Tricyclic compounds, their preparation and therapeutic use as ERK5 inhibitors

Abstract

Compounds that can inhibit ERK5 are provided. Pharmaceutical compositions and their medical uses are also provided, including use in the treatment or prevention of conditions such as cancer. Formula (I)

Description

[0001] Compounds that can inhibit ERK5 are provided. Pharmaceutical compositions and their medical uses are also provided, including use in the treatment or prevention of conditions such as cancer. Summary of the Invention

[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 for its association with cancer development. Proteins involved in this pathway include extracellular signal-regulated kinase (ERK) proteins; among them, ERK5 (expressed by the MAPK7 gene) plays a vital role in cell proliferation, as well as epithelial development and neural differentiation (see, for example, Nishimoto et al., EMBOReports [European Society for Molecular Biology Report] (2006) 7(8):782-786). ERK5 is unique among ERK proteins for its large C-terminal domain containing a transcriptional activation domain (TAD) as well as nuclear localization signals and two proline-rich regions (see, for example, Guo et al., Exp Ther Med. [Journal of Experimental and Therapeutic Medicine]. (2020) 19:1997-2007). Autophosphorylation of TAD is essential for transcriptional activation (see, for example, Morimoto et al., J Biol Chem. (2007) 282(49):35449-35456).

[0003] ERK5 plays a crucial role in controlling cell proliferation and cell cycle progression, for example, through direct or indirect phosphorylation of MEF2C, cMYC, SGK1, RSK, FOS, and FRA1 (see, for example, Paudel et al., Int J Mol Sci [International Journal of Molecular Sciences]. (2021) 22:7594-7614; Terasawa et al., Genes to Cells [Journal of Genes to Cells] (2003) 8(3):263-273). ERK5's involvement in multiple biological pathways implies that its activity is associated with many aspects of cancer progression, including tumor angiogenesis, metastasis, inflammation, sustained proliferation, and evasion of growth inhibition. Therefore, it presents an attractive target for modulating disease pathology and treatment across a wide range of conditions. In previous studies, ERK5 inhibition or downregulation has been shown to block tumorigenesis in murine leukemia cells, reduce the growth of chronic myeloid leukemia cells, inhibit the growth of breast cancer and multiple myeloma cells, inhibit the proliferation of colon cancer cells, and must have an effect on the growth or survival of renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma and hepatocellular carcinoma cells (see, for example, Stecca et al., Int J Mol Sci [International Journal of Molecular Sciences]. (2019) 20:1426-1446).

[0004] Therefore, ERK5 inhibition represents a promising approach to addressing a variety of cancers. Several ERK5 inhibitors have been developed, some of which are under clinical review. For example, WO 2019 / 170543 (Bayer AG and Bayer Pharma AG) disclosed compounds that are alleged to be active as ERK5 inhibitors in the µM to nM concentration range.

[0005] Despite recent advancements in cancer treatment with the development of targeted and immunotherapies, effective treatment solutions remain unavailable for all cancer patients. Therefore, there is a need to identify and develop new drugs. This disclosure attempts to address this need by providing novel compounds that can be used as ERK5 inhibitors and for the treatment of ERK5-related diseases and conditions.

[0006] Therefore, the first aspect provides compounds having formula (I).

[0007]

[0008] Or its pharmaceutically acceptable salt, wherein:

[0009] Ring A is a (C5-C8) cycloalkane, (C6-C8) cycloalkene, or a 5- to 8-membered heterocyclic alkane, wherein ring A is optionally separated by one or more R groups. A replace,

[0010] Where R A Each time it appears, it is:

[0011] (a) Independently selected from -D, halogen, -OH, oxo, =N-OH, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl and 3- to 6-membered heterocyclic alkyl groups, wherein -(C1-C3)alkyl is optionally substituted by one or more groups selected from halogen and -OH each time it appears.

[0012] Each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens.

[0013] Each R'' is selected from -OH, -O(C1-C3)alkyl, and -(C1-C3)alkyl (e.g., -CH3); and / or

[0014] (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C4-C7) cycloalkyl ring or a 4- to 7-membered heteroalkyl ring, wherein the heteroalkyl ring and the cycloalkyl ring are optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl;

[0015] R 1 Selected from -H and halogens (e.g. -F);

[0016] R 2 Yes - (C6-C 10 ) aryl, wherein R 2 R appears in one or two B replace,

[0017] Each R B Independently selected from halogens, -OH, -NH2, -SF5, -(C1-C3)alkyl, and -O(C1-C3)alkyl, wherein -(C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted by one or more halogens each time they appear; and

[0018] n is 0, 1, or 2.

[0019] The premise is that when R 2 It is 4-(pentafluorosulfuryl)phenyl, R 1 If the molecule is -H and n is 1, then ring A is not an unsubstituted cyclopentane.

[0020] In the embodiments, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxacycloheptane, azacycloheptane, 1,4-oxaazacycloheptane, and thiocycloheptane, wherein ring A may optionally be represented by one or more R groups as previously defined herein. A replace.

[0021] In this embodiment, ring A is selected from: , , , , , , , , , , , , , , , , , , and The dashed bond indicates the point of fusion with the pyrrole ring, wherein ring A is optionally bounded by one or more R as previously defined herein. A replace.

[0022] In the embodiment, R 2 Selected from: , , and .

[0023] On the other hand, compounds having formula (II) are provided.

[0024]

[0025] Or its pharmaceutically acceptable salt, wherein:

[0026] Ring A is a (C5-C8) cycloalkane or a 6- to 7-membered heterocyclic alkane, wherein ring A is optionally separated by one or more R groups. A replace,

[0027] Where R A Each time it appears, it is:

[0028] (a) Independently selected from -OH, oxo, -NHR', -C(O)CH3, -(C1-C3)alkyl and -O(C1-C3)alkyl,

[0029] Each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens; or

[0030] (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring or a 4- to 6-membered heteroalkyl ring, wherein the heteroalkyl ring is optionally substituted with an oxo group;

[0031] R 1 Selected from -H and -F;

[0032] R B1 Selected from -H and -NH2; and

[0033] R B2 Selected from -OCF3 and -SF5,

[0034] The premise is that when R B1 It is -H,R B2 It is -SF5 and R 1 If it is -H, then ring A is not an unsubstituted cyclopentane.

[0035] In this embodiment, ring A is selected from: , , , , , , , , and The dashed bond indicates the point of fusion with the pyrrole ring, wherein ring A is optionally bounded by one or more R as previously defined herein. A replace.

[0036] In the embodiment, R B2 It is -OCF3.

[0037] In the embodiment, R 1 Yes, it is -F.

[0038] On the other hand, compounds having formula (III), formula (IV), formula (V), or formula (VI) are provided:

[0039]

[0040] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 As defined earlier in this document, the premise is that the compound is a compound having formula (V) and R1 If it is -H, then ring A is not an unsubstituted cyclopentane.

[0041] Another aspect provides compounds selected from the following group:

[0042] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0043] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0044] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone;

[0045] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(9),2(7),10,12-tetraen-13-yl)-1-piperidinyl] methyl ketone;

[0046] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-oxetane]-4-yl)-1-piperidinyl] methyl ketone;

[0047] -[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0048] -[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0049] -(racemic)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0050] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indol-6-one;

[0051] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0052] -(6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0053] -(6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0054] -[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0055] -[4-[(3S,8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0056] -[4-((2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0057] -[4-((2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0058] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0059] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-13-methyl-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0060] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0061] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0062] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadecan-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0063] -[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]indol-4-yl]-1-piperidinyl] methyl ketone;

[0064] -[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]indol-4-yl]-1-piperidinyl] methyl ketone;

[0065] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0066] -(7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0067] -(7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0068] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-azacyclobutane]-4-yl)-1-piperidinyl] methyl ketone;

[0069] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone;

[0070] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0071] -[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0072] -[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0073] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0074] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0075] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0076] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0077] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0078] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0079] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0080] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0081] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0082] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]methyl ketone;

[0083] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0084] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0085] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl]methyl ketone;

[0086] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0087] -[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0088] -[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0089] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0090] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0091] -[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0092] -[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0093] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0094] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0095] -1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-yl]acetone;

[0096] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0097] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0098] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0099] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0100] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0101] -[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0102] -[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0103] -4-Fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0104] -[4-[(6R)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0105] -[4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0106] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0107] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0108] -[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0109] -[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0110] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0111] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0112] -(6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0113] -(6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0114] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0115] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0116] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuter-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone; and

[0117] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuterium-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone,

[0118] And its pharmaceutically acceptable salts.

[0119] Another aspect provides pharmaceutical compositions comprising a compound as previously defined herein and at least one pharmaceutically acceptable excipient or carrier.

[0120] Other aspects provide compounds or pharmaceutical compositions, as previously defined herein, for use in therapy.

[0121] Other aspects provide compounds or pharmaceutical compositions, as previously defined herein, for use in the treatment or prevention of cancer.

[0122] In the embodiments, the cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

[0123] In the embodiments, 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. Detailed Implementation

[0124] Although specific embodiments of this disclosure will now be described with reference to the specification and examples, it should be understood that such embodiments are by way of example only and illustrate only a small number of the many possible specific embodiments that may represent the application of the principles of this disclosure. In view of the benefits of this disclosure, various changes and modifications will be apparent to those skilled in the art and are considered to be within the spirit and scope of this disclosure as further defined in the appended claims.

[0125] definition

[0126] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, exemplary methods, apparatus, and materials are described hereafter. All technical and patent disclosures referenced herein are incorporated herein by reference in their entirety.

[0127] Unless otherwise stated, the practices disclosed herein will employ conventional techniques such as chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, recombinant DNA, etc., all of which are within the scope of the art. See, for example, Michael R. Green and Joseph Sambrook, *Molecular Cloning* (4th edition, Cold Spring Harbor Laboratory Press, 2012); Ausubel et al., eds. (2007); *Current Protocols in Molecular Biology*; *Methods in Enzymology* series (Academic Press, Inc., New York); 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*. [Animal Cell Culture: A Basic Technique Manual], 5th Edition; edited by Gait. (1984) Oligonucleotide Synthesis; US Patent No. 4,683,195; edited by Hames and Higgins. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; edited by Hames and Higgins.(1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press, 1986); Perbal (1984) A Practical Guide to Molecular Cloning; edited by Miller and Calos. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); edited by Makrides. (2003) Gene Transfer and Expression in Mammalian Cells; edited by Mayer and Walker. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); edited by Herzenberg et al. (1996) Weir's Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3rd Edition (Cold Spring Harbor Laboratory Press, 2002); Sohail (ed.) (2004); GeneSilencing by RNA Interference: Technology and Application (CRC Press).

[0128] All numerical designations, such as pH, temperature, time, concentration, molecular weight, etc. (including ranges), are approximate values ​​that vary (+) or (-) in increments of, for example, 0.1 or 1.0, where appropriate. It should be understood that, although not always explicitly stated, all numerical designations are preceded by the term "about" to indicate a typical level of variability. For example, a numerical designation for a given value "about" may vary by ±10% of said value; alternatively, the variation may be ±5%, ±2%, or ±1% of that value. It should also be understood that, although not always explicitly stated, the reagents described herein are merely exemplary, and their equivalents are known in the art.

[0129] As used in the specification and claims, the singular forms “a / an” and “the” include plural references unless the context clearly indicates otherwise. For example, the term “cell” includes a plurality of cells, including mixtures thereof. Unless explicitly stated or obvious from the context, the term “or” as used herein should be understood as inclusive. The term “comprising” as used herein means the phrase “including but not limited to” and may be used interchangeably with it.

[0130] As used herein, the term “comprising / comprises” is intended to mean that a composition and method includes the listed elements without excluding other elements. When used to define a composition and method, “consistently composed of…” should mean excluding other elements that are of any significance to the stated purpose. Thus, a composition consisting essentially of elements as defined herein will not exclude trace contaminants from separation and purification methods, as well as pharmaceutically acceptable carriers such as phosphate-buffered saline, preservatives, etc. “Constitutes of…” should mean excluding more than one trace element of other components and substantial method steps for administering the composition of this disclosure or process steps for producing the composition or achieving the intended results. Examples defined by each of these transitional terms are within the scope of this disclosure. The term “comprising” as used herein is intended to cover and disclose corresponding statements in which the term “comprising” is replaced by “consistently composed of…” or “composes of…”.

[0131] The terms “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, racing animals, pets, and primates; for example, rats, rats, rabbits, apes, cattle, sheep, pigs, dogs, cats, horses, and humans. In a particular embodiment, the mammal is a human.

[0132] "Administration" is defined herein as the delivery of a drug or a composition containing such drug to a subject in a manner that causes the drug to come into contact with the subject's body (e.g., in the body). Such administration can be performed via any route, including but not limited to oral, transdermal (e.g., through the vagina, rectum, or oral mucosa), injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or into the central nervous system), or inhalation (e.g., oral or nasal). Administration can also include delivering a substance or composition to a portion of the surface of the subject's body, such as by topical application to the skin. Of course, pharmaceutical preparations are given in a form suitable for each route of administration.

[0133] “Treating or treating” a disease includes: (1) preventing the disease, i.e., preventing the development of clinical symptoms of the disease in patients who may be susceptible to the disease but have not yet experienced or shown symptoms of the disease; (2) suppressing the disease, i.e., stopping or reducing the development of the disease or its clinical symptoms; and / or (3) alleviating the disease, i.e., causing the disease or its clinical symptoms to subside.

[0134] The term "having" in relation to the term "treatment" refers to a patient or individual who has been diagnosed with or is susceptible to the disease. A patient may also be described as "at risk of having" the disease due to a family history of the disease or the presence of a gene mutation associated with it. Patients at risk of the disease have not yet developed all or some of the characteristic pathologies of the disease.

[0135] "Effective dose" or "therapeutic effective dose" is a quantity sufficient to achieve a beneficial or desired outcome. Effective doses can be administered, applied, or dosed, either once or multiple times. This delivery depends on many variables, including the time period for which a single dose unit is used, the bioavailability of the therapeutic agent, the route of administration, etc. However, it should be understood that the specific dose level of the therapeutic agent disclosed herein for any particular subject depends on a variety of factors, including, for example, the activity of the specific compound used, the subject's age, weight, general health condition, sex, and diet, the time of administration, the rate of excretion, the combination of drugs, the severity of the specific disorder being treated, and the form of administration. Therapeutic doses can often be adjusted to optimize safety and efficacy. Typically, dose-response relationships from in vitro and / or in vivo studies can initially provide useful guidance for the appropriate dose administered to a patient. Generally, it is desirable to administer a quantity of compound effective to achieve serum levels equivalent to concentrations found to be effective in vitro. The determination of these parameters is well known to those skilled in the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and are 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 in a single or divided dose and may fall outside the typical range given herein, depending on the physician's judgment.

[0136] As used herein, the terms “increased” and “enhanced” are used interchangeably and cover any measurable increase in biological function and / or biological activity and / or concentration. For example, an increase may be at least about 10%, such as at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, relative to a control or baseline amount or function, or activity or concentration, an increase may be at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, such as at least about 20, 25, 50, 100 times, or higher.

[0137] 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 an increased amount of the substance (e.g., the MAPK7 gene product or the ERK5 protein), although it can also indicate increased biological activity of the substance (e.g., constitutive phosphorylation activation and / or reduced differentiation of ERK5 phosphorylation sites). For example, an increase could be an amount of about 5%, such as about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, such as about 96%, 97%, 98%, 99%, or 100%. Therefore, an increase in the amount (or activity) of a substance (such as ERK5) relative to one or more control samples (such as individuals or groups of individuals without a disease or disorder (e.g., cancer) or internal controls, as determined by techniques known in the art, can be about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, such as about 20, 25, 50, 100 times, or higher. An "increased expression" or "increased activity" of ERK5 can also be determined if the expression and / or activity of ERK5 increases by one, two, three, four, five, or more standard deviations relative to the mean or median amount of ERK5 in a retrospective analysis of the sample control group, sample baseline group, or patient samples. Such control or baseline expression levels can be predetermined, measured before measuring the sample or cancer or the subject, or obtained from a database of such control samples, as practiced in the art.

[0138] As used herein, the term "pharmaceuticalally acceptable excipient" encompasses any standard pharmaceutical excipient, such as those described in Remington's Pharmaceutical Sciences (20th edition, Mack Publishing Co., 2000). Such excipients include carriers, such as phosphate-buffered saline solutions, water and emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. Pharmaceutical compositions may also contain stabilizers, preservatives, excipients, fillers, binders, lubricants, etc.

[0139] As used herein, the term "alkyl" means a saturated straight-chain or branched radical consisting essentially of carbon atoms and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. Other alkyl groups will be apparent to those skilled in the art given the benefits of this disclosure. The terms "(C1-C3)alkyl," "(C1-C6)alkyl," etc., have equivalent meanings of a saturated straight-chain or branched radical consisting essentially of 1 to 3 (or 1 to 6) carbon atoms and a corresponding number of hydrogen atoms. The definition of "alkyl" also applies in the context of other groups containing alkyl groups, 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 can be replaced by heteroatoms (or bonded to heteroatoms) via multiple bonds (e.g., double bonds); for example, a carbon atom in an alkyl group can be bonded to oxygen via a double bond (i.e., replaced by an oxo group to provide a carbonyl functional group). The presence of such a substituent does not prevent the carbon backbone of the radical from being considered an alkyl group.

[0140] As used herein, the term "cyclic group" means a saturated, partially or fully unsaturated or aromatic group having at least 3 to 10 ring-forming atoms (i.e., ring atoms). When a cyclic group is defined as having a certain number of members, the terms "member," "member," etc., are used to indicate the number of ring atoms in the cyclic group. For example, a 5-membered cyclic group (e.g., a 5-membered heterocyclic group) contains 5 ring atoms. It should be understood that a cyclic group can be part of a larger cyclic system; for example, bicyclic [4.3.0]nonane comprises two carbocyclic groups, namely a cyclohexyl group and a cyclopentyl group, which are fused to form a carbocyclic system constituting the molecule. The term "cyclic group" is intended to encompass both carbocyclic groups and heterocyclic groups. The term "carbocyclic" refers to a group having at least 3 to 9 ring-forming carbon atoms. The term "heterocycle" refers to a group having at least 3 to 10 ring-forming atoms, wherein at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., one or more heterocycle atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen.

[0141] As used herein, the term "spiro" or "spirocyclic" in relation to cyclic groups indicates that a first cyclic group in a polycyclic system is attached to a second cyclic group in the same polycyclic system, wherein the ring atoms of the first cyclic group and the ring atoms of the second cyclic group share only one common atom, i.e., the first and second cyclic groups share a common ring atom. For example, a spiro[5.5]undecyl group comprises two cyclohexyl rings that share a common carbon ring atom.

[0142] As used herein, the term "fusion" in relation to cyclic groups refers to the attachment of a first cyclic group to a second cyclic group in a polycyclic system, wherein the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have two common adjacent atoms, i.e., the first and second cyclic groups share two common ring atoms. For example, a bicyclic [4.4.0]decyl group comprises two cyclohexyl rings having two common adjacent carbon ring atoms.

[0143] As used herein, the term "bridging" in relation to cyclic groups refers to a first cyclic group in a polycyclic system being attached to a second cyclic group in the same polycyclic system, wherein the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have more than two common adjacent atoms, i.e., the first and second cyclic groups share three or more common ring atoms. For example, a bicyclic [3.3.1]nonyl group comprises two cyclohexyl rings having three common adjacent carbon ring atoms.

[0144] In the structural formulas described herein, any ring system (including any spirocyclic, fused, or bridged ring system) can be connected to other parts of the molecule via any atom having a suitable valence. For example, a bicyclic ring can be connected to another part of the molecule via a ring atom (e.g., a secondary carbon atom or a heteroatom such as N) or a bridgehead (e.g., a tertiary carbon atom). Spirocyclic, fused, and bridged rings can be fully unsaturated, partially unsaturated, or fully saturated, and can have aromatic characteristics in one or more of their constituent rings.

[0145] As used herein, the term "cycloalkane" means 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 having formula (I)) is typically fused to an aromatic ring (e.g., the pyrrole ring depicted in formula (I)) via a common carbon atom. The presence of unsaturated bonds (e.g., bonds with aromatic characteristics) in the fused moiety does not prevent the cyclic group from being considered a cycloalkane moiety. The term "(C5-C8)cycloalkane" means a saturated cyclic group containing 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 by heteroatoms (i.e., bonded to heteroatoms) via double bonds (e.g., cycloalkane substituted with oxo groups). The presence of such substituents does not prevent the cyclic group from being considered a cycloalkane moiety. Exemplary cycloalkane moieties include cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0146] 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 the cyclic moiety, wherein the cyclic alkene moiety is fused to another cyclic group. The cyclic alkene moiety described herein (e.g., ring A having formula (I)) is typically fused to an aromatic ring (e.g., the pyrrole ring depicted in formula (I)) via a common carbon atom. The presence of unsaturated bonds (e.g., bonds with aromatic characteristics) in the fused moiety is not decisive when the cyclic group is considered as the cyclic alkene moiety. To avoid ambiguity, the cyclic alkene ring also has additional unsaturated bonds besides those with unsaturated characteristics in the fused moiety. The term "(C6-C8) cyclic alkene" refers to an unsaturated cyclic group containing a total of 6, 7, or 8 ring carbon atoms, wherein the cyclic alkene moiety is fused to another cyclic group. One or more ring atoms of the cyclic alkene group can be substituted by heteroatoms (i.e., bonded to heteroatoms) via double bonds (e.g., cyclic alkenes substituted with oxo groups). The presence of such a substituent does not preclude the cyclic group from being considered a cyclic olefin moiety. An exemplary cyclic olefin moiety is cycloheptene.

[0147] As used herein, the term "cycloalkyl" means a saturated cyclic group (e.g., a saturated radical) having at least 3 to 9 ring-forming carbon atoms (i.e., ring atoms). A cycloalkyl group can be a cycloalkyl ring, wherein the ring is connected to another cyclic group in a spiro, fused, or bridged configuration, or it can be a cycloalkyl substituent, wherein the ring is connected to another atom via an external ring bond. For example, the cycloheptane moiety can be replaced by two substituents that together form a bridgehead, such that cycloheptane and the substituents together form a bicyclic [3.2.1]octane. The term "(C4-C7)cycloalkyl" indicates that the cycloalkyl group contains a total of 4, 5, 6, or 7 carbon atoms in the ring portion of the group, such as cyclohexyl (having 6 ring carbon atoms). One or more ring atoms of a cycloalkyl group can be replaced by heteroatoms via double bonds (i.e., bonded to heteroatoms) (e.g., cycloalkyl groups substituted with oxo groups). The presence of such substituents does not prevent the cyclic group from being considered a cycloalkyl group. A cycloalkyl group can be monocyclic or polycyclic (e.g., bicyclic). In the embodiments, the cycloalkyl group is monocyclic. Exemplary cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0148] As used herein, the term "aryl" refers to an aromatic radical having at least six carbon atoms forming a ring (i.e., ring atoms). It should be understood that aryl groups can be monocyclic or polycyclic (e.g., fused). Examples of aryl groups include phenyl and naphthyl. The term "(C6-C)" 10 "Aryl" indicates that the aryl group contains 6 to 10 carbon atoms in the ring portion of the group. In the examples, (C6-C 10 The aryl group is phenyl.

[0149] As used herein, the term "heterocyclic alkane" means a saturated cyclic group having at least 3 to 10 ring-forming atoms (i.e., ring atoms), wherein at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., one or more heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclic alkane moiety is fused to another cyclic group. Heterocyclic alkane moieties described herein (e.g., ring A having formula (I)) are typically fused to an aromatic ring (e.g., a pyrrole ring depicted in formula (I)) via a common carbon atom. The presence of unsaturated bonds (e.g., bonds with aromatic characteristics) in the fused moiety does not prevent the cyclic group from being considered a heterocyclic alkane moiety. In embodiments, one or more heterocyclic atoms are independently selected from the group consisting of nitrogen and oxygen. When a heterocyclic alkane moiety is described as "X to Y units" (where X and Y are integers), this means that the heterocyclic alkane moiety contains a total of X to Y ring atoms. For example, the term "5- to 8-membered heterocyclic alkanes" refers to 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 heterocyclic alkane moiety is fused to another cyclic group. One or more ring atoms of the heterocyclic alkane group can be replaced by a heteroatom via a double bond (i.e., bonded to a heteroatom) (e.g., a heterocyclic alkane substituted with an oxo group), but the heteroatom does not form part of the ring and is not included in the number of ring atoms. Such substituents (e.g., oxo groups) are typically located near the heteroatom (e.g., in the case of 2-oxetane-heptanone, also known as caprolactone, or 2-azaheptanone, also known as caprolactam). Any cyclic sulfur atom may optionally carry one or more side (i.e., acyclic) oxygen atoms, as found, for example, in sulfolane groups. The presence of any such substituents does not prevent the cyclic group from being considered a heterocyclic alkane moiety. Exemplary heterocyclic alkane moieties include tetrahydropyran, piperidine, oxetane, and azaheptanane.

[0150] As used herein, the term "heterocyclic alkyl" means a saturated cyclic group (e.g., a saturated radical) having at least 3 to 10 ring-forming atoms (i.e., ring atoms), wherein at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., one or more heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. A heterocyclic alkyl group may be a heterocyclic alkyl ring, wherein the ring is connected to another cyclic group in a spiro, fused, or bridged configuration, or it may be a heterocyclic alkyl substituent, wherein the ring is connected to another atom via an external bond. In embodiments, one or more heterocyclic atoms are independently selected from the group consisting of nitrogen and oxygen. When a heterocyclic alkyl group is described as "X to Y-membered" (where X and Y are integers), this means that the heterocyclic alkyl group contains a total of X to Y ring atoms. For example, the term "4- to 7-membered heterocyclic alkyl" means a saturated cyclic group containing a total of 4, 5, 6, or 7 ring atoms, wherein one or more are heterocyclic atoms, such as a tetrahydropyranyl group (6 ring atoms). Heterocyclic alkyl groups may have oxo-substituents (e.g., 2-oxopyrrolidinyl) typically adjacent to the heteroatom, but the oxygen atom of the oxo-substituent does not form part of the ring and is not included in the number of ring atoms. The presence of such substituents does not prevent the cyclic group from being considered a heterocyclic alkyl group. Any cyclic sulfur atom may optionally carry one or more side (i.e., acyclic) oxygen atoms, as found, for example, in sulfolane groups. Heterocyclic alkyl groups may be monocyclic or polycyclic (e.g., bicyclic). In the examples, the heterocyclic alkyl group is monocyclic. Exemplary heterocyclic alkyl groups include oxobutyryl, tetrahydrofuranyl, piperidinyl, and morpholinyl.

[0151] As used herein, the term "halo" means fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and can refer to a halogen radical or the halogen atom itself. Given the context in which the term is used in this disclosure, those skilled in the art will be able to readily identify it. In the embodiments, the halogen is fluorine.

[0152] As used herein, the term "CN" refers to a free radical having a carbon atom attached to a nitrogen atom via a triple bond. The CN group is attached via its carbon atom.

[0153] As used herein, the term "oxo group" refers to a radical in which an oxygen atom is attached via a double bond to the atom carrying the group. For example, when a carbon atom carries an oxo group, a carbon-oxygen double bond is formed. It should be understood that not all atoms within a given structure can be substituted by an oxo group, and this will depend on the valence of the atom to be substituted.

[0154] The compounds disclosed herein are described, in particular, by structural formulas. It should be understood that these formulas typically show only one form of the compound (e.g., resonance form, tautomer form, etc.), and some compounds may exist in more than one such form. This will be apparent to a skilled reader. This disclosure includes all possible tautomers of the compounds characterized by the structural formulas herein, including as a single tautomer or as any mixture of tautomers in any ratio. For example, the pyrrolopyridine moiety (as shown, for example, in formula (I), and which may be referred to as 1H-pyrrolo[2,3-b]pyridine or 7-azaindole) can be described by any of the following tautomer forms, which are used interchangeably throughout this specification:

[0155]

[0156] It should also be understood that some of the compounds of the present invention may exist in one or more isomers (e.g., stereoisomers). This disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc., of the compounds described above and below, as well as their cis and trans forms and conformational isomers. Purification and separation of isomers can be accomplished by the methods described below and techniques known in the art. For example, optical isomers of compounds can be obtained by resolving racemic mixtures of their diastereomer salts (e.g., using optically active acids or bases, or by forming covalent diastereomers). A different method for separating optical isomers involves using chiral chromatography with or without conventional derivatization (e.g., using an HPLC column with a chiral phase). Enzymatic separation with or without derivatization is also useful, and the optically active compounds of this disclosure can also be obtained by chiral synthesis using optically active raw materials. This disclosure includes all possible stereoisomers of the compounds described herein, as a single stereoisomer, or as any mixture of the stereoisomers in any ratio, such as (R)- or (S)-isomers.

[0157] The compounds disclosed herein 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 (see, for example, Berge et al., J Pharm Sci [Journal of Pharmaceutical Sciences]. (1977) 66:1-19).

[0158] As used herein, when used in combination with a salt, the term “pharmaceutically acceptable” means a salt of a currently disclosed compound that can be administered without any substantially undesirable one or more biological effects or any resulting harmful interactions with any other component of a pharmaceutical composition that may contain it.

[0159] A 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 substituents). In examples, the substituted group has 1 to 4 substituents, such as 1, 2, or 3 substituents. In examples, the substituted group has 1 or 2 substituents. In examples, the substituted group has 3 substituents.

[0160] The description of a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. The description of embodiments of variables or aspects herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0161] The compositions and methods provided herein may be combined with one or more of any other compositions and methods provided herein.

[0162] The following abbreviations and empirical formulas are used in this article:

[0163]

[0164] compound

[0165] In the first aspect, this disclosure provides compounds having formula (I).

[0166]

[0167] Or its pharmaceutically acceptable salt, wherein:

[0168] Ring A is a (C5-C8) cycloalkane, (C6-C8) cycloalkene, or a 5- to 8-membered heterocyclic alkane, wherein ring A is optionally separated by one or more R groups. A replace,

[0169] Where R A Each time it appears, it is:

[0170] (a) Independently selected from -D, halogen, -OH, oxo, =N-OH, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl and 3- to 6-membered heterocyclic alkyl groups, wherein -(C1-C3)alkyl is optionally substituted by one or more groups selected from halogen and -OH each time it appears.

[0171] Each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens.

[0172] Each R'' is selected from -OH, -O(C1-C3)alkyl, and -(C1-C3)alkyl (e.g., -CH3); and / or

[0173] (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C4-C7) cycloalkyl ring or a 4- to 7-membered heteroalkyl ring, wherein the heteroalkyl ring and the cycloalkyl ring are optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl;

[0174] R 1 Selected from -H and halogens (e.g. -F);

[0175] R 2 Yes - (C6-C 10 ) aryl, wherein R 2 R appears in one or two B replace,

[0176] Each R B Independently selected from halogens, -OH, -NH2, -SF5, -(C1-C3)alkyl, and -O(C1-C3)alkyl, wherein -(C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted by one or more halogens each time they appear; and

[0177] n is 0, 1, or 2.

[0178] The premise is that when R 2 It is 4-(pentafluorosulfuryl)phenyl, R 1 If the molecule is -H and n is 1, then ring A is not an unsubstituted cyclopentane.

[0179] On the other hand, this disclosure provides compounds having formula (I).

[0180]

[0181] Or its pharmaceutically acceptable salt, wherein:

[0182] Ring A is a (C5-C8) cycloalkane or a 5- to 8-membered heterocyclic alkane, wherein ring A is optionally separated by one or more R groups. A replace,

[0183] Where R A Each time it appears, it is:

[0184] (a) Independently selected from halogens, -OH, oxo groups, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl and 3- to 6-membered heterocyclic alkyl groups, wherein -(C1-C3)alkyl is optionally substituted by one or more halogens or -OH each time it appears.

[0185] Each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens.

[0186] Each R'' is selected from -OH and -CH3; and / or

[0187] (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C4-C7) cycloalkyl ring or a 4- to 7-membered heteroalkyl ring, wherein the heteroalkyl ring is optionally substituted with an oxo group;

[0188] R 1 Selected from -H and halogens (e.g. -F);

[0189] R 2 Yes - (C6-C 10 ) aryl, wherein R 2 R appears in one or two B replace,

[0190] Each R B Independently selected from halogens, -OH, -NH2, -SF5, -(C1-C3)alkyl, -O(C1-C3)alkyl, wherein -(C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted by one or more halogens each time they appear; and

[0191] n is 0, 1, or 2.

[0192] The premise is that when R 2 It is 4-(pentafluorosulfuryl)phenyl, R 1 If the molecule is -H and n is 1, then ring A is not an unsubstituted cyclopentane.

[0193] When an R appears A With another R that appears ATogether, they form a (C4-C7) cycloalkyl ring or a 4- to 7-membered heterocyclic alkyl ring, wherein the heterocyclic alkyl ring and the cycloalkyl ring are optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl groups, then the (C4-C7) cycloalkyl ring or the 4- to 7-membered heterocyclic alkyl ring can be spiro-, fused, or bridged to ring A. In the examples, one R appears A With another R that appears A Together they form a (C4-C7) cycloalkyl ring or a 4- to 7-membered heterocyclic alkyl ring, wherein the heterocyclic alkyl ring and the cycloalkyl ring are substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl, and wherein the (C4-C7) cycloalkyl ring or the 4- to 7-membered heterocyclic alkyl ring is spirobonded to ring A.

[0194] When an R appears A With another R that appears A Together they form (C4-C7) cycloalkyl rings or 4- to 7-membered heterocyclic alkyl rings, wherein when the heterocyclic alkyl ring is optionally substituted with an oxo group, the (C4-C7) cycloalkyl ring or the 4- to 7-membered heterocyclic alkyl ring can be spiro-, fused or bridged to ring A.

[0195] In the embodiments, ring A is a (C5-C8) cycloalkane or a 5- to 7-membered heterocycloalkane, wherein ring A is optionally surrounded by one or more R groups as defined herein. A replace.

[0196] In the embodiments, ring A is a (C5-C8) cycloalkane, wherein ring A is optionally surrounded by one or more R groups as defined herein. A Substitution. In the embodiments, ring A is cyclopentane, cyclohexane, cycloheptane, or cyclooctane, wherein ring A is optionally replaced by one or more R appearing. A Substitution. In the embodiments, ring A is a (C5-C7) cycloalkane, wherein ring A is optionally replaced by one or more appearing R... A Substitution. In the embodiments, ring A is cyclopentane, cyclohexane, or cycloheptane, wherein ring A is optionally replaced by one or more R appearing. A replace.

[0197] In the embodiments, ring A is a (C5-C6) cycloalkane, wherein ring A is surrounded by one or more R groups as defined herein. A Substitution. In the embodiments, ring A is a (C5-C6) cycloalkane, wherein ring A is replaced by one or two Rs as defined herein. A Replacement. In the embodiment, ring A is replaced by two appearing R. ASubstituted (C5-C6) cycloalkanes, wherein the two Rs appearing A Together with one or more intercalating carbon atoms, it forms a 4- to 6-membered heterocyclic alkyl ring.

[0198] In the embodiments, ring A is a (C6-C8) cyclic olefin, wherein ring A is optionally replaced by one or more R groups as defined herein. A Substitution. In the examples, ring A is cycloheptene, such as unsubstituted cycloheptene.

[0199] In the embodiments, ring A is a 5- to 8-membered heterocyclic alkane, wherein ring A is optionally surrounded by one or more R groups as defined herein. A Substitution. In the embodiments, ring A is a 5- to 7-membered heterocyclic alkane, wherein ring A is optionally replaced by one or more R groups as defined herein. A Substitution. In the embodiments, ring A is a 6- or 7-membered heterocyclic alkane, wherein ring A is optionally replaced by one or more R groups as defined herein. A replace.

[0200] In embodiments, the heterocyclic alkane contains two heteroatoms (e.g., independently selected from nitrogen, oxygen, or sulfur atoms) within its ring. In embodiments, the heterocyclic alkane contains two heteroatoms (e.g., independently selected from nitrogen, oxygen, or sulfur atoms) within its ring. In embodiments, the heterocyclic alkane contains two heteroatoms within its ring, wherein one heteroatom is a nitrogen atom and the other is selected from oxygen and sulfur. In embodiments, the first heteroatom is nitrogen and the second heteroatom is oxygen. In embodiments, the heterocyclic alkane contains one heteroatom within its ring, wherein the heteroatom is selected from nitrogen, oxygen, and sulfur atoms. In embodiments, the heterocyclic alkane contains one heteroatom (e.g., nitrogen or oxygen atom) within its ring.

[0201] In the embodiments, the heterocyclic alkane contains a heteroatom within its ring, wherein the heteroatom is a nitrogen atom, and the heterocyclic alkane contains R. A The substituent is selected from halogens, -OH, oxo groups, -C(O)R'', -(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3- to 6-membered heterocyclic alkyl groups, wherein the -(C1-C3)alkyl group is optionally substituted by one or more groups selected from halogens each time it appears, wherein each R'' is selected from -(C1-C3)alkyl (e.g., -CH3). In the examples, R A The substituent is bonded to the nitrogen atom within the heterocyclic alkane ring. In the examples, the R... A The substituents are selected from -CH3, -CH2CF3, cyclopropyl and oxetane (e.g., -oxetane-3-yl).

[0202] In the embodiments, the heterocyclic alkane contains R as an oxo group. ASubstituents. In the examples, the heterocyclic alkane contains a heteroatom (e.g., a nitrogen or oxygen atom) within its ring, and the heterocyclic alkane includes an R group that is an oxo group. A Substituents, wherein the oxo group is bonded to a carbon atom adjacent to a heteroatom (e.g., adjacent to a nitrogen or oxygen atom). In embodiments, the heterocyclic alkane contains a sulfur atom within its ring, and the heterocyclic alkane contains two R groups that are oxo groups. A Substituents, wherein the oxo substituents are all bonded to a sulfur atom (i.e., to form a cyclic sulfone group). In embodiments, the heterocyclic alkane contains two heteroatoms within its ring (e.g., wherein the two heteroatoms are bonded to each other), one heteroatom being a sulfur atom and the other heteroatom being a nitrogen atom, and the heterocyclic alkane comprises two R groups that are oxo groups. A Substituents, wherein the oxo substituents are all bonded to the sulfur atom (i.e., to form a cyclic sulfonamide group).

[0203] In the embodiments, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, cycloheptene, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxacycloheptane, azacycloheptane, 1,4-oxaazacycloheptane, and thiocycloheptane, wherein ring A may optionally be represented by one or more R groups as defined herein. A Substitution. In the examples, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxacycloheptane, azacycloheptane, 1,4-oxaazacycloheptane, and thiocycloheptane, wherein ring A may optionally be replaced by one or more R as defined herein. A Replacement. In an embodiment, ring A is replaced by one or more Rs as defined herein. A Substituted cyclohexane. In the examples, ring A is replaced by one or more R groups as defined herein. A Substituted cycloheptanes. In the examples, ring A is replaced by one or more R groups as defined herein. A Substituted cyclooctane. In the examples, ring A is replaced by one or more Rs as defined herein. A Substituted oxacycloheptanes. In the examples, ring A is formed by one or more R groups as defined herein. A Substituted nitrogen-containing heptanes.

[0204] In this embodiment, ring A is selected from: , , , , , , , , , , , , , , , , ... , , , , , and The dashed bond indicates the point of convergence with the pyrrole ring, wherein ring A is optionally bounded by one or more R as defined herein. A replace.

[0205] In this embodiment, ring A is selected from: , , , , , , , , , , , , , , , , , , and The dashed bond indicates the point of convergence with the pyrrole ring, wherein ring A is optionally bounded by one or more R as defined herein. A replace.

[0206] In the embodiment, ring A is affected by one or more occurrences of R. A Replace, where R A Each time it appears, it is independently selected from -D, halogen, -OH, oxo, =N-OH, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl and 3- to 6-membered heterocyclic alkyl; wherein each time the -(C1-C3)alkyl appears, it is optionally substituted by one or more groups selected from halogen and -OH; wherein each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl and 3- to 4-membered heterocyclic alkyl substituted by one or more halogens; and wherein each R'' is selected from -OH, -O(C1-C3)alkyl and -(C1-C3)alkyl (e.g. -CH3).

[0207] In the embodiment, ring A is affected by one or more occurrences of R. A Replace, where R AEach R' is independently selected from halogens, -OH, oxo groups, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl, and 3- to 6-membered heterocyclic alkyl groups; wherein -(C1-C3)alkyl is optionally substituted with one or more halogens or -OH each time it appears; wherein each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens; and wherein each R'' is selected from -OH and -CH3.

[0208] In the embodiment, ring A is affected by one or more occurrences of R. A Replace, where R A Each time it appears, it is independently selected from -D, halogen (e.g., F), -OH, oxo group, =N-OH, -NHR', -CN, -C(O)R'', -CH3, -CF3, -CH2CF3, -CH2OH, -C(CH3)2CH2OH, -OCH3, -cyclopropyl, oxetane (e.g., oxetane-3-yl), and morpholino (e.g., 4-morpholino); wherein each R' is selected from -H, -CH2CH2F, cyclopropyl, and oxetane (e.g., oxetane-3-yl); and wherein each R'' is selected from -OH, -OCH3, and -CH3.

[0209] In the embodiments, ring A is a (C6-C7) cycloalkane, wherein ring A is separated by an R. A Replace, where R A =N-OH (i.e., oxime). In embodiments, the oxime is a mixture of E and Z isomers. In embodiments, the oxime is E-oxime. In other embodiments, the oxime is Z-oxime.

[0210] In the embodiment, ring A is affected by one or more occurrences of R. A Replace, where R A Each time it appears, it is independently selected from halogen, -OH, oxo, -NHR', -CN, -C(O)R'', -CH3, -CF3, -CH2CF3, -CH2OH, -OCH3, -cyclopropyl and -oxetane (e.g. -oxetane-3-yl); wherein each R' is selected from -H, -CH2CH2F, -cyclopropyl and -oxetane (e.g. -oxetane-3-yl); and wherein each R'' is selected from -OH and -CH3.

[0211] In other embodiments, ring A is formed by two appearing R. A Replace, where R A When it appears once, it is in conjunction with another R that appears. ATogether with one or more intercalating atoms, it forms a (C4-C7) cycloalkyl ring or a 4- to 7-membered heteroalkyl ring, wherein the heteroalkyl ring and the cycloalkyl ring are optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl groups. In an example, ring A is occupied by two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, it forms a (C4-C7) cycloalkyl ring or a 4- to 7-membered heterocyclic alkyl ring, wherein the heterocyclic alkyl ring is optionally substituted with an oxo group. The (C4-C7) cycloalkyl ring or the 4- to 7-membered heterocyclic alkyl ring may be spiro-, fused, or bridged to ring A.

[0212] In the embodiment, ring A is formed by two appearing R. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, it forms a 4- to 7-membered heterocyclic alkyl ring, wherein the heterocyclic alkyl ring is optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl groups. In an example, ring A is occupied by two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a 4- to 7-membered heterocyclic alkyl ring is formed, wherein the heterocyclic alkyl ring may optionally be substituted with an oxo group. In embodiments, the (C4-C7) cycloalkyl ring or the 4- to 7-membered heterocyclic alkyl ring is linked to ring A in a spiro or fused configuration. In embodiments, ring A is formed by two appearing R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a 4- to 7-membered heterocyclic alkyl ring is formed, wherein the 4- to 7-membered heterocyclic alkyl ring is connected to ring A in a spiro or fused configuration, and wherein the heterocyclic alkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl groups. In an example, ring A is occupied by two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a 4- to 7-membered heterocyclic alkyl ring is formed, wherein the 4- to 7-membered heterocyclic alkyl ring is connected to ring A in a spiro or fused configuration, and wherein the heterocyclic alkyl ring is optionally substituted with an oxo group.

[0213] In other embodiments, ring A is formed by two appearing R. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a (C4-C7) cycloalkyl ring is formed, wherein the (C4-C7) cycloalkyl ring is connected to ring A in a bridged configuration. In the embodiments, the (C4-C7) cycloalkyl ring is substituted with one or more -OH groups.

[0214] In the embodiment, ring A is formed by two appearing R. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring or a 4- to 6-membered heteroalkyl ring, wherein the heteroalkyl ring and the cycloalkyl ring are optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl groups. In an example, ring A is occupied by two R groups. A Replace, where R A Each time it appears, it is associated with another R that appears. A Together with one or more intercalating atoms, a (C5-C7) cycloalkyl ring or a 4- to 6-membered heterocyclic alkyl ring is formed, wherein the heterocyclic alkyl ring is optionally substituted with an oxo group. In embodiments, the (C5-C7) cycloalkyl ring or the 4- to 6-membered heterocyclic alkyl ring is linked to ring A in a spiro, fused, or bridged configuration. In embodiments, ring A is connected to ring A by two appearing R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a 4- to 6-membered heterocyclic alkyl ring is formed, wherein the heterocyclic alkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl groups. In an example, ring A is substituted with two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a 4- to 6-membered heterocyclic alkyl ring is formed, wherein the heterocyclic alkyl ring is optionally substituted with an oxo group. In embodiments, the (C5-C7) cycloalkyl ring or the 4- to 6-membered heterocyclic alkyl ring is linked to ring A in a spiro or fused configuration. In embodiments, ring A is connected to two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. ATogether with one or more intercalating atoms, a 4- to 6-membered heterocyclic alkyl ring is formed, wherein the 4- to 6-membered heterocyclic alkyl ring is connected to ring A in a spiro or fused configuration, and wherein the heterocyclic alkyl ring is optionally substituted with one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl groups. In an example, ring A is occupied by two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a 4- to 6-membered heterocyclic alkyl ring is formed, wherein the 4- to 6-membered heterocyclic alkyl ring is connected to ring A in a spiro or fused configuration, and wherein the heterocyclic alkyl ring is optionally substituted with an oxo group. In embodiments, the heterocyclic alkyl ring is selected from oxetane, azirne-butane (e.g., N-methylazirne), tetrahydrofuranyl, dioxolane, pyrrolidinyl (e.g., 2-pyrrolidone), tetrahydropyranyl, piperidinyl, and morpholinyl. In embodiments, the heterocyclic alkyl ring is selected from oxetane, azirne, tetrahydrofuranyl, dioxolane, pyrrolidinyl (e.g., 2-pyrrolidone), tetrahydropyranyl, piperidinyl, and morpholinyl.

[0215] In other embodiments, ring A is formed by two appearing R. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a (C5-C7) cycloalkyl ring is formed, wherein the (C5-C7) cycloalkyl ring is connected to ring A in a bridged configuration. In the embodiment, ring A is connected by two appearing R atoms. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a (C4-C7) cycloalkyl ring is formed, wherein the (C4-C7) cycloalkyl ring is optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2, and -(C1-C3)alkyl groups. In an example, ring A is occupied by two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. ATogether with one or more intercalating atoms, a (C4-C7) cycloalkyl ring is formed, wherein the (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 groups. In embodiments, the (C4-C7) cycloalkyl ring is selected from cyclobutyl groups optionally substituted with oxo (e.g., cyclobutane-2-keto), -C(O)OH, and -C(O)N(CH3)2 groups. In embodiments, ring A is formed by two R groups. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, a (C4-C7) cycloalkyl ring is formed, wherein the (C4-C7) cycloalkyl ring is connected to ring A in a spiro, bridged, or fused configuration, and wherein the cycloalkyl ring is optionally substituted by one or more groups selected from oxo, -C(O)OH, and -C(O)N((C1-C3)alkyl)2.

[0216] In the examples, ring A is unsubstituted. In the examples, ring A is an unsubstituted (C6-C8) cycloalkane. In the examples, ring A is unsubstituted cyclohexane. In the examples, ring A is unsubstituted cycloheptane. In the examples, ring A is unsubstituted cyclooctane. In the examples, ring A is an unsubstituted 7-membered cycloalkene. In the examples, ring A is an unsubstituted 5- to 7-membered heterocyclic alkane. In the examples, ring A is an unsubstituted 5-membered heterocyclic alkane. In the examples, ring A is an unsubstituted 6-membered heterocyclic alkane. In the examples, ring A is an unsubstituted 7-membered heterocyclic alkane.

[0217] In other embodiments, ring A is surrounded by one, two, or three Rs as defined herein. A Replacement. In embodiments, ring A is replaced by one or two Rs as defined herein. A Replacement. In the embodiment, ring A is replaced by an R that appears. A Replacement. In the embodiment, ring A is replaced by two appearing R. A Replacement. In the embodiment, ring A is replaced by three appearing R. A replace.

[0218] In the embodiments, for group R A Each time the -(C1-C3) alkyl group appears, it may optionally be replaced by one or more -OH groups, for example, independently selected from -CH2OH and -C(CH3)2OH. In the examples, for group R... A Each occurrence of the -(C1-C3) alkyl group is independently a methyl or ethyl group optionally substituted with one or more halogens or -OH groups. In the examples, for group R... AThe -(C1-C3)alkyl group, which may be optionally substituted with one or more halogens, is independently selected from -CH3, -CF3 and -CH2CF3 each time it appears.

[0219] In the embodiments, for group R A Each of the 3- to 6-membered heterocyclic alkyl groups is independently a morpholino group (e.g., 4-morpholino group).

[0220] In the embodiments, for group R', the -(C1-C3)alkyl group is independently an ethyl group optionally substituted with one or more halogens each time it appears. In the embodiments, for group R', the -(C1-C3)alkyl group optionally substituted with one or more halogens is independently -CH2CH2F each time it appears. In the embodiments, for group R', the -(C3-C4)cycloalkyl group is independently -cyclopropyl each time it appears. In the embodiments, for group R', the 3- to 4-membered heterocyclic alkyl group is independently -oxetane (e.g., -oxetane-3-yl) each time it appears.

[0221] In the embodiments, for the group R'', the -O(C1-C3)alkyl group is independently -OCH3 each time it appears. In the embodiments, for the group R'', the -(C1-C3)alkyl group is independently -CH3 each time it appears.

[0222] In this embodiment, ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and The dashed bonds indicate fusion points with the pyrrole ring. These structures depict ring A and one or more R... A (In the case where ring A is replaced).

[0223] In this embodiment, ring A is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and The dashed bonds indicate fusion points with the pyrrole ring. These structures depict ring A and one or more R... A(In the case where ring A is replaced).

[0224] In the embodiment, R 1 It is -H. In the embodiment, R 1 It is a halogen. In the embodiments, R 1 Yes, it is -F.

[0225] In the embodiment, R 2 It is R that appears as defined in this article, either as one or two. B Replacement -(C6-C 10 )Aryl. In the embodiments, R 2 It was caused by an R that appeared. B Replacement -(C6-C 10 )Aryl. In the embodiments, R 2 It is caused by two Rs appearing B Replacement -(C6-C 10 )Aryl. In the embodiments, R 2 It is R that appears as defined in this article, either as one or two. B Substituted phenyl. In the examples, R 2 It was caused by an R that appeared. B Substituted phenyl. In the examples, R 2 It is caused by two Rs appearing B Substituted phenyl groups.

[0226] In the embodiments, each R B Independently selected from halogens (e.g., -F), -OH, -NH2, -SF5, and -O (C1-C3) alkyl groups optionally substituted with one or more halogens (e.g., -F). In the examples, each R B Independently selected from halogens (e.g., -F), -OH, -NH2, and -O (C1-C3) alkyl groups optionally substituted with one or more halogens (e.g., -F). In the examples, each R B Independently selected from -NH2, -SF5, and -O (C1-C3) alkyl groups optionally substituted with one or more halogens (e.g., -F). In the examples, for group R... B Each occurrence of the -O (C1-C3) alkyl group is independently a -O (methyl) group optionally substituted with one or more halogens. In the examples, for group R... B The -O (C1-C3) alkyl group, optionally substituted with one or more halogens, is independently -OCF3 each time it appears. In the examples, each R B Independently selected from -NH2, -SF5, and -OCF3. In the embodiments, each R B It is independently selected from -NH2 and -OCF3.

[0227] In the embodiment, R2 It is caused by one or two Rs. B Replacement -(C6-C 10 ) aryl, wherein each R B Independently selected from -NH2, -SF5, and -OCF3. In the examples, R 2 It is caused by one or two Rs. B Replacement -(C6-C 10 ) aryl, wherein each R B Independently selected from -NH2 and -OCF3. In the examples, R 2 It is caused by one or two Rs. B Substituted phenyl groups, wherein each R B Independently selected from -NH2, -SF5, and -OCF3. In the examples, R 2 It is caused by one or two Rs. B Substituted phenyl groups, wherein each R B Independently selected from -NH2 and -OCF3. In the examples, R 2 It is caused by two Rs appearing B Substituted phenyl, one of which appears R B It is -NH2, and another R appears. B Selected from -SF5 and -OCF3. In an embodiment, R 2 It is caused by two Rs appearing B Substituted phenyl, one of which appears R B It is -NH2, and another R appears. B It is -OCF3. In the embodiment, R 2 It was caused by an R that appeared. B Substituted phenyl, wherein R B It is -OCF3.

[0228] In the embodiment, R 2 Selected from: , , and In the embodiment, R 2 Selected from: , and In the embodiment, R 2 yes or .

[0229] In this embodiment, n is 0 or 1. In this embodiment, n is 1 or 2. In this embodiment, n is 0. In this embodiment, n is 1. In this embodiment, n is 2.

[0230] In the embodiment, R1 It is -F and n is 1.

[0231] In the embodiments, the compound is a compound having formula (II).

[0232]

[0233] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 As defined in this article, R B1 Selected from -H and R as defined in this article B And R B2 Selected from R as defined in this article B In the embodiment, R B1 Selected from -H and -NH2. In the examples, R B2 Selected from -OCF3 and -SF5 (e.g., -OCF3). In an embodiment, R B1 Selected from -H and -NH2, and R B2 It is -OCF3.

[0234] In the embodiments, the compound is a compound having formula (II).

[0235]

[0236] Or its pharmaceutically acceptable salt, wherein:

[0237] Ring A is a (C5-C8) cycloalkane or a 6- to 7-membered heterocyclic alkane, wherein ring A is optionally separated by one or more R groups. A replace,

[0238] Where R A Each time it appears, it is:

[0239] (a) Independently selected from -OH, oxo, -NHR', -C(O)CH3, -(C1-C3)alkyl and -O(C1-C3)alkyl,

[0240] Each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens; or

[0241] (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring or a 4- to 6-membered heteroalkyl ring, wherein the heteroalkyl ring is optionally substituted with an oxo group;

[0242] R 1 Selected from -H and -F;

[0243] R B1Selected from -H and -NH2; and

[0244] R B2 Selected from -OCF3 and -SF5,

[0245] The premise is that when R B1 It is -H,R B2 It is -SF5 and R 1 If it is -H, then ring A is not an unsubstituted cyclopentane.

[0246] In the embodiments, ring A is a (C5-C8) cycloalkane or a 6- to 7-membered heterocycloalkane, wherein ring A is optionally replaced by one or two Rs as defined herein. A replace.

[0247] In the embodiments, ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydropyran, piperidine, oxacycloheptane, and azacycloheptane, wherein ring A may optionally be represented by one or more (e.g., one or two) R as defined herein. A replace.

[0248] In this embodiment, ring A is selected from: , , , , , , , , , , , , and The dashed bond indicates the fusion point with the pyrrole ring, wherein ring A is optionally bounded by one or more (e.g., one or two) R as defined herein. A replace.

[0249] In this embodiment, ring A is selected from: , , , , , , , , and The dashed bond indicates the fusion point with the pyrrole ring, wherein ring A is optionally bounded by one or more (e.g., one or two) R as defined herein. A replace.

[0250] In the embodiment, R AEach R' is independently selected from -OH, oxo, -NHR', -C(O)CH3, -CH3 and -OCH3, wherein each R' is selected from -CH2CH2F, -cyclopropyl and -oxetane (e.g. -oxetane-3-yl).

[0251] In other embodiments, two R appearing A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring or a 4- to 6-membered heteroalkyl ring, wherein the heteroalkyl ring is optionally substituted with an oxo group.

[0252] In the examples, ring A is unsubstituted. In the examples, ring A is an unsubstituted (C6-C8) cycloalkane. In the examples, ring A is an unsubstituted 5- to 6-membered heterocyclic alkane.

[0253] In other embodiments, ring A is surrounded by one or two Rs as defined herein. A Replacement. In the embodiment, ring A is replaced by an R that appears. A Replacement. In the embodiment, ring A is replaced by two appearing R. A Replacement. In the embodiment, ring A is replaced by two appearing R. A Replace, where R A When it appears once, it is in conjunction with another R that appears. A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring or a 4- to 6-membered heterocyclic alkyl ring, wherein the heterocyclic alkyl ring is optionally substituted with an oxo group. The (C5-C7) cycloalkyl ring or the 4- to 6-membered heterocyclic alkyl ring may be spiro-, fused, or bridged to ring A.

[0254] In the embodiment, ring A is formed by two appearing R. A Replace, R A Together with one or more intercalating atoms, a 4- to 6-membered heterocyclic alkyl ring is formed, wherein the heterocyclic alkyl ring is optionally substituted with an oxo group. The 4- to 6-membered heterocyclic alkyl ring can be spiro-, fused, or bridged to ring A. In an embodiment, ring A is formed by two appearing R groups. A Replace, R A A 4- to 6-membered heterocyclic alkyl ring is formed together with one or more intercalating atoms, wherein the 4- to 6-membered heterocyclic alkyl ring is bonded to ring A in a spiro or fused configuration, and wherein the heterocyclic alkyl ring is optionally substituted with an oxo group. In embodiments, the 4- to 6-membered heterocyclic alkyl ring comprises one or two independent cyclic heteroatoms selected from O and N. In embodiments, the 4- to 6-membered heterocyclic alkyl ring is selected from oxobutyranyl, azirheptabutyranyl, tetrahydrofuranyl, dioxolanecycloyl, pyrrolylyl (e.g., 2-pyrrolidoneyl), tetrahydropyranyl, and piperidinyl.

[0255] In the embodiment, ring A is formed by two appearing R. A Replace, R A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring, wherein the (C5-C7) cycloalkyl ring is bonded to ring A in a bridging configuration.

[0256] In the embodiments, for group R A The -(C1-C3) alkyl group is independently -CH3 each time it appears. In the examples, for group R... A Each time an -O(C1-C3) alkyl group appears, it is independently -OCH3.

[0257] In the embodiments, for group R', the -(C1-C3)alkyl group is independently an ethyl group optionally substituted with one or more halogens each time it appears. In the embodiments, for group R', the -(C1-C3)alkyl group is independently -CH2CH2F each time it appears.

[0258] In the examples, for group R', the -(C3-C4)cycloalkyl group is independently -cyclopropyl each time it appears. In the examples, for group R', the 3- to 4-membered heterocycloalkyl group is independently -oxetane (e.g., -oxetane-3-yl) each time it appears.

[0259] In the embodiments, the compound is a compound having formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0260] Ring A is a (C5-C8) cycloalkane or a 6- to 7-membered heterocyclic alkane, wherein ring A is optionally separated by one or two R groups. A replace,

[0261] Where R A Each time it appears, it is:

[0262] (a) Independently selected from -OH, oxo, -NHR', -C(O)CH3, -CH3 and -OCH3,

[0263] Each R' is selected from -CH2CH2F, -cyclopropyl, and -oxetane (e.g., -oxetane-3-yl); or

[0264] (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring or a 4- to 6-membered heteroalkyl ring, wherein the heteroalkyl ring is optionally substituted with an oxo group;

[0265] R 1 Selected from -H and -F;

[0266] R B1 Selected from -H and -NH2; and

[0267] R B2 Selected from -OCF3 and -SF5,

[0268] The premise is that when R B1 It is -H,R B2 It is -SF5 and R 1 If it is -H, then ring A is not an unsubstituted cyclopentane.

[0269] In this embodiment, ring A is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and The dashed bonds indicate fusion points with the pyrrole ring. These structures depict ring A and one or more R... A (In the case where ring A is replaced).

[0270] In the embodiment, R 1 Yes, it is -F.

[0271] In the embodiment, R B1Yes -H. In other embodiments, R B1 It is -NH2.

[0272] In the embodiment, R B2 It is -OCF3. In the embodiment, R B1 It is -H, and R B2 It is -OCF3. In other embodiments, R B1 It is -NH2, and R B2 It is -OCF3. In the embodiment, R B1 It is -NH2 and R B2 Yes -SF5.

[0273] In the embodiments, the compound is a compound having formula (III) or formula (IV).

[0274]

[0275] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 As defined herein. In the embodiments, the compound is a compound having formula (III) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound having formula (IV) or a pharmaceutically acceptable salt thereof. In the embodiments, R 1 It is -H. In the embodiment, R 1 Yes, it is -F.

[0276] In the embodiments, the compound is a compound having formula (V).

[0277]

[0278] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 As defined in this article, the premise is that when R 1 When -H is present, ring A is not an unsubstituted cyclopentane. In the examples, R... 1 It is -H. In the embodiment, R 1 Yes, it is -F.

[0279] In the embodiments, the compound is a compound having formula (VI).

[0280]

[0281] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 As defined herein. In embodiments, R 1 It is -H. In the embodiment, R 1 Yes, it is -F.

[0282] In the embodiments, the compounds are selected from the group consisting of:

[0283] -[4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0284] -[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0285] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,14-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one;

[0286] -trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0287] -trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0288] -trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0289] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0290] -[4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0291] -[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-4,4'-piperidin]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0292] -[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-oxetane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0293] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone;

[0294] -[4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indol-7,2'-dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0295] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-5,6,8,9-tetrahydropyrido[2,3-b]indol-7-one;

[0296] -[4-(3-fluoro-6-hydroxy-6-methyl-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0297] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl] methyl ketone;

[0298] -1-[12-fluoro-13-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4,8,10-triazatricyclic[7.4.0.02,7]tetadeca-1(9),2(7),10,12-tetraen-4-yl]acetone;

[0299] -[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecane-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0300] -[4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0301] -[4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0302] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)-1-piperidinyl] methyl ketone;

[0303] -[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0304] -cis-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0305] -cis-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0306] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(9),2(7),10,12-tetraen-13-yl)-1-piperidinyl] methyl ketone;

[0307] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-oxetane]-4-yl)-1-piperidinyl] methyl ketone;

[0308] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8,12-triazatricyclic[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one;

[0309] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8,13-triazatricyclic[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-12-one;

[0310] -[4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0311] -cis-[4-[4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0312] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-12-one;

[0313] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,12-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one;

[0314] -[4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0315] -[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-tetrahydropyran]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0316] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-tetrahydropyran]-4-yl)-1-piperidinyl] methyl ketone;

[0317] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-4,4'-tetrahydropyran]-12-yl)-1-piperidinyl] methyl ketone;

[0318] -[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0319] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] ketone;

[0320] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0321] -[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecano-1(12),2(6),8,10-tetraen-4,4'-tetrahydropyran]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0322] -[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecane-1(12),2(6),8,10-tetraen-4,3'-pyrrolidine]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0323] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indol-7-one;

[0324] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyridino[2,3-b]indol-7,2'-[1,3]dioxolane]-4-yl)-1-piperidinyl] methyl ketone;

[0325] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-3,3'-tetrahydrofuran]-12-yl)-1-piperidinyl] methyl ketone;

[0326] -[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-3,3'-tetrahydrofuran]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0327] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone;

[0328] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone;

[0329] -[4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyrido[2,3-b]indol-6,2'-[1,3]dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0330] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] ketone;

[0331] -[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecano-1(12),2(6),8,10-tetraen-3,3'-pyrrolidine]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0332] -[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0333] -[4-(3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0334] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-5,7,8,9-tetrahydropyrido[2,3-b]indol-6-one;

[0335] -[4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0336] -[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-azacyclobutane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0337] -[4-(12-fluoro-4,8,10-triazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0338] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0339] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8,13-triazatricyclic[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0340] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indol-6-one;

[0341] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0342] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-4-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(9),2(7),10,12-tetraen-13-yl)-1-piperidinyl] methyl ketone;

[0343] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0344] -[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)-1-piperidinyl] methyl ketone;

[0345] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)-1-piperidinyl] methyl ketone;

[0346] -[4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0347] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0348] -[4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0349] -[4-(12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0350] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0351] -trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0352] -[4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0353] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0354] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0355] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-13-methyl-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0356] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0357] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone; and

[0358] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadecan-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone,

[0359] And its pharmaceutically acceptable salts.

[0360] In the embodiments, the compounds are selected from the group consisting of:

[0361] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0362] -3-Fluoro-N,N-Dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0363] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0364] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-11-carboxylic acid methyl ester;

[0365] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxylic acid methyl ester;

[0366] -[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0367] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0368] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0369] -[4-(4'-fluorospiro[1,3-dioxolane-2,12'-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene]-3'-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0370] -[4-[4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0371] -[4-[4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0372] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0373] -[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0374] -[4-(4-fluoro-14-oxa-6,8,11-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0375] -[4-[(trans)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0376] -[4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0377] -[4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0378] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,2'-cyclobutane]-1'-one;

[0379] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0380] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0381] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-azacyclobutane]-4-yl)-1-piperidinyl] methyl ketone;

[0382] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone;

[0383] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0384] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0385] -[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-azacyclobutane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0386] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0387] -[4-[4-fluoro-12-(oxetane-3-yl)-6,8,12-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0388] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-azacyclobutane]-4-yl)-1-piperidinyl] ketone;

[0389] -[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0390] -[4-[4-fluoro-13-(oxetane-3-yl)-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0391] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone;

[0392] -[4-(12-cyclopropyl-4-fluoro-6,8,12-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0393] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0394] -[4-(13-cyclopropyl-4-fluoro-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0395] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0396] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0397] -[4-(3-fluoro-6-morpholino-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0398] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0399] -[4-(4-fluoro-12,12-dioxo-12λ) 6 -Thia-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0400] -[4-(4-fluoro-13,13-dioxo-13λ) 6-Thia-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0401] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0402] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0403] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0404] -[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0405] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0406] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxynitrile;

[0407] -[4-[3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0408] -[4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0409] -[4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0410] -1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,12-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-12-yl]acetone;

[0411] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0412] -1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-yl]acetone;

[0413] -[4-[4-fluoro-12-(2,2,2-trifluoroethyl)-6,8,12-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0414] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyridino[2,3-b]indol-6,1'-cyclobutane]-4-yl)-1-piperidinyl] methyl ketone;

[0415] -[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,1'-cyclobutane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0416] -[4-[4-fluoro-13-(2,2,2-trifluoroethyl)-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0417] -[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(pentafluoro-λ 6 [-thioalkyl)phenyl]methyl ketone;

[0418] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0419] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl] methyl ketone;

[0420] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0421] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0422] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0423] -[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0424] -[4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0425] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0426] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0427] -[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0428] -[4-(4-fluoro-6,8,12-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0429] -[4-(4-fluoro-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0430] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0431] -[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0432] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxynitrile;

[0433] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0434] -[4-[(cis)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadec-1(9),11,13,15-tetraen-15-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0435] -[4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0436] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0437] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-12-one;

[0438] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxynitrile;

[0439] -1-[13-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-12-fluoro-4,8,10-triazatricyclic[7.4.0.02,7]tetadeca-1(9),2(7),10,12-tetraen-4-yl]acetone;

[0440] -4-Fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0441] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-12-one;

[0442] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one;

[0443] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl] methyl ketone;

[0444] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0445] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl] methyl ketone;

[0446] -[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0447] -[4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0448] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-11,11-dimethyl-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0449] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-14-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0450] -[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0451] -[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0452] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0453] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,11-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-12-one;

[0454] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl)-1-piperidinyl] methyl ketone;

[0455] -[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0456] -[4-[3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0457] -[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0458] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,12-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-11-one;

[0459] -[4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0460] -[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(pentafluoro-λ 6 [-thioalkyl)phenyl]methyl ketone;

[0461] -[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(pentafluoro-λ 6 [-thioalkyl)phenyl]methyl ketone;

[0462] -[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-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0463] -[4-(4-fluoro-6,8,13-triazatetracyclo[7.7.0.02,7.011,15]hexadec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone

[0464] -[4-(14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadec-1(9),11,13,15-tetraen-15-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0465] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0466] -[4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0467] -[4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0468] -[4-[(cis)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraen-8-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0469] -[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-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0470] -[4-[12-fluoro-4-(2,2,2-trifluoroethyl)-4,8,10-triazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0471] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3,6,6-trifluoro-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone;

[0472] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-fluoro-4-(2,2,2-trifluoroethyl)-4,8,10-triazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl]-1-piperidinyl] methyl ketone;

[0473] -[4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0474] -[4-[(trans)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0475] -[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-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0476] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-11-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0477] -[4-[(cis)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0478] -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0479] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0480] -[4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0481] -[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0482] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0483] -4-Fluoro-13-methyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one;

[0484] -[4-(trifluoromethoxy)phenyl]-[4-(3,6,6-trifluoro-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone;

[0485] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8,14-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one;

[0486] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraen-8-yl)-1-piperidinyl] methyl ketone;

[0487] -[4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadecano-2(10),4,6,8-tetraen-8-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0488] -[4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0489] -[4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0490] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0491] -[4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0492] -[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0493] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecane-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl)-1-piperidinyl] methyl ketone;

[0494] -[4-[(cis)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0495] -[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0496] -[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-4,3'-pyrrolidine]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0497] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] ketone;

[0498] -[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5,12-pentaen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0499] -[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadecan-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0500] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0501] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxynitrile;

[0502] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-13-carboxynitrile;

[0503] -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxynitrile; and

[0504] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-deuter-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone,

[0505] And its pharmaceutically acceptable salts.

[0506] In embodiments where the compound has an enantiomeric form (e.g., where the compound has a chiral center, such as a chiral carbon atom), the compound exists as a racemic mixture of enantiomers. In embodiments where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (R) isomer. In other embodiments where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (S) isomer. Therefore, in the embodiments, the compound is selected from the group consisting of:

[0507] -(racemic)-[4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0508] -[4-[(6R)-3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0509] -[4-[(6S)-3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0510] -(racemic)-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0511] -(racemic)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0512] -(racemic)-trans-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0513] -(racemic)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0514] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0515] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0516] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0517] -(racemic)-2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] ketone; (racemic)-[4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0518] -[4-[(6R)-6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0519] -[4-[(6S)-6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0520] -(racemic)-[4-(3-fluoro-6-hydroxy-6-methyl-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0521] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl]methyl ketone;

[0522] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4R)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl]methyl ketone;

[0523] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4S)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl]methyl ketone;

[0524] -(racemic)-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecane-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0525] -[4-[(4R)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecane-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0526] -[4-[(4S)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecane-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0527] -(racemic)-[4-[3-fluoro-6-(2-fluoroethylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0528] -(racemic)-[4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0529] -(racemic)-cis-[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-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0530] -(racemic)-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-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0531] -(racemic)-[4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0532] -[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0533] -[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0534] -(racemic)-cis-[4-[4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0535] -[4-[(11S,15S)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0536] -[4-[(11R,15R)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0537] -(racemic)-[4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0538] -(racemic)-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0539] -[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0540] -[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0541] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] ketone;

[0542] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0543] -(racemic)-[4-[11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecane-1(12),2(6),8,10-tetraen-4,3'-pyrrolidine]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0544] -[4-[(4R)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-4,3'-pyrrolidine]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0545] -[4-[(4S)-11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-4,3'-pyrrolidine]-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0546] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-3,3'-tetrahydrofuran]-12-yl)-1-piperidinyl] methyl ketone;

[0547] -(racemic)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecano-1(8),2(6),9,11-tetraen-3,3'-tetrahydrofuran]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0548] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone;

[0549] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] ketone;

[0550] -(racemic)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-3,3'-pyrrolidine]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0551] -(racemic)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0552] -(racemic)-[4-(3-fluoro-6-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0553] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0554] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0555] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0556] -(racemic)-[4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0557] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0558] -(6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0559] -(6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0560] -(racemic)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0561] -[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0562] -[4-[(3S,8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0563] -(racemic)-[4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0564] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0565] -[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-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0566] -[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-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0567] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0568] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0569] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0570] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0571] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone; and

[0572] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone,

[0573] And its pharmaceutically acceptable salts.

[0574] In the embodiments, the compounds are selected from the group consisting of:

[0575] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0576] -[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]indol-4-yl]-1-piperidinyl] methyl ketone;

[0577] -[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]indol-4-yl]-1-piperidinyl] methyl ketone;

[0578] -(racemic)-3-fluoro-N,N-dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0579] -(trans)-3-fluoro-N,N-dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0580] -(cis)-3-fluoro-N,N-dimethyl-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxamide;

[0581] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0582] -(trans)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0583] -(cis)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indole-6,3'-cyclobutane]-1'-carboxylic acid;

[0584] -(racemic)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-11-carboxylic acid methyl ester;

[0585] -(11R)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-11-carboxylic acid methyl ester;

[0586] -(racemic)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxylic acid methyl ester;

[0587] -(12R)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxylic acid methyl ester;

[0588] -(11S)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-11-carboxylic acid methyl ester;

[0589] -(12S)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxylic acid methyl ester;

[0590] -(racemic)-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0591] -[4-[(6R)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0592] -[4-[(6S)-3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0593] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0594] -(6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0595] -(6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0596] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0597] -(6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0598] -(6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxylic acid;

[0599] -[4-[(12E / Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0600] -[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0601] -[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0602] -[4-[(13E / Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0603] -[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0604] -[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0605] -(racemic)-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0606] -(racemic)-[4-[(trans)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0607] -[4-[(3R,8S)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0608] -(racemic)-[4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0609] -[4-[(2S,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0610] -[4-[(2R,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0611] -(racemic)-[4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0612] -[4-[(3S,8R)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0613] -[4-[(2S,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0614] -[4-[(2R,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0615] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,2'-cyclobutane]-1'-one;

[0616] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0617] -(7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0618] -(7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0619] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0620] -(5R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0621] -(5S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0622] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E / Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone;

[0623] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone;

[0624] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0625] -(7R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0626] -(7S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile;

[0627] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0628] -(5R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0629] -(5S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxynitrile;

[0630] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0631] -(5R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0632] -(5S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0633] -(racemic)-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0634] -[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone; [4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0635] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E / Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0636] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0637] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0638] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0639] -(7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0640] -(7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0641] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E / Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0642] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0643] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0644] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E / Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0645] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0646] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0647] -(racemic)-[4-(3-fluoro-6-morpholino-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0648] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0649] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0650] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0651] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0652] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0653] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]methyl ketone;

[0654] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0655] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0656] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0657] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0658] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0659] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl]methyl ketone;

[0660] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone;

[0661] -(racemic)-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0662] -[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0663] -[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0664] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0665] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0666] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0667] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxynitrile;

[0668] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-(6R)-carboxynitrile;

[0669] -3-Fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-(6S)-carboxynitrile;

[0670] -[4-[(6E / Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0671] -[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0672] -[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0673] -(racemic)-[4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0674] -[4-[3-fluoro-(7R)-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0675] -[4-[3-fluoro-(7S)-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0676] -(racemic)-[4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0677] -[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0678] -[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0679] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0680] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0681] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0682] -(racemic)-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(pentafluoro-λ 6 [-thioalkyl)phenyl]methyl ketone;

[0683] -[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(pentafluoro-λ6 [-thioalkyl)phenyl]methyl ketone;

[0684] -[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(pentafluoro-λ 6 [-thioalkyl)phenyl]methyl ketone;

[0685] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-5-carboxylic acid;

[0686] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl] methyl ketone;

[0687] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4R)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl] methyl ketone;

[0688] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(4S)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl] methyl ketone;

[0689] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0690] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0691] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone;

[0692] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0693] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0694] -(6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0695] -(6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0696] -(racemic)-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0697] -(racemic)-[4-[3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0698] -[4-[(6R)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0699] -[4-[(6S)-3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0700] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0701] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0702] -(racemic)-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0703] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0704] -(6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0705] -(6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-pyrrolidine]-2'-one;

[0706] -(racemic)-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0707] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxynitrile;

[0708] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0709] -(racemic)-[4-[(cis)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadec-1(9),11,13,15-tetraen-15-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0710] -[4-[(11R,16R)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadec-1(9),11,13,15-tetraen-15-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0711] -[4-[(11S,16S)-14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadec-1(9),11,13,15-tetraen-15-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0712] -(racemic)-[4-[4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0713] -[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0714] -[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0715] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0716] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-6-carboxynitrile;

[0717] -4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-12-one;

[0718] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl] methyl ketone;

[0719] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl] methyl ketone;

[0720] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0721] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0722] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(trans)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl] methyl ketone;

[0723] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl] methyl ketone;

[0724] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl] methyl ketone;

[0725] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6-oxa-15,17-diazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone;

[0726] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-15-fluoro-5-oxa-11,13-diazatetracyclo[8.7.0.02,7.012,17]heptadec-1(10),12,14,16-tetraen-16-yl]-1-piperidinyl]methyl ketone;

[0727] -(racemic)-[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0728] -[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0729] -[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0730] -(racemic)-[4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0731] -[4-[(6R)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0732] -[4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0733] -(racemic)-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0734] -(racemic)-[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0735] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0736] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0737] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone;

[0738] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl)-1-piperidinyl] methyl ketone;

[0739] -(racemic)-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-tetrahydrofuran]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0740] -[4-[(7E / Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0741] -[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0742] -[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0743] -(racemic)-[2-amino-4-(pentafluoro-λ) 6 [-thioalkyl)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0744] -(racemic)-[4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0745] -[4-[(6R)-3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0746] -[4-[(6S)-3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0747] -(racemic)-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(pentafluoro-λ 6 [-thioalkyl)phenyl]methyl ketone;

[0748] -(racemic)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(pentafluoro-λ 6 [-thioalkyl)phenyl]methyl ketone;

[0749] -(racemic)-[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-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0750] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0751] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0752] -(racemic)-[4-(4-fluoro-6,8,13-triazatetracyclo[7.7.0.02,7.011,15]hexadec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0753] -(racemic)-[4-(14-fluoro-4,10,12-triazatetracyclo[7.7.0.02,6.011,16]hexadec-1(9),11,13,15-tetraen-15-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0754] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0755] -(6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0756] -(6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0757] -(racemic)-[4-[6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0758] -(racemic)-[4-[3-fluoro-6-hydroxy-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0759] -(racemic)-[4-[(cis)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraen-8-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0760] -[4-[(1R,12R)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraen-8-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0761] -[4-[(1S,12S)-7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadeca-2(10),4,6,8-tetraen-8-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0762] -(racemic)-[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-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0763] -[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-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0764] -[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-tetraen-8-yl]-1-piperidinyl] methyl ketone;

[0765] -(racemic)-[4-(12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0766] -(racemic)-[4-[(trans)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0767] -[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0768] -[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0769] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(cis)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0770] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0771] -(racemic)-[4-[(cis)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0772] -[4-[(11R,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0773] -(racemic)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0774] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0775] -(racemic)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one;

[0776] -(racemic)-[4-[4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0777] -[4-[(12R)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0778] -[4-[((12S)-4-fluoro-12-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0779] -(racemic)-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0780] -[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0781] -[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0782] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0783] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0784] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0785] -[4-[(11S,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0786] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadecano-2(10),4,6,8-tetraen-8-yl)-1-piperidinyl] methyl ketone;

[0787] -(racemic)-[4-(7-fluoro-3,5-diazatetracyclo[10.2.1.02,10.04,9]pentadecano-2(10),4,6,8-tetraen-8-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0788] -(racemic)-[4-[3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0789] -[4-[(6R)-3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0790] -[4-[(6S)-3-fluoro-6-(oxetane-3-ylamino)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0791] -(racemic)-[4-[6-(cyclopropylamino)-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0792] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone;

[0793] -(racemic)-[4-(3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0794] -(racemic)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodecano-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0795] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(8),2(6),9,11-tetraen-4,3'-tetrahydrofuran]-12-yl)-1-piperidinyl] methyl ketone;

[0796] -(racemic)-[4-[(cis)-4-fluoro-6,8,13-triazatetracyclo[7.6.0.02,7.011,15]pentadeca-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0797] -(racemic)-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone;

[0798] -(racemic)-[4-(11-fluorospiro[7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-4,3'-pyrrolidine]-12-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone;

[0799] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] ketone;

[0800] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0801] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0802] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0803] -(racemic)-4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxynitrile;

[0804] -(racemic)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-13-carboxynitrile;

[0805] -(racemic)-3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraene-12-carboxynitrile;

[0806] -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-deuter-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone;

[0807] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuter-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone; and

[0808] -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuterium-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone,

[0809] And its pharmaceutically acceptable salts.

[0810] In the embodiments, the compounds are selected from the compounds produced in Examples 1 to 294 (i.e., selected from the group consisting of compounds 1-294) and their pharmaceutically acceptable salts. In other embodiments, the compounds are selected from compounds obtainable by any one of the synthetic methods in Examples 1 to 294 (i.e., the method for synthesizing compounds 1-294) and their pharmaceutically acceptable salts. In the embodiments, the compounds are selected from the compounds produced in Examples 1 to 90 (i.e., selected from the group consisting of compounds 1-90) and their pharmaceutically acceptable salts. In other embodiments, the compounds are selected from compounds obtainable by any one of the synthetic methods in Examples 1 to 90 (i.e., the method for synthesizing compounds 1-90) and their pharmaceutically acceptable salts. In the embodiments, the compounds are selected from the compounds produced in Examples 91 to 294 (i.e., selected from the group consisting of compounds 91 to 294) and their pharmaceutically acceptable salts. In other embodiments, the compounds are selected from compounds obtainable by any one of the synthetic methods in Examples 91 to 294 (i.e., the method for synthesizing compounds 91 to 294) and their pharmaceutically acceptable salts.

[0811] In the embodiments, the compounds are selected from compounds produced in any of the following 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, 240, 245, 288, 289, 293 and 294 (…). That is, selected from the group consisting of the following 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, 204, 210, 222, 227, 228, 233, 240, 245, 288, 289, 293 and 294, and their pharmaceutically acceptable salts).

[0812] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone.

[0813]

[0814] Or its pharmaceutically acceptable salt.

[0815] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone.

[0816]

[0817] Or its pharmaceutically acceptable salt.

[0818] In the examples, the compound is (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone

[0819]

[0820] Or its pharmaceutically acceptable salt.

[0821] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(9),2(7),10,12-tetraen-13-yl)-1-piperidinyl] methyl ketone

[0822]

[0823] Or its pharmaceutically acceptable salt.

[0824] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyridino[2,3-b]indol-6,3'-oxetane]-4-yl)-1-piperidinyl] methyl ketone

[0825]

[0826] Or its pharmaceutically acceptable salt.

[0827] In the examples, the compound is [4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0828]

[0829] Or its pharmaceutically acceptable salt.

[0830] In the examples, the compound is [4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0831]

[0832] Or its pharmaceutically acceptable salt.

[0833] In the examples, the compound is (racemic)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0834]

[0835] Or its pharmaceutically acceptable salt.

[0836] In the examples, the compound is 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indol-6-one.

[0837]

[0838] Or its pharmaceutically acceptable salt.

[0839] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone

[0840]

[0841] Or its pharmaceutically acceptable salt.

[0842] In the examples, the compound is (6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one

[0843]

[0844] Or its pharmaceutically acceptable salt.

[0845] In the examples, the compound is (6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one

[0846]

[0847] Or its pharmaceutically acceptable salt.

[0848] In the examples, the compound is [4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0849]

[0850] Or its pharmaceutically acceptable salt.

[0851] In the examples, the compound is [4-[(3S,8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0852]

[0853] Or its pharmaceutically acceptable salt.

[0854] In the examples, the compound is [4-((2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0855]

[0856] Or its pharmaceutically acceptable salt.

[0857] In the examples, the compound is [4-((2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0858]

[0859] Or its pharmaceutically acceptable salt.

[0860] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone.

[0861]

[0862] Or its pharmaceutically acceptable salt.

[0863] In the examples, the compound is 3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-13-methyl-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one].

[0864]

[0865] Or its pharmaceutically acceptable salt.

[0866] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone

[0867]

[0868] Or its pharmaceutically acceptable salt.

[0869] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone.

[0870]

[0871] Or its pharmaceutically acceptable salt.

[0872] In the examples, 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-tetraen-3-yl)-1-piperidinyl] methyl ketone.

[0873]

[0874] Or its pharmaceutically acceptable salt.

[0875] In the examples, 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]indol-4-yl]-1-piperidinyl] methyl ketone

[0876]

[0877] Or its pharmaceutically acceptable salt.

[0878] In the examples, 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]indol-4-yl]-1-piperidinyl] methyl ketone

[0879]

[0880] Or its pharmaceutically acceptable salt.

[0881] In the examples, the compound is (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0882]

[0883] Or its pharmaceutically acceptable salt.

[0884] In the examples, the compound is (7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile.

[0885]

[0886] Or its pharmaceutically acceptable salt.

[0887] In the examples, the compound is (7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile.

[0888]

[0889] Or its pharmaceutically acceptable salt.

[0890] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-azacyclobutane]-4-yl)-1-piperidinyl] methyl ketone

[0891]

[0892] Or its pharmaceutically acceptable salt.

[0893] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0894]

[0895] Or its pharmaceutically acceptable salt.

[0896] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone

[0897]

[0898] Or its pharmaceutically acceptable salt.

[0899] In the examples, the compound is [4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0900]

[0901] Or its pharmaceutically acceptable salt.

[0902] In the examples, the compound is [4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0903]

[0904] Or its pharmaceutically acceptable salt.

[0905] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone

[0906]

[0907] Or its pharmaceutically acceptable salt.

[0908] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0909]

[0910] Or its pharmaceutically acceptable salt.

[0911] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone.

[0912]

[0913] Or its pharmaceutically acceptable salt.

[0914] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone.

[0915]

[0916] Or its pharmaceutically acceptable salt.

[0917] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone.

[0918]

[0919] Or its pharmaceutically acceptable salt.

[0920] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone.

[0921]

[0922] Or its pharmaceutically acceptable salt.

[0923] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0924]

[0925] Or its pharmaceutically acceptable salt.

[0926] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0927]

[0928] Or its pharmaceutically acceptable salt.

[0929] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone

[0930]

[0931] Or its pharmaceutically acceptable salt.

[0932] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]methyl ketone

[0933]

[0934] Or its pharmaceutically acceptable salt.

[0935] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone

[0936]

[0937] Or its pharmaceutically acceptable salt.

[0938] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone

[0939]

[0940] Or its pharmaceutically acceptable salt.

[0941] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone

[0942]

[0943] Or its pharmaceutically acceptable salt.

[0944] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl]methyl ketone

[0945]

[0946] Or its pharmaceutically acceptable salt.

[0947] In the examples, the compound is [4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0948]

[0949] Or its pharmaceutically acceptable salt.

[0950] In the examples, the compound is [4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0951]

[0952] Or its pharmaceutically acceptable salt.

[0953] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0954]

[0955] Or its pharmaceutically acceptable salt.

[0956] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0957]

[0958] Or its pharmaceutically acceptable salt.

[0959] In the examples, the compound is [4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0960]

[0961] Or its pharmaceutically acceptable salt.

[0962] In the examples, the compound is [4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0963]

[0964] Or its pharmaceutically acceptable salt.

[0965] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone

[0966]

[0967] Or its pharmaceutically acceptable salt.

[0968] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0969]

[0970] Or its pharmaceutically acceptable salt.

[0971] In the examples, the compound is 1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-yl] ethyl ketone.

[0972]

[0973] Or its pharmaceutically acceptable salt.

[0974] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone.

[0975]

[0976] Or its pharmaceutically acceptable salt.

[0977] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone.

[0978]

[0979] Or its pharmaceutically acceptable salt.

[0980] In the examples, the compound is (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone

[0981]

[0982] Or its pharmaceutically acceptable salt.

[0983] In the examples, the compound is (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0984]

[0985] Or its pharmaceutically acceptable salt.

[0986] In the examples, the compound is (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[0987]

[0988] Or its pharmaceutically acceptable salt.

[0989] In the examples, the compound is [4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0990]

[0991] Or its pharmaceutically acceptable salt.

[0992] In the examples, the compound is [4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0993]

[0994] Or its pharmaceutically acceptable salt.

[0995] In the examples, the compound is 4-fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-14-one.

[0996]

[0997] Or its pharmaceutically acceptable salt.

[0998] In the examples, the compound is [4-[(6R)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[0999]

[1000] Or its pharmaceutically acceptable salt.

[1001] In the examples, the compound is [4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1002]

[1003] Or its pharmaceutically acceptable salt.

[1004] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[1005]

[1006] Or its pharmaceutically acceptable salt.

[1007] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone

[1008]

[1009] Or its pharmaceutically acceptable salt.

[1010] In the examples, the compound is [4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1011]

[1012] Or its pharmaceutically acceptable salt.

[1013] In the examples, the compound is [4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1014]

[1015] Or its pharmaceutically acceptable salt.

[1016] In the examples, 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-tetraen-3-yl]-1-piperidinyl]methyl ketone

[1017]

[1018] Or its pharmaceutically acceptable salt.

[1019] In the examples, 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-tetraen-3-yl]-1-piperidinyl] methyl ketone

[1020]

[1021] Or its pharmaceutically acceptable salt.

[1022] In the examples, the compound is (6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one

[1023]

[1024] Or its pharmaceutically acceptable salt.

[1025] In the examples, the compound is (6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one.

[1026]

[1027] Or its pharmaceutically acceptable salt.

[1028] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone

[1029]

[1030] Or its pharmaceutically acceptable salt.

[1031] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone

[1032]

[1033] Or its pharmaceutically acceptable salt.

[1034] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuterium-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone

[1035]

[1036] Or its pharmaceutically acceptable salt.

[1037] In the examples, the compound is [2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuter-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone

[1038]

[1039] Or its pharmaceutically acceptable salt.

[1040] In the examples, the compounds disclosed herein are characterized based on their inhibitory activity against ERK5, for example, as measured by cell-based or cell-free assays as described in the examples below. In the examples, the compounds have an IC50 of less than about 10 µM against ERK5. 50 Values ​​(e.g., when measured according to a cell-free assay as described below). In the examples, the compounds have IC5 values ​​of less than about 5 µM, such as less than about 2 µM, 1 µM, 0.5 µM, 0.2 µM, 100 nM, or 50 nM for ERK5. 50 Value (e.g., when measured according to a cell-free assay as described below). In the examples, the compound has an IC50 of less than about 10 µM against ERK5. 50The value, when measured according to the cell-free assay described below. In the examples, the compound has an IC50 of less than about 5 µM, for example less than about 2 µM, 1 µM, 0.5 µM, 0.2 µM, 100 nM, or 50 nM against ERK5. 50 Value, when measured according to the cell-free assay described below. In the examples, the compound has an IC50 of less than about 10 µM against ERK5. 50 The value, when measured according to the cell-based assay described below. In the examples, the compound has an IC50 of less than about 5 µM, for example less than about 2 µM, 1 µM, 0.5 µM, 0.2 µM, 100 nM, or 50 nM against ERK5. 50 Values, when measured according to cell-based assays as described below.

[1041] In the embodiments, the compounds are selected from compounds in the following 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, 1 81, 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, 21 2, 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, 274275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293 and 294. In other embodiments, the compounds are selected from compounds in the following 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, 19 7, 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, 291, 292, 293, and 294. In other embodiments, the compounds are selected from compounds in the following 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, 6 6, 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, 18 3, 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, 291, 292, 293, and 294. In other embodiments, the compounds are selected from compounds in the following 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, 6 0, 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, 1 23, 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, 221222, 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, 25 8, 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. In other embodiments, the compounds are selected from compounds in the following 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, 1 24, 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, 17 5, 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, 26 0, 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, 293, and 294. In other embodiments, the compounds are selected from compounds in the following 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, 7 5, 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, 14 4, 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, 2 03, 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, 255256, 257, 258, 260, 262, 263, 264, 266, 267, 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 other embodiments, the compounds are selected from compounds in the following 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, 15 9, 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, 2 19, 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, 287, 288, 289, 290, 291, 292, 293, and 294.

[1042] In the embodiments, the compounds are selected from compounds in the following 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, 8 6, 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, 1 54, 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, 1 88, 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, 21 9, 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, 280, 281, 282, 283284, 285, and 287. In other embodiments, the compounds are selected from compounds in the following 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, 15 3, 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, 2 54, 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, 284285 and 287. In other embodiments, the compounds are selected from compounds in the following 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, 2 22, 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, 281, 282, 283, 284, 285, and 287. In other embodiments, the compounds are selected from compounds listed in the following 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, 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 other embodiments, the compounds are selected from compounds listed in the following 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, 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 other embodiments, the compounds are selected from compounds in the following 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, 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, 285. In other embodiments, the compounds are selected from compounds in the following 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, 1 50, 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, 281, 282, and 283.

[1043] Methods for producing the compounds disclosed herein and intermediate compounds

[1044] This disclosure also provides methods for preparing compounds as described herein, as well as intermediates for preparing said compounds.

[1045] Therefore, a method for preparing compounds having formula (I) as defined herein is provided.

[1046] ,

[1047] Or a pharmaceutically acceptable salt thereof, wherein the method comprises making a compound having the formula HE

[1048]

[1049] Reaction with compounds having formula J

[1050] ,

[1051] in:

[1052] Q is a group R as defined in this article. 2 (or its protected form), or together with the adjacent carbonyl group, forms an amine protecting group.

[1053] And among them, rings A and R 1 And n is as defined in this paper, and X is a halogen (e.g., I, Br or Cl).

[1054] In the embodiment, R 1 It is F.

[1055] In embodiments, the method includes a chiral separation step (e.g., separating a stereoisomer from a mixture of stereoisomers). In embodiments, the method includes a regioisomer separation step (e.g., separating a regioisomer from a mixture of regioisomers). In embodiments, the method includes a step of separating an E (or cis) isomer from a mixture of E and Z isomers. In embodiments, the method includes a step of separating a Z (or trans) isomer from a mixture of E and Z isomers. Those skilled in the art will recognize many methods for separating chiral, stereoisomers, and regioisomers, such as those described herein.

[1056] In the embodiments, Q is a group R as defined herein. 2 The protected form. In the examples, Q is a phenyl group having a protected amine substituent (optionally together with other substituents, such as the group -OCF3)).

[1057] In the embodiments, Q is a group R as defined herein. 2 Therefore, in the embodiments, the compound having the formula HE is the compound having the formula H.

[1058]

[1059] Where R 1 R 2 , n and X are as defined in this paper.

[1060] In the embodiments, the method of reacting compound H with compound J includes using a Pd catalyst. In the embodiments, the method includes using a Pd catalyst, a base, and a solvent. Those skilled in the art will understand that reference to "Pd catalyst" includes a Pd catalyst / ligand. In the embodiments, the Pd catalyst is bis(tri-tert-butylphosphine)palladium(0). In the embodiments, the base is 1,4-diazabicyclo[2.2.2]octane. In the embodiments, the solvent is DMF. Therefore, in the embodiments, the method includes using bis(tri-tert-butylphosphine)palladium(0) as a catalyst, 1,4-diazabicyclo[2.2.2]octane as a base, and DMF as a solvent.

[1061] In one embodiment, the method includes one or more steps shown in scheme 1. In another embodiment, the method includes all the steps shown in scheme 1. In another embodiment, the method includes step 6 of scheme 1. In another embodiment, the method includes one or more steps of method A. In another embodiment, the method is substantially as described in method A. In another embodiment, the method includes one or more steps of method D. In another embodiment, the method is substantially as described in method D.

[1062] In the examples, Q, together with the adjacent carbonyl group, is an amine protecting group (e.g., Boc). Therefore, in the examples, compounds having formula HE are compounds having formula E.

[1063]

[1064] Where R 1 , n and X are as defined in this paper.

[1065] In the embodiments, the method of reacting compound E with compound J includes using a Pd catalyst. In the embodiments, the method includes using a Pd catalyst, a base, and a solvent. Those skilled in the art will understand that reference to "Pd catalyst" includes a Pd catalyst / ligand. In the embodiments, the Pd catalyst is bis(tri-tert-butylphosphine)palladium(0). In the embodiments, the base is 1,4-diazabicyclo[2.2.2]octane. In the embodiments, the solvent is DMF. Therefore, in the embodiments, the method includes using bis(tri-tert-butylphosphine)palladium(0) as a catalyst, 1,4-diazabicyclo[2.2.2]octane as a base, and DMF as a solvent.

[1066] In an embodiment, the method includes one or more steps shown in scheme 3. In an embodiment, the method includes step 1 of scheme 3. In an embodiment, the method includes one or more steps in method E. In an embodiment, the method is substantially as described in method E.

[1067] On the other hand, this disclosure provides a method for preparing compounds having formula (I) as described herein.

[1068] ,

[1069] Or a pharmaceutically acceptable salt thereof, wherein the method comprises intramolecular cyclization of a compound having the formula MP.

[1070] ,

[1071] in:

[1072] Q is a group R as defined in this article. 2 (or its protected form), or together with the adjacent carbonyl group, it forms an amine protecting group; and

[1073] R 3 Selected from leaving groups that are compatible with H and nitrogen (e.g., Ts).

[1074] And among them, rings A and R 1 And n is as defined in this article.

[1075] In the embodiment, R 3 It is H. In the embodiment, R 3 It is Ts. In the embodiment, R 1 It is F.

[1076] In embodiments, the method includes a chiral separation step (e.g., separating a stereoisomer from a mixture of stereoisomers). In embodiments, the method includes a regioisomer separation step (e.g., separating a regioisomer from a mixture of regioisomers). In embodiments, the method includes a step of separating an E (or cis) isomer from a mixture of E and Z isomers. In embodiments, the method includes a step of separating a Z (or trans) isomer from a mixture of E and Z isomers. Those skilled in the art will recognize many methods for separating chiral, stereoisomers, and regioisomers, such as those described herein.

[1077] In the embodiments, intramolecular cyclization of a compound having the formula MP includes using a high-valent iodine reagent and optionally a solvent. In the embodiments, the high-valent iodine reagent is PIFA. In the embodiments, the solvent is THF. In the embodiments, intramolecular cyclization of a compound having the formula MP includes using PIFA and THF.

[1078] In the embodiments, Q is a group R as defined herein. 2 The protected form. In the examples, Q is a phenyl group having a protected amine substituent (optionally together with other substituents, such as the group -OCF3)).

[1079] In the embodiments, Q is a group R as defined herein. 2Therefore, in the embodiments, the compound having formula MP is the compound having formula M1.

[1080]

[1081] Among them, rings A and R 1 R 2 R 3 And n is as defined herein. In the embodiments, R 3 It is H (i.e., the compound is compound M as defined herein). In other embodiments, R 3 It is Ts (i.e., the compound is compound M' as defined herein).

[1082] In some embodiments, intramolecular cyclization includes the use of a silver (I) salt and optionally a solvent. In some embodiments, the silver (I) salt is Ag₂CO₃. In some embodiments, the solvent is THF. In some embodiments, intramolecular cyclization includes the use of Ag₂CO₃ and THF.

[1083] In an embodiment, the method includes one or more steps shown in scheme 2. In an embodiment, the method includes all the steps shown in scheme 2. In an embodiment, the method includes step 2 of scheme 2. In an embodiment, the method includes one or more steps shown in scheme 2A. In an embodiment, the method includes all the steps shown in scheme 2A. In an embodiment, the method includes step 3 of scheme 2A. In an embodiment, the method includes one or more steps of method C. In an embodiment, the method is substantially as described in method C.

[1084] In the embodiments, Q, together with the adjacent carbonyl group, is an amine protecting group (e.g., Boc). Therefore, in the embodiments, compounds having formula MP are compounds having formula P1.

[1085]

[1086] Among them, rings A and R 1 R 3 And n as defined herein. In an embodiment, R 3 It is H (i.e., the compound is compound P as defined herein). In other embodiments, R 3 It is Ts (i.e., the compound is compound P' as defined herein).

[1087] In an embodiment, the method includes one or more steps shown in scheme 4. In an embodiment, the method includes all the steps shown in scheme 4. In an embodiment, the method includes step 3 of scheme 4. In an embodiment, the method includes one or more steps of method F. In an embodiment, the method is substantially as described in method F. In an embodiment, the method includes all the steps of method F except for the N-toluenesulfonation and detoluenesulfonation steps.

[1088] In the embodiments, the compounds prepared by the methods described herein are selected from compounds having formula (I), (II), (III), (IV), (V) or (VI) as defined herein, and their pharmaceutically acceptable salts.

[1089] This disclosure also relates to intermediates that can be used to prepare the compounds disclosed herein. Those skilled in the art will understand that the methods described herein, in the context of preparing the compounds disclosed herein, can be used to provide such intermediates.

[1090] From this perspective, this disclosure provides compounds having the formula HE.

[1091]

[1092] Or a pharmaceutically acceptable salt thereof, wherein R 1 and n are as defined in this paper, and where:

[1093] Q is a group R as defined in this article. 2 (or its protected form), or together with the adjacent carbonyl group, it forms an amine protecting group (e.g., Boc); and

[1094] X is a halogen (e.g., I, Br, Cl).

[1095] In the embodiment, R 1 It is F.

[1096] In the embodiments, the compound is a compound having the formula H.

[1097]

[1098] Or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 , n and X are as defined in this paper.

[1099] In other embodiments, the compound is a compound having formula E.

[1100]

[1101] Or a pharmaceutically acceptable salt thereof, wherein R 1, n and X are as defined in this paper.

[1102] This disclosure also provides compounds having the formula MP.

[1103]

[1104] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 and n are as defined in this paper, and where:

[1105] Q is a group R as defined in this article. 2 (or its protected form), or together with the adjacent carbonyl group, it forms an amine protecting group (e.g., Boc); and

[1106] R 3 Selected from leaving groups that are compatible with H and nitrogen (e.g., Ts).

[1107] In the embodiment, R 3 It is H. In other embodiments, R 3 It is Ts. In the embodiment, R 1 It is F.

[1108] In the embodiments, the compound is a compound having the formula M1.

[1109]

[1110] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 R 2 R 3 And n is as defined herein. In the embodiments, the compound is a compound having the formula M or M'.

[1111] ,

[1112] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 R 2 And n is as defined in this article.

[1113] In the embodiments, the compound is a compound having the formula P1.

[1114]

[1115] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 R 3 And n is as defined herein. In the embodiments, the compound is a compound having the formula P or P'.

[1116]

[1117] Or a pharmaceutically acceptable salt thereof, wherein rings A and R1 And n is as defined in this article.

[1118] In the examples, the compounds are selected from:

[1119]

[1120] And its pharmaceutically acceptable salts.

[1121] It should be understood that the compounds disclosed herein can serve as precursors or intermediates for other compounds disclosed herein. For example, a compound carrying a ketone on ring A can be used as a precursor for a compound carrying an alkyl, hydroxyl, and / or other group at the ketone position. Therefore, this disclosure provides the following compounds that can be used as intermediates or precursors for the preparation of compounds as disclosed herein:

[1122]

[1123] And its pharmaceutically acceptable salts.

[1124] Pharmaceutical Composition

[1125] This disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[1126] In some embodiments, the pharmaceutical composition comprises a compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (III) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (V) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a compound having formula (VI) or a pharmaceutically acceptable salt thereof.

[1127] The pharmaceutical compositions disclosed herein can be formulated for application in solid or liquid form, for example using conventional carriers or excipients. The compositions may be suitable for, for example, 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 administration using techniques known in the art (e.g., as an ointment, patch, or spray to be applied to the skin).

[1128] Medical use

[1129] The compounds disclosed herein act as inhibitors of ERK5, which confers their utility in treating ERK5-related disorders and conditions. In particular, the compounds disclosed herein may be used to treat cancer.

[1130] From this perspective, this disclosure provides a treatment method comprising administering a therapeutically effective amount of the disclosed compound (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) to a subject in need. In a related aspect, this disclosure provides the use of the disclosed compound (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament. In another related aspect, this disclosure provides the use of the disclosed compound (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in a therapeutic application.

[1131] The compounds disclosed herein may be used to treat or prevent: diseases or harmful conditions in which ERK5 or its variants or mutants are known to play a role; diseases or disorders associated with increased MAPK7 (i.e., the ERK5 gene) expression and / or increased ERK5 activity; and diseases or disorders in which inhibiting or antagonizing ERK5 activity is beneficial.

[1132] In one aspect, this disclosure provides a method for treating or preventing ERK5-mediated diseases or disorders, or diseases or disorders involving ERK5, in a subject of need, the method comprising administering to the subject an effective amount of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing ERK5-mediated diseases or disorders, or diseases or disorders involving ERK5. In another related aspect, this disclosure provides a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) for treating or preventing ERK5-mediated diseases or disorders, or diseases or disorders involving ERK5.

[1133] On the other hand, this disclosure provides a method for treating or preventing ERK5-related diseases or disorders (e.g., cancer) in a subject in need, the method comprising administering to the subject an effective amount of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating or preventing ERK5-related diseases or disorders (e.g., cancer). In another related aspect, this disclosure provides the use of a compound of this disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the treatment or prevention of ERK5-related diseases or disorders (e.g., cancer).

[1134] On the other hand, this disclosure provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In a related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment or prevention of cancer. In another related aspect, this disclosure provides the use of a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof) in the treatment or prevention of cancer.

[1135] In the embodiments, the compound reduces angiogenesis, reduces or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., partially or completely), reduces evasion of growth inhibition, reduces or inhibits the growth of cancerous or precancerous cells, inhibits the proliferation of cancerous or precancerous cells, and / or reduces the survival of cancerous or precancerous cells.

[1136] In some embodiments, the cancer is characterized by increased MAPK7 (i.e., the ERK5 gene) expression and / or increased ERK5 activity. In some embodiments, the cancer has elevated ERK5 activity. In some embodiments, the cancer overexpresses ERK5. In some embodiments, the cancer is characterized by MAPK7 genomic amplification and / or constitutively active ERK5 signaling. In some embodiments, the cancer has genomically amplified ERK5. In some embodiments, the cancer has constitutively active ERK5 signaling.

[1137] In this embodiment, the cancer is a solid tumor (e.g., melanoma, carcinoma, or blastoma). In other embodiments, the cancer is leukemia (e.g., chronic lymphocytic leukemia, CLL; acute myeloid leukemia, AML; or chronic myeloid leukemia, CML).

[1138] In this embodiment, the cancer is a primary tumor. In other embodiments, the cancer is a secondary tumor (e.g., a metastatic tumor).

[1139] In the embodiments, the cancer is selected from breast cancer (e.g., ductal breast cancer 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., bile duct cancer), nervous system cancer (e.g., neuroblastoma), and melanoma.

[1140] In the embodiments, 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 lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström macroglobulinemia, and multiple myeloma.

[1141] In the embodiments, 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.

[1142] On the other hand, this disclosure provides a method for inhibiting ERK5 activity, the method comprising contacting ERK5 (e.g., cells containing ERK5) with a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof). In embodiments, the method is an in vitro or ex vivo method. In other embodiments, the method is an in vivo method. In a related aspect, this disclosure provides an in vitro method for inhibiting ERK5 activity in cells, the method comprising contacting cells with a compound of the disclosure (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof).

[1143] The compounds disclosed herein (e.g., compounds having formula (I)) and their pharmaceutically acceptable salts may be administered as pharmaceutical compositions, which may optionally contain one or more pharmaceutically acceptable excipients.

[1144] It should be understood that the methods and treatments of various aspects of this disclosure can be achieved by administering to a subject an effective amount of a compound of this disclosure in the form of a pharmaceutical composition (e.g., a compound having formula (I) or a pharmaceutically acceptable salt thereof), which may optionally contain one or more pharmaceutically acceptable excipients as described herein.

[1145] The compounds disclosed herein can be used alone (e.g., as a monotherapy) or in combination with one or more cancer therapies.

[1146] As generally described herein, the following non-limiting examples are provided to further illustrate this disclosure. Example

[1147] General synthesis scheme

[1148] The following scheme (Scheme 1) illustrates an exemplary manner for preparing compounds according to this disclosure and examples (e.g., compounds having formula (I)):

[1149]

[1150] Option 1

[1151] According to Scheme 1 (where rings A and R are...) 1 R 2 Compound C can be obtained in step 1 by Suzuki coupling between compound A and compound B (where -B(OR)2 is a borate ester group such as -B(Pin)) in the presence of a base such as tripotassium phosphate, using a palladium catalyst such as PdCl2(dppf)CH2Cl2. Compound C can then be hydrogenated to compound D in step 2 by hydrogenation at a hydrogen pressure (H2) of about 5 bar at, for example, 40°C using a catalyst such as Pd / C. Compound D can then be converted to compound E (where X can be I, Br, or Cl) in step 3 by halogenation with, for example, NIS, NBS, or NCS (i.e., X = I, Br, or Cl). Compound E can be N-deprotected in step 4 using HCl or TFA to give compound F. Compound H can then be prepared in step 5 by reacting compound F with 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. Then, in step 6, a palladium catalyst such as Pd(t-Bu3P)2 can be used to convert compound H (in the presence of compound J) to compound K in the presence of a base such as DABCO.

[1152] The following scheme (Scheme 2) illustrates an alternative method for preparing compound K from compound H:

[1153]

[1154] Option 2

[1155] According to Scheme 2 (where rings A and R are...) 1 R 2 In step 1, 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 borate ester group such as -B(Pin)) in the presence of a base such as potassium carbonate, using a palladium catalyst such as PdCl2(dppf)CH2Cl2. Compound K can then be obtained directly from compound M in step 2 in the presence of a hypervalent iodine(III) reagent such as PIFA.

[1156] In some cases, compound K can be prepared from compound H via an N-protected compound according to the following scheme (Scheme 2A):

[1157]

[1158] Option 2A

[1159] According to scheme 2A (where rings A and R are...) 1 R 2 In step 1, compound H' (where X can be I, Br, or Cl) can be obtained by toluenesulfonation of compound H with toluenesulfonyl chloride using a base such as sodium hydride. Then, in step 2, compound H' can be converted to compound M' via Suzuki coupling using a palladium catalyst such as PdCl2(dppf).CH2Cl2 in the presence of a base such as potassium carbonate, in the presence of compound L (where -B(OR)2 is a borate ester group such as -B(Pin)). Compound K' can be obtained from compound M' in step 3 in the presence of a hypervalent iodine(III) reagent (such as PIFA). Compound K' can be given by N-deprotection of compound K in step 4 using, for example, sodium hydroxide in EtOH.

[1160] The following scheme (Scheme 3) illustrates an alternative method for preparing compound K from compound E:

[1161]

[1162] Option 3

[1163] According to Scheme 3 (where rings A and R are...) 1 R 2Compound N can be, for example, as described above. In step 1, compound N can be obtained from compound E (where X can be I, Br, or Cl) in the presence of compound J, using a palladium catalyst such as Pd(t-Bu3P)2 and a base such as DABCO. Compound N can be N-deprotected in step 2 using HCl or TFA to give compound O. Then, in step 3, compound K can be prepared from compound O using carboxylic acid compound G, under conditions known to those skilled in the art such as TATU, in a solvent like DMF and in the presence of a base such as DIPEA.

[1164] The following scheme (Scheme 4) illustrates an alternative method for preparing compound N from compound E:

[1165]

[1166] Option 4

[1167] According to Scheme 4 (where rings A and R are...) 1 Compound E' can be obtained in step 1 by toluenesulfonation of compound E (where X can be I, Br, or Cl) with toluenesulfonyl chloride, for example, as described above. Compound E' can then 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. Compound N' can be obtained from compound P' in step 3 in the presence of a hypervalent iodine(III) reagent (such as PIFA). Compound N' can be given in step 4 by N-detoluenesulfonation using, for example, sodium hydroxide in EtOH.

[1168] The following scheme (Scheme 5) illustrates another exemplary method for preparing compound K via compound N:

[1169]

[1170] Option 5

[1171] According to Scheme 5 (where rings A and R are located), 1 R 2In step 1, compound R is obtained by acylation of compound Q in the presence of a base such as LDA. Compound R can be converted to compound S in step 2 by reduction with a hydride source such as DIBAL-H. Compound S can then be converted to compound T in step 3 by reaction with PBr3. Compound U can be obtained from compound T in step 4 in the presence of triethyl phosphite. In step 5, compound U is converted to compound W in the presence of compound V (where ring A' is a precursor of ring A, for example, with one less ring carbon atom than ring A) and a base such as potassium tert-butoxide. In step 6, compound W undergoes nucleophilic aromatic substitution with sodium azide to give compound X. Compound X is then converted to compound Y in step 7 in the presence of an iron catalyst and zinc powder; during step 7, ring A' in compound X undergoes rearrangement to give ring A in compound Y. In step 8, compound Z is provided by the Suzuki coupling reaction of compound Y with compound B (where -B(OR)2 is a borate ester 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 in step 9 by hydrogenation with a catalyst such as Pd / C at, for example, a hydrogen pressure (H2) of about 1 bar. Compound N can be N-deprotected in step 10 using HCl or TFA to give compound O. Then, in step 11, compound K can be prepared from compound O by reaction with carboxylic acid compound G using conditions known to those skilled in the art (such as EDCI and HOBt) in a solvent such as DMF in the presence of a base such as DIPEA.

[1172] The following scheme (Scheme 6) illustrates an alternative method for preparing compound N:

[1173]

[1174] Option 6

[1175] According to Scheme 6 (where rings A and R are...) 1 Compound AB can be obtained in step 1 by the condensation of compound AA with p-toluenesulfonylhydrazine. Compound P can be obtained in step 2 by a Barluenga-Valdés cross-coupling reaction with compound E (where X can be I, Br, or Cl) and compound AB in the presence of a base such as potassium carbonate, using a palladium catalyst such as Pd(OAc)2 and a phosphonium ligand such as tri-tert-butylphosphonium tetrafluoroborate. Compound N can be obtained from compound P in step 3 in the presence of a hypervalent iodine(III) reagent such as PIFA.

[1176] The following scheme (Scheme 7) illustrates an alternative method for preparing compound Z:

[1177]

[1178] Option 7

[1179] According to Scheme 7 (where rings A and R are...) 1 Compound AD can be obtained in step 1 by the Suzuki coupling reaction of compound AC with compound L using a palladium catalyst such as PdCl2(dppf) in the presence of a base such as sodium carbonate. In step 2, compound AD undergoes a nucleophilic aromatic substitution reaction with sodium azide to give compound AE. Then, in step 3, compound AE is converted to compound AF in the presence of an iridium catalyst and AgSbF6. Compound Z can be obtained in step 4 by the Suzuki coupling reaction of compound AF with compound B (where -B(OR)2 is a borate ester group such as -B(Pin)) using a palladium catalyst such as Pd(t-Bu3P)2 in the presence of a base such as tripotassium carbonate.

[1180] The following scheme (Scheme 8) illustrates an alternative method for preparing compound Z:

[1181]

[1182] Option 8

[1183] According to Scheme 8 (where rings A and R are...) 1 In step 1, compound AF can be obtained from compound AG (where X can be I, 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. Then, in step 2, compound AF can be converted to compound Z by Suzuki coupling using a palladium catalyst such as PdCl2(dppf)CH2Cl2 in the presence of a base such as cesium carbonate, where -B(OR)2 is a borate ester group such as -B(Pin)).

[1184] If necessary, protecting groups can be used in the above transformations, for example, in R 2 Or on the free -NH2 substituent of ring A. Given this disclosure, suitable protection strategies will be apparent to those skilled in the art. For example, compounds disclosed herein (e.g., compounds having formula (I)) (where R...) 2 It is replaced by -NH2 -(C6-C 10The aryl group can be prepared from the corresponding -NHBOC compound, which can be prepared by a method similar to the above scheme and subjected to N-deprotection using conditions described herein or otherwise known to those skilled in the art. The compounds disclosed herein (e.g., compounds having formula (I)) (where ring A is a heterocyclic alkane containing at least one nitrogen ring atom) can be prepared from the corresponding N-protected (e.g., NBOC) compound, which can be N-deprotected. Compounds where ring A is substituted with -OH or -NH2 can be prepared from the corresponding O-protected or N-protected compound, which can be prepared by a method similar to the above scheme and subjected to O-deprotection or N-deprotection using conditions described herein or otherwise known to those skilled in the art. Compounds where ring A is substituted with an oxo group (e.g., a ring containing a carbonyl group, i.e., a -(C=O) group) can be prepared from the corresponding acetal compound (-(O-CH2CH2-O)-), which can be prepared by a method similar to the above scheme and obtained by exposure to, for example, acidic reaction conditions.

[1185] Certain compounds disclosed herein may carry substituents capable of undergoing further transformation to prepare other compounds according to this disclosure (e.g., compounds having formula (I)). For example, compounds available according to the above scheme (e.g., like compound K) in which ring A is oxysubstituted (e.g., a ring containing a carbonyl group, i.e., a -(C=O)- group) may be subjected to chemical transformations such as: (1) nucleophilic addition; (2) reductive amination; and (3) reduction with a hydride reagent to give the corresponding compounds of this disclosure (e.g., compounds having formula (I)) in which, for example: (1) ring A is substituted with -OH and other substituents (e.g., selected from -(C1-C3)alkyl, -(C3-C6)cycloalkyl, 3- to 6-membered heterocyclic alkyl, -O(C1-C3)alkyl, and -CN, optionally substituted with one or more halogens or -OH); (2) ring A is substituted with -NHR', where R' may be, for example, as described above; and (3) ring A is substituted with -OH.

[1186] Compounds having one or more stereocenters can be purified, for example, using chiral separation techniques (such as chiral HPLC or SFC), to obtain individual isomers.

[1187] Experimental techniques

[1188] At 400 and 500 MHz 11H NMR spectra were recorded on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, and the chemical shifts (δ, in ppm) in the solvent dimethyl sulfoxide-d6 (DMSO-d6) were referenced to 2.5 ppm at the cited temperature. Coupling constants (J) are given in hertz.

[1189] Liquid chromatography / mass spectrometry (LC / MS) was performed using UV detection DAD 210 < l < 400 nm and column Acquity UPLC CSH C18 1.7 µm, size 2.1 x 50 mm, mobile phase H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H, and was obtained on a UPLC Acquity Waters instrument, a Sedere light scattering detector, and a SQD Waters mass spectrometer.

[1190] Unless otherwise noted, all synthetic reactions were carried out under an inert atmosphere. In the following examples, when 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 suppliers such as Sigma-Aldrich).

[1191] Examples 1 to 294 - Compounds

[1192] Tables 1a and 1b below list the specific compounds of the present disclosure together with their names and structures (Table 1a) and the methods for their preparation and characterization by NMR and LC / MS (Table 1b).

[1193] Table 1a:

[1194]

[1195] Table 1b:

[1196]

[1197] Preparation method

[1198] The compounds disclosed herein can be prepared according to methods A through J (see also Table 1b above). Each of those synthetic methods is illustrated by reference to the preparation of one or more specific compounds disclosed herein. Those skilled in the art will understand how the characteristics of the various synthetic steps (e.g., reactants, reagents, and conditions) shown in the illustrative examples can be modified when preparing other compounds according to this disclosure, and in particular according to the general synthetic schemes provided above.

[1199] Method A

[1200] Method A is illustrated by the preparation method in Example 56. Method A includes, for example, the steps found in Scheme 1 above.

[1201] Example 56: [4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyrido[2,3-b]indole-6,2'-[1,3]dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1202]

[1203] Step 1: tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate

[1204]

[1205] N-BOC-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (31.18 g, 100.84 mmol) and tripotassium phosphate (53.512 g, 252.1 mmol) were added to a solution of 5-fluoro-4-iodopyridin-2-amine (20 g, 84.03 mmol) in 1,4-dioxane (1 L) and water (110 mL) at room temperature. The entire mixture was then bubbled under argon for 15 min. A 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (3.43 g, 4.2 mmol) was then added and the entire mixture was refluxed under argon for 12 h. After 12 h, 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. The organic layer was then washed twice with water (2 x 250 mL), twice with brine (2 x 250 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel rapid chromatography (800 g SiO2) (eluting with a 75 / 25 mixture of heptane and ethyl acetate) to give 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.

[1206] Step 2: tert-butyl 4-(2-amino-5-fluoro-4-pyridyl)piperidine-1-carboxylate

[1207]

[1208] 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-pyridin-1-carboxylate (13 g, 44.3 mmol) in THF (47 mL) and EtOH (135 mL). The entire mixture was then subjected to hydrogenation at 40°C for 1.5 h with 5 bar H2. The mixture was then cooled to room temperature, filtered through a clarifier, and washed with EtOH (50 mL) and THF (40 mL). The resulting filtrate was concentrated under vacuum to give a light brown solid. The filtrate was then ground in pentane (100 mL), filtered, and dried under vacuum for 12 h to give 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 value 296.2, measured value 296.4.

[1209] Step 3: tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carboxylate

[1210]

[1211] NIS (33.1 g, 147 mmol) was added fractionally to a solution of tert-butyl piperidine-1-carboxylate (14.5 g, 49.1 mmol) in DMF (290 mL), followed by 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 NaHSO3 solution. Then 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). The combined organic layers were then washed with water (500 mL) and brine (300 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (SiO2 330 g) (eluting with a mixture of heptane / ethyl acetate from 95 / 5 to 60 / 40) to give 13.1 g (63.5% yield) of tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carboxylate as a light pink solid. LC / MS (m / z, M+H): calculated 422.1, found 422.3.

[1212] Step 4: 5-Fluoro-3-iodo-4-(4-piperidinyl)pyridine-2-amine dihydrochloride

[1213]

[1214] 1.14 g (2.71 mmol) of tert-butyl 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-1-carboxylate 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 to dryness to give 1.07 g (100% yield) of 5-fluoro-3-iodo-4-(4-piperidine)pyridyl-2-amine dihydrochloride as a solid. LC / MS (m / z, M+-2 HCl): Calculated 321.0, Found 321.0.

[1215] Step 5: [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1216]

[1217] 4-(trifluoromethoxy)benzoic acid (4.89 g, 23.7 mmol) was added in portions to a solution of 5-fluoro-3-iodo-4-(4-piperidinyl)pyridine-2-amine dihydrochloride (9.35 g, 23.7 mmol) in DMF (95 mL), followed by the addition of 16.5 mL of DIPEA (94.9 mmol) and TBTU (8.38 g, 26.1 mmol). The mixture was stirred for 60 minutes. After 60 minutes, ethyl acetate and water were added to the mixture. The organic layer was then washed three times with saturated NaHCO3 aqueous solution and brine, and the combined aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting orange residue was ground in diisopropyl ether and filtered to give 11.232 g (93% yield) of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone as a pale brown solid. LC / MS (m / z, M+): calculated 509.0, found 509.0.

[1218] Step 6: [4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyrido[2,3-b]indole-6,2'-[1,3]dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1219]

[1220] 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-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone (590 mg, 1.16 mmol) in DMF (2.5 mL). The entire mixture was then 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. The reaction mixture was then diluted with ethyl acetate, washed three times with water, and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were then washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was then purified by rapid silica gel chromatography (SiO2 120 g) (eluting with a 50 / 50 to 0 / 100 mixture of heptane / ethyl acetate) to give 439 mg (72.9% yield) of solid [4-(3-fluoro-5,7,8,9-tetrahydrospiro[pyridino[2,3-b]indol-6,2'-[1,3]dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone. LC / MS (m / z, M+H): calculated 520.2, found 520.4.

[1221] Method B

[1222] Method B is illustrated by the preparation method in Example 15. Method B includes, for example, the steps found in Scheme 2A above.

[1223] Example 15: [4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indol-7,2'-dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1224]

[1225] Step 1: N-[5-fluoro-3-iodo-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-2-pyridinyl]-4-methyl-benzenesulfonamide

[1226]

[1227] At 0°C under an argon atmosphere, sodium hydride (60% dispersion in oil, 176 mg, 4.4 mmol) was added to a solution of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone (described in step 5 of Example 56) (1120 mg, 2.2 mmol) in 15 mL of THF, and the resulting mixture was stirred at 0°C for 30 minutes. After 30 minutes, p-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 magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was then purified by rapid silica gel chromatography (SiO2 70 g) (eluting with a 100 / 0 to 0 / 100 mixture of DCM / [heptane / ethyl acetate 50 / 50]) to give 290 mg (20% yield) of N-[5-fluoro-3-iodo-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-2-pyridinyl]-4-methylbenzenesulfonamide as a white solid. LC / MS (m / z, M+H): calculated 664.0, found 664.1.

[1228] Step 2: N-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-2-pyridinyl]-4-methyl-benzenesulfonamide

[1229]

[1230] In 2–5 mL microwave-safe vials, potassium carbonate (242 mg, 1.75 mmol), dichlorobis(triphenylphosphine)palladium(II) (31 mg, 0.044 mmol), and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxacyclopentaborane (140 mg, 0.52 mmol) were added sequentially to a solution of N-[5-fluoro-3-iodo-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-2-pyridinyl]-4-methylbenzenesulfonamide (290 mg, 0.44 mmol) bubbled with argon in DMF (2.5 mL) and water (1.25 mL). The vials were sealed and subjected to microwave irradiation 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 magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was then purified by silica gel rapid chromatography (SiO2 25 g) (eluting with a 100 / 0 to 0 / 100 mixture of DCM / [heptane / ethyl acetate 50 / 50]) to give 255 mg (86% yield) of N-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-2-pyridinyl]-4-methylbenzenesulfonamide as a white solid. LC / MS (m / z, M+H): calculated 676.2, found 676.3.

[1231] Step 3: [4-[3'-fluoro-9'-(p-toluenesulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone

[1232]

[1233] At room temperature, under an argon atmosphere, a solution of N-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-2-pyridinyl]-4-methylbenzenesulfonamide (255 mg, 0.38 mmol) in THF (1.3 mL) and a few drops of acetonitrile were added. The reaction mixture was heated at 50°C to completely dissolve, 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, and the resulting residue was poured into a saturated aqueous solution of NaHCO3 and extracted three times with DCM. The combined organic layers were then dried over magnesium sulfate; filtered and concentrated. The resulting residue was purified by rapid silica gel chromatography (SiO2 25 g) (eluting with a 100 / 0 to 0 / 100 mixture of heptane / [heptane / AcOEt 50 / 50]) to give 167 mg (65% yield) of [4-[3'-fluoro-9'-(p-toluenesulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone as a white solid. LC / MS (m / z, M+H): calculated 674.2, found 674.3.

[1234] Step 4: [4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyrido[2,3-b]indol-7,2'-dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1235]

[1236] Sodium hydroxide (30 mg, 0.74 mmol) was added to a solution of 4-[3'-fluoro-9'-(p-toluenesulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone (167 mg, 0.25 mmol) in ethanol (0.5 mL) at room temperature under an argon atmosphere. The resulting mixture was then stirred at 80°C for 45 minutes. After 45 minutes, the entire mixture was cooled to room temperature, concentrated to dryness, and diluted with AcOEt and water. The aqueous layer was extracted three times with AcOEt, and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (SiO2 4 g) (eluting with a 100 / 0 to 0 / 100 mixture of DCM / [DCM / MeOH 90 / 10]) to give 88 mg (68% yield) of [4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyridino[2,3-b]indol-7,2'-dioxolane]-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone as a white solid. LC / MS (m / z, M+): calculated 519.2, found 519.0.

[1237] Method C

[1238] Method C is illustrated by the preparations in Examples 3, 4, 5, and 6. Method C includes, for example, the steps found in Scheme 2 above.

[1239] Example 3: (racemic)-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1240]

[1241] Step 1: (racemic)-[4-[2-amino-3-[4-[tert-butyl(dimethyl)silyl]oxycyclohexen-1-yl]-5-fluoro-4-pyridyl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1242]

[1243] In a 10–20 mL microwave-safe vial, a solution of [4-(2-amino-5-fluoro-3-iodo-4-pyridyl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone (500 mg, 0.98 mmol, prepared as described in step 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 (racemic)-tert-butyldimethyl[(4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)cyclohex-3-en-1-yl)oxy]silane (399 mg, 1.18 mmol) were added sequentially. 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. The organic layer was then washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid chromatography (SiO2 70 g) (eluted with a mixture of heptane / [heptane / AcOEt / MeOH 85 / 10 / 5] in a 100 / 0 to 0 / 100 ratio) to give 415 mg (71% yield) of (racemic)-[4-[2-amino-3-[4-[tert-butyl(dimethyl)silyl]oxycyclohexen-1-yl]-5-fluoro-4-pyridyl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone as a pale brown solid. LC / MS (m / z, M+H): calculated 594.3, found 594.4.

[1244] Step 2: (racemic)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1245]

[1246] (racemic)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone was prepared using 415 mg (0.7 mmol) of (racemic)-[4-[2-amino-3-[4-[tert-butyl(dimethyl)silyl]oxycyclohexen-1-yl]-5-fluoro-4-pyridinyl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone according to the scheme described in step 3 of Example 15, to give 100 mg (21% yield) was a white solid of (racemic)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone. LC / MS (m / z, M+H): calculated 592.2, found 592.3.

[1247] Step 3: (racemic)-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1248]

[1249] Add 0.42 mL of HCl in 4 N solution of dioxane (0.17 mmol) to a solution of (racemic)-[4-[7-[tert-butyl(dimethyl)silyl]oxy-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone (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 to dryness, and the residue was purified by rapid silica gel chromatography (SiO2 9 g) (eluting with a mixture of 100 / 0 to 0 / 100 of DCM / [DCM / MeOH(NH3 7N) 90 / 10]) to give 55 mg (68% yield) of racemic 4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone as a white solid. LC / MS (m / z, M+H): calculated 478.2, found 478.2.

[1250] Example 4: 4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,14-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one

[1251]

[1252] 4-Fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,14-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one was prepared according to the scheme described in step 6 of Example 56, using [4-(2-amino-5-fluoro-3-iodo-4-pyridinyl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] methyl ketone (100 mg, 0.19 mmol, described in step 5 of Example 56) and azaheptan-2,6-dione (83 mg, 0.59 mmol) to give 20 mg (20% yield) was a white solid of 4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,14-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-one. LC / MS (m / z, M+H): calculated 491.4, found 491.2.

[1253] Example 5: (racemic)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1254]

[1255] Step 1: (racemic)-trans-(13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-6-carboxylic acid tert-butyl ester

[1256]

[1257] (racemic)-trans-13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-6-carboxylic acid tert-butyl ester was prepared according to the scheme described in step 6 of Example 56 using [4-(2-amino-5-fluoro-3-iodo-4-pyridinyl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone (350 mg, 0.69 mmol, described in step 5 of Example 56) and (racemic)-trans-N-Boc-octahydroisoquinoline-6-one (522 mg, 2.06 mmol) to give 258 mg (55% yield) was a white solid of (racemic)-trans-(13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-6-carboxylic acid tert-butyl ester. LC / MS (m / z, M+H): calculated 617.6, found 617.4.

[1258] Step 2: (racemic)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1259]

[1260] A solution of (racemic)-trans-(13-fluoro-12-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-6-carboxylic acid tert-butyl ester (265 mg, 0.43 mmol) in MeOH (2 mL) was added to a solution of dioxane (1.07 mL, 4.3 mmol). The resulting mixture was stirred at room temperature for 4 hours, then concentrated to dryness and diluted with 2 mL of NH3 in MeOH (7 N). Silica gel was added to the mixture, which was then concentrated, and the resulting residue was purified by silica gel rapid chromatography (SiO2 12 g) (eluted with DCM / MeOH / NH4OH 90 / 10 / 1) to give 212 mg (95% yield) as a white solid, (racemic)-trans-[4-[13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone. LC / MS (m / z, M+): calculated 517.2, found 517.0.

[1261] Example 6: (racemic)-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-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone

[1262]

[1263] (Raceous)-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-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone was prepared according to the scheme described in step 6 of Example 56 using [4-(2-amino-5-fluoro-3-iodo-4-pyridinyl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone (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 give 166 mg (57% yield) as a gray solid, (racemic)-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-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone. LC / MS (m / z, M+): calculated 489.2, found 489.0.

[1264] Method D

[1265] Method D is illustrated by the preparations in Examples 7, 46, 8, and 9. Method D includes, for example, the steps found in Scheme 1 above.

[1266] Example 7: (racemic)-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-tetraen-3-yl]-1-piperidinyl] methyl ketone

[1267]

[1268] Step 1: N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl]tert-butyl carbamate

[1269]

[1270] N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl] tert-butyl carbamate was prepared according to the scheme described in step 5 of Example 56, using 5-fluoro-3-iodo-4-(4-piperidinyl)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 give 13.207 g (89% yield) of N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl] tert-butyl carbamate as a light brown solid. LC / MS (m / z, M+): Calculated value 624.1, measured value 624.0.

[1271] Step 2: (racemic)-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-tetraen-3-yl]-1-piperidinyl] methyl ketone

[1272]

[1273] (racemic)-trans-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecano-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone was prepared according to the scheme described in step 6 of Example 56 using N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl] tert-butyl carbamate (350 mg, 0.56 mmol) and (racemic)-trans-hexahydro-1H-cyclopenta[c]furan-5-one (212 mg, 1.68 mmol) to give 125 mg (44% yield) as a pale brown solid, (racemic)-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-tetraen-3-yl]-1-piperidinyl] methyl ketone. LC / MS (m / z, M+): calculated 504.2, found 504.0.

[1274] Examples 46, 8, and 9: (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] ketone, and [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone, isomers 1 and 2

[1275]

[1276] Step 1: (racemic)-4-[tert-butyl(dimethyl)silyl]oxycycloheptanone

[1277]

[1278] To a solution of (racemic)-4-hydroxycycloheptanone (527 mg, 4.1 mmol) in DCM (14 mL), tert-butyldimethylchlorosilane (682 mg, 4.52 mmol) and imidazole (420 mg, 6.17 mmol) were added, and the resulting mixture was stirred at room temperature for one hour. After one hour, tert-butyldimethylchlorosilane (158 mg, 1.26 mmol) and imidazole (126 mg, 1.85 mmol) were added, and the resulting mixture was stirred for another two hours. The mixture was then filtered, and the filtrate was concentrated under vacuum. The resulting residue was diluted with AcOEt, washed with a saturated aqueous solution of NaHCO3, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting colorless oil was then purified by rapid silica gel chromatography (SiO2 40 g) (eluting with AcOEt / heptane 5 / 95) to give 852 mg (85% yield) of (racemic)-4-[tert-butyl(dimethyl)silyl]oxycycloheptanone as a colorless oil.

[1279] Step 2: (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone and (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[13-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone

[1280]

[1281] (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone and (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[13-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone [2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate was prepared according to the scheme described in step 6 of Example 56, using N-[2-[4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidin-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate tert-butyl ester (350 mg, 0.5 mmol, described in step 1 of Example 7) and 4-[tert-butyl(dimethyl)silyl]oxycycloheptanone (367 mg, 1.61 mmol) to give 153 mg (42% yield) was a 75 / 25 mixture of (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[12-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone and (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[13-[tert-butyl(dimethyl)silyl]oxy-4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone. LC / MS (m / z, M+): calculated 621.3, found 621.5.

[1282] Step 3: (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone and (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone

[1283]

[1284] (Raceous)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone and (raceous)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone were prepared according to the scheme described in step 2 of Example 5, using 150 mg (0.24 mmol) of a mixture of the two regioisomers described in the previous step, to be given by rapid silica gel chromatography (SiO2 12 g) (eluted with DCM / MeOH / NH4OH 96 / 4 / 0.4):

[1285] 71 mg (58% yield) of (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone as a pale brown solid. LC / MS (m / z, M+): calculated 506.5, found 506.0; and

[1286] 24 mg (20% yield) of (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone (Example 17) as a pale brown solid. LC / MS (m / z, M+): calculated 506.2, found 506.0.

[1287] Step 4: [2-Amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone, isomers 1 and 2. (Examples 8 and 9)

[1288]

[1289] Chiral separation of ((racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone (63 mg, 0.12 mmol) was performed using a Chiralpak AD-H column (5 µm, 250 x 30 mm) with (heptane 70 / EtOH 30) + 0.1% TEA (flow rate 40 mL / min, UV detection at 254 nm) to yield: 17 mg (27% yield) [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone, isomer 1. LC / MS (m / z, M+H): calculated 507.2, found 507.4; and 7 mg (11% yield) [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone, isomer 2. LC / MS (m / z, M+H): calculated 507.2, found 507.4; and 7 mg (11% yield) [2-amino-4-(trifluoromethoxy)phenyl]-[4-[4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] ketone, isomer 2. M+H): Calculated value 507.2, measured value 507.4.

[1290] Method E

[1291] Method E is illustrated by the preparation method in Example 25. Method E includes, for example, the steps found in Scheme 3 above.

[1292] Example 25: [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)-1-piperidinyl] methyl ketone

[1293]

[1294] Step 1: 4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)piperidine-1-carboxylic acid tert-butyl ester

[1295]

[1296] In a 2–5 mL microwave-safe 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 4-(2-amino-5-fluoro-3-iodo-4-pyridyl)piperidine-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 min. Then, 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 min). After 3 hours, the reaction mixture was concentrated to dryness, and the resulting residue was purified by silica gel rapid chromatography (SiO2 30 g) (eluting with heptane / AcOEt 7 / 3) to give 169 mg (63% yield) of tert-butyl 4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)piperidine-1-carboxylate as a solid. LC / MS (m / z, M+): calculated 375.4, found 375.0.

[1297] Step 2: 12-Fluoro-13-(4-piperidinyl)-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraene dihydrochloride

[1298]

[1299] A solution of 4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)piperidin-1-carboxylic acid tert-butyl ester (169 mg, 0.45 mmol) in MeOH (2 mL) was added to a 4 N solution of dioxane (2 mL, 8 mmol) and the resulting mixture was stirred at room temperature for 24 hours and then concentrated to dryness to give 157 mg (100% yield) of 12-fluoro-13-(4-piperidinyl)-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraendi hydrochloride. LC / MS (m / z, M+H-2HCl): Calculated 276.3, Found 276.3.

[1300] Step 3: [2-Amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)-1-piperidinyl] methyl ketone

[1301]

[1302] Under an argon atmosphere, N,N-diisopropylethylamine (0.25 mL, 1.45 mmol) was added to a solution of 12-fluoro-13-(4-piperidinyl)-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraenedihydrochloride (80 mg, 0.22 mmol) in DMF (2 mL), and the resulting mixture was stirred at room temperature for 30 minutes. Then, 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. The organic layer was then dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel rapid chromatography (SiO2 20 g) (eluting with DCM / [DCM / MeOH / NH4OH 90 / 10 / 4] 90 / 10) to give 10 mg (9% yield) of solid [2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-3-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(13),2(7),9,11-tetraen-13-yl)-1-piperidinyl] methyl ketone. LC / MS (m / z, M+H): calculated 479.2, found 479.3.

[1303] Method F

[1304] Method F is illustrated by the preparation of Examples 50 and 51. Method F includes, for example, the steps found in Scheme 4 above.

[1305] Examples 50 and 51: 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-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-piperidinyl] methyl ketone

[1306]

[1307] Step 1: 4-[5-fluoro-3-iodo-2-(p-toluenesulfonylamino)-4-pyridyl]piperidine-1-carboxylic acid tert-butyl ester

[1308]

[1309] 4-[5-fluoro-3-iodo-2-(p-toluenesulfonylamino)-4-pyridyl]piperidine-1-carboxylic acid tert-butyl ester was prepared using the regimen described in step 1 of Example 15, with 1000 mg, 2.37 mmol, as described in step 3 of Example 56, to give 438 mg (32% yield) of 4-[5-fluoro-3-iodo-2-(p-toluenesulfonylamino)-4-pyridyl]piperidine-1-carboxylic acid tert-butyl ester as a white solid. LC / MS (m / z, M+H): calculated 576.1, found 576.2.

[1310] Step 2: 4-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-2-(p-toluenesulfonylamino)-4-pyridyl]piperidine-1-carboxylic acid tert-butyl ester

[1311]

[1312] 4-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-2-(p-toluenesulfonylamino)-4-pyridyl]piperidine-1-carboxylic acid tert-butyl ester was prepared according to the scheme described in step 2 of Example 15, using 4-[5-fluoro-3-iodo-2-(p-toluenesulfonylamino)-4-pyridyl]piperidine-1-carboxylic acid tert-butyl ester (435 mg, 0.76 mmol) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxacyclopentaborane (241 mg, 0.91 mmol) to give 425 mg (95% yield) tert-butyl 4-[3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-5-fluoro-2-(p-toluenesulfonylamino)-4-pyridyl]piperidine-1-carboxylate. LC / MS (m / z, M+H): calculated 588.2, found 588.4.

[1313] Step 3: 4-[3'-fluoro-9'-(p-toluenesulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]piperidin-1-carboxylic acid tert-butyl ester

[1314]

[1315] 4-[3'-fluoro-9'-(p-toluenesulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]piperidin-1-carboxylic acid tert-butyl ester was prepared according to the scheme described in step 3 of Example 15 using 4-[3-(1,4-dioxolane[4.5]dec-7-en-8-yl)-5-fluoro-2-(p-toluenesulfonylamino)-4-pyridyl]piperidin-1-carboxylic acid tert-butyl ester (530 mg, 0.9 mmol) to give 350 mg (66% yield) of tert-butyl 4-[3'-fluoro-9'-(p-toluenesulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]piperidin-1-carboxylic acid. LC / MS (m / z, M+H): calculated 586.2, found 586.3.

[1316] Step 4: 4-(3'-Fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyridino[2,3-b]indole]-4'-yl)piperidine-1-carboxylic acid tert-butyl ester

[1317]

[1318] 4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indole]-4'-yl)piperidine-1-carboxylic acid tert-butyl ester was prepared according to the scheme described in step 4 of Example 15 using 4-[3'-fluoro-9'-(p-toluenesulfonyl)spiro[1,3-dioxolane-2,7'-6,8-dihydro-5H-pyrido[2,3-b]indole]-4'-yl]piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.26 mmol) to give 105 mg (95% yield) of 4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indole]-4'-yl)piperidine-1-carboxylic acid tert-butyl ester as a white solid. LC / MS (m / z, M+H): Calculated value 432.2, measured value 432.4.

[1319] Step 5: A mixture of 3-fluoro-4-(4-piperidinyl)-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one hydrochloride and 3'-fluoro-4'-(4-piperidinyl)spiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indole] hydrochloride.

[1320]

[1321] At room temperature, fuming 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-tetrahydropyrido[2,3-b]indole]-4'-yl)piperidine-1-carboxylate (105 mg, 0.24 mmol) in THF (0.5 mL), and the resulting mixture was stirred at room temperature for 16 hours. Sixteen hours later, fuming HCl (0.06 mL, 0.73 mmol) was added, and the resulting mixture was stirred at room temperature for another 3 hours. The mixture was then filtered, and the filtrate was concentrated to dryness to give 60 mg of a mixture of crude 3-fluoro-4-(4-piperidinyl)-5,6,8,9-tetrahydropyrido[2,3-b]indole-7-one hydrochloride and 3'-fluoro-4'-(4-piperidinyl)spiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indole] hydrochloride as a yellow solid. Specifically, LC / MS (m / z, M+H-HCl): calculated value 288.1, measured value 288.2 and LC / MS (m / z, M+H-HCl): calculated value 332.2, measured value 332.2.

[1322] Step 6: 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-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-piperidinyl] methyl ketone

[1323]

[1324] 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indol-7-one and [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3'-fluorospiro[1,3-dioxolane-2,7'-5,6,8,9-tetrahydropyrido[2,3-b]indol]-4'-yl)-1-piperidinyl] methyl ketone were prepared according to the scheme described in step 3 of Example 25, using 60 mg of the crude previous mixture, 2-amino-4-(trifluoromethoxy)benzoic acid (42 mg, 0.19 mmol), and triethylamine (0.13 mL, 0.93 mmol) instead of DIPEA, for rapid silica gel chromatography (SiO2 12 g) (with heptane / [DCM / MeOH 95 / 5)). After elution from 100 / 0 to 0 / 100, the following is given:

[1325] 15 mg (16% yield) of 4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-5,6,8,9-tetrahydropyrido[2,3-b]indol-7-one as a white solid. LC / MS (m / z, M+H): calculated 491.2, found 491.3; and

[1326] 8 mg (8% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-5,6,8,9-tetrahydrospiro[pyridino[2,3-b]indol-7,2'-[1,3]dioxolane]-4-yl)-1-piperidinyl] methyl ketone as a white solid. LC / MS (m / z, M+H): Calculated 535.2, Found 535.3

[1327] Method G

[1328] Method G is illustrated by the preparation of Examples 70 and 71. Method G includes, for example, the steps found in Scheme 7 above.

[1329] Examples 70 and 71: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] ketone, isomers 1 and 2

[1330]

[1331] Step 1: 2,4-Dichloro-3-(4-methoxycyclohexen-1-yl)pyridine

[1332]

[1333] A mixture of 2,4-dichloropyridine (3.45 g, 12.59 mmol), 2-(4-methoxycyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (3 g, 12.59 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride (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 under a nitrogen atmosphere for 3 hours. 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 and washed with brine (2 x 100 mL), dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by silica gel rapid chromatography (0%–15% ethyl acetate in petroleum ether) to give 2.9 g (89% yield) of the target product as a yellow solid. LCMS; ESI m / z 258 (M + H)+.

[1334] Step 2: 2-Azide-4-chloro-3-(4-methoxycyclohexen-1-yl)pyridine

[1335]

[1336] A mixture of 2,4-dichloro-3-(4-methoxycyclohexen-1-yl)pyridine (2.9 g, 11.2 mmol), sodium azide (1.46 g, 22.46 mmol), and acetic acid (5 mL) in water (20 mL), ethanol (10 mL), and acetic acid (5 mL) was stirred at 110°C under a nitrogen atmosphere for 18 hours. 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 and washed with brine (2 x 100 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (0%–40% ethyl acetate in petroleum ether) to give 0.98 g (33% yield) of the target product as a yellow solid. LCMS: ESI m / z 265.1 (M + H)⁺.

[1337] Step 3: (racemic)-4-chloro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole

[1338]

[1339] A mixture of 2-azido-4-chloro-3-(4-methoxycyclohexen-1-yl)pyridine (0.980 g, 3.7 mmol), silver hexafluoroantimonate (V) (0.763 g, 2.22 mmol), and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (0.885 g, 1.11 mmol) in toluene (15 mL) was stirred at 130°C under an argon atmosphere for 72 hours. After 72 hours, the mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic layers were combined and washed with brine (2 x 50 mL), dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by rapid silica gel chromatography (0%–95% ethyl acetate in petroleum ether) to give 0.55 g (63% yield) of (racemic)-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)+.

[1340] Step 4: (racemic)-4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester

[1341]

[1342] A mixture of (racemic)-4-chloro-7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (0.550 g, 2.32 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (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) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 100°C under an argon atmosphere for 16 hours. 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 and washed with brine (2 x 50 mL), dried over Na2SO4, filtered, concentrated, and the residue purified by silica gel rapid chromatography (0-35% ethyl acetate in petroleum ether) to give 0.6 g (67% yield) of racemic 4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow oil. LCMS: ESI m / z 384.1 (M + H)+.

[1343] Step 5: (racemic)-4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)piperidine-1-carboxylic acid tert-butyl ester

[1344]

[1345] A mixture of racemic 4-[5-(2,5-dihydrofuran-3-yl)-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-3-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.637 g, 1.28 mmol), 5% Pd / C (0.5 g), and 20% Pd(OH)2 / C (0.5 g) in methanol (80 mL) was stirred at room temperature under 1 atm H2 for 96 hours. After 96 hours, the mixture was filtered and concentrated. The resulting residue was purified by preparative HPLC to give 237 mg (39% yield) of racemic 4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyridolo[2,3-b]indol-4-yl)piperidine-1-carboxylic acid tert-butyl ester as a white solid. LCMS: ESI m / z 386.1 (M + H)+.

[1346] Step 6: (racemic)-7-methoxy-4-(4-piperidinyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole hydrochloride

[1347]

[1348] At room temperature, 1.14 mL of a solution of (racemic)-4-(7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl)piperidin-1-carboxylic acid tert-butyl ester (117 mg, 0.3 mmol) in MeOH (2 mL) was added to a solution of 4 N HCl in dioxane (4.55 mmol), and the resulting mixture was stirred at room temperature for 1 hour and concentrated to dryness to give 108 mg (100% yield) of (racemic)-7-methoxy-4-(4-piperidinyl)-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.

[1349] Step 7: (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone

[1350]

[1351] (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-4-yl]-1-piperidinyl] methyl ketone was prepared according to the scheme described in step 5 of Example 56 using (racemic)-7-methoxy-4-(4-piperidinyl)-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 give 126 mg (85% yield) as a pale brown solid of (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] ketone. LC / MS (m / z, M+H): Calculated 489.2, Found 489.2.

[1352] Step 8: [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] ketone, isomers 1 and 2

[1353]

[1354] Chiral separation of (racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] ketone (123 mg, 0.25 mmol) was performed using a Chiralcel OD-I column (20 µm, 350 x 76.5 mm) with (60% heptane / 40% EtOH) + 0.1% TEA (flow rate 400 mL / min, UV detection at 265 nm) to give 52 mg (42% yield) of [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] ketone isomer 1. LC / MS (m / z, M+H): Calculated value 489.2, Found value 489.4; and 59 mg (48% yield) [2-amino-4-(trifluoromethoxy)phenyl]-[4-[7-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] ketone, isomer 2. LC / MS (m / z, M+H): Calculated value 489.2, Found value 489.4.

[1355] Method H

[1356] Method H is illustrated by the preparation method in Example 72. Method H includes, for example, the steps found in Scheme 8 above.

[1357] Example 72: [2-amino-4-(pentafluoro-λ)] 6 [-thioalkyl)phenyl]-[4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)-1-piperidinyl] methyl ketone

[1358]

[1359] Step 1: 12-Chloro-7,9-diazatricyclo[6.4.0.02,6]dodecane-1(12),2(6),8,10-tetraene

[1360]

[1361] In a 10–20 mL microwave-safe vial, cyclopentanone (495 mg, 5.6 mmol), 1,4-diazabicyclo[2.2.2]octane (661 mg, 5.6 mmol), and bis(tris-tert-butylphosphine)palladium(0) (97 mg, 0.19 mmol) were added to a solution of 4-chloro-3-iodopyridin-2-amine (500 mg, 1.87 mmol) in 10 mL of DMF. 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, and the resulting filtrate was washed three times with water and brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by rapid silica gel chromatography (SiO2 20 g) (eluting with heptane / AcOEt 85 / 15) to give 84 mg (23% yield) of 12-chloro-7,9-diazatricyclo[6.4.0.02,6]dodecane-1(12),2(6),8,10-tetraene as a white solid. LC / MS (m / z, M+H): calculated 193.0, found 192.9.

[1362] Step 2: 4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

[1363]

[1364] In 2–5 mL microwave-safe vials, 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]dodecane-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 minutes. After 50 minutes, additional Pd(dppf)Cl2·DCM (20 mg, 0.02 mmol) and N-BOC-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (100 mg, 0.3 mmol) were added, and the reaction mixture was microwaved at 160°C for another 40 minutes. The mixture was then diluted with DCM, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel rapid chromatography (SiO2 80 mg) (eluting with heptane / AcOEt 60 / 40 to 50 / 50) to give 113 mg (63% yield) of tert-butyl 4-(7,9-diazatricyclo[6.4.0.02,6]dodecane-1(12),2(6),8,10-tetraen-12-yl)-3,6-dihydro-2H-pyridine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 340.2, measured value 340.2.

[1365] Step 3: 4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)piperidine-1-carboxylic acid tert-butyl ester

[1366]

[1367] Ammonium formate (77 mg, 1.23 mmol) and Pd / C (10%) (126 mg, 0.12 mmol) were added to a solution of 4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (267 mg, 0.79 mmol) in EtOH (10 mL), and the resulting mixture was stirred under reflux for 2 h, followed by stirring at room temperature for 12 h. Then, ammonium formate (400 mg, 6.4 mmol) and Pd / C (10%) (59 mg, 0.06 mmol) were added, and the resulting mixture was refluxed for one hour, then cooled to room temperature, filtered, and the resulting filtrate was concentrated, diluted with AcOEt, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to dryness to give 240 mg (89% yield) of white foamy 4-(7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraen-12-yl)piperidine-1-carboxylate tert-butyl. LC / MS (m / z, M+H): calculated 342.2, found 342.3.

[1368] Step 4: 12-(4-piperidinyl)-7,9-diazatricyclo[6.4.0.02,6]dodec-1(12),2(6),8,10-tetraene dihydrochloride

[1369]

[1370] To a solution of tert-butyl piperidine-1-carboxylate (234 mg, 0.68 mmol) in MeOH / DCM (3 mL / 0.5 mL), a solution of i-PrOH (1.37 mL, 6.85 mmol) in 5 / 6 M HCl was added dropwise, and the resulting mixture was stirred at room temperature for 4 hours. After 4 hours, a solution of i-PrOH (1.37 mL, 6.85 mmol) in 5 / 6 M HCl was added, and the resulting mixture was stirred at room temperature for another 1 hour. The mixture was concentrated to dryness, 1 mL of MeOH was added, followed by a solution of i-PrOH (1.37 mL, 6.85 mmol) in 5 / 6 M HCl. The reaction mixture was stirred at room temperature for 2 hours, concentrated, diluted with MeOH, and concentrated to dryness three times. The resulting residue was ground in Et2O and filtered to give 202 mg (94% yield) of 12-(4-piperidinyl)-7,9-diazatricyclo[6.4.0.02,6]dodecane-1(12),2(6),8,10-tetraenedihydrochloride as a white solid. LC / MS (m / z, M+H-2HCl): calculated 242.2, found 242.2.

[1371] Step 5: [2-Amino-4-(pentafluoro-λ)] 6 [-thioalkyl)phenyl]-[4...

Claims

1. A compound having formula (I) Or its pharmaceutically acceptable salt, wherein: Ring A is a (C5-C8) cycloalkane, (C6-C8) cycloalkene, or a 5- to 8-membered heterocyclic alkane, wherein ring A is optionally separated by one or more R groups. A replace, Where R A Each time it appears, it is: (a) Independently selected from -D, halogen, -OH, oxo, =N-OH, -NHR', -CN, -C(O)R'', -(C1-C3)alkyl, -O(C1-C3)alkyl, -(C3-C6)cycloalkyl and 3- to 6-membered heterocyclic alkyl groups, wherein -(C1-C3)alkyl is optionally substituted by one or more groups selected from halogen and -OH each time it appears. Each R' is selected from -H, -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens. Each R'' is selected from -OH, -O(C1-C3)alkyl, and -(C1-C3)alkyl (e.g., -CH3); and / or (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C4-C7) cycloalkyl ring or a 4- to 7-membered heteroalkyl ring, wherein the heteroalkyl ring and the cycloalkyl ring are optionally substituted by one or more groups selected from oxo, -C(O)OH, -C(O)N((C1-C3)alkyl)2 and -(C1-C3)alkyl; R 1 Selected from -H and halogens (e.g. -F); R 2 Yes - (C6-C 10 ) aryl, wherein R 2 R appears in one or two B replace, Each R B Independently selected from halogens, -OH, -NH2, -SF5, -(C1-C3)alkyl, and -O(C1-C3)alkyl, wherein -(C1-C3)alkyl and -O(C1-C3)alkyl are optionally substituted by one or more halogens each time they appear; and n is 0, 1, or 2. The premise is that when R 2 It is 4-(pentafluorosulfuryl)phenyl, R 1 If -H is present and n is 1, then ring A is not an unsubstituted cyclopentane.

2. The compound of claim 1, wherein, Ring A is selected from cyclopentane, cyclohexane, cycloheptane, cyclooctane, tetrahydrofuran, tetrahydropyran, piperidine, morpholine, oxacycloheptane, azacycloheptane, 1,4-oxaazacycloheptane, and thiocycloheptane, wherein ring A may optionally be one or more of the R as defined in claim 1. A replace.

3. The compound according to claim 1 or claim 2, wherein, Ring A is selected from: , , , , , , , , , , , , , , , , , , and The dashed key indicates the point of convergence with the pyrrole ring, wherein ring A is optionally formed by one or more R as defined in claim 1. A replace.

4. The compound according to any one of claims 1-3, wherein, R 2 Selected from: , , and .

5. A compound having formula (II) Or its pharmaceutically acceptable salt, wherein: Ring A is a (C5-C8) cycloalkane or a 6- to 7-membered heterocyclic alkane, wherein ring A is optionally separated by one or more R groups. A replace, Where R A Each time it appears, it is: (a) Independently selected from -OH, oxo, -NHR', -C(O)CH3, -(C1-C3)alkyl and -O(C1-C3)alkyl, Each R' is selected from -(C1-C3)alkyl, -(C3-C4)cycloalkyl, and 3- to 4-membered heterocyclic alkyl groups optionally substituted with one or more halogens; or (b) with another R that appears A Together with one or more intercalating atoms, it forms a (C5-C7) cycloalkyl ring or a 4- to 6-membered heteroalkyl ring, wherein the heteroalkyl ring is optionally substituted with an oxo group; R 1 Selected from -H and -F; R B1 Selected from -H and -NH2; and R B2 Selected from -OCF3 and -SF5, The premise is that when R B1 It is -H,R B2 It is -SF5 and R 1 If it is -H, then ring A is not an unsubstituted cyclopentane.

6. The compound of claim 5, wherein, Ring A is selected from: , , , , , , , , and The dashed bond indicates the point of fusion with the pyrrole ring, wherein ring A is optionally bounded by one or more R as defined in any of the preceding claims. A replace.

7. The compound of claim 5 or claim 6, wherein, R B2 It is -OCF3.

8. The compound according to any one of claims 1-7, wherein, R 1 Yes, it is -F.

9. A compound having formula (III), formula (IV), formula (V) or formula (VI): Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1 As defined in any of the preceding claims, provided that the compound is a compound having formula (V) and R 1 If it is -H, then ring A is not an unsubstituted cyclopentane.

10. A compound selected from the group consisting of: -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone; -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl)-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(12-fluoro-5-oxa-8,10-diazatricyclo[7.4.0.02,7]tetadeca-1(9),2(7),10,12-tetraen-13-yl)-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluorospiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-oxetane]-4-yl)-1-piperidinyl] methyl ketone; -[4-[(12R)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[4-[(12S)-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -(racemic)-[4-(4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone; -4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-5,7,8,9-tetrahydropyrido[2,3-b]indol-6-one; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone; -(6R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one; -(6S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one; -[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone; -[4-[(3S,8S)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[4-((2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone; -[4-((2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl)-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-oxa-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone; -3-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-4-fluoro-13-methyl-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-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]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-methoxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-6,8-diazatricyclo[7.6.0.02,7]pentadecan-1(9),2,4,6-tetraen-3-yl)-1-piperidinyl] methyl ketone; -[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]indol-4-yl]-1-piperidinyl] methyl ketone; -[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]indol-4-yl]-1-piperidinyl] methyl ketone; -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-6-(1-hydroxy-1-methyl-ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -(7R)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile; -(7S)-4-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-3-fluoro-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-7-carboxynitrile; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-(3-fluoro-1'-methyl-spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,3'-azacyclobutane]-4-yl)-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6E)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6Z)-3-fluoro-6-hydroxyimino-5,7,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyridino[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12E)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12Z)-4-fluoro-12-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13E)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13Z)-4-fluoro-13-hydroxyimino-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5R)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(5S)-3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3R,8R)-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(3S,8S))-13-fluoro-6,15,17-triazatetracyclo[8.7.0.03,8.011,16]heptadec-1(10),11,13,15-tetraen-12-yl]-1-piperidinyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2S,7R)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(2R,7S)-12-fluoro-5,14,16-triazatetracyclo[7.7.0.02,7.010,15]hexadec-1(9),10,12,14-tetraen-11-yl]-1-piperidinyl] methyl ketone; -[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[4-[(12R)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone; -[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl] ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7R)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(7S)-3-fluoro-7-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -1-[4-fluoro-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-13-yl]acetone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]methyl ketone; -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-(4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl)-1-piperidinyl] methyl ketone; -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-7-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -(racemic)-[2-amino-4-(trifluoromethoxy)phenyl]-[4-[3-fluoro-5-(hydroxymethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[4-[(13R)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[4-[(13S)-4-fluoro-13-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -4-Fluoro-11,11-dimethyl-3-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]-6,8,13-triazatricyclo[7.5.0.02,7]tetradec-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]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[4-[(6S)-6-amino-3-fluoro-6-(trifluoromethyl)-5,7,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6R)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(6S)-3-fluoro-6-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-yl]-1-piperidinyl] methyl ketone; -[4-[(7E)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[4-[(7Z)-3-fluoro-7-hydroxyimino-5,6,8,9-tetrahydropyrido[2,3-b]indol-4-yl]-1-piperidinyl]-[4-(trifluoromethoxy)phenyl]methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11R,15S)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(11S,15R)-4-fluoro-13-oxa-6,8-diazatetracyclo[7.6.0.02,7.011,15]pentadecan-1(9),2,4,6-tetraen-3-yl]-1-piperidinyl] methyl ketone; -(6R)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-6,4'-pyrrolidine]-2'-one; -(6S)-3-fluoro-4-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidinyl]spiro[5,7,8,9-tetrahydropyrido[2,3-b]indol-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]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-4-fluoro-12-hydroxy-12-methyl-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl] methyl ketone; -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12R)-12-deuter-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone; and -[2-amino-4-(trifluoromethoxy)phenyl]-[4-[(12S)-12-deuterium-4-fluoro-12-hydroxy-6,8-diazatricyclo[7.5.0.02,7]tetradec-1(9),2(7),3,5-tetraen-3-yl]-1-piperidinyl]methyl ketone, And its pharmaceutically acceptable salts.

11. A pharmaceutical composition comprising a compound as described in any one of claims 1-10 and at least one pharmaceutically acceptable excipient or carrier.

12. The compound according to any one of claims 1-10 or the pharmaceutical composition according to claim 11, for use in a therapeutic manner.

13. The compound according to any one of claims 1-10 or the pharmaceutical composition according to claim 11, for use in the treatment or prevention of cancer.

14. The compound or pharmaceutical composition used according to claim 13, wherein, This cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

15. The compound or pharmaceutical composition used according to claim 13 or claim 14, wherein, The cancers selected include 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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