Carboline compounds and their use

Abstract

Uses of p-carboline compounds of formula (I) and dihydroorotate dehydrogenase (DHODH): [Case 1] JPEG2026524862000215.jpg2339(I) (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 (as defined herein) or forms thereof are provided herein.

Description

[Technical Field]

[0001] The use of β-carboline compounds and dihydroorotate dehydrogenase (DHODH) is provided herein. [Background technology]

[0002] Dihydroorotic acid dehydrogenase (DHODH) is located in the inner mitochondrial membrane and acts in the de novopyrimidine nucleotide synthesis pathway, catalyzing the dehydration of dihydroorotic acid (DHO) to orotic acid (ORO), leading to the production of uridine monophosphate (UMP) (Munier-Lehmann et al., J Med Chem 2015; 58(2):860-877). UMP is then converted to uridine (U) and cytosine (C) triphosphates, supplying the cellular pool of pyrimidine nucleotides.

[0003] DHODH is the rate-limiting enzyme for the de novo synthesis of pyrimidine ribonucleotides. Therefore, DHODH inhibitors are used to treat autoimmune diseases and are in clinical trials for cancer and viral infections. Generally, DHODH inhibitors exhibit beneficial immunosuppressive and antiproliferative activity, with a remarkable effect against activated lymphocyte proliferation. Examples of such DHODH inhibitors include, for example, leflunomide, teriflunomide, brequinal, maritimus (FK778), redoxal, BAY2402234, ASLAN003, and emvodostat (PTC299). DHODH is the rate-limiting enzyme for the de novo synthesis of pyrimidine ribonucleotides. Therefore, DHODH inhibitors are used to treat autoimmune diseases and are in clinical trials for cancer and viral infections. Generally, DHODH inhibitors exhibit beneficial immunosuppressive and antiproliferative activity, with a remarkable effect against activated lymphocyte proliferation. For example, many existing DHODH inhibitors have been reported, including leflunomide, teriflunomide, brachynal, maritimus (FK778), redoxal, BAY2402234, ASLAN003, and emvodostat (PTC299). Although some DHODH inhibitors currently under development show promise, there is a continuing need for therapeutically beneficial compounds useful as DHODH inhibitors, and new compositions thereof.

Summary of the Invention

[0004] A compound of formula (I) or a form thereof:

Chemical

[0005] Another embodiment provided herein is a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharmaceutically acceptable excipient. Another aspect provided herein is a method of treating a disease or disorder for which dihydroorotate dehydrogenase (DHODH) inhibition is suitable, using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof. [Modes for carrying out the invention]

[0006] In one embodiment, a compound of formula (I) or a form thereof: [ka] (In the formula, R 1 is hydrogen, halo, hydroxyl, C1-8 The heteroaryl is an alkoxy, amino, or heteroaryl, where the heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has 1, 2, or 3 R 1A They may be substituted with substituents, R 1A is C 1-8 It is alkyl, R 2 is hydrogen, halo, hydroxyl, C 1-8 Alkyl, C 1-8 It is an alkoxy or amino, R 3 is hydrogen, hydroxyl, or amino, R 4 is halo, hydroxy, cyano, C 1-8 Alkyl, C 1-8 Alkenil, C 2-8 Alkinyl, C 1-8 Alkoxy, C 1-8 Alkylthio or thiocarbonyl, C 1-8 Alkyl includes halo, hydroxy, cyano, oxo, and C. 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkenyl, heteroaryl, or heterocyclyl, C 1-8 Alkenyls are halo, hydroxy, and C. 1-8 Alkoxycarbonyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkyl or heterocyclyl groups, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo; the heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members; the heterocyclyl is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members or a polycyclic ring having 13 to 16 ring members; C3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heteroaryl, and heterocyclyl may be substituted with one, two, or three R 4A substituents, R 4A is halo, hydroxy, cyano, oxo, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylthio, or thiocarbonyl, and C 1-8 alkyl may be substituted with one, two, or three substituents independently selected from halo, and C 1-8 alkoxy may be substituted with one, two, or three substituents independently selected from halo, R 5 is heteroaryl, and heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and heteroaryl may be substituted with one, two, or three R 5A substituents, R 5A is halo, cyano, C 1-8 alkyl, C 1-8 alkylthio, C 1-8 alkoxy, or heterocyclyl, and C 1-8 alkyl may be substituted with one, two, or three substituents independently selected from halo, and C 1-8 alkoxy may be substituted with one, two, or three substituents independently selected from halo, and heterocyclyl is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, and heterocyclyl may be substituted with one or two R 5B substituents, R 5B is halo, hydroxy, cyano, oxo, C 1-8 alkyl, C 1-8 alkyl, C 1-8 alkylthio, C 1-8 alkoxy, or thiocarbonyl, and C 1-8The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo. The compounds provided herein are selected from the group consisting of free acids, free bases, salts, hydrates, solvates, anhydrides, racemates, enantiomers, diastereomers, stereoisomers, and tautomers.

[0007] Another embodiment provided herein is a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharmaceutically acceptable excipient. Another aspect provided herein is a method of treating a disease or disorder for which dihydroorotate dehydrogenase (DHODH) inhibition is suitable, using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof. Another embodiment includes a compound of formula (I) or a form thereof, in which the form is a salt thereof.

[0008] Another aspect is R 1 However, hydrogen, halo, hydroxy, C 1-8 The heteroaryl is an alkoxy, amino, or heteroaryl, wherein the heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has 1, 2, or 3 R 1A This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 1 However, hydrogen, halo, hydroxy, C 1-8 The heteroaryl is an alkoxy or heteroaryl, wherein the heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has one R 1A This includes compounds of formula (I), which may be substituted with substituents.

[0009] Another aspect is R 1 The compound comprises a compound of formula (I), which is a halo selected from chloro, bromo, fluoro, or iodine. Another aspect is R 1The compound comprises a compound of formula (I), which is a halo selected from chloro, bromo, or fluoro. Another aspect is R 1 However, C is selected from methoxy or ethoxy. 1-8 It contains compounds of formula (I) that are alkoxy. Another aspect is R 1 However, C selected from methoxy 1-8 It contains compounds of formula (I) that are alkoxy. Another aspect is R 1 It is a heteroaryl, and the heteroaryl is one R 1A The compound comprises a compound of formula (I) selected from a monocyclic ring having five ring members, which may be substituted with substituents.

[0010] Another aspect is R 1 It is a heteroaryl, and the heteroaryl is one R 1A The compound comprises a compound of formula (I), which is a monocyclic ring having five ring members selected from triazolyls that may be substituted with substituents. Another aspect is R 1 However, one R 1A The compound comprises a compound of formula (I) which is a triazolyl selected from 1H-1,2,3-triazol-1-yl or 2H-1,2,3-triazol-2-yl, which may be substituted with substituents. Another aspect is R 1A C 1-8 It contains a compound of formula (I) that is alkyl. Another aspect is R 1A However, C is selected from methyl, ethyl, or propyl. 1-8 It contains a compound of formula (I) that is alkyl. Another aspect is R 1A However, C is selected from methyl 1-8 It contains a compound of formula (I) that is alkyl.

[0011] Another aspect is R 1 However, hydrogen, halo, hydroxy, C 1-8The heteroaryl is an alkoxy or heteroaryl, wherein the heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has one R 1A R may be substituted with substituents, 1A C 1-8 It contains a compound of formula (I) that is alkyl. Another aspect is R 1 However, the compound is hydrogen, chloro, bromo, fluoro, hydroxy, methoxy, 1H-1,2,3-triazolyl, or 2H-1,2,3-triazolyl, and 1H-1,2,3-triazolyl and 2H-1,2,3-triazolyl are one R 1A R may be substituted with substituents, 1A This includes compounds of formula (I) in which is methyl. Another aspect is R 1 However, the compound is hydrogen, chloro, bromo, fluoro, hydroxy, methoxy, 1H-1,2,3-triazole-1-yl, or 2H-1,2,3-triazole-2-yl, and 1H-1,2,3-triazole-1-yl and 2H-1,2,3-triazole-2-yl are one R 1A R may be substituted with substituents, 1A This includes compounds of formula (I) in which is methyl.

[0012] Another aspect is R 2 However, hydrogen, halo, hydroxy, C 1-8 Alkyl, C 1-8 It contains a compound of formula (I) that is alkoxy or amino. Another aspect is R 2 However, it includes a compound of formula (I) which is hydrogen or a halo. Another aspect is R 2 The compound comprises a compound of formula (I), which is a halo selected from chloro, bromo, fluoro, or iodine. Another aspect is R 2 However, it includes compounds of formula (I) which are fluorocarbons selected as halos. Another aspect is R 2 However, it includes compounds of formula (I) that are hydrogen or fluoro. Another aspect is R 3However, it includes a compound of formula (I) which is hydrogen, hydroxyl, or amino. Another aspect is R 3 However, it contains a compound of formula (I) which is hydrogen or amino. Another aspect is R 2 However, it is hydrogen or halo, and R 3 However, it contains a compound of formula (I) which is hydrogen or amino. Another aspect is R 2 However, it is hydrogen or fluoro, R 3 However, it contains a compound of formula (I) which is hydrogen or amino.

[0013] Another aspect is R 4 However, halo, hydroxy, cyano, C 1-8 Alkyl, C 1-8 Alkenil, C 2-8 Alkinyl, C 1-8 Alkoxy, C 1-8 Alkylthio or thiocarbonyl, C 1-8 Alkyl is halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkenyl, heteroaryl, or heterocyclyl, C 1-8 Alkenyls are halo, hydroxy, C 1-8 Alkoxycarbonyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkyl or heterocyclyl groups, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo, the heteroaryl may be selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heterocyclyl may be selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members or a polycyclic ring having 13 to 16 ring members, C 3-8 Cycloalkyl, C3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A This includes compounds of formula (I), which may be substituted with substituents.

[0014] Another aspect is R 4 However, hydroxy, C 1-8 Alkyl, C 1-8 Alkenil, C 2-8 Alkinyl or thiocarbonyl, C 1-8 Alkyl is halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkenyls or heterocyclyls, C 1-8 Alkenyls are halo, hydroxy, C 1-8 Alkoxycarbonyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkyl or heterocyclyl groups, wherein the heterocyclyl is selected from monocyclic rings having 3 to 7 ring members, bicyclic rings having 6 to 10 ring members, bicyclic rings having 7 or 8 ring members, or polycyclic rings having 13 to 16 ring members, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls and heterocyclyls have 1, 2, or 3 R 4A R may be substituted with substituents, 4A However, oxo, C 1-8 It includes compounds of formula (I) that are alkyl, thiocarbonyl, or hydroxyl.

[0015] Another aspect is R 4 However, halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8C selected from methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, (methyl)ethyl, (methyl)propyl, (methyl)butyl, or (methyl)pentyl, which may be substituted with one, two, or three substituents independently selected from cycloalkenyl or heterocyclyl. 1-8 The alkyl group is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A This includes compounds of formula (I), which may be substituted with substituents.

[0016] Another aspect is R 4 However, halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 A C selected from methyl, ethyl, propyl, butyl, isobutyl, pentyl, or (methyl)butyl, which may be substituted with one, two, or three substituents independently selected from cycloalkenyl or heterocyclyl. 1-8 The alkyl group is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A This includes compounds of formula (I), which may be substituted with substituents.

[0017] Another aspect is R 4 However, halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 C selected from methyl, ethyl, propyl, butyl, isobutyl, pentyl, or (2-methyl)butyl, which may be substituted with one, two, or three substituents independently selected from cycloalkenyl or heterocyclyl. 1-8 The alkyl group is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A This includes compounds of formula (I), which may be substituted with substituents.

[0018] Another aspect is R 4 C 1-8 It is alkyl, C 1-8 Alkyl is halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 The heterocyclil may be substituted with one, two, or three substituents independently selected from cycloalkenyls or heterocyclils, wherein the heterocyclil is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A This includes compounds of formula (I), which may be substituted with substituents.

[0019] Another aspect is R 4 However, halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 C selected from methyl, ethyl, propyl, butyl, isobutyl, pentyl, or (2-methyl)butyl, which may be substituted with one, two, or three substituents independently selected from cycloalkenyl or heterocyclyl. 1-8 The alkyl group is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A This includes compounds of formula (I), which may be substituted with substituents.

[0020] Another aspect is R 4However, (2-oxo)propyl, (2,2-difluoro)ethyl, (2,2,2-trifluoro)ethyl, [(3-fluoro)(2-methyl)]propyl, [(6-chloro)(2,6-dimethyl)]heptyl, [(3,3,3-trifluoro)(2-methyl)]propyl, (2-cyano)ethyl, (2-cyano)propyl, [(2-hydroxy)(3-cyano)]propyl, [(2-hydroxy)(4-cyano)]butyl, (2-methoxy)propyl, (3-methoxy)butyl (2,2-dimethoxy)ethyl, [3-(methoxy)-2-(methoxymethyl)]propyl, (2-methoxycarbonyl)ethyl, (2-methoxycarbonyl)propyl, (3-methoxycarbonyl)propyl, (4-methoxycarbonyl)butyl, (3-methoxycarbonyl)isobutyl, (5-methoxycarbonyl)pentyl, (2-ethoxycarbonyl)ethyl, (2,2-diethoxycarbonyl)ethyl, (2-methoxycarbonyl)propenyl, (3-methoxy (Cicarbonyl)propenyl, (2-aminocarbonyl)propyl, (3-aminocarbonyl)propyl, (4-aminocarbonyl)butyl, (5-aminocarbonyl)pentyl, [(2-methyl)(3-aminocarbonyl)]propyl, (2,3-dimethylcarbonyloxy)propyl, (2-hydroxy)propyl, (3-hydroxy)propyl, (2-hydroxy)butyl, (4-hydroxy)butyl, (2-hydroxy)isobutyl, (5-hydroxy)pentyl, (6-hydroxy)hexyl, (2,3-dihydroxy)propyl, (2,4-dihydroxy)butyl, (3,4-dihydroxy)butyl, (2-hydroxymethyl)propyl, [(1-hydroxy)(2-methyl)]propyl, [(2-hydroxy)(2-methyl)]propyl, [(4-hydroxy)(2-methyl)]butyl, [(5-hydroxy)(2-methyl)]pentyl, [(6-hydroxy)(2,6-dimethyl)]heptyl, [(5,6-dihydroxy)(2,6-dimethyl)heptyl, (3-hydroxy){(2-hydroxy)methyl}]propyl, (3-methoxy)(2-hydroxy)propyl, (4-methoxy)(2-hydroxy)butyl, (3-methylcarbonyloxy)(2-hydroxy)propyl, (5-carboxy)pentyl, (cyclopentenyl)methyl, (cyclopenta-2-enyl)methyl, (oxetan-2-yl)methyl, (pyrrolidine-3-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (piperidine-3-yl)methyl, (piperidine-4-yl)methyl, (2-oxo-piperidine-3-yl)methyl , C may be substituted with a selection from (tetrahydro-2H-pyran-2-yl)methyl, (tetrahydro-2H-pyran-3-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (1,4-dioxan-2-yl)methyl, (1,3-dioxan-2-yl)methyl, (1,3-dioxan-4-yl)methyl, (1,3-dioxan-5-yl)methyl, (1,3-dioxolan-2-yl)methyl, (1,3-dioxolan-4-yl)methyl, (1,3-dioxan-2-one-5-yl)methyl, (3,6-dihydro-2H-pyran-2-yl)methyl, or (3,6-dihydro-2H-pyran-3-yl)methyl. 1-8 It contains a compound of formula (I) that is alkyl.

[0021] Another aspect is R 4However, (2-oxo)propa-1-yl, (2,2-difluoro)ethyl-1-yl, (2,2,2-trifluoro)ethyl-1-yl, [(3-fluoro)(2-methyl)]propa-1-yl, [(6-chloro)(2,6-dimethyl)]hepta-1-yl, [(3,3,3-trifluoro)(2-methyl)]propa-1-yl, (2-cyano)ethyl-1-yl, (2-cyano)propa-1-yl, [(2-hydroxy)(3-cyano)]propa-1-yl, [(2-hydroxy (4-Cyano)buta-1-yl, (2-Methoxy)propa-1-yl, (3-Methoxy)buta-1-yl, (2,2-Dimethoxy)ethanol-1-yl, [3-(Methoxy)-2-(Methoxymethyl)]propa-1-yl, (2-Methoxycarbonyl)ethanol-1-yl, (2-Methoxycarbonyl)propa-1-yl, (3-Methoxycarbonyl)propa-1-yl, (4-Methoxycarbonyl)buta-1-yl, (3-Methoxycarbonyl)isobuta-1-yl, (5-Me (Toxycarbonyl)penta-1-yl, (2-ethoxycarbonyl)etha-1-yl, (2,2-diethoxycarbonyl)etha-1-yl, (2-methoxycarbonyl)propa-1-en-1-yl, (3-methoxycarbonyl)propa-2-en-1-yl, (2-aminocarbonyl)propa-1-yl, (3-aminocarbonyl)propa-1-yl, (4-aminocarbonyl)buta-1-yl, (5-aminocarbonyl)penta-1-yl, [(2-methyl)(3-aminocarbonyl) (Nocarbonyl)propa-1-yl, (2,3-dimethylcarbonyloxy)propa-1-yl, (2-hydroxy)propa-1-yl, (3-hydroxy)propa-1-yl, (2-hydroxy)buta-1-yl, (4-hydroxy)buta-1-yl, (2-hydroxy)isobuta-1-yl, (5-hydroxy)penta-1-yl, (6-hydroxy)hexa-1-yl, (2,3-dihydroxy)propa-1-yl, (2,4-dihydroxy)buta-1-yl, (3,4-dihydroxy)buta-1-yl, (2-hydroxymethyl)propa-1-yl, [(1-hydroxy)(2-methyl)]propa-1-yl, [(2-hydroxy)(2-methyl)]propa-1-yl, [(4-hydroxy)(2-methyl)]buta-1-yl, [(5-hydroxy)(2-methyl)]penta-1-yl, [(6-hydroxy)(2,6-dimethyl)]hepta-1-yl, [(5,6-dihydroxy)(2,6-dimethyl)] Hepta-1-yl, [(3-hydroxy){(2-hydroxy)methyl}]propa-1-yl, [(3-methoxy)(2-hydroxy)]propa-1-yl, [(4-methoxy)(2-hydroxy)]buta-1-yl, [(3-methylcarbonyloxy)(2-hydroxy)]propa-1-yl, (5-carboxy)penta-1-yl, (cyclopentenyl)methyl, (cyclopenta-2-enyl)methyl, (oxetan-2-yl)methyl, ( Pyrrolidine-3-yl)methyl, (tetrahydrofuran-2-yl)methyl, (tetrahydrofuran-3-yl)methyl, (piperidine-3-yl)methyl, (piperidine-4-yl)methyl, (2-oxopiperidine-3-yl)methyl, (tetrahydro-2H-pyran-2-yl)methyl, (tetrahydro-2H-pyran-3-yl)methyl, (tetrahydro-2H-pyran-4-yl)methyl, (1,4-dioxan-2-yl)methyl , C may be substituted with a selection from (1,3-dioxan-2-yl)methyl, (1,3-dioxan-4-yl)methyl, (1,3-dioxan-5-yl)methyl, (1,3-dioxolan-2-yl)methyl, (1,3-dioxolan-4-yl)methyl, (1,3-dioxan-2-one-5-yl)methyl, (3,6-dihydro-2H-pyran-2-yl)methyl, or (3,6-dihydro-2H-pyran-3-yl)methyl. 1-8 It contains a compound of formula (I) that is alkyl.

[0022] Another aspect is R 4However, C selected from ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, (methyl)ethenyl, (methyl)propenyl, (methyl)butenyl, (methyl)pentyl, (methyl)hexyl, (methyl)heptenyl, (cyclohexylidene)methyl, or (oxanylidene)methyl. 1-8 It is an alkenyl, C 1-8 The compounds of formula (I) include those in which the alkenyl is substituted with one, two, or three substituents selected from halo, methoxycarbonyl, and hydroxyl.

[0023] Another aspect is R 4 However, C may be substituted with a selection from ethenyl, propenyl, butenyl, isobutenyl, hexenyl, pentenyl, (methyl)propenyl, (methyl)butenyl, (methyl)heptenyl, (cyclohexylidene)methyl, or (oxanylidene)methyl. 1-8 It is an alkenyl, C 1-8 The compounds of formula (I) include those in which the alkenyl is substituted with one, two, or three substituents selected from halo, methoxycarbonyl, and hydroxyl.

[0024] Another aspect is R 4 C selected from ethanol-1-en-1-yl, propane-2-en-1-yl, butane-3-en-1-yl, isobutane-1-en-1-yl, hexane-3-en-1-yl, (2-methyl)propane-2-en-1-yl, (2-methyl)butane-3-en-1-yl, (2,6-dimethyl)hepta-5-en-1-yl, (cyclohexylidene)methyl, or (oxane-4-ylidene)methyl. 1-8 It is an alkenyl, C 1-8 The compounds of formula (I) include those in which the alkenyl is substituted with one, two, or three substituents selected from halo, methoxycarbonyl, and hydroxyl.

[0025] Another aspect is R 4However, C may be substituted with a selection from (3-difluoro)propa-2-en-1-yl, (2-methoxycarbonyl)propa-1-en-1-yl, (3-methoxycarbonyl)propa-2-en-1-yl, (2-hydroxymethyl)propa-1-en-1-yl, [(3-hydroxy){(2-hydroxy)methyl}]propa-1-en-1-yl, (cyclohexylidene)methyl, or (oxan-4-ylidene)methyl. 1-8 It contains compounds of formula (I) that are alkenyls. Another aspect is R 4 However, C selected from ethinyl, propynyl, butynyl, isobutynyl, pentynyl, or hexynyl. 2-8 It contains compounds of formula (I) that are alkynyl compounds. Another aspect is R 4 However, C selected from propynyl or butynyl 2-8 It contains compounds of formula (I) that are alkynyl compounds.

[0026] Another aspect is R 4 However, C is selected from propane-2-in-1-yl or butane-3-in-1-yl. 2-8 It contains compounds of formula (I) that are alkynyl compounds. Another aspect is R 4A However, halo, hydroxy, cyano, oxo, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 It is an alkoxy or thiocarbonyl, and C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The compound comprises a compound of formula (I) in which the alkoxy may be substituted with one, two, or three substituents independently selected from the halo. Another aspect is R 4A However, hydroxy, oxo, C 1-8 It contains a compound of formula (I) which is alkyl or thiocarbonyl. Another aspect is R 4A However, C is selected from methyl 1-8 It contains a compound of formula (I) that is alkyl. Another aspect is R4A The compounds include those of formula (I), which are hydroxy, oxo, methyl, or thiocarbonyl.

[0027] Another aspect is R 4 However, hydroxy, C 1-8 Alkyl, C 1-8 Alkenil, C 2-8 Alkinyl or thiocarbonyl, C 1-8 Alkyl is halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, Carboxy, C 3-8 Cycloalkyl, C 3-8 It is substituted with one, two, or three substituents independently selected from cycloalkenyl, heteroaryl, or heterocyclyl compounds, C 1-8 Alkenyls are halo, hydroxy, C 1-8 Alkoxycarbonyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkyl or heterocyclyl groups, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo, the heteroaryl may be selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heterocyclyl may be selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members or a polycyclic ring having 13 to 16 ring members, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A R may be substituted with substituents, 4A However, oxo, C 1-8 It includes compounds of formula (I) that are alkyl, thiocarbonyl, or hydroxyl.

[0028] Another aspect is R 4 However, C is selected from methyl, ethyl, propyl, butyl, isobutyl, pentyl, or (2-methyl)butyl.1-8 Alkyl; C selected from ethanol-1-en-1-yl, propane-2-en-1-yl, butane-3-en-1-yl, isobutane-1-en-1-yl, hexane-3-en-1-yl, (2-methyl)propane-2-en-1-yl, (2-methyl)butane-3-en-1-yl, or (2,6-dimethyl)hepta-5-en-1-yl 1-8 Alkenyl; or C selected from prop-2-in-1-yl or but-3-in-1-yl 2-8 It is an alkynyl and may be substituted C 1-8Alkyl compounds include (2-oxo)propa-1-yl, (2,2-difluoro)ethyl-1-yl, (2,2,2-trifluoro)ethyl-1-yl, [(3-fluoro)(2-methyl)]propa-1-yl, [(6-chloro)(2,6-dimethyl)]hepta-1-yl, [(3,3,3-trifluoro)(2-methyl)]propa-1-yl, (2-cyano)ethyl-1-yl, (2-cyano)propa-1-yl, [(2-hydroxy)(3-cyano)]propa-1-yl, [(2-hydroxy) (Loxy)(4-cyano)]buta-1-yl, (2-methoxy)propa-1-yl, (3-methoxy)buta-1-yl, (2,2-dimethoxy)ethal-1-yl, [3-(methoxy)-2-(methoxymethyl)]propa-1-yl, (2-methoxycarbonyl)ethal-1-yl, (2-methoxycarbonyl)propa-1-yl, (3-methoxycarbonyl)propa-1-yl, (4-methoxycarbonyl)buta-1-yl, (3-methoxycarbonyl)isobuta-1-yl, (5 (2-Methoxycarbonyl)penta-1-yl, (2-Ethoxycarbonyl)etha-1-yl, (2,2-Diethoxycarbonyl)etha-1-yl, (2-Methoxycarbonyl)propa-1-en-1-yl, (3-Methoxycarbonyl)propa-2-en-1-yl, (2-Aminocarbonyl)propa-1-yl, (3-Aminocarbonyl)propa-1-yl, (4-Aminocarbonyl)buta-1-yl, (5-Aminocarbonyl)penta-1-yl, [(2-Methyl)(3-A Minocarbonyl)propa-1-yl, (2,3-dimethylcarbonyloxy)propa-1-yl, (2-hydroxy)propa-1-yl, (3-hydroxy)propa-1-yl, (2-hydroxy)buta-1-yl, (4-hydroxy)buta-1-yl, (2-hydroxy)isobuta-1-yl, (5-hydroxy)penta-1-yl, (6-hydroxy)hexa-1-yl, (2,3-dihydroxy)propa-1-yl, (2,4-dihydroxy)buta-1-yl, (3,4-dihydroxy)buta-1-yl, (2-hydroxymethyl)propa-1-yl, [(1-hydroxy)(2-methyl)]propa-1-yl, [(2-hydroxy)(2-methyl)]propa-1-yl, [(4-hydroxy)(2-methyl)]buta-1-yl, [(5-hydroxy)(2-methyl)]penta-1-yl, [(6-hydroxy)(2,6-dimethyl)]hepta-1-yl, [(5,6-dihydroxy)(2,6-dimethyl)]hepta-1-yl Buta-1-yl, [(3-hydroxy){(2-hydroxy)methyl}]propa-1-yl, [(3-methoxy)(2-hydroxy)]propa-1-yl, [(4-methoxy)(2-hydroxy)]buta-1-yl, [(3-methylcarbonyloxy)(2-hydroxy)]propa-1-yl, (5-carboxy)penta-1-yl, (cyclopentenyl)methyl, (cyclopenta-2-enyl)methyl, (oxetan-2-yl)methyl, (P (Loridine-3-yl)methyl, (Tetrahydrofuran-2-yl)methyl, (Tetrahydrofuran-3-yl)methyl, (Piperidine-3-yl)methyl, (Piperidine-4-yl)methyl, (2-Oxo-piperidine-3-yl)methyl, (Tetrahydro-2H-pyran-2-yl)methyl, (Tetrahydro-2H-pyran-3-yl)methyl, (Tetrahydro-2H-pyran-4-yl)methyl, (1,4-Dioxan-2-yl)methyl, (1,3-dioxan-2-yl)methyl, (1,3-dioxan-4-yl)methyl, (1,3-dioxan-5-yl)methyl, (1,3-dioxolan-2-yl)methyl, (1,3-dioxolan-4-yl)methyl, (1,3-dioxan-2-on-5-yl)methyl, (3,6-dihydro-2H-pyran-2-yl)methyl, or (3,6-dihydro-2H-pyran-3-yl)methyl; C may be selected and substituted from these. 1-8The compound comprises a compound of formula (I) in which the alkenyl is selected from (3-difluoro(diflouro))propa-2-en-1-yl, (2-hydroxymethyl)propa-1-en-1-yl, [(3-hydroxy)(2-hydroxymethyl)]propa-1-en-1-yl, (2-methoxycarbonyl)propa-1-en-1-yl, (3-methoxycarbonyl)propa-2-en-1-yl, (cyclohexylidene)methyl, or (oxan-4-ylidene)methyl.

[0029] Another aspect is R 5 The heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has 1, 2, or 3 R 5A This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5 The heteroaryl is selected from a monocyclic ring having 5 or 6 ring members, and the heteroaryl has 1, 2, or 3 R 5A This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5 However, the heteroaryl is selected from oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, pyridinyl, or pyrimidinyl, and the heteroaryl has 1, 2, or 3 R 5A This includes compounds of formula (I), which may be substituted with substituents.

[0030] Another aspect is R 5 However, the heteroaryl is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3,4-2H-tetrazolyl, pyridinyl, or pyrimidinyl, wherein the heteroaryl has 1, 2, or 3 R 5A This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5However, the heteroaryl is selected from 1,2,4-oxadiazole-3-yl, 1,3,4-oxadiazole-2-yl, 1,2,4-thiadiazole-5-yl, 1,3,4-thiadiazole-2-yl, 1,2,4-triazine-3-yl, 1,3,5-triazine-2-yl, 1,2,3,4-2H-tetrazol-5-yl, pyridine-2-yl, pyrimidine-2-yl, or pyrimidine-4-yl, wherein the heteroaryl has 1, 2, or 3 R 5A This includes compounds of formula (I), which may be substituted with substituents.

[0031] Another aspect is R 5A However, halo, cyano, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 Selected from alkoxy or heterocyclyl, C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo, and the heterocyclyl may be selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, and the heterocyclyl may have one or two R 5B This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5A The compound comprises a compound of formula (I), which is a halo selected from fluoro or chloro.

[0032] Another aspect is R 5A However, C selected from methyl, ethyl, difluoromethyl, or trifluoromethyl 1-8 It contains a compound of formula (I) that is alkyl. Another aspect is R 5A However, C is selected from methylthio. 1-8 It contains a compound of formula (I) which is alkylthio. Another aspect is R 5A However, C selected from methoxy or difluoromethoxy 1-8It contains compounds of formula (I) that are alkoxy. Another aspect is R 5A The heterocyclyl is selected from a monocyclic ring having 3 to 7 ring members, and the heterocyclyl has 1 or 2 R 5B This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5A However, the heterocyclyl is selected from piperazinyl or morpholinil, and the heterocyclyl has 1 or 2 R 5B This includes compounds of formula (I), which may be substituted with substituents.

[0033] Another aspect is R 5A However, the heterocyclyl is selected from piperazine-1-yl or morpholine-4-yl, and the heterocyclyl is one R 5B This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5A The compound is selected from fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methylthio, methoxy, piperazine-1-yl, or morpholine-4-yl, where piperazine-1-yl or morpholine-4-yl each has one R 5B This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5B However, halo, hydroxy, cyano, oxo, C 1-8 Alkyl, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 Selected from alkoxy or thiocarbonyl, C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The compound comprises a compound of formula (I) in which the alkoxy may be substituted with one, two, or three substituents independently selected from the halo. Another aspect is R 5B C 1-8 The compound comprises a compound of formula (I) selected from alkyl groups. Another aspect is R 5BHowever, C is selected from methyl 1-8 It contains a compound of formula (I) that is alkyl.

[0034] Another aspect is R 5 The heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has 1, 2, or 3 R 5A R may be substituted with substituents, 5A However, halo, cyano, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 It is an alkoxy or heterocyclyl, and C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo, and the heterocyclyl may be selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 to 8 ring members, or a polycyclic ring having 13 to 16 ring members, and the heterocyclyl may have one or two R 5B R may be substituted with substituents, 5B However, halo, hydroxy, cyano, oxo, C 1-8 Alkyl, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 It is an alkoxy or thiocarbonyl, and C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The compound comprises a compound of formula (I) in which the alkoxy may be substituted with one, two, or three substituents independently selected from the halo.

[0035] Another aspect is R 5 The heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has 1, 2, or 3 R 5A R may be substituted with substituents, 5A However, halo, cyano, C 1-8Alkyl, C 1-8 Alkylthio, C 1-8 It is an alkoxy or heterocyclyl, and C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo, and the heterocyclyl may be selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, and the heterocyclyl may have one or two R 5B R may be substituted with substituents, 5B C 1-8 It is alkyl, C 1-8 The compound comprises a compound of formula (I) in which the alkyl group may be substituted with one, two, or three substituents independently selected from the halo.

[0036] Another aspect is R 5 The heteroaryl is selected from a monocyclic ring having 5 or 6 ring members, and the heteroaryl has 1, 2, or 3 R 5A This includes compounds of formula (I), which may be substituted with substituents. Another aspect is R 5 However, the heteroaryl is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3,4-2H-tetrazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, or pyrimidinyl, wherein the heteroaryl has 1, 2, or 3 R 5A R may be substituted with substituents, 5A The compound is fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methylthio, methoxy, piperazinyl, or morpholinyl, and piperazinyl and morpholinyl each have one R 5B R may be substituted with substituents, 5B However, C is selected from methyl 1-8 It contains a compound of formula (I) that is alkyl.

[0037] Another aspect is R 5 The heteroaryl is selected from 1,2,4-oxadiazole-3-yl, 1,3,4-oxadiazole-2-yl, 1,2,4-thiadiazole-5-yl, 1,3,4-thiadiazole-2-yl, 1,2,3,4-2H-tetrazol-5-yl, 1,2,4-triazine-3-yl, 1,3,5-triazine-2-yl, pyridine-2-yl, pyrimidine-2-yl, or pyrimidine-4-yl, wherein the heteroaryl is selected from a monocyclic ring having 5-8 ring members or a bicyclic ring having 9-10 ring members, and the heteroaryl has 1, 2, or 3 R 5A R may be substituted with substituents, 5A The compound is fluoro, chloro, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methylthio, methoxy, piperazine-1-yl, or morpholine-4-yl, where piperazine-1-yl and morpholine-4-yl each have one R 5B R may be substituted with substituents, 5B However, C is selected from methyl 1-8 It contains a compound of formula (I) that is alkyl.

[0038] Another embodiment includes a compound of formula (I) in which the form of the compound is selected from the group consisting of its free acid, free base, salt, hydrate, solvate, anhydride, racemate, enantiomer, diastereomer, stereoisomer, and tautomer. The compound of formula (I) or the form thereof is,

[0039] [Table 1] TIFF2026524862000005.tif237153 TIFF2026524862000006.tif232153 TIFF2026524862000007.tif227153 TIFF2026524862000008.tif226153 TIFF2026524862000009.tif225153 TIFF2026524862000010.tif217154 TIFF2026524862000011.tif209158 TIFF2026524862000012.tif227158 TIFF2026524862000013.tif216153 TIFF2026524862000014.tif206158 TIFF2026524862000015.tif232158 TIFF2026524862000016.tif220158 TIFF2026524862000017.tif225156 TIFF2026524862000018.tif226156 TIFF2026524862000019.tif226158 TIFF2026524862000020.tif226158 TIFF2026524862000021.tif228153 TIFF2026524862000022.tif228154 TIFF2026524862000023.tif230154 TIFF2026524862000024.tif228153 TIFF2026524862000025.tif218153 TIFF2026524862000026.tif230153 TIFF2026524862000027.tif229153 TIFF2026524862000028.tif218153 TIFF2026524862000029.tif229153 TIFF2026524862000030.tif227153 TIFF2026524862000031.tif228153 TIFF2026524862000032.tif231153 TIFF2026524862000033.tif227153 TIFF2026524862000034.tif237153 TIFF2026524862000035.tif229153 TIFF2026524862000036.tif223153 TIFF2026524862000037.tif117153 The compound comprises a compound selected from the group consisting of the following, and the form of the compound is selected from the group consisting of its free acid, free base, salt, hydrate, solvate, anhydride, racemic mixture, enantiomer, diastereomer, stereoisomer, and tautomer. The compound of formula (I) or the form thereof is,

[0040] [Table 2] TIFF2026524862000039.tif237153 TIFF2026524862000040.tif221153 TIFF2026524862000041.tif227153 TIFF2026524862000042.tif205153 TIFF2026524862000043.tif210153 TIFF2026524862000044.tif220153 TIFF2026524862000045.tif215153 TIFF2026524862000046.tif211153 TIFF2026524862000047.tif190153 TIFF2026524862000048.tif184153 TIFF2026524862000049.tif225153 TIFF2026524862000050.tif225153 TIFF2026524862000051.tif210153 TIFF2026524862000052.tif205153 TIFF2026524862000053.tif205153 TIFF2026524862000054.tif204153 TIFF2026524862000055.tif200153 TIFF2026524862000056.tif206153 TIFF2026524862000057.tif185153 TIFF2026524862000058.tif212153 TIFF2026524862000059.tif211153 TIFF2026524862000060.tif227153 TIFF2026524862000061.tif232153 TIFF2026524862000062.tif232153 TIFF2026524862000063.tif168153 It includes a compound (Cpd) selected from the group consisting of ( 1 The compound number indicates that the compound was isolated in salt form. The form of the compound is selected from the group consisting of its free acid, free base, salt, hydrate, solvate, anhydride, racemate, enantiomer, diastereomer, stereoisomer, and tautomer.

[0041] One embodiment provided herein is a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharmaceutically acceptable excipient. One aspect provided herein is the use of a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, for treating or improving a disease or disorder by inhibiting dihydroorotate dehydrogenase. Another aspect provided herein is the use of a compound of formula (I) or a form thereof to treat or improve a disease or disorder by inhibiting dihydroorotate dehydrogenase. Another aspect provided herein is the use of a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and pharmaceutically acceptable excipients, for treating or improving a disease or disorder by inhibiting dihydroorotate dehydrogenase.

[0042] One embodiment provided herein is a method of using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, for treating or improving a disease or disorder in a subject requiring such treatment, the method of use comprising administering an effective amount of the compound of formula (I), or a form thereof, or a pharmaceutical composition thereof to the subject to inhibit dihydroorotate dehydrogenase. Another embodiment provided herein is a method of using a compound of formula (I) or a form thereof for treating or improving a disease or disorder in a subject requiring it, the method of use comprising administering an effective amount of the compound of formula (I) or a form thereof to the subject to inhibit dihydroorotate dehydrogenase. Another embodiment provided herein is a method of use of a pharmaceutical composition comprising a compound of formula (I) or a form thereof and a pharmaceutically acceptable excipient for treating or improving a disease or disorder in a subject requiring such treatment, the method comprising administering an effective amount of the pharmaceutical composition to the subject to inhibit dihydroorotate dehydrogenase.

[0043] definition Chemical terms used above and throughout this specification will be understood by those skilled in the art to have the meanings set forth below, unless otherwise specifically defined.

[0044] As used herein, the term "C 1-4 "Alkyl", "C 1-6 "Alkyl" or "C 1-8 "Alkyl" generally refers to saturated hydrocarbon groups having 1 to 8 carbon atoms in a linear or branched configuration, including but not limited to methyl, ethyl, n-propyl (also called propyl or propanyl), isopropyl, n-butyl (also called butyl or butanil), isobutyl, sec-butyl, tert-butyl, n-pentyl (also called pentyl or pentanyl), n-hexyl (also called hexyl or hexanil), n-heptyl (also called heptyl or heptanil), and n-octyl (also called octyl or octanil). 1-4 Alkyl, C 1-6 Alkyl, or C1-8 The alkyl group may be substituted with substituent species as described herein, where possible due to available valence. As used herein, the term "C 1-4 Alkenil, "C 1-6 "Alkenil" or "C 1-8 "Alkenyl" generally refers to a partially unsaturated hydrocarbon group having 2 to 8 carbon atoms and one or more carbon-carbon double bonds in a linear or branched configuration, including, but not limited to, methylidene, ethenyl (also called vinyl), allyl, propenyl, etc. 1-4 Alkenil, C 1-6 Alkenyl, or C 1-8 The alkenyl group may be substituted with substituent species as described herein, where possible due to available valence.

[0045] As used herein, the term "C 2-4 Alkinyl, C 2-6 "Alkinyl" or "C 2-8 "Alkynyl" generally refers to a partially unsaturated hydrocarbon group having 2 to 8 carbon atoms and one or more carbon-carbon triple bonds in a linear or branched configuration, including, but not limited to, ethynyl and propynyl. 2-4 Alkinyl, C 2-6 Alkinyl, or C 2-8 The alkynyl group may be substituted with substituent species as described herein, where possible due to available valencies. As used herein, the term "C 1-4 "alkoxy", "C 1-6 "alkoxy" or "C 1-8 "Alkoxy" generally refers to a compound having 1 to 8 carbon atoms in a linear or branched configuration, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., with the formula: -OC. 1-4 Alkyl, -OC 1-6 Alkyl, -OC 1-8 This refers to an alkyl saturated hydrocarbon group.1-4 Alkoxy, C 1-6 Alkoxy, C 1-8 The alkoxy group may be substituted with substituent species as described herein, where possible due to available valence.

[0046] As used herein, the term "C 3-8 "Cycloalkyl" generally refers to saturated monocyclic, bicyclic, or polycyclic hydrocarbon ring groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In certain embodiments, C 3-8 Cycloalkyls are not limited to these, but include C3 cycloalkyls, C4 cycloalkyls, and C 5-6 Includes cycloalkyls, etc. 3-8 The cycloalkyl ring group may be substituted with substituent species as described herein, where possible due to available valence. As used herein, the term "(C 3-8 Cycloalkyl)C 1-8 "Alkyl" is defined by the formula: -C 1-8 Alkyl-C 2-8 It refers to a cycloalkyl group. In certain embodiments, (C 3-8 Cycloalkyl)C 1-8 Alc is not limited to this, but (C 3-8 Contains cycloalkyl(methyl)methyl, etc. (C 3-8 Cycloalkyl)C 1-8 C of alkyl 3-8 The cycloalkyl moiety may be substituted with substituent species as described herein, where possible due to available valencies.

[0047] As used herein, the term "C 3-8 "Cycloalkenyl" generally refers to a partially unsaturated monocyclic, bicyclic, or polycyclic hydrocarbon ring group, including, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. In certain embodiments, C 3-8Cycloalkenyls are not limited to these, but include C3 cycloalkenyls, C4 cycloalkenyls, and C 5-6 Includes cycloalkenyls, etc. 3-8 The cycloalkenyl ring group may be substituted with substituent species as described herein, where possible due to available valencies.

[0048] As used herein, the term “aryl” generally refers to monocyclic, bicyclic, or polycyclic aromatic carbon atom ring groups, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azlenyl, and phenantrenyl. In certain embodiments, the aryl monocyclic or bicyclic ring group is phenyl or naphthyl, respectively. The aryl ring group may be substituted with substituent species as described herein, where possible due to available valences.

[0049] As used herein, the term "heteroaryl" generally refers to an aromatic ring system selected from monocyclic rings having 5 or 6 ring members or bicyclic rings having 9 or 10 ring members, where the ring members are independently selected from C (carbon), N (nitrogen), O (oxygen), or S (sulfur), and one or more ring members may be selected from one or more N, O, or S, where structural stability allows, and the remaining ring members are selected from C. In certain embodiments, the heteroaryl ring system group may be substituted with one, two, or three substituents on the C or N ring member, where available valence allows. In certain embodiments, the term "heteroaryl" may refer to a monocyclic ring having 5 to 8 ring members or a bicyclic ring having 9 to 10 ring members, where the heteroaryl may be substituted with one, two, or three substituents, where available valence allows.

[0050] In certain embodiments, heteroaryl groups may include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, 1,2,3,4-2H-tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridadinyl, triazinyl, indolyl, indazolyl, indolidinyl, isoindolyl, and other cyclic groups. In certain aspects, the nomenclature of heteroaryl groups may differ, as in the non-restrictive examples, that furanyl may also be called furyl, thienyl may also be called thiophenyl, and pyridinyl may also be called pyridyl.

[0051] In certain embodiments, terms relating to heteroaryl groups may include, for example, the term pyrrolyl may include 1H-pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, etc.; the term pyrazolyl may include 1H-pyrazolyl, etc.; the term imidazolyl may include 1H-imidazolyl, etc.; the term triazolyl may include 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, etc.; the term oxadiazolyl may include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc.; the term thiadiazolyl may include 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, etc. The terms may include: the term tetrazolyl may include 1H-tetrazolyl, 2H-tetrazolyl, 1,2,3,4-2H-tetrazolyl, etc.; the term indol may include 1H-indolly, etc.; the term indazolyl may include 1H-indazolyl, 2H-indazolyl, etc.; the term triazinyl may include 1,2,4-1H-triazinyl, 1,3,5-1H-triazinyl, 2,4,6-1H-triazinyl, etc.; the term benzimidazolyl may also include 1H-benzimidazolyl; and the term prinyl may also include 9H-prinyl, etc., as is an example of a non-restrictive definition, other positional isomers may also be included.

[0052] As used herein, the term “heterocyclyl” generally refers to a saturated or partially unsaturated monocyclic ring system having 3 to 7 ring members, a bicyclic ring system having 6 to 10 ring members, a bicyclic ring system having 7 or 8 ring members, or a polycyclic ring system having 13 to 16 ring members, where the ring members are independently selected from C (carbon), N (nitrogen), O (oxygen), or S (sulfur), and one or more ring members may be selected from one or more N, O, or S where structural stability allows, and the remaining ring members are selected from C. In certain embodiments, the heterocyclyl ring system group may be substituted with one, two, or three substituents on the C or N ring member where available valence allows.

[0053] In certain embodiments, the term “heterocyclyl” may refer to a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, and the heterocyclyl may be substituted with 1, 2, or 3 substituents, where available valences allow.

[0054] In certain aspects, heterocyclyl groups are not limited to these, but include oxyranil, oxetanil, azetidinil, tetrahydrofuranil, pyrrolinil, pyrrolidinil, pyrazolinil, pyrazolidinil, imidazolinil, imidazolidinil, isoxazolinil, isoxazolidinil, isothiazolinil, isothiazolidinil, oxazolinil, oxazolidinil, thiazolinil, thiazolidinil, triazolinil, triazolidinil, oxadiazolinil, oxadiazolidinil, thiadiazolinil, thiadiazolidinil, tetrazolinil, tetra Zolidinyl, pyranil, 2H-pyranil, dihydro-2H-pyranil, tetrahydro-2H-pyranil, thiopyranil, 1,3-dioxanil, 1,4-dioxanil, 1,3-dioxolanil, 1,2,5,6-tetrahydropyridinil, 1,2,3,6-tetrahydropyridinil, piperidinil, piperazinil, morpholinil, thiomorpholinil, 1,4-diazepanil, 1,3-benzodioxolyl, 1,4-benzodioxanil, 2,3-dihydro-1,4-benzodioxynil, hexahydropyrrolo-[3,4-b]pyrrole-(1H)-yl, ( 3aS,6aS)Hexahydropyrrolo-[3,4-b]pyrrole-(1H)-yl, (3aR,6aR)Hexahydropyrrolo[3,4-b]pyrrole-(1H)-yl,Hexahydropyrrolo-[3,4-b]pyrrole-(2H)-yl, (3aS,6aS)Hexahydropyrrolo-[3,4-b]pyrrole-(2H)-yl, (3aR,6aR)Hexahydropyrrolo-[3,4-b]pyrrole-(2H)-yl,Hexahydropyrrolo-[3,4-c]pyrrole-(1H)-yl, (3aR,6aS)Hexahydropyrrolo-[3,4-c]pyrrole-(1H) -yl, (3aR,6aR)hexahydropyrrolo-[3,4-c]pyrrole-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazine-(1H)-yl, (7R,8aS)hexahydropyrrolo-[1,2-a]pyrazine-(1H)-yl, (8aS)hexahydropyrrolo-[1,2-a]pyrazine-(1H)-yl, (8aR)hexahydropyrrolo-[1,2-a]pyrazine-(1H)-yl, (8aS)octahydropyrrolo-[1,2-a]pyrazine-(1H)-yl, (8aR)octahydropyrrolo-[1,2-a]pyrazine-(1H)-yl, hexahydropyrrolo-[1,2-a]pyrazine-(2H)-one, octahydro-2H-pyrido[1,2-a]pyradinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S) -3-azabicyclo[3.1.0]hexyl, 3-oxa-8azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octa-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]octa-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-dia Zabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanyl, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diaza It may contain cyclic groups such as bicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, 4,7-diazaspiro[2.5]-octanyl, azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, and 6,9-diazaspiro[4.5]decyl.

[0055] In certain embodiments, heterocyclyl groups may include, for example, the term pyranyl may include 2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-pyranyl, oxanyl, etc.; the term tetrahydrofuranyl may also include oxolanil, etc.; the term 1,3-dioxolanil may also include 1,3-dioxanil; the term triazolyl may also include 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1,2,4-triazolyl, etc.; the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, etc.; the term thiadiazolyl may also include 1,2,4- This may include thiadiazolyl, 1,3,4-thiadiazolyl, etc.; the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl, 1,2,3,4-2H-tetrazolyl, etc.; the term indolyl may also include 1H-indolyl, etc.; the term indazolyl may also include 1H-indazolyl, 2H-indazolyl, etc.; the term triazinyl may also include 1H-1,2,4-triazinyl, 1H-2,4,6-triazinyl, etc.; the term benzimidazolyl may also include 1H-benzimidazolyl; the term prinyl may also include 9H-prinyl, etc. Other positional isomers, including non-restrictive examples, may also be included.

[0056] As used herein, the term "C 1-8 "(C) 1-8 (alkoxycarbonyl) or "(C 1-8 The "alkoxy)carbonyl" is represented by the formula: -C(=O)-OC 1-8 Refers to an alkyl group. In certain embodiments, C 1-8 Alkoxycarbonyls include, but are not limited to, methoxycarbonyls. As used herein, the term "C 1-8 "Alkylcarbonyloxy" is represented by the formula: -OC(=O)-C 1-8 Refers to an alkyl group. In certain embodiments, C 1-8 Alkylcarbonyloxys include, but are not limited to, methylcarbonyloxys. As used herein, the term "C 1-8 "Alkylthio" is defined by the formula: -SC 1-8Refers to the alkyl group. 1-8 Alkylthio includes, but is not limited to, methylthio and others. As used herein, the term "aminocarbonyl" refers to the group of the formula: -C(=O)-NH2.

[0057] As used herein, the term "carbonyl" refers to a group of the formula -C(=O)-, where C(=O) is a bonded structure in which an additional atom is bonded to a carbon atom. As used herein, the term "carboxyl" refers to the group of the formula: -C(=O)-OH. As used herein, the term "cyano" refers to a group of the formula -C≡N or -CN. As used herein, the term "halo" or "halogen" generally refers to halogen atomic groups, including fluoro, chloro, bromo, and iodine. As used herein, the term "hydroxy" refers to the group of the formula: -OH. As used herein, the term "nitro" refers to the group of formula :-NO2. As used herein, the term "oxo" refers to the base of the formula :=O. As used herein, the term "thiocarbonyl" refers to the group of the formula: -C(=S)-.

[0058] As used herein, the term “substituent” means a position-variable group on an atom of a core molecule that replaces one or more hydrogens on a specified atom, substituted at a specified atomic position, provided that the substitution does not exceed the normal valence of the specified atom and that the substitution results in a stable compound. Combinations of substituents and / or variable groups are permitted only if such combinations result in a stable compound. Those skilled in the art should note that any carbon and heteroatom having a valence that appears to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atoms to satisfy the described or shown valence. In certain examples, one or more substituents having a double bond (e.g., “oxo” or “=O”) as a bonding site may be described, shown or enumerated within a group of substituents herein, and the structure may only show a single bond as a bonding site to the core structure of formula (I). Those skilled in the art will understand that although only a single bond is shown, a double bond is intended for those substituents.

[0059] As used herein, with respect to the definitions of chemical terms provided herein, the term “etc.” means, but is not limited to, all other variations that result in a stable compound, if possible by means of isomers (including chain, branched, or regioisomers), hydration of cyclic systems (including saturation or partial unsaturation of monocyclic, bicyclic, or polycyclic cyclic structures), and available valences. For the purposes of this specification, if a compound of formula (I) or one or more substituted variable groups of the same form includes a functional group incorporated into the compound of formula (I), each functional group appearing at any position in the disclosed compound may be independently selected and may be independently and / or optionally substituted as appropriate. As used herein, the terms “independently selected” or “each selected” refer to a functional variable group in the list of substituents that may appear more than once on the structure of formula (I), and the substitution pattern in each occurrence is independent of the pattern in any other occurrence. Furthermore, the use of a substituted variable group in any formula or structural genus of the compounds described herein includes the substitution of a genus substituent with a species substituent contained within a particular genus, for example, aryl may be replaced with phenyl or naphthalenyl, and the resulting compound is understood to fall within the range of compounds described herein. As used herein, the term “may be substituted” means any substitution at the specified substituted variable group, group, radical or part.

[0060] Form of compounds As used herein, the term “form” means a compound of formula (I) having a form selected from the group consisting of its free acid, free base, salt, hydrate, solvate, anhydride, racemate, enantiomer, diastereomer, stereoisomer, and tautomer. In certain embodiments described herein, the compound of formula (I) is in the form of its free acid, free base, or salt. In certain embodiments described herein, the compound of formula (I) is in the form of a salt thereof. In certain embodiments described herein, the compound of formula (I) is in the form of its hydrate, solvate, or anhydrous form. In certain embodiments described herein, the form of the compound of formula (I) is its stereoisomer, racemate, enantiomer, or diastereomer. In certain embodiments described herein, the form of the compound of formula (I) is its tautomer. In certain embodiments described herein, the form of the compound of formula (I) is a pharmaceutically acceptable form. In certain embodiments described herein, the compound of formula (I) or a form thereof is isolated for use.

[0061] As used herein, the terms “dihydroorotate dehydrogenase inhibition” or “DHODH inhibition” refer to the inhibition of pyrimidine synthesis via the de novo pathway in the presence of a DHODH inhibitor, such as the compounds disclosed herein.

[0062] As used herein, the term “isolated” means a compound of formula (I) or the physical state of its form after it has been isolated and / or purified from a synthetic process (e.g., from a reaction mixture) or a natural source or a combination thereof, to a purity sufficient to be characterized by standard analytical techniques described herein or known to those skilled in the art, according to one or more isolation or purification processes (e.g., chromatography, recrystallization) described herein or known to those skilled in the art.

[0063] As used herein, the term “protected” means that, when the compound is subjected to a reaction, the functional group in the compound of formula (I) or its form is modified so that undesirable side reactions do not occur at the protected site. Suitable protecting groups are recognized by those skilled in the art and by referring to standard textbooks such as, for example, TW Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino, and carboxylic acids. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, etc. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl, aryl, or arylalkyl esters. In certain cases, the protecting group may also be a polymer resin such as Wang resin or 2-chlorotrityl chloride resin. Protecting groups are well known to those skilled in the art and can be added or removed according to standard techniques such as those described herein. It will also be understood by those skilled in the art that such protected derivatives of the compounds described herein may not have pharmacological activity themselves, but may be administered to a subject and subsequently metabolized in the body to form the pharmacologically active compounds described herein. Thus, such derivatives may be described as “prodrugs.” All prodrugs of the compounds described herein are included within the scope of use described herein.

[0064] As used herein, the term “prodrug” means the compound of formula (I) or a form of the compound (e.g., a drug precursor) that is converted in vivo to produce the active form thereof. Conversion may occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), such as hydrolysis and / or metabolism in the blood, liver, and / or other organs and tissues. Considerations of the use of prodrugs are provided in T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0065] In one example, if the compound of formula (I) or a form thereof contains a carboxylic acid functional group, the prodrug may include an ester formed by the substitution of a hydrogen atom of an acidic group with a functional group such as an alkyl group. In another example, if the compound of formula (I) or a form thereof contains a hydroxyl functional group, the prodrug form may be prepared by substituting the hydrogen atom of the hydroxyl group with another functional group such as an alkyl, alkylcarbonyl, or phosphonic acid ester. In yet another example, if the compound of formula (I) or a form thereof contains an amine functional group, the prodrug form may be prepared by substituting one or more amine hydrogen atoms with a functional group such as an alkyl or substituted carbonyl group. Pharmacokinetically acceptable prodrugs of the compounds of formula (I) or a form thereof include, where appropriate, those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonic acid esters, amino acid esters, phosphonic acid esters, and monophosphate, diphosphate, or triphosphate esters, or alkyl substituents. As described herein, it will be understood by those skilled in the art that one or more of such substituents may be used to provide the compounds of formula (I) or a form thereof as a prodrug.

[0066] One or more compounds described herein may exist in a non-solvated form and in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol, and the description herein is intended to encompass both solvated and non-solvated forms. As used herein, the term “solvate” means the physical association of a compound described herein with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain examples, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. As used herein, “solvate” encompasses both the solution phase and the isolateable solvate. Non-limiting examples of suitable solvates include ethanolates, methanelates, and the like. As used herein, the term “hydrate” means a solvate in which the solvent molecule is water. As used herein, the term “anhydrous” means one or more compounds in a crystalline form that does not contain water.

[0067] Compounds of formula (I) may form salts intended to be included within the scope of this specification. References to compounds of formula (I) or forms thereof in this specification are understood to include references to their salt forms unless otherwise indicated. The term “salt,” as used herein, refers to acidic salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, if a compound of formula (I) or form thereof contains both a basic moiety, such as an amine moiety, and an acidic moiety, such as a carboxylic acid, but not limited to these, zwitterions (“intramolecular salts”) may be formed and are included in the term “salt” as used herein.

[0068] The term “pharmaceutically acceptable salt” as used herein means a salt of a compound described herein that is safe and effective for use in mammals (i.e., physiologically acceptable) and has biological activity, although other salts are also useful. Salts of the compound of formula (I) can be formed, for example, by reacting the compound of formula (I) or a form thereof in a medium such as a medium on which the salt precipitates, or in an aqueous medium, with a certain amount of acid or base, for example, an equivalent amount, followed by freeze-drying. pharmaceutically acceptable salts include salts of one or more acidic or basic groups present in the compounds described herein. Specific embodiments of acid addition salts include, but are not limited to, acetates, ascorbic acid salts, benzoates, benzenesulfonates, bisulfates, bitartrates, borates, bromides, butyrates, chlorides, citrates, camphorates, camphor sulfonates, ethanesulfonates, formates, fumarates, gentisinates, glucons, glucaroneates, glutamates, iodides, isonicotinates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, pamoates, pantothenates, phosphates, propionates, sugarates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), trifluoroacetates, and the like. Certain embodiments of acid addition salts include chlorides, bromides, or dichlorides.

[0069] In addition, acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York, and in The Orange Book (Food & Drug Administration, Washington, DC, on their websites). These disclosures are incorporated herein by reference. Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, and zinc salts. All such acidic and basic salts are intended to fall within the range of pharmaceutically acceptable salts as described herein. In addition, all such acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of this specification. Compounds of formula (I) and their forms may also exist in tautomerized forms. All such tautomerized forms are intended and intended to fall within the range of compounds of formula (I) or their forms as described herein. The compound of formula (I) or its form may contain asymmetric or chiral centers and therefore may exist in different stereoisomers. This specification is intended to include all stereoisomers of the compound of formula (I) and mixtures thereof, including racemic mixtures.

[0070] The compounds described herein may contain one or more chiral centers and may therefore exist as racemic mixtures (R / S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (if one chiral center is present). In one particular embodiment, the compounds described herein are (S) isomers and may exist as an enantiomerically pure composition containing substantially only (S) isomers. In another particular embodiment, the compounds described herein are (R) isomers and may exist as an enantiomerically pure composition containing substantially only (R) isomers. As those skilled in the art will recognize, if more than one chiral center is present, the compounds described herein may also exist as (R,R), (R,S), (S,R), or (S,S) diastereomer isomers or mixtures of isomers, as defined by the IUPAC Nomenclature Recommendation.

[0071] As used herein, the term “substantially pure” means a compound consisting of substantially a single isomer in amounts of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or an amount equal to 100% of a single isomer. In one aspect of this specification, a compound of formula (I) or a form thereof that is substantially a pure single isomer may exhibit stronger activity than other substantially pure isomers of the compound of formula (I) or a racemic mixture thereof. In another aspect of this specification, the compound of formula (I) or a form thereof is isolated as an enantiomer or diastereomer mixture, which may or may not be more active than a single isolated substantially pure enantiomer or diastereomer of the compound of formula (I).

[0072] In another aspect of this specification, the compound of formula (I) or a form thereof may be isolated as a diastereomer mixture (having four possible diastereomers SS, RS, RR, and SR), where each diastereomer in the mixture may have two chiral centers (each chiral center having two possible enantiomers: R or S). The diastereomers may also be isolated by a single chiral center to obtain a mixture of two diastereomers, where each diastereomer in the mixture may have one fixed chiral center and the other chiral center may have two possible enantiomers: R or S (i.e., an enantiomer-like diastereomer), and the mixture may or may not be more active than a single isolated substantially pure diastereomer of the compound of formula (I). In another aspect of this specification, the compound of formula (I) or a form thereof is isolated as a racemic mixture having a combination of diastereomers, comprising four possible enantiomers or two possible diastereomers, each of which mixtures may or may not be more active than a single isolated substantially pure enantiomer or diastereomer of the compound of formula (I).

[0073] As used herein, the term “racemate” refers to a 50 / 50 mixture of two compounds having asymmetrical mirror images. As used herein, the term “enantio-enriched” refers to a mixture of two asymmetrical enantiomers containing more than 50% of one of the pair of enantiomers. In one aspect of this specification, the compound of formula (I) or the form thereof is a substantially pure (S) enantiomer present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%. In one aspect of this specification, the compound of formula (I) or the form thereof is a substantially pure (R) enantiomer present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%. In one aspect of this specification, the compound of formula (I) or the form thereof is a substantially pure enantiomer or diastereomer present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100%.

[0074] In addition, this specification encompasses all geometric and positional isomers. For example, if the compound of formula (I) or its form incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are included within the scope of this specification. Diastereomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers and diastereomers can be separated by the use of a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Furthermore, some of the compounds of formula (I) may be atropisomers (e.g., substituted biaryls) and are considered part of this specification.

[0075] All stereoisomers of the compound (e.g., geometric isomers, optical isomers, etc.) (including salts, solvates, esters, and prodrugs of the compound, and salts, solvates, and esters of prodrugs), including enantiomers (which may even exist in the absence of a chiral carbon), rotational isomers, atropisomers, and diastereomers, which may exist due to a chiral carbon on various substituents, such as positional isomers (e.g., 4-pyridyl and 3-pyridyl), are intended within the scope of this specification. The individual stereoisomers of the compounds described herein may, for example, substantially not contain other isomers, or may exist as a racemic mixture as described above. The compounds of formula (I), as well as the polymorphic and amorphous forms of salts, solvates, hydrates, esters, and prodrugs of the compounds of formula (I), are further intended to be included herein.

[0076] Use of compounds Aspects of this specification relate to methods of use of the compound of formula (I) or a form thereof for treating or improving a disorder or condition by inhibiting dihydroorotate dehydrogenase (DHODH) in a subject requiring such treatment, comprising administering an effective amount of the compound of formula (I) or a form thereof to the subject. Another aspect provided herein is a method of treating a disease or disorder for which dihydroorotate dehydrogenase inhibition is suitable using the compound of formula (I), or a form thereof, or a pharmaceutical composition thereof. Another aspect provided herein is a method of treating a disease or disorder for which dihydroorotate dehydrogenase inhibition is suitable in a subject requiring such treatment, comprising administering an effective amount of the compound of formula (I), or a form thereof, or a pharmaceutical composition thereof to the subject.

[0077] In addition to its use as a monotherapy, this compound is useful in combination therapy with current standard drugs, exhibiting additive or synergistic activity with one or more known drugs. Combination therapies comprising the compounds described herein in combination with one or more known drugs may be used to treat disorders, regardless of whether the disorder is responsive to known drugs. Certain embodiments of this specification include the use of a compound or form thereof of formula (I) in combination therapy for treating a disorder or condition in a subject requiring it, which involves administering an effective amount of a compound or form thereof of formula (I) and an effective amount of one or more agents.

[0078] As used herein, the term “to treat” means to prevent the development of a disease, disorder, or condition in a person who is susceptible to a disease, disorder, or condition but has not yet been diagnosed with a disease, disorder, or condition. As used herein, the term “improve” means to inhibit a disease, disorder or condition, i.e., to halt its development, and / or to reduce a disease, disorder or condition, i.e., to cause a regression of the disease, disorder and / or condition. As used herein, the term “subject” refers to any animal or living organism that possesses the capacity for perception and voluntary movement and requires oxygen and organic food. In certain embodiments, the subject is a mammal or a warm-blooded vertebrate. In other embodiments, the subject is a human. As used herein, the term “patient” may be used interchangeably with “subject” and “human.” As used herein, the terms “effective dose” or “therapeutic effective dose” mean an amount of the compound of formula (I), or its form, composition, or pharmaceutical product, that achieves a target plasma concentration effective in treating or improving a disease or condition in question, as described herein, and thus produces the desired therapeutic, ameliorative, inhibitory, or preventive effect in a subject requiring it. In one embodiment, the effective dose may be the amount required to treat a disorder or condition in a subject or patient, more specifically in a human.

[0079] Dosage and administration One aspect provided herein is the use of a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, for treating or improving a disease or disorder by inhibiting dihydroorotate dehydrogenase. Another aspect provided herein is the use of a compound of formula (I) or a form thereof to treat or improve a disease or disorder by inhibiting dihydroorotate dehydrogenase. Another aspect provided herein is the use of a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and pharmaceutically acceptable excipients, for treating or improving a disease or disorder by inhibiting dihydroorotate dehydrogenase.

[0080] One embodiment provided herein is a method of using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, for treating or improving a disease or disorder in a subject requiring such treatment, the method of use comprising administering an effective amount of the compound of formula (I), or a form thereof, or a pharmaceutical composition thereof to the subject to inhibit dihydroorotate dehydrogenase. Another embodiment provided herein is a method of using a compound of formula (I) or a form thereof for treating or improving a disease or disorder in a subject requiring it, the method of use comprising administering an effective amount of the compound of formula (I) or a form thereof to the subject to inhibit dihydroorotate dehydrogenase. Another embodiment provided herein is a method of use of a pharmaceutical composition comprising a compound of formula (I) or a form thereof and a pharmaceutically acceptable excipient for treating or improving a disease or disorder in a subject requiring such treatment, the method comprising administering an effective amount of the pharmaceutical composition to the subject to inhibit dihydroorotate dehydrogenase. In one embodiment, a method of using a compound of formula (I) or a form thereof for treating or improving a disease or disorder in a subject requiring it, comprising administering an effective amount of the compound of formula (I) or a form thereof to the subject to inhibit dihydroorotate dehydrogenase, wherein the compound of formula (I), or a form thereof or a pharmaceutical composition thereof, can be administered to the subject requiring it by various routes in an amount that is beneficial or therapeutic.

[0081] In one embodiment, the route of administration is not limited to these, but includes oral, intravenous, intradermal, intrathecal, intramuscular, subcutaneous, nasal, inhalation, percutaneous, topical, permucosal, intracranial, epidural, and bursal. In another embodiment, the compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, may be administered orally to a subject in need of it, in an effective amount of the compound of formula (I), or a form thereof, for inhibiting dihydroorotate dehydrogenase, as provided herein. In another embodiment, the compound of formula (I), or its form or pharmaceutical composition, may be administered orally with or without food or water. In another embodiment, the compound of formula (I), or its form or pharmaceutical composition, may be administered systemically (e.g., parenterally) to an object requiring it. In another embodiment, the compound of formula (I), or its form or pharmaceutical composition, may be administered (e.g., orally) via a route that allows the compound of formula (I), or its form or pharmaceutical composition, to cross the blood-brain barrier. In another embodiment, the compound of formula (I), or its form or pharmaceutical composition, may be administered in combination with one or more additional treatments that may be administered by the same or different routes of administration. In another embodiment, the dosage and frequency of administration of an effective amount of a compound of formula (I), or its form or pharmaceutical composition, that inhibits dihydroorotate dehydrogenase to treat or improve a disease or disorder in a subject requiring such treatment, may be determined by a practicing physician, taking into account factors relevant to the subject requiring treatment, while minimizing any side effects.

[0082] Factors that may be considered include the severity of the disease state, the subject's overall health, age, weight, and sex, diet, timing and frequency of administration, drug combinations, sensitivity to response, and tolerability / response to treatment. The dosage and frequency of administration of the compound of formula (I), or its form or pharmaceutical composition thereof, may be adjusted over time to provide an effective amount of the compound of formula (I), or its form or pharmaceutical composition thereof, in order to maintain the desired effect. In one embodiment, the term “effective dose” refers to the amount of compound of formula (I), or its form or pharmaceutical composition, administered to a patient as monotherapy, the effective dose being in the range of about 0.001 mg / kg / day to about 500 mg / kg / day, or about 0.01 mg / kg / day to about 500 mg / kg / day, or about 0.1 mg to about 500 mg / kg / day, or about 1.0 mg / day to about 500 mg / kg / day, for a patient or subject with a body weight between about 40 and about 200 kg (this dose may be adjusted for patients or subjects above or below this range, in particular for children not reaching 40 kg). Dosage may be given as a dose per kilogram, a dose per square meter, or a flat dose expressed in units of mass (e.g., milligrams, grams). In another aspect, the effective dose is the amount administered to the subject, which may increase or decrease depending on the subject's response. The effective dose for a subject also depends on various factors, including the subject's weight, size, and health. A typical adult subject is expected to have a median weight in the range of approximately 60 to 100 kg. Therefore, the effective dose for a given patient may be determined according to the skill and judgment of a skilled practitioner in the art.

[0083] In one embodiment, the daily monotherapy dose may be adjusted based on the subject's or patient's body weight, and the compound of formula (I), or its form or pharmaceutical composition, may be approximately 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, It can be formulated for delivery as monotherapy in doses of 0.55, 0.60, 0.65, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 10, 20, 50, 75, or 100 mg / kg / day or any range in between.

[0084] In another embodiment, the daily dose may be adjusted based on the subject's or patient's body weight and administered as a single, divided, or continuous dose. In another embodiment, the daily dose of the compound of formula (I), or its form or pharmaceutical composition, may be administered once, twice, three times, or more times per day. In another embodiment, the compound of formula (I), or the form or pharmaceutical composition thereof, may be administered once, twice, three times, or more times per week. In another embodiment, the effective dose may be a dose administered to the subject twice a week on different days, such that the second dose in a given week is three days after the first dose, and the first dose in the following week is four days after the second dose of the previous week. In another embodiment, the subject may be administered one or more doses of the compound of formula (I), or its form or pharmaceutical composition, and the effective dose may not be the same for each dose.

[0085] In one embodiment, the effective amount of the compound of formula (I), or its form or pharmaceutical composition, may be in the range of about 0.001 mg / kg / day to about 500 mg / kg / day. The term “effective amount” or “therapeutic effective amount” of the compound of formula (I), or its form or pharmaceutical composition, for use in the manufacture of a pharmaceutical or in a method for treating or improving a disease or disorder in a subject requiring such treatment, is an amount sufficient to produce a therapeutic benefit by inhibiting dihydroorotate dehydrogenase. The therapeutically effective dose of the compound of formula (I), or its form or pharmaceutical composition, is intended to include doses administered daily, weekly, or bi-weekly, selected from amounts within the range of approximately 0.01 ng to approximately 3500 mg; approximately 0.1 ng to approximately 3500 mg; approximately 0.1 μg to approximately 3500 mg; approximately 0.1 mg to approximately 3500 mg; approximately 1 mg to approximately 3500 mg; approximately 1 mg to approximately 3000 mg; approximately 0.05 mg to approximately 1500 mg; approximately 0.5 mg to approximately 1500 mg; approximately 1 mg to approximately 1500 mg; approximately 5 mg to approximately 1500 mg; approximately 10 mg to approximately 600 mg; approximately 0.5 mg to approximately 2000 mg; or approximately 5.0 mg to approximately 1500 mg.

[0086] In one embodiment, the effective amount of the compound of formula (I), or its form or pharmaceutical composition, may be initially estimated from cell culture assays or from a suitable animal model such as a human, mouse, chimpanzee, marmoset, or tamarin animal model. A suitable animal model may also be used to determine an appropriate concentration range and route of administration. Therapeutic efficacy and toxicity are determined by standard pharmaceutical procedures in cell culture or experimental animals, e.g., ED 50 (Therapeutic dose effective in 50% of the population) and LD 50 This can be determined by the dose that is lethal to 50% of the population. The dose-to-toxicity ratio is called the therapeutic index, or ratio LD50. 50 / ED 50 It can be expressed as follows. In another embodiment, the effective dose is such that a large therapeutic index is achieved. In another embodiment, the dose administered is such that the ED has little or no toxicity. 50 This results in a certain range of plasma concentrations, including [specific component]. The dosage may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration. More specifically, the concentration-biogenic (pharmacodynamic) relationships observed for the compound of formula (I), or its form or pharmaceutical composition, suggest target plasma concentrations in the ranges of approximately 0.001 μg / mL to approximately 50 μg / mL, approximately 0.01 μg / mL to approximately 20 μg / mL, approximately 0.05 μg / mL to approximately 10 μg / mL, or approximately 0.1 μg / mL to approximately 5 μg / mL. To achieve such plasma concentrations, the compound of formula (I), or its form or pharmaceutical composition, may be administered to patients weighing between approximately 40 and approximately 100 kg in single, divided, or continuous doses, varying in doses from 0.001 μg to 100,000 mg, depending on the route of administration (these doses may be adjusted for patients above or below this weight range, particularly for children weighing less than 40 kg).

[0087] In another embodiment, a method for preventing, treating or improving a disease or disorder in a subject requiring such treatment by inhibiting dihydroorotate dehydrogenase comprises administering an effective amount to the subject of a compound of formula (I), or a form thereof or a pharmaceutical composition thereof, wherein the effective amount is approximately 50 mg to approximately 400 mg, approximately 100 mg to approximately 200 mg, approximately 125 mg to approximately 175 mg, approximately 100 mg to approximately 300 mg, or approximately 100 mg to approximately 400 mg, administered orally once, two or three times per week. The dosage is selected from among doses within the following ranges: approximately 150mg to 200mg, approximately 150mg to 300mg, approximately 150mg to 400mg, approximately 200mg to 300mg, approximately 225mg to 275mg, approximately 225mg to 300mg, approximately 275mg to 300mg, approximately 200mg to 225mg, approximately 200mg to 275mg, approximately 200mg to 400mg, approximately 250mg to 300mg, approximately 250mg to 400mg, and approximately 250mg to 350mg. In another embodiment, a method for preventing, treating or improving a disease or disorder in a subject requiring such treatment by inhibiting dihydroorotate dehydrogenase comprises administering an effective amount to the subject of a compound of formula (I), or a form thereof or a pharmaceutical composition, the effective amount of which is administered once, twice, or three times every other week. In another embodiment, a method for preventing, treating or improving a disease or disorder in a subject requiring such treatment by inhibiting dihydroorotate dehydrogenase comprises administering an effective amount of the compound of formula (I), or a form thereof, or a pharmaceutical composition, to the subject, the effective amount being administered once, twice, or three times at two-week intervals.

[0088] Pharmaceutical composition Aspects of this specification include the use of a compound of formula (I) or a form thereof in a pharmaceutical composition for treating or improving a disorder or condition described herein in a subject requiring such treatment, and the use comprising administering an effective amount of a compound of formula (I) or a form thereof mixed with one or more pharmaceutically acceptable excipients. Aspects of this specification include the use of the compound of formula (I) or a pharmaceutical composition in a similar form in the preparation of a kit comprising a compound of formula (I) or a pharmaceutical composition in a similar form and instructions for use for administering the compound to treat or improve a disease or condition in a subject requiring such treatment. As used herein, the term “composition” means any product containing a specified component in a specified amount, and any product resulting directly or indirectly from a combination of a specified component in a specified amount.

[0089] The pharmaceutical compositions described herein may be formulated to achieve a physiologically compatible pH in the range of approximately pH 3 to approximately pH 11. In certain embodiments, the pharmaceutical composition is formulated to achieve a pH of approximately pH 3 to approximately pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of approximately pH 5 to approximately pH 8. The term "pharmaceutically acceptable excipient" refers to an excipient for the administration of pharmaceuticals, such as the compounds described herein. A pharmaceutically acceptable excipient may be determined, in part, by the specific composition being administered, as well as by the specific mode of administration and / or dosage form. Non-exclusive examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, and diluents. Therefore, a wide variety of suitable formulations of the pharmaceutical compositions of the compounds described herein exist (see, for example, Remington's Pharmaceutical Sciences).

[0090] Suitable excipients may include carrier molecules containing large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acid, polyglycolic acid, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose, also known as HPMC), and stearic acid; liquids such as oils, water, saline, glycerol, and ethanol; wetting or emulsifying agents; and pH buffering agents. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

[0091] The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. Formulations suitable for oral administration include solids, liquid solutions, emulsions, and suspensions, while inhalation formulations suitable for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids that can be restored with a physiologically compatible solvent before administration. When intended for oral use, for example, tablets, lozenges, aqueous or oily suspensions, non-aqueous solutions, dispersible powders or granules (including finely powdered particles or nanoparticles), emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation.

[0092] Suitable pharmaceutically acceptable excipients for use with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrants such as croscarmellose sodium, cross-linked povidone, corn starch, or alginate; binders such as povidone, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate may be used alone or with wax. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as cellulose, lactose, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a non-aqueous or oily medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

[0093] In other embodiments, the pharmaceutical compositions described herein may be formulated as suspensions containing the compound of formula (I) or a form thereof mixed with one or more pharmaceutically acceptable excipients suitable for the preparation of suspensions. In yet another embodiment, the pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for the preparation of suspensions by the addition of one or more excipients.

[0094] Excipients suitable for use in connection with suspending agents include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose (methylcelluose), sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickeners such as carbomer, beeswax, solid paraffin, or cetyl alcohol. Suspending agents may also contain one or more preservatives such as acetic acid, p-hydroxybenzoate methyl and / or n-propyl; one or more colorants; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin.

[0095] The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and gum tragacanth; naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavorings. Syrups and elixirs may be formulated using sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, or colorings. In addition, the pharmaceutical compositions described herein may be in the form of sterile injection preparations, such as sterile aqueous emulsions or oily suspensions. Such emulsions or suspensions may be formulated according to known techniques using the appropriate dispersing or wetting and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension in a parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. The sterile injection preparation may also be prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixatives may be used as solvents or suspension media. For this purpose, any non-irritating fixative containing synthetic mono- or di-glycerides may be used. In addition, fatty acids such as oleic acid may similarly be used in the preparation of injections.

[0096] The compounds described herein are substantially insoluble in water and may be slightly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but may generally be soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and propylene glycol esters of medium-chain fatty acids. Accordingly, compounds modified by substitution or addition of chemical or biochemical moieties to make the compounds more suitable for delivery (e.g., increasing solubility, bioactivity, palatability, and reducing adverse reactions) are intended herein, for example, by esterification, glycosylation, or PEGylation. In certain embodiments, the compounds described herein are formulated for oral administration in lipid-based compositions suitable for low-solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds. Accordingly, the pharmaceutical compositions described herein may contain an effective amount of the compound of formula (I) or a form thereof together with at least one pharmaceutically acceptable excipient selected from medium-chain fatty acids or their propylene glycol esters (e.g., propylene glycol esters of edible fatty acids such as caprylic and caprin fatty acids) and a pharmaceutically acceptable surfactant such as polysorbate 20 or 80 (also referred to as Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

[0097] In other embodiments, the bioavailability of poorly soluble compounds can be enhanced using particle size optimization techniques, which include the preparation of nanoparticles or nanosuspensions using techniques known to those skilled in the art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline, or crystalline forms. In alternative embodiments, the pharmaceutical composition may further include one or more water-soluble enhancers, such as cyclodextrins. Non-limiting examples of cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, and maltotriosyl derivatives of α-, β-, and γ-cyclodextrins, as well as hydroxypropyl-β-cyclodextrin (HPBC). In certain embodiments, the pharmaceutical composition may further include HPBC in the range of about 0.1% to about 20%, about 1% to about 15%, or about 2.5% to about 10%. The amount of water-soluble enhancer used may depend on the amount of compound in the composition.

[0098] Common synthetic methods for preparing compounds As disclosed herein, general methods for preparing compounds of formula (I) or forms thereof as described herein are available by standard, well-known synthetic methodologies. Many of the starting materials are commercially available, or, if unavailable, can be prepared using techniques known to those skilled in the art, using the following routes. The synthetic schemes provided herein involve multiple reaction steps, each of which is intended to be independent and may be carried out with or without any preceding or succeeding step. In other words, each of the individual reaction steps of the synthetic schemes provided herein individually is contemplated.

[0099] Scheme A: The compound of formula (I) can be prepared as described in scheme A below.

[0100] [ka]

[0101] Scheme B: The compound of formula (I) can be prepared as described in scheme B below. [ka] [Examples]

[0102] The following examples include non-limiting and representative examples of embodiments of the compounds of formula (I) described herein. The examples include non-limiting methods for preparing specific compounds of formula (I). Specific synthesis examples To aid in understanding the range of compounds of formula (I) or their forms as described herein, the following general specific synthesis examples are included. In particular, these examples illustrate the preparation of a particular representative compound. Those skilled in the art will understand that the techniques described in these examples are representative of techniques described by those skilled in the art, which function well in the practice of synthesis and thus constitute a preferred form for that practice. However, those skilled in the art should understand that many modifications may be made in the particular methods disclosed in light of this disclosure, and that similar or analogous results may still be obtained without departing from the spirit and scope of this specification.

[0103] Except in the following examples, unless otherwise indicated, all figures representing amounts of components, reaction conditions, experimental data, etc., used herein and in the claims should be understood to be modified by the term “approximately.” Therefore, all such figures represent approximations that may vary depending on the desired properties to be obtained by the reaction or as a result of variable experimental conditions. Thus, within the expected range of experimental reproducibility, the term “approximately” in the context of the data obtained refers to a range of data provided that may vary according to a standard deviation from the mean. Similarly, with respect to the experimental results provided, the data obtained may be rounded up or down to present the data consistently without loss of significant figures. While the numerical ranges and parameters characterizing the compounds or forms thereof of formula (I) described herein are approximations, the numerical values ​​shown in the examples are reported as accurately as possible. However, any numerical value inherently contains a standard deviation, which is a range of values ​​that inevitably arises from experimental error.

[0104] In the synthesis flow schemes shown below, the term "Rac" indicates that the starting material or final product is a racemic mixture having the relative configurations shown. The relative configurations of the compounds in the racemic mixture may or may not be determined. 2D-NMR data for specific racemic mixtures were obtained without assigning specific diastereomers to their configurations. In one example shown herein, the racemic mixture of compounds is shown as a diastereomer having a (S,S) relative configuration, where the resulting isolated product contains the absolute configurations of the (S,S) and (R,R) diastereomers. In other examples shown herein, the racemic mixture of compounds is shown as a diastereomer having a (S,S) relative configuration, where the resulting isolated product contains the absolute configurations of the (S,S) and (S,R) enantiomers. In other examples shown herein, the racemic mixture is shown without specifying relative configuration (i.e., flat bond lines), in which case the resulting isolation product contains the absolute configurations of (S,S), (R,R), (S,R), and (R,S) diastereomers. The above structural formula and nomenclature tables reflect the individual diastereomers or enantiomers expected to be present in the resulting racemic mixture.

[0105] Relative stereochemistry was determined based on NMR; when the NMR data clearly indicated the relative stereochemistry, it was assigned; when the NMR data was unclear, the relative stereochemistry was assigned based on the understanding of those skilled in the art. In some examples, absolute stereochemistry was determined based on biological data; here, based on biological activity, the most active enantiomer at C1 was known to be the (S) enantiomer, while the (R) enantiomer was known to be relatively less active. As described herein, in some cases, absolute stereochemistry was determined based on the absolute stereochemistry of the chiral acid or catalyst used. In other cases, as described herein, absolute stereochemistry was determined based on the asymmetric synthesis of one diastereomer, and comparative NMR was used to determine the absolute stereochemistry of the other diastereomer in the racemic mixture.

[0106] Reagents and solvents were used as purchased (from various suppliers) unless otherwise specified. Unless otherwise specified, all reactions were carried out under an inert atmosphere. Where applicable, the term "Celite" is used to refer to the trademark name CELITE® (a trademark for diatomaceous earth), as shown in the following examples. Where applicable, chromatographic separation was performed using commonly available techniques and equipment, for example, by using the ISCO CombiFlash® Rf system. Where applicable, NMR spectra were obtained using commonly available techniques and equipment, for example, by using a Bruker Avance III with a deuterated solvent, such as DMSO-d6 or residual solvent, as a standard. 500 The values ​​were obtained by means of a spectrometer, etc. Where applicable, the melting point was determined using commonly available techniques and instruments, for example, using SRS OptiMelt® MPA100 (value obtained as is, without correction / calibration). Where applicable, TLC or LCMS analysis was performed using commonly available techniques and instruments, for example, using an Aldrich 254 nm glass support plate (60 Å, 250 μm) visualized using UV and I2 staining. Where applicable, ESI mass spectra were obtained using commonly available techniques and instruments, for example, values ​​are given as [M+H] unless otherwise indicated. + or [MH] - The products were obtained by using the ACQUITY UPLC® system, as indicated by the following method. Where applicable, the structure or relative configuration of the products was confirmed by analyzing the relative chemical shifts of the relevant signals using NMR spectroscopy with chiral components. Where applicable, the structure of the products was determined by 2D-NMR spectroscopy including COSY, HSQC, HMBC, and NOESY.

[0107] To ensure that the terms used herein are not ambiguous to those skilled in the art, the following abbreviations are provided: [Table 3] TIFF2026524862000067.tif222154 TIFF2026524862000068.tif138154

[0108] (Example 1) Synthesis of 2,4-bis(difluoromethyl)-6-(trichloromethyl)-1,3,5-triazine [ka]

[0109] Ammonia (approximately 50 mL) was concentrated in a 100 mL three-necked round-bottom flask at -78°C, and difluoroacetonitrile (NCCHF2) (5.71 g, 74.2 mmol) was added to the system in one step under an inert atmosphere. The reaction mixture was stirred at -78°C for 4 hours and then heated to room temperature overnight. The remaining ammonia was removed from the reaction mixture by rotary evaporation. The resulting solid was flushed with argon and dissolved in dichloromethane (50 mL). Trichloroacetonitrile (NCCCl3) (7.44 mL, 74.2 mmol) was added by syringe at 0°C. After stirring at 0°C for 4 hours, difluoroacetic anhydride (26.6 g, 148 mmol) was added to the solution at 0°C, and the mixture was slowly heated to room temperature overnight. The solvent and the resulting organic acid were removed by rotary evaporation, and the crude product was purified by column chromatography eluting with 0-80% hexane:CH2Cl2 to obtain 2,4-bis(difluoromethyl)-6-(trichloromethyl)-1,3,5-triazine as a clear oil (11.2 g, 37.5 mmol, yield 51%). 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (t, J = 56 Hz, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 174.0, 170.8 (t, J = 26 Hz), 110.5 (t, J = 242 Hz), 93.6; 19F NMR (377 MHz, DMSO-d6) δ 123.72 (d, 52.8 Hz). The product obtained as described in Example 1 above was used as a component in other examples provided herein to obtain additional compounds.

[0110] (Example 2) General procedure A for asymmetric carboline synthesis [ka]

[0111] Step 1: Place 3-methylbutanoic acid (38.8 g, 380 mmol), diisopropylethylamine (89.2 g, 690 mmol), and N,N-dimethylformamide (400 mL, 5170 mmol, 14.9 mg) into a three-necked round-bottom flask. Add the HATU (170 g, 438.154 mmol) solution in N,N-dimethylformamide (400 mL, 5170 mmol) and stir at ambient temperature for 5 minutes. Add 2-(5-chloro-1H-indole-3-yl)ethaneamine hydrochloride (80 g, 346.14 mmol) and stir the mixture at ambient temperature for 14 hours. Water (2 L) was added to the reaction mixture, the solid was filtered, washed with water, and dried under vacuum to obtain N-[2-(5-chloro-1H-indole-3-yl)ethyl]-3-methyl-butanamide (87 g, 312.1 mmol, yield 90.2%) as an amorphous solid.

[0112] Step 2: N-[2-(5-chloro-1H-indole-3-yl)ethyl]-3-methyl-butanamide (87 g, 312.1 mmol) was placed in a round-bottom flask and suspended in dry acetonitrile (500 mL). Phosphoryl chloride (30 mL, 323 mmol) was added all at once, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to 10°C, quenched by adding MeOH, and the resulting solid was filtered and washed with acetonitrile. The resulting solid was then suspended between saturated aqueous solution of NaHCO3 and DCM (5% MeOH). The two-phase mixture was stirred, and after all the solids had dissolved, the organic phase was separated, and the aqueous phase was extracted three times with DCM (5% MeOH). The combined organic phases were dried with Na2SO4, and volatile matter was removed under reduced pressure to obtain 6-chloro-1-isobutyl-4,9-dihydro-3H-pyrido[3,4-b]indole (37 g, 141.9 mmol, yield 45.5%) as an amorphous solid.

[0113] Step 3: 6-chloro-1-isobutyl-4,9-dihydro-3H-pyrido[3,4-b]indole (4.7 g, 18 mmol) in dichloromethane (50 mL, 780.0 mmol) was placed in a three-necked round-bottom flask equipped with an argon inlet. RuCl[(R,R)-TsDpen](mesitylene) (250 mg, 0.361 mmol) and triethylamine formate complex 5:2 (16 g, 36.253 mmol) were added, the flask was placed under an argon atmosphere, and the resulting mixture was stirred at 25°C for 1 hour, after which volatile matter was removed under reduced pressure. The residue was suspended in acetonitrile, filtered, and the solid was washed with K2CO3 (2M aqueous solution). The mixture was then vacuum dried to obtain enantiomer (1S)-6-chloro-1-isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3.7g, 14 mmol, 78% yield) as an amorphous solid. MS m / z 263.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1H), 7.36 (s, 1H), 7.27 (d, J = 8.38 Hz, 1H), 6.98 (d, J = 8.50 Hz, 1H), 3.94 (d, J = 9.63 Hz, 1H), 3.28-3.32 (m, 1H), 3.06-3.15 (m, 1H), 2.77-2.87 (m, 1H), 2.54-2.55 (m, 1H), 2.17 (br s, 1H), 1.88-1.99 (m, 1H), 1.62-1.70 (m, 1H), 1.45-1.54 (m, 1H), 0.98 (d, J = 6.38 Hz, 3H), 0.93 (d, J = 6.63 Hz, 3H) The product obtained as described in Example 2 above was used as a component in other examples provided herein to obtain additional compounds.

[0114] (Example 3) Synthesis of compound 135 [ka]

[0115] Step 1: In a round-bottom flask with a magnetic stirrer, 21 g of 5-chlorotryptamine hydrochloride (85.6 mmol) and ethyl formate (an excess amount sufficient to completely immerse the solid) were added. The reaction mixture was flushed with nitrogen and continued under nitrogen. 22 mL of triethylamine (158 mmol) was added, and the reaction mixture was heated under reflux at 100°C for 48 hours. After 48 hours, LC-MS analysis indicated that the reaction was complete. The reaction mixture was concentrated to dryness to obtain crude N-[2-(5-chloro-1H-indole-3-yl)ethyl]formamide as a grayish-white solid. 22.7 g, yield 119%, the product contains triethylamine hydrochloride. The product was used directly in the next step without further purification.

[0116] Step 2: N-[2-(5-chloro-1H-indole-3-yl)ethyl]formamide (17.4 g, 78.1 mmol) and acetonitrile (175 mL) were placed in a round-bottom flask with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. The reaction mixture was cooled to 0°C in an ice bath. Phosphoryl chloride (22 mL, 237 mmol) was added dropwise to the reaction mixture. The reaction mixture was removed from the ice bath and stirred overnight. After 16 hours, the reaction mixture was filtered and the filter cake was washed with acetonitrile (2 × 50 mL). The solid was dried on a filter. The product, 6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-2-ium, was isolated as a white solid salt (10 g) containing an unspecified counterion. The product was used directly in the next step without further purification.

[0117] Step 3: 6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-2-ium (5 g, 24.3 mmol) and THF (100 mL) were placed in a round-bottom flask equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. Allyl magnesium bromide in diethyl ether (1 mol / L, 98 mL, 98 mmol) was added. The reaction mixture was stirred for 4 hours, at which point all starting materials had been consumed, as determined by LC-MS analysis. The reaction mixture was quenched with saturated NH4Cl, extracted with 10% MeOH in DCM, and concentrated to obtain a racemic mixture of crude 1-allyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a yellowish-brown solid. MS m / z 247.0 [M+H] + . 1H NMR (DMSO-d6, 400MHz) 10.92(s, 1H),7.37 (d, J=1.6 Hz, 1H),7.27 (d, J=8. Hz, 1H), 6.99 (dd, J=2.0, 8.4 Hz, 1H), 5.97-5.80 (m, 1H), 5.14-5.02 (m, 2H), 4.00 (dd, J=3.2, 8.0 Hz, 1H), 3.16-3.10 (m, 1H), 2.85-2.78 (m, 1H), 2.67-2.61 (m, 1H), 2.59-2.51 (m, 2H), 2.44-2.36 (m, 1H). The product obtained as described in step 3 above was used as a component in other examples provided herein to obtain additional compounds.

[0118] Step 4: 1-allyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (19 mg, 0.08 mmol), 4-DMAP (10 mg, 0.08 mmol), acetonitrile (0.5 mL), and 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (35 mg, 0.10 mmol) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture turned black, and 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine was added to the solution. After 5 minutes, LC-MS determined that the reaction was complete. The reaction mixture was directly concentrated and purified by silica gel chromatography to obtain a racemic mixture of the title compound as a white solid (21 mg, yield 59%). MS m / z 460.0 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.77-2.96 (m, 4 H) 3.55-3.68 (m, 1 H) 4.93-5.05 (m, 2 H) 5.08-5.22 (m, 1 H) 5.75-5.91 (m, 1 H) 5.92-6.02 (m, 1 H) 7.04-7.16 (m, 1 H) 7.34-7.43 (m, 1 H) 7.47-7.56 (m, 1 H) 11.16-11.28 (m, 1 H) Additional compounds described herein can be prepared by using the procedure described in Example 3 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0119] [Table 4]

[0120] (Example 4) General procedure for the synthesis of diol diastereomers [ka]

[0121] Step 1: A racemic mixture of 1-allyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.97 g, 3.9 mmol) and 4-DMAP (180 mg, 1.5 mmol) were placed in a round-bottom flask with a magnetic stirrer. The reaction flask was flushed with nitrogen and the reaction was continued under nitrogen. DCM (10 mL), THF (10 mL), triethylamine (1.5 mL, 11 mmol), and Boc2O (1.9 mL, 8.8 mmol) were added to the reaction mixture. The reaction mixture was stirred overnight. After stirring for 16 hours, the reaction was determined to be complete by LC-MS analysis. The resulting mixture was directly concentrated and purified by silica gel chromatography to obtain a racemic mixture of crude di-tert-butyl1-allyl-6-chloro-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate as a white solid (1.7 g, 97% yield). The product was used directly in the next step without further purification.

[0122] Step 2: A racemic mixture of di-tert-butyl1-allyl-6-chloro-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate (105 mg, 0.23 mmol), potassium osmium(VI) dihydrate (8 mg, 0.02 mmol), and N-methylmorpholine N-oxide (40 mg, 0.34 mmol) was placed in a screw-cap vial equipped with a magnetic stirrer. The reaction flask was flushed with nitrogen and the reaction was continued under nitrogen. Acetone (1.5 mL) and water (1 mL) were added, and the reaction mixture was stirred at room temperature for 16 hours. After 16 hours, LC-MS analysis indicated that the reaction was complete. The reaction mixture was quenched with sodium sulfite solution, extracted with RINKAN, and the organic layer was dried over sodium sulfate and concentrated to dryness. The crude product was purified by silica gel chromatography to obtain racemic di-tert-butyl(S)-6-chloro-1-((S)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate and di-tert-butyl(R)-6-chloro-1-((R)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate. A racemic mixture (Rac1) was obtained, along with a racemic mixture (Rac2) of di-tert-butyl(S)-6-chloro-1-((R)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate and di-tert-butyl(R)-6-chloro-1-((S)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate.

[0123] Step 3: A racemic mixture of di-tert-butyl(S)-6-chloro-1-((S)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate and di-tert-butyl(R)-6-chloro-1-((R)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate (Rac1) (225 mg, 0.47 mmol) and hydrochloric acid in dioxane (5 mL, 20 mmol, 4 mol / L) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and stirred at room temperature for 24 hours. After 24 hours, a precipitate formed, and the reaction was determined to be complete by LC-MS. The mixture was filtered, and the filtered cake was washed with dioxane. The solid was dried under vacuum to obtain a racemic mixture (Rac3) of (S)-3-((S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol hydrochloride and (R)-3-((R)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol hydrochloride as a white solid. (129 mg, yield 87%) MS m / z 281.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (br s, 1 H) 2.05-2.19 (m, 2 H) 2.92 (br s, 2 H) 3.37-3.37 (m, 1 H) 3.39-3.48 (m, 1 H) 3.57 (s, 3 H) 3.77 (br s, 1 H) 4.83 (br s, 2 H) 5.34 (br s, 1 H) 5.76 (s, 1 H) 7.11 (br d, J=8.63 Hz, 1 H) 7.38 (d, J=8.63 Hz, 1 H) 7.54 (s, 1 H) 8.92 (br d, J=8.38Hz, 1H) 9.64 (br s, 1 H) 11.36 (s, 1 H)

[0124] Step 4: Using the procedure in Step 3, di-tert-butyl(S)-6-chloro-1-((R)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate and di-tert-butyl(R)-6-chloro-1-((S)-2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate Using a racemic mixture of (Rac2), a racemic mixture of (S)-3-((R)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol hydrochloride and (R)-3-((S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol hydrochloride was obtained (Rac4), MS m / z 281.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.85 (dt, J=14.54, 9.36 Hz, 1 H) 2.36 (br d, J=14.76 Hz, 1 H) 2.84-2.98 (m, 2 H) 3.28-3.50 (m, 8 H) 3.91 (br d, J=4.75 Hz, 1 H) 4.79 (br s, 1 H) 7.07-7.14 (m, 1 H) 7.39 (m, J=8.63 Hz, 1 H) 7.54 (s, 1 H) 9.10 (br s, 1 H) 9.32 (br s, 1 H) 11.35 (s, 1 H) The product obtained as described in Example 4 above was used as a component in other examples provided herein to obtain additional compounds.

[0125] (Example 5) General procedure B for the synthesis of diol diastereomers [ka] 6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-2-ium chloride (3.5 g, 14.6 mmol) was placed in a flask and suspended in 180 mL of a 2:1 MeOH / water mixture. Sodium bicarbonate (15 g, 17.5 mmol) was added, and the slurry was stirred at room temperature for 5 minutes, followed by the addition of 3-oxopentanedioic acid (3.4 g, 23.3 mmol). The mixture was stirred at room temperature for 2 hours, after which the solid was collected by filtration. The solid was washed with water followed by acetonitrile, and then vacuum dried to obtain 3.5 g (11 mmol, yield 79%) of a racemic mixture of 4-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-3-oxobutanoic acid.

[0126] The water / acetonitrile filtrate was collected, basicized with 2M NaOH aqueous solution, and extracted three times with DCM. The combined organic layers were concentrated under reduced pressure to obtain a racemic mixture of 1-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-2-one as a byproduct (150 mg, 0.6 mmol, 4% yield). The product obtained as described in Example 5 above was used as a component in other examples provided herein to obtain additional compounds.

[0127] (Example 6) Synthesis of compounds 92A and 92B and compounds 93A and 93B [ka]

[0128] Step 1: A racemic mixture of 4-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-3-oxo-butanoic acid (6.1 g, 20 mmol) was suspended in MeOH (120 mL), and 3 M HCl (60 mL) was added to the MeOH. The mixture was stirred at room temperature for 16 hours. The suspension was concentrated under reduced pressure, and the solid was washed with methanol to obtain 3.3 g (9.1 mmol, yield 46%) of a racemic mixture of methyl 4-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-3-oxo-butanoate hydrochloride, which was used directly in the next step.

[0129] Step 2: A racemic mixture of methyl-4-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-3-oxobutanoate hydrochloride (840 mg, 2.4 mmol) and 4-dimethylaminopyridine (1.0 g, 8.0 mmol) were suspended in MeCN (50 mL). 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (1.6 g, 4.7 mmol) was added to the mixture at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain a racemic mixture of methyl-4-[2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]-3-oxo-butanoate (560 mg, 1.1 mmol, yield 44%). MS m / z 358.1[M+H] + .

[0130] Step 3: A racemic mixture of methyl-4-[2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]-3-oxobutanoate (520 mg, 1.0 mmol) was placed in a flask and flushed with argon. The substance was dissolved in DCM (15 mL) and cooled to 0°C. A 1 M solution of DIBAL-H (1 mol / L) in hexane (4.9 mL, 4.9 mmol) was added dropwise, and the mixture was then heated to room temperature and stirred for 3 hours. The solution was cooled to 0°C and quenched with 5 mL of 2 M aqueous NaOH solution. The mixture was heated to room temperature and stirred for 30 minutes, after which the organic layer was partitioned and washed with water and brine. The organic layer was concentrated, and the crude residue was purified by silica gel chromatography to obtain a racemic mixture (110 mg, yield 22%) of compound 92A (3R)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol and compound 92B (3S)-4-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol and compound 93A A racemic mixture of (3S)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol and compound 93B (3R)-4-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol (92 mg, yield 19%) was obtained.

[0131] Compound 92A / B MS m / z 508.1 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 6.05 (dd, J = 9.7, 4.9 Hz, 1H), 4.94 (dd, J = 13.4, 5.2 Hz, 1H), 4.49 (d, J = 5.5 Hz, 1H), 4.31 (t, J = 4.9 Hz, 1H), 3.79 (s, 1H), 3.72-3.51 (m, 1H), 3.48 (dd, J = 10.0, 5.4 Hz, 2H), 2.83 (ddd, J = 32.9, 13.7, 4.8 Hz, 2H), 2.21-1.89 (m, 2H), 1.80-1.62 (m, 1H), 1.58-1.40 (m, 1H). The relative configurations between diastereomers were not determined; NMR data were obtained without assigning them to specific diastereomers.

[0132] Compound 93A / B MS m / z 508.0 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.05 (dd, J = 8.6, 2.1 Hz, 1H), 6.13 (dd, J = 9.4, 4.0 Hz, 1H), 4.93 (dd, J = 13.1, 5.2 Hz, 1H), 4.40 (d, J = 5.4 Hz, 1H), 4.32 (t, J = 5.0 Hz, 1H), 3.77-3.53 (m, 2H), 3.47 (q, J = 6.0 Hz, 2H), 2.83 (ddd, J = 27.2, 13.7, 5.1 Hz, 2H), 2.26-1.94 (m, 2H), 1.54 (q, J = 6.4 Hz, 2H). The relative stereochemistry between diastereomers was not determined; NMR data were obtained without assigning them to specific diastereomers.

[0133] (Example 7) Synthesis of compounds 89A and 89B [ka]

[0134] A racemic mixture of (S)-3-((S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol hydrochloride (20 mg, 0.06 mmol), DIPEA (1 mL), and acetonitrile (1 mL) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 1 hour, at which point a solution was formed. 4-DMAP (9 mg, 0.07 mmol) and 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (26 mg, 0.08 mmol) were added to the reaction mixture. After 15 minutes, the reaction was determined to be complete by LC-MS. The reaction mixture was concentrated under a nitrogen atmosphere and purified by reverse-phase preparative HPLC to obtain a racemic mixture of compound 89A (S)-3-((S)-2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol and compound 89B (R)-3-((R)-2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol as a white solid. (9 mg, yield 29%) MS m / z 494.0 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ ppm 1.94-2.04 (m, 1 H) 2.13-2.22 (m, 1 H) 2.68-2.91 (m, 2 H) 3.21-3.31 (m, 3 H) 3.49 (br s, 1 H) 3.58 (td, J=12.73, 4.31 Hz, 1 H) 4.50-4.60 (m, 2 H) 4.94 (br dd, J=13.01, 5.00 Hz, 1 H) 6.12-6.18 (m, 1 H) 7.06 (d, J=8.74 Hz, 1 H) 7.33 (d, J=8.63 Hz, 1 H) 7.47 (s, 1 H) 11.20 (s, 1 H). Relative stereochemistry was not determined; NMR data were obtained without assignment to specific diastereomers. Additional compounds described herein can be prepared by using the procedure described in Example 7 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0135] [Table 5]

[0136] (Example 82) Synthesis of compounds 79A and 79B [ka]

[0137] Step 1: A racemic mixture of di-tert-butyl 6-chloro-1-(2,3-dihydroxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate (43 mg, 0.09 mmol), DCM (0.4 mL), 4-DMAP (10 mg, 0.09 mmol), NEt3 (0.045 mL, 0.32 mmol), and acetic anhydride (0.022 mL, 0.23 mmol) was placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was placed directly onto a silica gel column for purification to obtain a single product. The product was used directly in the next step without further analysis or purification.

[0138] Step 2: A racemic mixture of di-tert-butyl 6-chloro-1-(2,3-diacetoxypropyl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,9-dicarboxylate (40 mg, 0.07 mmol), DCM (0.5 mL), and trifluoroacetic acid (0.5 mL) was placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was stirred overnight at room temperature. After 16 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was quenched with triethylamine, dissolved in ethylammonium compounds, washed with saturated NaCl (3×), dried over NaSO4, and concentrated. The concentrate was used directly in the next step without further purification or analysis.

[0139] Step 3: A racemic mixture of 3-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diyldiacetate (20 mg, 0.06 mmol), acetonitrile (1 mL), 4-DMAP (9 mg, 0.07 mmol), and 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (26 mg, 0.08 mmol) was placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 15 minutes. After 15 minutes, the reaction was determined to be complete by LC-MS. The reaction mixture was directly concentrated under nitrogen and purified by reverse-phase preparative HPLC to obtain a racemic mixture of compound 79A (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-1,2-diyldiaacetate and compound 79B (2R)-3-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-1,2-diyldiaacetate as a white solid. (9 mg, yield 36%) MS m / z 578.0 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.99 (d, J=4.25 Hz, 6 H) 2.33-2.41 (m, 2 H) 2.74-2.89 (m, 2 H) 3.59-3.69 (m, 1 H) 4.01 (dd, J=12.19, 5.07 Hz, 1 H) 4.29 (dd, J=11.94, 2.44 Hz, 1 H) 4.88-4.97 (m, 2 H) 6.01-6.07 (m, 1 H) 7.08 (br d, J=8.50 Hz, 1 H) 7.34 (d, J=8.63 Hz, 1 H) 7.48 (s, 1 H) 11.39 (s, 1 H)

[0140] (Example 9) Synthesis of compounds 199A and 199B [ka]

[0141] A racemic mixture of 3-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol (29 mg, 0.058 mmol, 1.0 equivalent), pyridine (0.2 mL), and 15% phosgene in 100 mL (0.041 mL, 0.4 mmol) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 15 minutes. After 15 minutes, the reaction was determined to be complete by LC-MS. The reaction mixture was directly concentrated and purified by silica gel chromatography to obtain a racemic mixture of compound 199A (4S)-4-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-one and compound 199B (4R)-4-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-one as a white solid. (15 mg, yield 49%) MS m / z 520.0 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.38-2.47 (m, 1 H) 2.72-2.92 (m, 2 H) 3.28-3.33 (m, 1 H) 3.53-3.62 (m, 1 H) 4.17 (t, J=7.69 Hz, 1 H) 4.53 (t, J=8.25 Hz, 1 H) 4.88-4.98 (m, 2 H) 6.13 (br d, J=9.88 Hz, 1 H) 7.08 (br d, J=8.63 Hz, 1 H) 7.36 (d, J=8.50 Hz, 1 H) 7.50 (s, 1 H) 11.36 (s, 1 H)

[0142] Additional compounds described herein can be prepared by using the procedure described in Example 9 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following: [Table 6]

[0143] (Example 10) Synthesis of compounds 194A and 194B [ka]

[0144] A racemic mixture of 3-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol (430 mg, 0.9 mmol) and DCM (25 mL) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. 4-DMAP (100 mg, 0.8 mmol), pyridine (0.75 mL, 9.3 mmol), and thiophosgene (0.1 mL, 1 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 30 minutes. After 30 minutes, the reaction was determined to be complete by LC-MS. The reaction mixture was quenched with 1N HCl, extracted with DCM, dried over Na2SO4, and concentrated. The concentrate was purified by silica gel chromatography to obtain a racemic mixture of compound 194A (4S)-4-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-thion and compound 194B (4R)-4-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-thion as a yellow solid. (400 mg, yield 86%) MS m / z 538.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.58 (s, 1 H) 2.74-2.93 (m, 2 H) 3.56-3.66 (m, 1 H) 4.43-4.53 (m, 1 H) 4.75-4.87 (m, 1 H) 4.89-5.01 (m, 1 H) 5.15-5.25 (m, 1 H) 6.13-6.22 (m, 1 H) 6.18 (s, 1 H) 7.05-7.13 (m, 1 H) 7.33-7.43 (m, 1 H) 7.46-7.55 (m, 1 H) 11.31-11.43 (m, 1 H)

[0145] Additional compounds described herein can be prepared by using the procedure described in Example 10 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following: [Table 7]

[0146] (Example 11) Synthesis of compound 196 [ka]

[0147] (S)-4-(((S)-2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl)-1,3-dioxolan-2-thion and (R)-4-(((R)-2-(4,6-bis(trifluoromethyl)-1,3,5- A racemic mixture of liazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl)-1,3-dioxolan-2-thione (350 mg, 0.7 mmol), 2,2'-azobis(2-methylpropionitrile) (9 mg, 0.06 mmol), triphenyltin hydride (460 mg, 1.3 mmol), and toluene (15 mL) were added. The reaction mixture was flushed with nitrogen and maintained under nitrogen. The reaction mixture was heated at 100°C for 15 minutes. After 15 minutes, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was placed directly on silica gel and purified by silica gel chromatography to obtain a racemic mixture of 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[(1,3-dioxolan-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid. (100 mg, yield 30%) MS m / z 508.2 [M+H]+ 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (ddd, J=14.32, 10.07, 3.75 Hz, 1 H) 2.18 (td, J=11.98, 1.94 Hz, 1 H) 2.73-2.91 (m, 2 H) 3.20-3.31 (m, 2 H) 3.44-3.53 (m, 1 H) 3.54-3.62 (m, 1 H) 4.51-4.60 (m, 2 H) 4.95 (dd, J=13.13, 5.00 Hz, 1 H) 6.16 (dd, J=9.26, 3.50 Hz, 1 H) 7.06 (dd, J=8.57, 2.06 Hz, 1 H) 7.33 (d, J=8.50 Hz, 1 H) 7.47 (d, J=1.88 Hz, 1 H) 11.21 (br s, 1 H)

[0148] Additional compounds described herein can be prepared by using the procedure described in Example 11 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0149] [Table 8]

[0150] (Example 12) Synthesis of compounds 155A and 155B [ka]

[0151] Step 1: A screw-cap vial equipped with a magnetic stirrer contained a racemic mixture of (S)-3-((S)-6-chloro-2-(4-(trifluoromethyl)-1,3,5-triazine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol and (R)-3-((R)-6-chloro-2-(4-(trifluoromethyl)-1,3,5-triazine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)propan-1,2-diol (150 mg, 0.4 mmol), DCM (2 mL), NEt3 (0.06 mL, 0.4 mmol), and p-toluenesulfonyl chloride (70 mg, 0.4 mmol). The reaction mixture was stirred under nitrogen for 16 hours. After 16 hours, the reaction was determined to be complete by LC-MS. The reaction mixture was placed directly on silica gel and purified by silica gel chromatography. The title compound was isolated as a white solid (85 mg, 42% yield) and used directly in the next step.

[0152] Step 2: Sodium cyanide (35 mg, 0.71 mmol), a racemic mixture of (S)-3-((S)-6-chloro-2-(4-(trifluoromethyl)-1,3,5-triazine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-hydroxypropyl 4-methylbenzenesulfonate and (R)-3-((R)-6-chloro-2-(4-(trifluoromethyl)-1,3,5-triazine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-hydroxypropyl 4-methylbenzenesulfonate (87 mg, 0.13 mmol), and DMSO (1.0 mL) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen, continued under nitrogen, then heated to 60°C and stirred for 20 minutes. After 20 minutes, the reaction was determined to be complete by LC-MS. The mixture was diluted with deionized water, extracted with ethyl acetate, dried over Na2SO4, and concentrated under vacuum. The crude reaction mixture was purified by silica gel chromatography to obtain a racemic mixture of compound 155A (3R)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-hydroxybutanenitrile and compound 155B (3S)-4-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-hydroxybutanenitrile as a white solid. (10 mg, yield 20%) MS m / z 504.3 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ ppm 2.07-2.24 (m, 2 H) 2.60-2.68 (m, 1 H) 2.72-2.91 (m, 3 H) 3.50-3.63 (m, 1 H) 3.94-4.03 (m, 1 H) 4.94 (dd, 7.48 (d, J=1.88Hz, 1H) 11.11 (s, 1 H).

[0153] Additional compounds described herein can be prepared by using the procedure described in Example 12 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0154] [Table 9]

[0155] (Example 13) Synthesis of compound 154 [ka]

[0156] Cuprous iodide (200 mg, 1.0 mmol) was placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. THF (1 mL) was added to the reaction mixture. The reaction mixture was cooled to -40°C, and then methylmagnesium bromide solution in dibutyl ether (1.8 mL, 1.8 mmol) was added dropwise. The reaction mixture was stirred at -40°C for 15 minutes. A racemic mixture (300 mg, 0.46 mmol) of (S)-3-((S)-2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-hydroxypropyl 4-methylbenzenesulfonate and (R)-3-((R)-2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-hydroxypropyl 4-methylbenzenesulfonate in THF (1 mL) was added. The reaction mixture was stirred at -40°C for 1 hour. After 1 hour, the reaction was determined to be complete by LC-MS. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over Na2SO4, and concentrated to dryness. The crude concentrate was purified by silica gel chromatography and reverse-phase preparative HPLC to obtain (2R)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-2-ol as a white solid. (2.0 mg, yield 1%) MS m / z 494.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 0.72-0.85 (m, 3 H) 1.24-1.44 (m, 2 H) 1.88-2.11 (m, 2 H) 2.65-2.87 (m, 2 H) 3.34-3.46 (m, 1 H) 3.46-3.61 (m, 1 H) 4.28-4.42 (m, 1 H) 4.79-4.95 (m, 1 H) 5.97-6.11 (m, 1 H) 6.95-7.06 (m, 1 H) 7.18-7.35 (m, 1 H) 7.36-7.46 (m, 1 H) 11.07-11.20 (m, 1 H).

[0157] (Example 14) Synthesis of (R)-2-(3,6-dihydro-2H-pyran-3-yl)acetic acid [ka]

[0158] Step 1: [(3R,4R)-4-acetoxy-3,4-dihydro-2H-pyran-3-yl]acetate (1.7 g, 8.5 mmol) and DCM (6 mL) were placed in a screw-cap vial equipped with a magnetic stirring bar. The reaction mixture was flushed with nitrogen and maintained under nitrogen. Triethylsilane (0.85 mL, 5.31 mmol) was added in one step, followed by dropwise addition of boron trifluoride diethyl etherate (0.62 mL, 4.9 mmol) (Note: exothermic). The reaction mixture was stirred for 30 minutes and then quenched with saturated bicarbonate aqueous solution. The aqueous layer was extracted with DCM (3×). The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The crude material was purified by silica gel chromatography (5-50% Â in hexane) to obtain a clear oily substance, which was used directly in the next step without further purification or analysis.

[0159] Step 2: THF (30 mL) and diisopropylamine (3.6 mL, 26 mmol) were added to a flame-dried and argon-filled scintillation vial. The reaction mixture was cooled to -78°C, and then n-butyllithium (2.5 mol / L, 9.3 mL, 23 mmol) in hexane was added. The resulting lithium diisopropylamide (LDA) solution was stirred at -78°C for 10 minutes. (3S)-3,6-dihydro-2H-pyran-3-yl]acetate (3 g, 21 mmol) in THF (15 mL) was added dropwise to the LDA solution at -78°C. The reaction mixture was stirred at -78°C for 45 minutes. To the reaction mixture, tert-butyldimethylsilyl chloride (TBDMSCl) (4.26 g, 27.4 mmol) dissolved in N,N'-dimethylpropylene urea (DMPU) (15 mL) at -78 °C was added dropwise. The reaction mixture was stirred at -78 °C for 30 minutes, then placed in an ice bath and stirred for an additional 30 minutes. The mixture was then raised to room temperature and stirred for 2 hours, then diluted with n-pentane and washed with DI water (3 ×). The water was back-extracted with n-pentane. The n-pentane was passed through a drying tube and concentrated to dryness. The resulting oily substance was dissolved in toluene (90 mL), heated under nitrogen at 90 °C for 16 hours, and then directly concentrated to dryness. The crude oily substance was dissolved in THF (35 mL) and water (15 mL), heated at 70 °C for 3 hours, then diluted with saturated sodium bicarbonate and extracted with diethyl ether (2 ×). The aqueous layer was then acidified with 2N HCl to approximately pH 2. Next, the acidic aqueous layer was extracted with dichloromethane (DCM) (3×). The organic matter was passed through a drying tube and concentrated to obtain the desired product, (R)-2-(3,6-dihydro-2H-pyran-3-yl)acetic acid, as a crude oil (1.5 g, yield 52%). 1 H NMR (400 MHz, CHCl3-d) δ ppm 2.18-2.39 (m, 2 H) 2.41-2.54 (m, 1 H) 3.37-3.47 (m, 1 H) 3.64-3.77 (m, 1 H) 3.90-4.03 (m, 2 H) 5.54-5.73 (m, 2 H). The product obtained as described in Example 14 above was used as a component in other examples provided herein to obtain additional compounds.

[0160] (Example 15) Synthesis of compound 192 [ka]

[0161] Step 1: 2-[(2R)-1,4-dioxan-2-yl]acetic acid (125 mg, 0.7 mmol), THF (1.5 mL), NEt3 (0.22 mL, 1.6 mmol), HATU (315 mg, 0.8 mmol), and 2-(5-chloro-1H-indole-3-yl)ethylammonium chloride (168 mg, 0.7 mmol) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction was determined to be complete by LC-MS. The reaction mixture was diluted with Â, washed with 2N HCl, 2N NaOH, and saturated bicarbonate, dried over Na2SO4, and concentrated to dryness. The crude concentrate was purified by silica gel chromatography to obtain a white foamy substance (140 mg, 60% yield). The product was used directly in the next step without further purification.

[0162] Step 2: (R)-N-(2-(5-chloro-1H-indole-3-yl)ethyl)-2-(1,4-dioxan-2-yl)acetamide (400 mg, 1.2 mmol) was placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. Acetonitrile (10 mL) and phosphoryl chloride (0.25 mL, 2.7 mmol) were added to the reaction mixture. The reaction mixture was heated to 90°C for 30 minutes. After 30 minutes, the reaction was determined to be complete by LC-MS. The reaction mixture was cooled to 0°C and quenched with 20% NaOH until the pH was >11. The product was extracted with Â, dried over Na2SO4, and concentrated under vacuum. The product was purified using silica gel chromatography to obtain a solid (318 mg, yield 84%). The obtained substance was used directly in the next step without further purification.

[0163] Step 3: (R)-1-((1,4-dioxan-2-yl)methyl)-6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole (318 mg, 1.0 mmol) was placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. DCM (15 mL), triethylamine formate complex 5:2 (0.6 mL), and RuCl[(R,R)-TSDPEN](mesitylene) (20 mg, 0.03 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. After 1 hour, the product precipitated, and the reaction was determined to be complete by LC-MS. The reaction mixture was concentrated under vacuum and purified by reverse-phase column chromatography to obtain a white solid (120 mg, yield 37%). The product was used directly in the next step without further purification.

[0164] Step 4: (S)-1-(((R)-1,4-dioxan-2-yl)methyl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (65 mg, 0.2 mmol), acetonitrile (1 mL), and DIPEA (0.5 mL) were placed in a screw-cap vial equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. The reaction mixture was cooled to 0°C. 4-DMAP (23 mg, 0.2 mmol) and 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (70 mg, 0.21 mmol) were added to the reaction mixture. The reaction mixture was stirred for 15 minutes while increasing the temperature to room temperature. After 15 minutes, the reaction was determined to be complete by LC-MS. The product was concentrated under vacuum and purified by silica gel chromatography to obtain (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-{[(2R)-1,4-dioxan-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid. (65 mg, yield 67%) MS m / z 520.1 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.11 (m, 2 H) 2.71-2.91 (m, 2 H) 3.21-3.31 (m, 2 H) 3.37-3.46 (m, 1 H) 3.47-3.63 (m, 3 H) 3.68-3.77 (m, 1 H) 3.84 (dd, J=11.26, 2.13 Hz, 1 H) 4.94 (dd, J=13.32, 4.94 Hz, 1 H) 6.02 (dd, J=9.19, 4.44 Hz, 1 H) 7.08 (dd, J=8.63, 2.00 Hz, 1 H) 7.37 (d, J=8.50 Hz, 1 H) 7.48 (d, J=1.88 Hz, 1 H) 11.11 (s, 1 H)

[0165] Additional compounds described herein can be prepared by using the procedure described in Example 15 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0166] [Table 10]

[0167] (Example 16) General procedure for the synthesis of 2-(1,3-dioxan-5-yl)acetic acid [ka]

[0168] Step 1: A solution of diethyl 2-allylpropanediol (10.0 mL, 51.4 mmol) in THF (50 mL) was added dropwise to a stirred suspension of LAH (6.17 g, 154 mmol) in THF (200 mL) over 30 minutes at 0°C. The ice bath was removed, and the reaction mixture was stirred overnight at room temperature, at which point it was determined that the reaction was complete by TLC. After cooling to 0°C, 6.0 mL of water, 6.0 mL of 15% sodium hydroxide aqueous solution, and 18 mL of water were added to the reaction mixture in that order. The reaction mixture was stirred at room temperature for 15 minutes, a small amount of MgSO4 was added, and then stirred for another 15 minutes. The slurry was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 2-allylpropane-1,3-diol as a colorless oil (5.80 g, 49.9 mmol, yield 97.1%), which was used in the next step without further purification of the crude material. 1 H NMR (CDCl3, 400 MHz) δ 5.74-5.88 (m, 1H), 5.02-5.13 (m, 2H), 3.60-3.88 (m, 4H), 2.08 (t, J = 6.94 Hz, 2H), 1.84-1.93 (m, 1H)

[0169] Step 2: Lithium bromide (2.17 g, 25.0 mmol) and (1S)-(+)-camphor-10-sulfonic acid (3.00 g, 12.8 mmol) were added to a solution of 2-allylpropane-1,3-diol (5.80 g, 49.9 mmol) in dimethoxymethane (100 mL). The reaction mixture was stirred at 50°C for 24 hours, at which point it was determined that the reaction was complete by TLC. Water was added to the reaction mixture, and the aqueous layer was extracted with siRNA (3 × 150 ml). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The substance was purified by distillation at 18 mbar using a Buchi vacuum pump and a heating block set to 160°C. The substance was collected while boiling in the range of 58-60°C to obtain 5-allyl-1,3-dioxane (4.20 g, 32.8 mmol, yield 65.6%) as a colorless oily substance. 1H NMR (CDCl3, 400 MHz) δ 5.58-5.73 (m, 1H), 4.94-5.02 (m, 2H), 4.87-4.92 (m, 1H), 4.56-4.63 (m, 1H), 3.91-4.01 (m, 2H), 3.29-3.41 (m, 2H), 1.85-1.97 (m, 3H)

[0170] Step 3: 5-allyl-1,3-dioxane (4.20 g, 32.8 mmol) was dissolved in a mixture of ACN (82 mL) and water (82 mL) at room temperature. Ruthenium chloride (0.272 g, 1.31 mmol) and sodium periodate (31.5 g, 144 mmol) were added to the solution all at once (Note: Exothermic reaction!). The slurry was stirred at 0°C for 30 minutes, then raised to room temperature and stirred for 2 hours, at which point it was determined that the reaction was complete by TLC. The reaction mixture was quenched at 0°C with saturated NaHSO3 aqueous solution (150 ml) (Note: Exothermic event!), and then stirred for a further 1 hour. 2.0 M NaOH solution (approximately 200 ml) was added to adjust the pH to >9, and then the aqueous layer was washed with DCM (2 × 150 ml). 2 M HCl solution (approximately 100 ml) was added to the aqueous solution at 0°C to adjust the pH to <2. The aqueous layer was extracted with CHCl3 / IPA (3:1) (3 × 100 ml). The combined organic layers were dried over MgSO4, filtered, and then concentrated under reduced pressure to obtain 2-(1,3-dioxan-5-yl)acetic acid (3.40 g, 23.3 mmol, yield 71.0%) as a yellow oily substance. 1 H NMR (CDCl3, 400 MHz) δ 4.91 (d, J = 6.25 Hz, 1H), 4.81 (d, J = 6.25 Hz, 1H), 4.07 (dd, J = 11.38, 3.50 Hz, 2H), 3.66 (dd, J = 11.38, 6.50 Hz, 2H), 2.50 (d, J = 7.13 Hz, 2H), 2.25-2.35 (m, 1H) The product obtained as described in Example 16 above was used as a component in other examples provided herein to obtain additional compounds.

[0171] (Example 17) Procedure for the synthesis of 4-ethoxy-3-(ethoxycarbonyl)-4-oxobutanoic acid [ka]

[0172] Step 1: Diethylpropanediate (5 g, 31.2 mmol) was added dropwise to a suspension of sodium hydride in oil (60% by mass, 1.30 g, 32.5 mmol) in anhydrous THF (50 mL) at 0°C. After the addition was complete, the reaction mixture was stirred for 1 hour while raising the temperature to room temperature. The reaction mixture was then cooled to 0°C, and tert-butylbromoacetate (6.76 g, 32.9 mmol) was added dropwise to the mixture while stirring, forming a white suspension, which was stirred overnight at room temperature. Saturated ammonium chloride solution (15 mL) was added, and the mixture was extracted twice with diethyl ether (20 mL). The combined organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude 2-(tert-butyl)1,1-diethylethane-1,1,2-tricarboxylate was used in the next step without further purification.

[0173] Step 2: To a solution of 2-(tert-butyl)1,1-diethylethane-1,1,2-tricarboxylate in dichloromethane (100 mL), TFA (40 g, 333.27 mmol) was added. The mixture was stirred at ambient temperature for 3 hours. All volatile substances were evaporated, and the remaining oily substance was used without further purification. The product obtained as described in step 2 above was used as a component in other examples provided herein to obtain additional compounds.

[0174] [ka]

[0175] Step 3: Dissolve 4-ethoxy-3-(ethoxycarbonyl)-4-oxobutanoic acid in acetonitrile (70 mL) in 250 mL RBF equipped with a magnetic stirring bar, then immerse the solution in an ice bath and stir for 15 minutes. Add chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (10 g, 33.86 mmol) all at once, followed by the gradual addition of 1-methylimidazole (8.2 g, 95 mmol) while maintaining the internal temperature below 30°C using an ice bath. Stir the resulting mixture in an ice bath for 15 minutes, cool to approximately 10°C, then add 5-chlorotryptamine hydrochloride (8 g, 32.88 mmol) all at once. Stir the mixture at ambient temperature for 15 hours. Partition the mixture between ethyl acetate and water, wash the organic phase with brine, dry over MgSO4, and then concentrate under reduced pressure. The crude substance was purified using silica gel chromatography with elution in hexane at 0-100% ethyl acetate to obtain diethyl 2-[2-[2-(5-chloro-1H-indole-3-yl)ethylamino]-2-oxo-ethyl]propanedioate (7.92 g, yield 64.3%). (Trituration with DCM yielded a white solid). 1 H NMR (400 MHz, DMSO-d6) δ: 11.03 (br s, 1H), 8.11 (br t, J=5.6 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.18-7.29 (m, 1H), 7.06 (dd, J=8.5, 2.0 Hz, 1H), 3.98-4.28 (m, 4H), 3.76 (t, J=7.5 Hz, 1H), 3.24-3.42 (m, 3H), 2.77 (t, J=7.3 Hz, 2H), 2.61-2.71 (m, 2H), 1.18 (t, J=7.0 Hz, 6H).

[0176] Step 4: Diethyl 2-[2-[2-(5-chloro-1H-indole-3-yl)ethylamino]-2-oxo-ethyl]propanediate (3.2 g, 8.1 mmol) and ACN (20 mL) were added to 250 mL of RBF. The mixture was degassed under argon, and phosphorus(V) oxychloride (4.0 g, 25.30 mmol) was added thereto. The resulting mixture was stirred overnight at 60°C and then concentrated in a rotary evaporator to obtain a pale yellow foamy substance, diethyl 2-((6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methyl)malonate (3.95 g, approximately 85% by mass, 100% yield), which was used in the next step without further purification.

[0177] Step 5: Preparation of free imine: Diethyl 2-((6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methyl)malonate (965.0 mg, purity approximately 85%) was partitioned between dichloromethane and saturated NaHCO3 (with ice). The organic phase was washed with brine, dried over MgSO4, and then concentrated in a rotary evaporator while maintaining the water bath temperature below 30°C. The free basic form of the imine was unstable and was used immediately without further purification. Diethyl 2-[(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methyl]propanediolate (710.0 mg, 1.60 mmol, approximately 85% by mass), RuCl[(R,R)-Tsdpen](mesitylene) (35.0 mg, 3%), and acetonitrile (5 mL) were added to RBF, and the mixture was degassed under argon. Then, triethylamine formate complex 5:2 (0.95 mL, 2.2 mmol) was added dropwise at 0°C. After stirring for 5 minutes, the mixture was heated to room temperature and stirred for 30 minutes. TLC showed that the starting materials were completely consumed. The mixture was cooled in an ice bath and diluted with ethyl acetate (30 mL). A saturated aqueous solution of NaHCO3 was added until the pH was approximately 8, followed by the addition of tert-butoxycarbonyl tert-butylcarbonate (550.0 mg, 2.52 mmol) in ACN (0.5 mL). The resulting mixture was stirred at room temperature for 5 hours. The organic phase was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The remaining substance was purified by silica gel chromatography eluting with 0-60% ethyl acetate in hexane, and the first fraction was obtained as the desired product, diethyl 2-[[(1S)-2-tert-butoxycarbonyl-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]methyl]propanedioate (445.0 mg, 58% yield). 1H NMR ((400 MHz, CHCl3-d) δ: 8.47-8.69 (m, 1H), 7.37-7.50 (m, 1H), 7.22-7.33 (m, 1H), 7.11-7.17 (m, 1H), 5.02-5.50 (m, 1H), 4.14-4.57 (m, 5H), 3.72-3.81 (m, 1H), 3.04-3.25 (m, 1H), 2.71-2.91 (m, 1H), 2.59-2.71 (m, 1H), 2.44-2.54 (m, 1H), 2.21-2.35 (m, 1H), 1.49 (s, 9H), 1.30 (s, 6H)

[0178] Step 6: Diethyl 2-[(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methyl]propanediolate (445.0 mg, 0.93 mmol) and THF (2 mL) were added to 100 mL of RBF. The mixture was placed in an ice bath and degassed under argon. Then lithium borohydride (2.5 mL, 5.0 mmol, 2.0 mol / L) was added to the THF. The mixture was stirred at 60°C for 3 hours. At completion, it was quenched with a saturated aqueous solution of NH4Cl at 0°C, stirred for 30 minutes, and then extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The remaining substance was purified using silica gel chromatography with elution in dichloromethane at 0-10% methanol to obtain diethyl 2-[[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl]methyl]propanedioate (240.0 mg, yield 74%) as a grayish-white solid.

[0179] Step 7: To tert-butyl(1S)-6-chloro-1-[3-hydroxy-2-(hydroxymethyl)propyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (55 mg, 0.14 mmol), HCl in dioxane (0.5 mL, 4 mol / L) was added. The mixture was stirred at room temperature for 4 hours. After completion, the volatiles were evaporated, and the remaining solid (S)-6-chloro-1-(3-hydroxy-2-(hydroxymethyl)propyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-ium was used without further purification. The product obtained as described in Example 17 above was used as a component in other examples provided herein to obtain additional compounds.

[0180] (Example 18) Synthesis of compound 147 [ka]

[0181] A mixture of (S)-2-((6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl)propan-1,3-diol hydrochloride (40 mg, 0.12 mmol), DMAP (35 mg, 0.28 mmol), and acetonitrile (0.8 mL) was mixed with a solution of 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (80 mg, 0.24 mmol) in acetonitrile (0.2 mL, 99.8% by mass) under argon at 0°C. The mixture was stirred at room temperature for 90 minutes, then partitioned between ethyl acetate and 5% NH4OH aqueous solution. The organic phase was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The remaining oily substance was purified by silica gel chromatography using 0-100% ethyl acetate and hexane to obtain (S)-2-((2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl)propane-1,3-diol (36 mg, yield 65%) as a white powder. MS m / z 510.1 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ: 11.07 (s, 1H), 7.40 (d, J=1.8 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.00 (dd, J=8.5, 2.0 Hz, 1H), 5.95 (t, J=7.3 Hz, 1H), 4.77-4.94 (m, 1H), 4.29-4.42 (m, 1H), 4.20 (t, J=5.4 Hz, 1H), 3.63-3.63 (m, 1H), 3.44-3.67 (m, 2H), 3.39 (dt, J=10.4, 5.4 Hz, 1H), 3.13-3.29 (m, 1H), 2.62-2.91 (m, 2H), 1.91 (br t, J=7.0 Hz, 2H), 1.38-1.61 (m, 1H); 19 F NMR (400 MHz, DMSO-d6) δ: -72.09 (d, J=54.1 Hz). Additional compounds described herein can be prepared by using the procedure described in Example 18 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0182] [Table 11]

[0183] (Example 19) Synthesis of compound 49 [ka]

[0184] Step 1: A solution of n-butyllithium (10.0 mol / L) in hexane (6.7 mL, 67.0 mmol) was added dropwise to a solution of (4R)-4-benzyloxazolidine-2-one (10.0 g, 55.7 mmol) in tetrahydrofuran (230 mL) at -78 °C. After stirring for 1 hour, a solution of 5-chloropentanoyl chloride (8.5 mL, 64.0 mmol) in tetrahydrofuran (55 mL) was added dropwise. Stirring was continued at -78 °C for 30 minutes and overnight at room temperature. Saturated aqueous NaHCO3 (500 mL) and pharmaceutically acceptable ethyl acetate (200 mL) were added to separate the layers, and the aqueous layer was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. After evaporation, a solid substance was formed, and diethyl ether was added. The solid was filtered and then washed with diethyl ether to obtain the desired product, (4R)-4-benzyl-3-(5-chloropentanoyl)oxazolidine-2-one (12.5 g, 42.4 mmol, yield 76.2%), as a white solid. MS m / z 368.0 [M+73, MeOH + H2O adduct]. 1H NMR (CDCl3, 400 MHz) δ 7.29-7.42 (m, 3H), 7.23 (d, J = 6.88 Hz, 2H), 4.65-4.75 (m, 1H), 4.16-4.26 (m, 2H), 3.56-3.66 (m, 2H), 3.33 (dd, J = 13.38, 3.38 Hz, 1H), 2.89-3.08 (m, 2H), 2.80 (dd, J = 13.38, 9.63 Hz, 1H), 1.82-1.95 (m, 4H)

[0185] Step 2: To a stirred solution of (4R)-4-benzyl-3-(5-chloropentanoyl)oxazolidine-2-one (11.5 g, 38.8 mmol) in THF (100 mL), sodium bis(trimethylsilyl)amide (24.0 mL, 48.0 mmol, 2.00 mol / L) was added in THF at -78°C, and stirring was continued at the same temperature for 1 hour. Allyl iodide (7.3 mL, 77.7 mmol) was added to the reaction mixture, and the mixture was stirred at -78°C until the starting materials were consumed as determined by TLC. After 3 hours, the reaction mixture was quenched with saturated NH4Cl solution, heated to room temperature, and then extracted with RINKAN (2 × 250 mL). The extracts were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by column chromatography on an ISCO using 20% ​​siRNA / Hex to obtain (4R)-4-benzyl-3-[(2S)-2-(3-chloropropyl)penta-4-enoyl]oxazolidine-2-one (10.9 g, 32.7 mmol, yield 84.2%) as a colorless oil. The diastereomer ratio (>97 / 3) was determined in acetone-d6. 1 The results were obtained by 1H-NMR and calculated from the integral ratio of signals at 2.86 ppm (small amount of diastereomer) and 2.80 ppm (major diastereomer) in acetone-d6. MS m / z 336.8 [M+H]. 1H NMR (acetone-d6, 400 MHz) δ 7.14-7.27 (m, 5H), 5.66-5.82 (m, 1H), 4.93-5.06 (m, 2 H), 4.66-4.73 (m, 1H), 4.24 (t, J = 8.51 Hz, 1H), 4.10-4.15 (m, 1H), 3.78 (dt, J = 13.01, 6.63 Hz, 1H), 3.47 (t, J = 6.44 Hz, 2H), 3.09 (dd, J = 13.38, 3.13 Hz, 1H),2.80 (dd, J = 13.45, 8.82Hz, 1H), 2.33-2.46 (m, 1H), 2.15-2.27 (m, 1H), 1.60-1.78 (m, 3H), 1.50-1.60 (m, 1H)

[0186] Step 3: (4R)-4-benzyl-3-[(2S)-2-(3-chloropropyl)penta-4-enoyl]oxazolidine-2-one (11.82 g, 35.2 mmol) was dissolved in Et2O (80 mL), and water (0.63 mL, 35.2 mmol) was added. The mixture was cooled to 0°C, and lithium borohydride in THF (8.8 mL, 35.2 mmol, 4 mol / L) was added gradually over 10 minutes, and the reaction mixture was stirred at the same temperature for a further 2 hours. The reaction mixture was quenched by adding aqueous HCl (125 mL, 1.0 M). The aqueous layer was extracted with Et2O (3 × 150 mL), and the combined organic layers were washed with aqueous HCl (100 mL, 1.0 M) and brine (100 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was dissolved in 1:3 siRNA / Hex, the solution was loaded onto a cartridge containing 250 g of silica gel, and eluted with approximately 200 mL of 1:3 siRNA / Hex. The filtrate was evaporated to obtain the desired product, (2S)-2-(3-chloropropyl)penta-4-en-1-ol (4.47 g, 27.5 mmol, yield 78.1%), as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 5.77-5.89 (m, 1H), 5.04-5.13 (m, 2H), 3.54-3.61 (m, 4H), 2.16 (t, J = 6.88 Hz, 2H), 1.81-1.89 (m, 2H), 1.61-1.70 (m, 1H), 1.47-1.58 (m, 2H)

[0187] Step 4: Sodium hydride (60% by mass, 2.2 g, 55.0 mmol) and THF (14 mL) in oil were added to a round-bottom flask equipped with a mechanical stirrer. The suspension was cooled to 5-10°C in an ice bath and stirred for 5 minutes. A solution of (2S)-2-(3-chloropropyl)penta-4-en-1-ol (4.47 g, 27.5 mmol) in THF (14 mL) was added via an addition funnel over 25 minutes. The resulting creamy suspension was stirred at the same temperature for 30 minutes. The reaction mixture was raised to room temperature and stirred overnight, at which point it was determined that the TLC was complete. The reaction mixture was cooled to 0°C and quenched by adding H2O (100 mL) and HCl (1N, 100 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 × 100 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product as a yellow oily substance. This was purified by distillation in a heating block set at 25 mbar and 90-100°C. The substance distilled at 56-58°C was collected to obtain (3S)-3-allyltetrahydropyran (1.92 g, 15.2 mmol, yield 55.4%) as a colorless oily substance. Note: The crude substance was unstable and decomposed quickly. If necessary, the substance can be stored for a short time in a refrigerator under an inert atmosphere. 1 H NMR (DCM-d2, 400 MHz) δ 5.59-5.70 (m, 1H), 4.83-4.91 (m, 2H), 3.65-3.71 (m, 2H), 3.13-3.25 (m, 1H), 2.90 (t, J = 10.57 Hz, 1H), 1.68-1.84 (m, 3H), 1.40-1.53 ​​(m, 3H), 0.95-1.09 (m, 1H)

[0188] Step 5: (3S)-3-allyltetrahydropyran (1.90 g, 15.1 mmol) was dissolved in a mixture of ACN (38 mL) and water (38 mL) at room temperature. Ruthenium chloride (0.125 g, 0.60 mmol) and sodium periodate (14.5 g, 66.4 mmol) were added to the solution all at once (Note: exothermic reaction). The slurry was stirred at 0°C for 30 minutes, then raised to room temperature, and stirred for 2 hours, at which point it was determined that the reaction by TLC was complete. The reaction mixture was quenched at 0°C with saturated aqueous solution of NaHSO3 (150 mL) (Note: exothermic reaction) and stirred for 1 hour. 2.0 M NaOH solution (approximately 100 mL) was added to adjust the pH to >9, and the aqueous layer was washed with DCM (2 × 150 mL). Concentrated HCl solution (approximately 100 mL) was added to the aqueous solution at 0°C to adjust the pH to <2. The aqueous layer was extracted with CHCl3 / IPA (3:1) (3 × 100 mL). The combined organic layers were dried over MgSO4, filtered, and then concentrated under reduced pressure to obtain 2-[(3S)-tetrahydropyran-3-yl]acetic acid (1.87 g, 13.0 mmol, yield 86.2%) as a yellow oily substance. 1 According to the 1H NMR spectrum, it was pure. 1 H NMR (CDCl3, 400 MHz) δ 3.83-3.95 (m, 2H), 3.39-3.48 (m, 1H), 3.13-3.26 (m, 1H), 2.18-2.33 (m, 2H), 2.09-2.18 (m, 1H), 1.88-1.99 (m, 1H), 1.60-1.70 (m, 2H), 1.24-1.35 (m, 1H).

[0189] The product obtained as described in step 5 above was used as a component in other examples provided herein to obtain additional compounds. [ka]

[0190] Step 6: A solution of 2-(5-chloro-1H-indole-3-yl)ethylammonium chloride (9.62 g, 41.6 mmol) in DMF (200 mL) was added to a 500 mL three-necked round-bottom flask at room temperature. Then, 2-[(3S)-tetrahydropyran-3-yl]acetic acid (6.00 g, 41.6 mmol), DIPEA (22.0 mL, 126 mmol), and HATU (24.2 g, 62.4 mmol) were added in order. The mixture was stirred at room temperature for 1 hour, at which point the reaction was determined to be complete by ULC analysis. The reaction mixture was quenched with water (500 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was dissolved in siRNA, washed with 2M NaOH, 2M HCl, water, saturated NaHCO3, and brine, dried over Na2SO4, filtered, and then concentrated under reduced pressure to obtain N-[2-(5-chloro-1H-indole-3-yl)ethyl]-2-[(3S)-tetrahydropyran-3-yl]acetamide (12.91 g, 40.24 mmol, yield 96.7%) as a white solid. MS m / z 321.0 [M+H] 1 H NMR (400 MHz, DMSO-d6) δ 1.08-1.17 (m, 1H), 1.40-1.56 (m, 2H), 1.65-1.73 (m, 1H), 1.85-1.98 (m, 3H), 2.73-2.83 (m, 2H), 2.91-3.05 (m, 1H), 3.22-3.34 (m, 3H), 3.64-3.76 (m, 2H), 7.06 (dd, J = 8.57, 1.69 Hz, 1H), 7.19-7.25 (m, 1H), 7.35 (d, J = 8.63 Hz, 1H), 7.54-7.59 (m, 1H), 7.92 (br t, J = 5.44 Hz, 1H), 11.03 (br s, 1H)

[0191] Step 7: N-[2-(5-chloro-1H-indole-3-yl)ethyl]-2-[(3S)-tetrahydropyran-3-yl]acetamide (12.91 g, 40.24 mmol) was placed in a 250 mL round-bottom flask. The reaction vessel was flushed with nitrogen and then maintained under a nitrogen atmosphere. MeCN (80 mL) and POCl3 (9.4 mL, 100 mmol) were placed in the flask. The reaction mixture was heated at 50 °C for 1 hour, at which point LC-MS analysis showed that the starting material had been completely consumed. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with ethyl acetate and cooled to 0 °C. Saturated aqueous NaHCO3 solution was added, the layers were shaken vigorously and separated, and the aqueous layer was extracted with ethyl acetate (3 × 250 ml). The combined organic layers were dried over Na2SO4, filtered, concentrated, and dried overnight in a vacuum oven (50°C, 30 mbar) to obtain 6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-4,9-dihydro-3H-pyrido[3,4-b]indole as a yellow solid substance with an unknown component as a chlorophosphate or phosphate (14.56 g). MS m / z 303.1 [M+H], 1 H NMR (400 MHz, DMSO-d6) δ 1.26-1.36 (m, 1H), 1.38-1.51 (m, 1H), 1.55-1.64 (m, 1H), 1.72-1.80 (m, 1H), 2.01-2.11 (m, 1H), 2.79-2.91 (m, 1H), 2.93-3.05 (m, 1H), 3.12-3.21 (m, 1H), 3.21-3.28 (m, 2H), 3.28-3.36 (m, 1H), 3.69-3.78 (m, 1H), 3.78-3.85 (m, 1H), 3.91-3.99 (m, 2H), 7.47 (br d, J = 8.88 Hz, 1H), 7.61 (d, J = 8.88 Hz, 1H), 7.95 (s, 1H), 12.43 (br s, 1H), 12.67 (s, 1H)

[0192] Step 8: The pH was adjusted to approximately 9 by slowly adding about 300 ml of 2 M Na2CO3 aqueous solution to 6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-4,9-dihydro-3H-pyrido[3,4-b]indole (14.56 g), the product from Step 7. The heterogeneous mixture was then stirred for 30-60 minutes until all substances were dissolved. The resulting homogeneous solution was extracted with toluene (3 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain 12.51 g of free imine as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.21-1.28 (m, 1H), 1.41-1.50 (m, 1H), 1.52-1.60 (m, 1H), 1.77-1.86 (m, 1H), 2.00-2.07 (m, 1H), 2.42-2.50 (m, 1H), 2.69-2.78 (m, 3H), 3.08 (t, J = 10.32 Hz, 1H), 3.23-3.39 (m, 2H), 3.69-3.76 (m, 3H), 3.82 (br dd, J = 10.88, 3.25 Hz, 1H), 7.16- 7.21 (d, J = 8.63 Hz, 1H), 7.43 (d, J = 8.63 Hz, 1H), 7.62 (s, 1H), 11.51 (s, 1H). Under a nitrogen atmosphere, imine (12.51 g), RuCl[(R,R)-TsDPEN](mesitylene) (0.482 g, 0.727 mmol), and MeCN (58 mL) were added to a three-necked round-bottom flask at room temperature. Then, triethylamine formate complex 5:2 (47 mL, 110 mmol) was added, and the reaction mixture was stirred at room temperature for 40-60 minutes. The homogeneous solution became a suspension within 5 minutes. When it was confirmed by TLC and / or ULC that the imine starting material had been completely consumed, 200 ml of diethyl ether was added to the reaction mixture. The resulting solid was collected by vacuum filtration through fine glass frit, and the filtration cake was washed with diethyl ether (2 × 50 mL). The filtrate was evaporated and then diluted with DCM (20 mL) and diethyl ether (200 mL). The resulting solid was passed through fine glass frit and collected again by vacuum filtration, and washed with the minimum amount of diethyl ether. The combined solid was dried overnight in a vacuum oven (50°C, 30 mbar) to obtain (1S)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-ium formate (9.50 g, 27.1 mmol, yield 74.5%) as a pale yellow solid. MS m / z 305.1 [M+H, free base] 1H NMR (400 MHz, DMSO-d6) δ 1.15-1.26 (m, 1H), 1.41-1.64 (m, 3H), 1.69-1.80 (m, 1H), 1.83-1.95 (m, 1H), 2.00 (br d, J = 11.51 Hz, 1H), 2.58-2.69 (m, 2H), 2.88-3.04 (m, 2H), 3.16-3.26 (m, 1H), 3.26-3.37 (m, 1H), 3.68-3.83 (m, 2H), 4.15 (br d, J = 9.51 Hz, 1H), 7.02 (br d, J = 8.63 Hz, 1H), 7.30 (d, J = 8.50 Hz, 1H), 7.41 (s, 1H), 8.25 (s, 1H), 11.01 (s, 1H).

[0193] Step 9: The pH was adjusted to approximately 9 by adding approximately 200 ml of aqueous Na2CO3 to (1S)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-ium formate (5.91 g, 16.8 mmol), and the heterogeneous solution was stirred for 30-60 minutes until all substances were dissolved. The resulting homogeneous solution was extracted with toluene (3 × 150 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain (1S)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4.83 g, 15.8 mmol, yield 94.1%) as a yellow solid. MS m / z 305.1 [M+H], 1H NMR (400 MHz, DMSO-d6) δ 1.15-1.25 (m, 1H), 1.31-1.41 (m, 1H), 1.46-1.70 (m, 3H), 1.82-1.93 (m, 1H), 1.93-2.02 (m, 1H), 2.13-2.29 (m, 1H), 2.52-2.58 (m, 2H), 2.75-2.86 (m, 1H), 2.95-3.03 (m, 1H), 3.04-3.13 (m, 1H), 3.26-3.32 (m, 1H), 3.69-3.78 (m, 2H), 3.96 (br d, J = 9.51 Hz, 1H), 6.98 (br d, J = 8.50 Hz, 1H), 7.27 (d, J = 8.50 Hz, 1H), 7.36 (s, 1H), 10.88 (s, 1H) The product obtained as described in step 9 above was used as a component in other examples provided herein to obtain additional compounds.

[0194] [ka]

[0195] Step 10: To a mixture of (S)-6-chloro-1-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (500 mg, 1.64 mmol), DMAP (223 mg, 1.80 mmol), and acetonitrile (7 mL), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (539 mg, 1.81 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 60 minutes. At completion, the solution was diluted in ethyl acetate, and the organic layer was washed with saturated NH4Cl solution and 5% NH4OH aqueous solution. The organic phase was washed again with brine, dried over MgSO4, and then concentrated under reduced pressure. The remaining oily substance was purified using silica gel chromatography with elution of 0-100% ethyl acetate and hexane to obtain (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (853 mg, yield 65%) as a white powder. ESI-MS m / z 518.1 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 5.95 (dd, J = 10.7, 3.1 Hz, 1H), 4.91 (dd, J = 13.3, 5.0 Hz, 1H), 3.80-3.63 (m, 2H), 3.65-3.47 (m, 1H), 3.29 (d, J = 2.4 Hz, 1H), 3.00 (dd, J = 11.1, 9.7 Hz, 1H), 2.90-2.69 (m, 2H), 2.33 (d, J = 11.8 Hz, 1H), 1.88 (ddd, J = 14.0, 10.8, 3.1 Hz, 1H), 1.80-1.67 (m, 1H), 1.58 (td, J = 11.9, 3.7 Hz, 2H), 1.48-1.27 (m, 2H). Additional compounds described herein can be prepared by using the procedure described in Example 19 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0196] [Table 12] TIFF2026524862000100.tif225160 TIFF2026524862000101.tif86160

[0197] (Example 20) Procedure for the synthesis of tert-butyl(S)-1-((1,3-dioxan-5-yl)methyl)-6-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate [ka]

[0198] In an 8 mL vial equipped with a stirring bar, tert-butyl(1S)-6-chloro-1-[3-hydroxy-2-(hydroxymethyl)propyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (75.0 mg, 0.18 mmol), (1 S)-(+)-camphor-10-sulfonic acid (50.0 mg, 0.21 mmol), and lithium bromide (25.0 mg, 0.29 mmol) were added and the mixture was degassed under argon. Dimethoxymethane (1 mL) was added, and the mixture was stirred at room temperature for 3 days. The mixture was partitioned between ethyl acetate and water, the organic phase was washed with brine, dried over MgSO4, and then concentrated. The remaining oily substance was purified by silica gel chromatography using elution with 0-100% ethyl acetate in hexane to obtain tert-butyl(1S)-6-chloro-1-(1,3-dioxan-5-ylmethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (38.0 mg, yield 51.8%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 11.02-11.26 (m, 1H), 7.43 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.01-7.09 (m, 1H), 5.04-5.28 (m, 1H), 4.83-4.96 (m, 1H), 4.58-4.71 (m, 1H), 4.05-4.34 (m, 2H), 3.89-4.01 (m, 1H), 3.51-3.62 (m, 1H), 3.36-3.46 (m, 1H), 3.01-3.21 (m, 1H), 2.56-2.70 (m, 2H), 1.82-2.05 (m, 1H), 1.53-1.80 (m, 2H), 1.38-1.50 (m, 9H)

[0199] The product obtained as described in Example 20 above was used as a component in other examples provided herein to obtain additional compounds selected from, for example, the following:

[0200] [Table 13]

[0201] (Example 21) Synthesis of Compound 1 [ka]

[0202] (1S)-6-chloro-1-(2-methylpropa-1-enyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.767 mmol), acetonitrile (4 mL), 2-iodo-5-(trifluoromethyl)-1,3,4-oxadiazole (230 mg, 0.87 mmol), and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol) were placed in a 40 mL vial equipped with a stirring bar. The vial was sealed and the mixture was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel purification (hexane ethyl eluate) to obtain (1S)-6-chloro-1-(2-methylpropa-1-en-1-yl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (156 mg, 0.393 mmol, yield 45%), which was isolated as a grayish-white amorphous solid. MS m / z 395.1 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.08 (dd, J = 8.6, 2.1 Hz, 1H), 5.84 (d, J = 9.8 Hz, 1H), 5.45 (dt, J = 9.9, 1.5 Hz, 1H), 4.22 (dt, J = 13.2, 3.7 Hz, 1H), 3.64 (dt, J = 13.4, 8.0 Hz, 1H), 2.86 (dd, J = 7.9, 3.6 Hz, 2H), 1.97 (d, J = 1.3 Hz, 3H), 1.74 (d, J = 1.3 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ 64.59.

[0203] Additional compounds described herein can be prepared by using the procedure described in Example 21 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0204] [Table 14] TIFF2026524862000106.tif182162

[0205] (Example 22) Synthesis of Compound 4 and Compound 6 [ka]

[0206] 2-[(1S)-6-bromo-1-isobutyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-yl]-5-(trifluoromethyl)-1,3,4-oxadiazole (65 mg, 0.147 mmol), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (14 mg, 0.016 mmol), and cesium fluoride (82 mg, 0.540 mmol) were placed in an 8 mL vial equipped with a septum cap and a stirring bar, then the vial was sealed tightly and sparged with argon. Toluene (1.6 mL) was added, and the reaction mixture was placed in a stirring block preheated to 70°C and stirred for 10 minutes. Then methanol (0.05 mL, 1 mmol) was added by syringe, and the reaction mixture was stirred at 70°C for 3 hours. The dark suspension was cooled to ambient temperature, diluted with DCM, filtered, concentrated, dissolved in DMSO, filtered again, and subjected to preparative HPLC purification by elution with water and acetonitrile.

[0207] Both products were separated and then lyophilized. Compound 4(1S)-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (15 mg, 0.041 mmol, yield 28%) was isolated as a white amorphous solid. MS m / z 363.2 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 4.16 (d, J = 15.7 Hz, 1H), 3.62 (t, J = 13.1 Hz, 1H), 2.89 (t, J = 11.3 Hz, 1H), 2.75 (d, J = 15.5 Hz, 2H), 1.94 (t, J = 10.4 Hz, 1H), 1.74 (s, 2H), 1.14-1.02 (m, 3H), 0.94 (d, J = 5.4 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) δ -64.57.

[0208] Compound 6(1S)-6-methoxy-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (25 mg, 0.063 mmol, 43% yield) was isolated as a white amorphous solid. MS m / z 393.2 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 8.7, 2.5 Hz, 1H), 5.21 (d, J = 9.4 Hz, 1H), 4.16 (dd, J = 13.9, 5.4 Hz, 1H), 3.73 (s, 3H), 3.68-3.55 (m, 1H), 2.93-2.80 (m, 1H), 2.73 (dd, J = 15.5, 4.0 Hz, 1H), 1.93 (t, J = 10.5 Hz, 1H), 1.82-1.63 (m, 2H), 1.07 (d, J = 5.8 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -64.57.

[0209] Additional compounds described herein can be prepared by using the procedure described in Example 22 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0210] [Table 15] TIFF2026524862000109.tif86158

[0211] (Example 23) Synthesis of Compound 9 and Compound 10 [ka]

[0212] Step 1: (1S)-6-chloro-1-(tetrahydropyran-3-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (500 mg, 1.64 mmol) was placed in a vial and suspended in MeCN (15 mL). Then N,N-diisopropylethylamine (0.86 mL, 4.92 mmol) was added, followed by cyanogen bromide (170 mg, 1.61 mmol). The reaction mixture was stirred at room temperature for 3 hours, and then the solvent was concentrated under vacuum. Upon addition of 20 mL of water, a solid precipitate formed. The solid was collected by vacuum filtration to obtain (1S)-6-chloro-1-(tetrahydropyran-3-ylmethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carbonitride (520 mg, 1.58 mmol, 96% yield). MS m / z 328.1[MH] - .

[0213] Step 2: Sodium azide (240 mg, 3.70 mmol) was added to a vial containing triethylamine hydrochloride (507 mg, 3.68 mmol) and (1S)-6-chloro-1-(tetrahydropyran-3-ylmethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carbonitol (405 mg, 1.3 mmol) in 15 mL of toluene under nitrogen. The resulting suspension was stirred at 80°C for 2 hours and then cooled to 0°C. The resulting suspension was filtered, and the solid was washed with Et2O followed by water to obtain (1S)-6-chloro-1-(tetrahydropyran-3-ylmethyl)-2-(1H-tetrazole-5-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (446 mg, 1.20 mmol, 97% yield) as a white solid. MS m / z 370.2[MH] - .

[0214] Step 3: (1S)-6-chloro-1-(tetrahydropyran-3-ylmethyl)-2-(1H-tetrazole-5-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (98 mg, 0.26 mmol) was placed in a vial, back-packed with N2, and dissolved in DCM (5 mL). N,N-diisopropylamine (0.14 mL, 0.79 mmol) was added to the vial, and the solution was cooled to 0°C. (2,2-difluoroacetyl)2,2-difluoroacetate (90 mg, 0.53 mmol) was added to the mixture. The ice bath was removed, and the mixture was heated to 50°C and stirred for 4 hours. The mixture was cooled to room temperature, the organic layer was washed with saturated sodium bicarbonate solution, dried, concentrated, and the crude mixture was purified by HPLC to obtain the individual diastereomers of the title compound as white powders. The absolute configurations of individual diastereomers were determined by asymmetric synthesis of one diastereomer and subsequent comparative NMR to determine the absolute configuration of the other diastereomer in the racemic mixture.

[0215] Compound 9:MS m / z 423.1 [MH] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.43-7.15 (m, 2H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 5.24 (dd, J = 10.7, 3.4 Hz, 1H), 4.15 (dd, J = 13.8, 5.0 Hz, 1H), 3.79-3.68 (m, 2H), 3.60 (ddd, J = 13.8, 11.3, 4.8 Hz, 1H), 3.31 (d, J = 9.0 Hz, 1H), 3.04 (dd, J = 11.1, 9.3 Hz, 1H), 2.91-2.67 (m, 2H), 2.16-2.05 (m, 1H), 1.88-1.59 (m, 4H), 1.54-1.28 (m, 2H). Compound 10:MS m / z 423.1 [MH] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.44-7.15 (m, 2H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 5.37-5.01 (m, 1H), 4.14 (dd, J = 13.9, 5.0 Hz, 1H), 4.08-3.93 (m, 1H), 3.74 (dt, J = 11.2, 3.8 Hz, 1H), 3.62 (ddd, J = 14.0, 11.3, 4.9 Hz, 1H), 3.33-3.26 (m, 1H), 3.18 (dd, J = 11.1, 9.1 Hz, 1H), 2.86-2.70 (m, 2H), 1.93-1.64 (m, 5H), 1.52 (qt, J = 9.8, 4.3 Hz, 2H). Additional compounds described herein can be prepared by using the procedure described in Example 23 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0216] [Table 16]

[0217] (Example 24) Synthesis of compound 331 [ka]

[0218] (S)-6-chloro-1-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2-(2H-tetrazole-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (60 mg, 0.16 mmol) and sodium carbonate (18.8 mg, 0.18 mmol) were placed in a vial equipped with a stirring bar. The solid was dissolved in DMA (0.3 mL), and dimethyl sulfate (22.3 mg, 0.18 mmol) was added to the vial at room temperature.

[0219] The mixture was stirred at room temperature for 1 hour, after which 1 mL of water was added, and a precipitate formed. The solid was collected by filtration and purified by silica gel chromatography to obtain (S)-6-chloro-2-(1-methyl-1H-tetrazole-5-yl)-1-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (product containing impurities, structure determined by 2D-NOESY NMR) and compound 331(S)-6-chloro-2-(2-methyl-2H-tetrazole-5-yl)-1-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid (41 mg, yield 62%). MS m / z 385.2 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.95 (dd, J = 8.6, 2.1 Hz, 1H), 5.18 (d, J = 10.7 Hz, 1H), 4.07 (s, 3H), 4.04 (d, J = 5.4 Hz, 1H), 3.67 (d, J = 11.1 Hz, 2H), 3.48-3.34 (m, 1H), 3.22 (s, 1H), 3.08-2.92 (m, 1H), 2.77-2.64 (m, 1H), 2.53 (dd, J = 15.7, 4.1 Hz, 1H), 2.00 (d, J = 12.5 Hz, 1H), 1.75-1.53 ​​(m, 4H), 1.46-1.20 (m, 2H).

[0220] (Example 25) Synthesis of compound 337 [ka]

[0221] (1S)-6-chloro-1-isobutyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carbonitride (190 mg, 0.66 mmol) and 2,2,2-trifluoro-N'-hydroxyacetamidine (13 mg, 0.88 mmol) were placed in vials and dissolved in 8 mL of a 1:1 mixture of siRNA and THF. A 1.0 M solution of zinc chloride in diethyl ether (1.3 mL, 1.32 mmol) was added to the vial, and the mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure, the residue was redissolved in the minimum amount of methanol, and the solid precipitated from the solution by adding diethyl ether and collected by vacuum filtration. The organic solid was placed in a flask and dissolved in 10 mL of ethanol. Then 2 mL of concentrated aqueous HCl was added to the mixture. Once the addition was complete, the reaction mixture was heated to 100 °C and stirred for 15 hours. Then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethylethanol / hexane to obtain (1S)-6-chloro-1-(2-methylpropyl)-2-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid (92 mg, yield 35%). MS m / z 397.2 [MH] - ; 1 H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.08 (dt, J = 8.7, 1.5 Hz, 1H), 5.47-5.13 (m, 1H), 4.29 (dd, J = 13.8, 5.0 Hz, 1H), 3.68 (ddd, J = 13.6, 11.1, 5.1 Hz, 1H), 2.99-2.73 (m, 2H), 1.97 (ddd, J = 13.9, 10.6, 3.4 Hz, 1H), 1.82-1.56 (m, 2H), 1.08 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H).

[0222] (Example 26) Synthesis of compound 338 [ka]

[0223] Hydroxylamine hydrochloride (72 mg, 1.04 mmol), (1S)-6-chloro-1-isobutyl-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carbonitrile (150 mg, 0.52 mmol), and sodium carbonate (60 mg, 0.57 mmol) were placed in a vial and suspended in DMF (1.5 mL). The resulting mixture was stirred at 80°C for 30 minutes. The reaction solution was then cooled to 25°C, and toluene (3 mL), followed by pyridine (0.18 mL, 2.2 mmol) and trifluoroacetic anhydride (0.29 mL, 2.1 mmol) were added. The reaction solution was stirred at room temperature for 18 hours, after which it was concentrated under reduced pressure to a volume of approximately 2 mL. Water was then added, and the substance precipitated from the solution. The solid residue was collected by filtration and further purified by silica gel chromatography using DCM as the eluent. (1S)-6-chloro-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (103 mg, yield 50%) was obtained as a white solid. MS m / z 397.3 [MH] - ; 1H NMR (500 MHz, DMSO-d6) δ 11.20 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.05 (dd, J = 8.6, 2.1 Hz, 1H), 5.16 (dd, J = 10.9, 3.4 Hz, 1H), 4.12 (dd, J = 13.9, 5.4 Hz, 1H), 3.55 (td, J = 12.9, 4.4 Hz, 1H), 2.99-2.58 (m, 2H), 1.94 (ddd, J = 14.2, 10.8, 3.7 Hz, 1H), 1.72 (dddd, J = 43.8, 13.4, 8.1, 3.4 Hz, 2H), 1.07 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H). Additional compounds described herein can be prepared by using the procedure described in Example 26 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0224] [Table 17]

[0225] (Example 27) Synthesis of compounds 66, 67A / B, and 68A / B [ka]

[0226] Step 1: 4-toluenesulfonyl chloride (270 mg, 1.4 mmol) and 4-[2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]butan-1,3-diol (640 mg, 1.3 mmol) were placed in a round-bottom flask and dissolved in DCM (15 mL). The mixture was cooled to 0°C, and N,N-diisopropylethylamine (243 mg, 1.9 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were added. The mixture was slowly heated to room temperature and stirred for 18 hours. The solution was concentrated under reduced pressure, and the crude substance was purified by silica gel chromatography (eluate HCl / hexane) to obtain [4-[2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]-3-hydroxybutyl]4-methylbenzenesulfonate (408 mg, 0.6 mmol, yield 49%) as a white solid.

[0227] Step 2: Dissolve [4-[2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]-3-hydroxybutyl]4-methylbenzenesulfonate (81 mg, 0.13 mmol) in 4 mL of methanol. Add 1.4 mL, 6.2 mmol of 30% sodium methoxide in methanol to the mixture, and then stir at room temperature for 16 hours. The reaction mixture was quenched to approximately pH 5-6 by adding a 10% aqueous acetic acid solution, and then washed with saturated NaHCO3 (aqueous solution). The aqueous layer was extracted three times using DCM, the combined organic portion was dried and concentrated, and subjected to silica gel chromatography for purification to isolate the three individual reaction products.

[0228] The byproduct was isolated as a mixture of compound 66: diastereomer (0.4:0.6 ratio) 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(oxetan-2-ylmethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (7 mg, 0.014 mmol, yield 12%). MS m / z 490.1 [MH] - ; 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 9.36 (apparent d, J = 11.7 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 8.6, 2.1 Hz, 1H), 5.99 (t, J = 6.9 Hz, 0.6H, main diastereomer), 5.80 (t, J = 6.0 Hz, 0.4H, secondary diastereomer), 5.09-4.84 (m, 2H), 4.61-4.34 (m, 2H), 3.59-3.36 (m, 1H), 2.88-2.41 (m, 4H), 2.32 (t, J = 6.6 Hz, 1H), 2.29-2.11 (m, 1H), 2.01 (d, J = 1.9 Hz, 1H).

[0229] Compounds 67A and 67B were isolated as a racemic mixture: Compound 67A (2S)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol and Compound 67B (2R)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol (16 mg, 0.031 mmol, yield 25%). MS m / z 522.1 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.08 (dd, J = 8.5, 2.1 Hz, 1H), 6.04 (dd, J = 9.7, 4.8 Hz, 1H), 4.95 (dd, J = 13.2, 5.3 Hz, 1H), 4.53 (d, J = 5.7 Hz, 1H), 3.72 (s, 1H), 3.60 (td, J = 12.6, 4.5 Hz, 1H), 3.39 (td, J = 6.9, 6.4, 3.7 Hz, 2H), 3.18 (s, 2H), 2.99-2.70 (m, 2H), 2.25-1.99 (m, 2H), 1.96-1.78 (m, 1H), 1.58 (dq, J = 13.9, 6.4 Hz, 1H).

[0230] Compounds 68A and 68B were isolated as a racemic mixture: Compound 68A (2S)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol and Compound 68B (2R)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol (28 mg, 0.055 mmol, yield 44%). MS m / z 522.0 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.99 (dd, J = 8.6, 2.1 Hz, 1H), 6.06 (dd, J = 9.2, 4.0 Hz, 1H), 4.87 (dd, J = 13.2, 5.2 Hz, 1H), 4.41 (d, J = 5.5 Hz, 1H), 3.72-3.40 (m, 2H), 3.39-3.26 (m, 2H), 3.10 (s, 3H), 2.92-2.60 (m, 2H), 2.03 (dddd, J = 39.8, 14.2, 9.2, 3.6 Hz, 2H), 1.54 (p, J = 7.0 Hz, 2H). Additional compounds described herein can be prepared by using the procedure described in Example 27 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0231] [Table 18]

[0232] (Example 28) Synthesis of Compound 17 [ka]

[0233] A 20 mL vial contained cesium fluoride (86 mg, 0.566 mmol), tris(dibenzylideneacetone)dipalladium (0) (18 mg, 0.019 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (20 mg, 0.039 mmol), and (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-bromo-1-[[(3R)-tetrahydropyran-3-yl]methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (100 mg, 0.189 mmol). The vial was tightly sealed and placed under an argon atmosphere. Toluene (1.9 mL) was added, and the suspension was stirred at 100°C for 5 minutes. Then, 1H-triazole (26 mg, 0.376 mmol) in 1,4-dioxane (0.4 mL) was added, and the reaction mixture was stirred at 100°C for 14 hours. After cooling to ambient temperature, volatiles were removed, and the resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC. After lyophilization, the desired compound, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-{[(3R)-oxan-3-yl]methyl}-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (35 mg, 0.063 mmol, yield 35%), was isolated as a grayish-white powder. MS m / z 551.1 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.04 (s, 3H), 7.79 (dd, J = 8.5, 2.1 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 5.93 (d, J = 6.1 Hz, 1H), 4.95 (dd, J = 13.3, 5.2 Hz, 1H), 4.09 (d, J = 11.2 Hz, 1H), 3.74-3.56 (m, 2H), 3.34-3.17 (m, 2H), 2.95 (d, J = 11.9 Hz, 1H), 2.91-2.78 (m, 1H), 1.95 (t, J = 14.5 Hz, 2H), 1.77 (d, J = 12.8 Hz, 1H), 1.65 (s, 1H), 1.50 (d, J = 16.8 Hz, 2H), 1.23 (s, 1H).

[0234] Additional compounds described herein can be prepared by using the procedure described in Example 28 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following: [Table 19] TIFF2026524862000120.tif134158

[0235] (Example 29) Synthesis of compound 284 [ka]

[0236] In a 40 mL vial equipped with a stirring bar, septum cap, and nitrogen inlet, (1S)-6-chloro-1-(2-methylpropa-1-enyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.767 mmol), 4-dimethylaminopyridine (130 mg, 1.06 mmol), and acetonitrile (7.7 mL) were added, followed by the addition of 2,4-bis(difluoromethyl)-6-(trichloromethyl)-1,3,5-triazine (300 mg, 1.00 mmol). The vial was sealed, flushed with nitrogen, and stirred at ambient temperature. After stirring overnight, the reaction mixture was concentrated under reduced pressure, and the dark residue was adsorbed onto silica gel and subjected to ISCO purification (hexane Â). (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (324 mg, 0.737 mmol, yield 96%) was isolated as a grayish-white amorphous solid. MS m / z 437.7 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 6.95-6.59 (m, 2H), 6.53 (d, J = 9.7 Hz, 1H), 5.47 (dt, J = 9.6, 1.5 Hz, 1H ), 5.01 (dd, J = 13.2, 5.1 Hz, 1H), 3.60-3.44 (m, 1H), 2.89 (dd, J = 15.7, 3.6Hz, 1H), 2.82-2.69 (m, 1H), 2.04 (d, J = 1.3 Hz, 3H), 1.73 (d, J = 1.4 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) δ -123.24--123.78 (m). Additional compounds described herein can be prepared by using the procedure described in Example 29 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0237] [Table 20] TIFF2026524862000123.tif215156 TIFF2026524862000124.tif197156 TIFF2026524862000125.tif215156 TIFF2026524862000126.tif214156 TIFF2026524862000127.tif198156 TIFF2026524862000128.tif194156 TIFF2026524862000129.tif209156 TIFF2026524862000130.tif216156 TIFF2026524862000131.tif220156 TIFF2026524862000132.tif141156

[0238] (Example 30) Synthesis of compounds 54 and 55 [ka]

[0239] In a 20 mL vial, (1S)-6-chloro-1-(tetrahydropyran-2-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.328 mmol), 4-dimethylaminopyridine (81 mg, 0.656 mmol), acetonitrile (3.3 mL), and 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (220 mg, 0.658 mmol) were sequentially added, the vial was sealed, and stirred at ambient temperature for 3 hours. After this, volatile matter was removed under reduced pressure. The resulting dark residue was purified by silica gel chromatography (hexane: siRNA) to obtain diastereomer compounds 54 and 55 as white amorphous solids. The relative stereochemistry was not determined; NMR data were obtained without assignment to specific diastereomers.

[0240] Compound 54:MS m / z 518.2 [MH]-; 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.05 (dd, J = 8.6, 2.1 Hz, 1H), 6.22 (d, J = 9.7 Hz, 1H), 4.92 (dd, J = 13.3, 5.1 Hz, 1H), 3.85 (d, J = 11.3 Hz, 1H), 3.58 (td, J = 12.5, 4.4 Hz, 1H), 3.28-3.15 (m, 2H), 2.92-2.70 (m, 2H), 2.19-2.07 (m, 1H), 2.07-1.96 (m, 1H), 1.72 (s, 1H), 1.45 (q, J = 13.7 Hz, 4H), 1.32-1.12 (m, 1H).

[0241] Compound 55MS m / z 518.2 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.7, 2.1 Hz, 1H), 6.02 (d, J = 10.1 Hz, 1H), 4.94 (dd, J = 13.7, 5.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 2H), 3.44 (s, 1H), 3.13-2.95 (m, 1H), 2.86 (d, J = 13.9 Hz, 1H), 2.82-2.69 (m, 1H), 2.23-1.94 (m, 2H), 1.83 (d, J = 12.6 Hz, 1H), 1.75 (s, 1H), 1.39 (d, J = 5.7 Hz, 3H), 1.32-1.14 (m, 1H). Additional compounds described herein can be prepared by using the procedure described for Example 30 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0242] [Table 21] TIFF2026524862000135.tif166154

[0243] (Example 31) Synthesis of compound 98 [ka]

[0244] In a 20 mL vial, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-buta-3-enyl-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole (90 mg, 0.189 mmol), potassium osmium(VI) dihydrate (4 mg, 0.011 mmol), and 4-methylmorpholine N-oxide (30 mg, 0.248 mmol) were placed and suspended in acetone (5 mL) and water (1 mL). The mixture was stirred at ambient temperature for 14 hours. Volatile substances were removed under reduced pressure, and the resulting residue was dissolved in DMSO and subjected to preparative HPLC purification (water acetonitrile). After freeze-drying, 4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,2-diol (35 mg, 0.069 mmol, yield 36%) was obtained as a white amorphous solid. MS m / z 508.1 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.5, 2.1 Hz, 1H), 5.98-5.79 (m, 2H), 5.03 (d, J = 17.3 Hz, 1H), 4.99-4.90 (m, 2H), 3.59 (t, J = 10.7 Hz, 1H), 2.87 (d, J = 12.5 Hz, 1H), 2.82-2.70 (m, 1H), 2.25-2.03 (m, 4H). Additional compounds described herein can be prepared by using the procedure described in Example 31 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0245] [Table 22]

[0246] (Example 32) Synthesis of compound 165 [ka]

[0247] Step 1: Bis(pinacolato)diborone (117 mg, 0.461 mmol), potassium acetate (56 mg, 0.571 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63 mg, 0.076 mmol), and (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-bromo-1-isobutyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (200 mg, 0.383 mmol) were placed in a 20 mL container, sealed, and placed under an argon atmosphere. The solid was suspended in dioxane and stirred overnight at 100°C. After cooling to ambient temperature, volatiles were removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane siRNA). (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-isobutyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (130 mg, 0.228 mmol, yield 59%) was isolated as a grayish-white amorphous solid. MS m / z 568.1 [MH] - ; 1H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 7.80 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 5.97 (d, J = 10.3 Hz, 1H), 4.94 (dd, J = 13.1, 5.1 Hz, 1H), 3.58 (d, J = 13.9 Hz, 1H), 2.97-2.73 (m, 2H), 1.99 (t, J = 12.3 Hz, 1H), 1.78 (t, J = 12.0 Hz, 1H), 1.66 (s, 1H), 1.29 (s, 12H), 1.11 (d, J = 6.2 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).

[0248] [ka]

[0249] Step 2: In an 8 mL vial, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-isobutyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (130 mg, 0.228 mmol), tetrahydrofuran (1 mL), and water (1 mL) were added, followed by the addition of sodium perborate (100 mg, 1.16 mmol). The reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was then filtered, the aqueous phase was washed with DCM, the combined organic phase was dried over Na2SO4 to remove volatiles, and the residue was subjected to silica gel chromatography (hexane SiO). The product, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-ol (81 mg, 0.176 mmol, 77% yield), was isolated as a grayish-white solid. MS m / z 458.2 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.61 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.70 (s, 1H), 6.57 (dd, J = 8.4, 2.2 Hz, 1H), 5.91 (d, J = 10.3 Hz, 1H), 4.89 (d, J = 13.1 Hz, 1H), 3.58 (dt, J = 14.6, 8.1 Hz, 1H), 2.74 (d, J = 7.9 Hz, 2H), 2.04-1.90 (m, 1H), 1.75 (t, J = 12.5 Hz, 1H), 1.64 (s, 1H), 1.09 (d, J = 6.3 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H).

[0250] (Example 33) Synthesis of compound 188 [ka]

[0251] (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-bromo-1-[[(3S)-tetrahydropyran-3-yl]methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (120 mg, 0.21 mmol), [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (20 mg, 0.02 mmol), cesium fluoride (100 mg, 0.66 mmol), and toluene (1 mL) were placed in a scintillation vial. The reaction vial was flushed with argon, sealed, and the mixture was then heated to 50°C for 15 minutes, after which methanol (0.035 mL, 0.87 mmol) was added. The reaction vial was flushed again with argon, sealed, and the mixture was then stirred at 50°C for 16 hours. The mixture was directly concentrated and purified by silica gel chromatography to obtain the desired compound (29 mg, 26% yield).

[0252] Compound 188:ESI-MS m / z 514 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 10.88(s, 1H), 7.21(d, 1H, J=4.8Hz), 6.90(d, 1H, J=2.4Hz), 6.70 (q,1H, J=6.4Hz),5.92(q,1H, J=8Hz), 4.96(q, 1H, J=9.2Hz),3.83(s,3H), 3.71-3.55(m, 3H),3.29(t, 1H, J=2.4Hz), 2.99(t, 1H, J=10.4Hz), 2.80-2.75(m, 2H), 2.33-2.30(m, 1H), 1.86-1.73(m, 2H), 1.61-1.32 (m, 4H). Additional compounds described herein can be prepared by using the procedure described in Example 33 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0253] [Table 23]

[0254] (Example 34) Synthesis of compound 320 [ka]

[0255] (1S)-6-chloro-1-isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.380 mmol), cesium fluoride (170 mg, 1.119 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (33 mg, 0.038 mmol) were placed in an 8 mL vial, sealed, and placed under an argon atmosphere. 4-bromo-2-(trifluoromethyl)pyrimidine (100 mg, 0.427 mmol) in toluene (4 mL) was added, and the reaction mixture was stirred at 100 °C for 8 hours. After cooling to ambient temperature, volatile substances were removed under reduced pressure, and the residue was adsorbed onto silica gel and subjected to silica gel chromatography (hexane SiO). (1S)-6-chloro-1-(2-methylpropyl)-2-[2-(trifluoromethyl)pyrimidine-4-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (79 mg, 0.193 mmol, yield 51%) was isolated as a grayish-white solid. MS m / z 407.0 [MH] - ; 1 H NMR (500 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.37 (t, J = 4.4 Hz, 1H), 7.44 (s, 1H), 7.31 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 8.5 Hz, 1H), 6.16 (d, J = 10.7 Hz, 1H), 4.34 (d, J = 14.4 Hz, 1H), 4.02 (d, J = 7.4 Hz, 1H), 3.60 (s, 1H), 2.74 (d, J = 6.8 Hz, 2H), 1.68 (d, J = 13.3 Hz, 1H), 1.59 (s, 1H), 1.11 (s, 3H), 0.91 (s, 3H).

[0256] (Example 35) Synthesis of compound 268 [ka]

[0257] In an 8 mL vial equipped with a stirring bar and septum cap, (1S)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; formic acid (100 mg, 0.285 mmol), and 2-chloropyrimidine-4-carbonitrile (61 mg, 0.428 mmol) were added and suspended in 1 mL of 1-butanol. N,N-diisopropylethylamine (0.15 mL, 0.86 mmol) was added, and the vial was placed in a heating block preheated to 100 °C. The reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated and subjected to ISCO purification (hexane HCl 0-100%). The product, 2-[(1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl]pyrimidine-4-carbonitrile (72 mg, 0.176 mmol, 62% yield), was isolated as a grayish-white solid. MS m / z 406.3 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.69 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 4.7 Hz, 1H), 7.07-6.97 (m, 1H), 6.09-5.75 (m, 1H), 4.97-4.67 (m, 1H), 3.70 (t, J = 12.8 Hz, 2H), 3.39 (dt, J = 14.8, 8.7 Hz, 1H), 3.28 (d, J = 11.4 Hz, 1H), 3.02 (t, J = 10.3 Hz, 1H), 2.71 (br s, 2H), 2.32-2.05 (m, 1H), 1.88-1.67 (m, 2H), 1.67-1.47 (m, 2H), 1.48-1.21 (m, 2H). Additional compounds described herein can be prepared by using the procedure described in Example 35 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0258] [Table 24] TIFF2026524862000145.tif193158 TIFF2026524862000146.tif195158 TIFF2026524862000147.tif194158 TIFF2026524862000148.tif187158

[0259] (Example 36) Synthesis of compound 310 [ka]

[0260] (1S)-6-chloro-1-isobutyl-2-[4-(trichloromethyl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (50 mg, 0.095 mmol), morpholine (12 mg, 0.138 mmol), N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (393 mg, 3.041 mmol), and 4-dimethylaminopyridine (24 mg, 0.194 mmol) were placed in a 20 mL vial equipped with a stirring bar. The reaction mixture was then sealed and stirred at 70°C for 14 hours. After cooling to ambient temperature, the reaction was stopped by adding water (30 mL), extracted with siRNA (2 × 30 mL), washed with brine (20 mL), then dried over Na₂SO₄, and volatiles were evaporated under vacuum. The resulting residue was purified by preparative HPLC (water-acetonitrile). After lyophilization, (1S)-6-chloro-1-(2-methylpropyl)-2-[4-(morpholine-4-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (34 mg, 0.069 mmol, yield 72%) was isolated as a yellow amorphous solid. MS m / z 493.0 [MH] - ; 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.41-7.40 (d, J = 2.0 Hz 1H), 7.21-7.20 (d, J = 3.6 Hz, 1H), 7.09-7.08 (t, J = 2.0 Hz, 1H), 5.99-5.95 (dd, J = 4.8, 9.6 Hz, 1H), 5.01-4.96 (dd, J = 4.8, 9.6 Hz, 1H), 3.88-3.75 (m, 8H), 3.35-3.27 (m, 1H), 2.87-2.81 (m, 1H), 2.72-2.67 (dd, J = 4.8, 14.8 Hz, 1H), 1.93-1.86 (m, 1H), 1.77-1.59 (m, 1H), 1.12-1.07 (d, J = 6.4 Hz, 3H), 1.00-0.95 (d, J = 6.4 Hz, 3H).

[0261] Additional compounds described herein can be prepared by using the procedure described in Example 36 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following: [Table 25] TIFF2026524862000151.tif140160

[0262] (Example 37) Synthesis of compound 136 [ka]

[0263] Step 1: In a 250 mL round-bottom flask, 1-allyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1 g, 4.05 mmol) suspended in methanol (25 mL) and (2S)-3-phenyl-2-(p-tolylsulfonylamino)propanoic acid (1 g, 3.131 mmol) were placed and heated under reflux. Methanol (70 mL) was continuously added under reflux. After stirring under reflux for 1 hour, the reaction mixture was cooled to ambient temperature and the white solid was filtered off. The solid was suspended between ELISA (100 mL) and NH4OH aqueous solution (100 mL) and mixed until all the solid was dissolved. The organic phase was separated and concentrated under reduced pressure to obtain (1S)-1-allyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (295 mg, 1.20 mmol, 100% by mass), which had a higher proportion of one enantiomer (>98:2er).

[0264] Step 2: In a 20 mL vial, (1S)-1-allyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (135 mg, 0.547 mmol), 4-dimethylaminopyridine (100 mg, 0.810 mmol), acetonitrile (5.5 mL), and 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (275 mg, 0.822 mmol) were added, and the mixture was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, adsorbed onto Celite, and subjected to ISCO purified silica gel chromatography (hexane Â100%). (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(propa-2-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (240 mg, 0.520 mmol, 95% yield) was isolated as a grayish-white amorphous solid. MS m / z 460.2 [MH] - ; 1 H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.08 (dd, J = 8.7, 2.1 Hz, 1H), 5.95 (dd, J = 8.9, 4.4 Hz, 1H), 5.81 (ddt, J = 17.2, 10.1, 7.2 Hz, 1H), 5.13 (dd, J = 17.0, 2.1 Hz, 1H), 5.00 (d, J = 10.3 Hz, 1H), 4.97 (dd, J = 13.1, 5.1 Hz, 1H), 3.58 (td, J = 12.7, 4.2 Hz, 1H), 2.93-2.84 (m, 2H), 2.84-2.70 (m, 2H).

[0265] Additional compounds described herein can be prepared by using the procedure described in Example 37 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following: [Table 26]

[0266] (Example 38) Synthesis of compounds 78A and 78B [ka]

[0267] A racemic mixture of (2S)-3-[(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]propan-1,2-diol and (2R)-3-[(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]propan-1,2-diol (210 mg, 0.424 mmol), tetrahydrofuran (4 mL), triethylamine (0.09 mL, 0.6 mmol), and acetic anhydride (0.048 mL, 0.51 mmol) were placed in an 8 mL vial equipped with a stirring bar. The mixture was stirred at ambient temperature for 14 hours. Subsequently, the reaction mixture was concentrated under reduced pressure, and the resulting residue was adsorbed onto silica gel. The mixture was then purified by silica gel chromatography (0-40% hexane / SiO2) to obtain a racemic mixture (98 mg, 0.182 mmol, yield 43%) of compound 78A (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-hydroxypropyl acetate and compound 78B (2R)-3-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-hydroxypropyl acetate, which was isolated as a colorless amorphous solid. MS m / z 536.15 [MH]-; 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.48 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.6, 2.1 Hz, 1H), 6.17 (dd, J = 9.6, 4.0 Hz, 1H), 4.98-4.89 (m, 2H), 4.00-3.82 (m, 2H), 3.74 (s, 1H), 3.66-3.54 (m, 1H), 2.92-2.72 (m, 2H), 2.23-2.02 (m, 2H), 2.00 (s, 3H).

[0268] (Example 39) Synthesis of compound 187 [ka]

[0269] Step 1: 2-iodo-4-methylaniline (3.0 g, 12.9 mmol, 100% by mass) was suspended in an ice-cold aqueous solution of concentrated hydrochloric acid (10 mL, 121.8 mmol). A solution of sodium nitrite (0.850 g, 12.3 mmol) in 5 mL of water was added dropwise. After stirring at 0°C for 45 minutes, a solution of tin chloride (5.3 g, 27.7 mmol) in 6 mL of concentrated HCl was added to the mixture. The reaction mixture was raised to room temperature over 3 hours. The mixture was stirred at room temperature for 12 hours. The suspension was then diluted with water, and the aqueous layer was washed twice with DCM. The aqueous layer was basicized with 6 M NaOH solution until pH > 10. The suspension was extracted twice with DCM and once with ELISA, dried over MgSO4, and filtered. The crude substance was purified by silica gel chromatography, and (2-iodo-4-methylphenyl)hydrazine was isolated as a yellow solid (2.1 g yield 68%).

[0270] Step 2: A solution of 4,4-diethoxybutan-1-amine (7.2 g, 45 mmol) in water (80 mL) was placed in a round-bottom flask, followed by the successive addition of (4-chloro-2-iodophenyl)hydrazine (13.0 g, 48.4 mmol) and sulfuric acid (2.28 M, 8 mL, 18.2 mmol). The reaction mixture was stirred at 100 °C for 8 hours and then cooled to ambient temperature. The suspension was filtered, and the solid was washed with water. 2-(5-chloro-7-iodo-1H-indole-3-yl)ethaneamine (6.0 g, 19 mmol, yield 39%) was isolated as a brown solid.

[0271] Step 3: 2-[(3S)-tetrahydropyran-3-yl]acetic acid (450 mg, 3.12 mmol) was placed in a 40 mL vial and suspended in tetrahydrofuran (14 mL). Triethylamine (1.8 mL, 13 mmol) was added, followed by HATU (1.6 g, 4.1 mmol). The mixture was stirred at ambient temperature for 15 minutes, then 2-(5-chloro-7-iodo-1H-indole-3-yl)ethaneamine (1 g, 3.12 mmol) was added all at once, and stirring was continued at ambient temperature for 14 hours. The reaction mixture was then diluted with ELISA (50 mL), and the organic phase was sequentially washed with NaOH (2 M, 50 mL), hydrochloric acid (aqueous solution, 2 M, 50 mL), water (50 mL), NaHCO3 (saturated aqueous solution, 50 mL), and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and volatiles were removed under reduced pressure. The product, N-[2-(5-chloro-7-iodo-1H-indole-3-yl)ethyl]-2-[(3S)-tetrahydropyran-3-yl]acetamide (1.85 g, 4.14 mmol, yield 97%), was isolated as a yellowish-brown solid.

[0272] Step 4: In a 100 mL round-bottom flask, N-[2-(5-chloro-7-iodo-1H-indole-3-yl)ethyl]-2-[(3S)-tetrahydropyran-3-yl]acetamide (1.9 g, 4.3 mmol), acetonitrile (10 mL), and phosphoryl chloride (2.4 mL, 26 mmol) were added and stirred at ambient temperature for 16 hours. Volatile substances were removed under reduced pressure, the residue was dissolved in ELISA (200 mL), and washed with NH4OH (100 mL). The organic phase was concentrated, the residue was adsorbed onto silica gel, and subjected to silica gel chromatography (0-20% methanol gradient in DCM). The product, 6-chloro-8-iodo-1-[[(3S)-tetrahydropyran-3-yl]methyl]-4,9-dihydro-3H-pyrido[3,4-b]indole (1.74 g, 4.06 mmol, 95% yield), was isolated as a brown amorphous solid.

[0273] Step 5: In a 40 mL vial, 6-chloro-8-iodo-1-[[(3S)-tetrahydropyran-3-yl]methyl]-4,9-dihydro-3H-pyrido[3,4-b]indole (1.74 g, 4.06 mmol), RuCl[(R,R)-TsDpen](mesitylene) (140 mg, 0.202 mmol), acetonitrile (14 mL), and triethylamine formate complex 5:2 (3.4 mL, 8.1 mmol) were added. The mixture was purged with argon and stirred at ambient temperature while continuing to stir. After stirring for 16 hours, the reaction mixture was diluted with ELISA (100 mL) and washed with NaOH (1 M, 100 mL). The organic phase was dried over Na2SO4, filtered, volatiles were removed under reduced pressure, and the residue was adsorbed onto silica gel and subjected to silica gel chromatography (0-20% methanol gradient in DCM). The product, (1S)-6-chloro-8-iodo-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.684 g, 3.91 mmol, 96% yield), was isolated as a dark amorphous solid.

[0274] Step 6: (1S)-6-chloro-8-iodo-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.1 g, 2.6 mmol), dichloromethane (10 mL), di-tert-butyl dicarbonate (0.2 mL, 0.9 mmol), and triethylamine (0.6 mL, 4 mmol) were placed in a 20 mL vial and stirred at ambient temperature for 12 hours. Then, volatile matter was removed under reduced pressure, and the residue was adsorbed onto silica gel and subjected to silica gel chromatography (0-100% gradient of siRNA in hexane). The product, tert-butyl-(1S)-6-chloro-8-iodo-1-[[(3S)-tetrahydropyran-3-yl]methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (860 mg, 1.62 mmol, yield 63%), was isolated as a grayish-white amorphous solid.

[0275] Step 7: A 40 mL vial was filled with tert-butyl(1S)-6-chloro-8-iodo-1-[[(3S)-tetrahydropyran-3-yl]methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (290 mg, 0.546 mmol), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (142 mg, 0.164 mmol), and sodium tert-butoxide (200 mg, 2.08 mmol). The vial was placed under a nitrogen atmosphere, and the solid was suspended in toluene (4 mL, 38 mmol). Benzophenone imine (0.20 mL, 1.2 mmol) was added, and the reaction mixture was stirred at 100°C for 14 hours. After cooling to ambient temperature, volatile substances were removed under reduced pressure, and the residue was adsorbed onto silica gel and subjected to silica gel chromatography (0-100% gradient of ELISA in hexane). Tert-butyl-(1S)-8-(benzhydrideneamino)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (70 mg, 0.120 mmol, yield 22%) was isolated as a grayish-white amorphous solid.

[0276] Step 8: In a 20 mL vial, tert-butyl-(1S)-8-(benzhydrideneamino)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (70 mg, 0.120 mmol) and dichloromethane (5 mL) were added, followed by the addition of trifluoroacetic acid (0.5 mL, 7 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, after which volatile substances were removed under reduced pressure, the residue was dissolved, and the mixture was co-evaporated with acetonitrile (3 × 10 mL). The product, 1,1-diphenyl-N-[(1S)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-yl]methaneimine, was used in the next step without further purification.

[0277] Step 9: A vial containing 1,1-diphenyl-N-[(1S)-6-chloro-1-[[(3S)-tetrahydropyran-3-yl]methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-yl]methanymine (60 mg, 0.120 mmol) was filled with N,N-dimethylpyridine-4-amine (46 mg, 0.376 mmol), followed by a solution of 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (80 mg, 0.239 mmol) in acetonitrile (1.3 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The dark residue was then suspended in tetrahydrofuran (4 mL) and water (0.4 mL). Sodium acetate (30 mg, 0.366 mmol) was added, followed by hydroxylamine hydrochloride (87 mg, 1.252 mmol). The reaction mixture was sonicated for 2 minutes until a homogeneous solution was formed, and then stirred at ambient temperature for 1 hour. The reaction mixture was concentrated, dissolved in DMSO, and subjected to preparative HPLC purification (5-100% gradient of acetonitrile in water). After lyophilization, the product (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-amine (9 mg, 0.017 mmol, yield 13%) was isolated as a white amorphous solid. MS m / z 533.0 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 6.67 (s, 1H), 6.34 (d, J = 1.9 Hz, 1H), 5.98-5.84 (m, 1H), 5.23 (s, 2H), 4.89 (d, J = 12.3 Hz, 1H), 3.72 (t, J = 14.3 Hz, 2H), 3.61-3.50 (m, 1H), 3.01 (t, J = 10.3 Hz, 1H), 2.87-2.61 (m, 2H), 2.34 (d, J = 13.2 Hz, 1H), 1.89 (t, J = 12.4 Hz, 1H), 1.69 (t, J = 12.1 Hz, 1H), 1.59 (br s, 2H), 1.45 (m, 1H), 1.38-1.18 (m, 1H).

[0278] (Example 40) Synthesis of compound 292 [ka]

[0279] Step 1: 2-cyclohexylideneacetic acid (3 g, 21.4 mmol), DMF (24 mL), and DIPEA (11.4 mL) were placed in a round-bottom flask equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 5 minutes. 2-(5-chloro-1H-indole-3-yl)ethanamine hydrochloride (5.0 g, 21.7 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography to obtain a solid residue (5 g, 75% yield). The product was used directly in the next step without further purification or analysis.

[0280] Step 2: N-[2-(5-chloro-1H-indole-3-yl)ethyl]-2-cyclohexylidene-acetamide (500 mg, 1.6 mmol) was placed in a round-bottom flask equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and continued under nitrogen. Acetonitrile (5 mL) and phosphoryl chloride (0.75 mL, 8.2 mmol) were added to the reaction mixture. The reaction mixture was heated at 90°C for 4 hours. After 4 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was cooled to room temperature and concentrated under vacuum. Saturated sodium bicarbonate solution was added to the concentrate, extracted with Â, washed with brine, dried over Na₂SO₄, and concentrated to obtain a yellow oily substance (350 mg, yield 73%). The product was used directly in the next step without further purification or analysis.

[0281] Step 3: Imine 6-chloro-1-(cyclohexylidenemethyl)-4,9-dihydro-3H-pyrido[3,4-b]indole (750 mg, 2.5 mmol) was added as a solution in methanol (30 mL) to a round-bottom flask equipped with a magnetic stirrer. The reaction mixture was flushed with nitrogen and maintained under nitrogen. Sodium borohydride (405 mg, 10.7 mmol) was added to the reaction mixture all at once. The reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was cooled to 0°C and quenched with 1% acetic acid solution. The solution was adjusted to pH approximately 9 using 10% NaOH. The mixture was extracted with ethyl acetate, dried over Na₂SO₄, and concentrated under vacuum. (405 mg, yield 54%) The concentrate was used directly in the next step without further analysis or purification.

[0282] Step 4: 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (356 mg, 1.1 mmol) was added as a solution in THF (5.0 mL) to a round-bottom flask equipped with a magnetic stirring bar. The reaction mixture was flushed with nitrogen and maintained under nitrogen. 6-chloro-1-(cyclohexylidenemethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (80 mg, 0.3 mmol) and DIPEA (138 mg, 1.1 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 17 hours. After 17 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was concentrated under vacuum. The crude concentrate was purified by silica gel chromatography to obtain 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(cyclohexylidenemethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (8 mg, 0.01551 mmol, yield 5.8%) as a white solid. MS m / z 516.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.49 (d, J= 1.7 Hz, 1H), 7.37 (d, J= 8.6 Hz, 1H), 7.08 (dd, J= 8.6, 1.9 Hz, 1H), 6.01 (dd, J= 10.0, 3.7 Hz, 1H), 5.41 (s, 1H), 4.94 (dd, J= 13.3, 4.9 Hz, 1H), 3.63 (td, J= 12.9, 4.3 Hz, 1H), 2.89 (dd, J= 15.4, 3.5 Hz, 1H), 2.82 -2.72 (m, 1H), 2.70 -2.57 (m, 2H), 2.33 (d, J= 16.9 Hz, 1H), 1.95 -1.81 (m, 2H),1.64 (d, J= 16.6 Hz, 1H), 1.53 (d, J= 9.2 Hz, 1H), 1.34 (t, J= 14.0 Hz, 3H). Additional compounds described herein can be prepared by using the procedure described for Example 40 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0283] [Table 27]

[0284] (Example 41) Synthesis of compound 233 [ka]

[0285] Step 1: In a round-bottom flask equipped with a magnetic stirrer, 2-(5-chloro-1H-indole-3-yl)ethanamine hydrochloride (200 mg, 0.9 mL), 1,2-DCE (3 mL), (Z)-hepta-4-enal (145 mg, 1.3 mmol), and TFA (0.2 mL, 2.6 mmol) were added. The reaction mixture was flushed with nitrogen and maintained under nitrogen. The reaction mixture was heated at 90°C for 2 hours. After 2 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was concentrated under vacuum. The concentrate was ground with petroleum ether / Âi 20:1 and filtered. The filtered cake was dried under vacuum to obtain 6-chloro-1-[(Z)-hexa-3-enyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole;2,2,2-trifluoroacetaldehyde as a light brown solid. (300 mg, 90% yield). The product was used directly in the next step without further purification.

[0286] Step 2: In a round-bottom flask equipped with a magnetic stirring bar, 6-chloro-1-[(Z)-hexa-3-enyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2,2,2-trifluoroacetaldehyde (150 mg, 0.4 mmol), 1-butanol (3 mL), 2-chloro-4-(trifluoromethyl)pyrimidine (142 mg, 0.8 mL), and DIPEA (0.3 mL, 2 mmol) were added. The reaction mixture was flushed with nitrogen and maintained under nitrogen. The mixture was heated to 120°C and stirred for 16 hours. After 16 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was diluted with ethyl acetate, washed with DI water and saturated NaCl, dried over Na2SO4, and concentrated under vacuum. The concentrate was purified by silica gel chromatography to obtain 6-chloro-1-[(3Z)-hexa-3-en-1-yl]-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a pale yellow solid. (87 mg, yield 52%) MS m / z 435.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.32 (d, J =8.4 Hz, 1H), 7.052-7.048 (m, 1H), 7.04-7.03 (m, 1H), 5.95 (s, 1H), 5.41-5.29 (m, 2H), 4.96 (s, 1H), 3.44-3.35 (m, 1H), 2.73-2.69 (m, 2H), 2.19-1.98 (m, 4H), 1.96-1.90 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H). Additional compounds described herein can be prepared by using the procedure described in Example 41 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0287] [Table 28]

[0288] (Example 42) Synthesis of compound 144 [ka]

[0289] 3-[2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]propanoate (100 mg, 0.2 mmol) and DCM (10 mL) were placed in a round-bottom flask equipped with a magnetic stirring bar. The reaction mixture was flushed with nitrogen and maintained under nitrogen. The mixture was cooled to 0°C. DIBAL-H (2 mL, 2 mmol) in hexane was added to the mixture. The reaction mixture was removed from the ice bath and stirred at room temperature for 4 hours. After 4 hours, the reaction was determined to be complete by LC-MS analysis. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with DCM, dried over Na2SO4, and concentrated under vacuum. The concentrate was purified by preparative HPLC to obtain 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4b]indole-1-yl}propan-1-ol as a white solid (18 mg, 0.04 mmol, yield 19.0%). MS m / z 505.9 [M+H] + (DMSO-d6, 400MHz)11.26(s, 1H),7.49(d, J=1.2Hz, 1H), 7.36(d, J=8.0Hz, 1H), 7.08(dd, J=8.4, 1.6Hz,1H), 7.49(d, J=7.2Hz, 1H), 4.92(dd, J=13.6, 4.8Hz,1H), 3.55-3.43(m, 5H), 2.78-2.61(m, 3H), 2.48-2.19(m, 2H). Additional compounds described herein can be prepared by using the procedure described in Example 42 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0290] [Table 29] TIFF2026524862000162.tif65156

[0291] (Example 43) Synthesis of compound 277 [ka]

[0292] Step 1: In a round-bottom flask, 2-(5-chloro-1H-indole-3-yl)ethanamine hydrochloride (506 mg, 2.1893 mmol, 1.1 equivalents), diethyl 2-(2,2-diethoxyethyl)propanediate (550 mg, 1.991 mmol, 1.0 equivalent), 1,2-DCE (8 mL), and TFA (0.3 mL, 4 mmol, 2.0 equivalents) were added. The reaction mixture was heated to 90°C and stirred for 2 hours. The reaction mixture was analyzed by LC-MS and all starting materials were consumed. The reaction mixture was quenched by adding DI water, extracted with DCM (2×), dried over Na2SO4, concentrated, and purified by silica gel chromatography to obtain diethyl 2-[(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl]propanediate. (480 mg, 64% yield). The product was used directly in the next step without further purification or analysis.

[0293] Step 2: Diethyl 2-[(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl]propanediolate (100 mg, 0.26 mmol, 1.0 equivalent), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (106 mg, 0.32 mmol, 1.2 equivalents), DMF (5 mL), DIPEA (0.2 mL, 1 mmol, 4.0 equivalents), and 4-DMAP (1 mg, 0.01 mmol, 0.03 equivalents) were placed in a round-bottom flask equipped with a magnetic stirrer. The reaction mixture was stirred at room temperature for 16 hours. Analysis of the reaction mixture by LC-MS showed that all starting materials had been consumed. The reaction mixture was quenched by adding DI water, extracted with ELISA (2×), dried over Na₂SO₄, concentrated, and purified by reverse-phase preparative HPLC to obtain diethyl({2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propanedioate as a yellow solid. (8 mg, yield 5.1%) MS m / z 594.0 [M+H] + (CDCl3,400MHz),d: 8.93 (s, 1 H), 7.44-7.44 (d, J = 1.6 Hz, 1 H), 7.29-7.28 (m, 2 H ), 7.16-7.14 (dd, J = 8.4 Hz,1.6 Hz, 1 H), 5.96-5.93 (dd, J = 1.6 Hz, 8.0 Hz,1 H ), 5.21-5.16 (m, 1H), 4.37-4.17 (m, 4 H),3.73-3.69 (dd, J = 6.4 Hz,8.8 Hz,1 H ), 3.54-3.46 (m, 1 H), 2.92-2.88 (m, 1H), 2.69-2.62 (m, 1 H), 2.44-2.36 (m, 1 H), 1.32 -1.29 (t, J=7.2Hz,3 H),1.27-1.24(t, J=7.2Hz,3 H).

[0294] Additional compounds described herein can be prepared by using the procedure described in Example 43 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following: [Table 30]

[0295] (Example 44) Synthesis of compound 290 [ka]

[0296] Step 1: Methyl(E)-3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropa-2-enoate (3.0 g, 10.0 mmol), methanol (30 mL), and Boc2O (3.00 g, 13.3 mmol) were placed in a round-bottom flask equipped with a magnetic stirring bar. The reaction mixture was cooled to 0°C. Sodium borohydride (1.00 g, 26.4 mmol) was added to the reaction mixture. The mixture was stirred for 1 hour. After 1 hour at 0°C, the reaction was determined to be complete by LC-MS analysis. The mixture was diluted with ELISA, washed with DI water and brine, dried over Na2SO4, and concentrated under vacuum. The substance was purified by silica gel chromatography to obtain tert-butyl6-chloro-1-[(E)-3-methoxy-2-methyl-3-oxopropa-1-enyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate as a solid (2.00 g, 50% yield). The product was used directly in the next step without further purification or analysis.

[0297] Step 2: In a round-bottom flask equipped with a magnetic stirring bar, tert-butyl 4-[[6-[(3-chloro-4-pyridyl)amino]pyridine-3-carbonyl]amino]piperidine-1-carboxylate (2.00 g, 4.9 mmol), hydrochloric acid in dioxane (10 mL, 40 mmol), and DCM (10 mL) were added. The reaction mixture was stirred for 1 hour. The reaction mixture precipitated, and after 1 hour, the reaction was determined to be complete by LC-MS. The reaction mixture was filtered and allowed to dry under vacuum to obtain (E)-6-chloro-1-(3-methoxy-2-methyl-3-oxopropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-ium chloride as a solid (1.40 g, yield 93%). The product was used directly in the next step without further purification or analysis.

[0298] Step 3: In a round-bottom flask equipped with a magnetic stirrer, (E)-6-chloro-1-(3-methoxy-2-methyl-3-oxopropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-ium chloride (1.5 g, 2.9 mmol), 4-DMAP (0.58 g, 4.7 mmol), and acetonitrile (10 mL) were added. The reaction mixture was flushed with nitrogen and continued under nitrogen. The reaction mixture was cooled to 0°C. 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (1.60 g, 4.8 mmol) was added to the reaction mixture, and the reaction mixture was stirred for 2 hours. After 2 hours, the reaction was determined to be complete by LC-MS. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography to obtain methyl(2E)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropa-2-enoate as a white solid (1.50 g, yield 63%). MS m / z 518.0 [MH] -; (DMSO-d, 400MHz) 11.15(s,1H),7.55(d, J=2.0Hz, 1H), 7.36(d,J=8.8 Hz,1H), 7.10(q, J=6.8Hz, 1H), 6.73(q, J=9.2 Hz, 1H), 6.55 (d, J=10.0Hz, 1H), 5.01(q,J=9.2 Hz,1H), 3.70 (q, J=9.2 Hz, 1H), 3.66(s, 3H), 2.98(q,J=12.4Hz,1H), 2.85-2.77(m, 1H), 2.24(d,J=1.2 Hz,3H).

[0299] (Example 45) Synthesis of compound 261 [ka]

[0300] A mixture of 6-chloro-1-isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.5576 g, 2.12 mmol), 4,6-bis(difluoromethoxy)-2-(methylsulfonyl)pyrimidine (0.4607 g, 1.59 mmol), and K2CO3 (0.7010 g, 5.02 mmol) in DMF (8 mL) was heated under argon at 70°C for 20 hours. The reaction mixture was then cooled to room temperature, quenched with water and brine, and extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel (40g column) eluting with 0-40% ethyl acetate / hexane over 20 minutes, followed by reverse-phase HPLC (30×150mm preparative) eluting with 15-90% ACN / H2O over 20 minutes to obtain 0.1277g (17%) of 2-[4,6-bis(difluoromethoxy)pyrimidine-2-yl]-6-chloro-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. ESI-MS m / z 473.3 [M+H] + , 471.3 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.01-7.46 (m, 2H), 7.36 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 6.97 (br d, J = 8.5 Hz, 1H), 5.90 (s, 1H), 5.79 (br d, J = 8.9 Hz, 1H), 4.76 (br d, J = 11.9 Hz, 1H), 3.37-3.19 (m, 1H), 2.68-2.59 (m, 2H), 1.89-1.72 (m, 1H), 1.70-1.57 (m, 2H), 1.00 (br d, J = 5.4 Hz, 3H), 0.87 (br d, J = 5.5 Hz, 3H). Additional compounds described herein can be prepared by using the procedure described in Example 45 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0301] [Table 31]

[0302] (Example 46) Synthesis of compound 229 [ka]

[0303] Step 1: A mixture of 2-(5-chloro-1H-indole-3-yl)ethane-1-amine hydrochloride (500 mg, 2.16 mmol), 2-cyclobutylacetic acid (360 mg, 3.15 mmol), HATU (1.5 g, 3.9 mmol), and DIPEA (2.2 mL, 13 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was then quenched with water and extracted three times with ethyl acetate. The combined organic phase was dried over Na₂SO₄. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 450 mg (71.5%) of N-(2-(5-chloro-1H-indole-3-yl)ethyl)-2-cyclobutylacetamide as a white solid. ESI-MS m / z 290.0 (M+H) + .

[0304] Step 2: To a solution of N-(2-(5-chloro-1H-indole-3-yl)ethyl)-2-cyclobutylacetamide (400 mg, 1.37 mmol) in acetonitrile (10 mL), phosphoryl chloride (0.6 mL, 6 mmol) was added. The reaction mixture was stirred at 50 °C for 3 hours, and then the pH was adjusted to 8 with an aqueous solution of NaHCO3. The mixture was extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the crude product (300 mg, 80%) was obtained as a yellow solid, which was used directly in the next step without further purification. ESI-MS m / z 273.1 (M+H) + .

[0305] Step 3: A mixture of 6-chloro-1-(cyclobutylmethyl)-4,9-dihydro-3H-pyrido[3,4-b]indole (100 mg, 0.37 mmol), formate-triethylamine complex 5:2 (0.3 mL, 0.7 mmol), and RuCl[(R,R)-TsDPEN](mesitylene) (3 mg, 0.0043 mmol) in DMF (8 mL) was stirred at room temperature for 2 hours. The reaction mixture was then quenched with an aqueous solution of Na2CO3 and extracted three times with ethyl acetate. The combined organic phase was washed with brine and dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-10% MeOH / DCM to obtain 80 mg (79%) of (S)-6-chloro-1-(cyclobutylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a brown solid. ESI-MS m / z 275.1[M+H] + .

[0306] Step 4: (S)-6-chloro-1-(cyclobutylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (80 mg, 0.29 mmol) and 2-chloro-4,6-bis(trifluoromethyl)pyrimidine (90 mg, 0.36 mmol) were dissolved in acetonitrile (5 mL), to which DIPEA (0.15 mL, 0.86 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 80 mg (56%) of (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(cyclobutylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid. ESI-MS m / z 486.9 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H),7.43 (t, J = 2.4 Hz, 2H ), 7.33 (d, J = 8.4 Hz, 1H), 7.04 (q, J = 8.8 Hz, 1H), 5.82 (t, J = 7.0 Hz,1H ), 4.88 (q, J = 12.0 Hz,1H), 3.45-3.48 (m, 1H), 2.70-2.80 (m, 2H), 2.33-2.37 (m, 1H), 2.06-2.09 (m, 3H), 1.77-1.90(m, 4H), 1.55-1.65 (m, 1H). Additional compounds described herein can be prepared by using the procedure described for Example 46 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0307] [Table 32] TIFF2026524862000170.tif81158

[0308] (Example 47) Synthesis of compound 145 [ka]

[0309] Step 1: A mixture of 2-(5-chloro-1H-indole-3-yl)ethane-1-amine hydrochloride (4.65 g, 20.1 mmol), (E)-4-methoxy-3-methyl-4-oxobuta-2-enoic acid (2.90 g, 20.1 mmol), HATU (9.37 g, 24.1 mmol), and DIPEA (7 mL, 40 mmol) in THF (20 mL) was stirred at room temperature for 16 hours. The reaction mixture was then quenched with water and extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-80% ethyl acetate / hexane to obtain 5.5 g (85%) of methyl(E)-4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobuta-2-enoate as a yellow solid. ESI-MS m / z 321.2(M+H) + .

[0310] Step 2: To a solution of methyl(E)-4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobuta-2-enoate (4.00 g, 12.5 mmol) in acetonitrile (50 mL), phosphoryl chloride (3.5 mL, 38 mmol) was added. The reaction mixture was stirred at 90 °C for 0.5 hours. After evaporating the solvent under reduced pressure, the crude product (3.50 g, 92.7%) was used directly in the next step without further purification. ESI-MS m / z 303.2 (M+H) + .

[0311] Step 3: To a solution of methyl(E)-3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methyl acrylate (3.00 g, 9.91 mmol) and di-tert-butyl dicarbonate (3.00 g, 13.3 mmol) in MeOH (30 mL), NaBH4 (1.00 g, 26.4 mmol) was gradually added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water and brine, and extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-100% ethyl acetate / hexane to obtain 2.00 g (49.9%) of tert-butyl(E)-6-chloro-1-(3-methoxy-2-methyl-3-oxopropa-1-en-1-yl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate. ESI-MS m / z 405.3[M+H] + .

[0312] Step 4: To a solution of tert-butyl(E)-6-chloro-1-(3-methoxy-2-methyl-3-oxopropa-1-en-1-yl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (2.00 g, 4.94 mmol) in DCM (10 mL), hydrogen chloride solution (4.0 M in dioxane, 10 mL, 40 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The solid (1.40 g, 93%) of methyl(E)-3-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methyl acrylate HCl salt was collected by filtration. ESI-MS m / z 305.2 [M+H] + .

[0313] Step 5: A mixture of (E)-6-chloro-1-(3-methoxy-2-methyl-3-oxopropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-2-ium chloride (300 mg, 0.98 mmol) and Pd Lindler catalyst (5% by mass, 240 mg, 0.11 mmol) in THF (5 mL) was stirred at room temperature under hydrogen for 16 hours. The reaction mixture was then filtered. After evaporating the filtrate under reduced pressure, the crude product, methyl 3-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropanoate HCl salt (300 mg, 94%), was obtained as a yellow solid. ESI-MS m / z 307[M+H] + .

[0314] Step 6: To a mixture of methyl 3-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropanoate HCl (0.30 g, 0.93 mmol) and DMAP (2 equivalents) in acetonitrile (2 mL), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (0.34 g, 1.0 mmol) was added dropwise under N2 conditions at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-20% ethyl acetate / hexane to obtain 0.30 g (62%) of methyl 3-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropanoate as a white solid. ESI-MS m / z 520[MH] - .

[0315] Step 7: To a solution of methyl 3-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropanoate (100 mg, 0.19 mmol) in DCM (2 mL), DIBAL-H (1.0 M in hexane, 0.25 mL, 0.25 mmol) was added dropwise under N2 at -78°C. The reaction mixture was stirred at -78°C for 2 hours. After post-treatment, the residue was purified by preparative HPLC to obtain 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol as a white solid. ESI-MS m / z 492 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s,1H),7.46 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.8 Hz,1H), 7.06 (q, J = 6.4 Hz, 1H), 6.01 (q, J = 9.2 Hz, 1H), 4.91 (q, J = 8.4 Hz, 1H), 4.96 (t, J = 5.2 Hz, 1H), 3.59-3.51 (m, 1H), 3.25-3.17 (m, 2H), 2.86 (q, J = 11.6 Hz, 1H), 2.81-2.73 (m, 1H), 2.19 (t, J = 12.0 Hz, 1H), 1.71-1.64 (m, 1H), 1.56-1.47 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H). Additional compounds described herein can be prepared by using the procedure described in Example 47 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0316] [Table 33]

[0317] (Example 48) Synthesis of compound 329 [ka]

[0318] A mixture of (S)-6-chloro-1-isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.76 mmol), 2-fluoro-6-(trifluoromethyl)pyridine (188 mg, 1.14 mmol), and DIPEA (0.4 mL, 2 mmol) in NMP (2 mL) was heated under microwave at 160°C for 4 hours. The reaction mixture was then quenched with water and extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 95 mg (30.6%) of partially epimerized (1S)-6-chloro-1-(2-methylpropyl)-2-[6-(trifluoromethyl)pyridine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid. ESI-MS m / z 408.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.6, 2.4 Hz, 2H), 7.02-6.97 (m, 2H), 6.05 (d, J = 9.6 Hz, 1H), 4.32 (dd, J = 14.2, 4.0 Hz, 1H), 3.55-3.47 (m, 1H), 2.79-2.71 (m, 1H), 2.65 (dd, J = 15.6, 3.2 Hz, 1H), 1.92 (t, J = 10.6 Hz, 1H), 1.70-1.62 (m, 2H), 1.09 (d, J = 5.6 Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H). Additional compounds described herein can be prepared by using the procedure described in Example 48 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0319] [Table 34]

[0320] (Example 49) Synthesis of compound 70 [ka]

[0321] Step 1: Methyl 5-chloro-5-oxopentanoate (1.0 g, 6.07 mmol) was added at 0°C to a solution of 2-(5-chloro-1H-indole-3-yl)ethane-1-amine hydrochloride (1.2 g, 5.2 mmol) and TEA (2.2 mL, 16 mmol) in DCM (15 mL). The reaction mixture was allowed to stand slowly at room temperature overnight. After workup, the residue was purified by chromatography on silica gel to obtain 900 mg (54%) of methyl 5-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-5-oxopentanoate as a white solid. ESI-MS m / z 323.1[M+H] + .

[0322] Step 2: To a solution of methyl 5-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-5-oxopentanoate (1.8 g, 5.6 mmol) in acetonitrile (10 mL), phosphoryl chloride (2.6 mL, 28 mmol) was added. The reaction mixture was stirred at 90 °C for 16 hours. After evaporating the solvent under reduced pressure, the crude product (1.4 g, 82%) was used directly in the next step without further purification. ESI-MS m / z 305.1 (M+H) + . Step 3: To a solution of methyl 4-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)butanoate (200 mg, 0.656 mmol) and di-tert-butyl dicarbonate (220 mg, 0.978 mmol) in MeOH (3 mL), NaBH4 (40 mg, 1.06 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-25% ethyl acetate / hexane to obtain 180 mg (67.4%) of tert-butyl 6-chloro-1-(4-methoxy-4-oxobutyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate as a white solid. ESI-MS m / z 407.2[M+H] + .

[0323] Step 4: To a solution of tert-butyl 6-chloro-1-(4-methoxy-4-oxobutyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (180 mg, 0.44 mmol) in DCM (4 mL), hydrogen chloride solution (4.0 M in dioxane, 1 mL, 4 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, 130 mg (85.6%) of methyl 4-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)butanoate hydrochloride was obtained as a yellow solid. ESI-MS m / z 307.1[M+H] + .

[0324] Step 5: To a mixture of methyl 4-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)butanoate hydrochloride (130 mg, 0.38 mmol) and DMAP (100 mg, 0.81 mmol) in acetonitrile (2 mL), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (130 mg, 0.39 mmol) was added dropwise under N2 conditions at 0°C. The reaction mixture was stirred at room temperature for 0.5 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel, followed by preparative HPLC, to obtain 130 mg (65.7%) of methyl 4-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)butanoate as a white solid. ESI-MS m / z 522.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.06 (dd, J = 13.2, 2.4 Hz, 1H), 5.90-5.87 (m, 1H), 4.94 (dd, J = 13.4, 4.4 Hz, 1H), 3.57 (s, 3H), 3.56-3.51 (m, 1H), 2.89-2.85 (m, 1H), 2.80-2.72 (m, 1H), 2.46-2.34 (m, 2H), 2.08-1.99 (m, 2H), 1.67-1.60 (m, 2H).

[0325] Step 6: A mixture of methyl 4-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)butanoate (150 mg, 0.287 mmol) and ammonia solution (2.0 M in methanol, 3 mL, 6 mmol) was stirred in a sealed tube at 75°C for 48 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 90 mg (61.7%) of methyl 4-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butanoate as a white solid. ESI-MS m / z 508.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 7.07 (dd, J = 8.4, 2.0 Hz, 1H), 6.72 (s, 1H), 5.90-5.87 (m, 1H), 4.95 (dd, J = 13.2, 4.8 Hz, 1H), 3.58-3.51 (m, 1H), 2.89-2.85 (m, 1H), 2.80-2.72 (m, 1H), 2.15-2.04 (m, 3H), 1.99-1.91 (m, 1H), 1.68-1.55 (m, 2H).

[0326] Additional compounds described herein can be prepared by using the procedure described in Example 49 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0327] [Table 35]

[0328] (Example 50) Synthesis of compound 201 [ka]

[0329] Step 1: 2-(5-chloro-1H-indole-3-yl)ethane-1-amine (1.0 g, 5.1 mmol) was dissolved in MeOH (5 mL) and CHCl3 (5 mL). 40 mg of hydrochloric acid was added to adjust the pH to 2. Then, 1,1,3,3-tetramethoxypropane (1.80 g, 11.0 mmol) was added to the mixture. The reaction mixture was stirred at 75°C for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-10% MeOH / DCM to obtain a racemic mixture of 6-chloro-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.70 g, 46%) as a yellow solid. ESI-MS m / z 295[M+H] + .

[0330] Step 2: To a mixture of 6-chloro-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.50 g, 1.7 mmol) and DMAP (0.24 g, 1.9 mmol) in acetonitrile (5 mL), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (0.60 g, 1.8 mmol) was added dropwise under N2 conditions at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-20% ethyl acetate / hexane to obtain a racemic mixture (0.30 g, 35%) of compound 84 2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. ESI-MS m / z 508.2 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 7.49 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.07 (dd, J = 9.7, 3.7 Hz, 1H), 4.95 (dd, J = 13.3, 5.1 Hz, 1H), 4.53 (t, J = 5.5 Hz, 1H), 3.63 (dt, J = 12.7, 7.3 Hz, 1H), 3.28 (s, 3H), 3.13 (s, 3H), 2.95-2.72 (m, 2H), 2.29 (ddd, J = 19.8, (12.9, 7.4 Hz, 2H)

[0331] Step 3: A mixture of 2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.196 mmol), p-toluenesulfonic acid (10 mg, 0.057 mmol), trimethyl orthoformate (10 mg, 0.094 mmol), and ethylene glycol (40 mg, 0.64 mmol) in toluene (3 mL) was stirred at 80°C for 3 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain a racemic mixture (70 mg, 70%) of 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxolan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid. ESI-MS m / z 506 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.07 (q, J = 6.4 Hz, 1H), 6.11 (q, J = 5.6 Hz, 1H), 4.98-4.93 (m, 2H), 3.86-3.80 (m, 2H), 3.75-3.58 (m, 3H), 2.87 (q, J = 12.0 Hz, 1H), 2.80-2.72 (m, 1H), 2.43-2.30 (m, 2H). Additional compounds described herein can be prepared by using the procedure described for Example 50 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0332] [Table 36]

[0333] (Example 51) Synthesis of compound 38 [ka]

[0334] Compound 84, a mixture of 2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (120 mg, 0.235 mmol), p-toluenesulfonic acid (10 mg, 0.057 mmol), trimethyl orthoformate (12 mg, 0.113 mmol), and propane-1,3-diol (55 mg, 0.72 mmol) in toluene (3 mL) was stirred at 80°C for 3 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain compound 38, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 90 mg (73%) as a white solid. ESI-MS m / z 520 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.06 (q, J = 6.8 Hz, 1H), 6.11 (q, J = 7.2 Hz, 1H), 4.92 (q, J = 8.4 Hz, 1H), 4.65 (q, J = 2.0 Hz, 1H), 3.98 (q, J = 6.8 Hz, 1H), 3.84 (q, J = 6.4 Hz, 1H), 3.69-3.52 (m, 3H), 2.85 (q, J = 12.0 Hz, 1H), 2.79-2.71 (m, 1H), 2.31-2.17 (m, 2H), 1.87-1.77 (m, 1H), 1.31 (d, J = 13.2 Hz, 1H).

[0335] (Example 52) Synthesis of compound 161 [ka]

[0336] Step 1: A mixture of 2-(5-chloro-1H-indole-3-yl)ethane-1-amine hydrochloride (1.5 g, 6.5 mmol), 4-methoxy-3-methyl-4-oxobutanoic acid (1.1 g, 7.5 mmol), HATU (3.8 g, 9.8 mmol), and DIPEA (3.4 mL, 19 mmol) in DMF (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was then quenched with water and extracted three times with ethyl acetate. The combined organic phase was dried over Na₂SO₄. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel to obtain 1.4 g (67%) of methyl 4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobutanoate as a brown oily substance. ESI-MS m / z 323.1 (M+H) + .

[0337] Step 2: To a solution of methyl 4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobutanoate (1.3 g, 4.0 mmol) in acetonitrile (15 mL), phosphoryl chloride (2.0 mL, 22 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. After evaporating the solvent under reduced pressure, the crude product (0.9 g, 70%) was used directly in the next step without further purification. ESI-MS m / z 305.1 (M+H) + .

[0338] Step 3: A mixture of methyl 3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropanoate (0.9 g, 3 mmol) and ammonia solution (2.0 M methanol, 10 mL, 20 mmol) was stirred overnight in a sealed tube at room temperature. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel to obtain 0.7 g (80%) of 3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropanamide as a yellow solid. ESI-MS m / z 290.1[M+H] + .

[0339] Step 4: 3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropanamide (80 mg, 0.276 mmol) and di-tert-butyl dicarbonate (0.1 mL, 0.5 mmol) were dissolved in MeOH (2 mL), to which NaBH4 (50 mg, 1.32 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours, then quenched with water and brine, and extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-100% ethyl acetate / hexane to obtain 65 mg (60%) of tert-butyl 1-(3-amino-2-methyl-3-oxopropyl)-6-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate. ESI-MS m / z 292.2[M-100+H] + .

[0340] Step 5: To a solution of tert-butyl 1-(3-amino-2-methyl-3-oxopropyl)-6-chloro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (65 mg, 0.166 mmol) in DCM (2 mL), hydrogen chloride solution (4.0 M in dioxane, 0.5 mL, 2 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the crude product (50 mg, 92%) was obtained as a yellow solid. ESI-MS m / z 292.2 [M+H] + .

[0341] Step 6: 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (50 mg, 0.15 mmol) was added dropwise to a mixture of 3-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropanamide hydrochloride (50 mg, 0.152 mmol) and DMAP (40 mg, 0.324 mmol) in acetonitrile (2 mL) under N2 conditions at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel to obtain 50 mg (64.7%) of 3-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropanamide as a brown solid. ESI-MS m / z 507[M+H] + .

[0342] Step 7: 3-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropanamide (50 mg, 0.098 mmol) and DIPEA (0.04 mL, 0.2 mmol) were dissolved in THF (2 mL), to which trifluoroacetic anhydride (0.02 mL, 0.1 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1.5 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanenitrile. ESI-MS m / z 486.9 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 0.7 H), 11.25 (s, 0.3 H), 7.50-7.47 (m, 1H), 7.39 (d, J = 8.8 Hz, 0.3H), 7.36 (d, J = 8.8 Hz, 0.7H), 7.10-7.07 (m, 1H), 6.11-6.08 (m, 0.7H), 5.99-5.95 (m, 0.3H), 4.95-4.91 (m, 1H), 3.65-3.56 (m, 1H), 3.03-2.98 (m, 1H), 2.89-2.77 (m, 2H), 2.67-2.66 (m, 0.3H), 2.33-2.28 (m, 1.7 H), 1.44 (d, J = 6.8 Hz, 1H), 1.29 (d, J = 7.2 Hz, 2H). Additional compounds described herein can be prepared by using the procedure described in Example 52 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following: [Table 37]

[0343] (Example 53) Synthesis of compound 125 [ka]

[0344] A mixture of methyl(S)-5-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)pentanoate (200 mg, 0.373 mmol) and ammonia solution (2.0 M in methanol, 5 mL, 10 mmol) was stirred in a sealed tube at 75°C for 5 days. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 94 mg (48.3%) of 5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}pentanamide as a white solid. ESI-MS m / z 521.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 7.07 (dd, J = 8.6, 2.4 Hz, 1H), 6.68 (s, 1H), 5.89 (dd, J = 8.4, 4.8 Hz, 1H), 4.94 (dd, J = 13.2, 4.8 Hz, 1H), 3.59-3.52 (m, 1H), 2.87(dd, J = 15.0, 3.2 Hz, 1H), 2.80-2.73 (m, 1H), 2.06-1.99( m, 4H), 1.63-1.51 (m, 2H), 1.42-1.31 (m, 2H). Additional compounds described herein can be prepared by using the procedure described in Example 53 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0345] [Table 38]

[0346] (Example 54) Synthesis of Compound 175 [ka]

[0347] Step 1: Compound 84, consisting of 2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.40 g, 0.78 mmol) and TFA (0.11 mL, 1.5 mmol), was mixed in DCM (2 mL) and water (0.1 mL) and stirred at room temperature for 16 hours. NaHCO3 was added to the mixture to adjust the pH to 7. After aqueous post-treatment, the residue was purified by flash chromatography on silica gel eluted with 0-20% ethyl acetate / hexane to obtain 0.30 g (82%) of 2-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)acetaldehyde. ESI-MS m / z 462[MH] - .

[0348] Step 2: To a solution of 2-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)acetaldehyde (100 mg, 0.216 mmol) in DCM (2 mL), bis(2-methoxyethyl)aminosulfur trifluoride (50% by mass in THF, 150 mg, 0.339 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 68 mg (64.9%) of 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(2,2-difluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a yellow solid. ESI-MS m / z 483.9 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.09 (q, J = 6.4 Hz, 1H), 6.35-6.07 (m, 2H), 4.95 (q, J = 8.8 Hz, 1H), 3.69-3.62 (m, 1H), 2.88 (q, J = 12.0 Hz, 1H), 2.81-2.66 (m, 2H), 2.60-2.54 (m, 1H).

[0349] (Example 55) Synthesis of compound 137 [ka]

[0350] A mixture of 2-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)acetaldehyde (80 mg, 0.17 mmol), triphenylphosphine (140 mg, 0.53 mmol), and sodium 2-chloro-2,2-difluoroacetate (80 mg, 0.52 mmol) in DMF (2 mL) was stirred at 100°C for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 10 mg (12%) of 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(3,3-difluoropropa-2-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a yellow solid. ESI-MS m / z 495.9 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.06 (s, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.41 (q, J = 6.4 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 4.95 (q, J = 7.6 Hz, 1H), 4.63 (t, J = 25.6 Hz, 1H), 3.70-3.62 (m, 1H), 2.96 (q, J = 12.4 Hz, 1H), 2.88-2.66 (m, 3H).

[0351] (Example 56) Synthesis of compound 146 [ka]

[0352] Step 1: Diethyl 2-((6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methyl)malonate (1.00 g, 2.65 mmol) and di-tert-butyl dicarbonate (3 mL, 14 mmol) were dissolved in MeOH (20 mL), to which NaBH4 (0.51 g, 13 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, then quenched with water and brine, and extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was dissolved in MeOH (20 mL), and then NaBH4 (0.45 g, 12 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, then quenched with water and brine, and extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-10% MeOH / DCM to obtain 300 mg (32%) of tert-butyl 6-chloro-1-(3-hydroxy-2-(hydroxymethyl)propyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate as a yellow solid. ESI-MS m / z 296[M-100+H] + .

[0353] Step 2: A mixture of tert-butyl6-chloro-1-(3-hydroxy-2-(hydroxymethyl)propyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate (300 mg, 0.76 mmol) and TFA (60 μL, 0.80 mmol) in DCM (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was then quenched with ammonia solution (7N in MeOH). After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-10% MeOH / DCM to obtain 180 mg (80%) of 2-((6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl)propan-1,3-diol as a yellow oily substance, which was used directly in the next step. ESI-MS m / z 296[M+H] + .

[0354] Step 3: To a mixture of 2-((6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl)propan-1,3-diol (140 mg, 0.475 mmol) and DMAP (70 mg, 0.573 mmol) in acetonitrile (10 mL), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (175 mg, 0.523 mmol) was added dropwise under N2 conditions at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-10% MeOH / DCM, followed by preparative HPLC, to obtain 90 mg (37%) of 2-({2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propan-1,3-diol as a white solid. ESI-MS m / z 510.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.46 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.02-6.05 (m, 1H), 4.92-4.96 (m, 1H), 4.29-4.44 (m, 2H), 3.58-3.63 (m, 3H), 3.46-3.48 (m, 1H), 3.32-3.35 (m, 1H), 2.79-2.88 (m, 2H), 1.99-2.00 (m, 2H), 1.57 (br. s, 1H).

[0355] (Example 57) Synthesis of compound 246 [ka]

[0356] Step 1: Diethyl 2-[(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methyl]propanedioate (A, 7.0 g, 19 mmol), acetonitrile (100 mL), and RuCl[(R,R)-TsDPEN] (mesitylene) (350 mg, 0.5560 mmol, 99% by mass, 0.030) were placed in a round-bottom flask. The reaction mixture was cooled to 0°C. Triethylamine formate complex 5:2 (9.5 mL). The reaction mixture was heated to room temperature for 30 minutes. TLC analysis showed that the reaction had reached completion. The reaction mixture was diluted with RINKAN, and saturated sodium bicarbonate aqueous solution was added until the pH was approximately 8. After the pH reached approximately 8, Boc2O (5.5 g, 25 mmol) was added to the acetonitrile solution (30 mL). The reaction mixture was stirred at room temperature for 5 hours. At this point, the reaction was determined to be complete by LC-MS. The mixture was extracted with ethyl acetate and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate 19:1) to obtain a yellow oily substance (350 mg, yield 3%), which was used directly in the next step without further analysis or purification.

[0357] Step 2: In a 100 mL round-bottom flask, diethyl 2-[[(1S)-2-tert-butoxycarbonyl-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indole-1-yl]methyl]propanedioate (10.0 g, 20.9 mmol), THF (100 mL), and then lithium borohydride (2 mol / L) in THF (63.0 mL, 126 mmol) were added. The reaction mixture was stirred and heated at 60°C for 3 hours. After 3 hours, the reaction was determined to be complete by LC-MS. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate (3×). The organic phase was concentrated to obtain the residue, which was purified by silica gel chromatography to obtain the desired product (6.5 g, yield 79%) as a gray-yellow solid. The substance was used directly in the next step without further purification or analysis.

[0358] Step 3: In a 250 mL round-bottom flask, tert-butyl(1S)-6-chloro-1-[3-hydroxy-2-(hydroxymethyl)propyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (2.0 g, 5.1 mmol), lithium bromide (650 mg, 7.4846 mmol), PTSA (1.3 g, 7.5 mmol), THF (100 mL), and dimethoxymethane (2.0 mL) were added. The mixture was stirred at room temperature for 12 hours, and the reaction was determined to be complete by LC-MS. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (3×). The organic phase was concentrated to obtain the crude product (1.5 g), which was used directly in the next step without further purification or analysis.

[0359] Step 4: In a 100 mL round-bottom flask, tert-butyl(1S)-6-chloro-1-(1,3-dioxan-5-ylmethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carboxylate (1.5 g, 3.7 mmol), DCM (30.0 mL), and TFA (3.0 mL) were placed. The reaction mixture was stirred at room temperature for 3 hours and determined to be complete by LC-MS. The mixture was then concentrated directly and dissolved in ammonia in methanol. The solution was then concentrated to dryness. The residue was purified by silica gel chromatography to obtain the desired product (900 mg, 80% yield) as a gray-yellow solid, which was used in the next step without further purification.

[0360] Step 5: (1S)-6-chloro-1-(1,3-dioxan-5-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (60 mg, 0.2 mmol), 1-butanol (5 mL), followed by 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine (46 mg, 0.23 mmol) and DIPEA (102 mg, 0.79 mmol) were placed in a scintillation vial. The reaction mixture was covered with nitrogen and sealed. It was heated at 120°C for 16 hours. The reaction mixture was then poured into ethyl acetate and extracted with DI water (2 ×) and brine (2 ×). The organic matter was dried over sodium sulfate and concentrated. Purification by preparative HPLC yielded the title compound, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-[4-methyl-6-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (59 mg, yield 65.0%), as a white solid. ESI-MS m / z 467.1 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.03 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.00 (s, 1H), 5.92 (d, J = 36.0 Hz,1H), 5.00-4.82 (m, 2H), 4.62 (d, J = 5.6 Hz, 1H), 4.28 (s, 1H), 3.89 (d, J = 11.2Hz, 1H), 3.65 (t, J = 8.8 Hz, 1H), 3.43-3.33 (m, 2H), 2.71-2.70 (m, 2H), 2.45 (s,3H), 1.90-1.75 (m, 3H). Additional compounds described herein can be prepared by using the procedure described in Example 57 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds selected from the following:

[0361] [Table 39]

[0362] (Example 58) Synthesis of compound 173 [ka]

[0363] A mixture of 2-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)acetaldehyde (100 mg, 0.216 mmol), dimethyl(1-diazo-2-oxopropyl)phosphonate (100 mg, 0.500 mmol), and K2CO3 (60 mg, 0.434 mmol) in MeOH (2 mL) was stirred at room temperature for 2 hours. After post-treatment, the residue was purified by preparative HPLC to obtain 45 mg (45%) of 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(propa-2-in-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid. ESI-MS m / z 457.9 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.10 (q, J = 6.4 Hz, 1H), 6.01 (t, J = 6.0 Hz, 1H), 5.03 (q, J = 8.4 Hz, 1H), 3.82-3.75 (m, 1H), 3.07-3.00 (m, 2H), 2.93 (q, J = 12.8 Hz, 1H), 2.85 (t, J = 2.4 Hz, 1H), 2.80-2.72 (m, 1H).

[0364] (Example 59) Synthesis of compound 318 [ka]

[0365] A mixture of 2-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)acetaldehyde (100 mg, 0.216 mmol) and methyl(triphenylphosphoranylidene)acetate (90 mg, 0.269 mmol) in acetonitrile (2 mL) was stirred at 90°C for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel eluted with 0-20% ethyl acetate / hexane, followed by preparative HPLC, to obtain 16 mg of methyl(2E)-4-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}buta-2-enoate as a white solid. ESI-MS m / z 517.9 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.09 (q, J = 6.4 Hz, 1H), 6.88-6.80 (m, 1H), 6.01-5.94 (m, 2H), 4.98 (q, J = 8.8 Hz, 1H), 3.56 (s, 3H), 3.51 (q, J = 8.8 Hz, 1H), 3.05-2.95 (m, 2H), 2.91 (q, J = 12.0 Hz, 1H), 2.79-2.71 (m, 1H). Additional compounds described herein can be prepared by using the procedure described in Example 59 above, substituting appropriate starting materials, suitable reagents, and reaction conditions to obtain compounds such as those selected from the following:

[0366] [Table 40]

[0367] (Example 60) Synthesis of Compound 27 [ka]

[0368] A mixture of 2-((2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methyl)propan-1,3-diol (60.0 mg, 0.118 mmol), LiBr (12.3 mg, 0.142 mmol), dimethoxymethane (13.5 mg, 0.177 mmol), and p-TsOH (31.0 mg, 0.178 mmol) in 10 mL of DCM was stirred at room temperature for 3 hours. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted three times in DCM. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 14 mg (23%) of 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as a white solid. ESI-MS m / z 552.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 5.88 (d, J = 7.2 Hz, 1H), 4.88-4.93 (m, 1H), 4.82 (d, J = 6.0 Hz, 1H), 4.66 (d, J = 6.0 Hz, 1H), 4.22 (d, J = 8.0 Hz, 1H), 3.89 (d, J = 11.2 Hz, 1H), 3.70-3.73 (m, 1H), 3.56-3.63 (m, 1H), 3.42-3.45 (m, 1H), 2.74-2.87 (m, 2H), 1.99-2.03 (m,1H), 1.86-1.92 (m, 2H).

[0369] (Example 61) Synthesis of compound 88 [ka]

[0370] Step 1: A mixture of 2-(5-chloro-1H-indole-3-yl)ethane-1-amine hydrochloride (2.3 g, 10 mmol), methyl 3,3-dimethoxypropanoate (4.4 g, 30 mmol), and TFA (3.4 g, 30 mmol) in 1,2-dichloroethane (30 mL) was stirred overnight at 80°C. The reaction mixture was cooled to room temperature and filtered to obtain 2.0 g (72%) of methyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl) acetate as a white solid. ESI-MS m / z 279 (M+H) + .

[0371] Step 2: To a mixture of methyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl) acetate (200 mg, 0.72 mmol) and DMAP (110 mg, 0.90 mmol) in acetonitrile (6 mL), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (300 mg, 0.90 mmol) was added dropwise under N2 conditions at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel to obtain 190 mg (53.6%) of methyl 2-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl) acetate as a solid. ESI-MS m / z 494(M+H) + .

[0372] Step 3: Methyl 2-(2-(4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl) acetate (200 mg, 0.405 mmol) was added to a solution of methyl magnesium chloride (3.0 M in THF, 1 mL, 3.0 mmol) at 0°C in 10 mL of THF. The reaction mixture was slowly heated to room temperature overnight, then quenched with aqueous NH4Cl solution and extracted twice with DCM. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 32 mg (16%) of 1-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-2-ol as a solid. ESI-MS m / z 494 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.46 (m, 1H), 7.37-7.35 (d, J = 8.8 Hz, 1H), 7.07-7.05 (dd, J = 8.4, 2.4 Hz, 1H), 6.15-6.12 (m, 1H), 4.93-4.88 (m, 1H), 4.37( s, 1H), 3.66-3.59 (m, 1H), 2.88-2.77 (m, 2H), 2.21-2.15 (m, 1H), 2.02-1.98 (m, 1H),1.28 (s, 3H), 1.22 (s, 3H).

[0373] (Example 62) Synthesis of Compound 75 [ka]

[0374] Step 1: To a suspension of sodium hydride (60% in mineral oil, 400 mg, 10 mmol) in THF (20 mL), ethyl 2-(diethoxyphosphoryl) acetate (3.0 g, 13.4 mmol) was added at 0°C. After stirring the mixture at 0°C for 2 hours, 1,3-dimethoxypropan-2-one (1.0 g, 8.5 mmol) was slowly added. The reaction mixture was stirred at 0°C for 2 hours, then quenched with brine and extracted twice with DCM. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-20% ethyl acetate / hexane to obtain 1.1 g (69%) of ethyl 4-methoxy-3-(methoxymethyl)buta-2-enoate as a colorless oily substance. ESI-MS m / z 189[M+H] + .

[0375] Step 2: A mixture of ethyl 4-methoxy-3-(methoxymethyl)butanoate (400 mg, 2.12 mmol) and Pd / C (10% by mass, 100 mg, 0.094 mmol) in ethyl acetate (6 mL) was stirred at room temperature under hydrogen for 16 hours. The reaction mixture was then filtered. After evaporating the filtrate under reduced pressure, 310 mg (76.7%) of ethyl 4-methoxy-3-(methoxymethyl)butanoate was obtained as a colorless oil, which was used in the next step without further purification.

[0376] Step 3: To a solution of ethyl 4-methoxy-3-(methoxymethyl)butanoate (310 mg, 1.6 mmol) in MeOH (5 mL) and water (1 mL), LiOH (100 mg, 4 mmol) was added. The mixture was stirred at room temperature for 16 hours, then acidified with 2N HCl and extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the crude product (250 mg) was used in the next step without further purification. Step 4: The crude product was used according to Step 1 of the procedure in Example 46 to obtain N-(2-(5-chloro-1H-indole-3-yl)ethyl)-4-methoxy-3-(methoxymethyl)butanamide.

[0377] Step 5: N-(2-(5-chloro-1H-indole-3-yl)ethyl)-4-methoxy-3-(methoxymethyl)butanamide was used according to Step 2 of the procedure in Example 46 to obtain 6-chloro-1-(3-methoxy-2-(methoxymethyl)propyl)-4,9-dihydro-3H-pyrido[3,4-b]indole. Step 6: 6-chloro-1-(3-methoxy-2-(methoxymethyl)propyl)-4,9-dihydro-3H-pyrido[3,4-b]indole was used according to Step 3 of the procedure in Example 46 to obtain (S)-6-chloro-1-(3-methoxy-2-(methoxymethyl)propyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.

[0378] Step 7: (S)-6-chloro-1-(3-methoxy-2-(methoxymethyl)propyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was used according to Step 4 of the procedure in Example 46 to obtain compound 75 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[3-methoxy-2-(methoxymethyl)propyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. ESI-MS m / z 535.8 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.06 (dd, J = 7.6, 2.0 Hz, 1H), 5.97 (t, J = 5.2 Hz, 1H), 4.90 (dd, J = 14.0, 5.2 Hz, 1H), 3.59-3.53 (m, 1H), 3.51-3.43 (m, 2H), 3.25 (s, 3H), 3.18 (s, 3H), 2.88-2.73 (m, 3H), 2.01 (t, J = 7.2 Hz, 3H), 1.94-1.90 (m, 1H).

[0379] (Example 63) 289 synthesis [ka]

[0380] Step 1: A mixture of 3-acetoxy-2-oxopropyl acetate (10.0 g, 57.4 mmol) and tert-butyl 2-(triphenylphosphaneylidene) acetate (21.6 g, 57.4 mmol) in THF (150 mL) was stirred at 70°C for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel to obtain 11.5 g (73.6%) of tert-butyl 4-acetoxy-3-(acetoxymethyl)buta-2-enoate. ESI-MS m / z 272[M+H] + .

[0381] Step 2: A mixture of tert-butyl 4-acetoxy-3-(acetoxymethyl)buta-2-enoate (11.5 g, 42.2 mmol) and TFA (34.5 mL) in DCM (70 mL) was stirred at room temperature for 4 hours. After evaporating the mixture under reduced pressure, the residue was diluted with DCM and washed with brine. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, 7.0 g (77%) of 4-acetoxy-3-(acetoxymethyl)buta-2-enoic acid was obtained as an oily substance, which was used in the next step without further purification. ESI-MS m / z 217[M+H] + .

[0382] Step 3: 4-acetoxy-3-(acetoxymethyl)buta-2-enoic acid was used according to Step 1 of the procedure in Example 46 to obtain 2-(2-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-oxoethylidene)propane-1,3-diyldiacetate. Step 4: 2-(2-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-oxoethylidene)propan-1,3-diyldiacetate was used according to Step 2 of the procedure in Example 46 to obtain 2-((6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methylene)propan-1,3-diyldiacetate.

[0383] Step 5: 2-((6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)methylene)propan-1,3-diyldiacetate was used according to Step 3 of the procedure in Example 46 to obtain (S)-2-((6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methylene)propan-1,3-diyldiacetate.

[0384] Step 6: To a solution of (S)-2-((6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methylene)propan-1,3-diyldiaacetate (700 mg, 1.86 mmol) in MeOH (60 mL), 4.0 M HCl (2 mL) in 1,4-dioxane was added. The reaction mixture was stirred at 70°C for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by preparative HPLC to obtain 30 mg (5.5%) of (S)-2-((6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methylene)propan-1,3-diol as a solid. ESI-MS m / z 293[M+H] + .

[0385] Step 7: (S)-2-((6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)methylene)propane-1,3-diol was used according to Step 4 of the procedure in Example 46 to obtain 2-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methylidene)propane-1,3-diol. ESI-MS m / z 506 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.52-7.51 (m, 1H), 7.40-7.38 (d, J = 8.8 Hz, 1H), 7.10-7.06 (dd, J = 8.4, 1.6 Hz, 1H), 6.70-6.68 (d, J = 10 Hz, 1H), 5.75-5.72 (m, 1H), 5.03-4.98 (m, 1H), 4.97-4.95 (m,1H), 4.88-4.85 (m,1H), 4.59-4.54 (dd, J = 12.8, 1.2 Hz, 1H), 4.18-4.14 (m, 1H), 4.04-4.01 (m, 2H), 3.66-3.58 (m, 1H), 2.98-2.93 (m, 1H), 2.84-2.80 (m, 1H).

[0386] (Example 64) A combination of 316A or 316B or 317A or 317B [ka]

[0387] Step 1: Zinc (1.16 g, 17.7 mmol) and aluminum chloride (0.3 g, 2 mmol) were added to a mixture of methyl 2-cyanoacetate (500 mg, 5.05 mmol) and allyl bromide (800 mg, 6.6 mmol) in THF (10 mL) under nitrogen at 0°C. The reaction mixture was slowly heated to room temperature overnight. The mixture was then quenched with 1N HCl and extracted twice with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-10% ethyl acetate / hexane to obtain 400 mg (55.8%) of methyl 3-oxohexa-5-enoate as a pale yellow oil. ESI-MS m / z 143.1[M+H] + .

[0388] Step 2: Sodium borohydride (266 mg, 7.03 mmol) was added to a solution of methyl 3-oxohexa-5-enoate (1.0 g, 7.03 mmol) in THF (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then quenched with aqueous NH4Cl solution and extracted twice with DCM. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-75% ethyl acetate / hexane to obtain 650 mg (64%) of methyl 3-hydroxyhexa-5-enoate as a pale yellow oil. Step 3: A mixture of methyl 3-hydroxyhexa-5-enoate (500 mg, 3.47 mmol), allyl bromide (1.5 mL, 17 mmol), and silver oxide (4.0 g, 17 mmol) in ethyl acetate (15 mL) was stirred at room temperature for 90 hours. The mixture was filtered. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-5% ethyl acetate / hexane to obtain 450 mg (70.4%) of methyl 3-(allyloxy)hexa-5-enoate as a colorless oil.

[0389] Step 4: To a solution of methyl 3-(allyloxy)hexa-5-enoate (500 mg, 2.7 mmol) in DCM (10 mL), a second-generation Grubbs catalyst (70 mg, 0.08 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 20 hours. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-10% ethyl acetate / hexane to obtain 350 mg (82.6%) of methyl 2-(3,6-dihydro-2H-pyran-2-yl)acetate as a pale yellow oil. Step 5: To a solution of methyl 2-(3,6-dihydro-2H-pyran-2-yl)acetate (300 mg, 1.92 mmol) in MeOH (3 mL), lithium hydroxide monohydrate (650 mg, 15.5 mmol) and water (1 mL) were added. The mixture was stirred at room temperature for 4 hours, then acidified with 1 N HCl and extracted three times with DCM. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, it was used in the next step without further purification.

[0390] Step 6: The crude product was used according to Step 1 of the procedure in Example 46 to obtain N-(2-(5-chloro-1H-indole-3-yl)ethyl)-2-(3,6-dihydro-2H-pyran-2-yl)acetamide. Step 7: Obtained by using according to Step 2 of the procedure in Example 46. Step 8: Using the product according to Step 3 of the procedure in Example 46, (1S)-6-chloro-1-((3,6-dihydro-2H-pyran-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was obtained. Step 9: (1S)-6-chloro-1-((3,6-dihydro-2H-pyran-2-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole is used according to Step 4 of the procedure in Example 46, and further separated by chiral HPLC to obtain compound 316A (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2R)-3,6-dihydro-2H-pyran-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or compound 316B (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2S)-3,6-dihydro-2H-pyran-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole racemic mixture and compound 317A (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2S)-3,6-dihydro-2H-pyran-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or compound 317B A racemic mixture of (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2R)-3,6-dihydro-2H-pyran-2-yl]methyl}2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was obtained.

[0391] Compound 316A / B:ESI-MS m / z 515.9 [MH]-; 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.8, 2.0 Hz, 1H), 6.29-6.26 (m, 1H), 5.78-5.72 (m, 2H), 4.95-4.90 (m, 1H), 4.11-3.96 (m, 2H), 3.66-3.56 (m, 1H), 3.50-3.44 (m, 1H), 2.88-2.83 (m, 2H), 2.26-2.19 (m, 1H), 2.11-2.04 (m, 1H), 1.96–1.89 (m, 2H).

[0392] Compound 317A / B: ESI-MS m / z 515.9 [MH]-; 1 H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 6.07-6.04 (m, 1H), 5.79-5.75 (m, 1H), 5.69-5.66 (m, 1H), 4.97-4.92 (m, 1H), 3.91-3.87 (m, 1H), 3.72-3.69 (m, 2H), 3.64-3.57 (m, 1H), 2.90-2.85 (m, 1H), 2.80-2.75 (m, 1H), 2.25-2.21 (m, 2H), 2.17-2.12 (m, 1H), 2.05-1.94 (m, 1H).

[0393] (Example 65) Synthesis of Compound 148A Wakaru 148B and Compound 149A Wakaru 149B

change

[0394] Step 1: A mixture of methyl methacrylate (1.5 g, 15 mmol), phenyl formate (2.2 g, 18 mmol), formic acid (1.1 mL, 29 mmol), DPPF (830 mg, 1.5 mmol), and palladium acetate (170 mg, 0.76 mmol) in toluene (15 mL) was stirred under nitrogen at 90°C for 20 hours. The reaction mixture was then quenched with saturated NaHCO3 (100 mL) and washed twice with DCM. The aqueous layer was acidified with 2N HCl (60 mL) and extracted three times with DCM. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, 700 mg (32%) of 4-methoxy-3-methyl-4-oxobutanoic acid was obtained as a brown oil, which was used in the next step without further purification.

[0395] Step 2: 4-methoxy-3-methyl-4-oxobutanoic acid was used according to Step 1 of the procedure in Example 46 to obtain methyl 4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobutanoate. Step 3: Sodium borohydride (590 mg, 15.6 mmol) was added to a solution of methyl 4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobutanoate (1.0 g, 3.1 mmol) in THF (8 mL) and MeOH (2 mL). The reaction mixture was stirred at room temperature for 4 days. The mixture was then quenched with water and extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, 900 mg (99%) of N-(2-(5-chloro-1H-indole-3-yl)ethyl)-4-hydroxy-3-methylbutanamide was obtained and used in the next step without further purification.

[0396] Step 4: To a solution of N-(2-(5-chloro-1H-indole-3-yl)ethyl)-4-hydroxy-3-methylbutanamide (900 mg, 3.05 mmol), DMAP (50 mg, 0.4 mmol), and DIPEA (1.1 mL, 6.3 mmol) in THF (10 mL), acetic anhydride (620 mg, 6.07 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then quenched with water and extracted three times with DCM. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-10% MeOH / DCM to obtain 620 mg (60.2%) of 4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobutyl acetate as a colorless oil. ESI-MS m / z 337.1[M+H] + .

[0397] Step 5: 4-((2-(5-chloro-1H-indole-3-yl)ethyl)amino)-2-methyl-4-oxobutyl acetate was used according to Step 2 of the procedure in Example 46 to obtain 3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropyl acetate. Step 6: A mixture of 3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropyl acetate (500 mg, 1.57 mmol) and NaOH (190 mg, 4.75 mmol) in THF (10 mL) and water (2 mL) was stirred at room temperature for 2 hours. The mixture was then quenched with water and extracted three times with ethyl acetate. The combined organic phase was dried over Na2SO4. After evaporating the solvent under reduced pressure, the residue was purified by chromatography on silica gel eluted with 0-10% MeOH / DCM to obtain 400 mg (92%) of 3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropan-1-ol as a yellow solid. ESI-MS m / z 277.1[M+H] + .

[0398] Step 7: 3-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-yl)-2-methylpropan-1-ol was used according to Step 3 of the procedure in Example 46 to obtain 3-((S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropan-1-ol. Step 8: Use 3-((S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl)-2-methylpropan-1-ol according to Step 4 of the procedure in Example 46, and further separate by chiral HPLC to obtain compound 148A (2R)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol or compound 148B (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol and compound 149A (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol or compound 149B A racemic mixture of (2R)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol was obtained.

[0399] Compound 148A / B:ESI-MS m / z 494.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H ), 7.34 (d, J = 8.8 Hz, 1H ), 7.06 (dd, J = 8.8, 2.4 Hz, 1H), 6.01 (d, J = 8.8 Hz, 1H), 4.91 (dd, J = 13.2, 4.4 Hz, 1H), 4.59-4.32 (m, 1H), 3.58-3.47 (m, 1H), 3.28-3.16 (m, 2H), 2.86 (dd, J = 16.0, 4.4 Hz, 1H), 2.81-2.74 (m, 1H), 2.18 (t, J = 12.0 Hz, 1H), 1.69-1.43 (m, 1H), 1.55-1.48 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H).

[0400] Compound 149A / B: ESI-MS m / z 494.0 [M+H]+; 1 H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H ), 7.34 (d, J = 8.4 Hz, 1H...

Claims

1. A compound of formula (I) or a form thereof, wherein the form of the compound is selected from the group consisting of its free acid, free base, salt, hydrate, solvate, anhydride, racemate, enantiomer, diastereomer, stereoisomer, and tautomer. 【Chemistry 1】 (I) (In the formula, R 1 is hydrogen, halo, hydroxyl, C 1-8 The heteroaryl is an alkoxy, amino, or heteroaryl, the heteroaryl being selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl having 1, 2, or 3 R 1A They may be substituted with substituents, R 1A is C 1-8 It is alkyl, R 2 is hydrogen, halo, hydroxyl, C 1-8 Alkyl, C 1-8 It is an alkoxy or amino, R 3 is hydrogen, hydroxy, or amino, R 4 is halo, hydroxy, cyano, C 1-8 Alkyl, C 1-8 Alkenil, C 2-8 Alkinyl, C 1-8 Alkoxy, C 1-8 Alkylthio or thiocarbonyl, C 1-8 Alkyl includes halo, hydroxy, cyano, oxo, and C. 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, carboxy, C 3-8 Cycloalkyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkenyl, heteroaryl, or heterocyclyl, C 1-8 Alkenyls are halo, hydroxy, C 1-8 Alkoxycarbonyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkyl or heterocyclyl, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo; the heteroaryl is selected from a monocyclic ring having five or six ring members or a bicyclic ring having nine or ten ring members; the heterocyclyl is selected from a monocyclic ring having three to seven ring members, a bicyclic ring having six to ten ring members, a bicyclic ring having seven or eight ring members or a polycyclic ring having thirteen to sixteen ring members; C 3-8 Cycloalkyl, C 3-8 Cycloalkenyls, heteroaryls, and heterocyclyls have 1, 2, or 3 R 4A They may be substituted with substituents, R 4A These are halo, hydroxy, cyano, oxo, and C. 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkylthio or thiocarbonyl, C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo. R 5 A heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has 1, 2, or 3 R 5A They may be substituted with substituents, R 5A Halo, Cyano, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 It is an alkoxy or heterocyclyl, and C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo, the heterocyclyl is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members, and the heterocyclyl has one or two R 5B They may be substituted with substituents, R 5B These are halo, hydroxy, cyano, oxo, and C. 1-8 Alkyl, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 It is an alkoxy or thiocarbonyl, and C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo.

2. R 1 However, hydrogen, halo, hydroxy, C 1-8 The heteroaryl is an alkoxy or heteroaryl, wherein the heteroaryl is selected from a monocyclic ring having 5 or 6 ring members or a bicyclic ring having 9 or 10 ring members, and the heteroaryl has one R 1A R may be substituted with substituents, 1A C 1-8 The compound according to claim 1, wherein it is alkyl.

3. R 2 However, it is hydrogen or halo, R 3 The compound according to claim 1, wherein the compound is hydrogen or amino.

4. R 4 However, hydroxy, C 1-8 Alkyl, C 1-8 Alkenil, C 2-8 It is an alkynyl or thiocarbonyl, C 1-8 Alkyl is halo, hydroxy, cyano, oxo, C 1-8 Alkoxy, C 1-8 Alkoxycarbonyl, aminocarbonyl, C 1-8 Alkylcarbonyloxy, carboxy, C 3-8 Cycloalkyl, C 3-8 It may be substituted with one, two, or three substituents independently selected from cycloalkenyls or heterocyclyls, C 1-8 Alkenyls are halo, hydroxy, C 1-8 Alkoxycarbonyl, C 3-8 The heterocyclil may be substituted with one, two, or three substituents independently selected from cycloalkyl or heterocyclil, wherein the heterocyclil is selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 or 8 ring members, or a polycyclic ring having 13 to 16 ring members. 3-8 Cycloalkyl, C 3-8 Cycloalkenyls and heterocyclyls have 1, 2, or 3 R 4A R may be substituted with substituents, 4A However, oxo, C 1-8 The compound according to claim 1, wherein it is alkyl, thiocarbonyl, or hydroxyl.

5. R 5 The heteroaryl is selected from a monocyclic ring having 5-6 ring members or a bicyclic ring having 9-10 ring members, and the heteroaryl has 1, 2, or 3 R 5A R may be substituted with substituents, 5A However, halo, cyano, C 1-8 Alkyl, C 1-8 Alkylthio, C 1-8 It is an alkoxy or heterocyclyl, and C 1-8 The alkyl group may be substituted with one, two, or three substituents independently selected from the halo, C 1-8 The alkoxy may be substituted with one, two, or three substituents independently selected from the halo, and the heterocyclyl may be selected from a monocyclic ring having 3 to 7 ring members, a bicyclic ring having 6 to 10 ring members, a bicyclic ring having 7 to 8 ring members, or a polycyclic ring having 13 to 16 ring members, and the heterocyclyl may have one or two R 5B R may be substituted with substituents, 5B C 1-8 It is alkyl, C 1-8 The compound according to claim 1, wherein the alkyl group may be substituted with one, two, or three substituents independently selected from the halo.

6. (1S)-6-chloro-1-(2-methylpropa-1-en-1-yl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-bromo-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-methoxy-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-bromo-1-{[(3R)-oxan-3-yl]methyl}-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-6-bromo-1-{[(3S)-oxan-3-yl]methyl}-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropyl)-6-(2H-1,2,3-triazole-2-yl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropyl)-6-(2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropyl)-6-(4-methyl-2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-1-(2-methylpropyl)-6-(4-methyl-2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-1-(2-methylpropyl)-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-1-{[(3R)-oxan-3-yl]methyl}-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazin-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-[(1,3-dioxan-5-yl)methyl]-6-(2H-1,2,3-triazole-2-yl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-bromo-1-[(1,3-dioxan-5-yl)methyl]-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-bromo-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-bromo-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4S)-1,3-dioxan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4R)-1,3-dioxan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4S)-1,3-dioxan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4R)-1,3-dioxan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 5-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxan-2-one, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(4,6-dimethyl-1,3,5-triazine-2-yl)-1-[(oxan-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethyl-1,3,5-triazine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-bromo-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-6-chloro-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(oxan-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(oxan-3-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(oxan-3-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-bromo-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-fluoro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-fluoro-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(oxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2S)-oxan-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2R)-oxan-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(oxan-2-yl)methyl]-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(oxan-4-yl)methyl]-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-oxolan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3R)-oxolan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-oxolan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3R)-oxolan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-oxolan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3R)-oxolan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(oxolan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(oxetan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (2S)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol and (2R)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol, (2S)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol and (2R)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methoxybutan-2-ol, Methyl 4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-methylbutanoate, Methyl 4-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butanoate, Methyl 5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}pentanoate, Methyl 6-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}hexanoate, Methyl 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propanoate, Methyl 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanoate, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[3-methoxy-2-(methoxymethyl)propyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (2S)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-methoxypropan-2-ol and (2R)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-methoxypropan-2-ol, (2R)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-methoxypropan-2-ol and (2S)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-methoxypropan-2-ol, (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-hydroxypropyl acetate and (2R)-3-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-hydroxypropyl acetate, (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propane-1,2-diyldiacetate and (2R)-3-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propane-1,2-diyldiacetate, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2R)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2S)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2S)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2R)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2S)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2R)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2R)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2S)-2-methoxypropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2,2-dimethoxyethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, Ethyl {2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}acetate, (2S)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol and (2R)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol, (2R)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol and (2S)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol, 1-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-2-ol, (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propane-1,2-diol and (2R)-3-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propane-1,2-diol, (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propane-1,2-diol, (3R)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol and (3S)-4-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol, (3S)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol and (3R)-4-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,3-diol, 4-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1-ol, 5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}pentan-1-ol, (4S)-5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methylpentan-1-ol, (4R)-5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-methylpentan-1-ol, 4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-1,2-diol, (3R)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-methylbutan-1-ol, (6R)-7-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2,6-dimethylheptan-2-ol, (6S)-7-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2,6-dimethylheptan-2-ol, 7-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2,6-dimethylheptan-2,3-diol, 6-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}hexanoic acid, 6-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}hexane-1-ol, (1R,3S)-3-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)cyclopentan-1-ol, (1S,3S)-3-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)cyclopentan-1-ol, (1R,3R)-3-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)cyclopentan-1-ol, (1S)-6-chloro-1-(cyclopentylmethyl)-2-[4-(difluoromethyl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(cyclopentylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclopentylmethyl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclopentylmethyl)-2-[4-(4-methylpiperazine-1-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(4-methylpiperazine-1-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(difluoromethyl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-bromo-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(buta-3-in-1-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-butyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2R)-2-methylbutyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2-methylbutyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-pentyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1-methylpiperidine-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 4-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butanamide, 5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}pentanamide, (3S)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-methylbutanamide, 6-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}hexanamide, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(6-chloro-2,6-dimethylheptyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(buta-3-en-1-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2-methylbuta-3-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(buta-3-en-1-yl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(3Z)-hexa-3-en-1-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2,6-dimethylhepta-5-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2-methylpropa-2-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(propa-2-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(propa-2-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(3,3-difluoropropane-2-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (2S)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanamide or (2R)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanamide, (3S)-3-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)piperidine-2-one or (3R)-3-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)piperidine-2-one or (3R)-3-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)piperidine-2-one or (3S)-3-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)piperidine-2-one, (3S)-3-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1-methylpiperidine-2-one or (3R)-3-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1-methylpiperidine-2-one or (3R)-3-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1-methylpiperidine-2-one or (3S)-3-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1-methylpiperidine-2-one, 3-({2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1-methylpyrrolidine-2-one, 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-1-ol, 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol, 2-({2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propane-1,3-diol, 2-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propane-1,3-diol, (2R)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol or (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol, (2S)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol or (2R)-3-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol, 2-({(1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propane-1,3-diol, (2S)-3-{(1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propane-1,2-diol and (2R)-3-{(1R)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propane-1,2-diol, (2R)-1-{(1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol and (2S)-1-{(1R)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol, (2S)-1-{(1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol and (2R)-1-{(1R)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-ol, (2R)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}butan-2-ol, (3R)-4-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-hydroxybutanenitrile and (3S)-4-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-3-hydroxybutanenitrile, (4S)-5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-hydroxypentanenitrile and (4R)-5-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-hydroxypentanenitrile, (4R)-5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-hydroxypentanenitrile and (4S)-5-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-4-hydroxypentanenitrile, (1S)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol and (1R)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol, (1R)-1-{(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol and (1S)-1-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropan-1-ol, 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propanenitrile, 3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanenitrile, (2S)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanenitrile or (2R)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanenitrile, (2R)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanenitrile or (2S)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropanenitrile, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-ol, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-methoxy-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-methoxy-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-methoxy-1-(2-methylpropyl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 1-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propan-2-one, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2S)-3-fluoro-2-methylpropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2R)-3-fluoro-2-methylpropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2R)-3-fluoro-2-methylpropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(2S)-3-fluoro-2-methylpropyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(3,3,3-trifluoro-2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(propa-2-in-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2,2-difluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(cyclohexylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclohexylmethyl)-2-[4-(difluoromethyl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclohexylmethyl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclohexylmethyl)-2-[4-(4-methylpiperazine-1-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclohexylmethyl)-2-(4,6-dimethyl-1,3,5-triazine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclobutylmethyl)-2-(4,6-dimethyl-1,3,5-triazine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclopentylmethyl)-2-(4,6-dimethyl-1,3,5-triazine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclopropylmethyl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-({(1S)-6-chloro-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propane-1,3-diol, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-8-amine, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-methoxy-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-methoxy-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-methoxy-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,4-dioxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,4-dioxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2R)-1,4-dioxan-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2S)-1,4-dioxan-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (4S)-4-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-thion and (4R)-4-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-thion, (4R)-4-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-thion and (4S)-4-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-thion, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxolan-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4R)-1,3-dioxolan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4S)-1,3-dioxolan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4S)-1,3-dioxolan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(4R)-1,3-dioxolan-4-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (4S)-4-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-one and (4R)-4-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-one, (4R)-4-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-one and (4S)-4-({(1R)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)-1,3-dioxolan-2-one, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1,3-dioxolan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-[(1,3-dioxolan-2-yl)methyl]-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(2,2-dimethoxyethyl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(2-methoxypropyl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(3-methoxybutyl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, Methyl 3-{6-chloro-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}propanoate, (1S)-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(difluoromethyl)pyrimidine-2-yl]-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-6-chloro-2-[4-(difluoromethyl)pyrimidine-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(difluoromethyl)pyrimidine-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-6-chloro-2-[4-(difluoromethyl)pyrimidine-2-yl]-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-methyl-6-(trifluoromethyl)pyrimidine-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-[(oxan-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (S)-2-(4,6-bis(trifluoromethyl)pyrimidine-2-yl)-6-chloro-1-(((R)-tetrahydro-2H-pyran-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (S)-2-(4,6-bis(trifluoromethyl)pyrimidine-2-yl)-6-chloro-1-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-[(oxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-[(oxolan-3-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-[(oxolan-3-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-methoxy-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-[(1,4-dioxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and (1R)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-[(1,4-dioxan-2-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-({(1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propane-1,3-diol, (1S)-6-chloro-1-(2-methylpropyl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(difluoromethyl)pyrimidine-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-bromo-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-propyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-1-butyl-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(cyclopropylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(cyclobutylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(cyclopentylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclopentylmethyl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 1-(buta-3-en-1-yl)-6-chloro-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-[(3Z)-hexa-3-en-1-yl]-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(cyclopenta-2-en-1-yl)methyl]-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 3-({6-chloro-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)piperidine-2-one, (1S)-6-chloro-1-(cyclohexylmethyl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(cyclohexylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclohexylmethyl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclopentylmethyl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclopropylmethyl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclobutylmethyl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-7-fluoro-1-[(oxan-4-yl)methyl]-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(difluoromethyl)pyrimidine-2-yl]-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-[4-methyl-6-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethylpyrimidine-2-yl)-1-[(1,3-dioxan-5-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-(4-methylpyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-(4-ethylpyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4-ethylpyrimidine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4-methylpyrimidine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(4,6-dimethylpyrimidine-2-yl)-1-[(oxan-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethylpyrimidine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(5-fluoro-4,6-dimethylpyrimidine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(5-fluoro-4-methylpyrimidine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(5-fluoropyrimidine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(4-chloropyrimidine-2-yl)-7-fluoro-1-[(oxan-4-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethoxypyrimidine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethoxy)pyrimidine-2-yl]-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(difluoromethoxy)pyrimidine-2-yl]-6-chloro-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-7-fluoro-1-(2-methylpropyl)-2-(pyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(4,6-dimethylpyrimidine-2-yl)-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclopropylmethyl)-2-(4,6-dimethylpyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclobutylmethyl)-2-(4,6-dimethylpyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclopentylmethyl)-2-(4,6-dimethylpyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(cyclohexylmethyl)-2-(4,6-dimethylpyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[(1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl]pyrimidine-4-carbonitrile, 2-[(1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-yl]-5-fluoropyrimidine-4-carbonitrile, (1S)-6-chloro-2-[4-methoxy-6-(trifluoromethyl)pyrimidine-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-methoxy-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(1,3-dioxan-5-yl)methyl]-2-[4-methoxy-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-methoxy-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(4,6-dimethoxy-1,3,5-triazine-2-yl)-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethoxy-1,3,5-triazine-2-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-8-iodo-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, Diethyl ({2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propanedioate, Diethyl ({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methyl)propanedioate, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(cyclopenta-2-en-1-yl)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-ethenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(1E)-propa-1-en-1-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2-methylpropane-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(difluoromethyl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropane-1-en-1-yl)-2-[4-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropane-1-en-1-yl)-2-[4-(methylsulfanyl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[4-(4-methylpiperazine-1-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (2E)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropa-2-en-1-ol, 2-({(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}methylidene)propane-1,3-diol, Methyl(2E)-3-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}-2-methylpropane-2-enoate, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-[(oxan-4-ylidene)methyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(cyclohexylidenemethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-(cyclohexylidenemethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(4,6-dimethylpyrimidine-2-yl)-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1R)-6-chloro-2-(4,6-dimethylpyrimidine-2-yl)-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-(2-methylpropa-1-en-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-6-chloro-1-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-1-(2-methylpropyl)-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)pyrimidine-2-yl]-1-(2-methylpropyl)-6-(4-methyl-2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropyl)-6-(2H-1,2,3-triazole-2-yl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropane-1-en-1-yl)-6-(2H-1,2,3-triazole-2-yl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropane-1-en-1-yl)-6-(1H-1,2,3-triazole-1-yl)-2-[4-(trifluoromethyl)pyrimidine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-1-(2-methylpropyl)-6-(1H-1,2,3-triazol-1-yl)-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropa-1-en-1-yl)-6-(2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-1-(2-methylpropa-1-en-1-yl)-6-(4-methyl-2H-1,2,3-triazole-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropane-1-en-1-yl)-2-[4-(morpholin-4-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[4-(morpholine-4-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclopentylmethyl)-2-[4-(morpholine-4-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(cyclohexylmethyl)-2-[4-(morpholine-4-yl)-6-(trifluoromethyl)-1,3,5-triazine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(difluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3R)-3,6-dihydro-2H-pyran-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3R)-3,6-dihydro-2H-pyran-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(3S)-3,6-dihydro-2H-pyran-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2R)-3,6-dihydro-2H-pyran-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2S)-3,6-dihydro-2H-pyran-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2S)-3,6-dihydro-2H-pyran-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole or (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-1-{[(2R)-3,6-dihydro-2H-pyran-2-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, Methyl(2E)-4-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}buta-2-enoate, Methyl(2Z)-4-{2-[4,6-bis(trifluoromethyl)-1,3,5-triazine-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-yl}buta-2-enoate, (1S)-6-chloro-1-(2-methylpropyl)-2-[2-(trifluoromethyl)pyrimidine-4-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-2-(2-chloropyrimidine-4-yl)-1-(cyclopentylmethyl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[2-methoxy-6-(trifluoromethyl)pyrimidine-4-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[2-methoxy-6-(trifluoromethyl)pyrimidine-4-yl]-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[2-methoxy-6-(trifluoromethyl)pyrimidine-4-yl]-1-{[(3R)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(oxan-4-yl)methyl]-2-[4-(trifluoromethyl)pyridine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)pyridine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2-[4-(trifluoromethyl)pyridine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-[(oxan-4-yl)methyl]-2-[6-(trifluoromethyl)pyridine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[6-(trifluoromethyl)pyridine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[4-(trifluoromethyl)pyridine-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-(2-methyl-2H-tetrazole-5-yl)-1-{[(3S)-oxan-3-yl]methyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2-[5-(trifluoromethyl)-1,3,4-thiadiazole-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3S)-oxan-3-yl]methyl}-2-[3-(trifluoromethyl)-1,2,4-thiadiazole-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-{[(3R)-oxan-3-yl]methyl}-2-[3-(trifluoromethyl)-1,2,4-thiadiazole-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[3-(trifluoromethyl)-1,2,4-thiadiazole-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,2,4-oxadiazole-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, (1S)-6-chloro-2-[5-(difluoromethyl)-1,2,4-oxadiazole-3-yl]-1-(2-methylpropyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 6-Chloro-1-(2-methylpropyl)-2-[5-(trifluoromethyl)-1,2,4-triazin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, and A compound selected from the group consisting of 6-chloro-7-fluoro-1-(2-methylpropane-1-en-1-yl)-2-(pyrimidine-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, or a form thereof selected from the group consisting of free acid, free base, salt, hydrate, solvate, anhydride, racemate, enantiomer, diastereomer, stereoisomer, and tautomer.

7. A method of using a compound of formula (I) selected from either claim 1 or 6, or a form thereof, for treating or improving a disease or disorder in a subject requiring such treatment, comprising administering an effective amount of the compound of formula (I) or a form thereof to the subject to inhibit dihydroorotate dehydrogenase.

8. A pharmaceutical composition comprising a compound of formula (I) selected from either claim 1 or 6, or a form thereof, and a pharmaceutically acceptable excipient, for treating or improving a disease or disorder by inhibiting dihydroorotate dehydrogenase.

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