; (2) suppression of the disease, i.e., preventing or reducing the occurrence of the disease or its clinical symptoms; and / or (3) alleviation of the disease, i.e., causing the disease or its clinical symptoms to regress.

[0148] In relation to the term "treatment," the term "sick" refers to a patient or individual who has been diagnosed with the disease or is susceptible to it. Patients may also be referred to as "at risk of having" the disease due to a family history of the disease or the presence of gene mutations associated with the disease. In patients at risk of the disease, all or part of the characteristic pathology of the disease has not yet occurred.

[0149] An "effective dose" or "therapeutic effective dose" is an amount sufficient to achieve a beneficial or desired result. The effective dose may be administered as one or more doses, applications, or dosages. Such delivery depends on several variables, including the duration for which individual units of administration will be used, the bioavailability of the therapeutic agent, and the route of administration. However, it is understood that the specific dose level of the therapeutic agent of this disclosure for any particular subject depends on various factors, including, for example, the activity of the specific compound used, the subject's age, body weight, overall health status, sex, and diet, the time of administration, the rate of elimination, the combination of drugs, the severity of the specific disorder being treated, and the mode of administration. The therapeutic dose may generally be titrated to optimize safety and efficacy. Typically, dose-effect relationships from in vitro and / or in vivo studies can provide useful guidance on the appropriate dose for initial patient administration. Generally, one will want to administer an amount of the compound effective to achieve serum levels corresponding to the concentration found to be effective in vitro. The determination of these parameters is fully within the scope of the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and described in standard textbooks. Consistent with this definition, as used herein, the term "therapeutic effective dose" is an amount sufficient to treat (e.g., improve) one or more symptoms associated with the condition. The total daily dose may be administered as a single or divided dose and may fall outside the typical ranges presented herein at the physician's discretion.

[0150] As used herein, the terms “increased” and “elevated” are used interchangeably and encompass any measurable increase in biological function and / or biological activity and / or concentration. For example, the increase may be at least about 10%, e.g., at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, e.g., at least about 95%, 96%, 97%, 98%, 99%, or 100%. Therefore, the increase may be at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, e.g., at least about 20, 25, 50, 100 times, or more than the amount or function, or activity, or concentration of the control or baseline.

[0151] As used herein, the terms "increased expression" and / or "increased activity" of a substance such as ERK5 in a sample, cancer, or patient typically refer to a quantitative increase in the substance (e.g., MAPK7It refers to a gene product or ERK5 protein, but may also indicate an increase in the biological activity of the substance (e.g., congenital activation of ERK5 phosphorylation and / or identification of the phosphorylation site). For example, the increase may be about 5%, e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, e.g., about 96%, 97%, 98%, 99%, or 100%. Accordingly, when determined by techniques known in the art, the increase may be about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, e.g., about 20, 25, 50, 100 times, or more than the amount (or activity) of a substance such as ERK5 in a control sample or control samples, e.g., an individual or population not suffering from a disease or disorder (e.g., cancer), or an internal control. The subject may also be determined to have "increased expression" or "increased activity" of ERK5 if the expression and / or activity of ERK5 is increased by 1 standard deviation, 2 standard deviations, 3 standard deviations, 4 standard deviations, 5 standard deviations or more than the mean or median amount of ERK5 in a retrospective analysis of the control or baseline group or patient samples of the sample. As is done in the industry, these control or baseline expression levels may be determined in advance, measured before being measured in a sample, cancer, or subject, or obtained from a database of these control samples.

[0152] As used herein, the term “pharmaceuticalally acceptable excipients” encompasses any standard pharmaceutical excipients as described, for example, in the literature [Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000)]. Such excipients include carriers, such as phosphate-buffered saline solutions, water, and emulsions, such as oil / water or water / oil emulsions, and various types of wetting agents. Pharmaceutical compositions may also include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, etc.

[0153] As used herein, the term "alkyl" means a saturated linear or branched free radical essentially composed of a carbon atom and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. In light of the advantages of this disclosure, those skilled in the art will readily recognize other alkyl groups. The terms "(C1-C3)alkyl," "(C1-C6)alkyl," etc., have equivalent meanings, namely, a saturated linear or branched free radical essentially composed of 1 to 3 (or 1 to 6) carbon atoms and a corresponding number of hydrogen atoms. The definition of "alkyl" also applies to cases involving other groups containing an alkyl group, such as "-O(C1-C3)alkyl." The term "haloalkyl" means an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, trifluoroethyl, difluoroethyl, pentafluoroethyl, chloromethyl, etc. One or more carbon atoms in the backbone of an alkyl group may be replaced (or bonded to) heteroatoms by multiple bonds (e.g., double bonds); for example, a carbon atom of an alkyl group may be bonded to oxygen through a double bond (i.e., substituted with an oxo to provide a carbonyl functional group). Even if such substituents are present, it is not denied that the carbon backbone of the free radical is considered an alkyl group.

[0154] As used herein, the term “cyclic group” refers to a saturated, partially or completely unsaturated, or aromatic group having at least 3 to 10 atoms (i.e., ring atoms) that form a ring. Where a cyclic group is defined as having a specific number of members, terms “member,” “membered,” etc. are used to indicate the number of ring atoms of said cyclic group. For example, a pentatonic cyclic group (e.g., a pentatonic complex cyclic group) contains 5 ring atoms. It will be understood that a cyclic group may be part of a larger cyclic system; for example, bicyclo[4.3.0]nonane contains two carbon-cyclic groups, namely a cyclohexane group and a cyclopentane group, which fuse to form a carbon-cyclic system that constitutes the molecule. The term “cyclic group” is intended to include both carbon-cyclic and complex cyclic groups. The term “carbon-cyclic” refers to a group having at least 3 to 9 carbon atoms that form a ring. The term “heterocyclic” refers to a group of at least 3 to 10 atoms forming a ring, wherein at least 1 to 9 of the ring atoms are carbon and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atom(s)) are independently selected from the group consisting of nitrogen, sulfur, and oxygen.

[0155] In relation to cyclic groups, the terms “spiro” or “spirocyclic” as used herein indicate that a first cyclic group in a polycyclic system is attached to a second cyclic group in the polycyclic system, and that the ring atom of the first cyclic group and the ring atom of the second cyclic group have only one atom in common, that is, that the first and second cyclic groups share only one common ring atom. For example, a spiro[5.5]undecanyl group comprises two cyclohexyl rings having a single carbon ring atom in common.

[0156] With respect to cyclic groups, the term "fused" as used herein indicates that a first cyclic group in a polycyclic system is attached to a second cyclic group in said polycyclic system, and that the ring atoms of said first cyclic group and the ring atoms of said second cyclic group have two adjacent atoms in common, that is, said first and second cyclic groups share two common ring atoms. For example, a bicyclo[4.4.0]decanyl group comprises two cyclohexyl rings having two adjacent carbon ring atoms in common.

[0157] With respect to cyclic groups, the term “cross-linked” as used herein indicates that a first cyclic group in a polycyclic system is attached to a second cyclic group in the polycyclic system, and that the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have more than two adjacent atoms in common, that is, that the first and second cyclic groups share three or more common ring atoms. For example, a bicyclo[3.3.1]nonanyl group comprises two cyclohexayl rings having three adjacent carbon ring atoms in common.

[0158] In the structural formulas described herein, any ring system (including any spiro, fused, or cross-linked ring system) may be connected to other parts of the molecule through any atom having a suitable valence. For example, a dicyclic ring may be connected to another part of the molecule through a ring atom (e.g., a secondary carbon atom or a heteroatom such as N) or a bridge head (e.g., a tertiary carbon atom). Spiro, fused, and cross-linked rings may be completely unsaturated, partially unsaturated, or completely saturated, and may have aromaticity in one or more of their constituent rings.

[0159] As used herein, the term “cycloalkane” refers to a saturated cyclic group having at least 3 to 9 carbon atoms (i.e., ring atoms) forming a cyclic moiety, wherein the cycloalkane moiety is fused to another cyclic group. The cycloalkane moiety described herein (e.g., ring A of Formula I) is typically fused to an aromatic ring (e.g., the pyrrole ring shown in Formula I) through a common carbon atom. Even if unsaturation (e.g., a bond having aromatic properties) is present in the fused portion, it is not denied that the cyclic group is considered a cycloalkane moiety. The term “(C5-C8)cycloalkane” refers to a saturated cyclic group comprising a total of 5, 6, 7, or 8 ring carbon atoms, wherein the cycloalkane moiety is fused to another cyclic group. One or more ring atoms of the cycloalkane group may be substituted for heteroatoms by double bonds (i.e., bonded to heteroatoms) (e.g., cycloalkanes substituted with oxos). The presence of such substituents does not negate the fact that the corresponding cyclic group is considered a cycloalkane moiety. Exemplary cycloalkane moietyes include cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0160] As used herein, the term “cycloalkene” refers to an unsaturated cyclic group having at least 5 to 9 carbon atoms (i.e., ring atoms) forming a ring moiety, wherein the cycloalkene moiety is fused with another cyclic group. The cycloalkene moiety described herein (e.g., ring A of Formula I) is typically fused to an aromatic ring (e.g., the pyrrole ring shown in Formula I) through a common carbon atom. Even if unsaturation (e.g., a bond having aromatic properties) is present in the fused portion, it is not definitive that the corresponding cyclic group is considered a cycloalkene moiety. To avoid doubt, in addition to the bond having unsaturated properties in the fused portion, the cycloalkene ring also has additional unsaturation. The term “(C6-C8)cycloalkene” refers to an unsaturated cyclic group comprising a total of 6, 7, or 8 ring carbon atoms, wherein the cycloalkene moiety is fused with another cyclic group. One or more ring atoms of a cycloalkene group can be substituted for heteroatoms by double bonds (i.e., bonded to heteroatoms) (e.g., cycloalkenes substituted with oxos). The presence of such substituents does not negate the fact that the corresponding cyclic group is considered a cycloalkene moiety. An exemplary cycloalkene moiety is cycloheptene.

[0161] As used herein, the term “cycloalkyl” means a saturated cyclic group (e.g., a saturated free radical) having at least 3 to 9 carbon atoms (i.e., ring atoms) forming a ring. The cycloalkyl group may be a cycloalkyl ring connected to another cyclic group by a spiro, fused, or cross-linked arrangement, or a cycloalkyl substituent in which the ring is connected to another atom by a single cyclic bond. For example, a cycloheptane moiety may be taken together and substituted with two substituents that form a bridgehead, so that cycloheptane and the substituents together form bicyclo[3.2.1]octane. The term “(C4-C7)cycloalkyl” indicates that the ring portion of the cycloalkyl group contains a total of 4, 5, 6, or 7 carbon atoms, for example, cyclohexyl (having 6 ring carbon atoms). One or more ring atoms of the cycloalkyl group may be substituted with heteroatoms by double bonds (i.e., bonded to heteroatoms) (e.g., oxo-substituted cycloalkyl). The presence of such substituents does not negate the fact that the corresponding cyclic group is considered a cycloalkyl group. The cycloalkyl group may be monocyclic or polycyclic (e.g., dicyclic). In an embodiment, the cycloalkyl group is monocyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0162] As used herein, the term "aryl" refers to an aromatic free radical having at least six carbon atoms forming a ring (i.e., ring atoms). It will be understood that an aryl group can be monocyclic or polycyclic (e.g., fused). Examples of aryl groups include phenyl and naphthalenyl. The term "(C6-C 10 ")aryl" indicates that the aryl group includes 6 to 10 carbon atoms in the ring portion of the group. In an embodiment, (C6-C 10 )aryl is phenyl.

[0163] As used herein, the term “heterocycloalkane” means a saturated cyclic group having at least 3 to 10 atoms (i.e., ring atoms) forming a cyclic moiety, wherein at least 1 to 9 of the ring atoms are carbons and the remaining at least 1 to 9 ring atom(s) (i.e., heterocyclic atom(s)) are independently selected from the group consisting of nitrogen, sulfur, and oxygen, and the heterocycloalkane moiety is fused with another cyclic group. The heterocycloalkane moiety described herein (e.g., ring A of Formula I) is typically fused with an aromatic ring (e.g., the pyrrole ring shown in Formula I) through a common carbon atom. Even if unsaturation (e.g., a bond having aromatic properties) is present in the fused portion, it is not denied that the cyclic group is considered a heterocycloalkane moiety. In an embodiment, the heterocyclic atom(s) are independently selected from the group consisting of nitrogen and oxygen. When a heterocycloalkane moiety is described as "X to Y groups" (where X and Y are integers), this means that the heterocycloalkane moiety contains a total of X to Y ring atoms. For example, the term "5 to 8-group heterocycloalkane" means a saturated cyclic group containing a total of 5, 6, 7, or 8 ring atoms, one or more of which are heterocyclic atoms, wherein the heterocycloalkane moiety is fused with another cyclic group. One or more ring atoms of the heterocycloalkane group may be substituted for heteroatoms by double bonds (i.e., bonded to heteroatoms) (e.g., heterocycloalkane substituted with oxos), but the heteroatoms do not form part of the ring and are excluded from the number of ring atoms. These substituents (e.g., oxo groups) are typically located adjacent to the heteroatom (e.g., in the case of 2-oxepanone, also known as caprolactone, or 2-azepanone, also known as caprolactam).Any cyclic sulfur atom may optionally have one or more pendant (i.e., non-cyclic) oxygen atoms, as found, for example, in a sulforaviral group. The presence of any such substituent does not negate the fact that the corresponding cyclic group is considered a heterocycloalkane moiety. Exemplary heterocycloalkane moietyes include tetrahydropyran, piperidine, oxephane, and azephane.

[0164] As used herein, the term “heterocycloalkyl” means a saturated cyclic group (e.g., saturated free radical) having at least 3 to 10 atoms (i.e., ring atoms) forming a ring, wherein at least 1 to 9 of the ring atoms are carbons and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. The heterocycloalkyl group may be a heterocycloalkyl ring connected to another cyclic group by a spiro, fused, or cross-linked arrangement, or a heterocycloalkyl substituent in which the ring is connected to another atom by a single cyclic bond. In an embodiment, the heterocyclic atoms are independently selected from the group consisting of nitrogen and oxygen. Where the heterocycloalkyl group is described as “X to Y atoms (where X and Y are integers),” this means that the heterocycloalkyl group comprises a total number of X to Y ring atoms. For example, the term "4 to 7-membered heterocycloalkyl" means a saturated cyclic group comprising a total of 4, 5, 6, or 7 ring atoms, one or more of which are heterocyclic atoms, e.g., tetrahydropyranyl (6 ring atoms). The heterocycloalkyl group may have oxo substituents (typically adjacent to the heteroatoms) (e.g., 2-oxopyrrolidinyl), but the oxygen atoms of the oxo group do not form part of the ring and are excluded from the number of ring atoms. The presence of such substituents does not negate the fact that the corresponding cyclic group is considered a heterocycloalkyl group. Any cyclic sulfur atom may optionally have one or more pendant (i.e., non-cyclic) oxygen atoms, as found, e.g., in sulforalanyl groups. The heterocycloalkyl group may be monocyclic or polycyclic (e.g., dicyclic). In an embodiment, the heterocycloalkyl group is monocyclic.Exemplary heterocycloalkyl groups include oxetanyl, tetrahydrofuranyl, piperidinyl, and morpholinyl.

[0165] As used herein, the terms “halo” and “halogen” mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to halogen free radical groups or halogen atoms themselves. Those skilled in the art will be able to easily identify these terms by considering the context in which they are used in this disclosure. In an embodiment, the halogen is fluorine.

[0166] As used herein, the term "CN" refers to a free radical having a carbon atom connected to a nitrogen atom through a triple bond. The CN radical is attached through its carbon atom.

[0167] As used herein, the term "oxo" refers to a free radical in which an oxygen atom is connected to the atom possessing this radical via a double bond. For example, when a carbon atom possesses an oxo radical, it forms a carbon-oxygen double bond. It will be understood that not all atoms within a given structure can be substituted with an oxo, and this depends on the free valence of the atom to be substituted.

[0168] The compounds of the present disclosure are described particularly by their structural formulas. While these formulas typically represent only one form of the compound (e.g., resonance form, tautomeric form, etc.), it will be understood that a particular compound may exist in more than one of these forms. Those skilled in the art will readily understand this. The present disclosure includes all possible tautomeric forms of the compound characterized by the structural formulas of the present invention, and includes them as a single tautomeric form or as any mixture of tautomeric forms in any proportion. For example, the pyrrolopyridine moiety (e.g., as shown in Formula I, which may be referred to as 1H-pyrrolo[2,3-b]pyridine or 7-azindole) may be exemplified by any of the following tautomeric forms, which are used interchangeably throughout this description:

[0169]

[0170] It will also be understood that certain compounds of the present invention may exist in one or more isomer forms (e.g., stereoisomers). The present disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc. of the compounds described above and below, as well as cis- and trans- forms and their dimorphs. Purification and separation of isomers may be achieved by methods described below as well as by techniques known in the art. For example, optical isomers of a compound may be obtained by splitting a racemic mixture of its diastereomer salts (e.g., by using an optically active acid or base, or by forming a covalent diastereomer). Other processes for separating optical isomers include using chiral chromatography (e.g., an HPLC column using a chiral phase) with or without conventional derivatization. Enzymatic separation with or without derivatization may also be useful, and the optically active compounds of the present disclosure can likewise be obtained by chiral synthesis using optically active starting materials. The present disclosure includes all possible stereoisomers of the compounds described herein as a single stereoisomer, or as any mixture of said stereoisomers in any proportion, e.g., (R)- or (S)-isomers.

[0171] The compounds of the present disclosure may exist in the form of free acids or bases, or as addition salts with suitable acids or bases. Methods for forming salts are described below and are also known in the art (e.g., the literature [Berge et al. , see J Pharm Sci. (1977) 66:1-19).

[0172] As used herein, the term “pharmaceuticalally acceptable” when used in relation to salts means a salt of a currently disclosed compound that can be administered without the occurrence of any substantially undesirable biological effect(s) or without the occurrence of any harmful interaction(s) with any other component in a pharmaceutical composition that may be contained therein.

[0173] The group defined as "optionally substituted" may be unsubstituted or substituted with one or more substituents, e.g., 1, 2, 3, 4, 5, 6, or more. In an embodiment, the substituted group has 1 to 4 substituents, e.g., 1, 2, or 3 substituents. In an embodiment, the substituted group has 1 or 2 substituents. In an embodiment, the substituted group has 3 substituents.

[0174] References to a list of chemical groups in any definition of a variable herein include the definition of the variable as any single group or a combination of the listed groups. References to embodiments of a variable or mode herein include such embodiments as any single embodiment or as a combination with any other embodiment or part thereof.

[0175] The compositions and methods provided herein may be combined with one or more of any other compositions and methods provided herein.

[0176] The following abbreviations and empirical formulas are used in this document:

[0177] Ac Acetyl

[0178] AE ethyl acetate

[0179] ATP Adenosine triphosphate

[0180] Boc / BOC tert-butyloxycarbonyl

[0181] DABCO 1,4-Diazabicyclo[2.2.2]octane

[0182] DAD diode array detection

[0183] DCM dichloromethane

[0184] DIBAL-H Diisobutylaluminum hydride

[0185] DIPEA diisopropylethylamine

[0186] DMA dimethylacetamide

[0187] DMF N,N-dimethylformamide

[0188] DMSO dimethyl sulfoxide

[0189] 4EBP1 Eukaryotic translation initiation factor 4E-binding protein 1

[0190] EDC / EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0191] ERK Extracellular signal-regulated kinase

[0192] ESI Electrospray ionization

[0193] EtOAc / AcOEt ethyl acetate

[0194] FRET Forster resonance energy transfer

[0195] HATU Hexafluorophosphate, azabenzotriazole, tetramethyl uronum

[0196] HOBt Hydroxybenzotriazole

[0197] HPLC High-performance liquid chromatography

[0198] LC Liquid chromatography

[0199] LC / MS Liquid Chromatography / Mass Spectrometry

[0200] LDA Lithium di-isopropylamide

[0201] MAPK Mitogen-activated protein kinase

[0202] MS Mass spectrometry

[0203] MTBE methyl tert-butyl ether

[0204] NBS N-bromosuccinimide

[0205] NCS N-chlorosuccinimide

[0206] NIS N-iodoscinimide

[0207] NMP N-methyl-2-pyrrolidone

[0208] Pd / C Palladium / Carbon

[0209] PdCl2(dppf) [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0210] PE petroleum ether

[0211] PIFA [Bis(trifluoroacetoxy)iodo]benzene

[0212] Pin 2,3-dimethyl-2,3-butanedioleate

[0213] PTFE Poly(tetrafluoroethylene)

[0214] rac Racemic mixture

[0215] RPMI Roswell Park Memorial Institute badge

[0216] SEM 2-Trimethylsilylethoxymethyl

[0217] SFC Supercritical fluid chromatography

[0218] SGC Silica gel chromatography

[0219] TAD Enterprise Activation Domain

[0220] TATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide tetrafluoroborate

[0221] TBS tert-butyldimethylsilyl

[0222] TBTU 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylamium tetrafluoroborate

[0223] TEA triethylamine

[0224] TFA trifluoroacetic acid

[0225] THF Tetrahydrofuran

[0226] TosMIC Toluenesulfonylmethyl isocyanide

[0227] TPP 5,10,15,20-Tetraphenyl-21H,23H-Porphyrin / Meso-Tetraphenylporphyrin

[0228] Ts 4-Toluenesulfonyl (Tosyl)

[0229] UPLC Ultra-high performance liquid chromatography

[0230] UV ultraviolet rays

[0231] compound

[0232] In a first aspect, the present disclosure is a compound of Formula I.

[0233] [Chemical Formula I]

[0234]

[0235] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula,

[0236] Ring A is a (C5-C8)cycloalkane, a (C6-C8)cycloalkene, or a 5 to 8-membered heterocycloalkane, where ring A is R in one or more cases. A Optionally replaced with,

[0237] Here, each case R A Is

[0238] (a) independently selected from -D, halo, -OH, oxo, =N-OH, -NHR', -CN, -C(O)-R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3 to 6 heterocycloalkyl, wherein in each case the -(C1-C3)alkyl is optionally substituted with one or more groups selected from halo and -OH, and

[0239] Here, each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl optionally substituted with one or more halos, and

[0240] Here, each R'' is selected from -OH, -O(C1-C3)alkyl, and -(C1-C3)alkyl (e.g., -CH3);

[0241] (b) R in another case A and taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring and the cycloalkyl ring are optionally substituted with one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl;

[0242] R 1 is selected from -H and halo (e.g., -F);

[0243] R 2 -(C6-C 10 )aryl, and here R 2 is R in one or two cases B It is replaced with

[0244] (Here, each R B is independently selected from halo, -OH, -NH2, -SF5, -(C1-C3)alkyl, and -O(C1-C3)alkyl, wherein in each case -(C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted with one or more halos;

[0245] n is 0, 1, or 2, and

[0246] However, R 2 ga is 4-(pentafluorosulfanyl)phenyl, and R 1 If this is -H and n is 1, ring A is not unsubstituted cyclopentane.

[0247] In another aspect, the present disclosure relates to a compound of Formula I.

[0248] [Chemical Formula I]

[0249]

[0250] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula,

[0251] Ring A is a (C5-C8)cycloalkane or a 5 to 8-membered heterocycloalkane, where ring A is R in one or more cases. A Optionally replaced with,

[0252] Here, each case R A Is

[0253] (a) independently selected from halo, -OH, oxo, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3 to 6 heterocycloalkyl, wherein in each case the -(C1-C3)alkyl is optionally substituted with one or more halo or -OH groups, and

[0254] Here, each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl optionally substituted with one or more halos, and

[0255] Each R' is selected from -OH and -CH3 and / or;

[0256] (b) R in another case A and taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo;

[0257] R 1 is selected from -H and halo (e.g., -F);

[0258] R 2 -(C6-C 10 )aryl, and here R 2 is R in one or two cases B It is replaced with

[0259] (Here, each R B is independently selected from halo, -OH, -NH2, -SF5, -(C1-C3)alkyl, and -O(C1-C3)alkyl, wherein in each case (C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted with one or more halos;

[0260] n is 0, 1, or 2, and

[0261] However, R2 ga is 4-(pentafluorosulfanyl)phenyl, and R 1 If this is -H and n is 1, ring A is not unsubstituted cyclopentane.

[0262] R in one case A R in another case A When taken together to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, said heterocycloalkyl ring and said cycloalkyl ring are optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl, whereby the (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring may be bonded to ring A in a spiro, fused, or cross-linked arrangement. In an embodiment, R in one case A R in another case A It is taken together to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring and the cycloalkyl ring are substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl, and the (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring is bonded to ring A in a spiro arrangement.

[0263] R in one case A R in another case A When taken together to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, the heterocycloalkyl ring is optionally substituted with an oxo, and the (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring can be bonded to ring A in a spiro, fused, or cross-linked arrangement.

[0264] In an embodiment, ring A is a (C5-C8)cycloalkane or a 5 to 7-membered heterocycloalkane, wherein ring A is R in one or more cases as defined herein. A It is optionally replaced with.

[0265] In an embodiment, ring A is a (C5-C8)cycloalkane, where ring A is one or more cases of R as defined herein. A It is optionally substituted with. In an embodiment, ring A is cyclopentane, cyclohexane, cycloheptane, or cyclooctane, where ring A is R in one or more cases. A It is optionally substituted with. In an embodiment, ring A is a (C5-C7)cycloalkane, where ring A is R in one or more cases. A It is optionally substituted with. In an embodiment, ring A is cyclopentane, cyclohexane, or cycloheptane, where ring A is R in one or more cases. A It is optionally replaced with.

[0266] In an embodiment, ring A is a (C5-C6)cycloalkane, where ring A is one or more cases of R as defined herein. A It is substituted with. In an embodiment, ring A is a (C5-C6)cycloalkane, where ring A is R in one or both cases as defined herein. A It is replaced with. In the embodiment, ring A is R in two cases. A It is a (C5-C6) cycloalkane substituted with, where R in the two cases A It is taken together with an intervening carbon(s) to form a 4 to 6-membered heterocycloalkyl ring.

[0267] In an embodiment, ring A is a (C6-C8)cycloalkene, where ring A is one or more cases of R as defined herein. A It is optionally substituted with. In an embodiment, ring A is cycloheptene, e.g., unsubstituted cycloheptene.

[0268] In an embodiment, ring A is a 5 to 8-membered heterocycloalkane, wherein ring A is one or more cases of R as defined herein. A It is optionally substituted with. In an embodiment, ring A is a 5 to 7-membered heterocycloalkane, wherein ring A is one or more cases of R as defined herein. A It is optionally substituted with. In an embodiment, ring A is a 6 to 7-membered heterocycloalkane, wherein ring A is one or more cases of R as defined herein. A It is optionally replaced with.

[0269] In an embodiment, the heterocycloalkane comprises two heteroatoms (e.g., independently selected from nitrogen, oxygen, or sulfur atoms) within its ring. In an embodiment, the heterocycloalkane comprises two heteroatoms (e.g., independently selected from nitrogen, oxygen, or sulfur atoms) within its ring. In an embodiment, the heterocycloalkane comprises two heteroatoms within its ring, wherein one of the heteroatoms is a nitrogen atom and the other is selected from oxygen and sulfur. In an embodiment, the first heteroatom is nitrogen and the second heteroatom is oxygen. In an embodiment, the heterocycloalkane comprises one heteroatom within its ring, wherein the heteroatom is selected from a nitrogen atom, an oxygen atom, and a sulfur atom. In an embodiment, the heterocycloalkane comprises one heteroatom (e.g., a nitrogen or oxygen atom) within its ring.

[0270] In an embodiment, the heterocycloalkane comprises one heteroatom within its ring, wherein the heteroatom is a nitrogen atom, and the heterocycloalkane is selected from halo, -OH, oxo, -C(O)R'', -(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3 to 6-membered heterocycloalkyl R AIt comprises a substituent, wherein each case -(C1-C3)alkyl is optionally substituted with one or more groups selected from halos, and each R'' is selected from -(C1-C3)alkyl (e.g., -CH3). In an embodiment, R A The substituent is bonded to the nitrogen atom within the heterocycloalkane ring. In an embodiment, the R A Substituents are selected from -CH3, -CH2CF3, cyclopropyl, and oxetanyl (e.g., -oxetane-3-yl).

[0271] In an embodiment, the heterocycloalkane is an oxo R A It includes a substituent. In an embodiment, the heterocycloalkane includes one heteroatom (e.g., a nitrogen or oxygen atom) within its ring, and the heterocycloalkane is an oxo R A It includes a substituent, wherein the oxo is bonded to a carbon atom adjacent to the heteroatom (e.g., adjacent to a nitrogen or oxygen atom). In an embodiment, the heterocycloalkane includes a sulfur atom within its ring, and the heterocycloalkane has two Rs that are oxos. A It includes substituents, wherein both oxo substituents are bonded to a sulfur atom (i.e., form a cyclic sulfone group). In an embodiment, the heterocycloalkane contains two heteroatoms within its ring (e.g., the two heteroatoms are bonded to each other), wherein one heteroatom is a sulfur atom and the other heteroatom is a nitrogen atom, and the heterocycloalkane has two Rs that are oxo A It contains substituents, wherein both oxo substituents are bonded to the sulfur atom (i.e., form a cyclic sulfonamide group).

[0272] In an embodiment, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, cycloheptene, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxephane, azephane, 1,4-oxasephane, and thiephane, wherein ring A is R in one or more cases as defined herein. A It is optionally substituted with. In an embodiment, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxephane, azephane, 1,4-oxasephane, and thiephane, wherein ring A is R in one or more cases as defined herein. A It is optionally substituted with. In an embodiment, ring A is R in one or more cases as defined herein. A It is cyclohexane substituted with . In an embodiment, ring A is R in one or more cases as defined herein. A It is cycloheptane substituted with . In an embodiment, ring A is R in one or more cases as defined herein. A It is cyclooctane substituted with . In an embodiment, ring A is R in one or more cases as defined herein. A It is an oxephane substituted with . In an embodiment, ring A is R in one or more cases as defined herein. A It is an Aze plate substituted with .

[0273] In an embodiment, ring A is

[0274]

[0275] Selected from, where the dotted linkage indicates the fusion point with the pyrrole ring, and ring A is one or more of R cases as defined herein. A It is optionally replaced with.

[0276] In an embodiment, ring A is

[0277]

[0278] Selected from \, where the dotted linkage indicates the fusion point with the pyrrole ring, and ring A is one or more of R cases as defined herein. A It is optionally replaced with.

[0279] In an embodiment, ring A is R in one or more cases A It is replaced with, where R in each case A is independently selected from -D, halo, -OH, oxo, =N-OH, -NHR', -CN, -C(O)-R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3 to 6-membered heterocycloalkyl; wherein in each case, the -(C1-C3)alkyl is optionally substituted with one or more groups selected from halo and -OH; wherein each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl optionally substituted with -H and one or more halos; wherein each R'' is selected from -OH, -O(C1-C3)alkyl, and -(C1-C3)alkyl (e.g., -CH3).

[0280] In an embodiment, ring A is R in one or more cases A It is replaced with, where R in each case A is independently selected from halo, -OH, oxo, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3 to 6-membered heterocycloalkyl; wherein in each case, the -(C1-C3)alkyl is optionally substituted with one or more halos or -OH; wherein each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl optionally substituted with -H, one or more halos; wherein each R'' is selected from -OH and -CH3.

[0281] In an embodiment, ring A is R in one or more cases AIt is replaced with, where R in each case A is independently selected from -D, halo (e.g., F), -OH, oxo, =N-OH, -NHR', -CN, -C(O)-R'', -CH3, -CF3, -CH2CF3, -CH2OH, -C(CH3)2CH2OH, -OCH3, -cyclopropyl, oxetanyl (e.g., oxetane-3-yl), and morpholinyl (e.g., 4-morpholinyl); where each R' is selected from -H, -CH2CH2F, cyclopropyl, and oxetanyl (e.g., oxetane-3-yl); where each R'' is selected from -OH, -OCH3, and -CH3.

[0282] In an embodiment, ring A is a (C6-C7)cycloalkane, where ring A is R in one case. A It is replaced with, where R A is =N-OH (i.e., oxime). In an embodiment, the oxime is a mixture of the E isomer and the Z isomer. In an embodiment, the oxime is the E oxime. In another embodiment, the oxime is the Z oxime.

[0283] In an embodiment, ring A is R in one case. A It is replaced with, where R in each case A is independently selected from halo, -OH, oxo, -NHR', -CN, -C(O)R'', -CH3, -CF3, -CH2CF3, -CH2OH, -OCH3, -cyclopropyl, and -oxetanyl (e.g., -oxetane-3-yl); where each R' is selected from -H, -CH2CH2F, -cyclopropyl, and -oxetanyl (e.g., -oxetane-3-yl); where each R'' is selected from -OH and -CH3.

[0284] In another embodiment, ring A is R in two cases A It is replaced with, where one case R A is R in other cases Aand is taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring and the cycloalkyl ring are optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo. The (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring may be connected to ring A in a spiro, fused, or cross-linked arrangement.

[0285] In the embodiment, ring A is R in two cases A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo. In an embodiment, the (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring is connected to ring A in a spiro or fused arrangement. In an embodiment, ring A is R in both cases. A It is replaced with, where one case RA is R in other cases A and is taken together with intervening atoms(s) to form a 4 to 7-membered heterocycloalkyl ring, wherein the 4 to 7-membered heterocycloalkyl ring is connected to ring A in a spiro or fused arrangement, wherein the heterocycloalkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a 4 to 7-membered heterocycloalkyl ring, wherein the 4 to 7-membered heterocycloalkyl ring is connected to ring A in a spiro or fused arrangement, and the heterocycloalkyl ring is optionally substituted with an oxo.

[0286] In another embodiment, ring A is R in two cases A It is replaced with, where one case R A is R in other cases A It is taken together with an intervening atom to form a (C4-C7)cycloalkyl ring, and the (C4-C7)cycloalkyl ring is connected to ring A in a cross-linked arrangement. In an embodiment, the (C4-C7)cycloalkyl ring is substituted with one or more -OH groups.

[0287] In the embodiment, ring A is R in two cases A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring and the cycloalkyl ring are optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl. In an embodiment, ring A is R in both cases.A It is replaced with, where R in each case A is R in other cases A and is taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, said heterocycloalkyl ring is optionally substituted with an oxo. In an embodiment, the (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring is connected to ring A in a spiro, fused, or cross-linked arrangement. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a 4 to 6-membered heterocycloalkyl ring, said heterocycloalkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a 4 to 6-membered heterocycloalkyl ring, said heterocycloalkyl ring is optionally substituted with an oxo. In an embodiment, the (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring is connected to ring A in a spiro or fused arrangement. In an embodiment, ring A is R in both cases A It is replaced with, where one case R A is taken together with RA and intervening atoms(s) in other cases to form a 4 to 6-membered heterocycloalkyl ring, the 4 to 6-membered heterocycloalkyl ring is connected to ring A in a spiro or fused arrangement, and said heterocycloalkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl. In an embodiment, ring A is R in both casesA It is replaced with, where one case R A is taken together with RA and intervening atoms(s) in other cases to form a 4 to 6-membered heterocycloalkyl ring, wherein the 4 to 6-membered heterocycloalkyl ring is connected to ring A in a spiro or fused arrangement, and the heterocycloalkyl ring is optionally substituted with oxo. In an embodiment, the heterocycloalkyl ring is selected from oxetanyl, azetidinyl optionally substituted with methyl (e.g., N-methylazetidinyl), tetrahydrofuranyl, dioxolanyl, pyrrolidinyl optionally substituted with oxo (e.g., 2-pyrrolidinyl), tetrahydropyranyl, piperidinyl, and morpholinyl. In an embodiment, the heterocycloalkyl ring is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, oxo-optionally substituted pyrrolidinyl (e.g., 2-pyrrolidinonyl), tetrahydropyranyl, piperidinyl, and morpholinyl.

[0288] In another embodiment, ring A is R in two cases A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms to form a (C5-C7)cycloalkyl ring, wherein the (C5-C7)cycloalkyl ring is connected to ring A in a cross-linked arrangement. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl ring, said (C4-C7)cycloalkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases Aand is taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl ring, said (C4-C7)cycloalkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, and -C(O)N((C1-C3)alkyl)2. In an embodiment, the (C4-C7)cycloalkyl ring is selected from cyclobutyl (e.g., cyclobutane-2-onyl) optionally substituted with oxo, -C(O)OH, and -C(O)N(CH3)2. In an embodiment, ring A is R in both cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl ring, said (C4-C7)cycloalkyl ring is connected to ring A in a spiro, crosslinked, or fused arrangement, said cycloalkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, and -C(O)N((C1-C3)alkyl)2.

[0289] In an embodiment, ring A is unsubstituted. In an embodiment, ring A is an unsubstituted (C6-C8)cycloalkane. In an embodiment, ring A is an unsubstituted cyclohexane. In an embodiment, ring A is an unsubstituted cycloheptane. In an embodiment, ring A is an unsubstituted cyclooctane. In an embodiment, ring A is an unsubstituted heptocycloalkene. In an embodiment, ring A is an unsubstituted 5 to 7-membered heterocycloalkane. In an embodiment, ring A is an unsubstituted 5-membered heterocycloalkane. In an embodiment, ring A is an unsubstituted 6-membered heterocycloalkane. In an embodiment, ring A is an unsubstituted 7-membered heterocycloalkane.

[0290] In another embodiment, ring A is R in one, two, or three cases as defined herein. A It is replaced with. In an embodiment, ring A is R in one or both cases as defined herein. AIt is replaced with. In an embodiment, ring A is R in one case. A It is replaced with. In the embodiment, ring A is R in two cases. A It is replaced with. In the embodiment, ring A is R in three cases. A It is replaced with.

[0291] In the implementation example, R A In each case for the group, the -(C1-C3)alkyl group is optionally substituted with one or more -OH groups, for example, independently selected from -CH2OH and -C(CH3)2OH. In an embodiment, R A In each case for the group, the -(C1-C3)alkyl is independently methyl or ethyl, which is optionally substituted with one or more halos or -OH groups. In an embodiment, R A In each case, the -(C1-C3)alkyl group selectively substituted with one or more halos for the group is independently selected from -CH3, -CF3 and -CH2CF3.

[0292] In the implementation example, R A In each case for the group, the 3 to 6-membered heterocycloalkyl is independently morpholinyl (e.g., 4-morpholinyl).

[0293] In an embodiment, the -(C1-C3)alkyl for the R' group in each case is independently an ethyl optionally substituted with one or more halos. In an embodiment, the -(C1-C3)alkyl for the R' group in each case is independently -CH2CH2F. In an embodiment, the -(C3-C4)cycloalkyl for the R' group in each case is independently -cyclopropyl. In an embodiment, the 3 to 4-membered heterocycloalkyl for the R' group in each case is independently -oxetanyl (e.g., -oxetane-3-yl).

[0294] In an embodiment, the -O(C1-C3)alkyl group for each case of the R'' group is independently -OCH3. In an embodiment, the -O(C1-C3)alkyl group for each case of the R'' group is independently -CH3.

[0295] In an embodiment, ring A is

[0296] ,

[0297] ,

[0298] ,

[0299]

[0300] Selected from, where dotted lines indicate fusion points with the pyrrole ring. These structures are ring A when ring A is substituted and R in one or more cases. A City.

[0301] In an embodiment, ring A is

[0302] ,

[0303] ,

[0304] ,

[0305] ,

[0306] Selected from, where dotted lines indicate fusion points with the pyrrole ring. These structures are ring A when ring A is substituted and R in one or more cases. A City.

[0307] In the implementation example, R 1 is -H. In the implementation example, R 1 is a halo. In an embodiment, R 1 is -F.

[0308] In the implementation example, R 2 R in one or two cases as defined herein B -(C6-C replaced by 10 ) It is Aryl. In the implementation example, R2 is R in one case B -(C6-C replaced by 10 ) It is Aryl. In the implementation example, R 2 R in the two cases B -(C6-C replaced by 10 ) It is Aryl. In the implementation example, R 2 R in one or two cases as defined herein B It is a phenyl substituted with . In an embodiment, R 2 is R in one case B It is a phenyl substituted with . In an embodiment, R 2 R in the two cases B It is a phenyl substituted with .

[0309] In the embodiment, each R B is independently selected from halos (e.g., -F), -OH, -NH2, -SF5, and -O(C1-C3)alkyls optionally substituted with one or more halos (e.g., -F). In an embodiment, each R B is independently selected from halos (e.g., -F), -OH, -NH2, and -O(C1-C3)alkyls optionally substituted with one or more halos (e.g., -F). In an embodiment, each R B is independently selected from -O(C1-C3)alkyls optionally substituted with -NH2, -SF5, and one or more halos (e.g., -F). In an embodiment, R B In each case for the group, the -O(C1-C3)alkyl is independently an -O(methyl) optionally substituted with one or more halos. In an embodiment, R B In each case, the -O(C1-C3)alkyl group optionally substituted with one or more halos for the group is independently -OCF3. In an embodiment, each R B is independently selected from -NH2, -SF5, and -OCF3. In an embodiment, each R B It is independently selected from -NH2 and -OCF3.

[0310] In the implementation example, R 2 is R in one or two cases B -(C6-C replaced by 10 )aryl, and here each R B is independently selected from -NH2, -SF5, and -OCF3. In an embodiment, R 2 is R in one or two cases B -(C6-C replaced by 10 )aryl, and here each R B is independently selected from -NH2 and -OCF3. In an embodiment, R 2 is R in one or two cases B It is a phenyl substituted with , where each R B is independently selected from -NH2, -SF5, and -OCF3. In an embodiment, R 2 is R in one or two cases B It is a phenyl substituted with , where each R B is independently selected from -NH2 and -OCF3. In an embodiment, R 2 R in the two cases B It is a phenyl substituted with , where R in one case B is -NH2, and R in other cases B is selected from -SF5 and -OCF3. In an embodiment, R 2 R in the two cases B It is a phenyl substituted with , where R in one case B is -NH2, and R in other cases B is -OCF3. In the implementation example, R 2 is R in one case B It is a phenyl substituted with , where R B is -OCF3.

[0311] In the implementation example, R 2 Is

[0312]

[0313] Selected from. In an embodiment, R 2 Is

[0314]

[0315] Selected from. In an embodiment, R 2 Is am.

[0316] In an embodiment, n is 0 or 1. In an embodiment, n is 1 or 2. In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2.

[0317] In the implementation example, R 1 is -F, and n is 1.

[0318] In an embodiment, the compound is a compound of Formula II.

[0319] [Chemical Formula II]

[0320]

[0321] or a pharmaceutically acceptable salt thereof, wherein, in the above formula, Ring A and R 1 ...is as defined herein, and R B1 -H and R as defined herein B Selected from, R B2 R as defined herein B It is selected from. In an example implementation, R B1 It is selected from -H and -NH2. In an embodiment, R B2 is selected from -OCF3 and -SF5 (e.g., -OCF3). In an example implementation, R B1 It is selected from -H and -NH2, and R B2 is -OCF3.

[0322] In an embodiment, the compound is a compound of Formula II.

[0323] [Chemical Formula II]

[0324]

[0325] or a pharmaceutically acceptable salt thereof, wherein, in the above formula,

[0326] Ring A is a (C5-C8)cycloalkane or a 6- to 7-membered heterocycloalkane, where ring A is R in one or more cases. A Optionally replaced with,

[0327] Here, each case R A Is

[0328] (a) independently selected from -OH, oxo, -NHR', -C(O)CH3, -(C1-C3)alkyl, and -O(C1-C3)alkyl, and

[0329] Here, each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl selectively substituted with one or more halos;

[0330] (b) R in another case A and taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo;

[0331] R 1 is selected from -H and -F;

[0332] R B1 It is selected from -H and -NH2, and

[0333] R B2 is selected from -OCF3 and -SF5, and

[0334] However, R B1 This is -H and R B2 g is -SF5, and R 1 In the case of -H, ring A is not unsubstituted cyclopentane.

[0335] In an embodiment, ring A is a (C5-C8)cycloalkane or a 6- to 7-membered heterocycloalkane, wherein ring A is R in one or both cases as defined herein. A It is optionally replaced with.

[0336] In an embodiment, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydropyran, piperidine, oxephane, and azephane, wherein ring A is R in one or more cases (e.g., one or two cases) as defined herein. A It is optionally replaced with.

[0337] In an embodiment, ring A is

[0338]

[0339] Selected from, where the dotted linkage indicates the fusion point with the pyrrole ring, and ring A is one or more of (e.g., one or two cases) R as defined herein. A It is optionally replaced with.

[0340] In an embodiment, ring A is

[0341]

[0342] Selected from, where the dotted linkage indicates the fusion point with the pyrrole ring, and ring A is one or more of (e.g., one or two cases) R as defined herein. A It is optionally replaced with.

[0343] In the implementation example, R in each case A is independently selected from -OH, oxo, -NHR', -C(O)CH3, -CH3, and -OCH3, where each R' is selected from -CH2CH2F, -cyclopropyl, and -oxetanyl (e.g., -oxetane-3-yl).

[0344] In another implementation, R in two cases AIt is taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo.

[0345] In an embodiment, ring A is unsubstituted. In an embodiment, ring A is an unsubstituted (C6-C8)cycloalkane. In an embodiment, ring A is an unsubstituted 5 to 6-membered heterocycloalkane.

[0346] In another embodiment, ring A is R in one or two cases as defined herein. A It is replaced with. In an embodiment, ring A is R in one case. A It is replaced with. In the embodiment, ring A is R in two cases. A It is replaced with. In the embodiment, ring A is R in two cases. A It is replaced with, where one case R A is R in other cases A and is taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo. The (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring may be bonded to ring A in a spiro, fused, or cross-linked arrangement.

[0347] In an embodiment, R in two cases where ring A is taken together with intervening atoms(s) to form a 4 to 6-membered heterocycloalkyl ring A It is substituted with, wherein the heterocycloalkyl ring is optionally substituted with an oxo. The 4 to 6-membered heterocycloalkyl ring may be bonded to ring A in a spiro, fused, or cross-linked arrangement. In an embodiment, ring A is taken together with intervening atoms(s) to form the two cases of R that form the 4 to 6-membered heterocycloalkyl ring. AIt is substituted with, wherein the 4 to 6-membered heterocycloalkyl ring is bonded to ring A in a spiro or fused arrangement, and wherein the heterocycloalkyl ring is optionally substituted with an oxo. In an embodiment, the 4 to 6-membered heterocycloalkyl ring comprises one or two cyclic heteroatoms independently selected from O and N. In an embodiment, the 4 to 6-membered heterocycloalkyl ring is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl optionally substituted with an oxo (e.g., 2-pyrrolidinonyl), tetrahydropiperidinyl, and piperidinyl.

[0348] In an embodiment, ring A is taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl ring in two cases R. A It is substituted with, where the (C5-C7)cycloalkyl ring is bonded to ring A in a cross-linked arrangement.

[0349] In the implementation example, R A In each case for the group, the -(C1-C3)alkyl group is independently -CH3. In an embodiment, R A The -O(C1-C3)alkyl group in each case is independently -OCH3.

[0350] In an embodiment, the -(C1-C3)alkyl group for the R' group in each case is independently ethyl, which is optionally substituted with one or more halos. In an embodiment, the -(C1-C3)alkyl group for the R' group in each of the above cases is independently -CH2CH2F.

[0351] In an embodiment, the -(C3-C4)cycloalkyl for each case of the R' group is independently -cyclopropyl. In an embodiment, the 3 to 4 heterocycloalkyl for each case of the R' group is independently -oxetanyl (e.g., -oxetane-3-yl).

[0352] In an embodiment, the compound is a compound of Formula II or a pharmaceutically acceptable salt thereof, wherein, in the formula,

[0353] Ring A is a (C5-C8)cycloalkane or a 6- to 7-membered heterocycloalkane, where ring A is R in one or both cases. A Optionally replaced with,

[0354] Here, each case R A Is

[0355] (a) Independently selected from -OH, oxo, -NHR', -C(O)CH3, -CH3, and -OCH3, and

[0356] Here, each R' is selected from -CH2CH2F, -cyclopropyl, and -oxetanyl (e.g., -oxetane-3-yl);

[0357] (b) R in another case A and taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo;

[0358] R 1 is selected from -H and -F;

[0359] R B1 It is selected from -H and -NH2, and

[0360] R B2 is selected from -OCF3 and -SF5, and

[0361] However, R B1 This is -H and R B2 g is -SF5, and R 1 In the case of -H, ring A is not unsubstituted cyclopentane.

[0362] In an embodiment, ring A is

[0363] ,

[0364]

[0365] Selected from, where dotted lines indicate fusion points with the pyrrole ring. These structures are ring A when ring A is substituted and R in one or more cases. A City.

[0366] In the implementation example, R 1 is -F.

[0367] In the implementation example, R B1 is -H. In another implementation, R B1 It is -NH2.

[0368] In the implementation example, R B2 is -OCF3. In the implementation example, R B1 is -H, and R B2 is -OCF3. In other implementations, R B1 is -NH2, and R B2 is -OCF3. In the implementation example, R B1 is -NH2, and R B2 is -SF5.

[0369] In an embodiment, the compound is a compound of Formula III or Formula IV.

[0370] [Chemical Formula III]

[0371]

[0372] [Chemical Formula IV]

[0373]

[0374] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula, ring A and R 1 is as defined herein. In an embodiment, the compound is a compound of Formula III or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is a compound of Formula IV or a pharmaceutically acceptable salt thereof. In some embodiments, R 1 is -H. In the implementation example, R 1 is -F.

[0375] In an embodiment, the compound is a compound of formula V.

[0376] [Chemical Formula V]

[0377]

[0378] or a pharmaceutically acceptable salt thereof, wherein in the above formula, ring A and R 1 ...is as defined herein, provided that R 1 In the case of -H, ring A is not unsubstituted cyclopentane. In an embodiment, R 1 is -H. In the implementation example, R 1 is -F.

[0379] In an embodiment, the compound is a compound of formula VI.

[0380] [Chemical Formula VI]

[0381]

[0382] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula, ring A and R 1 is as defined herein. In an exemplary embodiment, R 1 is -H. In the implementation example, R 1 is -F.

[0383] In an embodiment, the compound is selected from the group consisting of the following:

[0384] - [4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0385] - [4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0386] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,14-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one;

[0387] - trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0388] - trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0389] - trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0390] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0391] - [4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0392] - [4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,4'-piperidine]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0393] - [4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-oxetane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0394] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0395] - [4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indole-7,2'-dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0396] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one;

[0397] - [4-(3-fluoro-6-hydroxy-6-methyl-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0398] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]methanone;

[0399] - 1-[12-fluoro-13-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene-4-yl]ethanone;

[0400] - [4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0401] - [4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0402] - [4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0403] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)-1-piperidyl]methanone;

[0404] - [4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0405] - cis-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0406] - cis-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0407] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene-13-yl)-1-piperidyl]methanone;

[0408] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-oxetane]-4-yl)-1-piperidyl]methanone;

[0409] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one;

[0410] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-12-one;

[0411] - [4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0412] - cis-[4-[4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0413] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-12-one;

[0414] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one;

[0415] - [4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]]methanone;

[0416] - [4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-tetrahydropyran]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0417] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-tetrahydropyran]-4-yl)-1-piperidyl]methanone;

[0418] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,4'-tetrahydropyran]-12-yl)-1-piperidyl]methanone;

[0419] - [4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0420] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0421] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0422] - [4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,4'-tetrahydropyran]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0423] - [4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,3'-pyrrolidine]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0424] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one;

[0425] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indole-7,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]methanone;

[0426] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-3,3'-tetrahydrofuran]-12-yl)-1-piperidyl]methanone;

[0427] - [4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-3,3'-tetrahydrofuran]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0428] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0429] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0430] - [4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyrido[2,3-b]indole-6,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0431] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0432] - [4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-3,3'-pyrrolidine]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0433] - [4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0434] - [4-(3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0435] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5,7,8,9-tetrahydropyrido[2,3-b]indole-6-one;

[0436] - [4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]]methanone;

[0437] - [4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-azetidine]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0438] - [4-(12-fluoro-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0439] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0440] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0441] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indole-6-one;

[0442] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0443] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-4-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene-13-yl)-1-piperidyl]methanone;

[0444] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0445] - [2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-(7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-12-yl)-1-piperidyl]methanone;

[0446] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-12-yl)-1-piperidyl]methanone;

[0447] - [4-(7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0448] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]]methanone;

[0449] - [4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0450] - [4-(12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0451] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0452] - trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0453] - [4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0454] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0455] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0456] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-13-methyl-6,8,13-triaztricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0457] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0458] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone; and

[0459] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone,

[0460] and pharmaceutically acceptable salts thereof.

[0461] In an embodiment, the compound is selected from the group consisting of the following:

[0462] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0463] - 3-fluoro-N,N-dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0464] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0465] - Methyl 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-11-carboxylate;

[0466] - Methyl 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carboxylate;

[0467] - [4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0468] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0469] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0470] - [4-(4'-fluorospiro[1,3-dioxolane-2,12'-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene]-3'-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0471] - [4-[4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0472] - [4-[4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0473] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0474] - [4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0475] - [4-(4-fluoro-14-oxa-6,8,11-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0476] - [4-[(trans)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0477] - [4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0478] - [4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0479] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,2'-cyclobutane]-1'-one;

[0480] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0481] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0482] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-azetidine]-4-yl)-1-piperidyl]methanone;

[0483] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0484] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0485] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0486] - [4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-azetidine]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0487] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0488] - [4-[4-fluoro-12-(oxetane-3-yl)-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0489] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-azetidine]-4-yl)-1-piperidyl]methanone;

[0490] - [4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0491] - [4-[4-fluoro-13-(oxetane-3-yl)-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0492] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0493] - [4-(12-cyclopropyl-4-fluoro-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0494] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0495] - [4-(13-cyclopropyl-4-fluoro-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0496] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0497] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0498] - [4-(3-fluoro-6-morpholino-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0499] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0500] - [4-(4-fluoro-12,12-dioxo-12λ 6 -thia-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0501] - [4-(4-fluoro-13,13-dioxo-13λ 6 -thia-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0502] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0503] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0504] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0505] - [4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0506] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0507] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carbonitrile;

[0508] - [4-[3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0509] - [4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0510] - [4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0511] - 1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-yl]ethanone;

[0512] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0513] - 1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-13-yl]ethanone;

[0514] - [4-[4-fluoro-12-(2,2,2-trifluoroethyl)-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0515] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,1'-cyclobutane]-4-yl)-1-piperidyl]methanone;

[0516] - [4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,1'-cyclobutane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0517] - [4-[4-fluoro-13-(2,2,2-trifluoroethyl)-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0518] - [4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]methanone;

[0519] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0520] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]methanone;

[0521] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0522] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0523] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidin]-2'-one;

[0524] - [4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0525] - [4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0526] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0527] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0528] - [4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0529] - [4-(4-fluoro-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0530] - [4-(4-fluoro-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0531] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidin]-2'-one;

[0532] - [4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0533] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carbonitrile;

[0534] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0535] - [4-[(cis)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),11,13,15-tetraene-15-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0536] - [4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0537] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0538] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatrisanclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-12-one;

[0539] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carbonitrile;

[0540] - 1-[13-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-12-fluoro-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene-4-yl]ethanone;

[0541] - 4-fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0542] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraen-12-one;

[0543] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one;

[0544] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0545] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0546] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0547] - [2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0548] - [4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0549] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-11,11-dimethyl-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0550] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-14-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0551] - [4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0552] - [2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0553] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0554] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,11-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-12-one;

[0555] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl)-1-piperidyl]methanone;

[0556] - [4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0557] - [4-[3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0558] - [2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0559] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-11-one;

[0560] - [4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0561] - [4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(pentafluoro-λ 6-sulfanyl)phenyl]methanone;

[0562] - [4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]methanone;

[0563] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0564] - [4-(4-fluoro-6,8,13-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0565] - [4-(14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),11,13,15-tetraene-15-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0566] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0567] - [4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0568] - [4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0569] - [4-[(cis)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0570] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0571] - [4-[12-fluoro-4-(2,2,2-trifluoroethyl)-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0572] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3,6,6-trifluoro-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0573] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-fluoro-4-(2,2,2-trifluoroethyl)-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl]-1-piperidyl]methanone;

[0574] - [4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0575] - [4-[(trans)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0576] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0577] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-11-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0578] - [4-[(cis)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0579] - 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0580] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0581] - [4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0582] - [4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0583] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0584] - 4-fluoro-13-methyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;

[0585] - [4-(trifluoromethoxy)phenyl]-[4-(3,6,6-trifluoro-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0586] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8,14-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one;

[0587] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl)-1-piperidyl]methanone;

[0588] - [4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0589] - [4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0590] - [4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0591] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0592] - [4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0593] - [4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0594] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl)-1-piperidyl]methanone;

[0595] - [4-[(cis)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0596] - [4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0597] - [4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,3'-pyrrolidine]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0598] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0599] - [4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5,12-pentane-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0600] - [4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0601] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0602] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carbonitrile;

[0603] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-13-carbonitrile;

[0604] - 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carbonitrile; and

[0605] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone,

[0606] and pharmaceutically acceptable salts thereof.

[0607] In an embodiment where the compound has a mirror image form (e.g., the compound has a chiral center such as a chiral carbon atom), the compound exists as a racemic mixture of the mirror images. In an embodiment where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (R) isomer. In another embodiment where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (S) isomer. Thus, in an embodiment, the compound is selected from the group consisting of the following:

[0608] - (rac)-[4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0609] - [4-[(6R)-3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0610] - [4-[(6S)-3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0611] - (rac)-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0612] - (rac)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0613] - (rac)-trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0614] - (rac)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0615] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0616] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0617] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0618] - (rac)-2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone (rac)-[4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0619] - [4-[(6R)-6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0620] - [4-[(6S)-6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0621] - (rac)-[4-(3-fluoro-6-hydroxy-6-methyl-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0622] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]methanone;

[0623] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4R)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]methanone;

[0624] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4S)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]methanone;

[0625] - (rac)-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0626] - [4-[(4R)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0627] - [4-[(4S)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0628] - (rac)-[4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0629] - (rac)-[4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0630] - (rac)-cis-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0631] - (rac)-cis-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0632] - (rac)-[4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0633] - [4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0634] - [4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0635] - (rac)-cis-[4-[4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0636] - [4-[(11S, 15S)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0637] - [4-[(11R, 15R)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0638] - (rac)-[4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0639] - (rac)-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0640] - [4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0641] - [4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0642] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0643] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0644] - (rac)-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,3'-pyrrolidine]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0645] - [4-[(4R)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,3'-pyrrolidine]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0646] - [4-[(4S)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,3'-pyrrolidine]-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0647] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-3,3'-tetrahydrofuran]-12-yl)-1-piperidyl]methanone;

[0648] - (rac)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-3,3'-tetrahydrofuran]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0649] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0650] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0651] - (rac)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-3,3'-pyrrolidine]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0652] - (rac)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0653] - (rac)-[4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0654] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0655] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0656] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0657] - (rac)-[4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0658] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0659] - (6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;

[0660] - (6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0661] - (rac)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0662] - [4-[(3R, 8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0663] - [4-[(3S, 8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0664] - (rac)-[4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0665] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0666] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(1R,12S)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0667] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(1S,12R)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0668] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0669] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0670] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0671] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0672] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone; and

[0673] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone,

[0674] and pharmaceutically acceptable salts thereof.

[0675] In an embodiment, the compound is selected from the group consisting of the following:

[0676] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0677] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0678] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0679] - (rac)-3-fluoro-N,N-dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0680] - (trans)-3-fluoro-N,N-dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0681] - (cis)-3-fluoro-N,N-dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0682] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0683] - (trans)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0684] - (cis)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0685] - (rac)-methyl 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-11-carboxylate;

[0686] - Methyl (11R)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-11-carboxylate;

[0687] - (rac)-methyl 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carboxylate;

[0688] - Methyl (12R)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carboxylate;

[0689] - Methyl (11S)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-11-carboxylate;

[0690] - Methyl (12S)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carboxylate;

[0691] - (rac)-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0692] - [4-[(6R)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0693] - [4-[(6S)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0694] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0695] - (6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0696] - (6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0697] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0698] - (6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0699] - (6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0700] - [4-[(12E / Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0701] - [4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0702] - [4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0703] - [4-[(13E / Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0704] - [4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0705] - [4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0706] - (rac)-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0707] - (rac)-[4-[(trans)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0708] - [4-[(3R,8S)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0709] - (rac)-[4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0710] - [4-[(2S,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0711] - [4-[(2R,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0712] - (rac)-[4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0713] - [4-[(3S,8R)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0714] - [4-[(2S,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0715] - [4-[(2R,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0716] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,2'-cyclobutane]-1'-one;

[0717] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0718] - (7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0719] - (7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0720] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0721] - (5R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0722] - (5S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0723] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E / Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0724] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0725] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0726] - (7R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0727] - (7S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;

[0728] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0729] - (5R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0730] - (5S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carbonitrile;

[0731] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0732] - (5R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0733] - (5S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0734] - (rac)-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0735] - [4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0736] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E / Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0737] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0738] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0739] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0740] - (7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0741] - (7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0742] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E / Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0743] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0744] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0745] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E / Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0746] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0747] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0748] - (rac)-[4-(3-fluoro-6-morpholino-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0749] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0750] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0751] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0752] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0753] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0754] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0755] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0756] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0757] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0758] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0759] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0760] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0761] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;

[0762] - (rac)-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0763] - [4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0764] - [4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0765] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0766] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0767] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0768] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carbonitrile;

[0769] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-(6R)-carbonitrile;

[0770] - 3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-(6S)-carbonitrile;

[0771] - [4-[(6E / Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0772] - [4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0773] - [4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0774] - (rac)-[4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0775] - [4-[3-fluoro-(7R)-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0776] - [4-[3-fluoro-(7S)-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0777] - (rac)-[4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0778] - [4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0779] - [4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0780] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0781] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0782] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0783] - (rac)-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]methanone;

[0784] - [4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]methanone;

[0785] - [4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]methanone;

[0786] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0787] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]methanone;

[0788] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4R)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]methanone;

[0789] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4S)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]methanone;

[0790] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0791] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0792] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0793] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;

[0794] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidin]-2'-one;

[0795] - (6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidine]-2'-one;

[0796] - (6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidine]-2'-one;

[0797] - (rac)-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0798] - (rac)-[4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0799] - [4-[(6R)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0800] - [4-[(6S)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0801] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0802] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0803] - (rac)-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0804] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidin]-2'-one;

[0805] - (6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidine]-2'-one;

[0806] - (6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-pyrrolidin]-2'-one;

[0807] - (rac)-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0808] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carbonitrile;

[0809] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0810] - (rac)-[4-[(cis)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),11,13,15-tetraene-15-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0811] - [4-[(11R,16R)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),11,13,15-tetraene-15-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0812] - [4-[(11S,16S)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),11,13,15-tetraene-15-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0813] - (rac)-[4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0814] - [4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0815] - [4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0816] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0817] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carbonitrile;

[0818] - 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraen-12-one;

[0819] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0820] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0821] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0822] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0823] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0824] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0825] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0826] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;

[0827] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadeca-1(10),12,14,16-tetraene-16-yl]-1-piperidyl]methanone;

[0828] - (rac)-[2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0829] - [2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0830] - [2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0831] - (rac)-[4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0832] - [4-[(6R)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0833] - [4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0834] - (rac)-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0835] - (rac)-[2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0836] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0837] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0838] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;

[0839] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl)-1-piperidyl]methanone;

[0840] - (rac)-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-tetrahydrofuran]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0841] - [4-[(7E / Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0842] - [4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0843] - [4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0844] - (rac)-[2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0845] - (rac)-[4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0846] - [4-[(6R)-3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0847] - [4-[(6S)-3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0848] - (rac)-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(pentafluoro-λ6 -sulfanyl)phenyl]methanone;

[0849] - (rac)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(pentafluoro-λ 6 -sulfanyl)phenyl]methanone;

[0850] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0851] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0852] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0853] - (rac)-[4-(4-fluoro-6,8,13-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0854] - (rac)-[4-(14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadeca-1(9),11,13,15-tetraene-15-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0855] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0856] - (6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;

[0857] - (6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0858] - (rac)-[4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0859] - (rac)-[4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0860] - (rac)-[4-[(cis)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0861] - [4-[(1R,12R)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0862] - [4-[(1S,12S)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0863] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0864] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(1R,12R)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0865] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(1S,12S)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl]-1-piperidyl]methanone;

[0866] - (rac)-[4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0867] - (rac)-[4-[(trans)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0868] - [4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0869] - [4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0870] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0871] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0872] - (rac)-[4-[(cis)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0873] - [4-[(11R,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0874] - (rac)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0875] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;

[0876] - (rac)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidin]-2'-one;

[0877] - (rac)-[4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0878] - [4-[(12R)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0879] - [4-[((12S)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0880] - (rac)-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0881] - [4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0882] - [4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0883] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0884] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0885] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0886] - [4-[(11S,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0887] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl)-1-piperidyl]methanone;

[0888] - (rac)-[4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraene-8-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0889] - (rac)-[4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0890] - [4-[(6R)-3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0891] - [4-[(6S)-3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0892] - (rac)-[4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0893] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;

[0894] - (rac)-[4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0895] - (rac)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0896] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraene-4,3'-tetrahydrofuran]-12-yl)-1-piperidyl]methanone;

[0897] - (rac)-[4-[(cis)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0898] - (rac)-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0899] - (rac)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-4,3'-pyrrolidine]-12-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;

[0900] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;

[0901] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0902] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0903] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0904] - (rac)-4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carbonitrile;

[0905] - (rac)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-13-carbonitrile;

[0906] - (rac)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-12-carbonitrile;

[0907] - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;

[0908] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone; and

[0909] - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone,

[0910] and pharmaceutically acceptable salts thereof.

[0911] In an embodiment, the compound is selected from compounds prepared in Examples 1 to 294 (i.e., from the group consisting of compounds 1 to 294) and pharmaceutically acceptable salts thereof. In another embodiment, the compound is selected from compounds obtainable by the synthesis method described in any one of Examples 1 to 294 (i.e., the synthesis method of compounds 1 to 294) and pharmaceutically acceptable salts thereof. In an embodiment, the compound is selected from compounds prepared in Examples 1 to 90 (i.e., from the group consisting of compounds 1 to 90) and pharmaceutically acceptable salts thereof. In another embodiment, the compound is selected from compounds obtainable by the synthesis method described in any one of Examples 1 to 90 (i.e., the synthesis method of compounds 1 to 90) and pharmaceutically acceptable salts thereof. In an embodiment, the compound is selected from compounds prepared in Examples 91 to 294 (i.e., from the group consisting of compounds 91 to 294) and pharmaceutically acceptable salts thereof. In another embodiment, the compound is selected from compounds obtainable by the synthesis method described in any one of Examples 91 to 294 (i.e., the synthesis method of compounds 91 to 294) and pharmaceutically acceptable salts thereof.

[0912] In the embodiments, the compound is Examples 8, 9, 14, 29, 30, 44, 59, 67, 68, 79, 81, 83, 85, 86, 87, 90, 91, 111, 122, 125, 126, 136, 137, 139, 144, 145, 146, 147, 149, 150, 154, 155, 156, 159, 160, 161, 168, 171, 172, 173, 183, 184, 185, 191, 192, 204, 210, 222, 227, 228, 233, Prepared from any one of 240, 245, 288, 289, 293, and 294 (i.e., compounds 8, 9, 14, 29, 30, 44, 59, 67, 68, 79, 81, 83, 85, 86, 87, 90, 91, 111, 122, 125, 126, 136, 137, 139, 144, 145, 146, 147, 149, 150, 154, 155, 156, 159, 160, 161, 168, 171, 172, 173, 183, 184, 185, 191, 192, It is selected from compounds (from the group consisting of 204, 210, 222, 227, 228, 233, 240, 245, 288, 289, 293, and 294 and their pharmaceutically acceptable salts).

[0913] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[0914]

[0915] Or it is a pharmaceutically acceptable salt thereof.

[0916] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[0917]

[0918] Or it is a pharmaceutically acceptable salt thereof.

[0919] In one embodiment, the compound is (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone

[0920]

[0921] Or it is a pharmaceutically acceptable salt thereof.

[0922] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene-13-yl)-1-piperidyl]methanone

[0923]

[0924] Or it is a pharmaceutically acceptable salt thereof.

[0925] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-oxetane]-4-yl)-1-piperidyl]methanone

[0926]

[0927] Or it is a pharmaceutically acceptable salt thereof.

[0928] In one embodiment, the compound is [4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0929]

[0930] Or it is a pharmaceutically acceptable salt thereof.

[0931] In one embodiment, the compound is [4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0932]

[0933] Or it is a pharmaceutically acceptable salt thereof.

[0934] In one embodiment, the compound is (rac)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0935]

[0936] Or it is a pharmaceutically acceptable salt thereof.

[0937] In one embodiment, the compound is 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indole-6-one

[0938]

[0939] Or it is a pharmaceutically acceptable salt thereof.

[0940] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone

[0941]

[0942] Or it is a pharmaceutically acceptable salt thereof.

[0943] In one embodiment, the compound is (6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one

[0944]

[0945] Or it is a pharmaceutically acceptable salt thereof.

[0946] In one embodiment, the compound is (6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one

[0947]

[0948] Or it is a pharmaceutically acceptable salt thereof.

[0949] In one embodiment, the compound is [4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0950]

[0951] Or it is a pharmaceutically acceptable salt thereof.

[0952] In one embodiment, the compound is [4-[(3S,8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0953]

[0954] Or it is a pharmaceutically acceptable salt thereof.

[0955] In one embodiment, the compound is [4-((2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0956]

[0957] Or it is a pharmaceutically acceptable salt thereof.

[0958] In one embodiment, the compound is [4-((2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[0959]

[0960] Or it is a pharmaceutically acceptable salt thereof.

[0961] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone

[0962]

[0963] Or it is a pharmaceutically acceptable salt thereof.

[0964] In one embodiment, the compound is 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-13-methyl-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one

[0965]

[0966] Or it is a pharmaceutically acceptable salt thereof.

[0967] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone

[0968]

[0969] Or it is a pharmaceutically acceptable salt thereof.

[0970] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone

[0971]

[0972] Or it is a pharmaceutically acceptable salt thereof.

[0973] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone

[0974]

[0975] Or it is a pharmaceutically acceptable salt thereof.

[0976] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[0977]

[0978] Or it is a pharmaceutically acceptable salt thereof.

[0979] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[0980]

[0981] Or it is a pharmaceutically acceptable salt thereof.

[0982] In one embodiment, the compound is (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[0983]

[0984] Or it is a pharmaceutically acceptable salt thereof.

[0985] In one embodiment, the compound is (7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile

[0986]

[0987] Or it is a pharmaceutically acceptable salt thereof.

[0988] In one embodiment, the compound is (7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile

[0989]

[0990] Or it is a pharmaceutically acceptable salt thereof.

[0991] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-azetidine]-4-yl)-1-piperidyl]methanone

[0992]

[0993] Or it is a pharmaceutically acceptable salt thereof.

[0994] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[0995]

[0996] Or it is a pharmaceutically acceptable salt thereof.

[0997] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[0998]

[0999] Or it is a pharmaceutically acceptable salt thereof.

[1000] In one embodiment, the compound is [4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1001]

[1002] Or it is a pharmaceutically acceptable salt thereof.

[1003] In one embodiment, the compound is [4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1004]

[1005] Or it is a pharmaceutically acceptable salt thereof.

[1006] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1007]

[1008] Or it is a pharmaceutically acceptable salt thereof.

[1009] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1010]

[1011] Or it is a pharmaceutically acceptable salt thereof.

[1012] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1013]

[1014] Or it is a pharmaceutically acceptable salt thereof.

[1015] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1016]

[1017] Or it is a pharmaceutically acceptable salt thereof.

[1018] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1019]

[1020] Or it is a pharmaceutically acceptable salt thereof.

[1021] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1022]

[1023] Or it is a pharmaceutically acceptable salt thereof.

[1024] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1025]

[1026] Or it is a pharmaceutically acceptable salt thereof.

[1027] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1028]

[1029] Or it is a pharmaceutically acceptable salt thereof.

[1030] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone

[1031]

[1032] Or it is a pharmaceutically acceptable salt thereof.

[1033] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone

[1034]

[1035] Or it is a pharmaceutically acceptable salt thereof.

[1036] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone

[1037]

[1038] Or it is a pharmaceutically acceptable salt thereof.

[1039] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone

[1040]

[1041] Or it is a pharmaceutically acceptable salt thereof.

[1042] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone

[1043]

[1044] Or it is a pharmaceutically acceptable salt thereof.

[1045] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone

[1046]

[1047] Or it is a pharmaceutically acceptable salt thereof.

[1048] In one embodiment, the compound is [4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1049]

[1050] Or it is a pharmaceutically acceptable salt thereof.

[1051] In one embodiment, the compound is [4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1052]

[1053] Or it is a pharmaceutically acceptable salt thereof.

[1054] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1055]

[1056] Or it is a pharmaceutically acceptable salt thereof.

[1057] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1058]

[1059] Or it is a pharmaceutically acceptable salt thereof.

[1060] In one embodiment, the compound is [4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1061]

[1062] Or it is a pharmaceutically acceptable salt thereof.

[1063] In one embodiment, the compound is [4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1064]

[1065] Or it is a pharmaceutically acceptable salt thereof.

[1066] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1067]

[1068] Or it is a pharmaceutically acceptable salt thereof.

[1069] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1070]

[1071] Or it is a pharmaceutically acceptable salt thereof.

[1072] In one embodiment, the compound is 1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-13-yl]ethanone I

[1073]

[1074] Or it is a pharmaceutically acceptable salt thereof.

[1075] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1076]

[1077] Or it is a pharmaceutically acceptable salt thereof.

[1078] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1079]

[1080] Or it is a pharmaceutically acceptable salt thereof.

[1081] In one embodiment, the compound is (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone

[1082]

[1083] Or it is a pharmaceutically acceptable salt thereof.

[1084] In one embodiment, the compound is (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1085]

[1086] Or it is a pharmaceutically acceptable salt thereof.

[1087] In one embodiment, the compound is (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1088]

[1089] Or it is a pharmaceutically acceptable salt thereof.

[1090] In one embodiment, the compound is [4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1091]

[1092] Or it is a pharmaceutically acceptable salt thereof.

[1093] In one embodiment, the compound is [4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1094]

[1095] Or it is a pharmaceutically acceptable salt thereof.

[1096] In one embodiment, the compound is 4-fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one

[1097]

[1098] Or it is a pharmaceutically acceptable salt thereof.

[1099] In one embodiment, the compound is [4-[(6R)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1100]

[1101] Or it is a pharmaceutically acceptable salt thereof.

[1102] In one embodiment, the compound is [4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1103]

[1104] Or it is a pharmaceutically acceptable salt thereof.

[1105] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1106]

[1107] Or it is a pharmaceutically acceptable salt thereof.

[1108] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1109]

[1110] Or it is a pharmaceutically acceptable salt thereof.

[1111] In one embodiment, the compound is [4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1112]

[1113] Or it is a pharmaceutically acceptable salt thereof.

[1114] In one embodiment, the compound is [4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1115]

[1116] Or it is a pharmaceutically acceptable salt thereof.

[1117] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1118]

[1119] Or it is a pharmaceutically acceptable salt thereof.

[1120] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1121]

[1122] Or it is a pharmaceutically acceptable salt thereof.

[1123] In one embodiment, the compound is (6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one

[1124]

[1125] Or it is a pharmaceutically acceptable salt thereof.

[1126] In one embodiment, the compound is (6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one

[1127]

[1128] Or it is a pharmaceutically acceptable salt thereof.

[1129] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone

[1130]

[1131] Or it is a pharmaceutically acceptable salt thereof.

[1132] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone

[1133]

[1134] Or it is a pharmaceutically acceptable salt thereof.

[1135] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone

[1136]

[1137] Or it is a pharmaceutically acceptable salt thereof.

[1138] In one embodiment, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone

[1139]

[1140] Or it is a pharmaceutically acceptable salt thereof.

[1141] In an embodiment, the compound of the present disclosure is characterized by its inhibitory activity against ERK5, measured, for example, according to a cell-based assay or a cell-free assay described in the examples below. In an embodiment, the compound has an IC5 of less than about 10 μM for ERK5 (for example, when measured according to the cell-free assay described below). 50 The compound has an IC value of less than about 5 μM, e.g., about 2 μM, 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM for ERK5 (e.g., when measured according to the cell-free assay described below). In an embodiment, the compound has an IC value of less than about 5 μM, e.g., about 2 μM, 1 μM, 0.5 μM, 0.2 μM, 100 nM, or 50 nM for ERK5 (when measured, e.g., according to the cell-free assay described below). 50 It has a value. In an embodiment, the compound has an IC of less than about 10 μM for ERK5 when measured according to the cell-free assay described below. 50 The compound has an IC value of less than about 5 μM, e.g., about 2 μM, 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM for ERK5 when measured according to the cell-free assay described below. In an embodiment, the compound has an IC of less than about 5 μM, e.g., about 2 μM, 1 μM, 0.5 μM, 0.2 μM, 100 nM, or 50 nM for ERK5 when measured according to the cell-free assay described below. 50 It has a value. In an embodiment, the compound has an IC of less than about 10 μM for ERK5 when measured according to the cell-based assay described below. 50The compound has a value. In an embodiment, the compound has an IC of less than about 5 μM, e.g., about 2 μM, 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM for ERK5 when measured according to the cell-based assay described below. 50 It has a value.

[1142] In the embodiment, the compound is Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, It is selected from compounds of 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, and 294. In another embodiment, the compound is Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141,142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, The compound is selected from the compounds of 291, 292, 293, and 294. In other embodiments, the compound is selected from Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,It is selected from compounds of 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, and 294. In another embodiment, the compound is Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 96, 97, 98, 99, 100, 101, 102, 103, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196,197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, of 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, and 294 It is selected from compounds. In another embodiment, the compound is Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 73, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 97, 98, 100, 101, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130,131, 133, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 166, 167, 168, 169, 170, 171, 172, 173, 175, 177, 178, 179, 181, 182, 183, 184, 185, 186, 188, 189, 190, 191, 192, 193, 194, 195, 196, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, The compound is selected from the compounds of 293 and 294. In other embodiments, the compound is selected from Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 16, 17, 18, 19, 20, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 39, 41, 43, 44, 45, 46, 48, 50, 52, 53, 54, 55, 57, 58, 59, 60, 61, 63, 65, 66, 67, 68, 69, 75,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 97, 98, 100, 101, 107, 108, 109, 110, 111, 112, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 128, 129, 131, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 166, 167, 168, 169, 170, 171, 172, 173, 178, 179, 181, 182, 183, 184, 185, 186, 188, 190, 191, 192, 193, 194, 195, 196, 198, 199, 200, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 227, 228, 230, 231, 232, 233, 234, 236, 238, 239, 240, 241, 242, 243, 245, 246, 247, 249, 250, 252, 253, 254, 255, 256, 257, 258, 260, 262, 263, 264, 266, 267, It is selected from compounds of 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, and 294. In another embodiment, the compound is Examples 2, 3, 4, 5, 7, 8, 9, 13, 14, 16, 17, 18, 20, 23, 24, 25, 28, 29, 30, 31, 32, 33, 35, 38, 39, 41, 43, 44, 46,50, 52, 53, 54, 55, 57, 58, 59, 61, 63, 65, 66, 67, 68, 69, 75, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 100, 108, 109, 110, 111, 112, 114, 115, 117, 118, 120, 121, 122, 123, 124, 125, 126, 128, 129, 131, 136, 137, 138, 139, 140, 141, 143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 166, 167, 168, 169, 170, 171, 172, 173, 178, 179, 181, 182, 183, 184, 185, 186, 188, 191, 192, 193, 194, 196, 198, 199, 200, 202, 203, 204, 205, 206, 207, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 223, 225, 226, 227, 228, 230, 232, 233, 234, 239, 240, 241, 242, 243, 245, 249, 250, 252, 254, 257, 258, 260, 262, 267, 269, 271, 272, 273, 274, 275, 276, 277, 278, 282, 286, It is selected from compounds of 287, 288, 289, 290, 291, 292, 293, and 294.

[1143] In the embodiment, the compound is Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228,229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, It is selected from compounds of 280, 281, 282, 283, 284, 285, and 287. In another embodiment, the compound is Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 115, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168,169, 170, 171, 172, 173, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 249, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, It is selected from compounds of 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, and 287. In another embodiment, the compound is Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 117, 118, 119, 120, 121,122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 178, 179, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 249, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 280, The compound is selected from the compounds of 281, 282, 283, 284, 285, and 287. In another embodiment, the compound is selected from Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 20, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 46, 48, 49, 50, 52, 54, 55, 57, 58, 59, 61, 62, 63, 64,65, 66, 67, 68, 69, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 96, 97, 99, 100, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 134, 135, 136, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 178, 179, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, The compound is selected from 240, 241, 242, 243, 244, 245, 246, 247, 249, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 280, 281, 282, 283, 285, and 287. In another embodiment, the compound is selected from Examples 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 16, 17, 20, 23, 24, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38, 41, 43, 44, 46, 48, 49, 52, 54, 55, 57, 58, 59, 61, 63, 64, 65, 66, 67, 68, 69, 75, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 97, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 117, 118, 120, 121, 122, 123, 124, 125, 126, 128, 129, 131, 134, 135, 136, 137, 138, 139, 140, 141, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 170, 171, 172, 173, 178, 181, 182, 183, 184, 185, 186, 188, 191, 192, 193, 194, 195, 196, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 216, 217, 218, 219, 220, 223, 225, 226, It is selected from compounds of 227, 228, 231, 232, 233, 234, 240, 241, 242, 243, 245, 246, 247, 249, 252, 254, 255, 256, 257, 258, 259, 260, 261, 262, 267, 269, 271, 272, 274, 275, 276, 277, 278, 281, 282, 283, 285, and 287. In another embodiment, the compound is Examples 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 14, 17, 20,23, 24, 30, 31, 32, 33, 34, 35, 38, 43, 44, 46, 48, 54, 58, 59, 61, 63, 65, 66, 67, 75, 78, 79, 80, 81, 82, 83, 85, 86, 87, and 90, 91, 92, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 117, 118, 122, 123, 124, 125, 126, 129, 131, 134, 135, 136, 137, 139, 140, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 164, 165, 166, 167, 168, 170, 171, 172, 173, 181, 183, 184, 185, 186, 188, 191, 192, 193, 194, 196, 198, 199, 200, 201, 202, It is selected from compounds of 203, 204, 205, 206, 207, 208, 209, 210, 212, 218, 223, 225, 226, 227, 228, 232, 233, 240, 241, 242, 243, 245, 252, 254, 255, 256, 257, 258, 259, 260, 261, 262, 269, 271, 274, 275, 276, 277, 278, 281, 282, 283, and 285. In another embodiment, the compound is Examples 2, 3, 5, 7, 8, 9, 14, 23, 30, 31, 32, 33, 34, 35, 38, 44, 46, 48, 54, 58, 59, 63, 65, 66, and 67, 78, 79, 80, 81, 82, 83, 85, 86, 90, 103, 105, 106, 109, 110, 111, 118, 122, 123, 125, 126, 129, 131, 134, 135, 136, 137, 139, 140, 144, 145, 146, 147, 149, 150, 153,154, 155, 156, 157, 160, 161, 166, 167, 168, 171, 172, 173, 183, 184, 185, 186, 188, 191, 192, 193, 194, 196, 200, 202, 203, 204, 205, 206, 207, 209, 210, 218, 223, 227, 228, 233, 240, 242, 243, 245, 254, 255, 256, 257, 260, 262, 271, 274, 277, It is selected from the compounds of 281, 282, and 283.

[1144] Manufacturing process of the compounds and intermediate compounds of the present disclosure

[1145] The present disclosure also provides a process for manufacturing a compound as described herein, and an intermediate for use in manufacturing said compound.

[1146] Accordingly, a compound of Formula I as defined herein

[1147] [Chemical Formula I]

[1148] ,

[1149] Or a process for manufacturing a pharmaceutically acceptable salt thereof is provided, wherein the process comprises a compound of the chemical formula HE

[1150] [Chemical formula HE]

[1151]

[1152] Compound of chemical formula J

[1153] [Chemical Formula J]

[1154]

[1155] Includes a step of reacting with:

[1156] In the above formula,

[1157] Q is R as defined herein 2 It is a group (or a protected version thereof), or taken together with an adjacent carbonyl to be an amine protecting group, and

[1158] Ring A, R 1 and n are as defined herein, and X is a halogen (e.g., I, Br, or Cl).

[1159] In the implementation example, R 1 is F.

[1160] In an embodiment, the process comprises a chiral separation step (e.g., for isolating one stereoisomer from a mixture of stereoisomers). In an embodiment, the process comprises a positional isomer separation step (e.g., for isolating one positional isomer from a mixture of positional isomers). In an embodiment, the process comprises a step in which an E (or cis) isomer is separated from a mixture of E and Z isomers. In an embodiment, the process comprises a step in which a Z (or trans) isomer is separated from a mixture of E and Z isomers. Those skilled in the art will be aware of many chiral, stereoisomer, and positional isomer separation methods, e.g., the methods illustrated herein.

[1161] In an embodiment, Q is R as defined herein. 2 It is a protected version of the group. In an embodiment, Q is a phenyl group having a protected amine substituent, optionally together with another substituent (e.g., -OCF3 group).

[1162] In an embodiment, Q is R as defined herein. 2 It is a compound. Therefore, in an embodiment, the compound of formula HE is a compound of formula H below:

[1163] [Chemical Formula H]

[1164]

[1165] In the above equation, R 1 , R 2 , n, and X are as defined herein.

[1166] In an embodiment, the process of reacting compound H with compound J involves the use of a Pd catalyst. In an embodiment, the process involves the use of a Pd catalyst, a base, and a solvent. Those skilled in the art will understand that the reference to "Pd catalyst" includes a Pd catalyst / ligand. In an embodiment, the Pd catalyst is bis(tri-tert-butylphosphine)palladium (0). In an embodiment, the base is 1,4-diazabicyclo[2.2.2]octane. In an embodiment, the solvent is DMF. Thus, in an embodiment, the process involves the use of bis(tri-tert-butylphosphine)palladium (0) as a catalyst, 1,4-diazabicyclo[2.2.2]octane as a base, and DMF as a solvent.

[1167] In an embodiment, the process comprises one or more of the steps shown in Reaction Scheme 1. In an embodiment, the process comprises all the steps shown in Reaction Scheme 1. In an embodiment, the process comprises step 6 of Reaction Scheme 1. In an embodiment, the process comprises one or more of the steps of Method A. In an embodiment, the process is substantially as described in Method A. In an embodiment, the process comprises one or more of the steps of Method D. In an embodiment, the process is substantially as described in Method D.

[1168] In an embodiment, Q taken together with an adjacent carbonyl is an amine protecting group (e.g., Boc). Thus, in an embodiment, the compound of formula HE is a compound of formula E below:

[1169] [Chemical Formula E]

[1170]

[1171] In the above equation, R 1 , n and X are as defined herein.

[1172] In an embodiment, the process of reacting compound E with compound J involves the use of a Pd catalyst. In an embodiment, the process involves the use of a Pd catalyst, a base, and a solvent. Those skilled in the art will understand that the reference to "Pd catalyst" includes a Pd catalyst / ligand. In an embodiment, the Pd catalyst is bis(tri-tert-butylphosphine)palladium (0). In an embodiment, the base is 1,4-diazabicyclo[2.2.2]octane. In an embodiment, the solvent is DMF. Thus, in an embodiment, the process involves the use of bis(tri-tert-butylphosphine)palladium (0) as a catalyst, 1,4-diazabicyclo[2.2.2]octane as a base, and DMF as a solvent.

[1173] In an embodiment, the process comprises one or more of the steps shown in Reaction Scheme 3. In an embodiment, the process comprises step 1 of Reaction Scheme 3. In an embodiment, the process comprises one or more of the steps of Method E. In an embodiment, the process is substantially as described in Method E.

[1174] In another aspect, the present disclosure relates to a compound of Formula I as defined herein.

[1175] [Chemical Formula I]

[1176] ,

[1177] or provides a process for manufacturing a pharmaceutically acceptable salt thereof, wherein the process comprises intramolecular cyclization of a compound of formula MP:

[1178] [Chemical Formula MP]

[1179] ,

[1180] In the above formula,

[1181] Q is R as defined herein 2 It is a group (or a protected version thereof), or taken together with an adjacent carbonyl to be an amine protecting group;

[1182] R3 is selected from H and nitrogen-compatible leaving groups (e.g., Ts), and

[1183] Ring A, R 1 , and n are as defined herein.

[1184] In the implementation example, R 3 is H. In the embodiment, R 3 is Ts. In the implementation example, R 1 is F.

[1185] In an embodiment, the process comprises a chiral separation step (e.g., for isolating one stereoisomer from a mixture of stereoisomers). In an embodiment, the process comprises a positional isomer separation step (e.g., for isolating one positional isomer from a mixture of positional isomers). In an embodiment, the process comprises a step in which an E (or cis) isomer is separated from a mixture of E and Z isomers. In an embodiment, the process comprises a step in which a Z (or trans) isomer is separated from a mixture of E and Z isomers. Those skilled in the art will be aware of many chiral, stereoisomer, and positional isomer separation methods, e.g., the methods illustrated herein.

[1186] In an embodiment, intramolecular cyclization of the compound of formula MP involves the use of a polyvalent iodine reagent and optionally a solvent. In an embodiment, the polyvalent iodine reagent is PIFA. In an embodiment, the solvent is THF. In an embodiment, intramolecular cyclization of the compound of formula MP involves the use of PIFA and THF.

[1187] In an embodiment, Q is R as defined herein. 2 It is a protected version of the group. In an embodiment, Q is a phenyl group having a protected amine substituent, optionally together with another substituent (e.g., -OCF3 group).

[1188] In an embodiment, Q is R as defined herein. 2It is a compound. Therefore, in an embodiment, the compound of formula MP is the compound of formula M1 below:

[1189] [Chemical Formula M1]

[1190]

[1191] In the above equation, ring A, R 1 , R 2 , R 3 , and n are as defined herein. In an embodiment, R 3 is H (i.e., the compound is compound M as defined herein). In another embodiment, R 3 is Ts (i.e., the compound is compound M' as defined herein).

[1192] In an embodiment, intramolecular cyclization involves the use of a silver(I) salt and optionally a solvent. In an embodiment, the silver(I) salt is Ag2CO3. In an embodiment, the solvent is THF. In an embodiment, intramolecular cyclization involves the use of Ag2CO3 and THF.

[1193] In an embodiment, the process comprises one or more of the steps shown in Reaction Scheme 2. In an embodiment, the process comprises all the steps shown in Reaction Scheme 2. In an embodiment, the process comprises step 2 of Reaction Scheme 2. In an embodiment, the process comprises one or more of the steps shown in Reaction Scheme 2A. In an embodiment, the process comprises all the steps shown in Reaction Scheme 2A. In an embodiment, the process comprises step 3 of Reaction Scheme 2A. In an embodiment, the process comprises one or more of the steps of Method C. In an embodiment, the process is substantially as described in Method C.

[1194] In an embodiment, Q taken together with an adjacent carbonyl is an amine protecting group (e.g., Boc). Thus, in an embodiment, the compound of formula MP is the compound of formula P1 below:

[1195] [Chemical Formula P1]

[1196]

[1197] In the above equation, ring A, R 1 , R 3 , and n are as defined herein. In an embodiment, R 3 is H (i.e., the compound is compound P as defined herein). In another embodiment, R 3 is TS (i.e., the compound is compound P' as defined herein).

[1198] In an embodiment, the process comprises one or more of the steps shown in Reaction Scheme 4. In an embodiment, the process comprises all the steps shown in Reaction Scheme 4. In an embodiment, the process comprises step 3 of Reaction Scheme 4. In an embodiment, the process comprises one or more of the steps of Method F. In an embodiment, the process is substantially the same as described in Method F. In an embodiment, the process comprises all the steps of Method F, except for the N-tosylation and detosylation steps.

[1199] In an embodiment, the compound produced by the process defined herein is selected from compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein and pharmaceutically acceptable salts thereof.

[1200] The present disclosure also relates to intermediates useful for the manufacture of the compounds of the present disclosure. Those skilled in the art will understand that the processes described herein may be used to provide such intermediates in the process of manufacturing the compounds of the present disclosure.

[1201] From this aspect, the present disclosure relates to a compound of the formula HE.

[1202] [Chemical formula HE]

[1203]

[1204] or provides a pharmaceutically acceptable salt thereof, wherein R in the above formula 1 and n are as defined herein, where

[1205] Q is R as defined herein 2 It is a group (or a protected version thereof), or taken together with an adjacent carbonyl to be an amine protecting group (e.g., Boc);

[1206] X is a halogen (e.g., I, Br, Cl).

[1207] In the implementation example, R 1 is F.

[1208] In an embodiment, the compound is a compound of the formula H.

[1209] [Chemical Formula H]

[1210]

[1211] or a pharmaceutically acceptable salt thereof, wherein R in the above formula 1 , R 2 , n, and X are as defined herein.

[1212] In an embodiment, the compound is a compound of formula E.

[1213] [Chemical Formula E]

[1214]

[1215] or a pharmaceutically acceptable salt thereof, wherein R in the above formula 1 , n, and X are as defined herein.

[1216] The present disclosure also covers compounds of the formula MP.

[1217] [Chemical Formula MP]

[1218]

[1219] or provides a pharmaceutically acceptable salt thereof, wherein, in the above formula, ring A, R 1 , and n are as defined above, and

[1220] Q is R as defined herein 2 It is a group (or a protected version thereof), or taken together with an adjacent carbonyl to be an amine protecting group (e.g., Boc);

[1221] R 3 It is selected from H and nitrogen-compatible leaving groups (e.g., Ts).

[1222] In the implementation example, R 3 is H. In another embodiment, R 3 is Ts. In the implementation example, R 1 is F.

[1223] In an embodiment, the compound is a compound of formula M1.

[1224] [Chemical Formula M1]

[1225]

[1226] or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , R 3 , and n are as defined above. In an embodiment, the compound is a compound of formula M or formula M'.

[1227] [Chemical Formula M]

[1228]

[1229] [Chemical Formula M']

[1230] ,

[1231] or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 2 , and n are as defined herein.

[1232] In an embodiment, the compound is a compound of formula P1.

[1233] [Chemical Formula P1]

[1234]

[1235] or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , R 3 , and n are as defined herein. In an embodiment, the compound is a compound of formula P or formula P'.

[1236] [Chemical Formula P]

[1237]

[1238] [Chemical Formula P']

[1239]

[1240] or a pharmaceutically acceptable salt thereof, wherein ring A, R 1 , and n are as defined herein.

[1241] In an embodiment, the compound is selected from the following:

[1242]

[1243]

[1244]

[1245] and pharmaceutically acceptable salts thereof.

[1246] It will be understood that the compounds of the present disclosure may serve as precursors or intermediates for other compounds of the present disclosure. For example, a compound having a ketone on ring A may be used as a precursor for a compound having an alkyl group, a hydroxyl group, and / or other groups at the ketone position. Accordingly, the present disclosure provides the following compounds that may be useful as intermediates or precursors in the preparation of compounds as disclosed herein:

[1247]

[1248]

[1249]

[1250] and pharmaceutically acceptable salts thereof.

[1251] Pharmaceutical composition

[1252] The present disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[1253] In an embodiment, the pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound of Formula II or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound of Formula III or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound of Formula IV or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound of Formula V or a pharmaceutically acceptable salt thereof. In an embodiment, the pharmaceutical composition comprises a compound of Formula VI or a pharmaceutically acceptable salt thereof.

[1254] The pharmaceutical composition of the present disclosure may be formulated to be administered in solid or liquid form, for example, using conventional carriers or excipients. The composition may be suitable for oral administration (e.g., as a solution, suspension, tablet, or capsule), parenteral administration (e.g., as a solution, dispersion, suspension, or emulsion, or as a dry powder for reconstitution), or topical application (e.g., as a cream, ointment, patch, or spray applied to the skin) using techniques known in the art.

[1255] Medical use

[1256] The compounds of the present disclosure act as inhibitors of ERK5 and are useful for the treatment of ERK5-related disorders and conditions. In particular, the compounds of the present disclosure are useful for the treatment of cancer.

[1257] In this aspect, the present disclosure provides a therapeutic method comprising the step of administering a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject in need thereof. In a related aspect, the present disclosure provides a use of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical agent. In a further related aspect, the present disclosure provides a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) for therapeutic use.

[1258] The compounds of the present disclosure are useful for treating or preventing the following: diseases or harmful conditions known to be caused by ERK5 or variants or mutants thereof; increased MAPK7 Diseases or disorders associated with (i.e., ERK5 gene) expression and / or increased ERK5 activity; and diseases or disorders where inhibition or antagonism of ERK5 activity is beneficial.

[1259] In one embodiment, the present disclosure provides a method for treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder associated with ERK5, in a subject requiring treatment or prevention, said method comprising the step of administering an effective amount of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) to the subject. In a related embodiment, the present disclosure provides a use of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) in the manufacture of a drug for the treatment or prevention of a disease or disorder mediated by ERK5, or a disease or disorder associated with ERK5. In a further related embodiment, the present disclosure provides a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of a disease or disorder mediated by ERK5, or a disease or disorder associated with ERK5.

[1260] In another aspect, the present disclosure provides a method for treating or preventing a disease or disorder associated with ERK5 (e.g., cancer) in a subject requiring treatment or prevention, said method comprising the step of administering an effective amount of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the present disclosure provides a use of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) in the manufacture of a drug for treating or preventing a disease or disorder associated with ERK5 (e.g., cancer). In a further related aspect, the present disclosure provides a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) for use in treating or preventing a disease or disorder associated with ERK5 (e.g., cancer).

[1261] In another aspect, the present disclosure provides a method for treating or preventing cancer in a subject requiring treatment or prevention of cancer, said method comprising the step of administering an effective amount of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the present disclosure provides a use of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) in the manufacture of a drug for the treatment or prevention of cancer. In a further related aspect, the present disclosure provides a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of cancer.

[1262] In an embodiment, the compound results in a reduction in angiogenesis, a reduction or prevention of metastasis, a reduction in inflammation, a blockade of tumorigenesis (e.g., partial or complete blockade), a reduction in evasion of growth inhibition, a reduction or inhibition of cancerous or precancerous cell growth, inhibition of cancerous or precancerous cell proliferation, and / or a reduction in cancerous or precancerous cell survival.

[1263] In an embodiment, the cancer is increased MAPK7 It is characterized by expression (i.e., the ERK5 gene) and / or increased ERK5 activity. In an embodiment, the cancer has elevated ERK5 activity. In an embodiment, the cancer overexpresses ERK5. In an embodiment, the cancer MAPK7 It is characterized by genomic amplification and / or congenitally active ERK5 signaling. In an embodiment, the cancer has genomically amplified ERK5. In an embodiment, the cancer has congenitally active ERK5 signaling.

[1264] In an embodiment, the cancer is a solid tumor (e.g., melanoma, carcinoma, or blastoma). In another embodiment, the cancer is leukemia (e.g., chronic lymphocytic leukemia, CLL; acute myeloid leukemia, AML; or chronic myeloid leukemia, CML).

[1265] In one embodiment, the cancer is a primary tumor. In another embodiment, the cancer is a secondary tumor (e.g., a metastatic tumor).

[1266] In an embodiment, the cancer is selected from breast cancer (e.g., ductal carcinoma or breast adenocarcinoma), liver cancer, kidney cancer (e.g., hepatocellular carcinoma), prostate cancer, colorectal cancer (CRC), lung cancer (e.g., non-small cell lung cancer, NSCLC; lung adenocarcinoma; or lung squamous cell carcinoma), pancreatic cancer (e.g., adenocarcinoma), ovarian cancer, brain cancer (e.g., glioblastoma), cervical cancer (e.g., adenocarcinoma), gastric cancer, skin cancer (e.g., melanoma), cholangiocarcinoma (e.g., cholangiocarcinoma), nervous system cancer (e.g., neuroblastoma), and melanoma.

[1267] In an embodiment, the cancer is selected from leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, or chronic lymphoblastic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström macroglobulinemia, and multiple myeloma.

[1268] In an embodiment, the cancer is selected from leukemia (e.g., chronic myeloid leukemia), breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

[1269] In another aspect, the present disclosure provides a method for inhibiting ERK5 activity, said method comprising the step of contacting ERK5 (e.g., a cell containing ERK5) with a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof). In an embodiment, the present method is an in vitro or in vitro method. In another embodiment, the present method is an in vivo method. In a related aspect, the present disclosure provides an in vitro method for inhibiting ERK5 activity in a cell, said method comprising the step of contacting a cell with a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof).

[1270] The compounds of the present disclosure (e.g., compounds of Formula I) and pharmaceutically acceptable salts thereof may be administered as a pharmaceutical composition that may optionally include one or more pharmaceutically acceptable excipients.

[1271] It will be understood that methods and treatments of various embodiments of the present disclosure may be achieved by administering an effective amount of a compound of the present disclosure (e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof) to a subject in the form of a pharmaceutical composition that may optionally include one or more pharmaceutically acceptable excipients as described herein.

[1272] The compounds of the present disclosure may be used alone (e.g., as monotherapy) or in combination with one or more cancer therapies.

[1273] Although described broadly herein, the following non-limiting embodiments are provided to further illustrate the present disclosure.

[1274] Examples

[1275] General synthesis reaction equation

[1276] Reaction Scheme 1 below illustrates an exemplary method for preparing a compound (e.g., a compound of Formula I) according to the present disclosure and embodiments:

[1277] [ Reaction Equation 1 ]

[1278]

[1279] Reaction Equation 1 (where ring A, R 1 , R 2 According to the formula (where , and n may be as described above, for example), compound C can be obtained by Suzuki coupling between compound A and compound B (where -B(OR)2 is a boronate group such as -B(Pin)) using a palladium catalyst such as PdCl2(dppf).CH2Cl2 in the presence of a base such as tribasic potassium phosphate in step 1. Compound C can be reduced to compound D by hydrogenation using a catalyst such as Pd / C at 40°C under a hydrogen pressure (H2) of about 5 bar, for example, in step 2. Subsequently, compound D can be converted to compound E (where X may be I, Br, or Cl) by halogenation using NIS, NBS, or NCS (i.e., X = I, Br, or Cl) in step 3, for example. Compound E can be N-deprotected using HCl or TFA in step 4 to obtain Compound F. Subsequently, Compound H can be prepared in step 5 by reacting Compound F with a carboxylic acid Compound G in a solvent such as DMF in the presence of a base such as DIPEA using conditions known to those skilled in the art, such as TBTU. Subsequently, Compound H can be converted to Compound K in step 6 using a palladium catalyst such as Pd(t-Bu3P)2 in the presence of a base such as DABCO in the presence of Compound J.

[1280] Reaction Scheme 2 below illustrates an alternative method for preparing compound K from compound H:

[1281] [ Reaction Equation 2 ]

[1282]

[1283] Reaction Equation 2 (where ring A, R 1 , R 2 According to the formula, , and n may be as described above, for example, compound M can be obtained by Suzuki coupling between compound H (where X can be I, Br, or Cl) and compound L (where -B(OR)2 is a boronic acid group such as -B(Pin)) using a palladium catalyst such as PdCl2(dppf).CH2Cl2 in the presence of a base such as potassium carbonate in step 1, for example. Subsequently, compound K can be obtained directly from compound M in the presence of a polyvalent iodine(III) reagent such as PIFA in step 2.

[1284] In some cases, compound K can be prepared from compound H via an N-protected compound according to the following reaction scheme, Reaction Scheme 2A:

[1285] [Reaction Equation 2A]

[1286]

[1287] Reaction Equation 2A (where ring A, R 1 , R 2According to the formula, , and n may be as described above, for example, compound H' (where X may be I, Br, or Cl) can be obtained, for example, by tosylating compound H with tosyl chloride using a base such as sodium hydride in step 1. Subsequently, compound H' can be converted to compound M' in the presence of compound L (where -B(OR)2 is a boronate group such as -B(Pin)) by Suzuki coupling using a palladium catalyst such as PdCl2(dppf).CH2Cl2 in the presence of a base such as potassium carbonate in step 2. Compound K' can be obtained from compound M' in the presence of a polyvalent iodine(III) reagent such as PIFA in step 3. Compound K' can be obtained by N-deprotection using sodium hydroxide in EtOH in step 4, for example.

[1288] Reaction Scheme 3 below illustrates an alternative method for preparing compound K from compound E:

[1289] [ Reaction Equation 3 ]

[1290]

[1291] Reaction Equation 3 (where ring A, R 1 , R 2According to the formula (where n, and n, may be as described above, for example), compound N can be obtained from compound E (where X can be I, Br, or Cl) in the presence of compound J in step 1 using a palladium catalyst such as Pd(t-Bu3P)2 in the presence of a base such as DABCO. Compound N can be deprotected using HCl or TFA in step 2 to obtain compound O. Subsequently, compound K can be prepared using compound O and carboxylic acid compound G in a solvent such as DMF in the presence of a base such as DIPEA in step 3 using conditions known to those skilled in the art, such as TATU.

[1292] Reaction Scheme 4 below illustrates an alternative method for preparing compound N from compound E:

[1293] [ Reaction Equation 4 ]

[1294]

[1295] Reaction Equation 4 (where ring A, R 1 According to the formula (where , and n may be as described above, for example), compound E' can be obtained in step 1 by tosylating compound E (where X may be I, Br, or Cl) with tosyl chloride using a base such as sodium hydride, for example. Subsequently, compound E' can be converted to compound P' by Suzuki coupling with compound L using a palladium catalyst such as PdCl2(dppf).CH2Cl2 in the presence of a base such as potassium carbonate, for example. Compound N' can be obtained from compound P' in step 3 in the presence of a polyvalent iodine(III) reagent such as PIFA. Compound N' can be obtained by N-detosylating using sodium hydroxide in EtOH, for example, in step 4.

[1296] Reaction Scheme 5 below illustrates an additional exemplary method for preparing compound K through compound N:

[1297] [ Reaction Equation 5 ]

[1298]

[1299] Reaction Equation 5 (where ring A, R 1 , R 2According to (where , and n may be as described above, for example), compound R can be obtained by the acylation of compound Q in the presence of a base such as LDA in step 1. Compound R can be converted to compound S by reduction using a hydride source such as DIBAL-H in step 2, for example. Subsequently, compound S can be converted to compound T by reaction with PBr3 in step 3. Compound U can be obtained from compound T in the presence of triethylphosphite in step 4. Compound U is converted to compound W in step 5 in the presence of compound V (where ring A' is a precursor of ring A, for example, having one fewer ring carbon atom than ring A) and a base such as potassium tert-butoxide. Compound W yields compound X in step 6 by nuclear affinity aromatic substitution using sodium azide. Subsequently, compound X is converted to compound Y in step 7 in the presence of an iron catalyst and zinc powder; During step 7, ring A' of compound X undergoes rearrangement to form ring A in compound Y. In step 8, compound Z is produced by Suzuki coupling reaction between compound Y and compound B (where -B(or)2 is a boronate group such as -B(Pin)) using a palladium catalyst such as PdCl2(dppf).CH2Cl2 in the presence of a base such as sodium carbonate. Compound Z can be reduced to compound N by hydrogenation using a catalyst such as Pd / C under a hydrogen pressure (H2) of about 1 bar, for example, in step 9. Compound N is N-deprotected using HCl or TFA in step 10 to obtain compound O. Subsequently, compound K can be prepared from compound O by reaction with carboxylic acid compound G in a solvent such as DMF in the presence of a base such as DIPEA in step 11, using conditions known to those skilled in the art, such as EDCI and HOBt.

[1300] Reaction Scheme 6 below illustrates an alternative method for preparing compound N:

[1301] [ Reaction Equation 6 ]

[1302]

[1303] Reaction Equation 6 (where ring A, R 1 According to the formula (where , and n may be as described above, for example), compound AB can be obtained in step 1 by the condensation of compound AA with p-toluenesulfonyl hydrazide. Compound P can be obtained in step 2 by the Varuenga-Valdes cross-coupling reaction between compound E (where X may be I, Br, or Cl) and compound AB using a palladium catalyst such as Pd(OAc)2 and a phosphonium ligand such as tri-tert-butylphosphonium tetrafluoroborate in the presence of a base such as potassium carbonate. Compound N can be obtained from compound P in step 3 in the presence of a polyvalent iodine(III) reagent such as PIFA.

[1304] Reaction Scheme 7 below illustrates an alternative method for preparing compound Z:

[1305] [ Reaction Equation 7 ]

[1306]

[1307] Reaction Equation 7 (where ring A, R 1According to (where , and n may be as described above, for example), compound AD can be obtained by Suzuki coupling reaction of compound AC and compound L using a palladium catalyst such as PdCl2(dppf) in the presence of a base such as sodium carbonate in step 1. Compound AD is obtained in step 2 by a nucleophilic aromatic substitution reaction using sodium azide to obtain compound AE. Subsequently, compound AE is converted to compound AF in step 3 in the presence of an iridium catalyst and AgSbF6. Compound Z can be obtained in step 4 by Suzuki coupling reaction of compound AF and compound B (where -B(OR)2 is a boronate group such as -B(Pin)) using a palladium catalyst such as Pd(t-Bu3P)2 in the presence of a base such as tribasic potassium carbonate.

[1308] Reaction Scheme 8 below illustrates an alternative method for preparing compound Z:

[1309] [ Reaction Equation 8 ]

[1310]

[1311] Reaction Equation 8 (where ring A, R 1 According to , and n, for example, as described above), compound AF can be obtained from compound AG (wherein XI, Br, or Cl) and compound J using a palladium catalyst such as Pd(Pt-Bu3)2 in the presence of a base such as DABCO in step 1. Subsequently, compound AF can be converted to compound Z by Suzuki coupling in the presence of compound B (wherein -B(OR)2 is a boronate group such as -B(Pin)) using a palladium catalyst such as PdCl2(dppf).CH2Cl2 in the presence of a base such as cesium carbonate in step 2, for example.

[1312] If necessary in the aforementioned transition, the protector is, for example, R 2Alternatively, it may be used in the free -NH2 substituent of ring A. Suitable protection strategies will be apparent to those skilled in the art from the context of this disclosure. For example, R 2 -(C6-C12) substituted with -NH2 10 Compounds of the present disclosure that are aryls (e.g., compounds of Formula I) can be prepared from corresponding -NHBOC compounds, which can be prepared by a method similar to the above reaction scheme, and can be N-deprotected using the conditions described herein or otherwise known to those skilled in the art. Compounds of the present disclosure that are heterocycloalkanes in which ring A comprises at least one nitrogen ring atom (e.g., compounds of Formula I) can be prepared from corresponding N-protected (e.g., NBOC) compounds that can be N-deprotected. Compounds in which ring A is substituted with -OH or -NH2 can be prepared from corresponding O-protected or N-protected compounds, which can be prepared by a method similar to the above reaction scheme, and can be O-deprotected or N-deprotected using the conditions described herein or otherwise known to those skilled in the art. A compound in which ring A is substituted with an oxo (e.g., a ring containing a carbonyl group, i.e., a -(C=O) group) can be prepared from a corresponding acetal compound (e.g., -(O-CH2CH2-O)-), which can be prepared by a method similar to the above reaction scheme, for example, by exposure to acidic reaction conditions.

[1313] Certain compounds of the present disclosure may have substituents that can undergo additional conversion reactions to produce additional compounds according to the present disclosure (e.g., compounds of Formula I). ​​For example, a compound in which ring A is substituted with an oxo (e.g., a ring containing a carbonyl group, i.e., a -(C=O)- group) as a compound obtainable according to the above reaction scheme (e.g., compound K) undergoes chemical conversions such as (1) nucleophilic addition; (2) reductive amination; and (3) reduction using a hydride reagent to obtain the corresponding compound of the present disclosure (e.g., compounds of Formula I), wherein, in these compounds, for example, (1) ring A is substituted with -OH, and additional substituents (e.g., selected from -(C1-C3)alkyl, -(C3-C6)cycloalkyl, 3 to 6-membered heterocycloalkyl, -O(C1-C3)alkyl, and -CN optionally substituted with one or more halos or -OH) are present; (2) ring A is substituted with -NHR' (where R' may be, for example, as described above); (3) ring A is substituted with -OH.

[1314] Compounds having one or more stereochemical centers can be purified using chiral separation techniques, such as chiral HPLC or SFC, to obtain distinct isomers.

[1315] Experimental techniques

[1316] At 400 and 500 MHz 1 H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, and the chemical shift (δ, in ppm) was based on 2.5 ppm at the specified temperature in the solvent dimethyl sulfoxide-d6 (DMSO-d6). The coupling constant (J) is provided in Hertz.

[1317] Liquid chromatography / mass spectra (LC / MS) were obtained using an Acquity Waters UPLC instrument, a Sedere light scattering detector, and an SQD Waters mass spectrometer. UV detection was performed using a DAD (210 < l < 400 nm), the column was an Acquity UPLC CSH C18 1.7 μm (dimensions 2.1 x 50 mm), and the mobile phase was H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H.

[1318] Unless otherwise specified, all synthesis reactions were performed under an inert atmosphere. In the following examples, where the source of the starting product is not specified, it should be understood that the product is a known compound (e.g., a compound commercially available from a supplier such as Sigma-Aldrich).

[1319] Examples 1 to 294 - Compounds

[1320] Tables 1a and 1b below list specific compounds of the present disclosure, their names and structures (Table 1a), and their preparation methods and characteristic analyses by NMR and LC / MS (Table 1b).

[1321] [Table 1a]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340]

[1341]

[1342]

[1343]

[1344]

[1345]

[1346]

[1347]

[1348]

[1349]

[1350]

[1351]

[1352]

[1353]

[1354]

[1355]

[1356]

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379] [Table 1b]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388]

[1389]

[1390]

[1391]

[1392]

[1393]

[1394]

[1395]

[1396]

[1397]

[1398]

[1399]

[1400]

[1401]

[1402]

[1403]

[1404]

[1405]

[1406]

[1407]

[1408]

[1409]

[1410]

[1411]

[1412]

[1413]

[1414]

[1415]

[1416]

[1417]

[1418]

[1419]

[1420]

[1421]

[1422]

[1423]

[1424]

[1425]

[1426]

[1427]

[1428]

[1429]

[1430]

[1431]

[1432]

[1433]

[1434]

[1435] manufacturing method

[1436] The compounds of the present disclosure may be prepared according to the following methods A through J (see Table 1b above). Each of these synthesis methods is illustrated with reference to the preparation of one or more specific compounds of the present disclosure. Those skilled in the art will understand how the characteristics of the various synthesis steps (e.g., reactants, reagents, and conditions) shown in the exemplary examples may be adjusted when preparing other compounds according to the present disclosure, particularly in consideration of the general synthesis equations provided above.

[1437] Method A

[1438] Method A is exemplified by the preparation of Example 56. Method A includes, for example, the steps identified in Reaction Scheme 1.

[1439] Example 56: [4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyrido[2,3-b]indole-6,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1440]

[1441] Step 1 : tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[1442]

[1443] N-BOC-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (31.18 g, 100.84 mmol) and tribasic potassium phosphate (53.512 g, 252.1 mmol) were added to a solution of 5-fluoro-4-iodopyridine-2-amine (20 g, 84.03 mmol) in 1,4-dioxane (1 L) and water (110 mL) at room temperature. Subsequently, the entire mixture was bubbling with argon for 15 minutes. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3.43 g, 4.2 mmol) was added, and the entire mixture was refluxed under an argon atmosphere for 12 hours. After 12 hours, the reaction mixture was cooled to room temperature, and 250 mL of ethyl acetate and 250 mL of water were added to the reaction mixture. Subsequently, the organic layer was washed twice with water (2 x 250 mL) and twice with brine (2 x 250 mL), dried over magnesium sulfate, and concentrated under vacuum. The resulting residue was purified by flash chromatography eluted with a 75 / 25 heptane / ethyl acetate mixture on silica gel (SiO2 800 g) to obtain 17.93 g (72.7% yield) of tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate as a solid. LC / MS (m / z, M+H): Calculated 294.2, Found 294.2.

[1444] Step 2 : tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)piperidine-1-carboxylate

[1445]

[1446] Pd / C (10% wet, 2.36 g, 2.22 mmol) was added to a solution of tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (13 g, 44.3 mmol) in THF (47 mL) and EtOH (135 mL). Subsequently, the entire mixture was hydrogenated with H2 at 5 bar at 40°C for 1.5 hours. The entire mixture was then cooled to room temperature, filtered over a classel, and washed with EtOH (50 mL) and THF (40 mL). The resulting filtrate was concentrated under vacuum to obtain a light brown solid. Subsequently, the resulting solid was ground in pentane (100 mL), filtered, and dried under vacuum for 12 hours to obtain 12.68 g (96.9% yield) of tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)piperidine-1-carboxylate as a light brown solid. LC / MS (m / z, M+H): Calculated 296.2, Found 296.4.

[1447] Step 3 : tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carboxylate

[1448]

[1449] NIS (33.1 g, 147 mmol) was added in portions to a solution of tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)piperidine-1-carboxylate (14.5 g, 49.1 mmol) in a solution containing DMF (290 mL), followed by the addition of TFA (22.7 mL, 295 mmol), and the resulting mixture was stirred at room temperature for 48 hours. After 48 hours, the entire mixture was poured into 1.8 L of saturated aqueous solution of NaHSO3. Subsequently, 600 mL of ethyl acetate was added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 600 mL). Subsequently, the combined organic layer was washed with water (500 mL) and brine (300 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography eluted with a 95 / 5 to 60 / 40 heptane / ethyl acetate mixture on silica gel (SiO2 330 g) to obtain 13.1 g (63.5% yield) of tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carboxylate as a pale pink solid. LC / MS (m / z, M+H): Calculated 422.1, Found 422.3.

[1450] Step 4 : 5-fluoro-3-iodo-4-(4-piperidyl)pyridine-2-amine, dihydrochloride

[1451]

[1452] tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carboxylate (1.14 g, 2.71 mmol) was dissolved in 10 mL of 5 / 6 M HCl solution in isopropanol and stirred at room temperature for 4 hours. After 4 hours, the entire mixture was concentrated and dried to obtain 1.07 g (100% yield) of 5-fluoro-3-iodo-4-(4-piperidyl)pyridine-2-amine dihydrochloride as a solid. LC / MS (m / z, M+ -2 HCl): Calculated 321.0, Found 321.0.

[1453] Step 5: [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1454]

[1455] 4-(trifluoromethoxy)benzoic acid (4.89 g, 23.7 mmol) was added to a solution of 5-fluoro-3-iodo-4-(4-piperidyl)pyridine-2-amine, dihydrochloride (9.35 g, 23.7 mmol) in DMF (95 mL), and then 16.5 mL of DIPEA (94.9 mmol) and TBTU (8.38 g, 26.1 mmol) were added in portions. The entire mixture was stirred for 60 minutes. After 60 hours, ethyl acetate and water were added to the mixture. Subsequently, the organic layer was washed with a saturated aqueous solution of NaHCO3, washed three times with brine, and the combined aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting orange residue was ground in diisopropyl ether and filtered to obtain 11.232 g (93% yield) of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a light brown solid. LC / MS (m / z, M+): Calculated 509.0, Found 509.0.

[1456] Step 6:[4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyrido[2,3-b]indole-6,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1457]

[1458] Under an argon atmosphere, a solution of 1,4-diazabicyclo[2.2.2]octane (384 mg, 3.42 mmol), 1,4-dioxaspiro[4.5]decane-8-one (310 mg, 1.98 mmol), and bis(tri-tert-butylphosphine)palladium (0) (29 mg, 0.056 mmol) in DMF (2 mL) was added sequentially to a solution of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (590 mg, 1.16 mmol) in DMF (2.5 mL). Subsequently, the entire mixture was stirred at 170°C (bath temperature), DMF (3 mL) was added, and the mixture was stirred at this temperature for 12 hours, followed by stirring at room temperature for 24 hours. Next, the reaction mixture was diluted with ethyl acetate, washed three times with water, and the combined aqueous layer was extracted with ethyl acetate. Next, the combined organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. Subsequently, the resulting residue was purified by flash chromatography eluted with a 50 / 50 to 0 / 100 heptane / ethyl acetate mixture on silica gel (SiO2 120 g) to obtain 439 mg (72.9% yield) of [4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyrido[2,3-b]indole-6,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a solid. LC / MS (m / z, M+H): Calculated 520.2, Measured 520.4.

[1459] Method B

[1460] Method B is exemplified by the preparation of Example 15. Method B includes, for example, the steps identified in Reaction Scheme 2A.

[1461] Example 15 : [4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indole-7,2'-dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1462]

[1463] Step 1 : N-[5-fluoro-3-iodo-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-2-pyridyl]-4-methyl-benzenesulfonamide

[1464]

[1465] Sodium hydride (60% dispersion in oil, 176 mg, 4.4 mmol) was added to a solution (1120 mg, 2.2 mmol) of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (described in step 5 of Example 56) in THF (15 mL) under an argon atmosphere at 0°C, and the resulting mixture was stirred at 0°C for 30 minutes. After 30 minutes, para-toluenesulfonyl chloride (503 mg, 2.64 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 48 hours. After 48 hours, the reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. Subsequently, the resulting residue was purified by flash chromatography eluted on silica gel (SiO2 70 g) with a 100 / 0 to 0 / 100 DCM / [heptane / ethyl acetate 50 / 50] mixture to obtain 290 mg (20% yield) of N-[5-fluoro-3-iodo-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-2-pyridyl]-4-methyl-benzenesulfonamide as a white solid. LC / MS (m / z, M+H): Calculated 664.0, Found 664.1.

[1466] Step 2 : N-[3-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-5-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-2-pyridyl]-4-methyl-benzenesulfonamide

[1467]

[1468] In a 2 to 5 mL microwave vial, potassium carbonate (242 mg, 1.75 mmol), dichlorobis(triphenylphosphine)palladium(II) (31 mg, 0.044 mmol), and in a solution of N-[5-fluoro-3-iodo-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-2-pyridyl]-4-methyl-benzenesulfonamide (290 mg, 0.44 mmol) in argon-bubbled DMF (2.5 mL) and water (1.25 mL) 4 ,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-1,3,2-dioxaborolane (140 mg, 0.52 mmol) was added sequentially. The vial was sealed and microwaved at 80°C for 45 minutes. After 45 minutes, the reaction mixture was cooled to room temperature, the vial was opened, and the reaction mixture was diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. Subsequently, the resulting residue was purified by flash chromatography eluted on silica gel (SiO225 g) with a 100 / 0 to 0 / 100 DCM / [heptane / ethyl acetate 50 / 50] mixture to obtain 255 mg (86% yield) of N-[3-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-5-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-2-pyridyl]-4-methyl-benzenesulfonamide as a white solid. LC / MS (m / z, M+H): Calculated 676.2, Found 676.3.

[1469] Step 3 : [4-[3'-fluoro-9'-(p-tolylsulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1470]

[1471] In a solution of N-[3-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-5-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-2-pyridyl]-4-methyl-benzenesulfonamide (255 mg, 0.38 mmol) in THF (1.3 mL) and a few drops of acetonitrile under an argon atmosphere at room temperature, the reaction mixture was heated to 50°C for complete dissolution, then cooled to room temperature, and a solution of [bis(trifluoroacetoxy)iodo]benzene (125 μL, 0.57 mmol) in THF (1.3 mL) was slowly added, and the resulting reaction mixture was stirred at room temperature for 45 minutes. After 45 minutes, the entire mixture was concentrated under vacuum, the resulting residue was poured into a saturated aqueous solution of NaHCO3, and extracted three times with DCM. Subsequently, the combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography eluted with a 100 / 0 to 0 / 100 heptane / [heptane / AcOEt 50 / 50] mixture on silica gel (SiO2 25 g) to obtain 167 mg (65% yield) of [4-[3'-fluoro-9'-(p-tolylsulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+H): Calculated 674.2, Found 674.3.

[1472] Step 4 : [4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indole-7,2'-dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1473]

[1474] Sodium hydroxide (30 mg, 0.74 mmol) was added to a solution of 4-[3'-fluoro-9'-(p-tolylsulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (167 mg, 0.25 mmol) in ethanol (0.5 mL) under an argon atmosphere at room temperature. Subsequently, the resulting mixture was stirred at 80°C for 45 minutes. After 45 minutes, the entire mixture was cooled to room temperature, concentrated and dried, and diluted with AcOEt and water. The aqueous layer was extracted three times with AcOEt, the combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography eluted on silica gel (SiO2 4 g) with a 100 / 0 to 0 / 100 DCM / [DCM / MeOH 90 / 10] mixture to obtain 88 mg (68% yield) of [4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indole-7,2'-dioxolane]-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+): Calculated 519.2, Found 519.0.

[1475] Method C

[1476] Method C is exemplified by the preparation of Examples 3, 4, 5, and 6. Method C includes, for example, the steps identified in Reaction Scheme 2.

[1477] Example 3 : (rac)-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1478]

[1479] Step 1: (rac)-[4-[2-amino-3-[4-[tert-butyl(dimethyl)silyl]oxycyclohexene-1-yl]-5-fluoro-4-pyridyl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1480]

[1481] In a 10 to 20 mL microwave vial, a solution of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (500 mg, 0.98 mmol, prepared as described in 5 of Example 56) in DMF / water (6 mL / 3 mL) was bubbled with argon for 5 minutes. Then, potassium carbonate (543 mg, 3.93 mmol), dichlorobis(triphenylphosphine)palladium(II) (69 mg, 0.098 mmol), and (rac)-tert-butyldimethyl[(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxy]silane (399 mg, 1.18 mmol) were added in succession. The vial was sealed and microwaved at 80°C for 60 minutes. After 60 minutes, the reaction mixture was cooled to room temperature and diluted with ethyl acetate and a saturated aqueous solution of NaHCO3. Subsequently, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 70 g) eluted with a heptane / [heptane / AcOEt / MeOH 85 / 10 / 5] mixture in a ratio of 100 / 0 to 0 / 100 to obtain 415 mg (71% yield) of (rac)-[4-[2-amino-3-[4-[tert-butyl(dimethyl)silyl]oxycyclohexene-1-yl]-5-fluoro-4-pyridyl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a light brown solid. LC / MS (m / z, M+H): Calculated 594.3, Measured 594.4.

[1482] Step 2:(rac)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1483]

[1484] (rac)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone was prepared using 415 mg (0.7 mmol) of (rac)-[4-[2-amino-3-[4-[tert-butyl(dimethyl)silyl]oxycyclohexene-1-yl]-5-fluoro-4-pyridyl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone according to the protocol described in Step 3 of Example 15 to produce 100 mg (21% yield) of (rac)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone was obtained as a white solid. LC / MS (m / z, M+H): Calculated 592.2, Found 592.3.

[1485] Step 3 : (rac)-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1486]

[1487] 0.42 mL of 4 N HCl solution (0.17 mmol) in dioxane (0.17 mmol) was added to a solution of (rac)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (100 mg, 0.17 mmol) in methanol / DCM (1 mL / 1 mL). The resulting mixture was stirred at room temperature for 12 hours, then concentrated and dried, and the resulting residue was purified by flash chromatography eluted on silica gel (SiO29 g) with a 100 / 0 to 0 / 100 DCM / [DCM / MeOH(NH3 7N) 90 / 10] mixture to obtain 55 mg (68% yield) of (rac)-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone as a white solid. LC / MS (m / z, M+H): Calculated 478.2, Found 478.2.

[1488] Example 4 : 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,14-triaztricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one

[1489]

[1490] 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,14-triaztricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one was prepared according to the protocol described in Step 6 of Example 56 using [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (100 mg, 0.19 mmol, described in Step 5 of Example 56) and azepan-2,6-dione (83 mg, 0.59 mmol) to produce 20 mg (20% yield) of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (100 mg, 0.19 mmol, described in Step 5 of Example 56). 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,14-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-13-one was obtained as a white solid. LC / MS (m / z, M+H): Calculated 491.4, Found 491.2.

[1491] Example 5: (rac)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1492]

[1493] Step 1 : (rac)-trans-tert-butyl (13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-6-carboxylate

[1494]

[1495] (rac)-trans-tert-butyl-13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-6-carboxylate was prepared according to the protocol described in Step 6 of Example 56 using [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (350 mg, 0.69 mmol, described in Step 5 of Example 56) and (rac)-trans-N-Boc-octahydroisoquinoline-6-one (522 mg, 2.06 mmol) 258 mg (55% yield) of (rac)-trans-tert-butyl (13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-6-carboxylate was obtained as a white solid. LC / MS (m / z, M+H): Calculated 617.6, Found 617.4.

[1496] Step 2 : (rac)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1497]

[1498] A 4 N HCl solution (1.07 mL, 4.3 mmol) in dioxane was added to a solution of (rac)-trans-tert-butyl (13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-6-carboxylate (265 mg, 0.43 mmol) in 2 mL of MeOH. The resulting mixture was stirred at room temperature for 4 hours, then concentrated and dried, and diluted with 2 mL of 7 N NH3 solution in MeOH. Silica gel was added to the mixture and concentrated, and the resulting residue was flash-eluted on silica gel (SiO212 g) with 90 / 10 / 1 DCM / MeOH / NH4OH. 212 mg (95% yield) of (rac)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone was obtained as a white solid by purification by chromatography. LC / MS (m / z, M+): Calculated 517.2, Found 517.0.

[1499] Example 6 : (rac)-trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone

[1500]

[1501] (rac)-trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraen-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone was prepared according to the protocol described in Step 6 of Example 56 using [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (300 mg, 0.59 mmol, described in Step 5 of Example 56) and trans-hexahydro-1H-cyclopenta[c]furan-5-one (223 mg, 1.77 mmol) to produce 166 mg (57% yield) of (rac)-trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraen-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone (300 mg, 0.59 mmol, described in Step 5 of Example 56) and trans-hexahydro-1H-cyclopenta[c]furan-5-one (223 mg, 1.77 mmol). (rac)-trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone was obtained as a gray solid. LC / MS (m / z, M+): Calculated 489.2, Found 489.0.

[1502] Method D

[1503] Method D is exemplified by the preparation of Examples 7, 46, 8, and 9. Method D includes, for example, the steps identified in Reaction Scheme 1.

[1504] Example 7 : (rac)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1505]

[1506] Step 1 : tert-butyl N-[2-[4-(2-diamino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate

[1507]

[1508] tert-butyl N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate was prepared according to the protocol described in Step 5 of Example 56 using 5-fluoro-3-iodo-4-(4-piperidyl)pyridin-2-amine, dihydrochloride (9.35 g, 23.7 mmol, described in Step 4 of Example 56) and 2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy)benzoic acid (7.62 g, 23.7 mmol) to yield 13.207 g (89% yield) of tert-butyl l N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate was obtained as a light brown solid. LC / MS (m / z, M+): Calculated 624.1, Found 624.0.

[1509] Step 2 : (rac)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1510]

[1511] (rac)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone was prepared according to the protocol described in Step 6 of Example 56 using tert-butyl N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (350 mg, 0.56 mmol) and (rac)-trans-hexahydro-1H-cyclopenta[c]furan-5-one (212 mg, 1.68 mmol) to produce 125 mg (44%) (44%) (rac)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone was obtained as a light brown solid. LC / MS (m / z, M+): Calculated 504.2, Found 504.0.

[1512] Examples 46, 8, and 9 : (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone and [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone, isomers 1 and 2

[1513]

[1514] Step 1 : (rac)-4-[tert-butyl(dimethyl)silyl]oxycycloheptanone

[1515]

[1516] Tert-butyldimethylchlorosilane (682 mg, 4.52 mmol) and imidazole (420 mg, 6.17 mmol) were added to a solution of (rac)-4-hydroxycycloheptanone (527 mg, 4.1 mmol) in DCM (14 mL), and the resulting mixture was stirred at room temperature for 1 hour. After 1 hour, tert-butyldimethylchlorosilane (158 mg, 1.26 mmol) and imidazole (126 mg, 1.85 mmol) were added, and the resulting mixture was stirred for an additional 2 hours, then filtered, and the resulting filtrate was concentrated under vacuum. The residue thus obtained was diluted with AcOEt, washed with a saturated aqueous solution of NaHCO3, dried over sodium sulfate, filtered, and concentrated under vacuum. Subsequently, the generated colorless oil was purified by flash chromatography eluted with 5 / 95 AcOEt / heptane on silica gel (SiO2 40 g) to obtain 852 mg (85% yield) of (rac)-4-[tert-butyl(dimethyl)silyl]oxycycloheptanone as a colorless oil.

[1517] Step 2 : (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone and (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[13-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone

[1518]

[1519] (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone and (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[13-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone according to the protocol described in Step 6 of Example 56, tert-butyl N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (350 mg, 0.5 mmol, described in Step 1 of Example 7) and 4-[tert-butyl(dimethyl)silyl]oxycycloheptanone (367 mg, 1.61 mmol) were prepared to produce 153 mg (42% yield) of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone and A 75 / 25 mixture of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[13-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone was obtained, respectively. LC / MS (m / z, M+): Calculated 621.3, Found 621.5.

[1520] Step 3: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone and (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone

[1521]

[1522] (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone and (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone were prepared using 150 mg (0.24 mmol) of the mixture of the two positional isomers described in the previous step, according to the protocol described in Step 2 of Example 5, to form a 96 / 4 / 0.4 on silica gel (SiO212 g). After flash chromatography eluted with DCM / MeOH / NH4OH, the following were obtained:

[1523] 71 mg (58% yield) of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone as a light brown solid. LC / MS (m / z, M+): calculated 506.5, found 506.0; and

[1524] 24 mg (20% yield) of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone as a light brown solid (Example 17). LC / MS (m / z, M+): Calculated 506.2, Found 506.0.

[1525] Step 4 : [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone, isomers 1 and 2. (Examples 8 to 9)

[1526]

[1527] Chiral separation of ((rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone (63 mg, 0.12 mmol) was performed using a Chiralpak AD-H column (5 μm, 250 x 30 mm) eluted with (heptane 70 / EtOH 30) + 0.1% TEA (flow rate 40 mL / min, UV detection at 254 nm) to obtain the following: 17 mg (27% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone, isomer 1. LC / MS (m / z, M+H): calculated 507.2, found 507.4; and 7 mg (11% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone, isomer 2. LC / MS (m / z, M+H): calculated 507.2, measured value 507.4.

[1528] Method E

[1529] Method E is exemplified by the preparation of Example 25. Method E includes, for example, the steps identified in Reaction Scheme 3.

[1530] Example 25: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)-1-piperidyl]methanone

[1531]

[1532] Step 1: tert-butyl 4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)piperidine-1-carboxylate

[1533]

[1534] In a 2 to 5 mL microwave vial, 1,4-diazabicyclo[2.2.2]octane (240 mg, 2.14 mmol) and tetrahydropyran-3-one (107 mg, 1.07 mmol) were added to a solution of tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carboxylate (300 mg, 0.71 mmol, described in step 3 of Example 56) in DMF (6 mL), and the resulting mixture was bubbled with argon for 2 minutes. Subsequently, bis(tri-tert-butylphosphine)palladium (0) (24 mg, 0.04 mmol) was added, and the resulting mixture was microwaved at 160°C for 3 hours (2 x 90 mins). After 3 hours, the reaction mixture was concentrated and dried, and the resulting residue was purified by flash chromatography eluted with 7 / 3 heptane / AcOEt on silica gel (30 g SiO2) to obtain 169 mg (63% yield) of tert-butyl 4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)piperidine-1-carboxylate as a solid. LC / MS (m / z, M+): Calculated 375.4, Found 375.0.

[1535] Step 2 : 12-fluoro-13-(4-piperidyl)-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene, dihydrochloride

[1536]

[1537] A solution of 4 N HCl (2 mL, 8 mmol) in dioxane was added to a solution of tert-butyl 4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)piperidine-1-carboxylate (169 mg, 0.45 mmol) in MeOH (2 mL), the resulting mixture was stirred at room temperature for 24 hours, and then concentrated and dried to obtain 157 mg (100% yield) of 12-fluoro-13-(4-piperidyl)-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene, dihydrochloride. LC / MS (m / z, M+H -2HCl): Calculated 276.3, Measured 276.3.

[1538] Step 3 : [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)-1-piperidyl]methanone

[1539]

[1540] N,N-diisopropylethylamine (0.25 mL, 1.45 mmol) was added to a solution of 12-fluoro-13-(4-piperidyl)-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene, dihydrochloride (80 mg, 0.22 mmol) in DMF (2 mL) under an argon atmosphere, and the resulting mixture was stirred at room temperature for 30 minutes. Subsequently, 2-amino-4-(trifluoromethoxy)benzoic acid (68 mg, 0.30 mmol) and TATU (99 mg, 0.3 mmol) were added sequentially, and the entire mixture was stirred at room temperature for 90 minutes. After 90 minutes, the resulting mixture was diluted with AcOEt and water. Subsequently, the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography eluted with 90 / 10 DCM / [DCM / MeOH / NH4OH 90 / 10 / 4] on silica gel (SiO2 20 g) to obtain 10 mg (9% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(13),2(7),9,11-tetraene-13-yl)-1-piperidyl]methanone as a solid. LC / MS (m / z, M+H): Calculated 479.2, Found 479.3.

[1541] Method F

[1542] Method F is exemplified by the preparation of Examples 50 and 51. Method F includes, for example, the steps identified in Reaction Scheme 4.

[1543] Examples 50 and 51:4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one and [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indole-7,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]methanone

[1544]

[1545] Step 1 : tert-butyl 4-[5-fluoro-3-iod-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate

[1546]

[1547] Tert-butyl 4-[5-fluoro-3-iodo-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate was prepared according to the protocol described in Step 1 of Example 15 using tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carboxylate (1000 mg, 2.37 mmol, described in Step 3 of Example 56) to obtain 438 mg (32% yield) of tert-butyl 4-[5-fluoro-3-iodo-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated 576.1, Found 576.2.

[1548] Step 2 : tert-butyl 4-[3-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-5-fluoro-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate

[1549]

[1550] tert-butyl 4-[3-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-5-fluoro-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate was prepared according to the protocol described in Step 2 of Example 15 using tert-butyl 4-[5-fluoro-3-iodo-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate (435 mg, 0.76 mmol) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-1,3,2-dioxaborolane (241 mg, 0.91 mmol) to obtain 425 mg (95% yield) of 4-[3-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-5-fluoro-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate was obtained as a pale yellow solid. LC / MS (m / z, M+H): Calculated 588.2, Found 588.4.

[1551] Step 3 : tert-butyl 4-[3'-fluoro-9'-(p-tolylsulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]piperidine-1-carboxylate

[1552]

[1553] tert-butyl 4-[3'-fluoro-9'-(p-tolylsulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]piperidine-1-carboxylate was prepared using tert-butyl 4-[3-(1,4-dioxaspiro[4.5]dek-7-en-8-yl)-5-fluoro-2-(p-tolylsulfonylamino)-4-pyridyl]piperidine-1-carboxylate (530 mg, 0.9 mmol) according to the protocol described in Step 3 of Example 15 to obtain 350 mg (66% yield) of tert-butyl 4-[3'-fluoro-9'-(p-tolylsulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]piperidine-1-carboxylate was obtained as a white solid. LC / MS (m / z, M+H): Calculated 586.2, Found 586.3.

[1554] Step 4 : tert-butyl 4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indole]-4'-yl)piperidine-1-carboxylate

[1555]

[1556] tert-butyl 4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyridodo[2,3-b]indole]-4'-yl)piperidine-1-carboxylate was prepared using tert-butyl 4-[3'-fluoro-9'-(p-tolylsulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyridodo[2,3-b]indole]-4'-yl]piperidine-1-carboxylate (150 mg, 0.26 mmol) according to the protocol described in Step 4 of Example 15 to obtain 105 mg (95% yield) of tert-butyl 4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyridodo[2,3-b]indole]-4'-yl)piperidine-1-carboxylate was obtained as a white solid. LC / MS (m / z, M+H): Calculated 432.2, Found 432.4.

[1557] Step 5 : A mixture of 3-fluoro-4-(4-piperidyl)-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one, hydrochloride and 3'-fluoro-4'-(4-piperidyl)spiro[1,3-dioxolalan-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indole], hydrochloride

[1558]

[1559] Fumed HCl (0.06 mL, 0.73 mmol) was added to a solution of 4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyridodo[2,3-b]indole]-4'-yl)piperidine-1-carboxylate (105 mg, 0.24 mmol) in THF (0.5 mL) at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. After 16 hours, fumed HCl (0.06 mL, 0.73 mmol) was added, and the resulting mixture was stirred at room temperature for an additional 3 hours, then filtered, and the resulting filtrate was concentrated and dried to obtain a mixture of 60 mg of unpurified 3-fluoro-4-(4-piperidyl)-5,6,8,9-tetrahydropyridodo[2,3-b]indole-7-one, hydrochloride and 3'-fluoro-4'-(4-piperidyl)spiro[1,3-dioxolalan-2,7'-5,6,8,9-tetrahydropyridodo[2,3-b]indole], hydrochloride as a yellow solid. Respectively, LC / MS (m / z, M+H -HCl): calculated 288.1, measured 288.2 and LC / MS (m / z, M+H -HCl): calculated 332.2, measured 332.2.

[1560] Step 6: 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one and [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indole-7,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]methanone

[1561]

[1562] 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one and [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indole]-4'-yl)-1-piperidyl]methanone were prepared on silica gel (SiO212 g) using 60 mg of the previously unrefined mixture of 2-amino-4-(trifluoromethoxy)benzoic acid (42 mg, 0.19 mmol) and triethylamine (0.13 mL, 0.93 mmol) instead of DIPEA, according to the protocol described in Step 3 of Example 25. The following were obtained after flash chromatography eluted with heptane / [DCM / MeOH 95 / 5] at 100 / 0 to 0 / 100:

[1563] 15 mg (16% yield) of 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one as a white solid. LC / MS (m / z, M+H): calculated 491.2, found 491.3; and

[1564] 8 mg (8% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-5,6,8,9-tetrahydrospiro[2,3-b]indole-7,2'-[1,3]dioxolane]-4-yl)-1-piperidyl]methanone as a white solid. LC / MS (m / z, M+H): Calculated 535.2, Found 535.3

[1565] Method G

[1566] Method G is exemplified by the preparation of Examples 70 and 71. Method G includes, for example, the steps identified in Reaction Scheme 7.

[1567] Examples 70 and 71 : [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone, isomers 1 and 2

[1568]

[1569] Step 1 : 2,4-Dichloro-3-(4-methoxycyclohexene-1-yl)pyridine

[1570]

[1571] A mixture of 2,4-dichloropyridine (3.45 g, 12.59 mmol), 2-(4-methoxycyclohexene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3 g, 12.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (107 mg, 0.15 mmol), and sodium bicarbonate (4.01 g, 37.8 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was stirred at 80°C for 3 hours under a nitrogen atmosphere. After 3 hours, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated. The generated residue was purified by silica gel flash chromatography (0 to 15% ethyl acetate in petroleum ether) to obtain 2.9 g (89% yield) of the target product as a yellow solid. LCMS; ESI m / z 258 (M + H)+.

[1572] Step 2: 2-azido-4-chloro-3-(4-methoxycyclohexene-1-yl)pyridine

[1573]

[1574] A mixture of 2,4-dichloro-3-(4-methoxycyclohexene-1-yl)pyridine (2.9 g, 11.2 mmol) and sodium azide (1.46 g, 22.46 mmol) in water (20 mL), ethanol (10 mL), and acetic acid (5 mL) was stirred at 110°C for 18 hours under a nitrogen atmosphere. After 18 hours, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated and dried. The resulting residue was purified by silica gel flash chromatography (0 to 40% ethyl acetate in petroleum ether) to obtain 0.98 g (33% yield) of the target product as a yellow solid. LCMS: ESI m / z 265.1 (M + H)+.

[1575] Step 3 : (rac)-4-chloro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole

[1576]

[1577] A mixture of 2-azido-4-chloro-3-(4-methoxycyclohexene-1-yl)pyridine (0.980 g, 3.7 mmol), hexafluoroantimonate (V) (0.763 g, 2.22 mmol), and dichloro(pentamethylcyclopentadienyl)lithium(III) dimer (0.885 g, 1.11 mmol) in toluene (15 mL) was stirred at 130°C for 72 hours under an argon atmosphere. After 72 hours, the mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0 to 95% ethyl acetate in petroleum ether) to obtain 0.55 g (63% yield) of (rac)-4-chloro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole as a yellow oil. LCMS: ESI m / z 237.1 (M + H)+.

[1578] Step 4 : (rac)-tert-butyl 4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

[1579]

[1580] A mixture of (rac)-4-chloro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (0.550 g, 2.32 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.718 g, 2.32 mmol), bis(tri-tert-butylphosphine)palladium (0) (59 mg, 0.12 mmol), and tripotassium phosphate (1.480 g, 6.97 mmol) was stirred at 100°C for 16 hours under an argon atmosphere in 1,4-dioxane (20 mL) and water (4 mL). After 16 hours, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (0 to 35% ethyl acetate in petroleum ether) to obtain 0.6 g (67% yield) of (rac)-tert-butyl 4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyridodo[2,3-b]indole-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate as a yellow oil. LCMS: ESI m / z 384.1 (M + H)+.

[1581] Step 5 : (rac)-tert-butyl 4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)piperidine-1-carboxylate

[1582]

[1583] A mixture of (rac)-tert-butyl 4-[5-(2,5-dihydrofuran-3-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-3-yl]-3,6-dihydro-2H-pyridin-1-carboxylate (0.637 g, 1.28 mmol), 5% Pd / C (0.5 g), and 20% Pd(OH)2 / C (0.5 g) was stirred in methanol (80 mL) at room temperature under 1 atm of H2 for 96 hours. After 96 hours, the mixture was filtered and concentrated. The resulting residue was purified by preparative HPLC to obtain 237 mg (39% yield) of (rac)-tert-butyl 4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)piperidine-1-carboxylate as a white solid. LCMS: ESI m / z 386.1 (M + H)+.

[1584] Step 6 : (rac)-7-methoxy-4-(4-piperidyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole, hydrochloride

[1585]

[1586] To a solution of (rac)-tert-butyl 4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)piperidine-1-carboxylate (117 mg, 0.3 mmol) in MeOH (2 mL) at room temperature, 1.14 ml of 4 N HCl solution in dioxane (4.55 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour, concentrated, and dried to obtain 108 mg (100% yield) of (rac)-7-methoxy-4-(4-piperidyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole, hydrochloride as a yellow solid. LC / MS (m / z, M+H- 2HCl): Calculated 286.2, Found 286.1.

[1587] Step 7: (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone

[1588]

[1589] (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone was prepared according to the protocol described in Step 5 of Example 56, using (rac)-7-methoxy-4-(4-piperidyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole, hydrochloride (108 mg, 0.3 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (70 mg, 0.32 mmol) to obtain 126 mg (85% yield) of (rac)-7-methoxy-4-(4-piperidyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole, hydrochloride (108 mg, 0.3 mmol) and 2-amino-4-(trifluoromethoxy)benzoic acid (70 mg, 0.32 mmol) of 126 mg (85% yield). (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone was obtained as a light brown solid. LC / MS (m / z, M+H): Calculated 489.2, Found 489.2.

[1590] Step 8 : [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone, isomers 1 and 2

[1591]

[1592] Chiral separation of (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone (123 mg, 0.25 mmol) was performed using a Chiralcel OD-I column (20 μm, 350 x 76.5 mm) eluted with (heptane 60% / EtOH 40%) + 0.1% TEA (flow rate 400 mL / min, UV detection at 265 nm) to obtain the following: 52 mg (42% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone, isomer 1. LC / MS (m / z, M+H): calculated 489.2, found 489.4; and 59 mg (48% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone, isomer 2. LC / MS (m / z, M+H): calculated 489.2, found 489.4.

[1593] Method H

[1594] Method H is exemplified by the preparation of Example 72. Method H includes, for example, the steps identified in Reaction Scheme 8.

[1595] Example 72: [2-amino-4-(pentafluoro-λ 6 -sulfanyl)phenyl]-[4-(7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-12-yl)-1-piperidyl]methanone

[1596]

[1597] Step 1 : 12-chloro-7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene

[1598]

[1599] In a 10 to 20 mL microwave vial, cyclopentanone (495 mg, 5.6 mmol), 1,4-diazabicyclo[2.2.2]octane (661 mg, 5.6 mmol), and bis(tri-tert-butylphosphine)palladium (0) (97 mg, 0.19 mmol) were added to a solution of 4-chloro-3-iodopyridine-2-amine (500 mg, 1.87 mmol) in DMF (10 mL), the entire mixture was bubbled with argon for 10 minutes, and then microwaved at 165°C for 130 minutes. After 130 minutes, the reaction mixture was diluted with ethyl acetate, filtered, the resulting filtrate was washed three times with water, washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography eluted with 85 / 15 heptane / AcOEt on silica gel (SiO2 20 g) to obtain 84 mg (23% yield) of 12-chloro-7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene as a white solid. LC / MS (m / z, M+H): Calculated 193.0, Found 192.9.

[1600] Step 2 : tert-butyl 4-(7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene-12-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

[1601]

[1602] In a 2 to 5 mL microwave vial, cesium carbonate (431 mg, 1.32 mmol), Pd(dppf)Cl2.DCM (43 mg, 0.05 mmol), and N-BOC-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (275 mg, 0.85 mmol) were added to a solution of 12-chloro-7,9-diazatricyclo[6.4.0.02,6]dodeca-1(12),2(6),8,10-tetraene (120 mg, 0.53 mmol) in dioxane (4.5 mL) and water (0.4 mL), the entire mixture was bubbled with argon for 10 minutes and microwaved at 160°C for 50 m...

Claims

Claim 1 Compound of Chemical Formula I [Chemical Formula I] or a pharmaceutically acceptable salt thereof (in the above formula, Ring A is a (C5-C8)cycloalkane, a (C6-C8)cycloalkene, or a 5 to 8-membered heterocycloalkane, where ring A is R in one or more cases. A Optionally replaced with, Here, each case R A Is (a) independently selected from -D, halo, -OH, oxo, =N-OH, -NHR', -CN, -C(O)-R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3 to 6 heterocycloalkyl, wherein in each case the -(C1-C3)alkyl is optionally substituted with one or more groups selected from halo and -OH, and Here, each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl optionally substituted with one or more halos, and Here, each R'' is selected from -OH, -O(C1-C3)alkyl, and -(C1-C3)alkyl (e.g., -CH3); (b) R in another case A and taken together with intervening atoms(s) to form a (C4-C7)cycloalkyl or 4 to 7-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring and the cycloalkyl ring are optionally substituted with one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl; R 1 is selected from -H and halo (e.g., -F); R 2 -(C6-C 10 )aryl, and here R 2 is R in one or two cases B It is replaced with (Here, each R B is independently selected from halo, -OH, -NH2, -SF5, -(C1-C3)alkyl, and -O(C1-C3)alkyl, wherein in each case -(C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted with one or more halos; n is 0, 1, or 2, and However, R 2 ga is 4-(pentafluorosulfanyl)phenyl, and R 1 If this is -H and n is 1, ring A is not unsubstituted cyclopentane). Claim 2 In claim 1, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxephane, azephane, 1,4-oxasephane, and thiephane, wherein ring A is R in one or more cases as defined in claim 1. A A compound that is selectively substituted with Claim 3 In paragraph 1 or 2, ring A is Selected from, where the dotted linkage indicates the fusion point with the pyrrole ring, and ring A is one or more of R cases as defined in claim 1. A A compound that is selectively substituted with Claim 4 In any one of paragraphs 1 to 3, R 2 Is A compound selected from. Claim 5 Compound of Chemical Formula II [Chemical Formula II] or a pharmaceutically acceptable salt thereof (in the above formula, Ring A is a (C5-C8)cycloalkane or a 6- to 7-membered heterocycloalkane, where ring A is R in one or more cases. A Optionally replaced with, Here, each case R A Is (a) independently selected from -OH, oxo, -NHR', -C(O)CH3, -(C1-C3)alkyl, and -O(C1-C3)alkyl, and Here, each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3 to 4-membered heterocycloalkyl selectively substituted with one or more halos; (b) R in another case A and taken together with intervening atoms(s) to form a (C5-C7)cycloalkyl or 4 to 6-membered heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with an oxo; R 1 is selected from -H and -F; R B1 It is selected from -H and -NH2, and R B2 is selected from -OCF3 and -SF5, and However, R B1 This is -H and R B2 g is -SF5, and R 1 In the case of -H, ring A is not unsubstituted cyclopentane). Claim 6 In paragraph 5, ring A is Selected from, wherein the dotted linkage indicates a fusion point with the pyrrole ring, and ring A is R in one or more cases as defined in any one of claims 1 to 5. A A compound that is selectively substituted with Claim 7 In paragraph 5 or 6, R B2 is a compound that is -OCF3. Claim 8 In any one of paragraphs 1 through 7, R 1 A compound that is -F. Claim 9 Compound of Formula III, Formula IV, Formula V, or Formula VI: [Formula III] [Chemical Formula IV] [Chemical Formula V] [Chemical Formula VI] or a pharmaceutically acceptable salt thereof (wherein, ring A and R 1 ...is as defined in any one of claims 1 to 8, provided that the compound is a compound of formula V and R 1 In the case of -H, ring A is not unsubstituted cyclopentane). Claim 10 Compounds and pharmaceutically acceptable salts thereof selected from the group consisting of the following: - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone; - [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone; - (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraene-13-yl)-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-oxetane]-4-yl)-1-piperidyl]methanone;- [4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraen-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- (rac)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraen-3-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indole-6-one;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-3-yl)-1-piperidyl]methanone;- (6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;- (6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;- [4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(3S,8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-((2S, 7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-((2R, 7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl)-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;- 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-4-fluoro-13-methyl-6,8,13-triaztricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetadeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadeca-1(9),2,4,6-tetraene-3-yl)-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- (7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;- (7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carbonitrile;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-azetidine]-4-yl)-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-12-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadeca-1(9),10,12,14-tetraene-11-yl]-1-piperidyl]methanone;- [4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- 1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-13-yl]ethanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl)-1-piperidyl]methanone;- (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- (rac)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- 4-fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraen-14-one;- [4-[(6R)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidyl]methanone;- [4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indole-4-yl]-1-piperidyl]-[4-(trifluoromethoxy)phenyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraene-3-yl]-1-piperidyl]methanone;- (6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;- (6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,4'-pyrrolidine]-2'-one;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone;- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone; and- [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuterio-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),3,5-tetraene-3-yl]-1-piperidyl]methanone.; Claim 11 A pharmaceutical composition comprising a compound of any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient or carrier. Claim 12 A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in treatment. Claim 13 A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in the treatment or prevention of cancer. Claim 14 In Paragraph 13, cancer is increased MAPK7 A compound or pharmaceutical composition characterized by expression and / or increased ERK5 activity. Claim 15 A compound or pharmaceutical composition, wherein the cancer is selected from leukemia, breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

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