Carboline compounds and uses thereof

Abstract

β-Carboline Compounds and Their Use for Inhibiting Dihydroorotate Dehydrogenase (DHODH): JPEG2025501285000368.jpg4966 (in the formula, R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , Q 3 , Q 4 , R 7 , R 9 , and R 11 is as defined herein) or forms thereof provided herein.

Description

[Technical field]

[0001] Provided herein are β-carboline compounds and their uses for inhibiting dihydroorotate dehydrogenase (DHODH). [Background technology]

[0002] Dihydroorotate dehydrogenase (DHODH) is located in the inner mitochondrial membrane and acts in the de novo pyrimidine nucleotide synthesis pathway, catalyzing the dehydration of dihydroorotate (DHO) to orotic acid (ORO), resulting in 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) triphosphate to supply the cellular pool of pyrimidine nucleotides. Pyrimidine nucleotides are supplied by both de novo biosynthesis and salvage pathways, as shown in Figure 1. The salvage pathway regenerates nucleotides from nucleosides and free bases generated by DNA and RNA degradation. For highly proliferative activated T cells, malignant cancer cells, and rapidly replicating RNA viruses, de novo pyrimidine nucleotide synthesis is essential because the salvage pathway has insufficient capacity to meet the increasing demand for biosynthesis of nucleic acids and membrane phospholipids.

[0003] DHODH is the rate-limiting enzyme for de novo synthesis of pyrimidine ribonucleotides. Therefore, inhibitors of DHODH have been used to treat autoimmune diseases and are in clinical trials for cancer and viral infections. In general, inhibitors of DHODH show beneficial immunosuppressive and antiproliferative activity, and have a prominent effect on activated lymphocyte proliferation. For example, many existing DHODH inhibitors have been reported, including leflunomide, teriflunomide, brequinar, maritimus (FK778), redoxal, BAY2402234, ASLAN003, and emvodostat (PTC299). Leflunomide is used to treat rheumatoid arthritis, but is known to have off-target effects and a very long half-life. Embodostat was in clinical trials (Clinical Trials.gov Identifier: NCT03761069) for the treatment of acute myeloid leukemia, while BAY2402234 was tested for use in the treatment of acute myeloid leukemia and recurrent glioma. Embodostat has also been shown to inhibit RNA virus infection and was in clinical trials (Clinical Trials.gov Identifier: NCT04439071) for the treatment of COVID-19. Studies also show that embodostat can inhibit the cytokine storm associated with COVID-19 infection (see Luban et al, Virus Research 292 (2021), 190246).

[0004] Embodostat has the following structure: [ka] has. The following published patents and patent applications describe compositions, methods of making and / or using embodostat: WO 2005089764, U.S. Patent No. 7,601,840, WO 2010138644, U.S. Patent No. 11,458,126, WO 2010138758, U.S. Patent No. 9,351,964, WO 2019028171, U.S. Patent No. 11,458,126, WO 2020028778, U.S. Patent No. 20210205225, WO 2021226478, and U.S. Patent No. 10,947,231.

[0005] Although several DHODH inhibitors currently in development show promise, there is a continuing need for new, potent and therapeutically beneficial compounds useful as DHODH inhibitors, and new compositions thereof. Summary of the Invention

[0006] A compound of formula (I) or a form thereof: [ka] (In the formula, R 1 is hydrogen, deuterium, amino, nitro or fluoro; R 2 Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; R 3 is hydrogen, deuterium, amino or fluoro; R 4 is hydrogen, amino or hydroxy, Q 1 CR 5 or N, Q 2 CR 6 or N, Q1 and Q 2 cannot be simultaneously N, R 5 and R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and phenyl and heterocyclyl are each independently selected from 1, 2 or 3 R 12 may be substituted with a substituent; R 6 is hydrogen, deuterium, halo, C1-6 alkyl, halo-C 1-4 alkyl, phenyl or morpholinyl; Q 2 If N, then R 5 and R 6 is not a halo, R 5 , R 6 and R 7 cannot all become hydrogen at the same time, Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4 Alkyl, carboxyl - C 1-4 Alkyl, carboxyl - C 1-4 Alkylamino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C1-6 Alkyl or C 3-6 cycloalkyl) Provided herein is a form of the compound selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0007] Another aspect provided herein is a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharma- ceutically acceptable excipient. Another aspect provided herein is a method of using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, to treat a disease or disorder in which dihydroorotate dehydrogenase inhibition is appropriate. [Brief description of the drawings]

[0008] [Figure 1] 1 is a diagram showing the salvage and de novo pathways for pyrimidine synthesis. The term "dihydroorotate dehydrogenase inhibition" or "DHODH inhibition" refers to the inhibition of pyrimidine synthesis by the de novo pathway in the presence of a DHODH inhibitor, such as the compounds disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] In one embodiment, a compound of formula (I) or a form thereof: [ka] (In the formula, R 1 is hydrogen, deuterium, amino, nitro or fluoro; R 2 Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; R3 is hydrogen, deuterium, amino or fluoro; R 4 is hydrogen, amino or hydroxy, Q 1 CR 5 or N, Q 2 CR 6 or N, Q 1 and Q 2 cannot be simultaneously N, R 5 and R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and phenyl and heterocyclyl are each independently selected from 1, 2 or 3 R 12 may be substituted with a substituent; R 6 is hydrogen, deuterium, halo, C1-6 alkyl, halo-C1-4 alkyl, phenyl or morpholinyl; Q 2 If N, then R 5 and R 6 is not a halo, R 5 , R 6 and R 7 cannot all become hydrogen at the same time, Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4 Alkyl, Carboxyl-C 1-4 Alkyl, carboxyl - C 1-4 Alkyl - Amino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl) Provided herein is a form of the compound selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0010] Another embodiment includes a compound of formula (I) or a form thereof, wherein the form is a salt thereof. Another aspect is R 1 , R 3 and R 4 and n is 0 or 1. At least two of the following are hydrogen: Another aspect is R 1 , R 3 and R 4 is each hydrogen. Another aspect is R 1 is hydrogen, amino, nitro or fluoro.

[0011] Another aspect is R 2 But, Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Includes compounds of formula (I) which are alkoxy or (C1-4 alkyl)2 amino. Another aspect is R 2 is pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl.

[0012] Another aspect is R2 is chloro, fluoro, bromo, methyl, ethyl, ethenyl, nitro, methoxy, dimethyl-amino, 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 3-methyl-1H-pyrazol-1-yl, 4-methyl-1H-pyrazol-1-yl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazol-2-yl. Another aspect is R 2 is halo or 2H-1,2,3-triazol-2-yl. Another aspect is R 2 is halo. Another aspect is R 2 is halo, wherein halo is selected from chloro or bromo. Another aspect is R 2 is chloro, fluoro, bromo, methyl, ethenyl, nitro, methoxy, dimethyl-amino, 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazol-2-yl.

[0013] Another aspect is R 5 and R 7 But hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl, or heterocyclyl, where heterocyclyl is selected from morpholinyl, piperazinyl, and azetidinyl, and heterocyclyl is selected from one, two, or three R 12 This includes compounds of formula (I) which may be substituted with substituents. Another aspect is R 5 and R 7But hydrogen, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl, or heterocyclyl, where heterocyclyl is selected from morpholinyl, piperazinyl, and azetidinyl, and heterocyclyl is selected from one, two, or three R 12 This includes compounds of formula (I) which may be substituted with a substituent.

[0014] Another aspect is R 5 and R 7 is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, hydroxy-methyl, methyl-thio, methoxy, butoxy, amino, N,N-dimethyl-amino, N-methyl-N-butyl-amino, N,N-dibutyl-amino, methoxy-carbonyl, butoxy-carbonyl, phenyl, morpholinyl, 3,3-difluoro-azetidin-1-yl, 1-methylpiperazin-4-yl, or phenyl. Another aspect is R 5 and R 7 is methyl or trifluoromethyl. Another aspect is R 5 and R 7 is trifluoromethyl.

[0015] Another aspect is R 6 is selected from hydrogen, halo, methyl, trifluoromethyl, or phenyl. Another aspect is R 6 is selected from hydrogen, chloro, fluoro, bromo, methyl, trifluoromethyl, or phenyl. Another aspect is R 8 is hydrogen. Another aspect is R 9 But hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, amino - Sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 Alkoxy)carbonyl, hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkoxy C 1-4 Alkyl, Carboxyl-C 1-4 Alkyl, Carboxyl-C 1-4 alkylamino, carboxyl-C1-4 alkoxy-C1-4 alkylamino, C3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an unsaturated 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 7-8 membered bicyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heterocyclyl or heteroaryl is selected from 1, 2 or 3 R 12 This includes compounds of formula (I) which may be substituted with a substituent.

[0016] Another embodiment is R which is an optionally substituted heteroaryl. 9 but, [ka] and optionally substituted heterocyclyl is [ka] wherein the asterisk (*) indicates the point of attachment.

[0017] Another embodiment is R which is an optionally substituted heteroaryl. 9 is 1H-imidazolyl, 1H-pyrazolyl or 1H-1,2,4-triazolyl, and optionally substituted heterocyclyl is morpholinyl, piperazinyl, 4-methyl-piperazinyl, 3,3-dimethyl-piperazinyl, azetidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, (1S,4S)-2-oxa- The compounds of formula (I) include those selected from 5-azabicyclo[2.2.1]heptanyl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanyl, (3R,5S)-3,5-dimethylpiperazinyl, (3R)-3-methylpiperazinyl, (3S)-3-methylpiperazinyl, 4,7-diazaspiro[2.5]octanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

[0018] Another embodiment is R which is an optionally substituted heteroaryl. 9is 1H-imidazol-1-yl, 1H-pyrazol-1-yl or 1H-1,2,4-triazol-1-yl, and the optionally substituted heterocyclyl is morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 3,3-dimethyl-piperazin-1-yl, azetidin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, (1S,4S) - 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, (3R,5S)-3,5-dimethylpiperazin-1-yl, (3R)-3-methylpiperazin-1-yl, (3S)-3-methylpiperazin-1-yl, 4,7-diazaspiro[2.5]octan-7-yl, or 2-oxa-6-azaspiro[3.3]heptan-6-yl.

[0019] Another aspect is R 9 where: hydrogen, fluoro, chloro, bromo, cyano, methyl, isopropyl, trifluoromethyl, ethenyl, methylcarbonyl, amino, N-methylamino, N,N-dimethylamino, N-[(N,N-dimethylamino)ethyl]amino, methyl-thio, methyl-sulfonyl, amino-sulfonyl, methoxy, methoxyethoxy, methoxycarbonyl, hydroxy-methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1-hydroxy-but-3-en-4-yl, N-(hydroxyethyl)amino, methoxy-carbonyl-ethyl, hydroxy-ethoxy-methyl, carboxy-ethyl, carboxy-propyl, N-(carboxy-ethyl)amino, N-(carboxy-propyl)amino, N-(carboxy-methoxy-ethyl)amino, cyclopropyl, [ka] wherein the asterisk (*) indicates the point of attachment.

[0020] Another aspect is R 9where: hydrogen, fluoro, chloro, bromo, cyano, methyl, isopropyl, trifluoromethyl, ethenyl, methylcarbonyl, amino, lN-methylamino, N,N-dimethylamino, N-[(N,N-dimethylamino)ethyl]amino, methyl-thio, methyl-sulfonyl, amino-sulfonyl, methoxy, methoxyethoxy, methoxycarbonyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1-hydroxy-but-3-en-4-yl, N-(hydroxyethyl)amino, methoxy-carbonyl-ethyl, hydroxy-ethoxy-methyl, carboxy-ethyl, carboxy-propyl, N-(carboxy-ethyl)amino, N-(carboxy-propyl)amino, N-(carboxy-methoxy-ethyl)amino, cyclopropyl, 1H-imidazolyl, 1H-pyrazolyl, 1H-1,2,4-triazolyl, morpholinyl, piperazinyl, 4-methyl-piperazinyl, 3,3-dimethyl-piperazinyl, azetidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, (1S,4S)- ... This includes compounds of formula (I) which are cyclo[2.2.1]heptanyl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanyl, (3R,5S)-3,5-dimethylpiperazinyl, (3R)-3-methylpiperazinyl, (3S)-3-methylpiperazinyl, 4,7-diazaspiro[2.5]octanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

[0021] Another aspect is R 9where: hydrogen, fluoro, chloro, bromo, cyano, methyl, isopropyl, trifluoromethyl, ethenyl, methylcarbonyl, amino, N-methylamino, N,N-dimethylamino, N-[(N,N-dimethylamino)ethyl]amino, methyl-thio, methyl-sulfonyl, amino-sulfonyl, methoxy, methoxyethoxy, methoxycarbonyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1-hydroxy-but-3-en-4-yl, N-(hydroxyethyl)amino, methoxy-carbonyl-ethyl, hydroxy-ethoxy-methyl, carboxy-ethyl, carboxy-propyl, N-(carboxy-ethyl)amino, N-(carboxy-propyl)amino, N-(carboxy-methoxy-ethyl)amino, cyclopropyl, 1H-imidazol-1-yl, 1H-pyrazol-1-yl 1H-1,2,4-triazol-1-yl, morpholin-4-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, 3,3-dimethyl-piperazin-1-yl, azetidin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and (3S)-3-methylpiperazin-1-yl, 4,7-diazaspiro[2.5]octan-7-yl, or 2-oxa-6-azaspiro[3.3]heptan-6-yl.

[0022] Another aspect is R 9 But hydrogen, halo, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 The compound of formula (I) includes compounds in which the aryl group is selected from alkoxy, morpholinyl or 1-methyl-piperazin-4-yl. Another aspect is R 9is selected from hydrogen, halo, methyl, methoxy, trifluoromethyl, or hydroxy-methyl.

[0023] Another aspect is R 10 is hydrogen, fluoro or hydroxy. Another aspect is R 11 is hydrogen, fluoro or hydroxy. One embodiment of the compound of formula (I) is a compound of formula (Ia1), a compound of formula (Ia2), a compound of formula (Ib), a compound of formula (Ic), a compound of formula (Id), and a compound of formula (Ie) or a form thereof:

[0024] [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , Q 1 , Q 2 , Q 3 and Q 4 is as defined in the first aspect of formula (I) above) or a form thereof.

[0025] Another embodiment of the compound of formula (I) is a compound of formula (Ia1) or a form thereof: [ka] (In the formula, R 2 Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; Q 2 CR 6 or N, R 5 and R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and phenyl and heterocyclyl are each independently selected from 1, 2 or 3 R 12 may be substituted with a substituent; R 6 is hydrogen, deuterium, halo, C1-6 alkyl, halo-C 1-4 alkyl, phenyl or morpholinyl; Q 2 If N, then R 5 and R 6 is not a halo, R 5 , R 6 and R 7 cannot all become hydrogen at the same time, Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4 Alkyl, carboxyl - C 1-4 Alkyl, carboxyl - C 1-4 Alkylamino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl) or a form thereof, wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0026] Another embodiment of the compound of formula (Ia1) is R 2 is selected from chloro, bromo, ethyl, methoxy, nitro, dimethyl-amino, 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 3-methyl-1H-pyrazol-1-yl, 4-methyl-1H-pyrazol-1-yl, 2H-1,2,3-triazol-2-yl, and 4-methyl-2H-1,2,3-triazol-2-yl. Another embodiment of the compound of formula (Ia1) is R 2 is chloro, bromo, ethyl, methoxy, nitro, or dimethyl-amino. Another embodiment of the compound of formula (Ia1) is R 2 is selected from chloro, bromo and 2H-1,2,3 triazol-2-yl.

[0027] Another embodiment of the compound of formula (Ia1) is R 5 and R 7 is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, hydroxy-methyl, methyl-thio, methoxy, butoxy, amino, N,N-dimethyl-amino, N-methyl-N-butyl-amino, N,N-dibutyl-amino, methoxy-carbonyl, butoxy-carbonyl, morpholinyl, 3,3-difluoro-azetindin-1-yl, 1-methylpiperazin-4-yl, and phenyl. Another embodiment of the compound of formula (Ia1) is R 5 and R 7 is independently selected from hydrogen, methyl and trifluoromethyl. Another embodiment of the compound of formula (Ia1) is R 6 is hydrogen, fluoro, chloro, bromo, methyl or phenyl.

[0028] Another embodiment of the compound of formula (Ia1) is R 9 is hydrogen, fluoro, chloro, bromo, cyano, methyl, ethenyl, methyl-thio, methoxy, methoxyethoxy, hydroxy-methyl, methyl-carbonyl, N-(hydroxyethyl)amino, N[N,N-(dimethylamino)ethyl]amino, (carboxy-C 1-4 Alkyl)amino, (carboxy-C 1-4 Alkoxy-C 1-4 (alkyl)amino, [ka] wherein the asterisk (*) indicates the point of attachment.

[0029] Another aspect is R 9where: hydrogen, fluoro, chloro, bromo, cyano, methyl, isopropyl, trifluoromethyl, ethenyl, methylcarbonyl, amino, N-methylamino, N,N-dimethylamino, N-[(N,N-dimethylamino)ethyl]amino, methyl-thio, methyl-sulfonyl, amino-sulfonyl, methoxy, methoxy-ethoxy, methoxycarbonyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1-hydroxy-but-3-en-4-yl, N-(hydroxyethyl)amino, methoxy-carbonyl-ethyl, hydroxy-ethoxy-methyl, carboxy-ethyl, carboxy-propyl, N-(carboxy-ethyl)amino, N-(carboxy-propyl)amino, N-(carboxy-methoxy-ethyl)amino , cyclopropyl, 1H-imidazolyl, 1H-pyrazolyl, 1H-1,2,4-triazolyl, morpholinyl, piperazinyl, 4-methyl-piperazinyl, 3,3-dimethyl-piperazinyl, azetidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, (1S,4S)- ...

[0043] The compounds of formula (Ia1) include compounds of formula (Ia2) which are 2-oxa-6-azaspiro[2.2.1]heptanyl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanyl, (3R,5S)-3,5-dimethylpiperazinyl, (3R)-3-methylpiperazinyl, (3S)-3-methylpiperazinyl, 4,7-diazaspiro[2.5]octanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

[0030] Another embodiment of the compound of formula (Ia1) is R 9 is selected from hydrogen, methyl, fluoro, chloro, bromo, methoxy, morpholinyl and 1-methyl-piperazin-4-yl, methyl-thio and hydroxy-methyl. Another embodiment of the compound of formula (Ia1) is R 10 is hydrogen, fluoro, or hydroxy. Another embodiment of the compound of formula (Ia1) is R 11 is hydrogen, chloro, fluoro, or hydroxy.

[0031] Another embodiment of the compound of formula (Ia1) is R 2 is chloro, bromo or 2H-1,2,3 triazol-2-yl; Q 2 But, CR 6 or N, R 5 and R 7 is independently selected from hydrogen, methyl and trifluoromethyl; R 6 is hydrogen, bromo or fluoro; Q 3 is CH or N, R 9 is selected from hydrogen, methyl, fluoro, chloro, methoxy, morpholinyl, and 1-methyl-piperazin-4-yl, methyl-thio, and hydroxy-methyl; Q 4 But, CR 10 or N, R 10 is hydrogen or fluoro; R 11 is hydrogen or fluoro; Contains compounds.

[0032] Another embodiment of the compound of formula (I) is a compound of formula (Ia2) or a form thereof: [ka] (In the formula, R 2 Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; R 5 and R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl, or heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, and phenyl and heterocyclyl are each independently selected from 1, 2, or 3 R 12 may be substituted with a substituent; Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4 Alkyl, carboxyl - C 1-4 Alkyl, carboxyl - C1-4 Alkylamino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl) or a form thereof, wherein the compound is of formula (I) selected from The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0033] Another embodiment of the compound of formula (Ia2) is R 2is selected from chloro, bromo, ethyl, methoxy, nitro, dimethyl-amino, 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 3-methyl-1H-pyrazol-1-yl, 4-methyl-1H-pyrazol-1-yl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazol-2-yl. Another embodiment of the compound of formula (Ia2) is R 2 is chloro, bromo, ethyl, methoxy, nitro or dimethyl-amino. Another embodiment of the compound of formula (Ia2) is R 2 is selected from chloro, bromo or 2H-1,2,3 triazol-2-yl.

[0034] Another embodiment of the compound of formula (Ia2) is R 5 and R 7 is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, hydroxy-methyl, methyl-thio, methoxy, butoxy, amino, N,N-dimethyl-amino, N-methyl-N-butyl-amino, N,N-dibutyl-amino, methoxy-carbonyl, butoxy-carbonyl, morpholinyl, 3,3-difluoro-azetindin-1-yl, 1-methylpiperazin-4-yl, or phenyl. Another embodiment of the compound of formula (Ia2) is R 5 and R 7 is independently selected from hydrogen, methyl, or trifluoromethyl. Another embodiment of the compound of formula (Ia2) is R 6 is hydrogen, halo, methyl or phenyl.

[0035] Another embodiment of the compound of formula (Ia2) is R 9is hydrogen, halo, cyano, methyl, ethenyl, methyl-thio, methoxy, methoxyethoxy, hydroxy-methyl, methyl-carbonyl, N-(hydroxyethyl)amino, N[N,N-(dimethylamino)ethyl]amino, (carboxy-C 1-4 Alkyl)amino, (carboxy-C 1-4 Alkoxy-C 1-4 (alkyl)amino, [ka] wherein the asterisk (*) indicates the point of attachment.

[0036] Another aspect is R 9where: hydrogen, fluoro, chloro, bromo, cyano, methyl, isopropyl, trifluoromethyl, ethenyl, methylcarbonyl, amino, N-methylamino, N,N-dimethylamino, N-[(N,N-dimethylamino)ethyl]amino, methyl-thio, methyl-sulfonyl, amino-sulfonyl, methoxy, methoxy-ethoxy, methoxycarbonyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1-hydroxy-but-3-en-4-yl, N-(hydroxyethyl)amino, methoxy-carbonyl-ethyl, hydroxy-ethoxy-methyl, carboxy-ethyl, carboxy-propyl, N-(carboxy-ethyl)amino, N-(carboxy-propyl)amino, N-(carboxy-methoxy-ethyl)amino , cyclopropyl, 1H-imidazolyl, 1H-pyrazolyl, 1H-1,2,4-triazolyl, morpholinyl, piperazinyl, 4-methyl-piperazinyl, 3,3-dimethyl-piperazinyl, azetidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, (1S,4S)- ...

[0033] This includes compounds of formula (Ia2), which are (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanyl, (3R,5S)-3,5-dimethylpiperazinyl, (3R)-3-methylpiperazinyl, (3S)-3-methylpiperazinyl, 4,7-diazaspiro[2.5]octanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

[0037] Another embodiment of the compound of formula (Ia2) is R 9 is selected from hydrogen, methyl, fluoro, chloro, bromo, methoxy, methyl-thio, hydroxy-methyl, morpholinyl, or 1-methyl-piperazin-4-yl. Another embodiment of the compound of formula (Ia2) is R 10 is hydrogen, fluoro, or hydroxy. Another embodiment of the compound of formula (Ia2) is R 11 is hydrogen, chloro, fluoro, or hydroxy.

[0038] Another embodiment of the compound of formula (Ia2) is R 2 is chloro, bromo or 2H-1,2,3 triazol-2-yl; Q 2 But, CR 6 or N, R 5 and R 7 is independently selected from hydrogen, methyl or trifluoromethyl; R 6 is hydrogen, bromo or fluoro; Q 3 is CH or N, R 9 is selected from hydrogen, methyl, fluoro, chloro, bromo, methoxy, methyl-thio, hydroxy-methyl, morpholinyl or 1-methyl-piperazin-4-yl; Q 4 But, CR 10 or N, R 10 is hydrogen or fluoro; R 11 is hydrogen or fluoro; Contains compounds.

[0039] Another embodiment of the compound of formula (I) is represented by formula (Ib) or a form thereof: [ka] (In the formula, R 2 Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; R 6 is hydrogen, deuterium, halo, C1-6 alkyl, halo-C 1-4 alkyl, phenyl or morpholinyl; R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 Alkoxycarbonyl, phenyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and phenyl and heterocyclyl are each independently selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4Alkyl, carboxyl - C 1-4 Alkyl, carboxyl - C 1-4 Alkylamino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl) or a form thereof, wherein the compound is of formula (I) selected from The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0040] Another embodiment of the compound of formula (Ib) is R 2 is chloro. Another embodiment of the compound of formula (Ib) is R 6is hydrogen or trifluoromethyl. Another embodiment of the compound of formula (Ib) is R 7 is methyl or trifluoromethyl.

[0041] Another embodiment of the compound of formula (Ib) is R 9 is methyl or morpholinyl. Another embodiment of the compound of formula (Ib) is R 10 is hydrogen or fluoro.

[0042] Another embodiment of the compound of formula (Ib) is R 11 is hydrogen or fluoro.

[0043] Another embodiment of the compound of formula (Ib) is R 2 is chloro, R 6 is hydrogen or trifluoromethyl, R 7 is methyl or trifluoromethyl, Q 3 is CH or N, Q 4 But, CR 10 or N, R 9 is methyl or morpholinyl, R 10 is hydrogen or fluoro; R 11 is hydrogen or fluoro; Contains compounds.

[0044] Another embodiment of the compound of formula (I) is represented by formula (Ic) or a form thereof: [ka] (In the formula, R 1 is hydrogen, deuterium, amino, nitro or fluoro; R 2 Halo, C 1-4Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; Q 1 CR 5 or N, Q 2 CR 6 or N, Q 1 and Q 2 cannot be simultaneously N, R 5 and R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and phenyl and heterocyclyl are each independently selected from 1, 2 or 3 R 12 may be substituted with a substituent; R 6 is hydrogen, deuterium, halo, C1-6 alkyl, halo-C 1-4 alkyl, phenyl or morpholinyl; Q 2 If N, then R 5 and R 6 is not a halo, R 5 , R 6 and R 7 cannot all become hydrogen at the same time, Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4 Alkyl, carboxyl - C 1-4 Alkyl, carboxyl - C 1-4 Alkylamino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl) or a form thereof, wherein the compound is of formula (I) selected from The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0045] Another embodiment of the compound of formula (Ic) is R 1 is fluoro. Another embodiment of the compound of formula (Ic) is R 2 is chloro, fluoro, or methyl. Another embodiment of the compound of formula (Ic) is 1 CR 5 The present invention includes compounds in which Another embodiment of the compound of formula (Ic) is R 5 and R 7 is independently selected from hydrogen, chloro, methyl, trifluoromethyl, methoxy-carbonyl, and cyano. Another embodiment of the compound of formula (Ic) is R 6 is hydrogen, chloro, fluoro or methyl.

[0046] Another embodiment of the compound of formula (Ic) is R 9are hydrogen, fluoro, chloro, methyl, hydroxy-butyl, amino, N-methylamino, dimethylamino, cyano, trifluoromethyl, methyl-sulfonyl, amino-sulfonyl and 1-hydroxy-but-3-en-4-yl, [ka] The present invention includes compounds in which

[0047] Another embodiment of the compound of formula (Ic) is R 9 is hydrogen, fluoro, chloro, methyl, hydroxy-butyl, amino, N-methylamino, dimethylamino, cyano, trifluoromethyl, methyl-sulfonyl, amino-sulfonyl and 1-hydroxy-but-3-en-4-yl, 1H-imidazolyl, 1H-1,2,4-triazolyl or morpholinyl. Another embodiment of the compound of formula (Ic) is R 10 is hydrogen or fluoro. Another embodiment of the compound of formula (Ic) is R 11 is hydrogen or fluoro. Another embodiment of the compound of formula (I) is a compound of formula (Id) or a form thereof: [ka] (In the formula, R 2 Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; R 3 is hydrogen, deuterium, amino or fluoro; Q 1 CR 5 or N, Q 2 CR 6or N, Q 1 and Q 2 cannot be simultaneously N, R 5 and R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and phenyl and heterocyclyl are each independently selected from 1, 2 or 3 R 12 may be substituted with a substituent; R 6 is hydrogen, deuterium, halo, C1-6 alkyl, halo-C 1-4 alkyl, phenyl or morpholinyl; Q 2 If N, then R 5 and R 6 is not a halo, R 5 , R 6 and R 7 are not all hydrogen at the same time, Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4 Alkyl, carboxyl - C 1-4 Alkyl, carboxyl - C 1-4 Alkylamino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl) or a form thereof, wherein the compound is of formula (I) selected from The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0048] Another embodiment of the compound of formula (Id) is R 2 is chloro. Another embodiment of the compound of formula (Id) is R 3 is fluoro, hydroxy or amino. Another embodiment of the compound of formula (Id) is 1 CR 5 The present invention includes compounds in which Another embodiment of the compound of formula (Id) is R 5 and R 7 is independently selected from hydrogen, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, cyano, and N,N-dimethyl-amino. Another embodiment of the compound of formula (Id) is R 6 is hydrogen, chloro, fluoro or trifluoromethyl. Another embodiment of the compound of formula (Id) is R 8 is hydrogen or fluoro. In another embodiment of the compound of formula (Id), Q 4 If N, then R 8 is not H.

[0049] Another embodiment of the compound of formula (Id) is R 9is hydrogen, halo, methyl, isopropyl, hydroxy-methyl, hydroxy-ethyl, hydroxy-methyl, hydroxy-propyl, ethenyl, methoxy, dimethylamino, cyano, trifluoromethyl, cyclopropyl, methyl-sulfonyl, amino-sulfonyl, methoxy-carbonyl-ethyl, hydroxy-ethoxy-methyl, 1-hydroxy-but-3-en-4-yl, or morpholinyl. Another embodiment of the compound of formula (Id) is R 10 is hydrogen or fluoro. Another embodiment of the compound of formula (Id) is R 11 is hydrogen or fluoro.

[0050] Another embodiment of the compound of formula (I) is the compound of formula (Ie) or a form thereof: [ka] (In the formula, R 2 Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 alkyl)2amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; R 3 is hydrogen, deuterium, amino or fluoro; R 4 is hydrogen, amino or hydroxy, Q 1 CR 5 or N, Q 2 CR 6 or N, Q 1 and Q 2 cannot be simultaneously N, R 5 and R 7 are hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl)2amino, C 1-4 alkoxycarbonyl, phenyl and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and phenyl and heterocyclyl are each independently selected from 1, 2 or 3 R 12 may be substituted with a substituent; R 6 is hydrogen, deuterium, halo, C1-6 alkyl, halo-C 1-4 alkyl, phenyl or morpholinyl; Q 2 If N, then R 5 and R 6 is not a halo, R 5 , R 6 and R 7 cannot all become hydrogen at the same time, Q 3 CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 alkyl)2amino, (C 1-4 Alkyl)2amino(C 1-4 Alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, Amino-sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, HydroxyC 1-4 Alkoxy C 1-4 Alkyl, carboxyl - C 1-4 Alkyl, carboxyl - C 1-4 Alkylamino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl) or a form thereof, wherein the compound is of formula (I) selected from The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof.

[0051] Another embodiment of the compound of formula (Ie) is R 2 is chloro. Another embodiment of the compound of formula (Ie) is R 4 is hydrogen, fluoro, hydroxy or amino. Another embodiment of the compound of formula (Ie) is 1 CR 5 The present invention includes compounds in which Another embodiment of the compound of formula (Ie) is R 5 and R 7 is independently selected from hydrogen, methyl and trifluoromethyl.

[0052] Another embodiment of the compound of formula (Ie) is R 6 is hydrogen or fluoro. Another embodiment of the compound of formula (Ie) is R 9 is methyl, cyano or morpholinyl. Another embodiment of the compound of formula (Ie) is R 10 is hydrogen or fluoro.

[0053] Another embodiment of the compound of formula (Ie) is R 11 is hydrogen or fluoro.

[0054] The compound of formula (I) or an embodiment thereof is [ka] JPEG2025501285000019.jpg224162 JPEG2025501285000020.jpg226167 JPEG2025501285000021.jpg222168 JPEG2025501285000022.jpg226161 JPEG2025501285000023.jpg230164 JPEG2025501285000024.jpg225158 JPEG2025501285000025.jpg228165 JPEG2025501285000026.jpg240167 JPEG2025501285000027.jpg229165 JPEG2025501285000028.jpg229166 JPEG2025501285000029.jpg244152 JPEG2025501285000030.jpg250165 JPEG2025501285000031.jpg250160 JPEG2025501285000032.jpg228161 JPEG2025501285000033.jpg232161 JPEG2025501285000034.jpg229161 JPEG2025501285000035.jpg229164 JPEG2025501285000036.jpg250166 JPEG2025501285000037.jpg209159 JPEG2025501285000038.jpg224166 JPEG2025501285000039.jpg232162 JPEG2025501285000040.jpg237164 JPEG2025501285000041.jpg245149 JPEG2025501285000042.jpg245155 JPEG2025501285000043.jpg249160 JPEG2025501285000044.jpg245150 JPEG2025501285000045.jpg249161 JPEG2025501285000046.jpg246166 JPEG2025501285000047.jpg252165 JPEG2025501285000048.jpg250159 JPEG2025501285000049.jpg244152 JPEG2025501285000050.jpg252165 JPEG2025501285000051.jpg243151 JPEG2025501285000052.jpg250160 JPEG2025501285000053.jpg250158 JPEG2025501285000054.jpg250159 JPEG2025501285000055.jpg239167 JPEG2025501285000056.jpg244147 JPEG2025501285000057.jpg245153 JPEG2025501285000058.jpg212169 JPEG2025501285000059.jpg245155 JPEG2025501285000060.jpg217170 JPEG2025501285000061.jpg213165 JPEG2025501285000062.jpg250161 JPEG2025501285000063.jpg215165 JPEG2025501285000064.jpg83108, and the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer form thereof.

[0055] The compound of formula (I) or an embodiment thereof is

Table 1

[0056] Another embodiment of the compound of formula (I) or a form thereof is [Table 2] A compound (Cpd) salt selected from the group consisting of The form of the compound is selected from the group consisting of hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers, and tautomeric forms thereof.

[0057] One aspect provided herein is a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharma- ceutically 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 ameliorating 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 for treating or ameliorating 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 a pharma- ceutical acceptable excipient, for treating or ameliorating a disease or disorder by inhibiting dihydroorotate dehydrogenase.

[0058] One aspect provided herein is a method of using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, to treat or ameliorate a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof to inhibit dihydroorotate dehydrogenase. Another aspect provided herein is a method of using a compound of formula (I) or a form thereof to treat or ameliorate a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof to inhibit dihydroorotate dehydrogenase. Another aspect provided herein is a method of using a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharma- ceutically acceptable excipient, for treating or ameliorating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition to inhibit dihydroorotate dehydrogenase.

[0059] The compound of formula (I) or an embodiment thereof is [Table 3] JPEG2025501285000097.jpg250170 JPEG2025501285000098.jpg244170 JPEG2025501285000099.jpg250170 JPEG2025501285000100.jpg248170 JPEG2025501285000101.jpg248170 JPEG2025501285000102.jpg250170 JPEG2025501285000103.jpg251170 JPEG2025501285000104.jpg248170 JPEG2025501285000105.jpg243170 JPEG2025501285000106.jpg247170 JPEG2025501285000107.jpg251170 JPEG2025501285000108.jpg251170 JPEG2025501285000109.jpg253170 JPEG2025501285000110.jpg241170 JPEG2025501285000111.jpg242170 JPEG2025501285000112.jpg250170 JPEG2025501285000113.jpg246170 JPEG2025501285000114.jpg246170 JPEG2025501285000115.jpg240170 JPEG2025501285000116.jpg65170 ( 1 Compound numbers indicate that the compounds were isolated as salt forms, including compounds (Cpd) having dihydroorotate dehydrogenase inhibitory activity ≦10.0 nM; The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomeric, a diastereomeric, a stereoisomeric, and a tautomeric form thereof.

[0060] Another embodiment of the compound of formula (I) or a form thereof is [Table 4] and a compound (Cpd) salt having a dihydroorotate dehydrogenase inhibitory activity of ≦10.0 nM selected from the group consisting of: The form of the compound is selected from the group consisting of hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers, and tautomeric forms thereof.

[0061] The compound of formula (I) or an embodiment thereof is [Table 5] JPEG2025501285000119.jpg255170 JPEG2025501285000120.jpg242170 JPEG2025501285000121.jpg245170 JPEG2025501285000122.jpg201170 ( 1 Compound numbers indicate that the compounds were isolated as salt forms, including compounds (Cpd) having dihydroorotate dehydrogenase inhibitory activity ≦1.0 nM; The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer form thereof.

[0062] Another embodiment of the compound of formula (I) or a form thereof is [Table 6] and a compound (Cpd) salt having a dihydroorotate dehydrogenase inhibitory activity of ≦10.0 nM selected from the group consisting of: The form of the compound is selected from the group consisting of hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers, and tautomeric forms thereof.

[0063] One embodiment of the compound of formula (I) or a form thereof is [Table 7] JPEG2025501285000125.jpg249170 JPEG2025501285000126.jpg249166 JPEG2025501285000127.jpg251166 JPEG2025501285000128.jpg248170 JPEG2025501285000129.jpg243170 JPEG2025501285000130.jpg253170 JPEG2025501285000131.jpg250167 JPEG2025501285000132.jpg253170 JPEG2025501285000133.jpg251167 JPEG2025501285000134.jpg252170 JPEG2025501285000135.jpg251170 JPEG2025501285000136.jpg252170 JPEG2025501285000137.jpg253170 JPEG2025501285000138.jpg242170 JPEG2025501285000139.jpg252170 JPEG2025501285000140.jpg251170 JPEG2025501285000141.jpg249170 JPEG2025501285000142.jpg244170 JPEG2025501285000143.jpg242170 JPEG2025501285000144.jpg201170 ( 1 Compound numbers include compound (Cpd) which indicates that the compound was isolated as a salt form, The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomeric, a diastereomeric, a stereoisomeric, and a tautomeric form thereof.

[0064] Another embodiment of the compound of formula (I) or a form thereof is [Table 8] A compound (Cpd) salt selected from the group consisting of The form of the compound is selected from the group consisting of its hydrate, solvate, racemate, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms.

[0065] One embodiment of the compound of formula (I) or a form thereof is [Table 9] JPEG2025501285000147.jpg246170 JPEG2025501285000148.jpg243170 JPEG2025501285000149.jpg251166 JPEG2025501285000150.jpg249170 JPEG2025501285000151.jpg247170 JPEG2025501285000152.jpg250170 JPEG2025501285000153.jpg244170 JPEG2025501285000154.jpg248170 JPEG2025501285000155.jpg253170 JPEG2025501285000156.jpg248170 JPEG2025501285000157.jpg251167 JPEG2025501285000158.jpg247170 JPEG2025501285000159.jpg250170 JPEG2025501285000160.jpg244170 JPEG2025501285000161.jpg21170 ( 1 Compound numbers indicate that the compounds were isolated as salt forms, including compounds (Cpd) having dihydroorotate dehydrogenase inhibitory activity ≦10.0 nM; The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer form thereof.

[0066] Another embodiment of the compound of formula (I) or a form thereof is [Table 10] and a compound (Cpd) salt having a dihydroorotate dehydrogenase inhibitory activity of ≦10.0 nM selected from the group consisting of: The form of the compound is selected from the group consisting of hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers, and tautomeric forms thereof.

[0067] One embodiment of the compound of formula (I) or a form thereof is [Table 11] JPEG2025501285000164.jpg250170 JPEG2025501285000165.jpg245170 ( 1 Compound numbers indicate that the compounds were isolated as salt forms, including compounds (Cpd) having dihydroorotate dehydrogenase inhibitory activity ≦1.0 nM; The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer form thereof.

[0068] Another embodiment of the compound of formula (I) or a form thereof is [Table 12] and a compound (Cpd) salt having a dihydroorotate dehydrogenase inhibitory activity of ≦10.0 nM selected from the group consisting of: The form of the compound is selected from the group consisting of hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers, and tautomeric forms thereof.

[0069] One embodiment of the compound of formula (I) or a form thereof is [Table 13] JPEG2025501285000168.jpg250166 JPEG2025501285000169.jpg245170 JPEG2025501285000170.jpg250167 JPEG2025501285000171.jpg244170 JPEG2025501285000172.jpg242170 JPEG2025501285000173.jpg245170 JPEG2025501285000174.jpg151170 ( 1 Compound numbers include compound (Cpd) which indicates that the compound was isolated as a salt form, The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer form thereof.

[0070] Another embodiment of the compound of formula (I) or a form thereof is [Table 14] A compound (Cpd) salt selected from the group consisting of The form of the compound is selected from the group consisting of its hydrate, solvate, racemate, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms.

[0071] One embodiment of the compound of formula (I) or a form thereof is [Table 15] JPEG2025501285000177.jpg253170 JPEG2025501285000178.jpg245170 JPEG2025501285000179.jpg240170 JPEG2025501285000180.jpg243170 JPEG2025501285000181.jpg49170 ( 1 Compound numbers indicate that the compounds were isolated as salt forms, including compounds (Cpd) having dihydroorotate dehydrogenase inhibitory activity ≦10.0 nM; The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomeric, a diastereomeric, a stereoisomeric, and a tautomeric form thereof.

[0072] Another embodiment of the compound of formula (I) or a form thereof is [Table 16] and a compound (Cpd) salt having a dihydroorotate dehydrogenase inhibitory activity of ≦10.0 nM selected from the group consisting of: The form of the compound is selected from the group consisting of its hydrate, solvate, racemate, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms.

[0073] One embodiment of the compound of formula (I) or a form thereof is [Table 17] JPEG2025501285000184.jpg210170 ( 1 Compound numbers indicate that the compounds were isolated as salt forms, including compounds (Cpd) having dihydroorotate dehydrogenase inhibitory activity ≦1.0 nM; The form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomeric, a diastereomeric, a stereoisomeric, and a tautomeric form thereof.

[0074] definition The chemical terms used above and throughout the description herein shall be understood by those skilled in the art to have the meanings indicated below, unless specifically defined otherwise.

[0075] 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 up to eight carbon atoms in a straight or branched arrangement, including, but not limited to, methyl, ethyl, n-propyl (also called propyl or propanyl), isopropyl, n-butyl (also called butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also called pentyl or pentanyl), n-hexyl (also called hexyl or hexanyl), n-heptyl (also called heptyl or heptanyl), n-octyl (also called octyl or octanyl), and the like. 1-4 Alkyl, C 1-6 Alkyl or C 1-8 Alkyl groups may be optionally substituted, where available valences permit, with substituent types as described herein.

[0076] As used herein, the term "C 2-4 alkenyl", "C 2-6 alkenyl" or "C 2-8"Alkenyl" generally refers to partially unsaturated hydrocarbon groups having from 2 to 8 carbon atoms in a straight or branched arrangement and one or more carbon-carbon double bonds, including, but not limited to, ethenyl (also called vinyl), allyl, propenyl, and the like. 2-4 Alkenyl, C 2-6 Alkenyl, or C 2-8 Alkenyl groups may be optionally substituted, where available valences permit, with substituent types as described herein.

[0077] As used herein, the term "C 1-4 Alkoxy, C 1-6 Alkoxy" or "C 1-8 "Alkoxy" generally refers to an alkyl group of the formula: -OC having 1 to 8 carbon atoms in a straight or branched arrangement, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. 1-4 Alkyl, -OC 1-6 Alkyl, -OC 1-8 Refers to a saturated alkyl hydrocarbon group. 1-4 Alkoxy, C 1-6 Alkoxy, C 1-8 Alkoxy groups may be optionally substituted, where available valences permit, with substituent types as described herein.

[0078] As used herein, the term "C 3-6 "Cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon ring system radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like. In certain embodiments, C 3-6 Cycloalkyl includes, but is not limited to, C3 cycloalkyl, C4 cycloalkyl, C 5-6 Cycloalkyl, etc. 3-6 Cycloalkyl ring system radicals may be optionally substituted, where available valences permit, with such substituent types as described herein. As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring system radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl, etc. In certain embodiments, the aryl monocyclic or bicyclic ring system radical is phenyl or naphthyl, respectively. The aryl ring system radical may be substituted, where available valences permit, with substituent species as described herein.

[0079] As used herein, the term "heteroaryl" generally refers to a monocyclic aromatic carbon atom ring system group in which one or more carbon atom ring members are replaced by one or more heteroatoms, such as N, O, or S atoms, where structural stability permits. In certain embodiments, the heteroaryl ring system group may have 1, 2, or 3 carbon atom ring members replaced by heteroatom ring members independently selected from N, O, or S. In certain embodiments, the heteroaryl ring system group may be substituted with 1, 2, or 3 substituents, where available valences permit. In certain embodiments, the heteroaryl ring system group may include monocyclic, bicyclic, or polycyclic carbon atom ring system groups, such as 5-6 membered monocyclic, 7-8 membered monocyclic, or 9-10 membered bicyclic ring systems. In certain embodiments, heteroaryl groups can include ring systems such as, but not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, etc. Heteroaryl groups can be optionally substituted on carbon or nitrogen ring members, where available valences permit, with substituent types as described herein. In certain aspects, the nomenclature of heteroaryl groups may differ, such as, by way of non-limiting example, furanyl may also be referred to as furyl, thienyl may also be referred to as thiophenyl, and pyridinyl may also be referred to as pyridyl.

[0080] In certain embodiments, the terms relating to heteroaryl groups include, for example, the term pyrrolyl, which may include 1H-pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, etc.; the term pyrazolyl, which may include 1H-pyrazolyl, etc.; the term imidazolyl, which may include 1H-imidazolyl, etc.; the term triazolyl, which may include 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.; the term oxadiazolyl, which may include 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, and the like; the term tetrazolyl can include 1H-tetrazolyl, 2H-tetrazolyl, and the like; the term indolyl can include 1H-indolyl, and the like; the term indazolyl can include 1H-indazolyl, 2H-indazolyl, and the like; the term benzimidazolyl can also include 1H-benzimidazolyl; and the term purinyl can include 9H-purinyl, and the like.

[0081] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring system radical in which one or more carbon atom ring members are replaced by a heteroatom such as an O, S or N atom, where structural stability permits. In certain embodiments, a heterocyclyl ring system radical may have 1, 2, or 3 carbon atom ring members replaced by heteroatom ring members independently selected from N, O, or S. In certain embodiments, a heterocyclyl ring system radical may be substituted with 1, 2, or 3 substituents, where available valences permit. In certain embodiments, a heterocyclyl group may include a monocyclic, bicyclic or polycyclic carbon atom ring system radical, such as a 3- to 7-membered monocyclic, a 7- to 8-membered bicyclic, a 6- to 10-membered bicyclic or a 13- to 16-membered polycyclic ring system.

[0082] In certain aspects, heterocyclyl groups include, but are not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolin ... Trazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3a R,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-Hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-Hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-Hexahydropyrrolo[3,4-c]pyrrol-(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]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 3-oxa- 8-Azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[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-diazabicyclo[3.2 The ring system may include, for example, 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, 6,9-diazaspiro[4.5]decyl, etc.

[0083] Heterocyclyl groups may be optionally substituted on either carbon or nitrogen ring atoms, where available valences permit, with substituent types as described herein. In certain embodiments, the heterocyclyl group 1H-imidazol-1-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group 1H-pyrazol-1-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0084] In certain embodiments, the heterocyclyl group 1H-1,2,4-triazol-1-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group morpholin-4-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0085] In certain embodiments, the heterocyclyl group piperazin-1-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group 4-methyl-piperazin-1-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0086] In certain embodiments, the heterocyclyl group azetidin-1-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0087] In certain embodiments, the heterocyclyl group 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group 3-oxa-8-azabicyclo[3.2.1]octan-8-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0088] In certain embodiments, the heterocyclyl group (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0089] In certain embodiments, the heterocyclyl group 2-oxa-6-azaspiro[3.3]heptan-6-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group 3,3-dimethyl-piperazin-1-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0090] In certain embodiments, the heterocyclyl group (3R,5S)-3,5-dimethylpiperazin-1-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group 4,7-diazaspiro[2.5]octan-7-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0091] In certain embodiments, the heterocyclyl group (3R)-3-methylpiperazin-1-yl is [ka] where the asterisk (*) indicates the point of attachment. In certain embodiments, the heterocyclyl group (3S)-3-methylpiperazin-1-yl is [ka] where the asterisk (*) indicates the point of attachment.

[0092] As used herein, the term "C 1-4 Alkoxy-C 1-4 "Alkyl" means a group of the formula: -C 1-6 Alkyl-OC 1-6 Refers to an alkyl group. As used herein, the term "C 1-4 Alkoxy-C 1-4 "Alkoxy" means a group of the formula: -OC 1-4 Alkyl-OC 1-4 In certain embodiments, C 1-4 Alkoxy-C1-4 Alkoxy includes, but is not limited to, methoxy-ethoxy, and the like. As used herein, the term "C 1-4 Alkoxycarbonyl" or "(C 1-4 "Alkoxy)carbonyl" is a group represented by the formula: -C(=O)-OC 1-4 In certain embodiments, C 1-4 Alkoxycarbonyl includes, but is not limited to, methoxy-carbonyl, and the like. As used herein, the term "C 1-4 Alkoxycarbonyl C 1-4 Alkyl" or "(C 1-4 Alkoxy)carbonyl C 1-4 "Alkyl" means a group of the formula: -C 1-4 Alkyl-C(=O)-OC 1-4 In certain embodiments, C 1-4 Alkoxycarbonyl C 1-4 Alkyl includes, but is not limited to, methoxy-carbonyl-ethyl, and the like.

[0093] As used herein, the term "amino" refers to a group of the formula: -NH2. As used herein, the term "amino-sulfonyl" refers to a group of the formula: -SO2-NH2 or -S(=O)(=O)-NH2. As used herein, the term “(C 1-4 "Alkyl)amino" has the formula: -NH-C 1-4 In certain embodiments, (C 1-4 Alkyl)amino includes, but is not limited to, N-methyl-amino, and the like. As used herein, the term “(C 1-4 "N(C alkyl)2amino" has the formula: 1-4 alkyl)2 groups, each C 1-4 The alkyl groups can be the same or different. In certain embodiments, (C 1-4 Alkyl)2-amino includes, but is not limited to, N,N-dimethyl-amino, and the like. As used herein, the term “(C1-4 Alkyl)2amino-(C 1-4 "Alkyl)amino" is a group represented by the formula -NH-C 1-4 Alkyl-NH-(C 1-4 In certain embodiments, the (C 1-4 Alkyl)2amino-(C 1-4 Alkyl)amino includes, but is not limited to, N[N,N-dimethylamino)ethyl]amino, and the like.

[0094] As used herein, the term "C 1-4 "Alkylcarbonyl" means a group of the formula: -C(=O)-C 1-4 In certain embodiments, C 1-4 Alkylcarbonyl includes, but is not limited to, methyl-carbonyl, and the like. As used herein, the term "C 1-4 "Alkyl-sulfonyl" means a group of the formula: -SO2-C 1-4 Alkyl, -S(=O)(=O)-C 1-4 Alkyl or -S(=O)2-C 1-4 In certain embodiments, C 1-4 Alkyl-sulfonyl includes, but is not limited to, methyl-sulfonyl. As used herein, the term "C 1-4 "Alkylthio" means a group of the formula: -SC 1-4 Refers to an alkyl group. 1-4 Alkylthio includes, but is not limited to, methyl-thio, and the like. As used herein, the term "amino-C 1-4 "Alkyl" means a group of the formula: -C 1-4 Refers to the group alkyl-NH2. As used herein, the term “carboxyl C 1-4 "Alkyl" means a group of the formula: -C 1-4 It refers to the alkyl-C(=O)-OH group. As used herein, the term “carboxyl C 1-4 "Alkylamino" means a group of the formula: -NH-C 1-4 It refers to the alkyl-C(=O)-OH group. As used herein, the term “carboxyl C 1-4 Alkoxy C 1-4 "Alkylamino" means a group of the formula: -NH-C 1-4 Alkyl-OC 1-4 It refers to the alkyl-C(=O)-OH group.

[0095] As used herein, the term "halo" or "halogen" refers generally to halogen atom radicals including fluoro, chloro, bromo and iodo. As used herein, the term "halo-C 1-4 "Alkoxy" means a group of the formula: -OC 1-4 Refers to the alkyl-halo group, C 1-4 Alkyl is partially or fully substituted with one or more halogen atoms where available valences permit. As used herein, the term "halo-C 1-4 "Alkyl" means a group of the formula: -C 1-4 Refers to the alkyl-halo group, C 1-4 Alkyl is partially or fully substituted with one or more halogen atoms where available valences permit. In certain embodiments, halo-C 1-4 Alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, and the like.

[0096] As used herein, the term "hydroxy" refers to a group of the formula: --OH. As used herein, the term "hydroxy-C 1-4 "Alkyl" means a group of the formula: -C 1-4 Refers to the alkyl-OH group, C 1-4 Alkyl is partially or fully substituted with one or more hydroxy groups, where available valences permit. In certain embodiments, hydroxy-C 1-4 Alkyl includes, but is not limited to, hydroxy-methyl and the like.

[0097] As used herein, the term "hydroxy-C 2-4 "Alkenyl" means a group of the formula:2-4 Alkenyl-OH group, C 2-4 Alkenyls are partially or fully substituted with one or more hydroxy groups where available valences permit. As used herein, the term "hydroxy C 1-4 "Alkylamino" means a group of the formula: -NH-C 1-4 Refers to the alkyl-OH group, C 1-4 Alkyl is partially or fully substituted with one or more hydroxy groups where available valences permit. In certain embodiments, hydroxy C 1-4 Alkylamino includes, but is not limited to, N-(hydroxyethyl)amino, and the like. As used herein, the term "hydroxy C 1-4 Alkoxy C 1-4 "Alkyl" is a group of the formula -C 1-4 Alkyl-OC 1-4 Refers to the alkyl-OH group.

[0098] As used herein, the term "substituent" refers to a position variable on an atom of a core molecule that is substituted at a specified atomic position, replacing one or more hydrogens on the specified atom, provided that the normal valence of the specified atom is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Those skilled in the art should note that any carbon and heteroatom that has 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 valences described or shown. In certain instances, one or more substituents having a double bond (e.g., "oxo" or "=O") as a point of attachment may be described, shown, or listed in a substituent group herein, and the structure may only show a single bond as a point of attachment 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.

[0099] As used herein, with respect to the definitions of chemical terms provided herein, the term "such as" means that variations in chemical structures that might be expected by one of ordinary skill in the art include, but are not limited to, isomers (including chain, branched or positional structural isomers), hydration of ring systems (including saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring structures), and all other variations that result in stable compounds, where available valences permit. For purposes of this specification, when one or more substituted variables of a compound of formula (I) or a form thereof include functional groups that are incorporated into a compound of formula (I), each functional group appearing anywhere within the disclosed compounds may be independently selected and, where appropriate, independently and / or optionally substituted. As used herein, the term "independently selected" or "each selected" refers to a functional variable within a list of substituents that may occur more than one time on the structure of formula (I), and the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Furthermore, it is understood that the use of a genus of substituted variables on any formula or structure of the compounds described herein includes the replacement of the genus substituent with a species substituent included within the particular genus, for example, aryl may be replaced with phenyl or naphthalenyl, etc., and the resulting compound is included within the scope of the compounds described herein.

[0100] As used herein, the term "in each instance" or "in each instance, if present" means "...C 3-14 Cycloalkyl, C 3-14 Cycloalkyl-C 1-4 Alkyl, aryl, aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, heterocyclyl and heterocyclyl-C 1-4 When used before a phrase such as "alkyl", each of the C's when present alone or as a substituent is 3-14 It is intended to refer to cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems. As used herein, the term "optionally substituted" means optional substitution with the specified substituted variable, group, radical or moiety.

[0101] Compound Form 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, racemic, enantiomeric, diastereomeric, stereoisomeric, and tautomeric forms. In certain embodiments described herein, the compound of formula (I) is in the form of a free acid, a free base, or a salt thereof. In certain aspects described herein, the compounds of formula (I) are in the form of salts thereof. In certain embodiments described herein, the form of the compound of formula (I) is an isotopologue thereof. In certain embodiments described herein, the compounds of formula (I) are in the form of their stereoisomers, racemates, enantiomers or diastereomers. In certain embodiments described herein, the compounds of formula (I) may be in the form of a tautomer thereof. In certain embodiments described herein, the compound of formula (I) is in a pharma- ceutically acceptable form. In certain aspects described herein, the compound of formula (I) or a form thereof is isolated for use.

[0102] As used herein, the term "isolated" refers to the physical state of a compound of formula (I) or a form thereof 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, in sufficient purity to be characterized by standard analytical techniques described herein or known to one of skill in the art, following one or more isolation or purification processes (e.g., chromatography, recrystallization, etc.) described herein or known to one of skill in the art.

[0103] As used herein, the term "protected" means that a functional group in the compound of formula (I) or its form is in a modified form such that when the compound is subjected to a reaction, undesired side reactions do not occur at the protected site. Suitable protecting groups are recognized by those skilled in the art and by reference 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 acid. 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, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. In certain instances, the protecting group may also be a polymeric resin, such as Wang resin or 2-chlorotrityl-chloride resin. Protecting groups may be added or removed according to standard techniques well known to those skilled in the art and as 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 they may be administered to a subject and then metabolized in the body to form a compound described herein that is pharmacologically active. Thus, such derivatives may be described as "prodrugs". All prodrugs of the compounds described herein are included within the scope of the uses described herein.

[0104] As used herein, the term "prodrug" refers to a form of the compound (e.g., a drug precursor) that is converted in vivo to produce an active compound of formula (I) or a form thereof. The conversion can occur by various mechanisms (e.g., by metabolic and / or non-metabolic chemical processes), such as by hydrolysis and / or metabolism in blood, liver and / or other organs and tissues. A discussion of the use of prodrugs is provided by 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.

[0105] In one example, when the compound of formula (I) or a form thereof contains a carboxylic acid functional group, the prodrug may include an ester formed by replacing the hydrogen atom of the acidic group with a functional group such as an alkyl. In another example, when the compound of formula (I) or a form thereof contains a hydroxyl functional group, the prodrug form may be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as an alkyl, alkylcarbonyl, or phosphonate ester. In another example, when the compound of formula (I) or a form thereof contains an amine functional group, the prodrug form may be prepared by replacing one or more amine hydrogen atoms with a functional group such as an alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of the compound of formula (I) or a form thereof include those compounds substituted with one or more of the following groups, as appropriate: carboxylate ester, sulfonate ester, amino acid ester, phosphonate ester, and mono-, di-, or triphosphate ester, or alkyl substituent. It will be understood by those skilled in the art that one or more of such substituents may be used to provide the compound of formula (I) or a form thereof as a prodrug, as described herein.

[0106] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to encompass both solvated and unsolvated forms. As used herein, the term "solvate" refers to the physical association of a compound described herein with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonds, including hydrogen bonds. In certain instances, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. As used herein, the term "hydrate" refers to a solvate where the solvent molecule is water.

[0107] The compound of formula (I) may form salts which are intended to be included within the scope of this specification. Reference herein to the compound of formula (I) or a form thereof is understood to include reference to its salt form unless otherwise indicated. The term "salt" as used herein refers to acid salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. In addition, when the compound of formula (I) or a form thereof contains both a basic moiety, such as, but not limited to, an amine moiety, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and are included in the term "salt" as used herein.

[0108] The term "pharmaceutical acceptable salts" as used herein means salts of the compounds described herein that are safe and effective for use in mammals (i.e., physiologically acceptable) and have biological activity, although other salts are also useful. Salts of the compounds of formula (I) can be formed, for example, by reacting the compound of formula (I) or a form thereof with an amount of an acid or base, e.g., an equivalent amount, in a medium such as a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization. Pharmaceutically acceptable salts include salts of one or more of the acidic or basic groups present in the compounds described herein. Specific embodiments of acid addition salts include, but are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, and the like. Certain embodiments of acid addition salts include chlorides, bromides or dichlorides.

[0109] In addition, acids generally considered suitable for forming pharma- ceutically useful salts from basic pharmaceutical compounds are discussed, for example, by 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 website), the disclosures of which are incorporated herein by reference thereto.

[0110] Suitable base salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts. All such acid and base salts are intended to be included within the scope of pharma- ceutically acceptable salts as described herein, and are considered equivalent to the free form of the corresponding compound for purposes of this specification. Compounds of formula (I) and forms thereof may further exist in tautomeric forms, and all such tautomeric forms are contemplated and intended to be included within the scope of the compounds of formula (I) and forms thereof as described herein. The compounds of formula (I) or forms thereof may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. This specification is intended to include all stereoisomeric forms of the compounds of formula (I) and mixtures thereof, including racemic mixtures.

[0111] The compounds described herein may contain one or more chiral centers and therefore may 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 enantiomerically pure compositions that contain substantially only the (S) isomer. In another particular embodiment, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions that contain substantially only the (R) isomer. As one of ordinary skill 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) isomers as defined by the IUPAC nomenclature recommendations.

[0112] As used herein, the term "substantially pure" refers to a compound that consists of substantially a single isomer in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or equal to 100% of a single isomer. In one aspect of the present specification, a compound of formula (I) or a form thereof that is a substantially pure single isomer may exhibit a desired activity greater than other substantially pure isomers of the compound of formula (I) or a racemic mixture thereof.

[0113] In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (S) enantiomer form present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or an amount equal to 100%. In one aspect herein, the compound of formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount of 90% or more, 92% or more, 95% or more, 98% or more, 99% or more, or an amount equal to 100%. As used herein, a "racemate" is any mixture of isometric forms that is not "enantiomerically pure," including, but not limited to, mixtures in ratios of about 50 / 50, about 60 / 40, about 70 / 30, or about 80 / 20.

[0114] In addition, the present specification embraces all geometric and positional isomers. For example, when a compound of formula (I) or a form thereof incorporates a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are embraced within the scope of the present specification. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by using a chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric 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 to the corresponding pure enantiomers (e.g., hydrolysis). Some of the compounds of formula (I) may also be atropisomers (e.g., substituted biaryls) and are considered part of this specification.

[0115] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds (including salts, solvates, esters and prodrugs, and salts, solvates and esters of the prodrugs), including, for example, enantiomeric forms (which may exist even in the absence of an asymmetric carbon), rotamer forms, atropisomers, and diastereomeric forms, including those that may exist due to asymmetric carbons on various substituents, such as positional isomers (e.g., 4-pyridyl and 3-pyridyl, etc.), are contemplated within the scope of this specification. Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers or may be present as racemic mixtures as described above.

[0116] The term "isotopologue" refers to an isotope-enriched compound described herein that is identical to that listed herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein are, respectively:2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 35 Cl and 36 Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as Cl, each of which are within the scope of this specification. Certain isotopically enriched compounds described herein (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Additionally, deuterium (i.e. 2 Substitution with heavier isotopes, such as H), can offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Polymorphic crystalline and amorphous forms of the compounds of formula (I), and of the salts, solvates, hydrates, esters and prodrugs of the compounds of formula (I), are further intended to be included herein.

[0117] Use of the compound An embodiment of the present specification relates to a method of using a compound of formula (I) or a form thereof to treat or ameliorate a disorder or condition by inhibiting dihydroorotate dehydrogenase (DHODH) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof. Another embodiment provided herein is a method of treating a disease or disorder for which dihydroorotate dehydrogenase inhibition is appropriate using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof. Another embodiment provided herein is a method of treating a disease or disorder for which dihydroorotate dehydrogenase inhibition is appropriate in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof.

[0118] In addition to being used as a monotherapy, the compounds are useful in combination therapy with current standard drugs, which have additive or synergistic activity with one or more known drugs.Combination therapy comprising the compounds described herein in combination with one or more known drugs can be used to treat disorders, regardless of whether such disorders are responsive to known drugs. Certain aspects herein include the use of a compound of formula (I) or a form thereof in combination therapy for treating a disorder or condition in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof and an effective amount of one or more agents.

[0119] As used herein, the term "treating" refers to preventing a disease, disorder, or condition from occurring in a subject who may be susceptible to the disease, disorder, and / or condition, but has not yet been diagnosed as having the disease, disorder, and / or condition. As used herein, the term "ameliorating" refers to inhibiting the disease, disorder or condition, i.e., halting its development, and / or relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and / or condition. As used herein, the term "subject" refers to an animal or any living organism that has sentience and the power of voluntary movement, and requires oxygen and organic food. In certain aspects, the subject is a mammal or a warm-blooded vertebrate. In other aspects, the subject is a human. As used herein, the term "patient" may be used interchangeably with "subject" and "human." As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound of formula (I), or a form, composition, or medicament thereof, that achieves a target plasma concentration that is effective to treat or ameliorate the disease or condition in question as described herein, thus resulting in the desired therapeutic, ameliorative, inhibitory or preventative effect in a subject in need thereof. In one aspect, an effective amount can be the amount required to treat a disorder or condition in a subject or patient, more specifically a human.

[0120] 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 ameliorating 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 for treating or ameliorating 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 a pharma- ceutical acceptable excipient, for treating or ameliorating a disease or disorder by inhibiting dihydroorotate dehydrogenase.

[0121] One aspect provided herein is a method of using a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof, to treat or ameliorate a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a form thereof, or a pharmaceutical composition thereof to inhibit dihydroorotate dehydrogenase. Another aspect provided herein is a method of using a compound of formula (I) or a form thereof to treat or ameliorate a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof to inhibit dihydroorotate dehydrogenase. Another aspect provided herein is a method of using a pharmaceutical composition comprising a compound of formula (I) or a form thereof, and a pharma- ceutically acceptable excipient, for treating or ameliorating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of the pharmaceutical composition to inhibit dihydroorotate dehydrogenase. In one aspect, a method of use of a compound of formula (I) or a form thereof to treat or ameliorate a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof to inhibit dihydroorotate dehydrogenase, wherein the compound of formula (I) or a form thereof or a pharmaceutical composition may be administered to a subject in need thereof by various routes and in an amount that provides a beneficial or therapeutic effect.

[0122] In one aspect, routes of administration include, but are not limited to, oral, intravenous, intradermal, intrathecal, intramuscular, subcutaneous, intranasal, inhalation, transdermal, topical, transmucosal, intracranial, epidural, and intrasynovial. In another aspect, the compound of formula (I), or a form or pharmaceutical composition thereof, as provided herein, may be orally administered to a subject in need thereof in an effective amount of the compound of formula (I), or a form thereof, to inhibit dihydroorotate dehydrogenase. In another embodiment, a compound of formula (I), or a form or pharmaceutical composition thereof, may be administered orally, with or without food or water. In another embodiment, a compound of formula (I), or a form or pharmaceutical composition thereof, may be administered systemically (eg, parenterally) to a subject in need thereof. In another aspect, the compound of formula (I), or a form or pharmaceutical composition thereof, may be administered by a route that allows the compound of formula (I), or a form or pharmaceutical composition thereof, to cross the blood-brain barrier (e.g., orally). In another aspect, a compound of formula (I), or a form or pharmaceutical composition thereof, may be administered in combination with one or more additional therapeutics, which may be administered by the same route of administration or by a different route of administration. In another aspect, the dosage and frequency of administration of an effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, that inhibits dihydroorotate dehydrogenase to treat or ameliorate a disease or disorder in a subject in need thereof can be determined by a practitioner in light of factors related to the subject requiring treatment, while minimizing any side effects.

[0123] Factors that may be considered include the severity of the disease state, the overall health of the subject, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerability / response to treatment. The dosage and frequency of administration of the compound of formula (I), or a form or pharmaceutical composition thereof, may be adjusted over time to provide an effective amount of the compound of formula (I), or a form or pharmaceutical composition thereof, to maintain the desired effect. In one embodiment, the term "effective amount" refers to the amount of a compound of formula (I), or a form or pharmaceutical composition thereof, administered to a patient as monotherapy, the effective amount 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 / Kg / day to about 500 mg / Kg / day, or about 1.0 mg / day to about 500 mg / Kg / day, in a single, divided, or continuous dose for a patient or subject having a body weight in the range of between about 40 to about 200 Kg (the dose may be adjusted for patients or subjects above or below this range, particularly children who do not reach 40 Kg). Dosing may be administered 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 embodiment, the effective amount is the dose administered to a subject, which may be increased or decreased depending on the subject's response. The effective amount 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 within the range of between about 60 and about 100 kg. Thus, the effective amount for a given patient can be determined according to the skill and judgment of a practitioner skilled in the art.

[0124] In one aspect, the daily monotherapy dose may be adjusted based on the subject or patient's body weight, and the compound of formula (I), or a form or pharmaceutical composition thereof, may be administered at a dose of about 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 may be formulated for delivery as a monotherapy at 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 therebetween.

[0125] In another embodiment, the daily dose is adjusted based on the subject's or patient's body weight and may be administered as a single, divided, or continuous dose. In another embodiment, the daily dose of a compound of formula (I), or a form or pharmaceutical composition thereof, may be administered one or more times per day, such as once, twice, three or more times per day. In another embodiment, the dose of a compound of formula (I), or a form or pharmaceutical composition thereof, may be administered one or more times per week, such as once, twice, three times, or more than once per week. In another aspect, the effective amount may be a dose administered to a subject twice per week on different days, the second dose in one week being 3 days after the first and the first dose in the next week being 4 days after the second dose in the previous week. In another embodiment, a subject may be administered one or more doses of an effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, and the effective amount may not be the same for each dose.

[0126] In one aspect, an effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, may range from about 0.001 mg / Kg / day to about 500 mg / Kg / day. The term "effective amount" or "therapeutically effective amount" of a compound of formula (I), or a form or pharmaceutical composition thereof, for use in the manufacture of a medicament or in a method for treating or ameliorating a disease or disorder in a subject in need thereof is an amount sufficient to provide a therapeutic benefit by inhibiting dihydroorotate dehydrogenase. A therapeutically effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, is intended to include an amount selected from an amount within the range of about 0.01 ng to about 3500 mg, about 0.1 ng to about 3500 mg; about 0.1 μg to about 3500 mg; about 0.1 mg to about 3500 mg; about 1 mg to about 3500 mg; about 1 mg to about 3000 mg; about 0.05 mg to about 1500 mg; about 0.5 mg to about 1500 mg; about 1 mg to about 1500 mg; about 5 mg to about 1500 mg; about 10 mg to about 600 mg; about 0.5 mg to about 2000 mg; or about 5.0 mg to about 1500 mg, administered daily, weekly, or biweekly.

[0127] In one aspect, an effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, can be estimated initially by results from cell culture assays or from appropriate animal models, such as human or mouse, chimpanzee, marmoset, or tamarin animal models. Appropriate animal models can also be used to determine appropriate concentration ranges and routes of administration. Therapeutic efficacy and toxicity can be assessed by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 The dose ratio between toxic and therapeutic effects is called the therapeutic index, and the LD 50 / ED 50 In another embodiment, the effective amount is such that a large therapeutic index is achieved. In another embodiment, the dose administered is within the ED 50The dosage may vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0128] More specifically, the concentration-biological effect (pharmacodynamic) relationships observed for the compound of formula (I), or a form or pharmaceutical composition thereof, suggest target plasma concentrations in the range of about 0.001 μg / mL to about 50 μg / mL, about 0.01 μg / mL to about 20 μg / mL, about 0.05 μg / mL to about 10 μg / mL, or about 0.1 μg / mL to about 5 μg / mL. To achieve such plasma concentrations, the compound of formula (I), or a form or pharmaceutical composition thereof, may be administered to a patient weighing between about 40 and about 100 kg in single, divided, or continuous doses at doses ranging from 0.001 μg to 100,000 mg, depending on the route of administration (the dose may be adjusted for patients above or below this weight range, particularly children not reaching 40 kg).

[0129] In another aspect, a method for preventing, treating or ameliorating a disease or disorder in a subject in need thereof by inhibiting dihydroorotate dehydrogenase comprises administering to the subject an effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, wherein the effective amount is from about 50 mg to about 400 mg, about 100 mg to about 200 mg, about 125 mg to about 175 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, or about 150 mg to about 200 mg, or about 160 mg to about 300 mg, or about 175 mg to about 400 mg, or about 250 mg to about 500 mg, or about 300 mg to about 500 mg, or about 400 mg to about 600 mg, or about 50 mg to about 700 mg, or about 600 mg to about 800 mg, or about 700 mg to about 900 mg, or about 800 mg to about 1000 mg, or about 900 mg to about 1000 mg, or about 100 mg to about 200 mg, or about 150 mg to about 300 mg, or about 100 mg to about 400 mg, or about 150 mg to about 5 ...50 mg to about 200 mg, or about 150 mg to about 300 mg, or about 150 mg to about 400 mg, or about 150 mg to about 500 mg, or about 150 mg to about 200 mg, or about 150 mg to about 300 The dosage is selected from the dosage ranges of about 150 mg to about 200 mg, about 150 mg to about 300 mg, about 150 mg to about 400 mg, about 200 mg to about 300 mg, about 225 mg to about 275 mg, about 225 mg to about 300 mg, about 275 mg to about 300 mg, about 200 mg to about 225 mg, about 200 mg to about 275 mg, about 200 mg to about 400 mg, about 250 mg to about 300 mg, about 250 mg to about 400 mg, and about 250 mg to about 350 mg. In another aspect, a method for preventing, treating or ameliorating a disease or disorder in a subject in need thereof by inhibiting dihydroorotate dehydrogenase comprises administering to the subject an effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, wherein the effective amount is administered 1, 2 or 3 times every other week. In another aspect, a method for preventing, treating or ameliorating a disease or disorder in a subject in need thereof by inhibiting dihydroorotate dehydrogenase comprises administering to the subject an effective amount of a compound of formula (I), or a form or pharmaceutical composition thereof, wherein the effective amount is administered 1, 2 or 3 times every 2 weeks.

[0130] Pharmaceutical Compositions Aspects of the present specification include the use of a compound of formula (I) or a form thereof in a pharmaceutical composition for treating or ameliorating a disorder or condition described herein in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or a form thereof in admixture with one or more pharma- ceutically acceptable excipients. An embodiment of the present specification includes the use of a compound of formula (I) or a pharmaceutical composition in a form thereof in the preparation of a kit comprising the compound of formula (I) or a pharmaceutical composition in a form thereof and instructions for administering the compound to treat or ameliorate a disease or condition in a subject in need thereof. As used herein, the term "composition" means a product comprising the specified ingredients in the specified amounts, and any product that results directly or indirectly from the combination of the specified ingredients in the specified amounts.

[0131] The pharmaceutical composition may be formulated to achieve a physiologically compatible pH ranging from about pH 3 to about pH 11. In certain embodiments, the pharmaceutical composition is formulated to achieve a pH of about pH 3 to about pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of about pH 5 to about pH 8. The term "pharmaceutical acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as a compound described herein. A pharmaceutical acceptable excipient can be determined, in part, by the particular composition to be administered, as well as by the particular mode of administration and / or dosage form. Non-limiting examples of pharmaceutical acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, and the like. Thus, there are a wide variety of suitable formulations of pharmaceutical compositions of the compounds described herein (see, for example, Remington's Pharmaceutical Sciences).

[0132] Suitable excipients may be carrier molecules, including large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, 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), stearic acid; liquids such as oils, water, saline, glycerol, and ethanol; wetting or emulsifying agents; pH buffering substances, and the like. Liposomes are also included within the definition of pharma-ceutically acceptable excipients.

[0133] 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 reconstituted with a physiologically compatible solvent before administration. When intended for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, non-aqueous solutions, dispersible powders or granules (including micronized 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.

[0134] Pharmaceutically acceptable excipients suitable for use with tablets include, for example, inert diluents such as cellulose, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents such as croscarmellose sodium, cross-linked povidone, corn starch, or alginic acid; binders such as povidone, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, cellulose, lactose, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a non-aqueous or oily vehicle such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

[0135] In other aspects, the pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of formula (I) or a form thereof in admixture with one or more pharma- ceutically acceptable excipients suitable for the preparation of a suspension. In yet other aspects, the pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for the preparation of a suspension by the addition of one or more excipients.

[0136] Suitable excipients for use in connection with suspensions include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum arabic, dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate); and thickening agents such as carbomer, beeswax, hard paraffin, or cetyl alcohol. Suspensions may also contain one or more preservatives, such as acetic acid, methyl and / or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents, such as sucrose or saccharin.

[0137] The pharmaceutical compositions described herein may be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or arachis 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 soybean 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. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring agent or a coloring agent. In addition, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsions or suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables as well.

[0138] The compounds described herein may be substantially insoluble in water and slightly soluble in most pharma- ceutically acceptable protic solvents and vegetable oils, but generally may be soluble in medium chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium chain fatty acids. Thus, compounds modified by substitution or addition of chemical or biochemical moieties that render the compounds more suitable for delivery (e.g., increasing solubility, bioactivity, palatability, decreasing adverse reactions, etc.), for example, by esterification, glycosylation, PEGylation, etc., are contemplated herein. 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.Thus, the pharmaceutical compositions described herein can comprise an effective amount of the compound of formula (I) or a form thereof together with at least one pharma- ceutically 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 capric fatty acids) and a pharma-ceutically acceptable surfactant such as polysorbate 20 or 80 (also referred to as Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

[0139] In other aspects, the bioavailability of poorly soluble compounds may be enhanced using particle size optimization techniques, including the preparation of nanoparticles or nanosuspensions using techniques known to those of skill in the art. The form of the compound present in such preparations includes amorphous, partially amorphous, partially crystalline or crystalline forms. In alternative embodiments, the pharmaceutical composition may further comprise one or more water solubility enhancers, such as cyclodextrin. Non-limiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β- and γ-cyclodextrin, as well as hydroxypropyl-β-cyclodextrin (HPBC). In certain embodiments, the pharmaceutical composition further comprises 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 solubility enhancer used may depend on the amount of compound in the composition.

[0140] General synthetic methods for preparing compounds As disclosed herein, the general method for preparing the compounds of formula (I) or forms thereof as described herein can be utilized by standard well-known synthetic methodologies. Many of the starting materials are commercially available, or if not available, can be prepared using the following routes using techniques known to those skilled in the art. The synthetic schemes provided herein include multiple reaction steps, each of which is intended to be independent and can be carried out with or without any preceding or succeeding steps. In other words, each of the individual reaction steps of the synthetic schemes provided herein is intended to be alone.

[0141] In the general reaction scheme below, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Q 1 , Q 2 , Q 3 and Q 4 has the same meaning as described in the first aspect of formula (I) above, except as otherwise specified below. Scheme A: Compounds of formula (I) may be prepared as depicted in Scheme A below. Racemic tetrahydro-β-carbolines A3 can be prepared by Pictet-Spengler reaction of NH2-containing tryptamines A1 with aldehydes A2 using an acid catalyst (AcOH, TFA, TsOH, HCl, etc.) in a solvent (water, alcohol, dichloromethane, AcOH, etc.) as shown below.

[0142] [ka] Alternatively, as shown below, amide A4 can be cyclized under Bischler-Napieralski reaction conditions (such as in solvents such as ACN or toluene, or by heating with neat POCl3) to form dihydrocarboline A5, which can be further reduced to racemic tetrahydrocarboline A3 using a reagent such as NaBH4 in an alcoholic solvent. [ka]

[0143] Intermediate A3 can be further reacted with electrophile A6, preferably in the presence of a base such as a tertiary amine or an alkyl metal carbonate (Scheme A), to form racemic tetrahydro-β-carboline A7, as shown below. [ka]

[0144] Alternatively, racemic tetrahydro-β-carbolines A7 can be prepared from heteroaryl-containing tryptamines A8 and aldehydes A2 by the Pictet-Spengler reaction using an acid catalyst (AcOH, TFA, TsOH, HCl, etc.) in a solvent (water, alcohol, dichloromethane, AcOH, etc.). Tryptamines A8 can be prepared by reaction of tryptamine A1 with electrophiles A6 as shown below. [ka]

[0145] Enantiomeric enrichment of the product of Scheme A can be obtained using a variety of methods, including, but not limited to, asymmetric catalysis, chiral resolution, chiral chromatography, and the like, as further shown below.

[0146] Scheme B [ka] Alternatively (Scheme B), dihydro-β-carboline A5 can be reduced to chiral tetrahydro-β-carboline B1 by similar methods such as the asymmetric transfer hydrogenation reaction developed by Ryoji Noyori (see J. Am. Chem. Soc. 1996, 118, 4916-4917) or asymmetric hydrogenation using hydrogen gas. Combination of B1 with A6 gives enantiomerically enriched tetrahydro-β-carboline B2.

[0147] Scheme C: [ka] Alternatively (Scheme C), the racemic mixture of A3 can be converted to enantiomerically enriched B1 by the chiral resolution procedure described in U.S. Patent No. 7,601,840 B2. In this process, one enantiomer is selectively precipitated as a diastereomeric salt with a chiral amino acid derivative, which is subsequently converted to the free amine after treatment with a base such as aqueous ammonia or sodium hydroxide.

[0148] Scheme D: [ka] Pyrimidine building blocks A9 (X = halogen or SMe) can be prepared by condensation of functionalized amidines D2 with dicarbonyls D1, optionally catalyzed by acid (such as H2SO4) or in the presence of a dehydrating reagent such as POCl3. The thiomethyl analogs A10 can be further activated by further oxidation to sulfoxides or sulfones A11 using reagents such as 3-chlorobenzenecarboperoxoic acid.

[0149] Scheme E: [ka] Triazine building block E5 (Schemes E and Q 1 =CR 5 , Q 2 =N) can be prepared by reaction of trifluoromethylamidine E1 with trichloromethylacetonitrile E2, followed by condensation of the unisolated intermediate E3 with an acid anhydride E4.

[0150] Scheme F: [ka] Triazine building blocks F2 and F3 can be formed non-selectively by partial substitution of the F-atom in 1,3,5-trifluorotriazine with CF3, Scheme F.

[0151] Scheme G: [ka] A suitable leaving group X in G1 (Scheme G) can be displaced by a suitable nucleophile G2. Alternatively, a thiol group X in G1 can be displaced by an H-atom by hydrogenolysis.

[0152] Scheme H: [ka] The trichloromethyl group in H1 can be converted to a methyl group by reductive hydrogenolysis using a metal dissolved in acid, such as Zn in aqueous ammonium chloride, Scheme H. EXAMPLES

[0153] The following examples include non-limiting, representative illustrations of embodiments of compounds of formula (I) described herein. The examples include non-limiting methods for preparing specific compounds of formula (I). Specific Synthesis Examples In order to aid in the understanding of the scope of the compounds of formula (I) or forms thereof described herein, the following general specific synthetic examples are included. In particular, these examples illustrate the preparation of certain representative compounds. Those skilled in the art will understand that the techniques described in these examples represent techniques as described by those skilled in the art that work well in the practice of synthesis and therefore constitute preferred modes for the practice. However, it should be understood that those skilled in the art should understand in light of this disclosure that many modifications can be made in the specific methods disclosed and still achieve the same or similar results without departing from the spirit and scope of the present specification.

[0154] Except for the following examples, unless otherwise indicated, all numbers expressing amounts of ingredients, reaction conditions, experimental data, etc. used in the specification and claims should be understood to be modified by the term "about". Thus, all such numbers 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 "about" in the context of the data provided refers to the range of the data provided that may vary according to the standard deviation from the mean. Similarly, for the experimental results provided, the data provided may be rounded up or down to present the data consistently without losing significant figures.

[0155] Notwithstanding that the numerical ranges and parameters setting forth herein characterizing the compounds of formula (I) or forms thereof are approximations, the numerical values ​​set forth in the examples are reported as precisely as possible, however, any numerical values ​​inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0156] Reagents and solvents were used as purchased (from various vendors) unless otherwise noted. Where applicable, the term "Celite" is used as shown in the following examples to denote the trade name CELITE® (a trademark of diatomaceous earth). Where applicable, chromatographic separations were performed using commonly available techniques and equipment, such as by using an ISCO CombiFlash® Rf system. Where applicable, NMR spectra were obtained using commonly available techniques and equipment, such as a Bruker Avance III with deuterated solvents, such as DMSO-d6 or residual solvents, as standards. 500 Where applicable, melting points were determined using commonly available techniques and equipment, such as by using an SRS OptiMelt® MPA100 (values ​​as obtained without correction / calibration). Where applicable, TLC analyses were performed using commonly available techniques and equipment, such as by using Aldrich 254 nm glass-backed plates (60 Å, 250 μm) visualized using UV and I2 stain. Where applicable, ESI mass spectra were performed using commonly available techniques and equipment, such as by using an Aldrich 254 nm glass-backed plate ... Values ​​are [M+H] unless otherwise indicated. + or [MH] - The structures of the products were obtained by, for example, using an ACQUITY UPLC® system, as shown in Table 1. When applicable, the structures of the products were obtained by 2D NOESY (Nuclear Overhauser SpectroscopY) experiments.

[0157] In order to ensure that the terms used herein are not ambiguous to those of skill in the art, the following abbreviations are provided: [Table 18] JPEG2025501285000214.jpg249164 JPEG2025501285000215.jpg91167

[0158] Example 1 Synthesis of 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine [ka] In a round-bottom flask, trifluoroacetamidine (50 g, 379.29 mmol) was dissolved in dichloromethane (190 mL). The solution was placed in an ice-water bath at 0° C. and the internal temperature was monitored with a thermocouple probe. Trichloroacetonitrile (77 mL, 768 mmol) was added slowly via syringe. After the addition was complete, the exothermic reaction ceased and the mixture was stirred in the ice-water bath for an additional 10 min. Trifluoroacetic anhydride (64 mL, 455.2 mmol) was then added slowly via syringe. After stirring at 0° C. for 1 h, the mixture was poured into saturated sodium bicarbonate (250 mL) that had been pre-chilled in an ice-water bath and stirred vigorously for 10 min. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with dichloromethane (2×200 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting oil was purified by distillation at 60° C.-65° C. (measured at the still head) and 20 mbar to give 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (51.8 g, 41% yield) as a clear oil. 19 F NMR (DMSO-d 6, 400MHz) δ: -70.96 (s).

[0159] Example 2 Synthesis of 2-(trichloromethyl)-4-(trifluoromethyl)-1,3,5-triazine [ka] In a flask, formic acid (19 mL, 504 mmol) and acetic anhydride (42 mL, 446 mmol) were combined at 0° C., and the mixture was allowed to warm to room temperature and stirred for 2 h. Meanwhile, a separate RBF was flushed with argon, to which was added DCM (90 mL) followed by 2,2,2-trichloroacetonitrile (36 mL, 359 mmol). The solution was then placed in an ice bath at 0° C. and 2,2,2-trifluoroacetamidine (20 g, 178.49 mmol) was added dropwise at 0° C. After 5 min at 0° C., the reaction was complete. The reaction mixture was then placed in a −78° C. cooling bath and the formic acid / acetic anhydride mixture was added dropwise via syringe. The mixture was stirred at −78° C. for 5 min, then allowed to warm to ambient temperature and stirred for 16 h. The reaction was then poured into a solution of saturated sodium bicarbonate and ice (500 mL) and solid sodium bicarbonate (35 g) was added until the effervescence subsided and the pH reached 6-7 by pH paper. The aqueous layer was then extracted three times with DCM. The combined organic layers were dried over MgSO4 and concentrated on a rotovap (to 110 mbar, °C). The resulting oil was purified by distillation at 65 °C-85 °C (measured at the still head) and 11 mbar to give 2-(trichloromethyl)-4-(trifluoromethyl)-1,3,5-triazine (25 g, 53% yield) as a clear oil. 1 H NMR (DMSO-d 6, 400MHz) δ: 9.96 (s, 1H). 19 F NMR (DMSO-d 6, 400MHz) δ: -71.00 (s)

[0160] Example 3 Synthesis of 2-chloro-4,6-bis(trifluoromethyl)pyrimidine [ka] To a 100 mL round bottom flask equipped with a magnetic stir bar and reflux condenser was added chloroformamidine hydrochloride (7.26 g, 62.5 mmol) and acetonitrile (20 mL). The mixture was stirred to a suspension at room temperature and hexafluoroacetylacetone (6.79 mL, 48.0 mmol) was added, followed by concentrated sulfuric acid (0.05 mL, 0.9 mmol, 0.02 equiv.) and phosphoryl chloride (4.47 mL, 48.0 mmol). The resulting mixture was heated to reflux. After 2 h, the reaction mixture was cooled to room temperature and transferred to a distillation apparatus. After pre-distillation of acetonitrile slightly above room temperature, distillation at 100 mbar afforded 7.2 g of 2-chloro-4,6-bis(trifluoromethyl)pyrimidine as a clear, colorless oil, 60% yield; bp 68° C. at 100 mbar. 1 H NMR (CDCl 3, 400MHz) 7.94 (s,1H). 19 F NMR (CDCl 3, 400MHz) δ 69.68 (s)

[0161] Example 4 Synthesis of 2-(methylsulfonyl)-4,6-bis(trifluoromethyl)pyrimidine [ka]

[0162] Step 1: To a stirred suspension of 2-methylisothiourea (1.08 g, 12.0 mmol) in ethanol (10 mL, 172 mmol) was added hexafluoroacetylacetone (2.08 g, 10.0 mmol) and sulfuric acid (50 mg, 0.51 mmol). The suspended mixture was heated to reflux for 16 h, removed from the heat, and allowed to reach room temperature. The reaction was concentrated in vacuo to give 2-methylsulfanyl-4,6-bis(trifluoromethyl)pyrimidine (2.2 g, 8.4 mmol, 84% yield) which was used in the next step without further purification.

[0163] Step 2: To a stirred suspension of 2-methylsulfanyl-4,6-bis(trifluoromethyl)pyrimidine (2.2 g, 8.4 mmol) in dichloromethane (25 mL, 390.0 mmol), 3-chlorobenzenecarboperoxoic acid (4.3 g, 25 mmol) was added and the suspension mixture was heated to 45° C. and stirred for 2 h. The reaction was then cooled back to room temperature and concentrated in vacuo. The residue was purified by flash chromatography to give 1.8 g of 2-methylsulfonyl-4,6-bis(trifluoromethyl)pyrimidine as a clear oil in 73% yield. MS m / z 292.9 [MH] - (CDCl3, 400MHz) d: 8.18 (s, 1H), 3.48 (s, 3H). 19 F NMR (CDCl 3, 400MHz) δ: -70.25 (s).

[0164] Example 5 Synthesis of 2-morpholinopyrimidine-5-carboxylic acid [ka]

[0165] Step 1: Ethyl 2-chloropyrimidine-5-carboxylate (150 g, 803.9 mmol) was placed in a 3 L three-neck RBF equipped with a N2 inlet and dissolved in acetonitrile (1.5 L). Morpholine (74 g, 849.4 mmol) and potassium carbonate (333 g, 2.41 mol) were then added to the solution. The mixture was refluxed for 6 h, then cooled to room temperature and concentrated in vacuo. The resulting residue was suspended in water (1.5 L) and extracted with ethyl acetate (3 x 1.5 L). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated to give ethyl 2-morpholinopyrimidine-5-carboxylate (180 g, 758.7 mmol, 94.4% yield) as a pale yellow solid. The material was used in the next step without further purification. MS m / z 238.0 [M+H] + .

[0166] Step 2: Ethyl 2-morpholinopyrimidine-5-carboxylate (118 g, 497.3 mmol) was dissolved in a mixture of THF (100 mL) and water (500 mL) and then lithium hydroxide (36 g, 1.47 mol) was added. The mixture was stirred at 60° C. for 3 h. The mixture was then cooled to room temperature and concentrated in vacuo to remove the THF. The pH of the aqueous solution was then adjusted to 3-4 with 6N HCl to precipitate an organic solid. The material was collected by filtration to give 2-morpholinopyrimidine-5-carboxylic acid (100 g, 478.0 mmol, 96% yield) as a white solid. MS m / z 210.0 [M+H] + . 1 H NMR (DMSO): δ 12.83 (s, 1H), 8.78 (s, 2H), 3.87-3.76 (m, 4H), 3.74 -3.60 (m, 4H).

[0167] Example 6A General Procedure A for Asymmetric Carboline Synthesis [ka]

[0168] Step 1: A round bottom flask was charged with 2,3-difluoro-4-methyl-benzoic acid (50 g, 290.48 mmol), 2-(5-chloro-1H-indol-3-yl)ethan-1-amine hydrochloride (73 g, 318.62 mmol), N,N-diisopropylamine (100 mL, 600 mmol) and N,N-dimethylformamide (500 mL), followed by the addition of HATU (124 g, 319.6 mmol) in one portion. The reaction was stirred at ambient temperature for 6 h, at which point the reaction showed consumption of starting material and the desired product was observed by LCMS. The reaction mixture was poured into a separatory funnel and partitioned between EtOAc and water. The organic phase was washed with water (2×1000 mL) followed by brine (1×800 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The resulting solid was slurried in acetonitrile, filtered, the volatiles removed under reduced pressure, and the residue subjected to purification by silica gel chromatography (MeOH / DCM 0-10%) to afford N-[2-(5-chloro-1H-indol-3-yl)ethyl]-2,3-difluoro-4-methyl-benzamide (92.5 g, 265 mmol, 91.3% yield) as a yellow solid.

[0169] Step 2: In a round bottom flask, N-[2-(5-chloro-1H-indol-3-yl)ethyl]-2,3-difluoro-4-methyl-benzamide (46 g, 131.9 mmol) was dissolved in acetonitrile (500 mL). The vessel was flushed with nitrogen and the reaction was allowed to continue under a nitrogen atmosphere. Phosphoryl chloride (123 mL, 1320 mmol) was added and the reaction mixture was stirred at 90° C. for 6 h, at which time LCMS analysis indicated consumption of starting material and formation of desired product. The reaction mixture was concentrated in vacuo and the oily residue was poured into a separatory funnel and partitioned between EtOAc and saturated aqueous bicarbonate solution. The aqueous layer was extracted with EtOAc (2×1000 mL). The combined organic phases were concentrated in vacuo to give 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-4,9-dihydro-3H-pyrido[3,4-b]indole (B, 36 g, 108.8 mmol, 82.5% yield) as a yellow solid.

[0170] Step 3: A round bottom flask equipped with a stir bar was charged with 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-4,9-dihydro-3H-pyrido[3,4-b]indole (36 g, 108.8 mmol) and acetonitrile (1000 mL). RuCl(p-cymene)[(R,R)-Ts-DPEN] (4.24 g, 6.53 mmol) and formate triethylamine complex 5:2 (93 mL, 218.1 mmol) were added, the reaction vessel was flushed with argon, and the reaction was allowed to proceed under an argon atmosphere. The reaction mixture was stirred at 25° C. for 24 h, at which time LCMS analysis indicated consumption of starting material and formation of desired product. The reaction mixture was poured into a separatory funnel with EtOAc and water. The organic layer was washed with saturated aqueous Na2CO3 (2 x 1000 mL), then with brine (1 x 1000 mL), dried over Na2SO4, and concentrated in vacuo. The resulting solid was slurried in acetonitrile, filtered, and evaporated to dryness to give (1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (29 g, 87.14 mmol, 80.07% yield) as a white solid.

[0171] Step 4: (Removal of residual ruthenium): To the RBF was added (1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (58 g, 174.3 mmol), dichloromethane (500 mL), SiliaMetS® thiol (metal scavenger silica gel from SILICYCLE) (12 g), and the mixture was stirred for 3 hours at 25° C. The SiliaMetS thiol was then removed by filtration and washed twice with dichloromethane (100 mL). The combined organics were concentrated in vacuo and the residue was further triturated in EtOAc and PE to give (1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (55 g, 165.3 mmol, 94.83% yield) as a white solid. MS m / z 333 [M+H] + 1H NMR (DMSO-d 6, 6.70 (t, J = 6.8Hz, 1H), 5.37 (s, 1H), 3.04-2.99 (m, 1H), 2.96-2.90 (m, 1H), 2.87 (s, 1H), 2.74-2.61 (m, 2H), 1.99 (s, 3H). 98.3% ee

[0172] Example 6B General Procedure B for the Synthesis of Racemic Carbolines [ka] A 100 mL single-neck round-bottom flask was charged with a solution of 2-(5-chloro-1H-indol-3-yl)ethanamine; hydrochloride (1.2 g, 5.2 mmol) in 1,2-dichloroethane (10.0 mL, 126 mmol), followed by 2,3-difluoro-4-methyl-benzaldehyde (1.0 g, 6.4 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol). The mixture was stirred at 90° C. for 3 hours. After cooling to ambient temperature, the mixture was dried under reduced pressure to give a dark residue, which was washed with ethyl acetate:petroleum ether=1:10 (2×60.0 mL). The combined organic washing solutions were evaporated to dryness to give 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.2 g, 3.6 mmol, 69% yield) without further purification.

[0173] Example 7 Synthesis of MeO-pyrimidine containing carbolines [ka]

[0174] Step 1: The starting material 6-chloro-1-(2-chloropyrimidin-5-yl)-4,9-dihydro-3H-pyrido[3,4-b]indole was synthesized from the corresponding tryptamine and carboxylic acid as described in steps 1 and 2 of Example 6A. 6-Chloro-1-(2-chloropyrimidin-5-yl)-4,9-dihydro-3H-pyrido[3,4-b]indole (300 mg, 0.95 mmol, 1.0 equiv.) was dissolved in methanol (10 mL), and then sodium methoxide (850 mg, 15.7 mmol, 16.6 equiv.) was added. The mixture was stirred at room temperature for 1 h. Water was then added to the reaction mixture, and the organics were extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated. The material 6-chloro-1-(2-methoxypyrimidin-5-yl)-4,9-dihydro-3H-pyrido[3,4-b]indole (220 mg, 0.70 mmol, 74% yield) was thus obtained as a light brown solid and was used without further purification in the asymmetric reduction step described in Step 3 of Example 6A.

[0175] Example 8 Synthesis of compound 233 [ka] To a round bottom flask containing (1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (25.00 g, 75.12 mmol) was added 1-butanol (200 mL) to form a solution. N,N-diisopropylethylamine (40 mL, 229 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (18.00 g, 98.61 mmol) were added and the mixture was purged with nitrogen for 5 min. The reaction mixture was stirred at 80 °C for 4 h, then concentrated in vacuo and purified by flash chromatography (petroleum ether: EtOAc gradient 0-10%) to give compound 233 (32 g, 82% yield) as a white solid. MS m / z 479 [M+H] + 1 H NMR (DMSO-d6, 400MHz) δ 11.16 (s, 1H), 8.79(d, J = 4.8Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.31 (t, J = 8.4 Hz, 2H), 7.13 (d, J = 4.8 Hz, 1H), 7.09 (q, J = 6.4 Hz, 1H), 7.03 (t, J = 7.2Hz, 1H), 6.76 (t, J = 6.8 Hz, 1H), 4.90 (d, J = 7.2Hz, 1H), 3.40 (q, J = 11.2Hz, 1H), 2.93-2.83 (m, 2H), 2.60 (d, J = 1.6 Hz, 3H). 99%

[0176] Additional compounds described herein were prepared using the procedures described for compound 233 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 19] JPEG2025501285000226.jpg255170 JPEG2025501285000227.jpg239170 JPEG2025501285000228.jpg115170

[0177] Example 9 Synthesis of compound 412 [ka] To a mixture of (1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (50 mg, 0.15 mmol) and 2-chloro-5-fluoro-4,6-dimethyl-pyrimidine (36 mg, 0.22 mmol) in NMP (4 mL), N,N-diisopropylethylamine (60 mg, 0.46 mmol) was added, and the mixture was stirred in a microwave reactor at 210° C. for 4 h. The resulting mixture was directly purified by preparative HPLC to give compound 412 (15 mg, 0.033 mmol, 21.9% yield) as a white solid. MS m / z 457.1 [M+H] + ; 1 H NMR (DMSO-d4) δ: 11.10 (s, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.24 (s, 1H), 7.06 (q, J=6.4 Hz, 1H), 6.99 (t, J=7.6 Hz, 1H), 6.71 (t, J=6.8 Hz, 1H), 4.79 (q, J=7.2Hz, 1H), 3.28 (m, 1H), 2.79 (t, J=4.8 Hz, 2H), 2.30 (d, J=2.4 Hz, 6H), 2.24 (d, J=0.8 Hz, 3H), 22% ee (partial epimerization due to high temperature).

[0178] Additional compounds described herein were prepared using the procedures described for compound 412 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 20]

[0179] Example 10 Preparation of compound 283 [ka]

[0180] Step 1: Prepared according to general procedure B, 1-(4-bromo-2,3-difluoro-phenyl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (500 mg, 1.258 mmol, 81.6% yield) was isolated as a white solid.

[0181] Step 2: A 20 mL screw-cap vial was charged with 1-(4-bromo-2,3-difluoro-phenyl)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (300 mg, 0.7545 mmol), 2-chloro-4,6-dimethyl-1,3,5-triazine (162 mg, 1.1284 mmol) and 1-butanol (5 mL). Triethylamine (0.316 mL, 2.27 mmol) was then added and the resulting mixture was stirred at 100 °C for 2 h. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the resulting dark residue was subjected to preparative HPLC purification (water:acetonitrile gradient 5-100%) for purification. Compound 283 (310 mg, 0.614 mmol, 81.4% yield) was isolated as a white solid. MS m / z 506.0 [M+H] + ; 1 H NMR (DMSO-d6) δ: ppm 11.17 (s, 1H), 7.57 (s, 1H), 7.52 - 7.46 (m, 1H), 7.37 - 7.33 (m, 1H), 7.33 - 7.26 (m, 1H), 7.12 (dd, J=8.70, 1.98 Hz, 1H), 6.90 (s, 1H), 5.05 - 4.95 (m, 1H), 3.33-3.27 (m, 1H), 2.95 - 2.88 (m, 1H), 2.86 - 2.76 (m, 1H), 2.37 (s, 6H).

[0182] Additional compounds described herein were prepared using the procedures described for compound 283 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 21]

[0183] Example 11 Preparation of compound 284 [ka] To a screw-cap vial was added 1-(4-bromo-2,3-difluoro-phenyl)-6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (100 mg, 0.20 mmol), Pd(dba)3 (18 mg, 0.020 mmol), RuPhos (10 mg, 0.020 mmol) and cesium carbonate (129 mg, 0.40 mmol). The vial was flushed with nitrogen. 1,4-Dioxane (5 mL) and morpholine (23 mg, 0.26 mmol) were added via syringe. The reaction mixture was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo and purified by silica gel chromatography to give compound 284 (65 mg, 0.13 mmol, 64.21% yield) as a white solid. ESI-MS: m / z 511.1 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.53 (d, J = 2.1Hz, 1H), 7.36 - 7.24 (m, 2H), 7.09 (ddh, J = 8.6, 2.1Hz, 1H), 6.86 - 6.60 (m, 2H), 4.95 (dd, J = 13.4, 5.4 Hz, 1H), 3.73 (dd, J = 6.1, 3.3 Hz, 4H), 3.30 - 3.17 (m, 1H), 3.17 - 2.80 (m, 4H), 2.90 - 2.64 (m, 2H), 2.35 (d, J = 5.1Hz, 6H).

[0184] Example 12 Synthesis of compound 497 [ka]

[0185] Step 1: A 100 mL single-neck round-bottom flask was charged with a solution of 2-(5-chloro-1H-indol-3-yl)ethanamine; hydrochloride (1.2 g, 5.2 mmol) in 1,2-dichloroethane (10.0 mL, 126 mmol), followed by 2,3-difluoro-4-methyl-benzaldehyde (1.0 g, 6.4 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol). The mixture was stirred at 90° C. for 3 hours. After cooling to ambient temperature, the mixture was dried under reduced pressure to give a dark residue, which was washed with ethyl acetate:petroleum ether=1:10 (2×60.0 mL). The combined organic washing solutions were evaporated to dryness to give 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.2 g, 3.6 mmol, 69% yield), which was used without further purification.

[0186] Step 2: To a 100 mL three-necked round bottom flask containing a solution of 18-crown-6 (80.0 mg, 0.297 mmol), 2,4,6-trifluoro-1,3,5-triazine (0.5 mL, 6 mmol) and (trifluoromethyl)trimethylsilane (2.0 mL, 13 mmol) in tetrahydrofuran (20.0 mL), cesium fluoride (1.0 g, 6.6 mmol) was added in portions over 30 min at 0 °C. The mixture was then stirred at 0 °C for 30 min. Then, 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (A, 500 mg, 1.502 mmol) was added at 0 °C and the reaction mixture was stirred at 0 °C for 30 min. The mixture was then filtered, and the filtrate was concentrated to give a residue, which was purified by column flash (petroleum ether:ethyl acetate=10:1) to give the desired product, compound 497 (C, 100 mg, 0.1825 mmol, 12.15% yield) as a white solid material. MS m / z 548.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.05 - 7.12 (m, 2H), 6.84 - 6.88 (m, 1H), 4.93 - 4.97 (m, 1H), 3.54 - 3.59 (m, 1H), 2.91 - 3.06 (m, 2H), 2.27 (d, J = 1.6 Hz, 3H).

[0187] Additional compounds described herein were prepared using the procedures described for compound 497 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 22] JPEG2025501285000236.jpg42164

[0188] (Example 13) Preparation of compound 358 [ka]

[0189] Step 1: A 100 mL round bottom flask equipped with a stir bar was charged with 2-(5-chloro-1H-indol-3-yl)ethanamine (580 mg, 2.980 mmol), tetrahydrofuran (10 mL), N,N-diisopropylamine (1.0 mL, 5.960 mmol), followed by 2-methylsulfonyl-4,6-bis-(trifluoromethyl)pyrimidine (964 mg, 3.280 mmol). The flask was capped with a nitrogen inlet and stirred at 22 °C for 16 h, after which the volatiles were removed under reduced pressure. The resulting dark residue was subjected to silica gel chromatography (petroleum ether:ethyl acetate, gradient 0-40%) to afford the desired product, N-[2-(5-chloro-1H-indol-3-yl)ethyl]-4,6-bis(trifluoromethyl)pyrimidin-2-amine (350 mg, 0.856 mmol, 28.7% yield) as an amorphous yellow solid.

[0190] Step 2: An 8 mL screw-cap vial was successively charged with N-[2-(5-chloro-1H-indol-3-yl)ethyl]-4,6-bis(trifluoromethyl)pyrimidin-2-amine (80 mg, 0.196 mmol), 1,2-dichloroethane (1 mL), 2-morpholinopyrimidine-5-carbaldehyde (50 mg, 0.259 mmol) and trifluoroacetic acid (0.1 mL, 1 mmol), tightly capped and stirred at 95 °C for 6 h. After cooling to ambient temperature, the reaction mixture was quenched with aqueous NaHCO3 (sat., 10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over MgSO4, filtered and the volatiles removed to give a dark oil. After purification by preparative HPLC (water:acetonitrile gradient 10-100%), compound 358 (85 mg, 0.146 mmol, 74% yield) was isolated as a white amorphous solid. MS m / z 582.0 [MH] - ; 1H NMR (400 MHz, DMSO-d6) δ: 11.09 (s, 1H), 8.34 (s, 2H), 7.57 - 7.55 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.11 - 7.09 (m, 1H), 6.76 (s, 1H), 4.99 - 4.94 (m, 1H), 3.67 - 3.61 (m, 8H), 3.54 - 3.51 (m, 1H), 3.01 - 2.95 (m, 2H).

[0191] Additional compounds described herein were prepared using the procedures described for compound 358 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 23] JPEG2025501285000239.jpg87165

[0192] Example 14 Preparation of compound 144 [ka]

[0193] Step 1: A 100 mL round bottom flask equipped with a reflux condenser was successively charged with 2-(5-chloro-1H-indol-3-yl)ethanamine (5.0 g, 26 mmol), 1-butanol (25 mL), triethylamine (7.2 mL, 51 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (7.0 g, 38 mmol). The reaction mixture was stirred at reflux for 16 h, after which the volatiles were evaporated under reduced pressure and the resulting dark oily residue was subjected to silica gel chromatography (petroleum ether: EtOAc gradient 0-40%). After purification, N-[2-(5-chloro-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (7.0 g, 21 mmol, 80% yield) was isolated as an off-white amorphous solid.

[0194] Step 2: In an 8 mL vial equipped with a stir bar, N-[2-(5-chloro-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (50 mg, 0.147 mmol) and 2-butanol (3 mL) were added, then 4-chloro-2,3-difluoro-benzaldehyde (26 mg, 0.147 mmol) was added, followed by toxic acid (16 mg, 0.093 mmol) via microsyringe. The vial was stirred at 95° C. for 1 h. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the resulting dark residue was subjected to purification by preparative scale HPLC. After purification, compound 144 (57 mg, 0.778 mmol, 77.8% yield) was isolated as an amorphous white solid. MS m / z 496.9 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ: 11.14 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.28 - 7.20 (m, 1H), 7.15 (d, J = 5.2Hz, 1H), 7.09 (dd, J = 8.8, 2.0 Hz, 1H), 6.92 (t, J = 11.0 Hz, 1H), 4.97 - 4.84 (m, 1H), 3.48 - 3.36 (m, 1H), 2.97 - 2.78 (m, 2H).

[0195] Using the procedure described above for compound 144, and substituting the appropriate starting materials, suitable reagents and reaction conditions, additional compounds described herein were prepared: [Table 24] JPEG2025501285000242.jpg251170 JPEG2025501285000243.jpg253170 JPEG2025501285000244.jpg250170 JPEG2025501285000245.jpg250170 JPEG2025501285000246.jpg247162 JPEG2025501285000247.jpg250170 JPEG2025501285000248.jpg255170 JPEG2025501285000249.jpg253170 JPEG2025501285000250.jpg250163 JPEG2025501285000251.jpg238170 JPEG2025501285000252.jpg247170 JPEG2025501285000253.jpg253170 JPEG2025501285000254.jpg242170 JPEG2025501285000255.jpg252170 JPEG2025501285000256.jpg90170

[0196] Example 15 Preparation of compound 340 [ka] A 50 mL flask equipped with a stir bar was charged with 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 0.601 mmol) and tetrahydrofuran (10 mL). 2-Chloro-4,6-(bis-trifluoromethyl)pyrimidine (181 mg, 0.722 mmol) was added via syringe with stirring at 22° C., followed by N,N-diisopropylamine (0.21 mL, 1.200 mmol). The flask was stirred at 90° C. for 5 h. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the resulting dark oily residue was subjected to purification by silica gel column chromatography eluting with a gradient (0-15%) dichloromethane / methanol. Compound 340 (41 mg, 0.075 mmol, 12.5% ​​yield) was isolated as a yellow amorphous solid. MS m / z 544.9 [MH] - ; 1 H NMR (400 MHz, DMSO-d6) δ: 11.16 (s, 1H), 7.56 (s, 2H), 7.32-7.30 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.10-7.07 (dd, J = 2.0, 8.4 Hz, 1H), 7.05-7.01 (t, J = 7.2Hz, 1H), 6.83-6.80 (t, J = 7.2Hz, 1H), 4.91-4.87 (dd, J = 4.8, 13.6 Hz, 1H), 3.55-3.47 (m, 1H), 3.00-2.95 (dd, J = 4.8, 16.0 Hz, 1H), 2.91-2.85 (m, 1H), 2.25-2.25 (d, J = 1.2Hz, 3H).

[0197] Additional compounds described herein were prepared using the procedures described for compound 340 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following:

[0198] [Table 25] JPEG2025501285000259.jpg246170 JPEG2025501285000260.jpg238170 JPEG2025501285000261.jpg245170 JPEG2025501285000262.jpg230170 JPEG2025501285000263.jpg37170

[0199] Example 16A Preparation of compound 523 [ka] A 20 mL screw-capped vial equipped with a stir bar was charged with (1S)-6-bromo-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (450 mg, 1.19 mmol), DMAP (190 mg, 1.48 mmol) and acetonitrile (3 mL), capped and placed under an argon atmosphere. A solution of 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (550 mg, 1.64 mmol) in acetonitrile (2 mL) was then added via syringe. The reaction mixture was stirred at ambient temperature for 15 minutes, at which point reaction monitoring by LCMS indicated consumption of starting material and formation of the desired product. The mixture was partitioned between EtOAc and water, and the organic phase was washed with brine, dried over MgSO4, and then purified by silica-gel chromatography eluting with hexanes:EtOAc (0-20% gradient) to give compound 523 (550 mg, 77.8% yield) as an off-white amorphous solid. MS m / z 589.9 [MH] - ; 1H NMR (DMSO-d6, 400 MHz) δ: 11.20 (s, 1H), 7.74 (s, 1H), 7.3 - 7.3 (m, 1H), 7.2 - 7.2 (m, 2H), 7.0 - 7.2 (m, 1H), 6.86 (t, J = 7.3 Hz, 1H), 4.95 (br dd, J = 4.8, 13.3 Hz, 1H), 3.5 - 3.6 (m, 1H), 3.0 - 3.1 (m, 1H), 2.8 - 3.0 (m, 1H), 2.27 (s, 3H).

[0200] Additional compounds described herein were prepared using the procedures described for compound 523 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 26] JPEG2025501285000266.jpg251170

[0201] Example 16B Preparation of Compound 524 [ka]

[0202] An 8 mL screw cap vial equipped with a septum cap was charged with tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol), 2-di-tert-butylphosphino-3,4',5,'-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (12 mg, 0.02 mmol) and toluene (1 ml) and the mixture was degassed, back-filled with argon (3x), placed in a heating block preheated to 105 °C and stirred for 2 min. The dark solution was transferred by syringe to another 8 mL screw-cap vial containing an argon-sparged mixture of compound 523, (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-bromo-1-(2,3-difluoro-4-methyl-phenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (102 mg, 0.17 mmol), 2H-triazole (18 mg, 0.26 mmol), and tripotassium phosphate (78 mg, 0.36 mmol) suspended in toluene (1 ml) and 1,4-dioxane (0.2 mL). The resulting mixture was stirred at 105° C. for 2 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and water, and the organic phase was washed with brine, dried over MgSO4, and evaporated to dryness under reduced pressure. The dark oily residue was subjected to silica gel chromatography eluting with hexanes EtOAc (gradient 0-40%) to give compound 524 (72 mg, 72.0% yield) as a white solid. MS m / z 581.0 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz) δ: 11.28 (s, 1H), 8.16 (d, J = 1.3 Hz, 1H), 8.07 (s, 2H), 7.8 - 7.9 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.09 (br t, J = 7.5 Hz, 1H), 6.92 (br t, J = 7.3 Hz, 1H), 4.9 - 5.1 (m, 1H), 3.5 - 3.7 (m, 1H), 3.1 - 3.2 (m, 1H), 2.9 - 3.1 (m, 1H), 2.2 - 2.3 (m, 3H).

[0203] The following additional compounds described herein were prepared using the procedures described for compound 524 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following:

[0204] [Table 27] JPEG2025501285000269.jpg249164 JPEG2025501285000270.jpg177170

[0205] Example 16C Preparation of Compound 406 [ka]

[0206] Step 1: Ethyl 2-chloropyrimidine-5-carboxylate (25.0 g, 134 mmol) was dissolved in CH3CN (100 mL). Then K2CO3 (55.5 g, 402 mmol) and morpholine (12.3 g, 141 mmol) were added. The mixture was refluxed for 6 h and cooled to room temperature. The mixture was concentrated to give a residue. The residue was suspended in water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated and purified by combi-flash (eluent: gradient, 100% petroleum ether to petroleum ether:ethyl acetate = 4:1) to give ethyl 2-morpholinopyrimidine-5-carboxylate (31.5 g, 99.1% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 4.36 (q, 2H, J=7.2Hz), 3.95 (q, 4H, J=3.2Hz), 3.78 (q, 4H, J=3.2Hz), 1.38 (t, 3H, J=7.2Hz).

[0207] Step 2: Ethyl 2-morpholinopyrimidine-5-carboxylate (31.5 g, 133 mmol) was dissolved in THF (50 mL) and water (50 mL), then LiOH (10 g, 409.22 mmol) was added. The mixture was stirred at 35 °C for 3 h. The mixture was adjusted to pH 7 with aqueous HCl (2N) and then concentrated in vacuo to remove THF. The residue was adjusted to pH 3-4 with aqueous HCl (2N). The suspension was filtered. The filter cake was collected and dried in vacuum to give 2-morpholinopyrimidine-5-carboxylic acid (27 g, 97.2% yield) as a white solid. LCMS: ESI-MS: m / z: 210.1 [M+H] + , RT=1.367 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.78 (s, 2H), 3.83 (t, J =5.0 Hz, 4H), 3.67 (t, J =5.0 Hz, 4H).

[0208] Step 3: 2-Morpholinopyrimidine-5-carboxylic acid (27 g, 129.06 mmol) and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (33 g, 142.78 mmol) were combined and dissolved in DMF (300 mL). DIPEA (80 mL, 500 mmol) was then added. HATU (75 g, 193.303 mmol) was then added. The mixture was stirred at 25° C. for 20 h. The mixture was poured into a mixture of EtOAc (250 mL) and water (150 mL). The mixture was separated and the aqueous phase was extracted with EtOAc (2×100 mL). The organic phase was washed with brine (4×100 mL), dried over Na2SO4, and then filtered. The filtrate was concentrated in vacuo to give a residue, which was suspended in EtOAc (50 mL) and then filtered. The filter cake was collected and dried in vacuum to give N-[2-(5-chloro-1H-indol-3-yl)ethyl]-2-morpholino-pyrimidine-5-carboxamide (38 g, 76.32% yield) as a white solid. LCMS: ESI-MS: m / z: 386.1 [M+H] + , RT=1.774 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.78 (s, 2H), 8.51-8.48 (m, 1H), 7.59 (d, J =2.0 Hz, 1H), 7.35 (d, J =4.4 Hz, 1H), 7.26 (d, J =2.0 Hz, 1H), 7.06 (d, J =8.6, 2.0 Hz, 1H), 3.82-3.76 (m, 4H), 3.67-3.65 (m, 4H), 3.51-3.46 (m, 2H), 2.91 (t, J= 7.6 Hz, 2H).

[0209] Step 4: N-[2-(5-chloro-1H-indol-3-yl)ethyl]-2-morpholino-pyrimidine-5-carboxamide (130 g, 337.0 mmol) was mixed with dry acetonitrile (400 mL). Then POCl3 (219 mL, 2360 mmol) was added in one portion. The mixture was stirred at 90 °C for 6 h. The mixture was concentrated to give a residue. The residue was adjusted to PH = 9-10. The mixture was extracted with ethyl acetate (3 x 200 mL) and filtered. The filtrate was concentrated to give a residue. The residue was washed with ethyl acetate (50 mL) to give 4-[5-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl]morpholine (110 g, 88.76% yield) as a yellow solid. LCMS: ESI-MS: m / z: 368.0 [M+H] + , RT=1.850 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.75 (s, 2H), 7.71 (d, 1H, J=2.0 Hz),7.44 (d, 1H, J=8.8 Hz), 7.22 (dd, 1H, J=8.8 Hz, 2.0 Hz), 3.88-3.81 (m, 6H), 3.70 (t, 4H, J=4.8 Hz), 2.86 (t, 2H, J=8.2Hz).

[0210] Step 5: 4-[5-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl]morpholine (2.0 g, 5.4 mmol), RuCl[(R,R)-TsDPEN](mesitylene) (34.0 mg, 0.0540 mmol) were dissolved in DMF (8.7 mL, 110 mmol) and triethylamine formate complex 5:2 (5.0 mL, 12 mmol) was added. The mixture was stirred under N2 protection at 25 °C for 18 h and adjusted to PH = 9-10 with aqueous Na2CO3. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with brine (4 × 30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give a residue. The residue was suspended in CHCl / ethyl acetate (1:1 (v / v), 10 mL), filtered, the filter cake was collected and dried in vacuum to give 4-[5-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]morpholine (1.2 g, 60% yield) as a light brown solid. LCMS: ESI-MS: m / z: 370.1 [M+H] + , RT=1.414 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.23 ​​(s, 2H), 7.44 (d, J =2.0 Hz, 1H), 7.22 (d, J =8.4 Hz, 1H), 7.00 (dd, J =8.6, 2.0 Hz, 1H), 4.98 (s, 1H), 3.68-3.64 (m, 8H), 3.12-3.07 (m, 1H), 2.95-2.89 (m, 2H), 2.74-2.60 (m, 2H).Chiral HPLC: >99%ee value.

[0211] Step 6: In a three-necked bottle, (S)-4-(5-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl)morpholine (110 g, 297.5 mmol) was dissolved in CH3CN (1130 mL). N,N-Dimethylpyridin-4-amine (37.0 g, 299.8 mmol) was added slowly. Then, 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (120.0 g, 358.8 mmol) was added dropwise under N2 at 0 °C for 10 min. After the addition, the reaction was stirred at room temperature for 6 h. LCMS showed approximately 50% conversion at the 6 h time point with no 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine remaining. Additional 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (55 g, 164.5 mmol) was added dropwise to the very heterogeneous mixture, which was stirred at room temperature overnight. The mixture was concentrated to remove CH3CN and then purified by column flash (eluent: gradient, 100% petroleum ether to petroleum ether:ethyl acetate = 80:20) to give compound 406 (136 g, 78.18% yield) as a pale yellow solid. MS m / z 585.1 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 8.34 (s, 2H), 7.58 (d, J =2.0 Hz, 1H), 7.34 (d, J =8.4 Hz, 1H), 7.11 (dd, J =8.8, 2.0 Hz, 1H), 6.86 (s, 1H), 4.97 (dd, J =9.6, 5.2Hz, 1H), 3.70-3.61 (m, 8H), 3.58-3.51 (m, 1H), 3.06-3.01 (m, 1H), 2.90-2.82 (m, 1H).

[0212] (Example 17) Preparation of compound 498 [ka]

[0213] Step 1: In an 8 mL screw cap vial was placed 4-[5-[(1S)-6-bromo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-2-pyridyl]morpholine (104 mg, 0.25 mmol), 2-methylsulfanyl-4-methylsulfinyl-6-(trifluoromethyl)-1,3,5-triazine (80 mg, 0.31 mmol) and acetonitrile (2 mL), followed by the addition of 2,6-lutidine (60 mg, 0.55 mol) and the resulting mixture was stirred at ambient temperature for 3 h. The mixture was partitioned between EtOAc and brine (1:1). The organic phase was washed with brine, dried over MgSO4, and then purified by silica gel chromatography eluting with hexanes:EtOAc (0-70% gradient) to isolate 4-[5-[(1S)-6-bromo-2-[4-methylsulfanyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-2-pyridyl]morpholine (115 mg, 75.35% yield) as a white solid.

[0214] Step 2: An 8 mL screw cap vial equipped with a septum cap was charged with tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol), 2-di-tert-butylphosphino-3,4',5,'-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (12 mg, 0.02 mmol) and toluene (1 mL) and the mixture was degassed, back-filled with argon (3x), placed in a heating block preheated to 105 °C and stirred for 2 min. The dark solution was transferred by syringe to another 8 mL screw-cap vial containing an argon-sparged mixture of the pre-activated reaction of 4-[5-[(1S)-6-bromo-2-[4-methylsulfanyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-2-pyridyl]morpholine (115 mg, 0.19 mmol), tripotassium phosphate (100 mg, 0.46 mmol) suspended in toluene (1 mL) and 1,4-dioxane (0.2 mL). The resulting mixture was stirred at 100° C. for 8 h. After cooling to ambient temperature, the mixture was partitioned between EtOAc and water, and the organic phase was washed with brine, dried over MgSO4, and evaporated to dryness under reduced pressure. The dark oily residue was subjected to silica gel chromatography eluting with hexanes EtOAc (gradient 0-50%) to give 4-[5-[(1S)-2-[4-methylsulfanyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-6-(triazol-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-2-pyridyl]morpholine as an off-white solid.

[0215] Step 3: An 8 mL screw cap vial equipped with a septum cap and stir bar was charged with 4-[5-[(1S)-2-[4-methylsulfanyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-6-(triazol-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-2-pyridyl]morpholine (65 mg, 0.11 mmol), ethanol (1 mL), and Raney Nickel (200 mg, 1.17 mmol) and stirred for 18 hours at 22° C. The resulting dark suspension was filtered and the filter cake was rinsed with methanol. Volatiles were removed under reduced pressure to give a dark residue which was purified by reverse phase chromatography eluting with ACN / water (0.1% TFA modifier, 5-100% gradient), the desired fractions were combined and after lyophilization compound 498 (40 mg, 66.7% yield) was isolated as a white amorphous solid. MS m / z = 549.7 [M+H] + ; 1 H NMR (DMSO-d6) δ: 11.22 (s, 1H), 11.17 (s, 1H), 8.90 (s, 1H), 8.85 (s, 1H), 8.02-8.09 (m, 5H), 7.99 (s, 4H), 7.71-7.78 (m, 2H), 7.44-7.53 (m, 2H), 7.39 (s, 2H), 6.99 (s, 1H), 6.77-6.91 (m, 4H), 4.93-5.03 (m, 1H), 4.81-4.92 (m, 1H), 3.57-3.63 (m, 11H), 3.29-3.44 (m, 13H), 2.94-3.05 (m, 2H), 2.76-2.94 (m, 3H). NMR indicates the presence of two rotamers in a ratio of about 1:1.2, presumably due to hindered rotation about the N-C bond connecting the triazine to the core.

[0216] The following additional compounds described herein were prepared using the procedures described for compound 498 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 28]

[0217] (Example 18) Preparation of compound 419 [ka]

[0218] Step 1: To a 250 mL round bottom flask equipped with a magnetic stir bar and reflux condenser was added 2-chloropyrimidine-5-carboxylic acid (8.04 g, 49.2 mmol, 1.0 equiv). Acetonitrile (100 mL, 2 L / mol) was added followed by 1-methylimidazole (23 mL, 24 g, 289 mmol, 6.0 equiv) and 1-methylpiperazine (5.00 g, 48.9 mmol, 1.0 equiv) at room temperature. The reaction mixture was heated to reflux (90° C. heating block temperature) for 16 h and then cooled to room temperature. 5-Chlorotryptamine hydrochloride (11.8 g, 49.0 mmol, 1.0 equiv) was then added followed by TCFH (21 g, 73.3 mmol, 1.5 equiv). An exotherm was observed and the reaction reached a gentle reflux which eventually subsided after approximately 30 min. Measurement of a reaction aliquot by UPLC indicated essentially complete conversion at this point. After an additional 30 min, the reaction mixture was concentrated on a rotavap to give the crude product as an oil, which was divided into three portions and purified by silica gel chromatography (330 g silica each, gradient 0% to 100% MeOH in EtOAc; product elutes at 50-60% MeOH). The resulting partially purified material was concentrated to give a white paste, which was triturated with dichloromethane to give N-[2-(5-chloro-1H-indol-3-yl)ethyl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide (15.72 g, 39.4 mmol, 81% yield) as a white powder that was contaminated with <5% 1-methylimidazole. MS m / z 399 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.85 (s, 2H), 8.65 (t, J = 5.7 Hz, 1H), 7.59 (d, J = 2.1Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 8.6, 2.0 Hz, 1H), 4.78 (d, J = 14.2Hz, 2H), 3.59 - 3.34 (m, 6H), 3.12 - 2.98 (m, 2H), 2.92 (t, J = 7.3 Hz, 2H), 2.78 (s, 1H).

[0219] [ka] Step 2: N-[2-(5-chloro-1H-indol-3-yl)ethyl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide (5.00 g, 12.5 mmol, 1.00 equiv.) was suspended in acetonitrile (50 mL, 4 L / mol) at room temperature in a 250 mL round bottom flask equipped with a magnetic stir bar and reflux condenser. Phosphoryl chloride (4.8 mL, 7.7 g, 52 mmol, 4 equiv.) was added and the reaction mixture was heated to reflux. UPLC of a reaction aliquot at 3 h indicated complete conversion. The mixture was cooled to room temperature and acetonitrile and excess phosphorus oxychloride were removed on a rotavap. The resulting brown residue was cooled in an ice-water bath and carefully dissolved in approximately 5 mL of water (highly exothermic). 50% aqueous NaOH (4 equiv.) was added and the mixture was allowed to warm to room temperature and stirred overnight. The resulting slurry was dissolved in methanol and concentrated onto Celite. Purification by silica gel column chromatography (120 g silica, gradient from 5% MeOH to 100% MeOH in EtOAc with 5% anhydrous ammonia) afforded 6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-4,9-dihydro-3H-pyrido[3,4-b]indole (5.03 g, 12.5 mmol, 99%) as a yellow powder.

[0220] [ka]

[0221] Step 3: RuCl[(R,R)-TsDPEN] (mesitylene) (17 mg, 0.026 mmol, 0.010 equiv.) was dissolved in formate triethylamine complex 5:2 (1.1 mL, 2.6 mmol, 1.0 equiv.) at room temperature in a 20 mL vial equipped with a magnetic stir bar and a pressure relief cap. 6-Chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-4,9-dihydro-3H-pyrido[3,4-b]indole (1.00 g, 2.49 mmol, 1.0 equiv.) was added as a solid in one portion, followed by DMF (2.5 mL, 1 L / mol), which was used to rinse the walls of the vial. The septum was pierced with a needle to allow for the evacuation of carbon dioxide, which was rapidly formed at the start of the reaction. After 3 h, UPLC of a reaction aliquot indicated the reaction was not complete, and an additional 17 mg of ruthenium catalyst was added. After an additional 1 h, the reaction was deemed complete. The resulting mixture was concentrated onto Celite and purified by silica gel column chromatography (80 g silica, gradient 0% to 100% MeOH in EtOAc) to give (1S)-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (995 mg, 2.47 mmol, 99% yield) as a white solid.

[0222] [ka] Step 4: In a 50 mL round bottom flask equipped with a magnetic stir bar was added (1S)-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (1.05 g, 2.61 mmol, 1.0 equiv), EtOAc (24 mL, 9 L / mol) and saturated aqueous NaHCO3 (8 mL, 3 L / mol). 2-Methylsulfonyl-4,6-bis(trifluoromethyl)pyrimidine (1.55 g, 5.27 mmol, 2.0 equiv) was added in one portion and the resulting mixture was stirred at room temperature. UPLC analysis of a reaction aliquot showed complete conversion after 5 h. The reaction mixture was partitioned into a separatory funnel, the aqueous layer was extracted with EtOAc (3×50 mL), and the combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated on a rotavap. The crude oily residue obtained was purified by silica gel column chromatography (80 g silica, gradient 0%-100% MeOH (containing 5% NH3) in EtOAc) to give compound 419 (385 mg, 0.645 mmol, 25%) as a white solid. MS m / z 596.9 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.41 (s, 2H), 7.66 - 7.49 (m, 2H), 7.36 - 7.30 (m, 1H), 7.10 (dd, J = 8.6, 2.1Hz, 1H), 6.79 (s, 1H), 4.97 (dd, J = 13.6, 5.2Hz, 1H), 4.68 (d, J = 14.3 Hz, 2H), 3.49 (t, J = 10.6 Hz, 3H), 3.20 (t, J = 13.2Hz, 2H), 3.01 (d, J = 15.1Hz, 3H), 2.92 - 2.76 (m, 4H).

[0223] Using the procedure described above for compound 419, by substituting the appropriate starting materials, suitable reagents and reaction conditions, additional compounds described herein were prepared: [Table 29]

[0224] (Example 19) Preparation of Compound 409 [ka]

[0225] In a 50 mL round bottom flask equipped with a magnetic stir bar, 4-[5-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-2-pyridyl]morpholine (2.2 g, 6.0 mmol), 2-methylsulfonyl-4,6-bis(trifluoromethyl)pyrimidine (3 g, 9.2 mmol) and ethyl acetate (8 mL) were added and the mixture was degassed and backfilled with argon. Sodium bicarbonate (8 mL, 20 mmol, saturated aqueous solution) was then added under argon at 0° C. The mixture was stirred at room temperature overnight. It was then diluted with EtOAc, the phases were separated and the organic phase was washed with brine, dried over MgSO4 and then concentrated. The remaining oily residue was purified by silica gel chromatography eluting with 0-30% EtOAc in hexane to give compound 409 (2.7 g, 78% yield). MS m / z 583.5 [M+H] + ; 1H NMR (DMSO-d6, 400 MHz) δ: 11.13 (s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.45 (dd, J = 2.4, 8.9 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.09 (dd, J = 2.1, 8.6 Hz, 1H), 6.89 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 4.9 - 5.0 (m, 1H), 3.6 - 3.7 (m, 4H), 3.47 (br d, J = 4.0 Hz, 1H), 3.4 - 3.5 (m, 4H), 2.9 - 3.0 (m, 1H), 2.8 - 2.9 (m, 1H); mp: 148-152C.

[0226] Using the procedures described above for compound 409, and substituting the appropriate starting materials, suitable reagents and reaction conditions, additional compounds described herein were prepared: [Table 30]

[0227] (Example 20) Preparation of compound 17 [ka]

[0228] Crude 6-chloro-2-(4,6-dichloropyrimidin-2-yl)-7-fluoro-1-(p-tolyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole was prepared as a mother liquor in the preparation of 6-chloro-2-(4,6-dichloropyrimidin-2-yl)-7-fluoro-1-(p-tolyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole starting from 137 mg of 4,6-dichloro-N-[2-(5-chloro-6-fluoro-1H-indol-3-yl)ethyl]pyrimidin-2-amine as described in Example 4. The material was concentrated and dissolved in approximately 1 mL of ethanol. This solution in ethanol, Me2NH in water (7.9 mol / L) (0.5 mL, 4 mmol, 7.9 mol / L, 10) was added to a microwave vial equipped with a septum and stir bar and heated to 100° C. for 10 min. The mixture was concentrated, partitioned between water and DCM, and purified by flash chromatography (silica 12+5 g) eluting with an EtOAc / hexane gradient: 9% to 30%. The collected fractions were concentrated, dissolved in ethanol, precipitated with water, filtered, washed with water, and dried to give compound 017 as a white solid material (0.064 g, 0.14 mmol, 36% from 137 mg of 4,6-dichloro-N-[2-(5-chloro-6-fluoro-1H-indol-3-yl)ethyl]pyrimidin-2-amine). MS m / z 470.2 [M+H] + ; 1 H NMR (DMSO-d6) δ: 11.23 (br s, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.30 (br d, J=10.1Hz, 1H), 7.11-7.22 (m, 4H), 7.02 (br s, 1H), 6.05 (s, 1H), 4.78 (br s, 1H), 3.06 (br s, 7H), 2.77 (br s, 2H), 2.27 (s, 3H).

[0229] Additional compounds described herein were prepared using the procedures described for compound 17 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 31] JPEG2025501285000283.jpg119170

[0230] Example 21 Preparation of Compound 291 [ka]

[0231] To a screw-capped vial equipped with a septum and nitrogen needle was added 6-bromo-1-(p-tolyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (0.357 g, 0.733 mmol), [1,1'-bis(diphenylphophini)ferrocene]dichloropalladium(II) (0.029 g, 0.038 mmol). The vial was flushed with nitrogen and toluene (6 mL), tributyl(vinyl)tin (0.3 mL, 1 mmol) were added sequentially. The mixture was heated to 110 °C (heating block) for 1.5 h, then cooled to room temperature and loaded directly onto a silica gel column. Purification by flash chromatography eluting with a hexane / EtOAc gradient: 10% to 50% afforded compound 297 (0.261 g, 82% yield) as a white solid. MS m / z 435.2 [M+H] + ; 1H NMR (DMSO-H6) δ: 11.10 (br s, 1H), 8.84 (br s, 1H), 7.60 (s, 1H), 7.31-7.37 (m, 2H), 7.25-7.31 (m, 2H), 7.20-7.25 (m, 2H), 7.15 (d, J=4.9 Hz, 1H), 7.04-7.14 (m, 1H), 6.87 (dd, J=17.5, 10.8 Hz, 1H), 5.77 (d, J=17.7 Hz, 1H), 5.16 (d, J=11.0 Hz, 1H), 4.79-5.09 (m, 1H), 3.29-3.38 (m, 1H), 2.84-3.03 (m, 2H), 2.34 (s, 3H).

[0232] Example 22 Preparation of compound 292 [ka]

[0233] Step 1: To a single RBF was added (4-chloro-2-nitrophenyl)hydrazine (1.77 g, 9.25 mmol), 1H-isoindole-1,3(2H)-dione, 2-(4,4-dimethoxybutyl)- (2.57 g, 9.27 mmol), ethanol (30 mL), followed by 4N sulfuric acid (2.5 mL, 5.0 mmol). Warmed to 50° C. for 1 h. A thick suspension formed. The reaction mixture was diluted with water, filtered, washed with EtOH / water approx. 2 / 1, then water, and dried to give an orange solid, 2-[(4E)-4-[(4-chloro-2-nitro-phenyl)hydrazono]butyl]isoindoline-1,3-dione (3.50 g, 9.05 mmol, 98% yield). MS m / z 385.1 [MH] - .

[0234] Step 2: To a screw-cap vial equipped with a septum and nitrogen needle was added N-[(E)-butylideneamino]-4-chloro-2-nitro-aniline (0.57 g, 1.5 mmol), sulfolane (6 mL), and Eaton's reagent (3 mL). The mixture was heated to 80° C. for 1.5 h, then an additional 3 mL of Eaton's reagent was added and heated to 100° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with water, filtered, washed with water, ether, and dried to give 0.8 g of a brown solid, which was used in the next step. MS m / z 367.8 [MH] - .

[0235] Step 3: To a single-port RBF equipped with a septum and N2 inlet was added 2-[2-(5-chloro-7-nitro-1H-indol-3-yl)ethyl]isoindoline-1,3-dione from the preparation step, ethanol (50 mL), and hydrazine hydrate (0.5 mL, 10 mmol). The mixture was heated to 80° C. for 1.5 h, then 2 mL of aqueous N2H4 was added. After heating for an additional ½ h, the mixture was concentrated, diluted with water, partially concentrated, filtered, washed with water, and dried to give a brownish orange solid, 2-(5-chloro-7-nitro-1H-indol-3-yl)ethanamine (E, 0.216 g, 0.901 mmol, 61% yield), approx. 80% purity by HPLC. MS m / z 240.0 [M+H] + .

[0236] Step 4: To a screw-cap vial equipped with a septum and nitrogen needle was added 2-(5-chloro-7-nitro-1H-indol-3-yl)ethanamine (0.216 g, 0.901 mmol), p-tolualdehyde (0.176 g, 1.46 mmol), acetic acid (6 mL), methanesulfonic acid (0.1 mL, 2 mmol) and the mixture was heated to 110° C. for 5 h. Then an additional 0.25 mL of aldehyde was added and the mixture was heated to 140° C. for 2 days. The mixture was cooled, diluted with aqueous NaHCO3, extracted with DCM, concentrated and purified by chromatography using a gradient DCM / MeOH (containing 2% NH4OH) 1% to 100% to give a brown solid material, 6-chloro-8-nitro-1-(p-tolyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.129 g, 0.377 mmol), approximately 70% pure by UPLC. MS m / z 342.1 [M+H] + .

[0237] Step 5: To a microwave vial equipped with a septum and stir bar was added 6-chloro-8-nitro-1-(p-tolyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.129 g, 0.377 mmol), 2-chloro-4,6-dimethyl-1,3,5-triazine (0.053 g, 0.36 mmol), 1,4-dioxane (3 mL), triethylamine (0.15 mL, 1.1 mmol) and the vial was heated to 180° C. in a microwave oven for 30 minutes. The material was purified by flash chromatography eluting with a DCM / EtOAc gradient: 5% to 100% to give a dark orange glassy solid material, 6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-8-nitro-1-(p-tolyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (0.118 g, 0.263 mmol, 73% yield). MS m / z 449.6 [M+H] + .

[0238] Step 6: In a screw-cap vial equipped with a septum and nitrogen needle, 6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-8-nitro-1-(p-tolyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (0.114 g, 0.254 mmol), dichlorotin dihydrate (0.130 g, 0.576 mmol), ethanol (5 mL) were added and the mixture was heated to 70 °C for 2 h. Then, 0.27 g of SnCl2 x 2H2O was added and continued at 70 °C for 2 h. The mixture was partitioned between aqueous NaHCO3 and DCM, concentrated, and purified by flash chromatography eluting with a hexanes / EtOAc gradient from 20% to 100%. The isolated material was dissolved in ether, precipitated with hexane, and partially concentrated to give a white solid material, compound 292 (0.050 g, 0.12 mmol, 47% yield). MS m / z 419.2 [M+H] + . 1 H NMR (DMSO-d6) δ: 10.65 (s, 1H), 7.21-7.26 (m, 2H), 7.16-7.21 (m, 2H), 7.12 (s, 1H), 6.73 (d, J=1.5 Hz, 1H), 6.34 (d, J=1.5 Hz, 1H), 5.24 (br s, 1H), 4.92 (dd, J=13.1, 4.9 Hz, 1H), 3.11-3.21 (m, 1H), 2.67-2.84 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H).

[0239] Additional compounds described herein were prepared using the procedures described for compound 292 above, substituting the appropriate starting materials, suitable reagents and reaction conditions to provide compounds such as those selected from the following: [Table 32]

[0240] (Example 23) Preparation of Compound 362 [ka] In a 50 mL one-neck round-bottom flask, 4-[5-(6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl]morpholine (100 mg, 0.2704 mmol) and 2-chloro-6-methyl-pyrimidine-4-carbonitrile (70 mg, 0.45582 mmol) were dissolved in 1-butanol (5.0 mL, 55 mmol), and then N,N-diisopropylethylamine (0.3 mL, 2 mmol) was added into the mixture. The reaction mixture was stirred at 120° C. for 12 hours. The resulting mixture was concentrated under vacuum and purified by preparative HPLC to give compound 362 (C, 110 mg, 0.2259 mmol, 83.53% yield) as a light yellow solid. MS m / z = 486.9, [M+H]; 1 H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.32 (s, 2H), 7.54 (d, J=2.0 Hz,1H ), 7.31 (d, J=8.8 Hz, 1H), 7.17 (s, 1H), 7.08 (q,J =2.0 Hz, 1H), 6.81 (s, 1H), 4.94 (s, 1H), 3.66 (d, J=4.0 Hz, 4H), 3.61 (d, J=3.4 Hz, 4H) 3.30-3.31 (m, 1H), 2.90 (d, J=3.2Hz, 1H), 2.73-2.81 (m, 1H), 2.43 (s, 3H).

[0241] Additional compounds described herein were prepared using the procedures described for compound 362 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 33]

[0242] (Example 24) Preparation of Compound 369 [ka]

[0243] A 50 mL round bottom flask was charged with N-[2-(5-chloro-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.4403 mmol), 2-(4-methylpiperazin-1-yl)pyrimidine-5-carbaldehyde (112 mg, 0.54306 mmol), p-toluenesulfonic acid (45 mg, 0.26132 mmol) in 2-butanol (4 mL, 43.5 mmol). The mixture was stirred at 100° C. under nitrogen atmosphere for 6 h. LCMS showed almost complete conversion to the desired product. Purification by flash and preparative HPLC afforded compound 369 (80 mg, 0.1512 mmol, 34.35% yield) as a white solid. MS m / z = 529.0, [M+H]; 1 H NMR (400 MHz, DMSO) δ 11.10(s, 1H), 8.79(d, J = 4.8Hz, 1H), 8.32(s, 2H), 7.55 (d, J = 2Hz, 1H), 7.32(d, J = 8.4 Hz, 1H), 7.12 (d, J = 4.8Hz, 1H), 7.09 (q, J = 6.4 Hz, 1H), 6.80 (s, 1H), 5.00(t, J = 2.8 Hz, 1H), 3.70(s, 4H), 3.43(t, J = 3.2Hz, 1H), 2.94 (q, J = 12.4Hz, 1H), 2.81(m, 1H), 2.34(s, 4H), 2.21(s, 3H).

[0244] Additional compounds described herein were prepared using the procedures described for compound 369 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 34]

[0245] (Example 25) Preparation of compound 370 [ka]

[0246] Step 1: To a single-port RBF equipped with a N2 inlet was added 4-[5-(6-chloro-8-iodo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyrimidin-2-yl]morpholine (300 mg, 0.6063 mmol), 2-chloro-4,6-dimethyl-1,3,5-triazine (130 mg, 0.90548 mmol), and THF (5 mL, 61.4 mmol), followed by N,N-diisopropylamine (0.7 mL, 4 mmol). The reaction mixture was heated to 70° C. for 7 h, concentrated to dryness, and purified by column flash to give 4-[5-[6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-8-iodo-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]morpholine as a light brown solid (200 mg, 0.3317 mmol, 54.71% yield), MS m / z 603.1 [M+H]. + .

[0247] Step 2: To a solution of 4-[5-[6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-8-iodo-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]morpholine (200.0 mg, 0.3317 mmol) in 1,4-dioxane (4 mL, 46.85 mmol), tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (140.0 mg, 0.5514 mmol), potassium acetate (80.0 mg, 0.815 mmol) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.0 mg, 0.0389 mmol) were added and the mixture was then evacuated and backfilled with N and heated to 100 °C for 16 h.

[0248] The reaction mixture was concentrated and purified by column flash and preparative HPLC to give 4-[5-[6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]morpholine (C, 50 mg, 0.08293 mmol, 25.00% yield). MS m / z 603.6[M+H] + .

[0249] Step 3: To a solution of 4-[5-[6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]morpholine (50.0 mg, 0.0829 mmol) in THF (2 mL) was added hydrogen peroxide in water (0.4 mL, 35% by weight) and sodium hydroxide (0.4 mL, 0.4 mmol, 1 mol / L). The mixture was stirred for 30 min, concentrated in vacuo, and purified by preparative TLC to give the crude product. Further purification by preparative HPLC gave compound 370 (35 mg, 0.07099 mmol, 85.6% yield) as a white solid. MS: m / z = 493.0, [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 10.07 (s, 1H), 8.28 (s, 2H), 6.98 (d, J =2.0 Hz, 1H), 6.90 (s, 1H), 6.53-6.52 (m, 1H), 5.01- 4.97 (m, 1H), 3.66-3.61 (m, 8H), 3.28-3.21 (m, 1H), 2.87-2.67 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H).

[0250] Additional compounds described herein were prepared using the procedures described for compound 370 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 35]

[0251] (Example 26) Preparation of compound 272 [ka]

[0252] Step 1: 2-Iodo-4-methyl-aniline (3.0 g, 12.9 mmol) 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 min, a solution of tin dichloride (5.3 g, 27.7 mmol) in 6 mL of concentrated HCl was added to the mixture. The reaction mixture was allowed to warm to room temperature over 3 h and then stirred at room temperature for 12 h. The suspension was then diluted with water and the aqueous layer was washed twice with DCM. The aqueous layer was basified with 6M NaOH solution until pH>10. The suspension was extracted twice with DCM and once with EtOAc, dried over MgSO4, and filtered. The crude material was purified by silica gel chromatography and (2-iodo-4-methyl-phenyl)hydrazine was isolated as a yellow solid (2.1 g, 68% yield).

[0253] Step 2: (2-iodo-4-methyl-phenyl)hydrazine (500 mg, 2.0 mmol), N-(4,4-diethoxybutyl)-4-(trifluoromethyl)pyrimidin-2-amine (650 mg, 2.1 mmol) and zinc chloride (300 mg, 2.2 mmol) were placed in a 50 mL RBF to which 1.5 mL of dioxane was added. The solution was placed on a hot plate at 180 °C. The solvent was evaporated until a black tar remained, which was stirred at 180 °C for 5 minutes. The mixture was cooled to room temperature and purified by silica gel chromatography. N-[2-(7-iodo-5-methyl-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine was obtained as a yellow solid, 420 mg, 47% yield.

[0254] Step 3: To a mixture of N-[2-(7-iodo-5-methyl-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (420 mg, 0.94 mmol) and 2,3-difluoro-4-methyl-benzaldehyde (175 mg, 1.13 mmol) in a vial, trifluoroacetic acid (0.9 mL, 1.13 mmol) was added and flushed with argon. The mixture was dissolved in 4 mL of DCE and stirred at 80 °C overnight. The reaction mixture was quenched with 5 mL of a saturated aqueous solution of NaHCO3, and the aqueous layer was extracted with DCM. The organic fraction was dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography afforded 1-(2,3-difluoro-4-methyl-phenyl)-8-iodo-6-methyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole as a white solid, (320 mg, 58% yield).

[0255] Step 4: 1-(2,3-difluoro-4-methyl-phenyl)-8-iodo-6-methyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (160 mg, 0.27 mmol) was placed in a vial and sodium tert-butoxide (93 mg, 0.98 mmol), XPHOS PD G3 (4.8 mg, 0.054 mmol) and diphenylmethanimine (98 mg, 0.54 mmol) were added. The vial was flushed with argon, then 5 mL of toluene was added and the mixture was stirred at 100 °C overnight. The mixture was filtered through a plug of silica gel with ethyl acetate, then concentrated and used in the next step (yellow oil, 175 mg, 76% yield).

[0256] Step 5: N-[1-(2,3-difluoro-4-methyl-phenyl)-6-methyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-8-yl]-1,1-diphenyl-methanimine (175 mg, 0.28 mmol) was dissolved in methanol, 2.0 mL of 4N dioxane in HCl and 0.40 mL of H2O were added, stirred at room temperature for 4 hours, then concentrated in vacuo and purified by preparative HPLC. Compound 272 was obtained as a white solid (19 mg, 15% yield). MS m / z = 475.2 [M+H] + ; 1 H NMR (DMSO-d, 400MHz) δ 10.28 (s, 1H), 8.78 (d, J = 4.9 Hz, 1H), 7.20 (s, 1H), 7.12 (d, J = 4.9 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.84 (t, J = 7.3 Hz, 1H), 6.53 (s, 1H), 6.19 (d, J = 1.4 Hz, 1H), 4.90 (s, 1H), 4.83 (s, 2H), 3.42 (s, 1H), 2.86-2.74 (m, 2H), 2.26 (s, 3H), 2.25 (s, 3H).

[0257] Additional compounds described herein were prepared using the procedures described for compound 272 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 36]

[0258] Example 27 Preparation of 4-fluoro-5-methyl-1H-indole [ka]

[0259] Step 1: To a RBF was added 2-fluoro-1,3-dimethyl-4-nitro-benzene (5.0 g, 30 mmol), N,N-dimethylformamide dimethyl acetal (12.0 g, 101 mmol), triethylamine (10.0 g, 98.8 mmol) and N,N-dimethylformamide (15.0 mL). The mixture was stirred at 100° C. for 24 h, cooled by pouring into ice water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and then concentrated in vacuo to give (E)-2-(2-fluoro-3-methyl-6-nitro-phenyl)-N,N-dimethyl-ethenamine (9.6 g, 68% yield).

[0260] Step 2: To a RBF was added (E)-2-(2-fluoro-3-methyl-6-nitro-phenyl)-N,N-dimethyl-ethenamine (9.6 g, 30 mmol), iron powder (17.0 g, 304 mmol), acetic acid (50.0 mL, 873 mmol), and toluene (100.0 mL). The mixture was stirred at 100° C. for 4 h. The solid was collected by filtration and further purified by silica gel chromatography to give 4-fluoro-5-methyl-1H-indole (1.8 g, 40% yield).

[0261] (Example 28) Preparation of Compound 106 [ka]

[0262] Step 1: Phosphoryl chloride (24.0 g, 156 mmol) was added to a solution of DMF (50 mL) at 0° C. under N2 atmosphere. The mixture was warmed to room temperature and stirred for 1 h, then the mixture was cooled back to 0° C. and 5-chloro-6-fluoro-1H-indole (20.4 g, 120 mmol) in 350 mL of DMF was added dropwise to the mixture. The reaction was warmed to room temperature and stirred for 2 h. The reaction was cooled to 0° C. and quenched with 20 mL of 15% aqueous NaOH followed by 50 mL of water. The mixture was heated to 100° C. for 1 h and cooled to room temperature resulting in a slurry. It was filtered and the solid was washed with water and then dried to give the product 5-chloro-6-fluoro-1H-indole-3-carbaldehyde (19.6 g, 99.2 mmol, 82.3% yield) as a yellow solid. MS m / z 198.0[M+H] + .

[0263] Step 2: 5-Chloro-6-fluoro-1H-indole-3-carbaldehyde (43.9 g, 222 mmol) and ammonium acetate (22.31 g, 289.4 mmol) were dissolved in 300 mL of nitromethane and stirred at 75° C. for 2 h. The mixture was cooled to 0° C., resulting in the formation of a precipitate. The solid was collected by filtration, washed with water, and dried under vacuum to give the product 5-chloro-6-fluoro-3-[(E)-2-nitrovinyl]-1H-indole (34.8 g, 145 mmol, 65.1% yield) as a yellow solid. MS m / z 241.0 [M+H] + .

[0264] Step 3: Lithium aluminum hydride (15.0 g, 383 mmol) was placed in a flask under N2 atmosphere and suspended in 250 mL of THF. The mixture was cooled to 0° C. and a solution of 5-chloro-6-fluoro-3-[(E)-2-nitrovinyl]-1H-indole (15.0 g, 62.3 mmol) in 50 mL of THF was added dropwise. After the addition, the mixture was heated to 65° C. and stirred for 2 h. Upon completion, the mixture was cooled to 0° C. and quenched by the addition of 15 mL of water followed by the addition of 15 mL of 15% aqueous NaOH. The mixture was stirred at room temperature for 30 min, then MgSO4 was added and the solids were removed by filtration. The solution was concentrated under reduced pressure to give 2-(5-chloro-6-fluoro-1H-indol-3-yl)ethanamine (B, 12.11 g, 56.95 mmol, 91.4% yield) as a yellow oil. MS m / z 213.4[M+H] + .

[0265] Step 4: A mixture of 2-(5-chloro-6-fluoro-1H-indol-3-yl)ethanamine (300 mg, 1.4 mmol), 2-chloro-5-fluoro-4,6-dimethyl-pyrimidine (270 mg, 1.68 mmol) and Hunig's base (55 mg, 0.43 mmol) in 1-butanol (3 mL, 32.7 mmol) was stirred at 120° C. for 16 h. The solvent was then removed under reduced pressure and the mixture was purified by silica gel chromatography to give N-[2-(5-chloro-6-fluoro-1H-indol-3-yl)ethyl]-5-fluoro-4,6-dimethyl-pyrimidin-2-amine (270 mg, 0.80 mmol, 56.8% yield) as a light yellow solid. MS m / z 213.4 [M+H] + .

[0266] Step 5: To a stirred suspension of N-[2-(5-chloro-6-fluoro-1H-indol-3-yl)ethyl]-5-fluoro-4,6-dimethyl-pyrimidin-2-amine (50 mg, 0.15 mmol) in 3 mL of s-BuOH, 4-methylbenzaldehyde (B, 22 mg, 0.18 mmol) and TsOH (16 mg, 0.09 mmol) were added. The suspension mixture was heated to reflux for 1 h, then cooled to room temperature and concentrated. The crude material was purified by preparative HPLC to give compound 106 (26 mg, 0.059 mmol, 39.90% yield) as a white solid. MS: m / z = 439.0, [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 11.26 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.29(d, J = 10.4 Hz, 1H), 7.18 - 7.12 ( m, 4H), 7.02 ( s, 1H), 4.82 - 4.74(m,1H), 3.15 - 3.08 (m, 1H), 2.81-2.75 (m, 2H), 2.32 (d, J = 2.4Hz, 6H), 2.26 (s, 3H). Additional compounds described herein were prepared using the procedures described for compound 106 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 37] JPEG2025501285000298.jpg236170 JPEG2025501285000299.jpg253170 JPEG2025501285000300.jpg251170 JPEG2025501285000301.jpg249170 JPEG2025501285000302.jpg246170 JPEG2025501285000303.jpg120170

[0267] (Example 29) Preparation of compound 208 [ka]

[0268] To a solution of 6-chloro-1-(2,6-difluoro-3-pyridyl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (70 mg, 0.1447 mmol) in THF (1 mL) was added a solution of dimethylamine (2 mol / L) in THF (1 mL, 2 mmol) followed by triethylamine (0.1 mL, 0.8 mmol). The mixture was stirred at 80° C. for 4 h and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC to give compound 208 (D, 43 mg, 0.069 mmol 58% yield) as a white solid. MS m / z = 507.0 [MH] - ; 1 H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 7.14 - 7.04 (m, 2H), 6.42 - 6.39 (m, 1H), 4.96 - 4.82 (m, 1H), 3.31 - 3.28 (m, 1H), 2.97 (s, 6H), 2.90 - 2.73 (m, 2H).

[0269] Additional compounds described herein were prepared using the procedures described for compound 208 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 38]

[0270] (Example 30) Preparation of compound 156 [ka]

[0271] To a suspension of lithium aluminum hydride (40 mg, 1.05 mmol) in THF (10 mL) was added a solution of methyl 3-[4-[6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]propanoate (300 mg, 0.56 mmol) in THF (10 mL). The mixture was stirred at 25° C. for 2 h. The mixture was quenched by the sequential addition of water (40 uL) and 10% aqueous NaOH (40 uL). The suspension was stirred for 20 min, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using eluent PE:EA=3:1 to give compound 156 (170 mg, 0.34 mmol, 59.81% yield) as a yellow oil. MS m / z = 503.1, [M+H] - ; 1 H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 8.77 (s, 1H), 7.67 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 10.1Hz, 1H), 7.20 (q, J = 8.2Hz, 4H), 7.13-6.94 (m, 2H), 4.90 (s, 1H), 4.46 (t, J = 5.1Hz, 1H), 3.42-3.35 (m, 2H), 3.29-3.19 (m, 1H), 2.92-2.75 (m, 2H), 2.62-2.53 (m, 2H), 1.71-1.61 (m, 2H).

[0272] Additional compounds described herein were prepared using the procedures described for compound 156 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 39]

[0273] (Example 31) Preparation of Compound 399 [ka]

[0274] To the RBF was added (1S)-6-chloro-2-(4-chloro-1,3,5-triazin-2-yl)-1-(p-tolyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (150 mg, 0.3656 mmol), tetraethylammonium cyanide (150 mg, 0.902279 mmol) in acetonitrile (15 mL, 286 mmol) and the mixture was stirred at room temperature overnight. LCMS showed the desired product as the main peak. The mixture was purified by preparative HPLC followed by preparative TLC to give compound 399 (20 mg, 0.04989 mmol, 100% yield 13.65%) as a pale yellow solid. MS m / z = 401.0, [M+H] + ; (DMSO-d, 400MHz) 11.26 (d, J=12.4 Hz, 1H), 8.84 (d,J=22.8 Hz, 1H), 7.55 (s, 1H), 7.33 (q, J=4.0 Hz, 1H), 7.18 (d, J=2.0 Hz, 4H), 7.10 (t, J=1.6 Hz, 1.5 H), 6.97 (s, 0.5H), 4.81 (m, 1H), 3.25 (m, 1H), 2.87 (m, 2H), 2.28 (d, J=2.0 Hz, 3H).

[0275] Additional compounds described herein were prepared using the procedures described for compound 399 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 40]

[0276] Example 32 Preparation of Compound 416 [ka]

[0277] A three-necked RBF equipped with a N2 inlet was charged with 2-(5-bromo-1H-indol-3-yl)ethanamine (150 mg, 0.4507 mmol), N,N-diisopropylamine (0.25 mL, 1.4 mmol) in tetrahydrofuran (2 mL, 24.6 mmol) and treated with 2-methylsulfinyl-6-(trifluoromethyl)pyrimidine-4-carbonitrile (300 mg, 1.2756 mmol). The reaction was stirred at room temperature for 3 h. Concentration and purification by preparative HPLC afforded compound 416 (20 mg, 0.03970 mmol, 8.808% yield) as a white solid. MS m / z = 401.0, [MH] - (DMSO-d, 400MHz) 11.18 (s, 1H), 7.81 (s, 1H), 7.57 (s, 1H), 7.32 (t, J=2.8 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.09 (d, J=6.4 Hz, 1H), 7.05 (s, 1H), 6.80 (s, 1H), 4.83 (d, J=15.6 Hz, 1H), 3.49 (s, 1H), 2.99-2.85 (m, 2H), 2.26 (s,3H).

[0278] Additional compounds described herein were prepared using the procedures described for compound 416 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 41]

[0279] (Example 33) Preparation of Compound 426 [ka]

[0280] (1S)-6-Chloro-1-(p-tolyl)-2-[4-(trichloromethyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (80 mg, 0.1426 mmol) was mixed with ammonia (2 mol / L) in methanol (3 mL, 21 mmol, 7 mol / L). The mixture was stirred overnight at 40° C. in a sealed tube. The mixture was then concentrated and purified by preparative HPLC to give compound 426 (49 mg, 0.1068 mmol, 74.90% yield) as a white solid. MS m / z = 458.9, [M+H] + (DMSO-d, 400MHz) δ 11.24 (d, J = 24.8 Hz, 1H), 7.61-7.75 (m, 2H), 7.53 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.6 Hz, 1H), 7.24 (d, J = 8.0Hz, 1H), 7.16- 7.17 (m, 3H), 7.08 (dd, J =8.6 Hz, 1H), 7.03 (d, J =11.2Hz, 1H), 4.79-4.87 (m, 1H), 3.10-3.18 (m, 1H), 2.72-2.88 (m, 2H), 2.27 (d, J =2.8Hz, 3H).

[0281] Additional compounds described herein were prepared using the procedures described for compound 426 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 42] JPEG2025501285000314.jpg71170

[0282] (Example 34) Preparation of Compound 390 [ka]

[0283] To a screw-cap vial was added (1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2-[4-fluoro-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (50 mg, 0.10 mmol) and DMF (2 mL), followed by potassium cyanide (13 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 12 h. The organics were precipitated out of solution by the addition of 10 mL of water. The solid was collected by filtration and purified by silica gel chromatography to give compound 390 (38 mg, 0.075 mmol, 75% yield) as a white solid. MS m / z = 479.0, [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.26 (s, 1H), 7.57 (d, J = 2.1Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.19 - 6.99 (m, 3H), 6.86 - 6.67 (m, 1H), 5.09 (s, 1H), 3.54 (s, 1H), 2.99 (d, J = 15.8 Hz, 2H), 2.26 (s, 3H).

[0284] (Example 35) Preparation of compound 474 [ka] A three-necked RBF equipped with a N2 inlet was charged with (1S)-6-chloro-2-[4-fluoro-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (150 mg, 0.2738 mmol), sodium thiomethoxide (30 mg, 0.4066 mmol), and dichloromethane (2 mL, 31.20 mmol). The reaction was stirred at room temperature for 1 h. The solids were filtered off and the filtrate was concentrated to give compound 474 (100 mg, 0.1736 mmol, 63.41% yield) as crude. 50 mg of the crude was purified by preparative HPLC to give 10 mg of pure material. MS m / z = 576.0, [M+H] + (DMSO-d, 400MHz) 11.10 (s, 1H), 8.30 (d, J=12.4 Hz, 2H), 7.57 (q, J=2.8 Hz, 1H), 7.33 (q, J=6.4, 1H), 7.10 (q, J=6.8 Hz, 1H), 6.88 (d, J=72.8 Hz, 1H), 5.08-4.90 (m, 1H), 3.71 (s, 4H), 3.47-3.40 (m, 1H), 2.98 (q, J=8.0 Hz, 1H), 2.88-2.80 (m, 1H), 2.60 (d, J=32.8 Hz, 3H), 2.32 (s, 4H), 2.19 (s, 3H).

[0285] Additional compounds described herein were prepared using the procedures described for compound 474 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 43]

[0286] (Example 36) Preparation of compound 460 [ka]

[0287] A three-necked RBF equipped with a N2 inlet was charged with 4-[5-[(1S)-6-chloro-2-[4-methylsulfanyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]morpholine (90 mg, 0.1599 mmol) suspended in ethanol (4 mL, 68.7 mmol) and Raney Nickel (90 mg, 1.5334 mmol). The reaction was stirred at 50 °C overnight. The product was collected by filtration, washed twice with ethanol (1 mL), and then dried in a vacuum oven. The residue was purified by preparative HPLC to give compound 460 (45 mg, 0.08706 mmol, 54.46% yield) as a white solid. MS m / z = 517.0, [M+H] + (DMSO-d6, 400MHz) 11.15-11.01 (m, 1H), 8.96-8.90 (m, 1H), 8.35 (d, J=5.6 Hz, 2H), 7.57 (s, 1H), 7.35-7.31 (m, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.93-6.80 (m, 1H), 5.07-4.92 (m, 1H), 3.69-3.62 (m, 8H), 3.51-3.44 (m, 1H), 3.02-2.96 (m, 1H), 2.87-2.79 (m, 1H).

[0288] Additional compounds described herein were prepared using the procedures described for compound 460 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 44]

[0289] (Example 37) Preparation of compound 464 [ka]

[0290] To a solution of (1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-2-[4-(trichloromethyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (100 mg, 0.1674 mmol) in a mixture of ethanol (6.0 mL, 100 mmol) and water (2.0 mL, 110 mmol) in a 50.0 mL single-neck round-bottom flask, ammonium chloride (90.0 mg, 1.68 mmol) and zinc powder (110 mg, 1.682 mmol) were added. The mixture was stirred at room temperature for 2 hours until LCMS showed complete conversion to the desired product. The mixture was filtered and the filtrate was concentrated to give a residue that was purified by preparative HPLC to give compound 464 as a yellow solid. MS m / z = 493.9, [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J=10.8 Hz, 1H), 7.50 (s, 1H), 7.21-7.34 (m, 2H), 7.15 (d, J=8.4 Hz,1H), 6.77-6.85 (m, 2H), 5.20-5.28 (m, 1H), 3.46-3.52 (m, 1H), 2.88-2.97 (m, 2H), 2.55 (d, J=8.0 Hz, 3H), 2.29 (s, 3H).

[0291] Additional compounds described herein were prepared using the procedures described for compound 464 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 45]

[0292] (Example 38) Preparation of compound 471 [ka]

[0293] A 100 mL single-neck flask equipped with a N2 inlet was charged with (1S)-2-(5-bromopyrimidin-2-yl)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (150 mg, 0.3063 mmol), phenylboronic acid (41 mg, 0.33626 mmol), chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.1 mmol), potassium carbonate (84 mg, 0.607797 mmol), and water (3 mL, 166.530 mmol) in 1,4-dioxane (3 mL, 35.14 mmol). The mixture was stirred overnight at 90 °C under nitrogen. Analysis by LCMS showed conversion to the desired mass. The reaction mixture was extracted with DCM, and the organics were washed with water and dried over Na2SO4. The organics were then concentrated and purified by preparative HPLC to give the desired product as a white solid, compound 471 (66 mg, 0.1356 mmol, 44.25% yield). MS m / z = 487.0, [M+H] + (CDCl3,400MHz),δ: 8.59(s, 2H), 8.07(s, 1H), 7.50-7.41(m, 5H),7.35-7.32(m, 2H),7.24-7.22(m, 1H), 7.13-7.10(m, 1H), 6.84-6.82(m, 2H), 5.24-5.20(m, 1H), 3.55- 3.49(m, 1H), 2.99(m, 1H), 2.28(m, 3H).

[0294] Additional compounds described herein were prepared using the procedures described for compound 471 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 46]

[0295] (Example 39) Preparation of Compounds 476 and 477 [ka] JPEG2025501285000325.jpg35166

[0296] 18-crown-6 (0.32 g, 1.2 mmol) and 4.0 g of 4A molecular sieves (powder) were mixed in acetonitrile (50.0 mL). The mixture was cooled to 0° C. Then, 2,4,6-trifluoro-1,3,5-triazine (2.0 mL, 24 mmol) and (trifluoromethyl)trimethylsilane (8.9 mL, 60 mmol) were added. Cesium fluoride (4.0 g, 26 mmol) was added in portions over 25 min. The mixture was then stirred at 0° C. for 30 min (monitored by LC-MS) (after a mini-quench with N-methylpiperazine). (1S)-6-Chloro-1-(2,3-difluoro-4-methyl-phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2.0 g, 6.0 mmol) was added in one portion. The mixture was then stirred at room temperature for 1 h and quenched with N-methylpiperazine. The mixture was filtered. The filtrate was concentrated and purified by silica gel chromatography to give compound 476 (54 mg, 5.4% yield) as a white powder. MS m / z = 528.1, [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.8 (d, 1H, J=23.2Hz), 7.54 (d, 1H, J=2.0 Hz), 7.32 (t, 1H, J=8.2Hz), 7.23 (s, 0.6 H), 7.12-7.02 (m, 2.4 H), 6.77 (dt, 1H, J=50.8 Hz, 6.8 Hz), 4.89-4.76 (m, 1H), 3.85-3.66 (m, 4H), 3.42-3.37 (m, 1H), 2.91-2.76 (m, 2H), 2.51-2.34 (m, 4H), 2.26 (s, 3H), 2.22 (s, 3H). Compound 477 was isolated as a by-product from the same reaction mixture. MS m / z = 578.1, [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 11.10 (d, J=37.6 Hz,1H), 7.55 (s, 1H), 7.31 (d, J=8.4 Hz,1H), 7.22 (d, J=6.0 Hz,1H), 7.02-7.10 (m, 2H), 6.75-6.86 (m, 1H), 4.90- 4.93 (m, 1H), 3.76-3.88 (m, 4H), 3.39-3.46 (m, 1H), 2.77-2.95 (m, 2H), 2.44-2.51 (m, 4H), 2.26-2.77 (m, 6H).

[0297] Using the procedures described above for compound 476, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 47]

[0298] (Example 41) Preparation of Compound 492 [ka] Into a single-port RBF equipped with a N2 inlet, 1-(2,3-difluoro-4-methyl-phenyl)-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.3162 mmol) and 2-phenylsulfanyl-4,6-bis(trifluoromethyl)-1,3,5-triazine (100 mg, 0.3075 mmol), triethylamine (0.1 mL, 0.7 mmol) and THF (5 mL, 61.4 mmol) were added. The reaction mixture was stirred at 50° C. for 4 h. The desired product mass was observed by LCMS, cooled to room temperature, concentrated, and the residue was purified by preparative HPLC and silica gel chromatography to give compound 492 (20 mg, 0.03764 mmol, 11.90% yield) as a white solid. MS m / z = 531.0, [M+H] + (DMSO,400MHz), δ 11.08(s, 1H), 7.32-7.28(m, 2H), 7.22(s, 1H), 7.08-7.04(m, 1H), 6.97-6.92 (m, 1H),6.87-6.83(m, 1H), 4.95-4.91(m, 1H), 3.58-3.52(m,1H), 3.02- 2.90(m,2H), 2.26(dd, J=1.6, 3H).

[0299] (Example 42) Preparation of compound 511 [ka]

[0300] To a 5 mL screw cap vial was added tert-butyl (2R)-4-[5-[(1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]-2-methyl-piperazine-1-carboxylate (285 mg, 0.4088 mmol) dissolved in dichloromethane (2 mL, 31.20 mmol). Trifluoroacetic anhydride (0.6 mL, 4 mmol) was added at room temperature and the mixture was stirred for 1 h. After 1 h, the reaction was complete by LCMS. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to give compound 511 (180 mg, 0.3015 mmol, 73.75% yield) as a white solid. MS m / z = 597.2, [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.37 (s, 2H), 7.57 (d, J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.8Hz, 1H), 6.78 (s, 1H), 4.98 (dd, J = 13.6Hz, 1H), 4.52-4.56 (m, 2H), 3.48-3.55 (m, 1H), 3.19-3.22 (m, 1H), 2.98-3.12 (m, 3H), 2.80-2.88 (m, 3H), 1.17 (d, J = 6.4Hz, 3H).

[0301] Additional compounds described herein were prepared using the procedures described above for compound 511, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 48]

[0302] (Example 43) Preparation of Compound 521 [ka]

[0303] A mixture of methyl 4-[(1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)-1,3,5-triazine-2-carboxylate (100 mg, 0.1859 mmol) in THF (3 mL, 36.9 mmol) was cooled to -5°C and DIBAL-H (1 mol / L) in hexane (1.9 mL, 1.9 mmol) was added in small portions. The reaction mixture was stirred at -5°C for 2 h and then warmed to room temperature. The reaction mixture was filtered, the filtrate was evaporated and the residue was purified by preparative HPLC to give compound 521 (40 mg, 0.07845 mmol, 42.20% yield) as a yellow solid. MS m / z = 509.9, [M+H] + (CDCl3, 400MHz): 7.96 (s, 1H), 7.51 (s, 1H ), 7.29-7.27 (d, J = 8.8 Hz, 1H), 7.24-7.21 (dd, J = 1.6 Hz, 8.8 Hz,1H ), 7.17-7.14 (dd, J = 2.0 Hz, 8.8 Hz,1H), 6.90-6.76 (m, 2H), 5.27-5.18 (m, 1H), 4.67 (s, 2H), 3.58-3.51 (m, 1H), 3.30-3.24 (m, 1H), 2.99-2.96 (m, 2H), 2.29 (s, 3H).

[0304] (Example 44) Preparation of Compound 526 [ka] In a round bottom flask, [4-[(1S)-6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)-1,3,5-triazin-2-yl]methanol (1.0 g, 2.0 mmol), DCM (20 mL, 312.0 mmol) were added. The mixture was cooled to 0° C., diethylaminosulfur trifluoride (500 mg, 3.1019 mmol) was added, and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with saturated NaHCO3, the organic phase was dried over Na2SO4, and evaporated in vacuum. The residue was purified by preparative HPLC, and the resulting product was lyophilized to give compound 526 (139 mg, 0.2716 mmol, 14% yield). ESI-MS: m / z = 510.0 [MH]- (DMSO-d6,400MHz),: 11.19 (s, 1H), 7.58-7.56 (d, J = 4.8 Hz, 1H), 7.34-7.23 (m, 2H), 7.11-7.09 (dd, J = 2.0 Hz, 8.8 Hz,1H ), 7.07-7.04 (t, J = 2.4 Hz,1H), 6.85-6.80 (q, J = 2.4 Hz, 1H), 5.58-5.49 (m, 1H), 5.46-5.37 (m, 1H), 5.04-4.89 (dd, J = 4.8Hz, 13.2Hz,1H), 3.51-3.42 (m, 1H), 3.02-2.96 (dt, J = 4.4 Hz, 15.6 Hz,1H), 2.91-2.83 (td, J = 5.2Hz, 11.2Hz,1H), 2.26 (s, 3 H).

[0305] (Example 45) Preparation of compound 534 [ka]

[0306] A solution of 2-methoxyethanol (13 mg, 0.1709 mmol) in THF (3.0 mL, 37 mmol) was added to a 25 mL single-neck round-bottom flask. The mixture was cooled and maintained at 0° C. Sodium hydride (2 mg, 0.0791736 mmol) was added into the solution and the mixture was stirred at 0° C. for 15 minutes. (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(2-chloropyrimidin-5-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (30 mg, 0.05616 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was monitored by LCMS, where the desired product mass was detected. Water was added into the mixture and extracted with ethyl acetate. The organics were concentrated in vacuo and the crude residue was purified by silica gel chromatography to give compound 534 (20 mg, 0.03485 mmol, 62.05% yield, 0.6205) as a white solid. MS m / z = 574.9 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 8.56 (s, 2H), 7.60 (d, J=2.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.12 (q, J=8.0 Hz, 1H), 6.96 (s, 1H), 4.98 (q, J=12.0 Hz, 1H), 4.40 (q, J=8.0 Hz, 2H), 3.64 (q, J=4.0 Hz, 2H), 3.55-3.58 (m, 1H), 3.28 (s, 3H), 3.05 (q, J=16.0 Hz, 1H), 2.82-2.91 (m, 1H).

[0307] (Example 46) Preparation of Compound 535 [ka]

[0308] A round-bottom flask was charged with 5-[(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyrimidin-2-amine (250 mg, 0.3714 mmol) and purged with nitrogen. A solution of tetrabutylammonium fluoride (1 mol / L) in THF (0.5 mL, 0.5 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into a separatory funnel with EtOAc and water. The organics were washed with water, brine and dried over Na2SO4. The organics were concentrated and the residue was purified by preparative HPLC to give compound 535 (150 mg, 0.2684 mmol, 72.26% yield) as a white solid. MS m / z = 559.1 [M+H] + ; 1 H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.22 (S, 2H), 7.58 (d, J =2.0 Hz, 1H), 7.34 (d, J =8.4 Hz, 1H), 7.29 (t, J =6.0 Hz, 1H), 7.11 (dd, J = 8.8 Hz, 2.0 Hz,1H), 6.82 (s, 1H), 4.96 (dd, J = 13.2Hz, 5.2Hz,1H), 4.63 (t, J =5.6 Hz, 1H), 3.57-3.50 (m, 1H), 3.46 (dd, J = 12.0 Hz, 6.0 Hz, 2H),, 3.29 (d, 2H), 3.06-3.01 (m, 1H), 2.88-2.81 (m, 1H).

[0309] (Example 47) Preparation of 2-(5-chloro-4-fluoro-1H-indol-3-yl)ethanamine [ka]

[0310] Step 1: A solution of tert-butyl N-(4-chloro-3-fluoro-phenyl)carbamate (79 g, 321.6 mmol) in anhydrous tetrahydrofuran (640 mL) was cooled using a dry ice / acetone + liquid nitrogen bath, ensuring an internal temperature of -80 °C < T < -75 °C throughout the reaction. n-Butyllithium (2.5 M in hexanes, 405 mL, 1.011 mol) was added over 2 hours while ensuring that the droplets were well dispersed but not splashing. Once the addition was complete, the mixture was stirred for 40 minutes, and a solution of iodine (286 g, 1.127 mol) in anhydrous tetrahydrofuran (430 mL + 100 mL rinse) was added over 3 hours while maintaining an internal temperature of -80 °C < T < -75 °C. The reaction mixture was slowly warmed to -30 °C over 14 hours, at which point almost complete conversion from the starting material to the product was observed. A solution of NH4Cl (41.6 g in 160 mL of water), followed by a solution of NaHSO3 (184.8 g in 560 mL of water), was added while ensuring an internal T < -10 °C. The quenched mixture was warmed to 10 °C with stirring for 1.5 hours, then water (500 mL) was added, and 1370 mL of THF distillate was removed at 40 °C under reduced pressure. The mixture was stirred vigorously at 4 °C for 15 hours and filtered. After washing with water (400 mL), a beige solid was obtained with a colorless filtrate that contained no product according to HPLC. The solid was warm-soaked with hot (65 °C) ethanol (700 mL) for 1 hour and filtered while hot to remove insoluble material (3.5 g) that contained no product according to HPLC. The resulting clear red filtrate was concentrated under vacuum to a volume of 150 mL at 45 °C, at which point solids began to precipitate. Water (32 mL) was added to the stirred mixture, which was then slowly cooled to 4 °C over 1.5 hours. Filtered under vacuum, washed with ethanol / water, 2:1 (250 mL) at 4 °C, and the solid was dried under vacuum at 40 °C for 5 hours to obtain tert-butyl N-(4-chloro-3-fluoro-2-iodo-phenyl)carbamate (C, 103 g, 277.20 mmol, yield 86.206%) as a pale yellow solid.

[0311] Step 2: Phosphoryl chloride (22.0 g, 156 mmol) was added to a solution of DMF (250 mL) at 0° C. under N2 atmosphere. The mixture was warmed to room temperature and stirred for 1 h, then the mixture was cooled back to 0° C. and 5-chloro-4-fluoro-1H-indole (18.4 g, 109 mmol) in 50 mL of DMF was added dropwise to the mixture. The reaction was warmed to room temperature and stirred for 2 h. The reaction was cooled to 0° C. and quenched with 20 mL of 15% aqueous NaOH followed by 50 mL of water. The mixture was heated to 100° C. for 2 h and cooled to room temperature resulting in a slurry. It was filtered and the solid was washed with water and then dried to give the product 5-chloro-6-fluoro-1H-indole-3-carbaldehyde (17.6 g, 89.1 mmol, 82.1% yield) as a yellow solid. MS m / z 198.0[M+H] + .

[0312] Step 3: 5-Chloro-4-fluoro-1H-indole-3-carbaldehyde (9.5 g, 48 mmol) and ammonium acetate (5.0 g, 65 mmol) were dissolved in 80 mL of nitromethane and stirred at 75° C. for 2 h. The mixture was cooled to 0° C., resulting in the formation of a precipitate. The solid was collected by filtration, washed with water, and dried under vacuum to give the product 5-chloro-4-fluoro-3-[(E)-2-nitrovinyl]-1H-indole (10.3 g, 42.8 mmol, 89% yield) as a yellow solid. MS m / z 241.0 [M+H] + .

[0313] Step 4: Lithium aluminum hydride (7.6 g, 200 mmol) was placed in a flask under nitrogen atmosphere and suspended in 50 mL of THF. The mixture was cooled to 0° C. and a solution of 5-chloro-4-fluoro-3-[(E)-2-nitrovinyl]-1H-indole (9.6 g, 40 mmol) in 50 mL of THF was added dropwise. After addition, the mixture was heated to 65° C. and stirred for 2 h. Upon completion, the mixture was cooled to 0° C. and quenched by the addition of 8 mL of water followed by the addition of 8 mL of 15% aqueous NaOH. The mixture was stirred at room temperature for 30 min, then MgSO4 was added and the solids were removed by filtration. The solution was concentrated under reduced pressure to give 2-(5-chloro-6-fluoro-1H-indol-3-yl)ethanamine (8.2 g, 38.5 mmol, 96.4% yield) as a yellow oil. MS m / z 213.4 [M+H] + .

[0314] (Example 48) Preparation of Compound 199 [ka]

[0315] Step 1: A 100 mL round-bottom flask equipped with a reflux condenser was successively charged with 2-(5-chloro-4-fluoro-1H-indol-3-yl)ethanamine (1.8 g, 8.5 mmol), 1-butanol (20 mL), triethylamine (3.5 mL, 25 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.0 g, 11 mmol). The reaction mixture was stirred at reflux for 16 h, after which the volatiles were evaporated under reduced pressure and the resulting dark oily residue was subjected to silica gel chromatography (petroleum ether: EtOAc gradient 0-40%). After purification, N-[2-(5-chloro-4-fluoro-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (2.5 g, 7.0 mmol, 82% yield) was isolated as an off-white amorphous solid.

[0316] Step 2: An 8 mL vial equipped with a stir bar was charged with N-[2-(5-chloro-4-fluoro-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.279 mmol) and 2-butanol (3.0 mL), then 2-chloropyrimidine-5-carbaldehyde (50 mg, 0.351 mmol) was added followed by toxic acid (30 mg, 0.174 mmol) via microsyringe. The vial was stirred at 95° C. for 10 hours. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the resulting dark residue was dissolved in ethyl acetate (1 mL) resulting in the formation of a suspension. The solid was filtered to give crude 6-chloro-1-(2-chloropyrimidin-5-yl)-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (350 mg, 25% purity, 65% yield).

[0317] Step 3: In an 8 mL vial equipped with a stir bar was placed 6-chloro-1-(2-chloropyrimidin-5-yl)-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (350 mg, 0.181 mmol, 25% purity), tetrahydrofuran (5.0 mL), methylamine hydrochloride (63 mg, 0.93 mmol), and triethylamine (815 mg, 8.0 mmol). The reaction mixture was stirred at reflux overnight. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography. Compound 199 (63 mg, 0.132 mmol, 73% yield) was isolated as an off-white solid. MS m / z = 476.0 [MH] - ; 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.25 (s, 2H), 7.27 - 7.23 (m, 1H), 7.18 - 7.12 (m, 3H), 6.78 (s, 1H), 5.07 - 4.94 (m, 1H), 3.45 - 3.38 (m, 1H), 3.09 - 2.93 (m, 2H), 2.75 (d, J = 4.8 Hz, 3H).

[0318] Using the procedures described for compound 199 above, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following (*compounds are isolated as single enantiomers by chromatographic separation using preparative chiral SFC): [Table 49] JPEG2025501285000337.jpg249161 JPEG2025501285000338.jpg249160

[0319] (Example 49) Preparation of Compound 220 [ka]

[0320] Step 1: A 1 L round bottom flask was charged with 4,4-diethoxybutan-1-amine (12.00 g, 74.42 mmol) and (4-chloro-2-iodo-phenyl)hydrazine (20.0 g, 74.49 mmol) in water (200 mL). Sulfuric acid (20 mL, 25.6 mmol, 1.28 mol / L) was added and the reaction mixture was stirred at 100° C. for 8 h. After the reaction mixture was cooled to 25° C., the formed solid was filtered and the pH was adjusted to 7 by addition of NaHCO3. The resulting solid was filtered off and purified by flash chromatography (eluent MeOH / DCM) to give 2-(5-chloro-7-iodo-1H-indol-3-yl)ethanamine (10 g, 31.2 mmol, 42% yield) as an off-white solid.

[0321] Step 2: In a 100 mL round bottom flask equipped with a magnetic stir bar, 2-(5-chloro-7-iodo-1H-indol-3-yl)ethanamine (2.00 g, 6.24 mmol) was placed and suspended in 1-butanol (20 mL). 2-Chloro-4-(trifluoromethyl)pyrimidine (1.50 g, 8.22 mmol) and triethylamine (3.0 mL, 22 mmol) were added, the flask was equipped with a reflux condenser, and the reaction mixture was stirred at reflux for 16 h. After cooling to ambient temperature, the volatiles were removed under reduced pressure and the residue was purified by column chromatography (eluent petroleum ether / ethyl acetate). N-[2-(5-chloro-7-iodo-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (2.2 g, 4.7 mmol, 76% yield) was isolated as an off-white solid.

[0322] Step 3: A 50 mL round bottom flask equipped with a magnetic stir bar was charged with N-[2-(5-chloro-7-iodo-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (0.5 g, 1 mmol), 2-butanol (10 mL, 109 mmol), 2,3-difluoro-4-methyl-benzaldehyde (0.4 g, 3 mmol) and p-toluenesulfonic acid (0.15 g, 0.87 mmol). The flask was equipped with a reflux condenser and the mixture was stirred at 100° C. for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with saturated NaHCO3 (10 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL), the combined organic phases were concentrated under reduced pressure and the residue was subjected to purification by preparative HPLC. After lyophilization, 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-8-iodo-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (0.45 g, 0.74 mmol, 70% yield) was isolated as an amorphous off-white solid.

[0323] Step 4: In a 25 mL three-neck round bottom flask was placed 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-8-iodo-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (150 mg, 0.248 mmol) in 1,4-dioxane (2.0 mL), followed by 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (95 mg, 0.374 mmol), potassium acetate (50 mg, 0.509 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.026 mmol). The reaction was placed under a nitrogen atmosphere and stirred at 100° C. for 16 hours. After cooling to ambient temperature, the reaction mixture was filtered and the volatiles were removed under reduced pressure. The resulting residue was subjected to preparative TLC purification to give 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (150 mg, 0.149 mmol, 60% yield) as an amorphous brownish solid.

[0324] Step 5: A 20 mL vial equipped with a magnetic stir bar was charged with a solution of 6-chloro-1-(2,3-difluoro-4-methyl-phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indole (150 mg, 0.1488 mmol) in tetrahydrofuran (1.5 mL), followed by hydrogen peroxide in water (0.3 mL) and sodium hydroxide (0.2 mL, 0.2 mmol, 1 mol / L). The mixture was stirred at ambient temperature for 10 min, then the mixture was concentrated and the residue was subjected to preparative HPLC purification to give compound 220 (40 mg, 0.081 mmol, 54.3% yield) as a white powder. MS m / z = 493.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 10.05 (s, 1H), 8.79 (d, J = 4.4 Hz, 1H), 7.36 (s, 1H), 7.13 (d, J = 4.8 Hz, 1H), 7.04 - 7.00 (m, 1H), 6.98 (d, J = 5.6 Hz, 1H), 6.68 - 6.64 (m, 1H), 6.52 (d, J = 1.6 Hz, 1H), 4.92 - 4.73 (m, 1H), 3.32 - 3.25 (m, 1H), 2.80 - 2.79 (m, 2H), 2.26 (s, 3H).

[0325] Additional compounds described herein were prepared using the procedures described for compound 220 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following:

[0326] [Table 50]

[0327] (Example 50) Preparation of Compound 325 [ka]

[0328] Step 1: A 500 mL single-neck round-bottom flask was charged with a solution of (4-chloro-3-nitro-phenyl)hydrazine (20.0 g, 107 mmol) in ethanol (200 mL, 3430 mmol), followed by 2-(4,4-diethoxybutyl)isoindoline-1,3-dione (31.0 g, 106 mmol) and sulfuric acid (14.0 mL, 56.0 mmol, 4 mol / L). The mixture was stirred at 50° C. for 3 h, after which the mixture was filtered and the resulting solid was subjected to silica gel purification (petroleum ether:ethyl acetate=3:1) to obtain 2-[(4Z)-4-[(4-chloro-3-nitro-phenyl)hydrazono]butyl]isoindoline-1,3-dione (24.0 g, 62.0 mmol, 58.2% yield) as a yellow solid.

[0329] Step 2: A 250 mL single-neck round-bottom flask was charged with polyphosphoric acid (6.0 g) and acetonitrile (50.0 mL, 954 mmol) and stirred at 60° C. for 10 min, then 2-[(4Z)-4-[(4-chloro-3-nitro-phenyl)hydrazono]butyl]isoindoline-1,3-dione (3.0 g, 7.8 mmol) was added. The mixture was stirred at 90° C. for 30 min. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure to give a dark residue. The residue was treated with saturated aqueous Na2CO3 until the pH reached 8 and extracted with ethyl acetate (3×50.0 mL). The organic phases were combined and concentrated to give a dark residue, which was subjected to purification by silica gel chromatography (eluent dichloromethane:methanol=10:1). 2-[2-(5-chloro-4-nitro-1H-indol-3-yl)ethyl]isoindoline-1,3-dione (1.5 g, 4.1 mmol, 52% yield) was isolated as a yellow solid.

[0330] Step 3: A 100 mL single-neck round-bottom flask was charged with a solution of 2-[2-(5-chloro-4-nitro-1H-indol-3-yl)ethyl]isoindoline-1,3-dione (1.5 g, 4.1 mmol) in ethanol (20.0 mL, 343 mmol) and hydrazine (0.8 mL, 20 mmol). The mixture was stirred at 85° C. for 12 h. After cooling to ambient temperature, the mixture was concentrated to give a residue which was subjected to silica gel chromatography (eluent dichloromethane:methanol=1:1) to give 2-(5-chloro-4-nitro-1H-indol-3-yl)ethanamine (500 mg, 2.086 mmol, 51% yield) as a yellow solid.

[0331] Step 4: A solution of 2-(5-chloro-4-nitro-1H-indol-3-yl)ethanamine (800 mg, 3.338 mmol) in trifluoroacetic acid (1.5 mL, 20 mmol) and 2-morpholinopyrimidine-5-carbaldehyde (2.0 g, 10 mmol) was placed in a reaction tube under nitrogen atmosphere. The mixture was stirred in a microwave reactor at 150° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue that was washed with water, adjusted to pH=8 with aqueous Na2CO3, and then extracted with ethyl acetate (3×50 mL). The combined organic phase was concentrated to give a residue which was subjected to silica gel chromatography (dichloromethane:methanol=1:1) to give 4-[5-(6-chloro-5-nitro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl]morpholine (1.0 g, 2.4 mmol, 72% yield) as a yellow solid.

[0332] Step 5: A 50 mL one-neck round-bottom flask was charged with a solution of 4-[5-(6-chloro-5-nitro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl]morpholine (200 mg, 0.482 mmol) in tetrahydrofuran (10.0 mL), N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 2-chloro-4,6-dimethyl-1,3,5-triazine (210 mg, 1.463 mmol). The mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated to give a dark residue, which was subjected to purification by silica gel chromatography (dichloromethane:methanol = 10:1). Compound 325 (200 mg, 0.383 mmol, 79.5% yield) was isolated as a yellow solid. MS m / z = 521.9 [M+H] + ; 1 H NMR (400 MHz,CD3Cl) δ 8.41 (s, 1H), 8.34 (s, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.10 (s, 1H), 5.13 (d, J = 5.2Hz, 1H), 3.76 (d, J = 4.8 Hz, 4H), 3.72 (d, J = 4.0 Hz, 4H), 3.14 - 3.18 (m, 1H), 2.87 - 2.89 (m, 1H), 2.69 (q, J = 3.2Hz, 1H), 2.42 - 2.48 (m, 6H).

[0333] Additional compounds described herein were prepared using the procedures described for compound 325 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 51]

[0334] (Example 51) Preparation of compound 327 [ka] A 100 mL one-neck round-bottom flask was charged with a solution of 4-[5-[6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-5-nitro-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]morpholine (170 mg, 0.326 mmol) in tetrahydrofuran (10.0 mL), nickel (60 mg, 1.02 mmol) in water (5.0 mL) at 0° C., then hydrazine (23.0 μL, 0.689 mmol) was added, and the mixture was stirred at ambient temperature for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a dark residue, which was purified by column chromatography (eluent dichloromethane:methanol=10:1). Compound 327 (120 mg, 0.244 mmol, 74.9% yield) was isolated as an off-white solid. MS m / z = 492.0 [M+H] + ; 1 H NMR (400 MHz,CD3Cl) δ 8.35 (s, 2H), 7.95 (s, 1H), 7.01 (t, J = 5.4 Hz, 2H), 6.62 (d, J = 8.4 Hz, 1H), 5.13 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.75 (s, 4H), 3.73(s, 4H), 3.12 - 3.23 (m, 3H), 2.49 (m, 6H).

[0335] Additional compounds described herein were prepared using the procedures described for compound 327 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following:

[0336] [Table 52]

[0337] (Example 52) Preparation of Compound 331 [ka]

[0338] A 20 mL vial was charged with 2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-(2-morpholinopyrimidin-5-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-6-amine (100 mg, 0.219 mmol), paraformaldehyde (62 mg, 0.657 mmol), tetrahydrofuran (3 mL, 36.9 mmol) and sodium cyanoborohydride (36 mg, 0.573 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, after which the contents were concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give compound 331 (48 mg, 0.099 mmol, 45% yield). MS m / z = 484.1 [MH] - ; 1 H NMR (DMSO-d6, 400MHz) δ 10.49 (s, 1H), 8.30 (s, 2H), 7.15 - 7.13 (d, J = 8.8 Hz, 1H), 6.87 (s, 1H), 6.78 - 6.74 (m, 2H), 5.04 - 4.99 (dd, J = 4.8 Hz, 13.2Hz, 1H), 3.67 - 3.65 (m, 4H), 3.62 - 3.60 (m, 4H), 3.29 - 3.22 (m, 1H), 2.88 - 2.86 (m, 1H), 2.84 (s, 6H), 2.77 - 2.67 (m, 1H), 2.39 (s, 3H), 2.32 (s, 3H).

[0339] Using the procedures described above for compound 331, additional compounds described herein can be prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 53]

[0340] (Example 53) Preparation of compound 224 [ka]

[0341] A 100 mL three-neck round-bottom flask under argon was charged with a solution of 2-[6-chloro-7-fluoro-1-(4-vinylphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile (200 mg, 0.4652 mmol) in dichloromethane (20 mL), but-3-en-1-ol (200 mg, 2.774 mmol) and Grubbs' second generation catalyst (40 mg, 0.047 mmol). The mixture was stirred at 50° C. for 4 days. The solution was concentrated and the residue was subjected to purification by preparative HPLC to give compound 224 (40 mg, 0.084 mmol, 18% yield) as a white solid. MS m / z = 472.1 [MH] - ; 1 H NMR (DMSO-d6, 400MHz) δ 11.34 (s, 1H), 8.75 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.41 - 7.19 (m, 6H), 7.02 (s, 1H), 6.41 (d, J = 16.0 Hz, 1H), 6.35 - 6.20 (m, 1H), 4.82 (s, 1H), 4.59 (t, J = 5.3 Hz, 1H), 3.56 - 3.42 (m, 2H), 3.27 - 3.17 (m, 1H), 2.91 - 2.73 (m, 2H), 2.37 - 2.22 (m, 2H).

[0342] Additional compounds described herein were prepared using the procedures described for compound 224 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 54]

[0343] (Example 54) Preparation of Compound 240 [ka]

[0344] A 100 mL two-necked round bottom flask equipped with a stir bar under argon was charged with (E)-4-[4-[6-chloro-7-fluoro-2-(5-fluoro-4-methyl-pyrimidin-2-yl)-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]but-3-en-1-ol (30 mg, 0.062 mmol), ethyl acetate (0.5 mL) and platinum(IV) oxide (2 mg, 0.009 mmol). The atmosphere was replaced with hydrogen (1 atm) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was then filtered through a pad of Celite and concentrated under reduced pressure, and the resulting residue was subjected to purification by preparative TLC (ethyl acetate:petroleum ether=1:3) to give compound 240 (25 mg, 0.052 mmol, 83% yield) as a white solid. MS m / z = 481.0 [MH] - ; 1 H NMR (DMSO-d6, 400MHz) δ 11.31 (s, 1H), 8.37 (s, 1H), 7.64 (d, J = 7.2Hz, 1H), 7.30 (d, J = 10Hz, 1H), 7.18 (dd, J = 8.0 Hz, 15.6 Hz, 4H), 7.03 (s, 1H), 4.81 - 4.77 (m, 1H), 4.37 (t, J = 4.8Hz, 1H), 3.38 (dd, J = 6.0 Hz, 12Hz, 2H), 3.19 - 3.12 (m, 1H), 2.79 - 2.77 (m, 2H), 2.54 (d, J = 8.0 Hz, 2H), 2.36 (d, J = 1.6 Hz, 3H), 1.58 - 1.49 (m, 2H), 1.44 - 1.37 (m, 2H).

[0345] Additional compounds described herein were prepared using the procedures described for compound 240 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 55]

[0346] (Example 55) Preparation of compound 223 [ka]

[0347] A 20 mL vial equipped with a septum cap and a magnetic stir bar under argon atmosphere was charged with a solution of methyl 2-[[4-[6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]methoxy]acetate (130 mg, 0.237 mmol) in tetrahydrofuran (2 mL, 24.6 mmol). The vial was placed in a water-ice bath followed by the addition of lithium aluminum hydride (15 mg, 0.395 mmol) at 0° C. The mixture was allowed to warm to 25° C. and stirred for 2 h. The reaction was then quenched by the addition of ammonium chloride. The reaction mixture was concentrated under reduced pressure. The solid was purified by preparative HPLC to give compound 223 (57 mg, 0.109 mmol, 46% yield) as a white solid. MS m / z = 520.9, [M+H] + ; 1 H NMR (DMSO-d6, 400MHz) δ 11.33 (s, 1H), 8.79 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.31 (dd, J = 7.5Hz, 5H), 7.11 (d, J = 5.2Hz, 2H), 4.90 (br, 1H), 4.63 (t, J = 5.4 Hz, 1H), 4.46 (s, 2H), 3.51 (dd, J = 5.2Hz, 2H), 3.43 (t, J = 5.2Hz, 2H), 3.28 (s, 1H), 2.79 - 2.92 (m, 2H).

[0348] (Example 56) Preparation of compound 247 [ka]

[0349] Step 1: In a RBF, (3-bromo-4-chloro-phenyl)hydrazine hydrochloride (2.0 g, 7.8 mmol) and 2-(4,4-diethoxybutyl)isoindoline-1,3-dione (2.4 g, 8.2 mmol) in 6 mL of EtOH were heated to 60° C. for 1 h in the presence of a small amount of water (0.1 mL). After the addition of 0.5 mL of concentrated HCl solution, the mixture was heated to reflux for 14 h. LCMS showed complete consumption of the starting material and the desired product could be detected. The mixture was cooled to room temperature, filtered, and the filtrate was treated with saturated aqueous NaHCO3 to adjust the pH to 8 and extracted three times with ethyl acetate. The extracts were combined, concentrated in vacuo, and then further purified by silica gel column to give 2-[2-(4-bromo-5-chloro-1H-indol-3-yl)ethyl]isoindoline-1,3-dione (800 mg, 1.982 mmol, 26% yield) and 2-[2-(6-bromo-5-chloro-1H-indol-3-yl)ethyl]isoindoline-1,3-dione (800 mg, 1.982 mmol, 26% yield) as yellow solids.

[0350] Step 2: Compound 2-[2-(4-bromo-5-chloro-1H-indol-3-yl)ethyl]isoindoline-1,3-dione (140 mg, 0.3468 mmol) was then treated with hydrazine (80.0 mg, 2.00 mmol) in the presence of 8 mL of EtOH (2.00 mL, 34.3 mmol) and 2 mL of HO at room temperature for 15 h. The volatiles were removed under reduced pressure and the residue was extracted with CHCl (20 mL×3). The combined organic layers were washed with HO, dried, filtered, and then concentrated to give a residue which was purified by flash chromatography using 15% methanol, 1% NHOH in CHCl to give 2-(4-bromo-5-chloro-1H-indol-3-yl)ethanamine (75 mg, 0.27416 mmol, 79.06% yield).

[0351] Step 3: 2-(4-bromo-5-chloro-1H-indol-3-yl)ethanamine (100 mg, 0.36555 mmol) was dissolved in 1-butanol (2.00 mL, 21.8 mmol), then 2-chloro-4-(trifluoromethyl)pyrimidine (80 mg, 0.43828 mmol), triethylamine (75 mg, 0.74118 mmol) were added. The mixture was stirred at 120 °C for 15 h. LCMS showed most of the starting material was consumed, then the organic layer was concentrated by rotovap. The product was purified by flash chromatography (silica): the crude mixture was dissolved in a minimum volume of EtOAc, then loaded onto a column and eluted with EtOAc / hexane to give the target compound N-[2-(4-bromo-5-chloro-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine as a yellow solid.

[0352] Step 4: A three-necked round-bottom flask equipped with a nitrogen inlet was charged with N-[2-(4-bromo-5-chloro-1H-indol-3-yl)ethyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.238 mmol), 4-chlorobenzaldehyde (40 mg, 0.285 mmol), p-toluenesulfonic acid (25 mg, 0.144 mmol) and the solid was suspended in 1-butanol (2 mL). The reaction mixture was stirred at 120° C. for 14 h. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. After purification by preparative HPLC, compound 247 (100 mg, 0.184 mmol, 77% yield) was obtained as a pale yellow solid. MS m / z = 541.0 [M+H] + ; 1H NMR (DMSO-d6, 400MHz) δ 11.60 (s, 1H), 8.80 (d, J = 8.0Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.37 - 7.34 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 4.93 - 4.82 (m, 1H), 3.38 - 3.34 (m, 1H), 3.28 - 3.22 (m, 1H), 3.11 - 2.03 (m, 1H).

[0353] (Example 57) Preparation of Compound 322 [ka] A three-necked round bottom flask equipped with a stir bar was placed under nitrogen atmosphere and charged with 6-chloro-2-(4-chloro-1,3,5-triazin-2-yl)-1-(p-tolyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole (150 mg, 0.366 mmol), iron acetylacetonate (50 mg, 0.137 mmol) and tetrahydrofuran (3 mL, 37 mmol). The reaction mixture was placed in an acetone-dry ice bath and stirred at -78°C. Methylmagnesium chloride in tetrahydrofuran (0.3 mL, 0.9 mmol, 3 mol / L) was then added dropwise and the reaction mixture was stirred at 0°C for 2 h and then at ambient temperature for 16 h. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was concentrated and the resulting residue was purified by preparative HPLC to give compound 322 (35 mg, 0.090 mmol, 25% yield) as a white solid. MS m / z = 390.0 [M+H] + ; 1H NMR (DMSO-d6, 400MHz) δ 11.23 (d, J = 3.2Hz, 1H), 8.57 (d, J = 23.6 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.18 - 7.11 (m, 5H), 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 4.94 - 4.86 (m, 1H), 3.19 - 3.14 (m, 1H), 2.90 - 2.75 (m, 2H), 2.40 (d, J = 4.0 Hz, 3H), 2.27 (s, 3H).

[0354] Additional compounds described herein were prepared using the procedures described for compound 322 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 56]

[0355] (Example 58) Preparation of compound 384 [ka] TIFF2025501285000356.tif49150

[0356] Step 1: 5-Chlorotryptamine hydrochloride (340 mg, 1.5 mmol) and 5-methyl-3-methylsulfonyl-1,2,4-triazine (256 mg, 1.5 mmol) were placed in a vial and dissolved in 10 mL of dioxane. Hunig's base (0.54 mL, 3.1 mmol) was added to the mixture, which was then heated to 80° C. with stirring for 12 hours. The solution was concentrated in vacuo and the crude material was purified by silica gel chromatography to give N-[2-(5-chloro-1H-indol-3-yl)ethyl]-5-methyl-1,2,4-triazin-3-amine (256 mg, 0.87 mmol, 57% yield) as a white solid.

[0357] Step 2: N-[2-(5-chloro-1H-indol-3-yl)ethyl]-5-methyl-1,2,4-triazin-3-amine (250 mg, 0.87 mmol), 2-morpholinopyrimidine-5-carbaldehyde (176 mg, 0.91 mmol) and p-toluenesulfonic acid (76 mg, 0.43 mmol) were placed in a vial, sealed and flushed with Ar. Dissolved in 10 mL of 2-BuOH and heated to 100° C. for 18 h. Then cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography to give compound 384 as a white solid, (120 mg, 0.26 mmol, 30% yield). MS m / z = 463.3, [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.23 - 10.83 (m, 1H), 8.64 (t, J = 3.7 Hz, 1H), 8.35 (t, J = 3.5 Hz, 2H), 7.55 (d, J = 4.6 Hz, 1H), 7.40 - 7.24 (m, 1H), 7.10 (t, J = 6.9 Hz, 1H), 6.92 (s, 1H), 5.05 (d, J = 13.3 Hz, 1H), 4.04 - 3.50 (m, 8H), 3.40 (t, J = 11.7 Hz, 1H), 2.89 (dd, J = 38.6, 14.1Hz, 2H), 2.41 (s, 3H).

[0358] (Example 59) Preparation of compound 383 [ka] JPEG2025501285000358.jpg53166

[0359] Step 1: 5-Chlorotryptamine hydrochloride (2 g, 8.7 mmol) was added to a vial containing 3-methylsulfanyl-5-(trifluoromethyl)-1,2,4-triazine (100 mg, 0.5 mmol%) and dissolved in 5 mL of n-BuOH, then Hunig's base (0.22 mL, 1.3 mmol) was added to the mixture. The vial was sealed, flushed with Ar, and heated to 120° C. for 18 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography to give N-[2-(5-chloro-1H-indol-3-yl)ethyl]-5-(trifluoromethyl)-1,2,4-triazin-3-amine (111 mg, 0.3 mmol, 63% yield) as a white solid.

[0360] Step 2: N-[2-(5-chloro-1H-indol-3-yl)ethyl]-5-(trifluoromethyl)-1,2,4-triazin-3-amine (111 mg, 0.32 mmol), 2-morpholinopyrimidine-5-carbaldehyde (65 mg, 0.34 mmol) and p-toluenesulfonic acid (28 mg, 0.16 mmol) in a vial were flushed with Ar and dissolved in 3 mL of 2-BuOH. Stirred at 100° C. for 18 h, then cooled to room temperature, concentrated in vacuo and precipitated from methanol. Compound 383 (45 mg, 0.09 mmol, 27% yield) was obtained as a white solid. MS m / z = 517.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.23 (t, J = 3.6 Hz, 1H), 8.36 (d, J = 3.9 Hz, 2H), 7.58 (d, J = 4.4 Hz, 1H), 7.36 - 7.17 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.79 (br s, 1H), 3.88 - 35.09, (br s, 1H).49 (m, 9H), 3.09 - 2.77 (m, 2H).

[0361] Additional compounds described herein were prepared using the procedures described for compound 383 above, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 57]

[0362] (Example 60) Preparation of compound 538 [ka]

[0363] Step 1. In a 50 mL RBF, 6-chloro-1-(2-chloropyrimidin-5-yl)-4,9-dihydro-3H-pyrido[3,4-b]indole (500 mg, 1.58 mmol) in acetonitrile (10 mL) was added along with methyl 4-aminobutanoate hydrochloride (400 mg, 2.6 mmol) and Hunig's base (0.9 mL, 5 mmol). The mixture was stirred at 50° C. for 5 hours, diluted with ethyl acetate (50 mL), washed with water (20 mL×3) and brine (20 mL×2), dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by flash chromatography (eluent: NH3 in DCM / MeOH = 90 / 10) to give methyl 4-[[5-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl]amino]butanoate (450 mg, 1.13 mmol, 71.7% yield) as a white solid material.

[0364] Step 2. In a 50 mL RBF equipped with a N2 inlet, methyl 4-[[5-(6-chloro-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)pyrimidin-2-yl]amino]butanoate (450 mg, 1.13 mmol), formate triethylamine complex 5:2 (1.0 mL, 2.4 mmol) and acetonitrile (25 mL) were added at 25 °C. RuCl[(R,R)-TsDPEN] (mesitylene) (14 mg, 0.02 mmol) was added and the mixture was stirred for 16 h. The mixture was quenched with a saturated aqueous solution of NaHCO3, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo. The residue was purified by flash chromatography (eluent: NH3 in DCM / MeOH = 92 / 8) to give methyl 4-[[5-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]amino]butanoate (330 mg, 0.82 mmol, 73% yield) as a brown solid material.

[0365] Step 3. In a 50 mL RBF was added a solution of methyl 4-[[5-[(1S)-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]amino]butanoate (330 mg, 0.83 mmol) in acetonitrile (20 mL), 2-(trichloromethyl)-4,6-bis(trifluoromethyl)-1,3,5-triazine (331 mg, 0.99 mmol) and DMAP (100 mg, 0.82 mmol). The mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (eluent: PE / EA=75 / 25) to give methyl 4-[[5-[(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]amino]butanoate (350 mg, 0.57 mmol, 69% yield) as a white solid material.

[0366] Step 4. In a 25 mL RBF, methyl 4-[[5-[(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyrimidin-2-yl]amino]butanoate (200 mg, 0.33 mmol), water (2 mL), THF (2 mL) and lithium hydroxide monohydrate (34 mg, 0.81 mmol) were added at room temperature. The mixture was stirred for 3 h. The mixture was adjusted to pH=6-7 by adding 1N HCl and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by preparative HPLC to give compound 538 (120 mg, 0.20 mmol, 61% yield) as a white solid material. MS m / z = 600.8 [M+H] + ; 1 H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.20 (s, 2H), 7.57 (d, J = 2.4 Hz, 1H), 7.48 (t, J = 5.6Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.10 (dd, J = 8.8, 2.0 Hz, 1H), 6.81 (s, 1H), 4.95 (dd, J = 13.2, 5.2Hz, 1H), 3.49-3.56 (m, 1H), 3.24 (q, J = 13.0, 6.8 Hz, 2H), 3.02 (dd, J = 15.2, 3.2Hz, 1H), 2.80-2.88 (m, 1H), 2.23 (t, J = 7.2Hz, 2H), 1.66-1.73 (m, 2H).

[0367] Additional compounds described herein were prepared using the procedures described above for compound 538, substituting the appropriate starting materials, suitable reagents, and reaction conditions to provide compounds such as those selected from the following: [Table 58]

[0368] Biological Examples The following in vitro biological examples demonstrate the utility of the described compounds as DHODH inhibitors. In order to describe the present description in more detail and to facilitate understanding of the present description, the following biological examples are provided to illustrate the scope of the present description, but should not be construed as limiting the scope of the present description. Such variations of the present description that may be currently known or may be developed in the future, which would be within the scope of the recognition of a person skilled in the art, are considered to be within the scope of the present description and the scope described in the claims.

[0369] (Example 61) MOLM-13 cell proliferation assay The following assay was performed to measure the proliferation of MOLM-13 cells in the presence of each compound studied. This assay was included as an indicator of DHODH inhibition because MOLM-13 cell growth is known to depend on the synthesis of pyrimidines using the de novo pathway, which can be blocked by inhibition of DHODH. 1. MOLM-13 cells were cultured in RPMI 1640 medium + 10% fetal bovine serum (FBS). Only low passage cells (<20) were used for compound testing. 2. On day 1, log-phase growing Molm-13 cells were counted and cultured at 10 5 Diluted to cells / mL. 3. Add 100 µL of diluted MOLM-13 cells to a 96-well white plate at 10 4 Cells were seeded to a final density of 100 cells / well. 4. 0.5 μL of 200× pre-diluted compound or DMSO control was added to each well. Final DMSO concentration was 0.5%. 5. After 72 hours of incubation at 37° C., 5% CO2, the plates were removed and cooled to room temperature, then 50 μL of CellTiter-Glo® (Promega) was added and the composition was mixed for 10 minutes at room temperature. 6. The plate was then read on a ViewLux (Speed-fast, Gain-high, Binning-1x, 5 seconds).

[0370] As shown in Table 1, the IC 50 (nM) was calculated for each compound (Cpd). [Table 59] JPEG2025501285000363.jpg250141 JPEG2025501285000364.jpg250139 JPEG2025501285000365.jpg199146

[0371] Example 62 -MOLM-13 Uridine Rescue Assay Some compounds were also tested in a uridine rescue assay. In the uridine rescue assay, additional plates of MOLM-13 cell cultures were prepared using the procedure in Example 1 above, to which 100 μM uridine was added in step 3 of the process. The IC 50 (nM) Results are shown in Table 2 below.

[0372] [Table 60]

[0373] Results of the above uridine rescue assay for all compounds tested in the presence of uridine rescued cell growth in the MOLM assay compared to the absence of uridine (see Table 1). These results indicate that the compounds described herein function as DHODH inhibitors in the de novo pyrimidine synthesis pathway.

[0374] While certain embodiments have been described in detail above, those skilled in the art will clearly understand that numerous modifications are possible without departing from those teachings and are intended to be encompassed within the scope of the claims set forth herein.

Claims

1. A compound of formula (I) or a form thereof, wherein the form of the compound is selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer thereof. 【Chemistry 1】 (In the formula, R 1 is hydrogen, deuterium, amino, nitro or fluoro; R 2 Ha, Haro, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy, (C 1-4 Alkyl) 2 amino, pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl; R 3 is hydrogen, deuterium, amino or fluoro; R 4 is hydrogen, amino or hydroxy, Q 1 is CR 5 or N, Q 2 is CR 6 or N, Q 1 and Q. 2 cannot be simultaneously N, R 5 and R 7 is hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl) 2 Amino, C 1-4 alkoxycarbonyl, phenyl, and heterocyclyl, where heterocyclyl is a saturated or partially unsaturated 3- to 7-membered monocyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, and phenyl and heterocyclyl are each independently selected from 1, 2, or 3 R 12 may be substituted with a substituent; R 6 is hydrogen, deuterium, halo, C 1-6 Alkyl, halo-C 1-4 alkyl, phenyl or morpholinyl; Q 2 If N, then R 5 and R 6 is not a halo, R 5 , R 6 and R 7 cannot all become hydrogen at the same time, Q 3 is CR 8 or N, R 8 is hydrogen or deuterium, R 9 is hydrogen, deuterium, halo, cyano, hydroxy, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl) 2 Amino, (C 1 - 4 Alkyl) 2 Amino (C 1 - 4 alkyl)amino, C 1-4 Alkylthio, C 1-4 Alkyl-sulfonyl, amino-sulfonyl, C 1 - 4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkoxy, (C 1-4 alkoxy)carbonyl, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, Hydroxy C 1-4 Alkoxy C 1-4 Alkyl, carboxyl-C 1-4 Alkyl, carboxyl - C 1-4 Alkyl - Amino, carboxyl - C 1-4 Alkoxy - C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an aromatic 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic, 7-8 membered bicyclic, or 13-16 membered polycyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O or S, and each heteroaryl or heterocyclyl is selected from 1, 2 or 3 R 12 may be substituted with a substituent; Q 4 is CR 10 or N, R 10 is hydrogen, deuterium, fluoro or hydroxy; R 11 is hydrogen, deuterium, fluoro or hydroxy; R 8 , R 9 , R 10 and R 11 cannot simultaneously become hydrogen, R 12 is halo, hydroxy, C 1-6 Alkyl or C 3-6 cycloalkyl)

2. R 2 The compound of claim 1, wherein is pyrrolyl, pyrazolyl, 3-methyl-pyrazolyl, 4-methyl-pyrazolyl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazolyl-2-yl.

3. R 2 But, Halo, C 1-4 Alkyl, C 2-4 Alkenyl, Nitro, C 1-4 Alkoxy or (C 1 - 4 Alkyl) 2 The compound of claim 1 which is amino.

4. R 2 is chloro, fluoro, bromo, methyl, ethyl, ethenyl, nitro, methoxy, dimethyl-amino, 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 3-methyl-1H-pyrazol-1-yl, 4-methyl-1H-pyrazol-1-yl, 2H-1,2,3-triazol-2-yl, or 4-methyl-2H-1,2,3-triazol-2-yl.

5. R 5 and R 7 is hydrogen, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, Hydroxy-C 1-4 Alkyl, C 1-4 Alkyl-thio, C 1-4 Alkoxy, amino, (C 1-4 Alkyl) 2 Amino, C 1-4 alkoxycarbonyl, phenyl, or heterocyclyl, where heterocyclyl is selected from morpholinyl, piperazinyl, and azetidinyl, and heterocyclyl is selected from one, two, or three R 12 The compound according to claim 1, which may be substituted with a substituent.

6. R 5 and R 7 is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, isopropyl, fluoro-methyl, difluoro-methyl, trifluoromethyl, trichloromethyl, hydroxy-methyl, methyl-thio, methoxy, butoxy, amino, N,N-dimethyl-amino, N-methyl-N-butyl-amino, N,N-dibutyl-amino, methoxy-carbonyl, butoxy-carbonyl, phenyl, morpholinyl, 3,3-difluoro-azetidin-1-yl, 1-methylpiperazin-4-yl, or phenyl.

7. R 6 The compound of claim 1 , wherein is hydrogen, chloro, fluoro, bromo, methyl, trifluoromethyl, or phenyl.

8. R 9 But hydrogen, deuterium, halo, cyano, C 1-4 Alkyl, halo-C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkylcarbonyl, amino, (C 1-4 alkyl)amino, (C 1-4 Alkyl) 2 Amino, (C 1-4 Alkyl) 2 Amino (C 1-4 alkyl)amino, C 1-4 Alkylthio, C 1 - 4 Alkyl-sulfonyl, amino - Sulfonyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, (C 1-4 Alkoxy) carbonyl, hydroxy C 1-4 Alkyl, Hydroxy C 2-4 Alkenyl, Hydroxy C 1-4 Alkylamino, (C 1-4 Alkoxy)carbonyl C 1-4 Alkyl, Hydroxy C 1-4 Alkoxy C 1-4 Alkyl, carboxyl-C 1-4 Alkyl, carboxyl-C 1-4 Alkylamino, Carboxyl-C 1-4 Alkoxy-C 1-4 Alkylamino, C 3-6 cycloalkyl, heteroaryl or heterocyclyl, where heteroaryl is an unsaturated 5-6 membered monocyclic ring having 1, 2 or 3 heteroatom ring members independently selected from N, O, or S, and heterocyclyl is a saturated or partially unsaturated 7-8 membered bicyclic ring system having 1, 2 or 3 heteroatom ring members independently selected from N, O, or S, and each heterocyclyl or heteroaryl is selected from 1, 2 or 3 R 12 The compound according to claim 1, which may be substituted with a substituent.

9. R 9 is hydrogen, fluoro, chloro, bromo, cyano, methyl, isopropyl, trifluoromethyl, ethenyl, methylcarbonyl, amino, lN-methylamino, N,N-dimethylamino, N-[(N,N-dimethylamino)ethyl]amino, methyl-thio, methyl-sulfonyl, amino-sulfonyl, methoxy, methoxy-ethoxy, methoxycarbonyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, 1-hydroxy-but-3-en-4-yl, N-(hydroxyethyl)amino, methoxy-carbonyl-ethyl, hydroxy-ethoxy-methyl, carboxy-ethyl, carboxy-propyl, N-(carboxy-ethyl)amino, N-(carboxy-propyl)amino, N-(carboxy-methoxy-ethyl)a imino, cyclopropyl, 1H-imidazolyl, 1H-pyrazolyl, 1H-1,2,4-triazolyl, morpholinyl, piperazinyl, 4-methyl-piperazinyl, 3,3-dimethyl-piperazinyl, azetidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, (1S,4S)- ... The compound of claim 1, which is cyclo[2.2.1]heptanyl, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptanyl, (3R,5S)-3,5-dimethylpiperazinyl, (3R)-3-methylpiperazinyl, (3S)-3-methylpiperazinyl, 4,7-diazaspiro[2.5]octanyl, or 2-oxa-6-azaspiro[3.3]heptanyl.

10. 6-chloro-2-(5-chloropyrimidin-2-yl)-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-fluorophenyl)-2-(5-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-chloropyrimidin-2-yl)-7-fluoro-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4,6-dichloropyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-1-(6-methoxypyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-fluorophenyl)-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-chloropyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chlorophenyl)-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,4-difluorophenyl)-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 6-chloro-2-(4-chloropyrimidin-2-yl)-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-N,N-dimethylpyrimidin-2-amine; 6-chloro-2-(4-chloropyrimidin-2-yl)-7-fluoro-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4,6-dichloropyrimidin-2-yl)-7-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-[6-chloro-7-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-N,N-dimethylpyrimidin-4-amine; 4-[6-chloro-2-(4-chloropyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-7-fluoro-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-2-(5-fluoropyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-chloropyrimidin-2-yl)-5-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-ethylpyrimidin-2-yl)-7-fluoro-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-fluorophenyl)-2-[4-(propan-2-yl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-fluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-7-fluoro-1-(4-fluorophenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 6-chloro-1-(4-chlorophenyl)-5-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chlorophenyl)-2-(5-chloropyrimidin-2-yl)-5-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-chloropyrimidin-2-yl)-5-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chlorophenyl)-2-(5-chloropyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(2-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-cyclopropylphenyl)-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 4-[6-chloro-8-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 5-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-N,N-dimethylpyridin-2-amine; 6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-1-[4-(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(3,4-difluorophenyl)-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chlorophenyl)-7-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chlorophenyl)-2-(4-chloropyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(4-chlorophenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 6-chloro-2-(5-chloropyrimidin-2-yl)-7-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-methylphenyl)-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-chloropyrimidin-2-yl)-7-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-7-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 6-chloro-1-(4-cyclopropylphenyl)-7-fluoro-2-(pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-chloro-6-methylpyrimidin-2-yl)-7-fluoro-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(6-fluoropyridin-3-yl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]pyridin-2-ol; 6-chloro-2-(5-chloropyrimidin-2-yl)-5-fluoro-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-1-[4-(propan-2-yl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-(4-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[6-chloro-2-(5-chloropyrimidin-2-yl)-5-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 6-chloro-2-(4-chloropyrimidin-2-yl)-7-fluoro-1-[4-(propan-2-yl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(4-methylpyrimidin-2-yl)-1-[4-(propan-2-yl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{6-chloro-7-fluoro-1-[4-(propan-2-yl)phenyl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}pyrimidine-4-carbonitrile; 4-[6-chloro-5-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 6-chloro-2-(5-chloropyrimidin-2-yl)-7-fluoro-1-[4-(propan-2-yl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(3-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[6-chloro-2-(5-chloropyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 6-chloro-5-fluoro-1-(4-fluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[6-chloro-7-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 6-chloro-2-(5-chloropyrimidin-2-yl)-5-fluoro-1-[4-(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(4-cyanophenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; {4-[6-chloro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}methanol; 6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-7-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-2-(5-fluoropyrimidin-2-yl)-1-[4-(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluorophenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 4-[2-(4-bromopyrimidin-2-yl)-6-chloro-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 6-chloro-1-(4-chlorophenyl)-5-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-ethenylphenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chlorophenyl)-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-[4-(trifluoromethyl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-[4-(trifluoromethyl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-chloropyrimidin-2-yl)-1-(2,3-difluorophenyl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; {4-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}methanol; 6-chloro-1-(4-ethenylphenyl)-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-chloropyrimidin-2-yl)-7-fluoro-1-[4-(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(4-methylpyrimidin-2-yl)-1-[4-(trifluoromethyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5,6-difluoro-2-(5-fluoropyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5,6-difluoro-1-(4-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-(5-chloropyrimidin-2-yl)-5,6-difluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-(5-chloropyrimidin-2-yl)-5,6-difluoro-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{4-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}ethan-1-ol; Methyl 2-[6-chloro-1-(4-chlorophenyl)-5-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carboxylate; 4-{6-chloro-7-fluoro-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}benzonitrile; 4-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}benzonitrile; 6-chloro-5-fluoro-1-(4-fluorophenyl)-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-1-(2-methylpyrimidin-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(2-methylpyrimidin-5-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 5-[6-chloro-7-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-N,N-dimethylpyrimidin-2-amine; 5-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-N,N-dimethylpyrimidin-2-amine; 6-chloro-7-fluoro-1-(4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-methylphenyl)-2-[5-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-fluorophenyl)-2-[5-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-[4-(propan-2-yl)phenyl]-2-[5-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}benzonitrile; 6-chloro-2-(5-chloropyrimidin-2-yl)-7-fluoro-1-(2-methylpyrimidin-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-[6-chloro-2-(5-chloropyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-N,N-dimethylpyrimidin-2-amine; 6-chloro-7-fluoro-1-[4-(methanesulfonyl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; Methyl 2-[6-chloro-1-(4-cyanophenyl)-5-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carboxylate; 6-chloro-7-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-1-[4-(methanesulfonyl)phenyl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-5-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methylpyrimidine-4-carbonitrile; 2-[6-chloro-5-fluoro-1-(4-fluorophenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methylpyrimidine-4-carbonitrile; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-5-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}benzene-1-sulfonamide; 6-chloro-5-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-5-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methoxyphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{6-chloro-7-fluoro-1-[4-(trifluoromethyl)phenyl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}pyrimidine-4-carbonitrile; 5-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-N,N-dimethylpyridin-2-amine; 6-chloro-7-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-[6-chloro-7-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-N,N-dimethylpyridin-2-amine; 4-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzene-1-sulfonamide; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-2-(4,6-dimethylpyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-chloropyrimidin-2-yl)-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-chloropyrimidin-2-yl)-1-(2,3-difluorophenyl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-[5-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(4-methylphenyl)-2-(5-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-(4-methylphenyl)-2-(5-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-(5-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-(5-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-[5-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chloro-2,3-difluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-7-fluoro-1-(5-fluoropyridin-3-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-(5-fluoropyridin-3-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-[4-(methanesulfonyl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}benzene-1-sulfonamide; 2-[6-chloro-7-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methylpyrimidine-4-carbonitrile; 2-[6-chloro-1-(2,3-difluorophenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methylpyrimidine-4-carbonitrile; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methylpyrimidine-4-carbonitrile; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-7-fluoro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 3-(4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenyl)propan-1-ol; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-3-fluoro-N,N-dimethylpyridin-2-amine; 3-{4-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}propan-1-ol; 5-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-3-fluoro-N,N-dimethylpyridin-2-amine; (1S)-6-chloro-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoropyrimidine-4-carbonitrile; 6-chloro-7-fluoro-1-(4-methylphenyl)-2-(4,5,6-trimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; Methyl 3-(4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenyl)propanoate; Methyl 3-{4-[6-chloro-7-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}propanoate; (4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenyl)methanol; (3E)-4-(4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenyl)but-3-en-1-ol; 4-(4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenyl)butan-1-ol; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-2-(4,5,6-trimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-N,N-dimethylaniline; 6-chloro-1-(2,3-difluorophenyl)-7-fluoro-2-(4,5,6-trimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(4-bromo-2,3-difluorophenyl)-6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-2,3-difluoro-N,N-dimethylaniline; 5-fluoro-6-methyl-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-7-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoropyrimidine-4-carbonitrile; 2-[(1R)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 5-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-N,N-dimethylpyridin-2-amine; 5-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-N,N-dimethylpyrimidin-2-amine; (1R)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1R)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1R)-6-chloro-1-(4-chlorophenyl)-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(4-chlorophenyl)-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluorophenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoropyrimidine-4-carbonitrile; 6-chloro-1-(2,6-difluoropyridin-3-yl)-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1R)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,6-difluoropyridin-3-yl)-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1R)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}benzonitrile; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1R)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-(pyrimidin-5-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-5-fluoro-6-methyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-5-fluoro-1-[2-(1H-imidazol-1-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-[6-chloro-5-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-N,N-dimethylpyridin-2-amine; 6-chloro-2-(5-chloropyrimidin-2-yl)-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 5-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-N-methylpyrimidin-2-amine; 6-chloro-5-fluoro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-[6-chloro-5-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-N,N-dimethylpyrimidin-2-amine; 6-chloro-5-fluoro-1-(pyridin-3-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1R)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-5-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-ol; 5-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-6-fluoro-N,N-dimethylpyridin-2-amine; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-6-fluoro-N,N-dimethylpyridin-2-amine; 6-chloro-5-fluoro-2-(5-fluoropyrimidin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 5-[6-chloro-5-fluoro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]pyrimidin-2-amine; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoropyrimidine-4-carbonitrile; 2-[6-chloro-7-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4,6-dicarbonitrile; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4,6-dicarbonitrile; 2-[6-chloro-5-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoropyrimidine-4-carbonitrile; 2-chloro-5-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenol; 2-chloro-5-[6-chloro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenol; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-ol; 5-chloro-2-[6-chloro-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenol; 5-chloro-2-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenol; 2-[(4-{6-chloro-7-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenyl)methoxy]ethan-1-ol; 2-(6-chloro-7-fluoro-1-{4-[(1E)-4-hydroxybut-1-en-1-yl]phenyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)pyrimidine-4-carbonitrile; 5-{6-chloro-5-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidin-2-amine; 6-chloro-5-fluoro-1-(2-fluoropyridin-3-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluorophenyl)-7-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4,6-dicarbonitrile; 2-[6-chloro-5-fluoro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4,6-dicarbonitrile; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4,6-dicarbonitrile; 6-chloro-5-fluoro-1-[2-(1H-1,2,4-triazol-1-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-fluoro-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methylpyrimidine-4-carbonitrile; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-(6-chloro-5-fluoro-1-{4-[(1E)-4-hydroxybut-1-en-1-yl]phenyl}-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)pyrimidine-4-carbonitrile; (3E)-4-{4-[6-chloro-5-fluoro-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}but-3-en-1-ol; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(5-fluoropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (3E)-4-{4-[6-chloro-7-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}but-3-en-1-ol; 4-{4-[6-chloro-7-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}butan-1-ol; (3E)-4-{4-[6-chloro-5-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}but-3-en-1-ol; (3E)-4-{4-[6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-5-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}but-3-en-1-ol; (3E)-4-{4-[6-chloro-5-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}but-3-en-1-ol; (3E)-4-{4-[6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}but-3-en-1-ol; 4-{4-[6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}butan-1-ol; 4-{4-[6-chloro-5-fluoro-2-(5-fluoro-4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}butan-1-ol; 5-bromo-6-chloro-1-(4-chlorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 4-{4-[6-chloro-7-fluoro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl}butan-1-ol; 6-chloro-1-(4-chlorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-ol; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-6-fluorophenol; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2-fluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-3-fluorobenzonitrile; 3-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-2-fluorophenol; 2-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-5-methylphenol; 5-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-2-methylphenol; 6-chloro-1-(2-fluoro-3-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[4-(1H-imidazol-1-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[4-(1H-pyrazol-1-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[4-(morpholin-4-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-1-(2,3,4-trifluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-bromo-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(4-methylphenyl)-6-nitro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-5-nitro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chloro-2-fluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(4-bromo-2-fluorophenyl)-6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[4-(4H-1,2,4-triazol-4-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(4-bromo-2,3-difluorophenyl)-6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-6-methyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-6-methyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-amine; 6-chloro-1-[2-fluoro-4-(1H-imidazol-1-yl)phenyl]-2-(pyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-fluoro-4-(1H-imidazol-1-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-6-methyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-ol; 6-chloro-1-[2-fluoro-4-(morpholin-4-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}-2,3-difluorobenzonitrile; 6-chloro-1-[2,3-difluoro-4-(morpholin-4-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; Butyl 2-[6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carboxylate; Butyl 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carboxylate; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-amine; 1-(4-bromo-2,3-difluorophenyl)-6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2,3-difluoro-4-(morpholin-4-yl)phenyl]-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2,3-difluoro-4-(1H-imidazol-1-yl)phenyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(4-methylphenyl)-6-(2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-N,N,6-trimethyl-1,3,5-triazin-2-amine; 6-ethenyl-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-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-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-methyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-[4-methyl-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-N,N-dimethyl-1,3,5-triazin-2-amine; 6-bromo-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-bromo-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(1H-pyrazol-1-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-Methoxy-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 1-(2,3-difluoro-4-methylphenyl)-6-nitro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-N,N-dimethylpyrimidin-4-amine; 2-[6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-N,N-dimethylpyrimidin-4-amine; 6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-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-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-amine; 6-chloro-2-(4-methylpyrimidin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-nitro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(1H-pyrrol-1-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; N,N-dibutyl-4-{6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-6-methyl-1,3,5-triazin-2-amine; 1-[6-(morpholin-4-yl)pyridin-3-yl]-6-(2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; N-butyl-4-{6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-N,6-dimethyl-1,3,5-triazin-2-amine; 2-(4-butoxy-6-methyl-1,3,5-triazin-2-yl)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,6-dichloropyridin-3-yl)-2-[4-(trifluoromethyl)pyrimidin-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-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-amine; 6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 6-chloro-1-(4-methylphenyl)-2-(4-methyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-nitro-2-[4-(trifluoromethyl)pyrimidin-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-[6-(morpholin-4-yl)pyridin-3-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-(morpholin-4-yl)pyrimidin-5-yl]-5-nitro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-5-nitro-2-[4-(trifluoromethyl)pyrimidin-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-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-amine; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-5-amine; N,N-dimethyl-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-amine; 1-(2,3-difluoro-4-methylphenyl)-N,N-dimethyl-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-amine; 2-(4,6-dimethyl-1,3,5-triazin-2-yl)-N,N-dimethyl-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-6-amine; 6-chloro-1-(4-methylphenyl)-2-(4-methylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-nitro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-ol; 6-chloro-2-[4-(difluoromethyl)pyrimidin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-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-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-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-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-5-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-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-ol; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2-fluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-[2-(azetidin-1-yl)pyrimidin-5-yl]-6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-[2-(azetidin-1-yl)pyrimidin-5-yl]-6-chloro-2-(4,6-dimethyl-1,3,5-triazin-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-(methylsulfanyl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-ol; 6-chloro-1-(4-chlorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4,6-dimethylpyrimidin-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(4-methylpyrimidin-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-amine; 6-chloro-2-(4-methylpyrimidin-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}phenol; 6-chloro-1-(3-fluoro-4-methylphenyl)-2-[4-(trifluoromethyl)pyrimidin-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-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}pyrimidine-4-carbonitrile; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}pyrimidine-4-carbonitrile; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-6-methylpyrimidine-4-carbonitrile; 2-[6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 6-chloro-2-(5-fluoropyrimidin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-fluoro-4-methylpyrimidin-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-fluoro-4-methylpyrimidin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-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-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-8-ol; 6-chloro-1-(3-fluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-{6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridin-3-yl}-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-{6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridin-3-yl}-2-[4-(trifluoromethyl)pyrimidin-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-{6-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridin-3-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-{6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridin-3-yl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4-carbonitrile; 2-[6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methylpyrimidine-4-carbonitrile; 6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-fluoropyrimidin-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[5-(trifluoromethyl)-1,2,4-triazin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-(5-methyl-1,2,4-triazin-3-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoropyrimidine-4-carbonitrile; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(methylsulfanyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)-1,3,5-triazine-2-carbonitrile; 6-chloro-1-[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoropyrimidine-4-carbonitrile; (1S)-6-chloro-2-(5-fluoropyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-(5-fluoro-4-methylpyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-1-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{(1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-5-fluoropyrimidine-4-carbonitrile; 2-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]pyrimidine-4,6-dicarbonitrile; 2-{(1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}pyrimidine-4,6-dicarbonitrile; 4-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-1,3,5-triazine-2-carbonitrile; 2-{(1S)-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-5-fluoropyrimidine-4-carbonitrile; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(5-fluoropyrimidin-2-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-(4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[5-(trifluoromethyl)-1,2,4-triazin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-methyl-1,3,5-triazine-2-carbonitrile; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoro-6-methylpyrimidine-4-carbonitrile; 4-{(1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-1,3,5-triazine-2-carbonitrile; 4-{(1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-6-methyl-1,3,5-triazine-2-carbonitrile; 2-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)pyrimidine-4-carbonitrile; 2-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-5-fluoro-6-methylpyrimidine-4-carbonitrile; (1S)-6-chloro-1-(4-methylphenyl)-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)pyrimidin-2-yl]-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{(1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-5-fluoro-6-methylpyrimidine-4-carbonitrile; 6-chloro-1-(4-fluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,4-difluorophenyl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{(1S)-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-5-fluoro-6-methylpyrimidine-4-carbonitrile; 2-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)pyrimidine-4-carbonitrile; 4-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)-1,3,5-triazin-2-amine; 4-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)-1,3,5-triazin-2-amine; 6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2-[4-(morpholin-4-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2-[5-(trifluoromethyl)-1,2,4-triazin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-methylphenyl)-2-[5-(trifluoromethyl)-1,2,4-triazin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[6-(trifluoromethyl)-1,2,4-triazin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-fluoro-6-(morpholin-4-yl)pyridin-3-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-{(1S)-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-6-(trifluoromethyl)pyrimidine-4-carbonitrile; 2-{(1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-6-(trifluoromethyl)pyrimidine-4-carbonitrile; 4-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-N,N-dimethyl-6-(trifluoromethyl)-1,3,5-triazin-2-amine; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[(1S)-6-chloro-1-(4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-N,N-dimethyl-6-(trifluoromethyl)-1,3,5-triazin-2-amine; (1S)-6-chloro-1-(4-methylphenyl)-2-[4-(morpholin-4-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{(1S)-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-N,N-dimethyl-6-(trifluoromethyl)-1,3,5-triazin-2-amine; 4-{(1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl}-N,N-dimethyl-6-(trifluoromethyl)-1,3,5-triazin-2-amine; (1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(morpholin-4-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2-[4-(morpholin-4-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-{6-chloro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}benzonitrile; 4-[6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzonitrile; 6-chloro-1-(4-chlorophenyl)-2-(4,6-dimethyl-1,3,5-triazin-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-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,4-difluorophenyl)-2-(4,6-dimethyl-1,3,5-triazin-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-fluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 4-[6-chloro-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]-3-fluorobenzonitrile; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-[6-(morpholin-4-yl)pyridin-3-yl]-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-(4-methyl-2H-1,2,3-triazol-2-yl)-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-[4-(3,3-difluoroazetidin-1-yl)pyrimidin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-[4-(3,3-difluoroazetidin-1-yl)-6-methyl-1,3,5-triazin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[6-(trifluoromethyl)-1,2,4-triazin-3-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-fluoro-6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-(5-bromopyrimidin-2-yl)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(4-methylphenyl)-2-[4-methyl-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(4-chloro-2-fluorophenyl)-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(4-phenylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-(5-bromopyrimidin-2-yl)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-(5-phenylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-(5-phenylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[4-(methylsulfanyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2-(4-phenylpyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-fluoro-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(4-methylpiperazin-1-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-[4-(4-methylpiperazin-1-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[4-(4-methylpiperazin-1-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-(4-methyl-2H-1,2,3-triazol-2-yl)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-[6-(morpholin-4-yl)pyridin-3-yl]-6-(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-[6-(morpholin-4-yl)pyridin-3-yl]-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-bromo-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-[4-(methylsulfanyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-6-fluoro-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-6-fluoro-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-6-fluoro-2-[4-(methylsulfanyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[2-(3,3-dimethylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-1-[6-(morpholin-4-yl)pyridin-3-yl]-6-(2H-1,2,3-triazol-2-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)pyrimidin-2-yl]-6-bromo-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-6-(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-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-(2,3-difluoro-4-methylphenyl)-6-(2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-5-yl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; Methyl 4-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)-1,3,5-triazine-2-carboxylate; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(trichloromethyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-[4-(difluoromethyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-2-[4-(difluoromethyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-[2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[4-(morpholin-4-yl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(difluoromethyl)-6-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-{2-[(3R)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[2-(4,7-diazaspiro[2.5]octan-7-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-6-(2H-1,2,3-triazol-2-yl)-2-[4-(trifluoromethyl)pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-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-triazin-2-yl]-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-{2-[(3S)-3-methylpiperazin-1-yl]pyrimidin-5-yl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-bromo-1-(2,3-difluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-(2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-(4-methyl-2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; {4-[(1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-6-(trifluoromethyl)-1,3,5-triazin-2-yl}methanol; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-(2-methoxypyrimidin-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-bromo-1-(2,3-difluoro-4-methylphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-(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-(2,3-difluoro-4-methylphenyl)-6-(4-methyl-2H-1,2,3-triazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-6-chloro-1-(2,3-difluoro-4-methylphenyl)-2-[4-(fluoromethyl)-6-(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-triazin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-nitro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-1-(2,3-difluoro-4-methylphenyl)-6-(4-methyl-1H-pyrazol-1-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-(2,3-difluoro-4-methylphenyl)-6-(3-methyl-1H-pyrazol-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; N 2 -(5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidin-2-yl)-N 1 , N 1 - dimethylethane-1,2-diamine; Methyl 5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidine-2-carboxylate; 1-(5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidin-2-yl)ethan-1-one; (1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[2-(2-methoxyethoxy)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; 2-[(5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidin-2-yl)amino]ethan-1-ol; 2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-1-[2-(2-methoxyethoxy)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole; N-(5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidin-2-yl)-β-alanine; 4-[(5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidin-2-yl)amino]butanoic acid; and {2-[(5-{(1S)-2-[4,6-bis(trifluoromethyl)-1,3,5-triazin-2-yl]-6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl}pyrimidin-2-yl)amino]ethoxy}acetic acid or a form thereof selected from the group consisting of salts, hydrates, solvates, racemates, enantiomers, diastereomers, stereoisomers, and tautomers.

11. 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[6-(morpholin-4-yl)pyridin-3-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole formate (1:1); 2-[4,6-bis(trifluoromethyl)pyrimidin-2-yl]-6-chloro-1-[2-(morpholin-4-yl)pyrimidin-5-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole formate (1:1); and (1S)-6-Chloro-1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-2-[4-(trifluoromethyl)-1,3,5-triazin-2-yl]-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole formate (1:1) or a form thereof selected from the group consisting of a salt, a hydrate, a solvate, a racemate, an enantiomer, a diastereomer, a stereoisomer, and a tautomer.

12. 17. A method of using a compound of formula (I) or a form thereof selected from any of claims 1, 10 or 11 for treating or ameliorating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or a form thereof to inhibit dihydroorotate dehydrogenase.

13. 18. A pharmaceutical composition comprising a compound of formula (I) or a form thereof selected from any of claims 1, 10 or 11 and a pharma- ceutically acceptable excipient for treating or ameliorating a disease or disorder by inhibiting dihydroorotate dehydrogenase.

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