BR112017028051B1 - CARBOLINE COMPOUNDS, VETERINARY COMPOSITION COMPRISING THEM AND USE OF SAID COMPOUNDS FOR TREATMENT OF AN ENDOPARASITAL INFECTION IN AN ANIMAL - Google Patents

Abstract

CARBOLINE ANTI-PARASITICS. The present invention provides compounds having Formula (1) which are gamma-carbolines, wherein R1a, R1b, R1c, R1d, R2, R3 and "----" are defined herein; veterinary acceptable salts thereof and stereoisomers thereof, which act as parasiticides, in particular endoparasiticides.

Description

FIELD OF THE INVENTION

[001] This invention relates to carboline derivatives that have parasiticidal activity. The compounds of interest are gamma-carboline derivatives. The invention also relates to processes for making said gamma-carboline derivatives, compositions and methods for using the same.

FUNDAMENTALS

[002] There is a continuing need for the supply of new agents for the control of parasitic infestations that present a threat to human and animal health. In particular, new agents are needed to control endoparasitic infestations in animals, due to the increasing prevalence of parasites and, in particular, nematodes, which are resistant to many of the agents currently approved for this indication. Compounds currently available for endoparasitic treatment of animals do not always demonstrate satisfactory activity, satisfactory speed of action or a long duration of action and many are no longer effective as a result of genetic resistance. The gamma-carbolines of the present invention have been shown to impart antiparasitic activity, particularly endoparasitic activity.

[003] Beta-carboline derivatives have been described in publications WO 2002/088123 and WO 2011/038163. These β-derivatives purportedly modulate aminergic G-protein-linked receptors, 5-HT6 receptors, and cGMP-specific PDE receptors for the treatment of cognitive disorders, cardiovascular disorders, erectile dysfunction, and other neurotransmitter-mediated disorders, not parasiticidal activity. Publication WO 2003/014118 generically describes hexahydro- and tetrahydro-1H-pyrido[4,3-b]indoles as 5-HT ligands capable of treating 5-HT6 modulated diseases, for example, conditions that originate in the central nervous system (pain, dementia, neurodegenerative disorders, hypertension, sleep and others). However, this application publication does not describe or exemplify any piperidine-substituted derivatives or amide (urea) substitutions of the indole moiety that have been shown to impart nematicidal activity to the compounds of the present invention. Other antiparasitic indoles have been described in application publication WO 2005/061500, WO 2005/058897 and WO 2013/017678, however these are spiroindoline derivatives. The prior art citations do not exemplify the gamma-carboline derivatives of the present invention or processes for making the same, nor does the prior art indicate that such compounds would be useful against a spectrum of parasitic species, particularly endoparasites.

[004] Despite the availability of effective broad-spectrum antiparasitic agents, there remains a need for safer, more convenient, effective, and environmentally friendly products that will overcome the ever-present threat of resistance development.

[005] The present invention overcomes one or more among several disadvantages of the properties of existing compounds or rather the same. In particular, the present invention provides new gamma-carboline derivatives that demonstrate such antiparasitic properties.

SUMMARY

[006] The present invention provides compounds of Formula (1) which are gamma-carbolines, veterinary acceptable salts thereof and stereoisomers thereof, which act as parasiticides, in particular endoparasiticides; therefore, the compounds of Formula (1) can be used to control and prevent endoparasitic infections in animals. The invention also contemplates the control and prevention of diseases of mosquito and sand fly origin, for example, heartworm infection and leishmaniasis, respectively.

[007] Thus, according to the invention, there is provided a compound having Formula (1) on what

[008] R1a, R1b, R1c and R1d are independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C3C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloalkoxy C1-C6, -C(O)NRaRb, cyano, -S(O)pR, phenyl, pyridinyl, saturated or partially saturated 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from the group consisting of N, S and O, and wherein said heterocyclic ring, phenyl or pyridinyl moiety are optionally and independently substituted by at least one substituent selected from the group consisting of oxo, cyano, halo and C1-C6 alkyl; or R1a and R1b or R1b and R1c or R1c and R1d together form a tetrahydrofuran ring or phenyl ring;

[009] R2 is phenyl or a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from the group consisting of N, S or O, and wherein said phenyl or heteroaryl ring is optionally and independently substituted by at at least one R5 substituent selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 alkoxy and C3-C6 cycloalkyl;

[010] R3 is C1-C4 alkylaryl, C1-C4 alkylheteroaryl, C2-C6 alkenylaryl or C2-C6 alkenylheteroaryl; and wherein each aryl and heteroaryl moiety is optionally and independently substituted by at least one R4 substituent selected from the group consisting of halo, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 haloalkoxy and -S(O)pR; and wherein the alkenyl moiety is optionally substituted with halo;

[011] Ra and Rb are independently selected from the group consisting of H and C1-C6 alkyl;

[012] R is H or C1-C6 alkyl;

[013] p is the integer 0, 1 or 2; and wherein the solid line accompanied by the dashed line “ ” represents a single or double bond, and veterinary acceptable salts thereof and stereoisomers thereof.

[014] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1) or Formula (1.2) of Formula (1)

[015] wherein R1a, R1b, R1c and R1d are independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1 haloalkyl -C6, C1-C6 haloalkoxy, -C(O)NRaRb, cyano, -S(O)pR, phenyl, pyridinyl, saturated or partially saturated 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from the group which consists of N, S and O, and wherein said heterocyclic ring, phenyl or pyridinyl moiety are optionally and independently substituted by at least one substituent selected from the group consisting of oxo, cyano, halo and C1-C6 alkyl; or R1a and R1b or R1b and R1c or R1c and R1d together form a tetrahydrofuran ring or phenyl ring; Ring A is phenyl or a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from the group consisting of N, S or O; and wherein the alkenyl moiety is optionally substituted with halo; Ring B is naphthyl, quinolinyl or isoquinolinyl; and wherein each of the Ring A and Ring B portions is optionally and independently substituted by at least one R4 substituent selected from the group consisting of halo, cyano, C1-C6 alkoxy, C1C6 haloalkyl, C1-C6 alkyl C6, C1-C6 haloalkoxy and -S(O)pR; and R2 is phenyl, pyridinyl, thiazolyl, pyridazinyl or pyrrolyl, each optionally and independently substituted by at least one R5 substituent selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl and cyclopropyl. The variable n is an integer that is 0, 1, 2, 3, 4, or 5; and when n is 2 or more, then each R4 can be the same or different from each other. A preferred n is the integer 1, 2, 3 or 4. Even more preferred, n is the integer 1, 2 or 3. The variable p is an integer that is 0, 1 or 2. A preferred p is the integer 0 or 2. Preferred Ra and Rb are independently hydrogen and methyl. The most preferred Ra and Rb are hydrogen. Preferred R is methyl.

[016] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1) or Formula (1.2) of Formula (1); R1a, R1b, R1c and R1d are independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1 haloalkoxy -C6, -C(O)NRaRb, cyano, and -S(O)pR; Ring A is phenyl, pyridinyl, or thiophene; Ring B is naphthyl, quinolinyl or isoquinolinyl; and wherein each of Ring A and Ring B is optionally and independently substituted by at least one R4 substituent selected from halo, cyano, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy C6 and -S(O)2CH3; and R2 is phenyl, pyridinyl, thiazolyl, pyridazinyl or pyrrolyl, each optionally and independently substituted by at least one R5 substituent selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl and cyclopropyl; and n is the integer 0, 1, 2, 3, 4 or 5; and when n is 2 or more, then each R4 can be the same or different from each other; and veterinary acceptable salts thereof and stereoisomers thereof. A preferred n is the integer 1, 2, 3 or 4. Even more preferred, n is the integer 1, 2 or 3. The variable p is an integer that is 0, 1 or 2. A preferred p is the integer 0 or 2. Preferred Ra and Rb are independently hydrogen and methyl. The most preferred Rae Rb are hydrogen. Preferred R is methyl.

[017] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1) of Formula (1); R1a, R1b, R1c and R1d are independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1 haloalkoxy -C6, -C(O)NH2, cyano, -S(O)2CH3; Ring A is phenyl, pyridinyl, or thiophene; each of which is optionally and independently substituted with at least one R4 substituent selected from halo, cyano, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and -S(O)2CH3; and R2 is pyridinyl, thiazolyl, pyridazinyl or pyrrolyl, each optionally and independently substituted by at least one R5 substituent selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl and cyclopropyl; and veterinary acceptable salts thereof and stereoisomers thereof.

[018] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1), wherein R1a, R1b, R1c and R1d are independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)NH2, cyano, -S(O)2CH3; Ring A is phenyl optionally substituted with at least one R4 substituent selected from the group consisting of halo, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 haloalkoxy and -S(O) pR; and wherein the alkenyl moiety is optionally substituted with halo; and R2 is pyridinyl or thiazolyl, each optionally and independently substituted with at least one R5 substituent selected from the group consisting of halo, methyl, -CF3, -OCH3, -OCH2CH3, hydroxyl and cyclopropyl, and veterinary acceptable salts thereof and stereoisomers thereof.

[019] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1), wherein R1a, R1b, R1c and R1d are independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)NH2, cyano, -S(O)2CH3; Ring A is phenyl substituted with at least one R4 substituent selected from the group consisting of halo, cyano, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkyl, C1-C6 haloalkoxy and -S(O)2CH3 ; and wherein the alkenyl moiety is optionally substituted with fluorine; and R2 is pyridinyl substituted with at least one R5 substituent selected from the group consisting of halo, methyl, -CF3, -OCH3, hydroxyl, -OCH2CH3 and cyclopropyl, and veterinary acceptable salts and stereoisomers thereof.

[020] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1a) of Formula (1.1)

[021] R1a, R1b, R1c and R1d are independently selected from the group consisting of H, chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, - S(O)2CH3, -C(O)NH2, phenyl, pyridinyl, morpholinyl, azathienyl and pyrrolidinyl; and wherein the phenyl and pyridinyl are optionally substituted by at least one substituent selected from halo, cyano or oxo; R4a, R4b, R4c, R4d and R4e are independently selected from the group consisting of H, methyl, fluorine, chlorine, bromine, -CF3, cyano, -OCF3, -OCH3 and -S(O)2CH3; and R5a and R5b are independently selected from the group consisting of H, chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3 and -OCH2CH3; and veterinary acceptable salts thereof and stereoisomers thereof.

[022] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1a), wherein R1a, R1b, R1c and R1d are independently selected from the group consisting of H, chlorine , fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S(O)2CH3, and -C(O)NH2; R4a, R4b, R4c, R4d and R4e are independently selected from the group consisting of H, fluorine, chlorine, bromine, -CF3, cyano, -OCF3, -OCH3, methyl and -S(O)2CH3; and R5a and R5b are independently selected from the group consisting of H, chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3, and -OCH2CH3; and veterinary acceptable salts thereof and stereoisomers thereof.

[023] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1a), wherein R1a, R1b, R1c and R1d are independently selected from the group consisting of H, chlorine , fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S(O)2CH3, and -C(O)NH2; R4a, R4b, R4c, R4d and R4e are independently selected from the group consisting of H, fluorine, chlorine, bromine, -CF3, methyl, cyano, -CF3, -OCH3 and -S(O)2CH3; and one of R5a or R5b is H and the other is fluorine, chlorine, bromine, methyl, -CF3, -OCH3, -OCH2CH3, hydroxyl or cyclopropyl, and veterinary acceptable salts thereof and stereoisomers thereof.

[024] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1a), wherein at least one of R1a, R1b, R1c and R1d is H and the others are independently selected from starting from the group consisting of chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S(O)2CH3 and -C(O)NH2; R4a, R4b, R4c, R4d, and R4e are independently selected from the group consisting of H, fluorine, chlorine, bromine, -CF3, methyl, cyano, -OCF3, -OCH3, and -S(O)2CH3; and one of R5a or R5b is H and the other is fluorine, chlorine, bromine, methyl, -CF3, -OCH3, -OCH2CH3, hydroxyl, or cyclopropyl, and veterinary acceptable salts thereof and stereoisomers thereof.

[025] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1a), wherein at least two of R1a, R1b, R1c and R1d are H and the others are independently selected from starting from the group consisting of chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S(O)2CH3 and -C(O)NH2; R4a, R4b, R4c, R4d and R4e are independently selected from the group consisting of H, fluorine, chlorine, bromine, -CF3, methyl, cyano, -OCF3, -OCH3 and -S(O)2CH3; and one of R5a or R5b is H and the other is fluorine, chlorine, bromine, methyl, -CF3, -OCH3, -OCH2CH3, hydroxyl, or cyclopropyl, and veterinary acceptable salts thereof and stereoisomers thereof.

[026] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1a), wherein at least two of R1a, R1b, R1c and R1d are H and the others are independently selected from from the group consisting of chloro, fluoro, cyano and -CF3; R4a, R4b, R4c, R4d and R4e are independently selected from the group consisting of H, fluorine, chlorine, bromine, -CF3 and cyano; and one of R5a or R5b is H and the other is fluorine, chlorine, bromine, methyl, -CF3, -OCH3, -OCH2CH3, hydroxyl or cyclopropyl, and veterinary acceptable salts thereof and stereoisomers thereof.

[027] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1a) selected from the group consisting of: ((E)-2-(3-(4-chloro-3) ,5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole -5-carboxamide; (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3 -(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3- (4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4 ,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl) methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-8-cyano-N-((2-fluoropyridin-4-yl )methyl)-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; ( E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide; and (E)-8-cyano-2-(3-(4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H -pyrido[4,3-b]indole-5-carboxamide, and veterinary acceptable salts and stereoisomers thereof.

[028] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1), wherein Ring A is pyridinyl optionally substituted by at least one R4 substituent independently selected from the group consisting of fluorine , chlorine, bromine, -CF3, cyano, -OCF3, -OCH3, methyl and -S(O)2CH3; R2 is pyridinyl optionally substituted with one or two R5 substituents independently selected from the group consisting of chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3, -OCH2CH3, and wherein R1a, R1b, R1c and R1d are independently selected from the group consisting of H, chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S(O)2CH3, and -C (O)NH2; and veterinary acceptable salts thereof and stereoisomers thereof.

[029] In yet another aspect, the compounds of the present invention include a compound having Formula (1.1), wherein Ring A is thiophene optionally substituted by one or two R4 substituents independently selected from the group consisting of fluorine , chlorine, bromine, -CF3, cyano, -OCF3, -OCH3, methyl and -S(O)2CH3; R2 is pyridinyl optionally substituted with one or two R5 substituents independently selected from the group consisting of chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3, -OCH2CH3, and wherein R1a, R1b, R1c and R1d are independently selected from the group consisting of H, chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S(O)2CH3, and -C( O)NH2; and veterinary acceptable salts thereof and stereoisomers thereof.

[030] In yet another aspect, the compounds of the present invention include a compound having Formula (1.2a) of Formula (1.2) wherein Ring B is naphthyl, quinolinyl or isoquinolinyl optionally and independently substituted by at least one R4 substituent selected from the group consisting of H, fluorine, chlorine, bromine, -CF3, cyano, -OCF3, -OCH3, methyl, and -S(O)2CH3; R1a, R1b, R1c and R1d are independently selected from the group consisting of H, chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S(O )2CH3 and -C(O)NH2; and wherein R5a and R5b are independently selected from the group consisting of H, chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3 and -OCH2CH3; and n is the integer 0, 1, 2, 3, 4 or 5; and when n is 2 or more, then each R4 can be the same or different from each other; and veterinary acceptable salts thereof. In yet another aspect of the invention, Ring B is naphthyl and n is the integer 0 or 1. In yet another aspect of the invention, Ring B is quinolinyl and n is the integer 0 or 1. invention, Ring B is isoquinolinyl and n is the integer 0 or 1.

[031] In yet another aspect, the compounds of the present invention include a compound having Formula (1) which is selected from any one of Examples 1 to 517, veterinary acceptable salts thereof, and stereoisomers thereof.

[032] In yet another aspect, the invention is a veterinary composition comprising a compound having Formula (1), veterinary acceptable salts thereof and stereoisomers thereof. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1) and further comprising a veterinary acceptable carrier. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1) and further comprising a veterinary acceptable carrier and, optionally, at least one additional antiparasitic agent. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1) and further comprising a veterinary acceptable carrier, and at least one additional antiparasitic agent.

[033] In yet another aspect, the invention is a veterinary composition comprising a compound having Formula (1.1), veterinary acceptable salts thereof and stereoisomers thereof, or a compound having Formula (1.2), and veterinary salts acceptable thereof. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1.1) or a compound having Formula (1.2) and further comprising a veterinary acceptable carrier. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1.1) or a compound having Formula (1.2), and further comprising a veterinary acceptable carrier and, optionally, at least one additional antiparasitic agent. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1.1) or a compound having Formula (1.2) and further comprising a veterinary acceptable carrier and at least one additional antiparasitic agent.

[034] In yet another aspect, the invention is a veterinary composition comprising a compound having Formula (1.1a), veterinary acceptable salts thereof and stereoisomers thereof. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1.1a) and further comprising a veterinary acceptable carrier. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1.1a) and further comprising a veterinary acceptable carrier and, optionally, at least one additional antiparasitic agent. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1.1a) and further comprising a veterinary acceptable carrier and at least one additional antiparasitic agent.

[035] In yet another aspect, the invention is a veterinary composition comprising a compound having Formula (1.1a) selected from the group consisting of (E)-2-(3-(4-chloro-3, 5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole- 5-carboxamide; (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; and (E)-8-cyano-2-(3-(4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H -pyrido[4,3-b]indole-5-carboxamide, and veterinary acceptable salts thereof and stereoisomers thereof, and further comprising a veterinary acceptable carrier and, optionally, at least one additional antiparasitic agent. In yet another aspect of the invention is a veterinary composition comprising one of these compounds of Formula (1.1a) and further comprising a veterinary acceptable carrier and at least one additional antiparasitic agent.

[036] In yet another aspect, the invention is a veterinary composition comprising a compound having Formula (1) selected from any one of Examples 1 to 517, veterinary acceptable salts thereof and stereoisomers thereof. In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1) selected from any one of Examples 1 to 517 and further comprising a veterinary acceptable carrier and, optionally, at least one additional antiparasitic agent . In yet another aspect of the invention is a veterinary composition comprising a compound having Formula (1) selected from any one of Examples 1 to 517 and further comprising a veterinary acceptable carrier and at least one additional antiparasitic agent.

[037] In yet another aspect, the invention is a method of treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a compound having Formula (1), veterinary acceptable salts thereof and stereoisomers thereof, to an animal in need of it. In yet another aspect of the invention is a method of treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a compound having Formula (1.1) or Formula (1.2) to an animal in need thereof. In yet another aspect of the invention is a method of treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a compound having Formula (1.1a) to an animal in need thereof and, optionally, combining a compound having presents Formula (1.1a) with at least one additional antiparasitic agent.

[038] In yet another aspect of the invention is a method of treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a compound having Formula (1.1a) selected from the group consisting of (E)- 2-(3-(4-chloro-3,5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro- 5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; and (E)-8-cyano-2-(3-(4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H -pyrido[4,3-b]indole-5-carboxamide, veterinary acceptable salts thereof and stereoisomers thereof, to an animal in need thereof, and optionally, combining one of these compounds of Formula (1.1a) with at least an additional antiparasitic agent. In yet another aspect of the invention is a method of treating an animal in need thereof with one of these compounds of Formula (1.1a) and veterinary acceptable salts thereof and stereoisomers thereof, combined with at least one additional antiparasitic agent.

[039] In yet another aspect, the invention is a method of treating an animal for a parasitic infection comprising administering a compound having Formula (1) selected from any one of Examples 1 to 517, veterinary acceptable salts of same and stereoisomers thereof. In yet another aspect of the invention is a method of treating an animal for a parasitic infection comprising administering a compound having Formula (1) selected from any one of Examples 1 to 517 combined with at least one additional antiparasitic agent.

[040] In yet another aspect of the invention, the animal is a companion or farm animal and said parasitic infection is an endoparasitic infection, and in which the compound having Formula (1), Formula (1.1), Formula (1.2), Formula (1.1a), or Formula (1.2a), veterinary acceptable salts thereof and stereoisomers thereof, is administered orally, topically or parenterally. A preferred companion animal is a dog and a preferred livestock animal is a cow. In one aspect of the invention, the compound is administered orally. In another aspect of the invention, the compound is administered parenterally. In yet another aspect of the invention, the compound is administered topically.

[041] In yet another aspect, the invention uses a compound having Formula (1), Formula (1.1), Formula (1.2), Formula (1.1a) or Formula (1.2a), veterinary acceptable salts thereof and stereoisomers thereof for the manufacture of a medicament for treating a parasitic infection in an animal in need thereof. The medicament can be administered to the animal orally, topically or parenterally.

DETAILED DESCRIPTION DEFINITIONS

[042] For purposes of the present invention, as described and claimed in this report, the following terms and phrases are defined in this report:

[043] “Additional antiparasitic agents” used in this report, unless otherwise indicated, refer to other compounds or veterinary products that provide a therapeutically effective amount of said agents that are useful for treating a parasitic infection in an animal , as described in this report.

[044] “Alkoxy”, as used in this report, unless otherwise indicated, refers to an oxygen moiety that has another alkyl substituent. The alkyl portion (i.e., alkyl portion) of an alkoxy group has the same definition below. Examples of non-limiting alkoxy include: methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy, iso-propoxy, n-butoxy and the like.

[045] “Alkyl”, as used in this report, unless otherwise indicated, refers to saturated monovalent hydrocarbon alkane radicals of the general formula CnH2n + 1. The alkane radical may be straight or branched and may be unsubstituted or substituted. For example, the term "C1-C6 alkyl" refers to a monovalent, straight or branched aliphatic group containing 1 to 6 carbon atoms. Non-exclusive examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, t-butyl, n-propyl, n-butyl, i-butyl, s-butyl, n- pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, hexyl and the like. The alkyl moiety can be bonded to the chemical moiety by any of the carbon atoms in the aliphatic chain. Alkyl groups are optionally substituted as described in this report. Even when used in compound words, such as haloalkyl, said alkyl moiety has the same meaning as defined in this report and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. Non-limiting examples of the word haloalkyl compound include: difluoromethyl, trifluoromethyl and the like. Even when used in compound words, such as alkylaryl, said alkyl and aryl moieties have the same meaning as defined herein. Non-limiting examples of the word alkylaryl compound include: benzyl, ethylbenzyl, propylbenzene, iso-butylbenzene, sec-butylbenzene, ethylnaphthalene, propylnaphthylene, 2,2-diphenylethyl, and the like.

[046] “Alkenyl”, as used in this report, unless otherwise indicated, refers to a straight or branched, aliphatic, unsaturated hydrocarbon chain that has at least one site of olefinic unsaturation (that is, that has at least one least a portion of the formula C=C) and, preferably, having from 2 to 6 carbon atoms. Non-exclusive examples of alkenyl include: ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-methyl-1-propenyl and the like. Even when used in compound words, such as alkenylaryl or alkenylheteroaryl, said alkenyl, aryl and heteroaryl moieties have the same meaning as defined in this report and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. Non-word limiting examples of the alkenylaryl compound include: propenylbenzene, ethenylbenzene, butenylbenzene and the like. Non-word limiting examples of the alkenylheteroaryl compound include: propenylpyridine, propenylthiazole, butenylpyridine, ethenylimidazole, ethenylpyridine, and the like.

[047] “Animal”, as used in this report, unless otherwise indicated, refers to an individual animal that is a mammal, bird or fish. Specifically, mammal refers to a vertebrate animal that is both human and non-human, which are members of the taxonomic class Mammalia. Non-exclusive examples of non-human mammals include companion and livestock animals. Non-exclusive examples of a companion animal include: dog, cat and horse. A preferred companion animal is a dog. Non-exclusive examples of farmed animals include: swine, camel, rabbits, goat, sheep, deer, elk and cattle. Preferred livestock are cattle and pigs. Beef cattle is more preferred. Specifically, bird refers to a vertebrate animal in the taxonomic class Aves. Birds are feathered, winged, bipedal, endothermic, and oviparous. Non-exclusive examples of bird include domestic fowl (eg chicken, turkey, duck and goose), all of which are also referred to in this report as fowl. Specifically, fish refers to the taxonomic class Chondrichthyes (cartilaginous fish, e.g., sharks and rays) and Osteichthyes (bony fish) that live in water, have gills or mucus-covered skin for breathing, fins, and have scales. Non-exclusive examples of fish include shark, salmon, trout, whitefish, catfish, tilapia, whiting, tuna, halibut, flounder, plaice, striped sea bass, eel, yellowtail, grouper, and the like.

[048] "Aryl", as used in this report, unless otherwise indicated, refers to a 6- to 10-membered aromatic mono- or polycyclic ring containing 6 to 10 carbon atoms, respectively. Preferred aryls include phenyl and naphthyl. The aryl group can be attached to the chemical moiety by any one of the carbon atoms within the monocyclic or fused ring. Furthermore, when used in compound words such as alkylaryl or alkenylaryl, said alkyl, alkenyl and aryl moieties have the same meaning as defined in this report and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. Non-exclusive examples of alkylaryl include: -C-phenyl, -C-naphthyl and the like. Non-exclusive examples of alkenylaryl include: -C=C-phenyl, -C-C=C-phenyl, -C-C=C-C-phenyl, and the like. Arils are optionally replaced as described in this report.

[049] “Compounds” and “Compounds of the present invention” used in this report, unless otherwise indicated, refer to a compound having Formula (1), Formula (1.1), Formula (1.1a), Formula (1.2) and Formula (1.2a), stereoisomer thereof, and veterinary acceptable salt thereof.

[050] “Comprises”, as used in this report, unless otherwise indicated, refers to an inclusive meaning, that is, it will mean an inclusion of not only the components listed directly in the references, but also other components or unspecified elements. This reasoning will also be used when the term “understood” or “comprising” is used in relation to one or more Steps in a method or process.

[051] “Cycloalkyl”, as used in this report, unless otherwise noted, includes fully saturated or partially saturated carbocyclic alkyl moieties. Non-limiting examples of partially saturated cycloalkyls include: cyclopropene, cyclobutene, cycloheptene, cyclooctene, cyclohepta-1,3-diene and the like. Preferred cycloalkyls are 3- to 6-membered saturated monocyclic rings (C3-C6 cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be attached to the chemical moiety by any of the carbon atoms within the ring. Cycloalkyl groups are optionally substituted with at least one substituent defined in this report. Even when used in compound words, such as alkylcycloalkyl, said alkyl and cycloalkyl moiety has the same meaning as defined in this report and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. Examples of C1-C6 alkyl C3-C6 cycloalkyl include, methylcyclopropane (C1 alkyl C3 cycloalkyl or CH2cyclopropane), ethylcyclopropane (C2 alkyl C3 cycloalkyl or -CH2CH2cyclopropane), methylcyclobutane (C4 alkyl cycloalkyl or CH2cyclobutane), ethylcyclobutane (C2 alkyl C4 cycloalkyl or CH2CH2cyclobutane), methylcyclo- hexane (C1C6 alkylcycloalkyl or CH2cyclohexane) and the like. Cycloalkyl moieties are optionally substituted as described in this report.

[052] The “E/Z notation” or “E and Z geometric isomers” used in this report, unless otherwise indicated, refer to the International Union of Pure and Applied Chemistry (IUPAC) preferred method of describing stereochemistry of double bonds in organic chemistry. It is an extension of the cis/trans notation that can be used to describe double bonds that have three or four substituents. After a defined set of rules (Cahn-Ingold-Prelog priority rules), each substituent on a double bond is assigned a priority. E (from entgegen, the German word for “opposite”). If the two higher priority groups are on the same side of the double bond, the bond is given the Z configuration (from zusammen, the German word for "together").

[053] “Halogen” or “halo”, as used in this report, unless otherwise indicated, refers to fluorine, chlorine, bromine and iodine. Furthermore, when used in compound words such as "haloalkyl", "haloalkoxy", "haloalkenyl" or "haloalkynyl", said alkyl, alkoxy, alkenyl and alkynyl may be partially or completely replaced by halogen atoms which can be the same or different and said alkyl, alkoxy, alkenyl and alkynyl moiety has the same meaning as defined above and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. Examples of "haloalkyl" include F3C-, ClCH2-, CF3CH2- and CF3CCI2- and the like. The term "haloalkoxy" is defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF3O-, CCl3CH2O-, HCF2CH2CH2O-, CF3CH2O- and the like. The term "haloalkenyl" is defined analogously to the term "haloalkyl", except that the aliphatic chain contains at least one carbon-carbon double bond. Examples of "haloalkenyl" include CF3C=C-, CCl3C=C-, HCF2C=C-, CF3C=CC- and the like. The term "haloalkynyl" is defined analogously to the term "haloalkyl", except that the aliphatic chain contains at least one carbon-carbon triple bond. Examples of "haloalkynyl" include F3CCEC-, CbCCEC-, HF2CCEC- and the like.

[054] “Heteroaryl” or “Het”, as used in this report, unless otherwise indicated, refers to a 5- to 6-membered monocyclic aromatic ring or an 8- to 10-membered fused aromatic ring, where said monocyclic and fused ring portion contains one or more heteroatoms independently selected from N, O or S, preferably from one to four heteroatoms. Non-exclusive examples of monocyclic heteroaryls include pyrrolyl, furanyl, thiophene, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. Non-exclusive examples of fused heteroaryls include: benzofuranyl, benzothiophene, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole, quinolinyl, isoquinolinyl and the like. The heteroaryl group may be attached to the chemical moiety by any of the carbon atoms or nitrogen heteroatoms within the monocyclic or fused ring. Furthermore, when used in compound words such as alkylheteroaryl, said alkyl and heteroaryl moiety has the same meaning as defined in this report and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. Non-exclusive examples of alkylheteroaryl include: C1-heteroaryl (e.g., -C-pyridinyl; -C-quinolinyl; -C-isoquinolinyl), ethylpyridine, ethylpyrimidine, ethylpyridazine, and the like. Heteroaryls are optionally substituted as described in this report.

[055] “Heterocycle”, as used in this report, unless otherwise indicated, refers to a partially saturated or saturated 3- to 7-membered monocyclic ring containing one or more heteroatoms independently selected from N, O or S , preferably from one to four heteroatoms. The heterocyclic ring may be part of a fused ring moiety. Non-exclusive examples of heterocycle include oxirane, tiarane, aziridine, oxetane, azetidine, thiathane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, piperidine, piperazine, tetrahydropyridine, 2H-azirine, 2,3-di- hydroazete, 3,4-dihydro-2H-pyrrole, morpholine, azathiane and the like. The heterocycle group may be attached to the chemical moiety by any of the carbon atoms or nitrogen heteroatoms within the ring. Furthermore, when used in compound words such as alkylheterocycle, said alkyl moiety and heterocycle have the same meaning as defined in this report and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. For example, C1 alkyl heterocycle is C-heterocycle, C2 alkyl heterocycle is -C-C-heterocycle, and the like. Heterocycles are optionally substituted as described in this report.

[056] “Optionally replaced” is used in this report interchangeably with the phrase replaced or not replaced. Unless otherwise noted, an optionally substituted group can have one substituent at each substitutable position in the group, and each substitution is independent of the other. An optionally substituted group also cannot have substituents. Therefore, the phrase "optionally substituted by at least one substituent" means that the number of substituents can range from one to a number of chemically available positions for substitution.

[057] “Parasites”, as used in this report, unless otherwise indicated, refer to endoparasites and ectoparasites. Endoparasites are parasites that live inside the body of their host and include helminths (eg, trematodes, cestodes, and nematodes) and protozoans. Preferred endoparasites are gastrointestinal worms and heartworm. Ectoparasites are organisms of the phylum Arthropoda (eg arachnids, insects and crustaceans (eg copepods-sea lice) that feed through or under the skin of their host. Preferred arachnids are of the order Acarina, for example ticks and mites. Preferred insects are mosquitoes, fleas, flies, biting flies (stable fly, horn fly, blow fly, horse fly and the like), moths and lice. Preferred compounds of the present invention can be used for the treatment of parasites, i.e. treatment of a parasitic infection or infestation.

[058] “Protective group” or “Pg”, as used in this report, unless otherwise indicated, refers to a substituent that is commonly used to block or protect an amine in the compound, thereby protecting its functionality , considering the reaction of other functional groups in the compound. Non-exclusive examples of an amine protecting group include: acyl groups (e.g., formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl , acylisothiocyanate, aminocaproyl, benzoyl and the like), acyloxy groups (e.g., 1-tert-butyloxycarbonyl (Boc, BOC), methoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilyl-ethoxycarbonyl , vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and the like), diphenylmethane and benzylcarbamates.

[059] “R4 substituent”, as used in this report, unless otherwise indicated, refers to a substituent that is still defined as R4a, R4b, R4c, R4d and R4e, which are defined in this report, in particular, for the compounds of Formula (1.1a) and Formula (1.2a).

[060] “Substituent R5”, as used in this report, unless otherwise indicated, refers to a substituent that is still defined as R5a and R5b, which are defined in this report, particularly for compounds of the Formula ( 1.1a) and Formula (1.2a).

[061] “Therapeutically effective amount”, as used in this report, unless otherwise indicated, refers to a concentration of the active agent in a composition sufficient to induce the desired biological response to the target parasites after administration of the composition to the animal , as measured by methods known in the art and/or described in the examples in this report. In some instances, an "effective amount" of the active agent in the composition will provide at least 70% efficacy against the target parasite compared to an untreated control. In other examples, an "effective amount" of the active agent will provide at least 80% efficacy, or at least 85% compared to untreated controls. More typically, "an effective amount" of the active agent will provide at least 90%, at least 93%, at least 95%, or at least 97% efficacy against the target parasite. In certain examples, including prevention of Dirofilaria immitis, the term "effective amount" may provide efficacy as high as 100%. As is understood in the art, a therapeutically effective amount may be presented in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired goal of treatment, e.g., (i) treating the infection or infestation particular parasitic infection, (ii) alleviate, ameliorate or eliminate one or more symptoms of the particular parasitic infection or infestation, or (iii) prevent or delay the onset of one or more symptoms of the particular infection or parasitic infestation described in this report.

[062] “Treatment”, “treat” and the like, as used in this report, unless otherwise indicated, refer to the reversal, alleviation or inhibition of the infection, infestation or parasitic condition. As used in this report, these terms also cover, depending on the condition of the animal, preventing the onset of a disorder or condition, or of symptoms associated with a disorder or condition, including reducing the severity of a disorder or condition or symptoms associated with the even before affliction with said infection or infestation. Thus, treatment can refer to administering the compounds of the present invention to an animal that is not at the time of administration afflicted with the infection or infestation. Treatment also includes preventing the recurrence of an infection or infestation or symptoms associated with it, as well as references to “control” (e.g., kill, repel, expel, disable, detain, eliminate, alleviate, minimize, and eradicate) . Treatment methods are synonymous with using the compound for treatment and use for preparing a drug for treatment.

[063] "Veterinary acceptable", as used in this report, unless otherwise indicated, indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising a formulation, composition and/or the animal which will be treated accordingly.

[064] "Veterinary acceptable salts", as used in this report, unless otherwise indicated, are those salts that retain at least some biological activity of the free compound (without salt) and that can be administered as drugs or pharmaceuticals to an animal. An acceptable veterinary salt considers ionic interactions and not a covalent bond. As such, an N-oxide is not considered a salt. Non-limiting examples of salts include acid addition salts, organic acids and organic bases. Other examples of veterinary acceptable salts include those listed in Berge et. al., Pharmaceutical Salts, J.Pharm. Sci. (1977), 66(1):1 to 19. Veterinary acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a base or suitable acid, respectively, and isolation of the salt formed during subsequent purification.

[065] The present invention provides compounds of Formula (1), stereoisomers thereof, particularly geometric isomers, veterinary acceptable salts thereof, as well as veterinary compositions that are useful as antiparasitic agents for animals, in particular, compounds that act as endoparasiticides in companion and farm animals.

[066] The compounds of the present invention can be synthesized by synthetic routes that include processes analogous to those well known in the chemical art, particularly in light of the description contained in this report. Starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, "Reagents for Organic Synthesis", 1; 19, Wiley, New York (1967, 1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin , including supplements (also available via the Beilstein online database)). For illustrative purposes, the reaction schemes depicted below demonstrate potential routes to synthesize the compounds of the present invention and key intermediates. For a more detailed description of the individual Reaction Steps, see the Examples section below. One skilled in the art will appreciate that other suitable starting materials, reagents and synthetic routes can be used to synthesize the compounds of the present invention and a variety of derivatives thereof. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to the skilled artisan.

[067] The gamma-carbolines of the present invention described in this report exist in different stereoisomeric forms. Unless otherwise specified, it is intended that all stereoisomeric forms of the compounds of the present invention, as well as mixtures thereof, including diastereomeric and geometric mixtures, form part of the present invention. Therefore, all “E” and “Z” isomers of the compounds of Formula (1), Formula (1.1) and Formula (1.1a) are considered.

[068] For illustrative purposes, the reaction schemes depicted below demonstrate potential pathways to synthesize key intermediates and compounds of the present invention. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other suitable starting materials, reagents and synthetic routes can be used to synthesize the intermediates and compounds of the present invention and a variety of derivatives thereof. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry. Schemes 1 to 4 outline useful general procedures for preparing and isolating compounds of the present invention. It is to be understood, however, that the invention, as fully described in this report and cited in the claims, is not intended to be limited by the details of the following schemes or modes of preparation. In preparing the compounds of the present invention, protection of the remote functionality of the intermediates from undesired reactions can be accomplished with a protecting group. The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an amine protecting group is a substituent attached to an amine that blocks or protects the amine functionality of the compound or intermediate. Suitable amine protecting groups include: 1-tert-butyloxycarbonyl (Boc or BOC), acyl groups including: formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl , o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like; and acyloxy groups, including: methoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethyl-propynyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4- dichlorobenzyloxycarbonyl and the like. Similarly, diphenylmethane and benzylcarbamates can be used as amine protecting groups. The preferred amine protecting group is 1-tert-butyloxycarbonyl. Suitable protecting groups and their respective uses are easily determined by a person skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[069] In the Schemes and Examples below, the following catalysts/reagents and mixed abbreviations include: mobile phase (MP); room temperature (RT); equivalent (eq); minute (min); time (h); round bottom flask (RBF); saturated (sat); N,N-dimethyl formamide (DMF); acetonitrile (ACN, Acn or MeCN); dichloromethane (DCM); methyl tert-butyl ether (MTBE); triethylamine (TEA or Et3N); methanol (MeOH), tetrahydrofuran (THF); ethyl acetate (EtOAc); trifluoroacetic acid (TFA); 4-dimethylaminopyridine (DMAP); isopropylmagnesium chloride (iPrMgCl); t-butyloxycarbonyl (BOC, boc); palladium (Pd); isopropyl alcohol (IPA); hydrochloric acid (HCl); dichloromethane (CH2Cl2); diethyl ether (Et2O); dimethyl sulfoxide (DMSO); 1,1'-Bis(diphenylphosphino)ferrocene (Pd(DPPF2)Cl2); zinc cyanide (Zn(CN2)); zinc acetate (Zn(OAc)2); dichloroethane (DCE); dimethyl acetamide (DMA); thin layer chromatography (TLC); sodium triacetoxyborohydride (STAB); lithium diisopropylamide (LDA); n-butyllithium (n-BULi); di-tert-butyl pyrocarbonate (Boc2O); and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos).Scheme 1 - Fischer Indole Carboline Formation

[070] Scheme 1 describes Fischer's indole synthesis scheme. R1a, R1b, R1c and R1d are defined in this report. The ratio of isomeric products (analogs) varies depending on the aniline or hydrazine starting material. Commercially available aniline (s1.1) is converted to the corresponding hydrazine (s1.2) via diazotization at 0 °C using nitrous acid (prepared in situ from sodium nitrite and a mineral acid, typically hydrochloric acid) , the intermediate diazonium salt is then reduced without isolation using stannous chloride dihydrate in concentrated hydrochloric acid at 0 °C. Cyclization to carboline (s1.4) is performed by Fischer's indole synthesis of hydrazine (s1.2) and commercially available piperidin-4-one (s1.3) in IPA with hydrochloric acid in dioxane at temperatures up to reflux . The piperidine moiety (s1.5) is BOC protected using commercially available di-tert-butyl dicarbonate, triethylamine as base in dichloromethane at 0 °C to room temperature. Scheme 2 - Formation of urea

[072] R1a, R1b, R1c, R1d and R2 are defined in this report. Ureas (s2.8) are synthesized first by forming an isocyanate intermediate (s2.9) from a commercially available methanamine (s2.7) using triphosgene and aqueous potassium carbonate or pyridine as the base in dichloromethane as the solvent at 0°C. °C. Carboline (s1.5) is deprotonated using sodium hydride base in THF solvent at 0 °C, followed by subsequent reaction with isocyanate intermediate (s2.9) to provide ureas (s2.8). Alternatively, the ureas (s2.8) can be synthesized by forming a carbamoyl chloride intermediate (s2.6) using phosgene, triphosgene or CDI and pyridine or triethylamine as the base in dichloromethane or DCE as the solvent at 0 °C, followed by addition of a commercially available methanamine (s2.7) at 0 °C and then warming to room temperature. Scheme 3 – Replacement of Piperidine

[073] R1a, R1b, R1c, R1d, R2, R4, n, ring A and ring B are defined in this report. Deprotection of the BOC group in (s2.8) is performed by treatment with trifluoroacetic acid in dichloromethane at room temperature. The amine (s3.1) was then alkylated using a reductive amination procedure with an easily prepared or commercially available aldehyde intermediate (s3.2). Mixing the amine (s3.1) and aldehyde (s3.2) with sodium triacetoxyborohydride and triethylamine in an organic solvent (typically dimethylformamide or dichloromethane) at room temperature gives the substituted piperidine (s3.4). The amine (s3.1) can alternatively be alkylated using a reductive alkylation procedure with a commercially available aldehyde (s3.3b) using sodium triacetoxyborohydride as the reducing agent and triethylamine in an organic solvent (typically dimethylformamide or dichloromethane) in the room temperature gives the substituted piperidine (s3.5).Scheme 4 - Alternating Synthesis

[074] Alternatively, substituted gamma-carboline compounds can be prepared in 3 to 4 steps using the alternative reactive steps depicted in Scheme 4. The gamma-carboline core is prepared via standard Fischer Indole chemistry, optionally followed by substitution of the halide X by other substituents (such as nitriles) through conventional palladium cross-linking chemistry.

[075] The amine side chain is then added via reductive amination, by reacting the excess aldehyde with the gamma-carboline core in the presence of a standard reducing agent (for example, sodium triacetoxyborohydride, cyanoborone -sodium hydride, sodium borohydride and the like (preferably sodium triacetoxyborohydride)) in polar solvents such as THF, DCM, MeOH, iPrOH, DMF, DMA and the like, preferably DMF or DMA. The tail part of the urea is then inserted by reacting a slight excess of isocyanate reagent in the presence of a base such as trimethylamine, Hunig's base or pyridine; in polar solvents such as THF, DMF, DMA and the like, preferably DMF or DMA.

[076] By reversing the order of the reductive amination step and urea formation, the BOC protecting group can be omitted, thereby reducing the number of synthetic steps. R4, R5 and n are defined in this report. The letter “m” is an integer 0, 1 or 2.

[077] It will be appreciated by those skilled in the art that certain compounds within the compositions of the invention can exist and be isolated as geometric isomers. The present invention encompasses the specific diastereomers of each compound, as well as mixtures of different diastereomers of the compounds of the invention that have the useful properties described in this report.

[078] The compounds within the compositions of the present invention may also be present in different solid forms, such as different crystalline forms or in the form of an amorphous solid. The present invention encompasses different crystalline forms as well as amorphous forms of the inventive compounds.

[079] Furthermore, compounds within the compositions of the invention may exist as hydrates or solvates, wherein a certain stoichiometric amount of water or a solvent is associated with the molecule in crystalline form. Compositions of the invention can include hydrates and solvates of the active agents.

[080] Also considered within the scope of the invention are acid or base salts, where applicable, of the compounds of the invention provided in this report.

[081] The term “acid” considers all veterinary acceptable inorganic or organic acids. Inorganic acids include inorganic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, fatty acids and veterinary acceptable sulfonic acids. Non-limiting organic acids include: carbonic acid, formic acid, acetic acid, citric acid, propionic acid, isopropionic acid, valeric acid, glycolic acid, lactic acid, chloroacetic acid, benzoic acid, salicylic acid, oxalic acid, malic acid, succinic acid , tartaric acid, fumaric acid and maleic acid, butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and phenylesteric acid, gluconic acid, glycoheptonic acid and lactobionic acid and the like.

[082] The term "base" considers all veterinary acceptable inorganic or organic bases, including alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates. Salts formed with such bases include, for example, the alkali and alkaline earth metal salts, including, but not limited to, the lithium, sodium, potassium, aluminum, magnesium, or calcium salts. Salts formed with organic bases include the common hydrocarbon and heterocyclic amine salts, which include, for example, ammonium (NH 4 ) salts, alkyl- and dialkylammonium salts, and cyclic amine salts, such as the morpholine and piperidine salts.

[083] The free base carbolines are converted into salt form by excess addition of HCl gas in an ethereal solution and/or DCM and subsequent filtration or evaporation of the solvent. Alternatively, salts can also be formed by stoichiometric addition of HCl (4M solution in methanol or dioxane) or addition of citric acid to a solution of the free base in MeOH, DCM, EtOH, IPA and the like, and mixtures thereof, followed by by filtration or evaporation of the solvent.

[084] A person skilled in the art will recognize that, in some cases, after the introduction of a given reagent, as depicted in the schemes, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of the compounds of the Formula ( 1).

[085] The present invention includes all isotopically labeled, veterinary acceptable compounds of Formula (1), in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen such as 13N and 15N, oxygen such as 15O, 17O and 18O and sulfur such as 35S.

[086] The qualified person will evaluate that the compounds of the present invention can be prepared by methods, except those described in this report as incorporated in this report by reference, by adapting the methods described in this report and/or adapting the methods known in the art, for example , the technique described in this report, or using standard manuals such as “Comprehensive Organic Transformations - A Guide to Functional Group Transformations”, RC Larock, Wiley-VCH (1999 or later editions).

[087] The compounds of Formula (1) are useful as antiparasitic agents, therefore, another aspect of the present invention is a veterinary composition comprising a therapeutically effective amount of a compound having Formula (1), stereoisomers thereof, and at least least one veterinary acceptable carrier. The compounds of the present invention (including the compositions and processes used therein) can also be used in the manufacture of a drug for the therapeutic applications described in this report.

[088] The compound of the present invention can be administered alone or in an appropriate formulation for the specific use considered, for the particular species of host animal that will be treated and for the parasite involved. In general, it will be administered as a formulation in association with at least one veterinary acceptable carrier. The term "carrier" is used in this report to describe any ingredient (e.g. excipient, diluents and the like) except the compound of the present invention or any additional veterinary agent (e.g. antiparasitic). The choice of carrier will, in large part, depend on factors such as the particular mode of administration, the carrier's effect on solubility and stability, and the nature of the dosage form. In addition to the carriers, the amount of the compound of the present invention that is administered and the dosage regimen for treating a condition or disorder with the compound depends on a variety of factors, including the age, weight, sex and medical condition of the animal, the severity disease, route and frequency of administration and thus can vary widely.

[089] In another aspect, the veterinary composition comprises a compound having Formula (1) with at least one veterinary acceptable carrier. The concentration range will vary depending on the composition (eg oral, topical or injectable). For an oral dose, the range of actives (i.e., compound of the present invention) is from about 0.1 to 50 mg/kg, preferably from about 0.2 to 25 mg/kg, and even more preferably , from about 0.25 to 10 mg/kg, and more preferably from about 0.5 to 7 mg/kg or 1 to 5 mg/kg. For a topical solution, the active range is from about 0.1 to 1000 mg/mL, and preferably from about 0.5 to 500 mg/mL, and most preferably from about 1 to 250 mg /ml, and even more preferably from about 2 to 200 mg/ml. Depending on the final volumes of topical solutions, the concentration of actives may change from that described above. In general, injectable doses tend to be, but not always, lower in concentration.

[090] The formulations can be prepared using conventional dissolution and mixing procedures. Such compositions and methods for their preparation can be found, for example, in 'Remington's Veterinary Sciences', 19th Edition (Mack Publishing Company, 1995; and "Veterinary Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980 (ISBN 0-8247-6918-X).

[091] A typical formulation is prepared by mixing a compound having Formula (1) with at least one veterinary acceptable carrier. Suitable carriers are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, starches, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carriers will depend on the means and purpose for which the compound of the present invention is to be applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe to administer to an animal. Formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other additives known to provide an elegant presentation of the drug (i.e., a compound of the present invention or veterinary composition thereof) or aid in the manufacture of the veterinary product (i.e., drug). The compound of the present invention will typically be formulated into veterinary dosage forms to provide an easily manageable dosage form for administration.

[092] The methods by which the compound of the present invention can be administered include oral, topical, and injectable (e.g., parenteral and subcutaneous) administration. The particular route selected by the skilled practitioner depends on factors such as the physicochemical properties of the therapeutic agent, the condition of the host, and economics. In certain cases, it is convenient and effective to administer veterinary drugs orally by placing the therapeutic agent in a solid or liquid matrix that is suitable for oral delivery. These methods include chewable drug delivery formulations. The problem associated with administering oral formulations to animals is that the therapeutic agent often provides an unpleasant taste, aroma or texture, which causes the animals to reject the composition. This is further exacerbated by compositions that are hard and difficult to swallow.

[093] The compound of the present invention can be orally administered by capsule, bolus, tablet, powders, expectorant lozenges, chewing gum, multi and nanoparticulates, gels, solid solution, films, sprays or liquid form. This is a preferred method of administration and, as such, it is desirable to develop the compound for oral administration. Such formulations may be used as fillers in soft or hard capsules, soft or hard savory chewing gum, which typically comprise at least one veterinary acceptable carrier, for example, water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents, flavors, and/or suspending agents. Liquid forms include suspensions, solutions, syrups, potions and elixirs. Liquid formulations can also be prepared by reconstituting a solid, for example from a sachet. Oral potions are commonly prepared by dissolving or suspending the compound of the present invention in a suitable medium (eg, triethylene glycol, benzyl alcohol and the like). The compound of the present invention can also be formulated with a food substance, for example a dietetic mixture (food pellets or bird powder).

[094] The compound of the present invention can be topically administered to the skin or mucosa, that is dermally or transdermally. This is another preferred method of administration and, as such, it is desirable to develop the compound of the present invention to be suitable for such formulations, for example liquid forms. Typical formulations for this purpose include pour-on, spot-on, multispot-on, stripe-on, comb-on, roll-on, dip, spray, mousse, shampoo, powder formulation, gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin plasters, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, N-methyl formamide, glycol monomethyl ethers, polyethylene glycol, propylene glycol and the like. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955 to 958 by Finnin and Morgan (October 1999). Pour-on or spot-on formulations can be prepared by dissolving the active ingredients in an acceptable liquid carrier such as butyl digol, liquid paraffin or a non-volatile ester, optionally with the addition of a volatile component such as propan- 2-ol or a glycol ether. Alternatively, pour-on, spot-on or spray formulations can be prepared by means of encapsulation, to leave a residue of active agent on the surface of the animal, this effect can ensure that the compound of the present invention shows increased persistence of action and be more durable, for example, it can be faster in water. Topical formulations contemplated in this report may comprise from about 0.1 mg/kg to 50 mg/kg of a compound of the present invention, and, more preferably, from about 1 mg/kg to 10 mg/kg of a compound of the present invention. invention, and even more preferably from 1 mg/kg to 5 mg/kg.

[095] The compounds of the present invention can also be administered topically through a support matrix, for example, a synthetic or natural resin, plastic, fabric, leather or other polymeric system in the form of a necklace or ear tag. Said ear collar or tag may be coated, impregnated, overlaid, by any means, so as to provide a veterinary acceptable amount of a compound of the present invention alone, or with at least one veterinary acceptable carrier, and, optionally, an antiparasitic agent. additive, or veterinary acceptable salts thereof. Such formulations are prepared in a conventional manner, in accordance with standard medicinal or veterinary practice. Furthermore, these formulations will vary with respect to the weight of the active compound contained therein, depending on the species of host animal to be treated, the severity and type of infection or infestation, and the body weight of the animal. The volume of applied composition can be from about 0.2 ml/kg to 5 ml/kg, and preferably from about 1 ml/kg to 3 ml/kg.

[096] Agents can be added to the formulations of the present invention to improve the persistence of such formulations on the surface of the animal to which they will be applied, for example, to improve their persistence on the animal's coat. Particularly, it is preferred to include such agents in a formulation that is to be applied as a pour-on or spot-on formulation. Examples of such agents include acrylic copolymers and, in particular, fluorinated acrylic copolymers. One particular suitable reagent is the trademark “Foraperle” reagent (Redline Products Inc, Texas, USA). Certain topical formulations may include off-taste additives to minimize oral exposure.

[097] The compounds of the present invention can also be administered by injection. Injectable (eg, subcutaneous and parenteral) formulations may be prepared in the form of a sterile solution, which may contain other substances, for example, salts or sufficient glucose to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils, such as sesame oil, glycerides, such as triacetin, esters, such as benzyl benzoate, isopropyl myristate, and propylene glycol fatty acid derivatives, as well as organic solvents, such as pyrrolidin-2- one and glycerol formal. The formulations are prepared by dissolving or suspending the compounds of the present invention alone or with at least one additional antiparasitic agent in the liquid carrier such that the final formulation contains from about 0.01 to 30% by weight of the active ingredients.

[098] Devices suitable for injectable administration include needle injectors (including microneedle), needleless injectors, and infusion techniques. Injectable formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), but for some applications may be more suitably formulated as a sterile non-aqueous solution or as a a dry powder form that can be used in combination with a suitable vehicle, such as sterile pyrogen-free water. Preparation of injectable formulations under sterile conditions, for example by lyophilization, can be readily accomplished using standard veterinary techniques well known to those skilled in the art. The solubility of a compound of the present invention used in the preparation of an injectable solution can be increased by the use of appropriate formulation techniques, such as the incorporation of solubility enhancing agents.

[099] The administration of the compound of the present invention is considered once a month. However, an extended-acting formulation may include dosing once every 2, 3, 4, 5, or 6 months.

[0100] Such formulations are prepared in a conventional manner, in accordance with standard medicinal or veterinary practice. Furthermore, these formulations will vary with respect to the weight of active compound contained therein, depending on the species of host animal to be treated, the severity and type of infection or infestation, and the body weight of the animal.

[0101] The composition of the present invention can be administered alone, as described above, or in combination with at least one other additional antiparasitic agent to form a multi-component parasiticide that provides an even broader spectrum of veterinary utility. Thus, the present invention also encompasses a veterinary combination composition comprising an effective amount of the compound of the present invention in combination with at least one other additional antiparasitic agent and may further comprise at least one veterinary acceptable carrier.

[0102] The following list of additional antiparasitic agents together with the compound of the present invention can be used to illustrate possible combinations, but does not impose any limitation. Non -limiting examples of additional antiparasitic agents include: amitraz, aminoacetonitriles, albendazole, Cambendazole, phenbendazole, flubendandozole, tiabendazole, mebendazole, octadepsipeptides, oxfendazole, oxybendazole, parademide, parbendazole, pipezinas, praziquanzin OL, tetramisol, triclabendazole, levamisol, pirantel ( including the salt forms - pamoate, citrate and tartrate), oxantel, morantel, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin, dimadectin, latidectin, lepimectin, milbemycin, milbemycin oxime, demiditraz, emodepside, fipronil, methoprene, diethylcarbamazine, hydroprene, cynoprene, lufenuron, metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyfen, closantel, clorsulone, novaluron, fluazuron, spinosad, sarolaner ((S)-1-(5'-(5-(3,5-dichloro- 4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetidin-3,1'-isobenzofuran]-1-yl)-2-(methylsulfonyl) -ethan-1-one), fluralaner (4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-2-methyl-N- (2-oxo-2-((2,2,2-trifluoroethyl)amino)-ethyl)benzamide), afoxolaner (4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl) -4,5-dihydro-isoxazol-3-yl)-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-1-naphthamide), lotilaner (3-methyl -N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)- 4,5-dihydro-1,2-oxazol-3-yl]thiophene-2-carboxamide); and mixtures thereof. Additional preferred antiparasitic agents include moxidectin, doramectin, selamectin, abamectin, milbemycin, milbemycin oxime, pyrantel, praziquatel, and levamisole.

[0103] The veterinary composition for application to an animal can be packaged in various forms, depending on the method used to administer the compound of the present invention or combination thereof. In general, an article for distribution includes a container having the veterinary composition deposited therein in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as vials (plastic and glass), sachets, ampoules, plastic pouches, metal cylinders and the like. The container may also include a tamper-evident assembly to prevent indiscreet access to the contents of the package. In addition, the container has a marking deposited thereon that describes the contents of the container. Markup can also include appropriate warnings.

[0104] The compounds of the present invention (including the compositions and processes used therein) can also be used in the manufacture of a medicament for the therapeutic applications described in this report.

[0105] The compounds of the present invention, stereoisomers thereof, and compositions comprising a therapeutically effective amount of a compound having Formula (1) and at least one veterinary acceptable carrier are useful as ectoparasiticides for the control and treatment of overt infections or infestations by said ectoparasite in an animal. The compounds of the present invention have utility as an ectoparasiticide, in particular as an acaricide and insecticide. They can, in particular, be used in the fields of veterinary medicine, livestock and in the maintenance of public health: against acarids, insects and copepods which are parasitic on vertebrates, particularly warm-blooded vertebrates, including companion animals, farm animals and poultry and cold-blooded vertebrates such as fish.

[0106] The compounds of the present invention are useful for the treatment of parasitic worms categorized as cestodes (tapeworms), nematodes (roundworms) and trematoids (flatworms or flukes). Gastrointestinal roundworms include, for example, Ostertagia ostertagi (including inhibited larvae), O. lyrata, Haemonchus placei, H. similis, H. contortus, Toxocara canis, T. leonina, T. cati, Trichostrongylus axei, T. colubriformis, T. longispicularis, Cooperia oncophora, C. pectinata, C. punctata, C. surnabada (syn. mcmasteri), C. spatula, Ascaris suum, Hyostrongylus rubidus, Bunostomum phlebotomum, Capillaria bovis, B. trigonocephalum, Strongyloides papillosus, S. ransomi, Oesophagostomum radiatum, O. dentatum, O. columbianum, O. quadrispinulatum, Trichuris spp. and the like. Other parasites include: hookworms (eg, Ancylostoma caninum, A.tubaeforme, A.braziliense, Uncinaria stenocephala); lungworms (eg Dictyocaulus viviparus and Metastrongylus spp); eye worms (eg, Thelazia spp); parasitic stage larvae (eg Hypoderma bovis, H. lineatum, Dermatobia hominis); kidney flukes (eg Stephanurus dentatus); blowfly (eg, Cochliomyia hominivorax (larvae); filarial nematodes of the superfamily Filarioidea and the Family Onchocercidae. Non-limiting examples of filarial nematodes within the Family Onchocercidae include the genus Brugia spp. (ie, B. malayi, B. pahangi, B. timori and the like), Wuchereria spp. (i.e., W. bancrofti and the like), Dirofilaria spp. (D. immitis, D. repens, D. ursi, D. tenuis, D. spectans, D. lutrae and the like), Dipetalonema spp.(ie D reconditionum, D.repens and the like), Onchocerca spp.(ie O. gibsoni, O. gutturosa, O. volvulus and the like), Elaeophora spp.(E. bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri and the like), Mansonella spp. (ie M. ozzardi, M. perstans and the like) and Loa spp. (ie L. loa) In another aspect of the invention, the compound of the present invention is useful for treating endoparasiticidal infection from filarial nematodes within the genus Dirofilaria (i.e., D. immitis, D. repens, D. ursi, D. tenuis, and the like). .

[0107] The compounds of the present invention can also be used against ectoparasites, alone or in combination with at least one additional antiparasitic agent. Some non-limiting examples of ectoparasites include: ticks (eg Ixodes spp., (eg I. ricinus, I. hexagonus), Rhipicephalus spp., (eg R. sanguineus), Boophilus spp., Amblyomma spp. (e.g. A. maculatum, A. triste, A. parvum, A. cajennense, A. ovale, A. oblongoguttatum, A. aureolatum, A. cajennense), Hyalomma spp., Haemaphysalis spp., Dermacentor spp. (e.g. example, D. variabilis, D. andersoni, D. marginatus), Ornithodorus spp., and the like); mites (eg Dermanyssus spp., Sarcoptes spp., (eg S. scabiei), Psoroptes spp., (eg P/bovis), Otodectes spp., Chorioptes spp., Demodex spp., (eg , D. folliculorum, D. canis and D. brevis) and the like); biting and sucking lice (e.g., Damalinia spp., Linognathus spp., Cheyletiella spp., Haematopinus spp., Solenoptes spp., Trichodectes spp., Felicola spp., and the like); fleas (e.g., Siphonaptera spp., Ctenocephalides spp., and the like); biting flies, flies and mosquitoes (e.g. Tabanidae spp., Haematobia spp., Musca spp., Stomoxys spp., Dematobia spp., Cochliomyia spp., Simuliidae spp., Ceratopogonidae spp., Psychodidae spp., Aedes spp. , Culex spp., Anopheles spp., and the like); moths (for example, insects within the genus Cimex and family Cimicidae); and larvae (eg Hypoderma bovis, H.lineatum); and copepods (eg, sea louse within the Order Siphonostomatoida, including the genera Lepeophtheirus and Caligus).

[0108] The compounds of the present invention and compositions comprising the compounds of the present invention in combination with at least one other antiparasitic agent are of particular value in the control of ectoparasites and endoparasites that are harmful to, or propagate, or act as vectors of disease in animals company, breeding, birds and fish. Ectoparasites and endoparasites that can be treated with a combination of a compound having Formula (1) and an additional antiparasitic agent include those described in this report.

[0109] Any of the compounds of the present invention or a suitable combination of a compound of the present invention and, optionally, with at least one additional antiparasitic agent can be directly administered to the animal and/or indirectly through the application of the same to the local environment in which the animal lives (such as a mattress, fenced land, and the like). Direct administration includes contacting the skin, fur or feathers of an animal with the compounds or by feeding or injecting the animal with the compounds.

[0110] The compound having Formula (1), stereoisomers thereof, veterinary acceptable salts thereof, and combinations with at least one additional antiparasitic agent, as described in this report, are of value for the treatment and control of the various stages of life cycle of parasites including egg, nymph, larval, juvenile, and adult stages.

[0111] The present invention also relates to a method for administering a compound of the present invention alone or in combination with at least one additional antiparasitic agent and, optionally, at least one veterinary acceptable carrier, to animals in good health comprising the application to said animal to reduce or eliminate the potential for human infection or parasitic infestation from parasites carried by the animal and to improve the environment in which the animals inhabit.

[0112] The present invention also relates to a method for administering a compound of the present invention alone or in combination with at least one additional antiparasitic agent and, optionally, at least one veterinary acceptable carrier, to a human in good or bad health comprising application to said human to reduce or eliminate the potential for human parasitic infection or infestation from human-borne parasites and to improve the environment in which the human inhabits.

[0113] The present invention also relates to a method for administering a compound of the present invention alone or in combination with at least one additional antiparasitic agent and, optionally, at least one veterinary acceptable carrier, to a plant or soil to prevent parasitic infection the plant.

[0114] The reactions shown below were generally performed under a positive pressure of argon or nitrogen or with a drying tube, at room temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for introducing substrates and reagents via syringe. The glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed using pre-coated silica gel plates supported with 60 F 254 glass and eluted with appropriate solvent ratios (v/v). Reactions were evaluated by TLC or LCMS and terminated as judged by consumption of starting material. Visualization of the TLC plates was done with UV light (wavelength 254 nM) or with an appropriate heat-activated TLC visualization solvent. Flash column chromatography (Still et al., J. Org. Chem. 43, 2923, (1978) was performed using silica gel (RediSep Rf) or various MPLC systems, such as Biotage or ISCO purification system.

[0115] Conventional separation and purification methods and/or techniques known to a person of ordinary skill in the art can be used to isolate the compounds of the present invention, as well as the various intermediates related thereto. Such techniques will be well known to a person of ordinary skill in the art and may include, for example, all types of chromatography (e.g. high pressure liquid chromatography (HPLC), column chromatography using common adsorbents such as silica gel , and thin layer chromatography (TLC), recrystallization, and differential (ie, liquid-liquid) extraction techniques.

[0116] The structures of the compound in the examples below were confirmed by one or more of the following methods: proton resonance magnetic spectroscopy and mass spectroscopy. Proton magnetic resonance (1H NMR) spectra were determined using a Bruker spectrometer operating at a field strength of 400 megahertz (MHz). Chemical substitutions are reported in parts per million (ppm) from an internal tetramethylsilane standard. Mass spectral (MS) data were obtained using an Agilent atmospheric pressure chemical ionization mass spectrometer. Method: Acquity UPLC with chromatography performed on a Waters BEH C18 column (2.1 x 50 mm, 1.7 μm) at 50 °C. The mobile phase was a binary gradient of acetonitrile (containing 0.1% trifluoroacetic acid) and water (5 to 100%).

[0117] Certain aspects of the present invention are illustrated by the following examples. It is to be understood, however, that aspects of the invention are not limited to the specific details of these Examples, as other variations thereof will be known or apparent in light of the present disclosure, to a person skilled in the art.

[0118] The compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include diastereomers, for example, cis/trans (E/Z) isomers. A person skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomers or when separated from the other stereoisomers. Additionally, the skilled person knows how to selectively separate, enrich and/or prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers.

EXAMPLES

[0119] The following examples were prepared, in accordance with the Schemes and preparations presented in this report. Examples of mass and NMR data are shown in Table 3. Aldehyde Intermediates: Intermediate 1: (E)-3-(4-chloro-3,5-difluoro-phenyl)prop-2-enal; (E)-3-(4-chloro-3,5-difluorophenyl)acrylaldehyde Step 1: 4-chloro-3,5-difluoro-benzaldehyde

[0120] To a solution of 5-bromo-2-chloro-1,3-difluoro-benzene (5.0 g, 21 mmol) in THF at -40 °C (dry ice/acetonitrile bath) was slowly added complex of isopropylmagnesium chloride-lithium chloride (1.3 mol/L) in THF (22 mL, 29 mmol). The reaction was stirred for 15 minutes. Then DMF (3.1 mL, 40 mmol) was added. The reaction mixture was slowly warmed to -20 °C while stirring for 2 hours. Citric acid was added and the reaction mixture was extracted with EtOAc (2 x 75 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude material was chromatographed (80 g Redi-Sep column) eluting from 100% hexanes to 10:90 EtOAc:hexanes to afford the intermediate (3.25 g, 70%) as a solid. 1H-NMR (400 MHz, CDCl3) δ: 7.52 - 7.56 (m, 2H), 9.95 (t, 1H).Step 2: Preparation of Intermediate 1. To a 4-chloro solution -3,5-difluoro-benzaldehyde (4.0 g, 22.6 mmol) in toluene (100 mL) was added (triphenylphosphonylidene)acetaldehyde (7.7 g, 25.3 mmol). The reaction mixture was heated at 85°C for 18 hours. Then, the reaction mixture was cooled and concentrated under vacuum. The crude material was chromatographed (220 g Redi-Sep column) eluting from 100% hexanes to 10:90 EtOAc:hexanes to give the title compound (3.3 g, 72%) as a solid. 1H NMR (400 MHz, CDCl3) δ: 6.66 - 6.72 (m, 1H), 7.19 - 7.23 (m, 2H), 7.37 (d, 1H), 9 .75 (d, 1H).

[0121] The following aldehyde intermediates (I-2 to I-16 and I-19 to I-27) in Table 1 were prepared following the same procedure as Step 2 of Intermediate 1, but using one of the respective commercially available benzaldehydes: 4-methylsulfonylbenzaldehyde; 4-chloro-3-fluoro-benzaldehyde; 2,4-dichloro-benzaldehyde; 4-bromo-2-fluoro-benzaldehyde; 4-chloro-2,6-difluoro-benzaldehyde; 4-chloro-2-fluoro-benzaldehyde; 4-bromo-3-fluoro-benzaldehyde; 2,4,6-trifluorobenzaldehyde; 2-bromo-5-fluoro-benzaldehyde; 5-bromo-2-fluoro-benzaldehyde; 3-bromo-4-fluoro-benzaldehyde; 2,3,4-trifluorobenzaldehyde; 4-bromo-2,3-difluoro-benzaldehyde; 4-chloro-2,3-difluoro-benzaldehyde; pentafluoro-benzaldehyde; 3,5-dichloro-4-fluoro-benzaldehyde; 2-fluoro-5-formylbenzonitrile; 2-fluoro-4-formylbenzonitrile; 3-fluoro-5-(trifluoromethoxy)benzaldehyde; 2,4-difluoro-5-bromo-benzaldehyde; 3,5-difluoro-4-methoxy-benzaldehyde; 4-chloro-2-fluoro-3-methoxy-benzaldehyde; 2-fluoro-3,6-dichloro-benzaldehyde; and 4-bromo-2,5-difluoro-benzaldehyde. Aldehyde Intermediate 17 was synthesized using the procedure in the Journal of Fluorine Chemistry (130 (2009) 175 to 196). Table 1. Aldehyde Intermediates (I - #) Prepared from Commercially Available Benzaldehydes Intermediate 18: (E)-3-(5-(trifluoromethyl)pyridin-2-yl)prop-2-enal; (E)-3-(5-(trifluoromethyl)pyridin-2-yl)acrylaldehyde

[0122] To commercially available 2-bromo-5-trifluoromethylpyridine (295 g, 1.3 mol) in DCM (4 L) at -2 °C was added iPrMgCl (2 M in Et2O, 750 ml, 1.5 mol) for 3 minutes, then stirred at 0 to 6 °C for 40 minutes [jacket at 0 °C, gentle and gradual exotherm brought to temp. pot at 6 °C maximum after about 15 minutes]. The mixture was cooled to -20 °C, then DMF (200 mL, 2.6 mol) was added in one portion [exotherm to 6 °C]. The mixture was slowly re-cooled to 0 °C over 20 minutes, then quenched by adding 1.5 L saturated NaHCO 3 in one portion [temperature to 12 °C]. The mixture was stirred at 12°C for 15 minutes, then filtered through a pad of celite. The layers have been separated. The filtered solids were washed with 1 L DCM and this was then used to re-extract the aqueous layer. The combined organics were dried over MgSO 4 , filtered through a 1 kg silica pad, washed with 5 L DCM and evaporated (bath temp 35°C). The brown oil was dissolved in 2 L hexane and washed with 2 x 1 L 12% brine to remove DMF. The organics were filtered through a pad of MgSO4 and concentrated to low volume. This oil was distilled at 35 °C and 20 in Hg to remove hexane, then at 56 °C and 26 in Hg to provide the product 5-(trifluoromethyl)-picolinaldehyde (154 g, about 90% purity, 0.79 mol, 61 %) as a light yellow wet crystal. A solution of 5-(trifluoromethyl)picolinaldehyde (150 g, about 90% purity, 0.77 mol) in DCM (1.5 L) was bubbled with nitrogen for 5 minutes and cooled to 9 °C. (Formylmethylene)triphenylphosphorane (257 g, 0.85 mol) was added in one portion [exotherm to 19 °C] and the reaction stirred at 20 °C for 60 minutes. The mixture was filtered through a pad of magnesol (100g) and washed with DCM (400ml). The filtrate was evaporated at 40°C. The residue was triturated with MTBE (150 ml), then diluted with hexane (300 ml) and filtered, washing with MTBE/hexane. The filtrate was diluted with DCM to solubilize a small amount of oil which was separated and then chromatographed (3 kg silica, 20 to 35% MTBE in hexane) to provide the desired product (60.3 g, 0.30 mol, 39% ) as a dark red solid. 1H NMR (500 MHz, CDCl3) δ 9.85 (d, 1H), 8.95 (s, 1H), 8.02 (dd, 1H), 7.66 (d, 1H), 7.55 (d, 1H), 7.19 (dd, 1H). Intermediate 28. (Z)-3-(4-chlorophenyl)-2-fluoroacrylaldehyde Step 1: Synthesis of (Z)-1-ethoxy-2-fluoro-2-trimethylsilanyl-1-trimethylsilanyloxy-ethylene

[0123] In a 250 mL round bottom flask, to a stirred solution of fluoro-acetic acid ethyl ester (7.5 gm, 70.68 mmols, 1eq) and trimethylsilyl chloride (19.73 mL, 155, 51 mmol, 2.2 eq) in dry THF (23 mL) at -78 °C was added dropwise a solution of LDA (21.07 mL, 155.51 mmol, 2.2 eq, LDA freshly prepared by means of the use of n-BuLi (62.19 mL, 155.51 mmol, 2.2 eq and diisopropyl amine (21.8 mL, 155.51 mmol, 2.2 eq) in dry THF (52.5 mL) to - 78 °C under a nitrogen atmosphere. The resulting slurry was stirred at -78 °C for 2 hours and then allowed to return to room temperature and then diluted with dry hexane (150 mL) and filtered. The filtrate was concentrated under reduced pressure to give yellow liquid (18 gm, crude) The crude product was used as such for the next step. MW 250.46.Step 2: Synthesis of (Z)-3-(4-chloro-phenyl)-acid ethyl ester 2-fluoro-acrylic

[0124] In a 500 mL round bottom flask to the stirred solution of 4-chloro-benzaldehyde (14 gm, 99.595 mmol, 1eq) and tetrabutylammonium acetate (1.501 gm, 4.98 mmol, 0.05 eq) in dichloromethane (150ml) was added (Z)-1-ethoxy-2-fluoro-2-trimethylsilanyl-1-trimethylsilanyloxy-ethene (34.922 gm, 139.43 mmol, 1.4 eq) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After completion of the starting material, the reaction mixture was quenched with aqueous (1M) HCl (75 mL) and brine (75 mL). The aqueous layer was extracted with dichloromethane (75 mL x 2). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give yellow oil as crude compound 20g. Purification was done by combiflash column chromatography (120 gm Redisep column). The compound was eluted by 0.5% ethyl acetate in hexane to give off-white solid (17 g, 74.66%). 1H NMR (400 MHz, CDCl3) δ: 1.35 - 1.38 (m, 3H), 4.31 - 4.36 (q, 2H), 6.86 (d, 1H), 7 .34 - 7.38 (m, 2H), 7.54 - 7.58 (m, 2H). LC-MS (m/z): Non-ionized. Step 3: Synthesis of (Z)-3-(4-Chloro-phenyl)-2-fluoro-prop-2-en-1-ol:

[0125] In a 500 mL round bottom flask to a stirred solution of (Z)-3-(4-chloro-phenyl)-2-fluoro-acrylic acid ethyl ester (9 gm, 39.361 mmol, 1 eq) in Dichloromethane (100ml) was added diisobutylaluminum hydride (1M in THF) (5.598gm, 39.36ml, 39.361mmols, 1eq) at -78°C. Then, the reaction mixture was stirred at room temperature for 15 hours. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was quenched with aqueous tartrate salt solution (100 mL). The aqueous layer was extracted with dichloromethane (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give yellow semisolid crude compound 10 g. 7.2 g of the crude compound from the previous batch was mixed and purified by combiflash (120 gm, Redisep column). The compound was eluted using 8% ethyl acetate in hexane to provide 8 g as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.93 (t, 1H), 4.24 - 4.29 (dd, 2H), 5.74 (d, 1H), 7.21 - 7 .31 (m, 2H), 7.40 - 7.44 (m, 2H). LC-MS (m/z): Non-ionized. Step 4: Synthesis of Intermediate 28.

[0126] In a 100 mL round bottom flask to a stirred solution of (Z)-3-(4-chloro-phenyl)-2-fluoro-prop-2-en-1-ol (4 gm, 21, 43 mmol, 3.0 eq) in chloroform (50 mL) was added MnO 2 (9.31 gm, 107.17 mmol, 5.0 eq). The resulting reaction mixture was heated at 60°C for 5 hours. The progress of the reaction was monitored by TLC. TLC showed unreacted starting material on TLC, so again MnO 2 (9.31 gm, 107.17 mmol, 5.0 eq) was added and the reaction continued at 60°C for 15 hours. After maximum consumption of starting material, the reaction mass was filtered on a Buchner funnel and washed with DCM (50 mL x 2). The filtrate was evaporated under reduced pressure to give yellow oil (5 gm, crude). Purification was done by combiflash column chromatography (40 gm Redisep column). The compound was eluted by 2% ethyl acetate in hexane to give off-white solid (2.2 gm, 55.56%). 1H NMR (400 MHz, CDCl3) δ: 6.57 (d, 1H), 7.41 (d, 2H), 7.64 (d, 2H), 9.35 (d, 1H). LC-MS (m/z): Non-ionized.

[0127] Commercially available aldehyde intermediates (I-#) were also used to prepare the compounds of the present invention and included: (E)-3-(2-chloro-4-fluorophenyl)acrylaldehyde (I-29); (E)-3-(2,4-difluorophenyl)-acrylaldehyde (I-30); (E)-3-(3-chloro-4-fluorophenyl)acrylaldehyde (I-31); (E)-3-(3,4-difluorophenyl)acrylaldehyde (I-32); (E)-3-(3,4,5-trifluorophenyl)acrylaldehyde (I-33); (E)-3-(3,5-difluorophenyl)acrylaldehyde (I-34); (E)-3-(3-chloro-2-fluoro-phenyl)acrylaldehyde (I-35); (E)-3-(2,3-difluorophenyl)acrylaldehyde (I-36); 4-[(E)-3-oxoprop-1-enyl]benzonitrile (I-37); (E)-3-(4-chlorophenyl)acrylaldehyde (I-38); (E)-3-(3,4-dichlorophenyl)acrylaldehyde (I-39); (E)-3-(4-fluorophenyl)acrylaldehyde (I-40); (E)-3-(pyridin-4-yl)acrylaldehyde (I-41); (E)-3-(2-bromo-4-fluorophenyl)acrylaldehyde (I-42); (E)-3-(4-bromothiophen-2-yl)acrylaldehyde (I-43); (E)-3-(4-methoxyphenyl)acrylaldehyde (I-44); (E)-3-(4-(trifluoromethoxy)-phenyl)acrylaldehyde (I-45); (E)-3-(4-(trifluoromethyl)phenyl)acrylaldehyde (I46); 6-bromo-2-naphthaldehyde (I-47); 7-chloroisoquinoline-3-carbaldehyde (I-48); 6-fluoro-2-naphthaldehyde (I-49); 2-chloroquinoline-6-carbaldehyde (I-50); 6-chloro-2-naphthaldehyde (I-51); (E)-3-(3-chloro-5-fluorophenyl)acrylaldehyde (I-52); (E)-3-(4-fluoro-3-methoxyphenyl)acrylaldehyde (I-53); (E)-3-fluoro-5-(3-oxoprop-1-en-1-yl)benzonitrile (I-54); (E)-3-chloro-5-(3-oxoprop-1-en-1-yl)benzonitrile (I-55); (E)-3-(3-bromo-5-fluorophenyl)acrylaldehyde (I-56); (E)-3-(3,5-dichlorophenyl)acrylaldehyde (I-57); cinnamaldehyde (I-58), (E)-3-(4-chloro-3-methyl-phenyl)acrylaldehyde (I-59); and (E)-3-(3-bromo-4-chlorophenyl)acrylaldehyde (I-60).

[0128] For the reactions and Examples described in this report, the Fischer indole reaction of a meta-substituted hydrazine and a piperidinone produces regio-isomers that can be separated by chromatography to obtain the individual 7' and 9' gamma- isomers carboline. For example, the reaction of (3-bromophenyl)hydrazine and piperidin-4-one hydrochloride will yield 7-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 9 -bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as shown in Step 1 of Example 1. Similar reactions occur for 3-chloro, -fluoro, -methyl, -methoxy, -trifluoromethyl, -trifluoromethoxy and the like, meta-substituted phenyl hydrazines.

[0129] Non-limiting examples of commercially available hydrazines used to prepare the compounds of the present invention included: (3-bromophenyl)hydrazine, (4-bromophenyl)hydrazine, m-tolylhydrazine, (3-trifluorophenyl)hydrazine, (4- fluorophenyl)hydrazine, (3-chlorophenyl)hydrazine, 4-hydrazinyl-2-(trifluoromethyl)benzonitrile, 2-fluoro-5-hydrazinylbenzonitrile, 5-hydrazinyl-2-methylbenzonitrile, 2-chloro-4-hydrazinyl-benzonitrile, 2- fluoro-4-hydrazinylbenzonitrile, (4-bromo-3-methylphenyl)hydrazine, (4-bromo-3-methoxyphenyl)hydrazine, (4-bromo-3-chlorophenyl)hydrazine, (4-bromo-3-fluorophenyl)hydrazine, (3,4-dibromophenyl)hydrazine, (4-chlorophenyl)hydrazine, (2-chlorophenyl)hydrazine, (3,4-dichlorophenyl)hydrazine, (3-chloro-4-fluorophenyl)hydrazine, (3-fluoro-5 -(trifluoromethyl)phenyl)hydrazine, (4-chloro-3-(trifluoromethyl)phenyl)hydrazine, (4-methoxy-3-(trifluoromethyl)phenyl)hydrazine, (4-methyl-3-(trifluoromethyl)phenyl)hydrazine , (3-(trifluoromethoxy)phenyl)hydrazine, (4-(trifluoromethoxy)phenyl)hydrazine, (4-(trifluoromethyl)phenyl)hydrazine, p-tolylhydrazine, naphthalen-2-ylhydrazine, (4-methylsulfanylphenyl) hydrazine, 2-chloro-5-hydrazinylbenzonitrile, (4-(methylsulfonyl)phenyl)hydrazine, 4-bromo-3-ethoxy-phenyl)-hydrazine and the like.

[0130] The pyridyl isocyanates were prepared, according to Scheme 2, using the appropriate commercially available substituted pyridyl methanamines, for example, (2,6-dichloropyridin-4-yl)methanamine, (2-chloropyridin-4 -yl)methanamine, (2-fluoropyridin-4yl)methanamine, (2-cyclopropylpyridin-4-yl)methanamine, 2-trifluoropyridin-4yl)methanamine, (2-hydroxypyridin-4-yl)methanamine, (2-cyclopropylpyridin-4yl) )methanamine, (2-methoxypyridin-4yl)methanamine, (2-chlorothiazol-5-yl)methanamine and the like. Alternatively, substituted phenylmethanamines, for example (4-fluorophenyl)methanamine, (4-chlorophenyl)methanamine and the like can be used.

[0131] In the Examples described below, the respective substituted pyridyl methanamine was used to prepare the respective pyridyl isocyanate. For example, (2-chloropyridin-4-yl)methanamine was used to prepare 2-chloro-4-(isocyanatomethyl)pyridine, in Example 1. Similarly, (2,6-dichloropyridin-4-yl)methanamine was used, along with in place of (2-chloropyridin-4-yl)methanamine to prepare 2,6-dichloro-4-(isocyanatomethyl)pyridine, in Example 187. Similar preparations were made for each of the respective ureas. Example 1. (E) HCl -2-(3-(4-chloro-3,5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide Step 1: 7-Bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 9-bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole:

[0132] To a solution of (3-bromophenyl)hydrazine (10.0 g, 53.5 mmol) in IPA (100 mL) was added piperidin-4-one HCl (7.9 g, 58.8 mmol) and HCl (40 mL of a 4.0 M dioxane solution). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled, filtered and rinsed with IPA to give the intermediate HCl salt as a mixture of regioisomers. LC-MS (m/z): [M+H] = 251, 253. Step 2: Calcium 7-bromo-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate tert-butyl

[0133] To a mixture of 7-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 9-bromo-2,3,4,5-tetrahydro -1H-pyrido[4,3-b]indole (12.5 g, 43.5 mmol) in CH 2 Cl 2 (150 mL) was added triethylamine (18.4 mL, 130.0 mmol) followed by BOC anhydride (8. 3 g, 47.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the organic phase was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude mixture was chromatographed (220 g Redi-Sep column) eluting from 100% hexanes to 25:75 EtOAc:hexanes, collecting the title compound as the first eluting peak. LC-Ms (m/z): [M+H-tbutyl] = 295, 297. The second eluting peak constituted the 9' regioisomer. Step 3: tert-Butyl 7-cyano-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate

[0134] To a solution of tert-butyl 7-bromo-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (6.4 g, 18 mmol) in DMF ( 100 mL) was added Zn(CN)2 (1.5 g, 13 mmol), Zn(OAc)2 (670 mg, 3.6 mmol), Pd(DPPF2)Cl2 (810 mg, 1.1 mmol), and zinc dust (480 mg, 7.3 mmol). The reaction mixture was purged with nitrogen and heated to 100°C for 18 hours. The reaction mixture was cooled and poured into ice water (100 mL). The resulting precipitate was filtered and washed with additional water. The precipitate was dissolved in CH2Cl2 (300 mL), dried (Na2SO4), and concentrated in vacuo. The crude material was chromatographed (120 g Redi-Sep column) eluting from 100% hexanes to 50:50 EtOAc:hexanes to provide the title compound as a solid. LC-MS (m/z): [M+Ht-butyl] = 242. Step 4: 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-cyano-3,4-dihydro-1H - tert-butyl pyrido[4,3-b]indole-2-carboxylate

[0135] To a stirred solution of tert-butyl 7-cyano-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (5.0 g, 16.8 mmol) in THF (75 mL) at 0 °C was added sodium hydride (1.2 g, 30.3 mmol). The reaction mixture was warmed to room temperature while stirring for 30 minutes. Then the mixture was again cooled to 0 °C in an ice bath and 2-chloro-4-(isocyanatomethyl)pyridine (3.4 g, 20.2 mmol) was added. The reaction was maintained at 0 °C while stirring for 15 minutes. The reaction was quenched with 5 mL of saturated NH 4 Cl, then ice water was added to the reaction mixture and it was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (Redi-Sep 120 g column) eluting from 25:75 EtOAc:hexanes to 40:60 EtOAc:hexanes to provide the title compound as a solid. LC-MS (m/z): [M+H-tbutyl] = 410. Step 5: N-[(2-chloro-4-pyridyl)methyl]-7-cyano-1,2,3,4-tetra -hydropyrido[4,3-b]indole-5-carboxamide

[0136] To a solution of 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-cyano-3,4-dihydro-1H-pyrido[4,3-b]indole-2-carboxylate of tert-butyl (5.2 g, 11.0 mmol) in DCM (100 mL) at 0 °C was added TFA (8.4 mL, 110 mmol). The reaction was warmed to room temperature and stirred for 18 hours. Toluene (35 mL) was added and the reaction was concentrated in vacuo. The resulting TFA salt was dissolved in EtOAc (175 mL) and saturated NaHCO 3 (75 mL) was added. The resulting precipitate was stirred at room temperature for 15 minutes, filtered, and dried under vacuum to give the title compound as a solid (3.53 g, 86%): LC-MS (m/z): [M+H ] = 366.Step 6: Preparation of Example 1. To a vial containing N-[(2-chloro-4-pyridyl)methyl]-7-cyano-1,2,3,4-tetrahydropyrido[4,3 -b]indole-5-carboxamide (90 mg, 0.25 mmol) was added (E)-3-(4-chloro-3,5-difluoro-phenyl)prop-2-enal (Intermediate 1) (60 mg , 0.30 mmol), and CH2Cl2 (5 mL). The mixture was stirred at room temperature for 15 minutes and sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours; then diluted with CH2Cl2 (50 mL), washed with saturated NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (24 g Redi-Sep column) eluting from 50:50 EtOAc:hexanes to 100% EtOAc. The purified product was subsequently dissolved in CH2Cl2 (10 mL) and HCl gas was bubbled in slowly until a precipitate formed. The mixture was diluted with diethyl ether (10 mL), stirred for 5 minutes, filtered, washed with additional diethyl ether, and dried under vacuum to provide the title compound as an HCl salt.

[0137] The following compounds were prepared similarly to Example 1, but using the respective aldehyde intermediate: Example 2, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2 -chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3); Example 3, (E)-N-[(2-chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(2,4-dichlorophenyl)allyl]-3,4-di -hydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-4); Example 4, (E)-N-((2-chloropyridin-4-yl)methyl)-9-cyano-2-(3-(2,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-4); Example 5, (E)-2-(3-(4-bromo-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-5); Example 6, (E)-2-(3-(4-chloro-2,6-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-6); Example 7, (E)-2-(3-(4-chloro-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 8, (E)-2-(3-(4-bromo-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-8); Example 9, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,4,6-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-9); Example 10, (E)-2-(3-(2-bromo-5-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-10); Example 11, (E)-2-(3-(5-bromo-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-11); Example 12, (E)-2-(3-(3-bromo-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-12); Example 13, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-13); Example 14, (E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-14); Example 15, (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-15); Example 16, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(perfluorophenyl)allyl)-1,2,3,4-tetrahydro-5H -pyrido[4,3-b]indole-5-carboxamide (I-16); Example 17, (E)-2-(3-(4-chloro-2,3,5,6-tetrafluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-17); Example 18, N-[(2-Chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(4-cyano-3-fluoro-phenyl)allyl]-3,4 HCl -dihydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 19, 2-[(E)-3-(5-Bromo-2,4-difluoro-phenyl)allyl]-N-[(2-chloro-4-pyridyl)methyl]-7-cyano-3 HCl ,4-dihydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-23); Example 20, N-[(2-Chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(3,5-difluoro-4-methoxy-phenyl)allyl]-3 HCl ,4-dihydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-24); Example 21, 2-[(E)-3-(4-chloro-2-fluoro-3-methoxy-phenyl)allyl]-N-[(2-chloro-4-pyridyl)methyl]-7-cyano HCl -3,4-dihydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-25); Example 22, N-[(2-Chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(3,6-dichloro-2-fluoro-phenyl)allyl]-3 HCl ,4-dihydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-26); Example 23, 2-[(E)-3-(4-Bromo-2,5-difluoro-phenyl)allyl]-N-[(2-chloro-4-pyridyl)methyl]-7-cyano-3 HCl ,4-dihydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-27); Example 24, (E)-2-(3-(2-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 25, (E)-2-(3-(2-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-9-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 26, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 27, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 28, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 29, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 30, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(3,5-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 31, (E)-2-(3-(3-chloro-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-35); Example 32, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,3-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-36); Example 33, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 34, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 35, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 36, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 37, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(pyridin-4-yl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-41); and Example 38, N-[(2-chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(4-fluoro-3-methoxy-phenyl)allyl]-3 HCl, 4-dihydro-1H-pyrido[4,3-b]indole-5-carboxamide (I-53) Example 39, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl HCl )-7-cyano-N-((2,6-dichloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1, but using (2,6-dichloropyridin-4-yl)methanamine and aldehyde intermediate, I-3.

[0138] The following compounds were prepared similarly to Example 1, but using (2-bromopyridin-4-yl)methanamine and the respective aldehyde intermediate: Example 40, (E)-N-((2-bromopyridin-4 -yl)methyl)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b ]indole-5-carboxamide (I-1) Example 41, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3); Example 42, (E)-N-((2-Bromopyridin-4-yl)methyl)-2-(3-(4-chloro-2-fluorophenyl)allyl)-7-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 43, (E)-N-((2-Bromopyridin-4-yl)methyl)-7-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-13); Example 44, (E)-N-((2-Bromopyridin-4-yl)methyl)-7-cyano-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 45, (E)-N-((2-Bromopyridin-4-yl)methyl)-7-cyano-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 46, (E)-N-((2-Bromopyridin-4-yl)methyl)-7-cyano-2-(3-(3,4,5-trifluorophenyl)-allyl)-1,2 HCl, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 47, (E)-N-((2-Bromopyridin-4-yl)methyl)-7-cyano-2-(3-(3,5-difluorophenyl)allyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 48, (E)-N-((2-Bromopyridin-4-yl)methyl)-2-(3-(4-chlorophenyl)allyl)-7-cyano-1,2,3,4-tetra HCl -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 49, (E)-N-((2-Bromopyridin-4-yl)methyl)-7-cyano-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-HCl tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40) The following compounds were prepared similarly to Example 1, but using (2-fluoropyridin-4-yl)methanamine and the intermediate Respective aldehyde: Example 50, (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-7-cyano-N-((2-fluoropyridin-4-yl)methyl)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-1) Example 51, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3); Example 52, (E)-2-(3-(4-chloro-2-fluorophenyl)allyl)-7-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 53, (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-7-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-15); Example 54, (E)-7-cyano-2-(3-(3-fluoro-5-(trifluoromethoxy)phenyl)allyl)-N-((2-fluoro-pyridin-4-yl)methyl)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-22); and Example 55, (E)-2-(3-(4-chlorophenyl)allyl)-7-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). Example 56, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-(pyridin-4-ylmethyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1, but using pyridin-3-yl-methanamine and aldehyde intermediate, I-3 Example 57, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((2-methylpyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1, but using (2-methylpyridin-4-yl)methanamine and aldehyde intermediate, I-3 Example 58, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((2,6-dimethylpyridin-4-yl)methyl)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1, but using (2,6-dimethylpyridin-4-yl)methanamine and aldehyde intermediate I -3 Example 59, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((2-methoxypyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared but using (2-methoxypyridin-4yl)methanamine and aldehyde intermediate, I-3 Example 60. (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1, but using (2-trifluoromethyl-pyridin-4yl)methanamine and aldehyde intermediate, I-3 Example 61, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-(pyridazin-4-ylmethyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1, but using pyridazin-4-yl-methanamine and aldehyde intermediate, I-3. Example 62, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((1-methyl-4,5-dihydro-1H-pyrrole) HCl 3-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1, but using (1-methyl-1H- pyrazol-4-yl)methanamine and aldehyde intermediate, I-3. Example 63, (E)-8-Cyano-N-((2-methoxypyridin-4-yl)methyl)-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide Step 1: 8-Bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride

[0139] In a 350 mL pressure flask, (4-bromophenyl)hydrazine hydrochloride (10.64 g, 47.61 mmol) and piperidin-4-one hydrochloride (7.39 g, 48.08 mmol) were suspended in 200 ml of isopropanol. HCl in dioxane (4.0 mol/L, 23.8 mL, 95.21 mmol) was added, the flask was capped, and the resulting solution was stirred at 80 °C overnight. The progress of the reaction was monitored via LCMS. After consumption of all starting materials the solids were stirred at 1000 RPM at 0°C for 2 hours. The solids were then filtered, dried under reduced pressure and used in the next step without further purification LC-Ms (m/z): [M+H] = 251.1. Step 2: 8-Bromo-1,3,4, tert-Butyl 5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0140] In a 500 mL round bottom flask, 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (13.82 g, 48, 06 mmol) was suspended in 200 mL of DCM at 0 °C, TEA (14.8 mL, 105.72 mmol) was added and the resulting solution was kept at 0 °C for 15 minutes. Boc2O (10.8 g, 49.02 mmol) was then added in one portion and the ice bath removed. The solution was stirred at 0°C to room temperature for 1.5 hours. The progress of the reaction was monitored via LCMS. After consumption of all starting materials, 200 mL of saturated NaHCO 3 was added and the resulting biphasic solution was stirred vigorously for 30 minutes. The solution was transferred into a separatory funnel and the aqueous layer was extracted 3 times with DCM. The organic layers were combined, dried over MgSO4 and volatiles removed under reduced pressure. The crude was purified on silica using flash chromatography using 0 to 50% EtOAc in hexanes on a 340 g column to provide the desired product as a pale yellow solid. LC-MS (m/z): [M+H] = 351.1.

[0141] For reactions in which the bromine substitution is converted to cyano, the following Step (3) can be carried out, as described below, or, alternatively, similarly to the cyanation step described in Example 1. If cyanation did not require , for example, conserve the bromine substitution (or other substituted moiety, eg Cl, F, methyl, methoxy and the like), then the cyanation steps can be bypassed. Step 3: 8-cyano-1,3, tert-butyl 4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate

[0142] To tert-butyl 8-bromo-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (6.4 g, 18 mmol) in DMF (100 mL) added Zn(CN)2 (1.5 g, 13 mmol), Zn(OAc)2 (670 mg, 3.6 mmol), Pd(DPPF2)Cl2 (810 mg, 1.1 mmol), and zinc (480 mg, 7.3 mmol). The reaction mixture was purged with nitrogen and heated to 100°C for 18 hours. The reaction mixture was cooled and poured into ice water (100 mL). The resulting precipitate was filtered and washed with additional water. The precipitate was dissolved in CH2Cl2 (300 mL), dried (Na2SO4), and concentrated in vacuo. The crude material was chromatographed (Redi-Sep 120 g column) eluting from 100% hexanes to 50:50 EtOAc:hexanes to provide the title compound as a solid (this procedure can be used to synthesize subsequent cyano compounds from of bromine precursors). Step 4: 8-cyano-5-(((2-methoxypyridin-4-yl)methyl)carbamoyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3 tert-butyl -b]indole-2-carboxylate

[0143] A 100 mL Schlenk flask was charged with tert-butyl 8-cyano-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1000 mg , 3.36 mmol) and anhydrous THF (40 mL). The resulting suspension was cooled to 0°C with an ice bath and NaH (404 mg, 60% disp, 10.09 mmol) was added in small portions. Gas evolved slowly and the reaction mixture changed from a yellowish-white suspension to a reddish-pink suspension. The ice bath was removed after 2 hours, and the reaction was warmed to room temperature over 10 minutes. Then, the mixture was again cooled to 0 °C. In a separate 25 mL round bottom flask, (2-methoxy-4-pyridyl)methanamine (0.69 g, 5.044 mmol) was dissolved in 10 mL of DCM at 0 °C. Triphosgene (1.56 g, 5.212 mmol) and triethylamine (4.71 mL, 33.6 mmol) were added and the resulting solution stirred at 0 °C for 30 minutes. The two solutions were mixed together by pouring the (2-methoxy-4-pyridyl)-methanamine solution into the indole solution quickly and in one portion. After stirring for 5 minutes at 0 °C, the reaction mixture was carefully quenched with addition of HCl (10 mL, 1.0 M) at 0 °C. The reaction mixture was diluted with water (20 mL) and saturated NaHCO 3 (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude was purified by flash chromatography using EtOAc in hexanes (0 to 70%) to provide the desired compound as an amorphous off-white solid. LC-MS (m/z): [M+Na] = 484.2. Step 5: Preparation of Example 63. In an 8 mL vial, 110 mg of 8-cyano-5-(((2-methoxypyridin- tert-Butyl 4-yl)methyl)carbamoyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate were dissolved in 5.0 mL of DCM and 183 µL of TFA was added at room temperature. The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction, volatiles were removed under reduced pressure. The crude was dissolved in 2.0 mL of DCM and 0.2 mL of MeOH after which 100 µL of TEA was added. The resulting solution was cooled to 0 °C and 53 mg of commercially available (E)-3-(3,4,5-trifluorophenyl)acrylaldehyde was added. After stirring for 15 minutes at 0°C, 155 mg of sodium triacetoxyborohydride was added and the resulting solution was stirred for 3 hours. After completion of the reaction monitored by LCMS, 3 mL of saturated NaHCO 3 solution was added and the resulting solution stirred for 1 hour at room temperature. The biphasic solution was passed through a phase separator cartridge and the aqueous layer washed with DCM. The organic volatiles were removed under a stream of N2, and the crude material was dissolved in 2.0 mL of EtOAc and placed in the freezer at -20 °C overnight. The resulting crystals were isolated by filtration, washed with cold EtOAc and Et2O and dried under high vacuum. The crystals were dissolved in DCM and Et2O, and a stream of HCl gas was passed through the solution to prepare the title compound (HCl salt).

[0144] The following compounds were prepared similarly to Example 63, but using the respective aldehyde intermediate: Example 64, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-8-cyano HCl -N-((2-methoxypyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3); Example 65, (E)-8-Cyano-2-(3-(2,4-dichlorophenyl)allyl)-N-((2-methoxypyridin-4-yl)methyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-4); Example 66, (E)-2-(3-(4-Bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-methoxypyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-5); Example 67, (E)-8-Cyano-2-(3-(2,4-difluorophenyl)allyl)-N-((2-methoxypyridin-4-yl)methyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 68, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-8-cyano-N-((2-methoxypyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); and Example 69, (E)-8-cyano-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-methoxypyridin-4-yl)methyl)-1,2,3 HCl, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39). Example 70, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-8-cyano-N-((2-ethoxypyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3) was prepared similarly to Example 63, but using (2-ethoxypyridin-4-yl)methanamine and aldehyde intermediate, I -3.

[0145] The following compounds were prepared similarly to Example 63, but using (2-chloropyridin-4-yl)methanamine and the respective aldehyde intermediate: Example 71, (E)-2-(3-(4-chloro) HCl -3,5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b ]indole-5-carboxamide (I-1) Example 72, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3); Example 73, (E)-2-(3-(4-Bromo-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-5); Example 74, (E)-2-(3-(4-chloro-2,6-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-6); Example 75, (E)-2-(3-(4-chloro-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 76, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(2,4,6-trifluorophenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-9); Example 77, (E)-2-(3-(2-Bromo-5-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, (I-10); Example 78, (E)-2-(3-(5-Bromo-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-11); Example 79, (E)-2-(3-(3-Bromo-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-12); Example 80, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-13); Example 81, (E)-2-(3-(4-Bromo-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-14); Example 82, (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-15); Example 83, (E)-N-((2-Chloropyridin-4-yl)methyl)-8-cyano-2-(3-(perfluorophenyl)allyl)-1,2,3,4-tetrahydro HCl -5H-pyrido[4,3-b]indole-5-carboxamide (I-16); Example 84, (E)-2-(3-(4-chloro-2,3,5,6-tetrafluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano HCl -1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-17); Example 85, (E)-2-(3-(4-Bromo-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-18); Example 86, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(3-fluoro-5-(trifluoromethoxy)phenyl)allyl)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I22); Example 87, (E)-2-(3-(2-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 88, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 89, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 90, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(3,5-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 91, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 92, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 93, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 94, (E)-2-(3-(2-Bromo-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-42); Example 95, (E)-2-(3-(3-chloro-5-cyanophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-55); Example 96, (E)-2-(3-(4-chloro-3-methylphenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-59); Example 97, (E)-2-(3-(3-Bromo-4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-60); and Example 98, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(3-cyano-4-fluorophenyl)allyl)-1,2 HCl, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-20).

[0146] The following compounds were prepared similarly to Example 63, but using (2-fluoropyridin-4-yl)methanamine and the respective aldehyde intermediate: Example 99, (E)-2-(3-(4-chloro) HCl -3,5-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b ]indole-5-carboxamide (I-1) Example 100, (E)-8-Cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(4-(methylsulfonyl)-phenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-2); Example 101, (E)-8-cyano-2-(3-(2,4-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-4); Example 102, (E)-2-(3-(4-bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-5); Example 103, (E)-2-(3-(4-chloro-2,6-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-6); Example 104, (E)-2-(3-(4-chloro-2-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 105, (E)-2-(3-(4-bromo-3-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-8); Example 106, (E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(2,4,6-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-9); Example 107, (E)-2-(3-(2-bromo-5-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-10); Example 108, (E)-2-(3-(5-bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-11); Example 109, (E)-2-(3-(3-Bromo-4-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-12); Example 110, (E)-8-Cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-13); Example 111, (E)-2-(3-(4-Bromo-2,3-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-14); Example 112, (E)-8-cyano-2-(3-(3,5-dichloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-19); Example 113, (E)-8-cyano-2-(3-(3-cyano-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-20). Example 114, (E)-2-(3-(2-chloro-4-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 115, (E)-8-cyano-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 116, (E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 117, (E)-8-cyano-2-(3-(3,5-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 118, (E)-2-(3-(3-chloro-2-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-35); Example 119, (E)-8-cyano-2-(3-(2,3-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-36); Example 120, (E)-8-cyano-2-(3-(4-cyanophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 121, (E)-2-(3-(4-chlorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 122, (E)-8-cyano-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 123, (E)-8-Cyano-2-(3-(4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra HCl -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 124, (E)-8-Cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(pyridin-4-yl)allyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-41); Example 125, (E)-2-(3-(2-bromo-4-fluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-42); Example 126, (E)-2-(3-(4-bromothiophen-2-yl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-43); and Example 127, (E)-8-cyano-2-(3-(3-cyano-5-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, (I-54). The following compounds were prepared similarly to Example 63, but using (2-trifluoromethylpyridin-4-yl)methanamine and the respective aldehyde intermediate: Example 128, (E)-2-(3-(4-chloro-2-fluorophenyl) allyl)-8-cyano-N-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5 -carboxamide (I-7) Example 129, (E)-8-cyano-2-(3-(2,4-difluorophenyl)allyl)-N-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30).

[0147] The following compounds were prepared similarly to Example 63, but using (2-bromopyridin-4-yl)methanamine and the respective aldehyde intermediate: Example 130, (E)-N-((2-bromopyridin-4-yl) )methyl)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-8-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b] indole-5-carboxamide (I-1) Example 131, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chloro-3-fluorophenyl)allyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3); Example 132, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chloro-2-fluorophenyl)allyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 133, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-13); Example 134, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(4-cyano-3-fluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 135, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(2-chloro-4-fluorophenyl)allyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 136, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 137, (E)-N-((2-Bromopyridin-4-yl)methyl)-2-(3-(3-chloro-4-fluorophenyl)allyl)-8-cyano-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 138, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 139, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 140, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(3,5-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 141, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chlorophenyl)allyl)-8-cyano-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 142, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40). Example 143, (Z)-2-(3-(4-chlorophenyl)-2-fluoroallyl)-8-cyano-N-((2-chloropyridin-4-yl)methyl)-1,2,3 HCl, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 63, but using (2-chloropyridin-4-yl)methanamine and aldehyde intermediate, I-28 Example 144, (Z)-2-(3-(4-chlorophenyl)-2-fluoroallyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 63, but using (2-fluoropyridin-4-yl)methanamine and aldehyde intermediate, I-28 Example 145, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-7-methyl-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39) Step 1: tert-butyl 7-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate; tert-Butyl 9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate.

[0148] To a solution of m-tolylhydrazine (4.0 g, 32.7 mmol) in IPA (40 mL) was added tert-butyl 4-oxopiperidin-1-carboxylate (6.5 g, 32, 6 mmol) and HCl (9.0 mL of a 4.0 M solution in dioxane). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was then cooled and concentrated under vacuum to provide the crude intermediate as a mixture of regioisomers. The mixture was purified by SFC chromatography (Berger multigram, column = 2EP 30 x 250 mm 5 µm, MP A = CO2 MP B = 0.1% NH4 in MeOH, 15%B, 100 mL/minute, 100 bar, 40 °C) to give tert-butyl 7-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (1.53 g, 16 %) as the first isomer of elution and 9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (1.9 g, 20%) as the second eluting isomer. 1st elution isomer: LC-Ms (m/z): [M+H-tbutyl] = 231.2nd elution isomer: LC-Ms (m/z): [M+H-tbutyl] = 231.Step 2: tert-Butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2-carboxylate.

[0149] To a stirred solution of 7-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (500 mg, 1.75 mmol) in THF (25 mL) at 0 °C NaH (210 mg, 5.2 mmol) was added. The reaction mixture was warmed to room temperature while stirring for 1 hour. Then the mixture was again cooled to 0 °C in an ice bath and 2-chloro-4-(isocyanatomethyl)pyridine (590 mg, 3.5 mmol) was added. The reaction was warmed to room temperature while stirring for an additional 1 hour. Ice water was added and the reaction was extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (Redi-Sep 40 g column) eluting from 25:75 EtOAc:hexanes to 50:50 EtOAc:hexanes to give the title compound (341 mg, 43%) as a solid. LC-MS (m/z): [M+H-tbutyl] = 399. Step 3: N-[(2-chloro-4-pyridyl)methyl]-7-methyl-1,2,3,4-tetra -hydropyrido[4,3-b]indole-5-carboxamide

[0150] To a solution of 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2-carboxylate tert-butyl (330 mg, 7.3 mmol) in DCM (15 mL) at 0 °C was added TFA (1 mL). The reaction was warmed to room temperature and stirred for 2 hours. Toluene (35 mL) was added and the reaction was concentrated in vacuo. The resulting TFA salt was dissolved in CH 2 Cl 2 (100 mL) and washed with saturated NaHCO 3 (50 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the free base intermediate (215 mg, 84%) as a solid. LC-MS (m/z): [M+H] = 355. Step 4: Preparation of Example 145. To a vial containing N-[(2-chloro-4-pyridyl)methyl]-7-methyl-1, 2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide (70 mg, 0.19 mmol) was added aldehyde intermediate I-39 (40 mg, 0.24 mmol), and CH2Cl2 (5 mL). The mixture was stirred at room temperature for 15 minutes and sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours; then diluted with CH2Cl2 (50 mL), washed with saturated NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude product was chromatographed (24 g Redi-Sep column) eluting from 50:50 EtOAc:hexanes to 90:10 EtOAc:MeOH to give the title compound (72 mg, 67%) as a solid.

[0151] The following compounds were prepared similarly to Example 145, but using the respective aldehyde intermediate: Example 146, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4 -yl)methyl)-7-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 147, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-9-methyl-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 148, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-9-methyl-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 149, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-9-methyl-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40); and Example 150, (E)-N-((2-chloropyridin-4-yl)methyl)-7-methyl-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, (I-46).

[0152] The following compounds were prepared similarly to Example 145, but using [3-(trifluoromethyl)phenyl]hydrazine and the respective aldehyde intermediate: Example 151, (E)-N-((2-chloropyridin-4-yl) methyl)-2-(3-(4-(methylsulfonyl)phenyl)allyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5 -carboxamide (I-2) Example 152, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3); Example 153, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 154, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-7-(trifluoromethyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 155, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-7-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide, (I-37); Example 156, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 157, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-9-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 158, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-7-(trifluoromethyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 159, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-9-(trifluoromethyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 160, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-7-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 161, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-9-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); and Example 162, (E)-N-((2-chloropyridin-4-yl)methyl)-9-(trifluoromethyl)-2-(3-(4-(trifluoromethyl)-phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46). The following compounds were prepared similarly to Example 145, but using [3-(trifluoromethyl)phenyl]hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 163, (E)-2-( 3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido [4,3-b]indole-5-carboxamide (I-3) Example 164, (E)-2-(3-(4-cyanophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 165, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 166, (E)-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39). Example 167, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-8-fluoro-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39) Step 1: tert-Butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2-carboxylate.

[0153] To a HCl solution of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 5.3 mmol) in CH2Cl2 ( 50 mL) was added N,N-diisopropylamine (2.3 mL, 13.0 mmol) followed by BOC anhydride (1.0 g, 5.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the organic phase was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude mixture was chromatographed (40 g Redi-Sep column) eluting from 100% hexanes to 40:60 EtOAc:hexanes to provide the title compound (1.49 g, 98%) as a solid. LC-MS (m/z): [M+H-tbutyl] = 235. Step 2: 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-8-fluoro-3,4-dihydro-1H tert-butyl-pyrido[4,3-b]indole-2-carboxylate.

[0154] The title compound was synthesized following the same procedure as Step 2 of Example 145 using 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-8-fluoro-3,4-dihydro-1H-pyrido tert-butyl [4,3-b]indole-2-carboxylate in place of tert-butyl 7-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate . LC-MS (m/z): [M+H-tbutyl] = 403. Step 3: N-[(2-chloro-4-pyridyl)methyl]-8-fluoro-1,2,3,4-tetra -hydropyrido[4,3-b]indole-5-carboxamide

[0155] The title compound was synthesized following the same procedure as Step 3 of Example 145 using 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-8-fluoro-3,4-dihydro-1H-pyrido tert-Butyl [4,3-b]indole-2-carboxylate in place of 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-methyl-3,4-dihydro-1H-pyrido[ tert-butyl 4,3-b]indole-2-carboxylate. LC-MS (m/z): [M+H] = 359.Step 4: Preparation of Example 167. The title compound was synthesized following the same procedure as in Step 4 of Example 145 using N-[(2-chloro- 4-pyridyl)methyl]-8-fluoro-1,2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide in place of N-[(2-chloro-4-pyridyl)methyl ]-7-methyl-1,2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide.

[0156] The following compounds were prepared similarly to Example 167, but using the respective aldehyde intermediate. Example 168, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-8-fluoro-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); and Example 169, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). Example 170, (E)-2-(3-(4-chlorophenyl)allyl)-8-fluoro-N-(4-fluorobenzyl)-1,2,3,4-tetrahydro-5H-pyrido[4, 3-b]indole-5-carboxamide was prepared similarly to Example 167, but using (4-fluorophenyl)methanamine and aldehyde intermediate, I-38 Example 171, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using 4-hydrazinyl-2-(trifluoromethyl)benzonitrile and aldehyde intermediate, I-38

[0157] The following compounds were prepared similarly to Example 145, but using 2-fluoro-5-hydrazinylbenzonitrile and the respective aldehyde intermediate: Example 172, (E)-2-(3-(4-chloro-3-fluorophenyl) allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole- 5-carboxamide (I-3) Example 173, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(4-cyanophenyl)allyl)-8-fluoro-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 174, (E)-2-(3-(4-chlorophenyl)allyl)-7-cyano-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 175, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-8-fluoro-2-(3-(4-fluorophenyl)allyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40). Example 176, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-8-methyl-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using 5-hydrazinyl-2-methylbenzonitrile and aldehyde intermediate, I-38 Example 177, (E)-7-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using 2-chloro-4-hydrazinylbenzonitrile and aldehyde intermediate, I-38 Example 178, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-7-fluoro-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using 2-fluoro-4-hydrazinylbenzonitrile and aldehyde intermediate, I-38

[0158] The following compounds were prepared similarly to Example 63, but without Step 3 (cyanation), and the respective aldehyde intermediate: Example 179, (E)-8-bromo-2-(3-(4-chloro- 3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide ( I-3) Example 180, (E)-8-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 181, (E)-8-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 182, (E)-8-Bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 183, (E)-8-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 184, (E)-8-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 185, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 186, (E)-8-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); and Example 187, (E)-8-bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I45).

[0159] The following compounds were prepared similarly to Example 63, but without Step 3 (cyanation), and using (2-fluoropyridin-4-yl)methanamine and the respective aldehyde intermediate: Example 188, (E)-8- bromo-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[ 4,3-b]indole-5-carboxamide (I-3) Example 189, (E)-8-Bromo-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 190, (E)-8-Bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 191, (E)-8-Bromo-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); and Example 192, (E)-8-bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). Example 193, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 63, but without Step 3 (cyanation), and using (2-chlorothiazol-5-yl)methanamine and aldehyde intermediate, I -38 Example 194, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-methyl-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared but using (4-bromo-3-methylphenyl)hydrazine and aldehyde intermediate, I-38 Example 195, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-methoxy-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared but using (4-bromo-3-methoxyphenyl)hydrazine and aldehyde intermediate, I-38 Example 196, (E)-8-bromo-7-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (4-bromo-3-chlorophenyl)hydrazine and aldehyde intermediate, I-38 Example 197, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-fluoro-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (4-bromo-3-fluorophenyl)hydrazine and aldehyde intermediate, I-38 Example 198, (E)-7,8-dibromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (3,4-dibromophenyl)hydrazine and aldehyde intermediate, I-38 Example 199, (E)-7-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (3-bromophenyl)hydrazine and aldehyde intermediate, I-30 The following compounds were prepared similarly to Example 145, but using (3-bromophenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 200, (E)-7-bromo-2- (3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3- b]indole-5-carboxamide (I-3) Example 201, (E)-7-Bromo-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 202, (E)-7-Bromo-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 203, (E)-7-Bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); and Example 204, (E)-7-Bromo-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32). The following compounds were prepared similarly to Example 145, but using (3-chlorophenyl)hydrazine and the respective aldehyde intermediate: Example 205, (E)-7-chloro-2-(3-(4-chloro-3-fluorophenyl) allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3) Example 206, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1,2 ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-18); Example 207, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1,2 ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-18); Example 208, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 209, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 210, (E)-7-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 211, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 212, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 213, (E)-7-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 214, (E)-9-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 215, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 216, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 217, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 218, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 219, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 220, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 221, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); Example 222, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); and Example 223, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46). The following compounds were prepared similarly to Example 145, but using (3-chlorophenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 224, (E)-7-chloro-2- (3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3- b]indole-5-carboxamide (I-3) Example 225, (E)-7-chloro-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 226, (E)-7-chloro-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 227, (E)-7-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 228, (E)-7-chloro-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 229, (E)-7-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 230, (E)-9-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). Example 231, (E)-9-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (3-chlorophenyl)hydrazine, (2-chlorothiazol-5-yl)methanamine, and the aldehyde intermediate, I -38

[0160] The following compounds were prepared similarly to Example 167, but using (4-chlorophenyl)hydrazine and the respective aldehyde intermediate: Example 232, (E)-8-chloro-2-(3-(4-chloro-3) -fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I -3) Example 233, (E)-8-chloro-2-(3-(4-chloro-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 234, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-cyano-4-fluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-20); Example 235, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 236, (E)-8-Chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-fluoro-5-(trifluoromethoxy)phenyl)allyl)-1 HCl, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I22); Example 237, (E)-8-chloro-2-(3-(2-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 238, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 239, (E)-8-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 240, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 241, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 242, (E)-8-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 243, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 244, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 245, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); Example 246, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46); Example 247, 8-Chloro-N-((2-chloropyridin-4-yl)methyl)-2-((6-chloroquinolin-2-yl)methyl)-1,2,3,4-tetrahydro HCl -5H-pyrido[4,3-b]indole-5-carboxamide (I-48); Example 248, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(pyridin-4-yl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-41); Example 249, (E)-8-Chloro-2-(3-(3-chloro-5-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-52); Example 250, (E)-8-Chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-cyano-5-fluorophenyl)allyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-54); Example 251, (E)-8-Chloro-2-(3-(3-chloro-5-cyanophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-55); Example 252, (E)-2-(3-(3-Bromo-5-fluorophenyl)allyl)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-56); and Example 253, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,5-dichlorophenyl)allyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-57). The following compounds were prepared similarly to Example 167, but using (4-chlorophenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 254, (E)-8-chloro-2- (3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3- b]indole-5-carboxamide (I-3) Example 255, (E)-8-chloro-2-(3-(4-chloro-2-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 256, (E)-8-chloro-2-(3-(2-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 257, (E)-8-chloro-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 258, (E)-8-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 259, (E)-8-chloro-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 260, (E)-8-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 261, (E)-8-chloro-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 262, (E)-8-Chloro-2-(3-(3-chloro-5-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-52); Example 263, (E)-8-Chloro-2-(3-(3-cyano-5-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-54); Example 264, (E)-2-(3-(3-Bromo-5-fluorophenyl)allyl)-8-chloro-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-56); and Example 265, (E)-8-chloro-2-(3-(3,5-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-57).

[0161] The following compounds were prepared similarly to Example 167, but using (2-chlorophenyl)hydrazine and the respective aldehyde intermediate: Example 266, (E)-6-chloro-N-((2-chloropyridin-4-yl )methyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5 -carboxamide (I-18) Example 267, (E)-6-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 268, (E)-6-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 269, (E)-6-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 270, (E)-6-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 271, (E)-6-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); and Example 272, (E)-6-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46). Example 273, (E)-6-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 167, but using (2-chlorophenyl)hydrazine, (2-chlorothiazol-5-yl)methanamine, and the aldehyde intermediate, I -38

[0162] The following compounds were prepared similarly to Example 145, but using (3,4-dichlorophenyl)hydrazine, and the respective aldehyde intermediate: Example 274, (E)-7,8-dichloro-2-(3-( 4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol- 5-carboxamide (I-3) Example 275, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 276, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 277, (E)-7,8-dichloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 278, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 279, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 280, (E)-7,8-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 281, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 282, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 283, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 284, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); and Example 285, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46).

[0163] The following compounds were prepared similarly to Example 145, but using (3,4-dichlorophenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 286, (E) HCl -7,8-dichloro-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-3) Example 287, (E)-7,8-dichloro-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-18); Example 288, (E)-7,8-Dichloro-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 289, (E)-7,8-Dichloro-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 290, (E)-7,8-Dichloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 291, (E)-7,8-Dichloro-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 292, (E)-7,8-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 293, (E)-8,9-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38).

[0164] The following compounds were prepared similarly to Example 145, but using (3,4-dichlorophenyl)hydrazine, (2-chlorothiazol-5-yl)methanamine, and the respective aldehyde intermediate: Example 294, (E)-7 ,8-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4 ,3-b]indole-5-carboxamide (I-38) Example 295, (E)-8,9-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). Example 296, (E)-8-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using 2-chloro-5-hydrazinylbenzonitrile and the aldehyde intermediate, I-38

[0165] The following compounds were prepared similarly to Example 145, but using (3-chloro-4-fluorophenyl)hydrazine and the respective aldehyde intermediate: Example 297, (E)-7-chloro-2-(3-(4 -chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-1,2,3,4-tetrahydro-5H-pyrido[4,3-b ]indole-5-carboxamide (I-3) Example 298, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-8-fluoro-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 299, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-8-fluoro-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 300, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-8-fluoro-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 301, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2 ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 302, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,5-difluorophenyl)allyl)-8-fluoro-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 303, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-8-fluoro-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 304, (E)-7-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 305, (E)-9-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 306, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-2-(3-(4-fluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 307, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-2-(3-(4-fluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); and Example 308, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46). The following compounds were prepared similarly to Example 145, but using (3-chloro-4-fluorophenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 309, (E)-7- chloro-2-(3-(4-chloro-3-fluorophenyl)allyl)-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro- 5H-pyrido[4,3-b]indole-5-carboxamide (I-3) Example 310, (E)-7-chloro-2-(3-(4-chloro-2-fluorophenyl)allyl)-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-1,2 ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 311, (E)-7-chloro-2-(3-(4-cyano-3-fluorophenyl)allyl)-8-fluoro-N-((2-fluoro-pyridin-4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 312, (E)-7-chloro-2-(3-(2,4-difluorophenyl)allyl)-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 313, (E)-7-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-8-fluoro-N-((2-fluoro-pyridin-4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 314, (E)-7-chloro-2-(3-(3,4-difluorophenyl)allyl)-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 315, (E)-7-chloro-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2 ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 316, (E)-7-chloro-2-(3-(3,5-difluorophenyl)allyl)-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 317, (E)-7-chloro-2-(3-(4-chlorophenyl)allyl)-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 318, (E)-9-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 319, (E)-7-chloro-8-fluoro-2-(3-(4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40).

[0166] The following compounds were prepared similarly to Example 145, but using (3-fluoro-5-(trifluoromethyl)phenyl)hydrazine instead of m-tolylhydrazine and the respective aldehyde intermediate: Example 320, (E)- N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-7-fluoro-9-(trifluoromethyl)-1,2,3,4-tetrahydro- 5H-pyrido[4,3-b]indole-5-carboxamide (I-37) Example 321, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-9-fluoro-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 322, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-fluoro-9-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 323, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-9-fluoro-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 324, (E)-N-((2-chloropyridin-4-yl)methyl)-7-fluoro-2-(3-(4-fluorophenyl)allyl)-9-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); and Example 325, (E)-N-((2-chloropyridin-4-yl)methyl)-9-fluoro-2-(3-(4-fluorophenyl)allyl)-7-(trifluoromethyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40).

[0167] The following compounds were prepared similarly to Example 145, but using (3-fluoro-5-(trifluoromethyl)phenyl)hydrazine instead of m-tolylhydrazine, (2-fluoropyridin-4-yl)methanamine instead of (2-chloropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 326, (E)-2-(3-(4-chlorophenyl)allyl)-7-fluoro-N-((2-fluoropyridin- 4-yl)methyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38) Example 327, (E)-2-(3-(4-chlorophenyl)allyl)-9-fluoro-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). Example 328, (E)-8-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (4-chloro-3-(trifluoromethyl)phenyl)hydrazine and the aldehyde intermediate , I-38 Example 329, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-methoxy-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (4-methoxy-3-(trifluoromethyl)-phenyl)hydrazine and the aldehyde intermediate , I-38 Example 330, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-methyl-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (4-methyl-3-(trifluoromethyl)phenyl)-hydrazine and the aldehyde intermediate , I-38

[0168] The following compounds were prepared similarly to Example 167, but using (4-(trifluoromethyl)phenyl)hydrazine and the respective aldehyde intermediate: Example 331, (E)-N-((2-chloropyridin-4-yl) )methyl)-2-(3-(4-cyanophenyl)allyl)-8-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37) Example 332, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 333, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-8-(trifluoromethyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 334, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-8-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); and Example 335, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-8-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45).

[0169] The following compounds were prepared similarly to Example 145, but using (3-(trifluoromethoxy)phenyl)hydrazine and the respective aldehyde intermediate: Example 336, (E)-2-(3-(4-chloro-3- fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole- 5-carboxamide (I-3) Example 337, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-dichlorophenyl)allyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-4); Example 338, (E)-2-(3-(4-bromo-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-5); Example 339, (E)-2-(3-(4-chloro-2,6-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-6); Example 340, (E)-2-(3-(4-chloro-2-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 341, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-2-(3-(2,4,6-trifluorophenyl)allyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-9); Example 342, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-18); Example 343, (E)-N-((2-chloropyridin-4-yl)methyl)-9-(trifluoromethoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-18); Example 344, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-cyano-4-fluorophenyl)allyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-20); Example 345, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 346, (E)-2-(3-(2-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 347, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 348, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 349, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 350, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 351, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-7-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 352, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-9-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37). Example 353, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 354, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-9-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 355, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 356, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-7-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 357, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-9-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 358, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)allyl)-7-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 359, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)allyl)-9-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 360, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I45); Example 361, (E)-N-((2-chloropyridin-4-yl)methyl)-9-(trifluoromethoxy)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I45); Example 362, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46); Example 363, (E)-N-((2-chloropyridin-4-yl)methyl)-9-(trifluoromethoxy)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46); Example 364, 2-((6-bromonaphthalen-2-yl)methyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-47); Example 365, 2-((7-chloroisoquinolin-3-yl)methyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-48); Example 366, N-((2-chloropyridin-4-yl)methyl)-2-((6-fluoronaphthalen-2-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-49); Example 367, N-((2-chloropyridin-4-yl)methyl)-2-((2-chloroquinolin-6-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-50); and Example 368, 2-((6-chloronaphthalen-2-yl)methyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-51).

[0170] The following compounds were prepared similarly to Example 145, but using (3-(trifluoromethoxy)phenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 369, (E)- 2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetrahydro- 5H-pyrido[4,3-b]indole-5-carboxamide (I-3) Example 370, (E)-2-(3-(2,4-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-4); Example 371, (E)-2-(3-(4-chloro-2-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7); Example 372, (E)-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 373, (E)-2-(3-(2-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 374, (E)-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 375, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 376, (E)-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 377, (E)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 378, (E)-2-(3-(3,5-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 379, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 379a, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-9-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 380, (E)-2-(3-(3-chloro-5-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-52); Example 381, (E)-2-(3-(3-cyano-5-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I54); Example 382, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-7-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38) and Example 383, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2- chlorothiazol-5-yl)methyl)-9-(trifluoromethoxy)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 145, but using (3-(trifluoromethoxy)phenyl)hydrazine, (2-chlorothiazol-5-yl)methanamine, and the aldehyde intermediate, I-38.

[0171] The following compounds were prepared similarly to Example 167, but using (4-(trifluoromethoxy)phenyl)hydrazine and the respective aldehyde intermediate: Example 384, (E)-2-(3-(4-chloro-3- fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole- 5-carboxamide (I-3) Example 385, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-2-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-18); Example 386, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 387, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-8-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 388, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 389, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-8-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 390, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-8-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 391, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 392, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-8-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 393, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-8-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 394, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)allyl)-8-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 395, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I45); Example 396, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46); Example 397, (E)-2-(3-(3-chloro-5-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I52); Example 398, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-cyano-5-fluorophenyl)allyl)-8-(trifluoromethoxy)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-54); Example 399, (E)-2-(3-(3-chloro-5-cyanophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]-5-carboxamide (I-55); and Example 400, (E)-2-(3-(3-bromo-5-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1 HCl, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I56).

[0172] The following compounds were prepared similarly to Example 167, but using (4-(trifluoromethoxy)phenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 401, (E)- 2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4-tetrahydro- 5H-pyrido[4,3-b]indole-5-carboxamide (I-3) Example 402, (E)-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 403, (E)-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 404, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 405, (E)-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 406, (E)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-2-(3-(3,4,5-trifluorophenyl)allyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-33); Example 407, (E)-2-(3-(3,5-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); and Example 408, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). Example 409, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-8-(trifluoromethoxy)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 167, but using (4-(trifluoromethoxy)phenyl)hydrazine, (2-chlorothiazol-5-yl)methanamine and the intermediate of aldehyde, I-38

[0173] The following compounds were prepared similarly to Example 167, but using (4-(trifluoromethyl)phenyl)hydrazine and the respective aldehyde intermediate: Example 410, (E)-2-(3-(4-chloro-3- fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole- 5-carboxamide (I-3) Example 411, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-8-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 412, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-8-(trifluoromethyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 413, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); and Example 414, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-8-(trifluoromethyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32). The following compounds were prepared similarly to Example 167, but using (4-(trifluoromethyl)phenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 415, (E)-2-( 3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido [4,3-b]indole-5-carboxamide (I-3) Example 416, (E)-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 417, (E)-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I30); Example 418, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 419, (E)-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 420, (E)-2-(3-(4-cyanophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 421, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 422, (E)-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39).

[0174] The following compounds were prepared similarly to Example 145, but using (3-(trifluoromethyl)phenyl)hydrazine and the respective aldehyde intermediate: Example 423, (E)-2-(3-(3-chloro-)HCl 4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b] indole-5-carboxamide (I-31) Example 424, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-7-(trifluoromethyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); and Example 425, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethyl)-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2 ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46).

[0175] The following compounds were prepared similarly to Example 145, but using (3-(trifluoromethyl)phenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde intermediate: Example 426, (E )-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21) Example 427, (E)-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I30); Example 428, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2 HCl ,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I31); and Example 429, (E)-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2, HCl 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I32). The following compounds were prepared similarly to Example 167, but using p-tolylhydrazine and the respective aldehyde intermediate: Example 430, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3 -(4-cyanophenyl)allyl)-8-methyl-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37) Example 431, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-methyl-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 432, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-8-methyl-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 433, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-8-methyl-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 434, (E)-N-((2-chloropyridin-4-yl)methyl)-8-methyl-2-(3-(4-(trifluoromethoxy)phenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); and Example 435, (E)-N-((2-chloropyridin-4-yl)methyl)-8-methyl-2-(3-(4-(trifluoromethyl)phenyl)allyl)-1,2,3, 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-46). Example 436, (E)-10-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8,9,10,11-tetrahydro-7H-benzoic [e]pyrido[4,3-b]indole-7-carboxamide was prepared similarly to Example 145, but using naphthalen-2-ylhydrazine and the aldehyde intermediate, I-38

[0176] The following compounds were prepared similarly to Example 145, but using (3-bromophenyl)hydrazine and the respective aldehyde intermediate: Example 437, (E)-7-bromo-2-(3-(4-chloro-3) -fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I -3) Example 438, (E)-7-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorophenyl)allyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-21); Example 439, (E)-7-Bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-31); Example 440, (E)-7-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 441, (E)-7-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 442, (E)-9-Bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 443, (E)-7-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 444, (E)-9-bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38). The following compounds were prepared similarly to Example 167, but using (4-methylsulfanylphenyl)hydrazine and the respective aldehyde intermediate: Example 445, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N -((2-chloropyridin-4-yl)methyl)-8-(methylthio)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I- 3) Example 446, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluorophenyl)allyl)-8-(methylthio)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-32); Example 447, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(methylthio)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and Example 448, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-8-(methylthio)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40). Example 449, (E)-8-cyano-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-hydroxypyridin-4-yl)methyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared according to the following scheme and reaction:

[0177] In a 5 mL vial, a suspension of 50 mg of (E)-8-cyano-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-fluoropyridin-4-yl )methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide in 1.0 mL of MeCN was treated with 1.0 mL of 1.0 HCl M and the resulting suspension was heated to 80°C for 24 hours. Upon completion of the reaction monitored by LCMS, the crude was cooled to room temperature and treated with 2.0 mL of 1.0 M HCl and the flask was placed in the freezer. The precipitate was collected by filtration. No further purification was required.

[0178] The following compounds were prepared similarly to Example 449, but using the respective aldehyde intermediate: Example 450, (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-8 HCl -cyano-N-((2-hydroxypyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-1) ; Example 451, (E)-2-(3-(4-Bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-hydroxypyridin-4-yl)methyl)-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-5); and Example 452, (E)-8-cyano-2-(3-(3,5-dichloro-4-fluorophenyl)allyl)-N-((2-hydroxypyridin-4-yl)methyl)-1 HCl, 2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-19). Example 453, (E)-2-(3-(2,4-difluorophenyl)allyl)-N-((2-hydroxypyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 449, but using (E)-2-(3-(2,4-difluorophenyl)allyl)-N- ((2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (Example 417) Example 454, (E)-2-(3-(4-cyanophenyl)allyl)-N-((2-hydroxypyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4 HCl -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 449, but using (E)-2-(3-(4-cyanophenyl)allyl)-N-(( 2-fluoropyridin-4-yl)methyl)-8-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (Example 420)

[0179] The following compounds were prepared similarly to Example 167, but using (4-(methylsulfonyl)phenyl)hydrazine and the respective aldehyde intermediate: Example 455, (E)-2-(3-(4-chloro-3- fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(methylsulfonyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole- 5-carboxamide (I-3) Example 456, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluorophenyl)allyl)-8-(methylsulfonyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 457, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(methylsulfonyl)-1,2,3,4-tetra -hydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 458, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-8-(methylsulfonyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); and Example 459, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-8-(methylsulfonyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40). Example 460, (E)-2-(3-(4-chlorophenyl)allyl)-8-(6-cyanopyridin-3-yl)-N-((2-fluoropyridin-4-yl)methyl)-1,2 ,3,4-Tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38) was prepared according to the following procedure.

[0180] (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (100 mg) was dissolved in dioxane/water (6:1, 7.0 mL). KOAc (71 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (44 mg) and Pd(PPh3)4 (5 mol %, 9, 0 mg) were added and the resulting solution was degassed with argon. The resulting solution was heated at 120°C for 60 minutes under low power millimeter wave irradiation and the reaction progress was monitored via LCMS. After cooling the mixture to room temperature, the crude solution was filtered through a Pd decontamination resin, the water was removed and the crude material was purified on a preparatory HPLC to give the title compound as a yellowish solid after drying. lyophilization. Example 461, (E)-8-(4-chlorophenyl)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38) was prepared similarly to Example 460, but using 2-(4-chlorophenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane Example 462, (E)-8-(3-chlorophenyl)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38) was prepared similarly to Example 460, but using 2-(3-chlorophenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane Example 463, (E)-2-(3-(4-chlorophenyl)allyl)-8-(4-fluorophenyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 460, but using 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane Example 464, (E)-2-(3-(4-chlorophenyl)allyl)-N5-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido [4,3-b]indole-5,7-dicarboxamide (I-38) was prepared according to the following procedure. In a vial of the mixture of (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (60 mg, 0.117 mmol, 1 eq.) and TMSCl (0.059 mL, 0.466 mmol, 4 eq.) was added water (0.008 mL, 0.466 mmol, 4 eq.). After stirring at room temperature for 16 hours, the crude material was purified by preparative HPLC to give a yellowish solid. The hydrochloride salt of the compound was prepared using ethereal HCl (2 mL) to give a yellowish solid.

[0181] The following compounds were prepared similarly to Example 464, but using the respective aldehyde intermediate: Example 465, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N5-((2 -chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indol-5,7-dicarboxamide (I-3); and Example 466, (E)-N5-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetrahydro-5H- pyrido[4,3-b]indole-5,7-dicarboxamide (I-40). Example 467, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N5-((2-chloropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5,8-dicarboxamide was prepared similarly to Example 464, but using (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N- ((2-chloropyridin-4-yl)methyl)-8-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide and the aldehyde intermediate, I-35 Example 468, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-ethoxy-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide Step 1: Synthesis of (4-bromo-3-ethoxy-phenyl)-hydrazine HCl salt:

[0182] In a 250 mL round bottom flask, to a commercially available stirred solution of 4-bromo-3-ethoxyaniline hydrochloride salt (5.0 mg, 23.14 mmol, 1 eq.) was added concentrated HCl HCl (35 mL) at -5 °C to 0 °C followed by sodium nitrite (1.756 mg, 25.45 mol, 1.1 eq.) pre-dissolved in water (8 mL). The reaction mixture was stirred at -5 °C to 0 °C for 1 hour. Thereafter, a solution of SnCl2.2H2O (11.48 mg, 50.90 mmol, 2.2 eq.) in concentrated HCl (15 mL) was added dropwise. The internal reaction temperature was maintained at -5 °C during the addition. The resulting suspension was stirred at 0°C for 1 hour. The resulting precipitate was filtered, the solid was dried under reduced pressure to give yellowish solid (6.0 mg, HCl salt, crude). The raw product was used as such for the next step. LC-MS (m/z): 231.9 (M+H). Step 2: Synthesis of 8-Bromo-7-ethoxy-2,3,4,5-tetrahydro-1H-pyrido HCl salt [4,3-b]indole:

[0183] In a 100 mL round bottom flask add a stirred solution of (4-bromo-3-ethoxy-phenyl)-hydrazine hydrochloride salt (2.0 mg, crude, 7.489 mmol, 1 equivalent) in acid acetic acid (20 mL) and 1,4-dioxane HCl (20 mL), piperidin-4-one hydrochloride (1.204 mg, 8.99 mmol, 1.2 equivalents) was added at room temperature. The reaction mixture was heated at 120°C for 16 hours. The progress of the reaction was monitored by LCMS. After completion of the starting material, the reaction mixture was evaporated under reduced pressure to give a brown solid (3 mg, crude). The crude compost was used as such for the next step. LC-MS (m/z): 295.2 (M+H). Step 3: Synthesis of 8-bromo-7-ethoxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester:

[0184] In a 100 mL round bottom flask to a stirred solution of 8-bromo-7-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b HCl salt ] crude indole (3.0 mg, crude, 9.059 mmol, 1 eq.) in THF (30 mL), TEA (10.082 mL, 72.468 mmol, 8 eq.) was added. Thereafter, BOC anhydride (3.291 mL, 13.588 mmol, 1.5 eq.) was added dropwise at room temperature and stirring was continued at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil as crude compound 4g. The crude compound was purified by combiflash (40 gm, Redisep column). The compound was eluted using 16% ethyl acetate in hexane to provide 410 mg of an off-white solid. 1H NMR (400 MHz, DMSO) δ: 1.38(t, J = 7.0 Hz, 3H), 1.43 (s, 9H), 2.72 (t, J = 5.32 Hz, 2H ), 3.66 (t, J = 5.64 Hz, 2H), 4.05 (q, J = 6.92 Hz, 2H), 4.46 (bs, 2H), 6.94 (s, 1H ), 7.59 (s, 1H), 10.87 (s, 1H). LC-MS (m/z): 393.0 (MH). Step 4: Synthesis of 8-Bromo-5-[(2-chloro-pyridin-4-ylmethyl)-carbamoyl]-7-ethoxy-1,3,4,5-tetrahydro-pyrido tert-butyl ester [4,3-b]indole-2-carboxylic acid

[0185] In a 25 mL round bottom flask to a stirred solution of NaH (60% in oil) (54.64 mg, 2.277 mmol, 3.0 eq.) in THF (3 mL) was added dropwise , 8-Bromo-7-ethoxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (300 mg, 0.759 mmol, 1.0 eq.) in THF (1.5 mL) at 0 °C. The resulting reaction mixture was brought to room temperature and stirred for 30 minutes. Thereafter, 2-chloro-4-isocyanatomethyl-pyridine (191.9 mg, 1.138 mmol, 1.5 eq.) in THF (1.5 mL) was added at 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with cold 6N hydrochloric acid (5 mL), followed by water (15 mL). The aqueous was extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a brown oil (400 mg, crude). Purification was by combiflash column chromatography (12 gm, Redisep column). The compound was eluted through 35% ethyl acetate in hexane to give a yellowish solid (85 mg, 19.86%). 1H NMR (400 MHz, DMSO) δ: 1.37 (t, J = 6.90 Hz, 3H), 1.44 (s, 9H), 2.97 (bs, 2H), 3.64 (t , J = 5.48 Hz, 2H), 4.05 (q, J = 6.84 Hz, 2H), 4.50 - 4.53 (m, 4H), 7.43 - 7.44 (m, 2H), 7.53 (s, 1H), 7.76 (s, 1H), 8.39 (d, J = 5.08 Hz, 1H), 8.49 (t, J = 5.60 Hz, 1H). LC-MS (m/z): 562.2 (MH). Step 5: Synthesis of the TFA salt of 8-bromo-7-ethoxy-1, (2-chloro-pyridin-4-ylmethyl)-amide, 2,3,4-tetrahydro-pyrido[4,3-b]indole-5-carboxylic

[0186] In a 10 mL flask to a stirred solution of 8-bromo-5-[(2-chloro-pyridin-4-ylmethyl)-carbamoyl]-7-ethoxy-1,3, tert-butyl ester, 4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid (150 mg, 0.266 mmol, 1 eq.) in DCM (2 mL) was added trifluoroacetic acid (0.5 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was concentrated under reduced pressure to provide 150 mg of a brown mass as TFA salt. The raw was used as such for the next Step. LC-MS (m/z): 465.2 (M+H). Step 6: Preparation of Example 468. In a 10 mL flask to a stirred solution of (2-chloro-pyridin-4- 8-Bromo-7-ethoxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indole-5-carboxylic acid ylmethyl)-amide (150 mg, 0.26 mmol, 1 eq .) in DMF (1.5 mL) was added TEA (0.181 mL, 1.298 mmol, 5 eq.) at room temperature. Thereafter, (E)-3-(4-chloro-phenyl)-propenal (51.90 mg, 0.312 mmol, 1.2 eq.) was added followed by sodium triacetoxyborohydride (110.08 mg, 0.519 mmol , 2 eq.). The resulting reaction mixture was stirred at room temperature for 2 hours. Reaction progress was monitored by TLC and LCMS. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give a brown mass. Purification was by preparative HPLC using ammonia buffer to provide a yellowish solid (31 mg). The HCl salt of the compound was prepared using ethereal HCl (3 mL) to give a yellowish solid.

[0187] The following compounds were prepared similarly to Example 468, but using commercially available 4-fluoro-3-(trifluoromethoxy)aniline and the respective aldehyde intermediate: Example 469, (E)-2-(3-(4-chlorophenyl) )allyl)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-7-(trifluoromethoxy)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b ]indole-5-carboxamide (I-38) Example 470, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)allyl)-8-fluoro-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); and Example 471. (E)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-2-(3-(4-fluorophenyl)allyl)-7-(trifluoromethoxy)-1,2, 3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40). Example 472, (E)-2-(3-(4-chlorophenyl)allyl)-8-fluoro-N-((2-fluoropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 4-fluoro-3-(trifluoromethoxy)aniline and (2-fluoropyridin-4 -yl)methanamine The following compounds were prepared similarly to Example 468, but using commercially available 1,3-dihydroisobenzofuran-5-amine and the respective aldehyde intermediate: Example 473, (E)-8-(3-(4-chloro) HCl -3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido [4,3-b]indole-5-carboxamide (I-3) Example 474, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(5-(trifluoromethyl)pyridin-2-yl)allyl)-1,3,6,7, 8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-18); Example 475, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(4-cyano-3-fluorophenyl)allyl)-1,3,6,7,8 HCl ,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-21); Example 476, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(2,4-difluorophenyl)allyl)-1,3,6,7,8,9 HCl -hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-30); Example 477, (E)-8-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,3,6,7,8 HCl ,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-31); Example 478, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(3,4-difluorophenyl)allyl)-1,3,6,7,8,9 HCl -hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide ((I-32); Example 479, (E)-N-((2-chloropyridin- 4-yl)methyl)-8-(3-(4-cyanophenyl)allyl)-1,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4, 3-b]indole-5-carboxamide (I-37); Example 480, (E)-8-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)- 1,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-38); Example 481, (E )-N-((2-chloropyridin-4-yl)methyl)-8-(3-(4-fluorophenyl)allyl)-1,3,6,7,8,9-hexahydro-5H-furo[ 3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-40); and Example 482, (E)-N-((2-chloropyridin-4-yl)methyl)-8- (3-(4-(trifluoromethyl)phenyl)allyl)-1,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole- 5-carboxamide (I-46) The following compounds were prepared similarly to Example 468, but using commercially available 1,3-dihydroisobenzofuran-5-amine, (2-fluoropyridin-4-yl)methanamine, and the intermediate of respective aldehyde: Example 483, (E)-8-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,3,6,7,8,9- hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-38) Example 484, (E)-8-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,3,6,7,8,9 -hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-3); Example 485, (E)-8-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,3,6,7,8,9 -hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-21); Example 486, (E)-8-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,3,6,7,8,9 HCl -hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-30); Example 487, (E)-8-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,3,6,7,8 HCl ,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-31); and Example 488, (E)-8-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,3,6,7,8,9- hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide (I-32). Example 489, (E)-8-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)methyl)-1,3,6,7,8,9-hexahydro -5H-furo[3,4-f]pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 1,3-dihydroisobenzofuran-5-amine and (2- chlorothiazol-5-yl)methanamine Example 490, (E)-9-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,3,7,8,9,10-hexahydro -6H-furo[3,4-e]pyrido[4,3-b]indole-6-carboxamide was prepared similarly to Example 468, but using commercially available 1,3-dihydroisobenzofuran-5-amine Example 491, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-8-(methylthio)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 5-amino-2-(methylthio)benzonitrile Example 492, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 4-bromo-3-(trifluoromethoxy)aniline Example 493, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-8-methoxy-1,2,3,4 -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using 5-amino-2-methoxybenzonitrile Example 494, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-methyl-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using 3-methyl-4-(trifluoromethoxy)aniline Example 495, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-fluoro-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide prepared similarly to Example 468, but using commercially available 3-fluoro-4-(trifluoromethoxy)aniline Example 496, (E)-7-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 3-chloro-4-(trifluoromethoxy)aniline Example 497, (E)-7-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 3-chloro-4-(trifluoromethoxy)aniline Example 498, (E)-8-Bromo-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethyl)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared but using 4-bromo-3-(trifluoromethyl)aniline Example 499, (E)-8-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 4-chloro-3-(trifluoromethyl)aniline Example 500, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(2-oxopyridin-1(2H)-yl)- 1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using 1-(4-aminophenyl)pyridin-2(1H)- commercially available Example 501, (E)-2-(3-(4-chlorophenyl)allyl)-8-cyclopropyl-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 4-cyclopropylaniline Example 502, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-8-(trifluoromethoxy)-1,2,3 ,4-Tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 5-amino-2-(trifluoromethoxy)benzonitrile. Example 503, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-7-(trifluoromethoxy)-1,2,3 ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 468, but using commercially available 4-amino-2-(trifluoromethoxy)benzonitrile Example 504, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-morpholino-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide Step 1: tert-Butyl 8-morpholino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0188] A 10 mL screw-cap teflon vial equipped with a magnetic stirrer bar was charged with XPhos precatalyst (144 mg, 0.30 mmol) and XPhos PdG2 (224 mg, 0.30 mmol ) and commercially available tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1.05 g, 3.0 mmol) . The flask was sealed with a teflon screw cap, evacuated and backfilled with N2 3 times. Morpholine (315 µL, 3.6 mmol) was added via syringe, followed by LiHMDS (1 M in THF, 7.2 mL, 7.2 mmol). The reaction mixture was heated at 65 °C overnight. The progress of the reaction was followed by LCMS. After consumption of all starting materials, the reaction mixture was cooled to room temperature and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1N HCl was added to quench the reaction. The last solution was poured into saturated NaHCO 3 solution, diluted with EtOAc and the aqueous layer extracted 3 times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and volatiles removed under reduced pressure. The crude material was purified by flash chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to provide the desired product as a light yellow solid (632 mg, 71% yield). LC-MS (m/z): [M+H] = 358.2 Step 2: 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-8-morpholino-1,3,4,5 tert-Butyl -tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0189] A 10 mL Teflon-stoppered flask was charged with tert-butyl 8-morpholino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (179 mg, 0.50 mmol), DMAP (6 mg, 0.05 mmol) and CDI (164 mg, 1.0 mmol) and MeCN (0.6 mL). The resulting solution was heated to 65°C for 1.5 hours. The reaction mixture was cooled to room temperature and (2-chloropyridin-4-yl)methanamine dihydrochloride (200 mg, 1.00 mmol) was added followed by 1.0 mL of MeCN and TEA (210 µL, 1.50mmol). The resulting suspension was heated to 65 °C for 30 minutes. The progress of the reaction was monitored via LCMS. After cooling the reaction mixture to room temperature, the crude material was transferred into a separatory funnel, diluted with 50 mL of DCM and 50 mL of 15% citric acid in H2O, and the layers were separated. The aqueous layer was extracted with DCM, the organic layers were combined, dried over MgSO4 and the volatiles removed under reduced pressure. The crude material was purified by flash chromatography on a 25 g silica column with EtOAc in Hexanes (0 to 75%) to provide the desired product as a white amorphous solid (198 mg, 0.652 mmol, 75%). LC-MS (m/z): [M+H] = 526.2. Step 3: Preparation of Example 504. In an 8 mL vial, 98 mg of 5-(((2-chloropyridin-4-yl) tert-butyl methyl)carbamoyl)-8-morpholino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate were dissolved in 5.0 mL of DCM and 284 µL of TFA was added at room temperature. The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction, volatiles were removed under reduced pressure. The crude was dissolved in 2.0 mL of DCM and 0.2 mL of MeOH after which 77 µL of TEA was added. The resulting solution was cooled to 0 °C and 41 mg of aldehyde intermediate I-3 was added. After stirring for 15 minutes at 0°C, 120 mg of sodium triacetoxyborohydride was added and the resulting solution was stirred for 3 hours. Upon completion of the reaction as monitored by LCMS, 3 mL of saturated NaHCO 3 solution was added and the resulting solution stirred for 1 hour at room temperature. The biphasic solution was passed through a phase separator cartridge and the aqueous layer washed with DCM. The organic volatiles were removed under a stream of N 2 , and the crude material was purified on KP-NH silica using flash chromatography (0 to 100% EtOAc in Hexanes). The crystals were dissolved in DCM and Et2O and a stream of HCl gas was passed through the solution. 32 mg of the title HCl salt was recovered by filtration as a white solid. Example 505, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl) HCl )methyl)-8-morpholino-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 504, but using aldehyde intermediate, I- 38. Example 506, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(pyrrolidin-1-yl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide Step 1: tert-Butyl 8-(pyrrolidin-1-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0190] A 10 mL screw-cap teflon vial equipped with a magnetic stirrer bar was charged with XPhos precatalyst (144 mg, 0.30 mmol) and XPhos Pd G2 (224 mg, 0.30 mmol ) and commercially available tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1.05 g, 3.0 mmol) . The flask was sealed with a teflon screw cap, evacuated and backfilled with N2 3 times. Pyrrolidine (347 µL, 4.2 mmol) was added via syringe, followed by LiHMDS (1 M in THF, 7.2 mL, 7.2 mmol). The reaction mixture was heated at 65 °C overnight. The progress of the reaction was followed by LCMS. After consumption of all starting materials, the reaction mixture was cooled to room temperature and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1N HCl was added to quench the reaction. The last solution was poured into saturated NaHCO 3 solution, diluted with EtOAc and the aqueous layer extracted 3 times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and volatiles removed under reduced pressure. The crude material was purified by flash chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to provide the desired product as a pale yellow solid (890 mg, 87% yield). LC-MS (m/z): [M+H] = 342.3. Step 2: 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-8-(pyrrolidin-1-yl)- tert-Butyl 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0191] A 10 mL Teflon stopper vial was charged with 8-(pyrrolidin-1-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2- tert-butyl carboxylate (905 mg, 2.651 mmol), DMAP (33 mg, 0.2651 mmol) and CDI (868 mg, 5.302 mmol) and MeCN (3.0 mL). The resulting solution was heated to 65°C for 1.5 hours. The reaction mixture was cooled to room temperature and (2-chloropyridin-4-yl)methanamine dihydrochloride (1.055 g, 5.302 mmol) was added followed by 5 mL of MeCN and TEA (1.11 mL, 7.953 mmol ). The resulting suspension was heated to 65 °C for 30 minutes. The progress of the reaction was monitored via LCMS. After cooling the reaction mixture to room temperature, the crude material was transferred into a separatory funnel, diluted with 50 mL of DCM and 50 mL of 15% citric acid in H2O, and the layers were separated. The aqueous layer was extracted with DCM, the organic layers were combined, dried over MgSO4 and the volatiles removed under reduced pressure. The crude material was purified by flash chromatography on a 25 g silica column with EtOAc in Hexanes (0 to 75%) to provide the desired product as a white amorphous solid (314 mg, 0.616 mmol, 23%). LC-MS (m/z): [M+H] = 510.2. Step 3: Preparation of Example 506. In an 8 mL vial, 105 mg of 5-(((2-chloropyridin-4-yl) tert-butyl methyl)carbamoyl)-8-(pyrrolidin-1-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate were dissolved in 5 .0 mL of DCM and 157 µL of TFA were added at room temperature. The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction, volatiles were removed under reduced pressure. The crude was dissolved in 2.0 mL of DCM and 0.2 mL of MeOH after which 86 µL of TEA was added. The resulting solution was cooled to 0 °C and 45 mg of aldehyde intermediate I-3 was added. After stirring for 15 minutes at 0°C, 133 mg of sodium triacetoxyborohydride was added and the resulting solution was stirred for 3 hours. Upon completion of the reaction as monitored by LCMS, 3 mL of saturated NaHCO 3 solution was added and the resulting solution stirred for 1 hour at room temperature. The biphasic solution was passed through a phase separator cartridge and the aqueous layer washed with DCM. The organic volatiles were removed under a stream of N2, and the crude material was purified on KP-NH silica using flash chromatography (0 to 100% EtOAc in Hexanes) to provide the title compound as a free amine as a solid. yellowish white. Example 507, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-8-(pyrrolidin-1-yl)- 1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 506, but using aldehyde intermediate, I-39. Example 508, HCl of ( E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-7-morpholino-1,2,3,4-tetrahydro-5H -pyrido[4,3-b]indole-5-carboxamide (I-39) Step 1: tert-Butyl 7-morpholino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0192] A 10 mL screw-cap teflon vial, equipped with a magnetic stirrer bar, was charged with SPhos precatalyst (45 mg, 0.30 mmol) and SPhos Pd G2 (58 mg, 0.30 mmol ) and tert-butyl 7-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1.05 g, 3.0 mmol). The flask was sealed with a teflon screw cap, evacuated and backfilled with N2 3 times. Morpholine (315 µL, 3.6 mmol) was added via syringe, followed by LiHMDS (1 M in THF, 7.2 mL, 7.2 mmol). The reaction mixture was heated at 65 °C overnight. The progress of the reaction was followed by LCMS. After consumption of all starting materials, the reaction mixture was cooled to room temperature and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1N HCl was added to quench the reaction. The last solution was poured into saturated NaHCO 3 solution, diluted with EtOAc and the aqueous layer extracted 3 times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and volatiles removed under reduced pressure. The crude material was purified by flash chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to provide the desired product as a pale yellow solid (570 mg, 53% yield). LC-MS (m/z): [M+H] = 358.2. Step 2: 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-7-morpholino-1,3,4, tert-Butyl 5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0193] A 100 mL Schlenk flask was charged with tert-butyl 7-morpholino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (360 mg , 1.00 mmol) and anhydrous THF (10 mL). The resulting suspension was cooled to 0°C with an ice bath and NaH (121 mg, 60% disp, 3.00 mmol) was added in small portions. The gas evolved slowly and the reaction mixture changed from a yellowish-white suspension to a reddish-pink suspension. The ice bath was removed after 2 hours, and the reaction was warmed to room temperature over 10 minutes. Then the mixture was again cooled to 0 °C (ice bath) and 2-chloro-4-(isocyanatomethyl)pyridine (255 mg, 1.50 mmol) in DCM (3.0 mL) was added slowly into a portion. After stirring for 5 minutes at 0 °C, the reaction mixture was carefully quenched with addition of HCl (3 mL, 1.0 M) at 0 °C. The reaction mixture was diluted with water (10 mL) and saturated NaHCO 3 (10 mL) and extracted with EtOAc (2 x 15mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude was purified by flash chromatography using EtOAc in Hexanes (0 to 70%) to provide the desired compound as an off-white amorphous solid (180 mg, 0.34 mmol, 34% yield). LC-MS (m/z): [M+H] = 526.2. Step 3: Preparation of Example 508. In an 8 mL vial, 90 mg of 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-7-morpholino-1,3,4,5-tetra- tert-butyl hydro-2H-pyrido[4,3-b]indole-2-carboxylate were dissolved in 5.0 mL of DCM and 131 µL of TFA were added at room temperature. The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction, volatiles were removed under reduced pressure. The crude was dissolved in 2.0 mL of DCM and 0.2 mL of MeOH after which 72 µL of TEA was added. The resulting solution was cooled to 0 °C and 41 mg of aldehyde intermediate I-39 was added. After stirring for 15 minutes at 0°C, 111 mg of sodium triacetoxyborohydride was added and the resulting solution was stirred for 3 hours. Upon completion of the reaction as monitored by LCMS, 3 mL of saturated NaHCO 3 solution was added and the resulting solution stirred for 1 hour at room temperature. The biphasic solution was passed through a phase separator cartridge and the aqueous layer washed with DCM. The organic volatiles were removed under a stream of N 2 , and the crude material was purified on KP-NH silica using flash chromatography (0 to 100% EtOAc in Hexanes). The crystals were dissolved in DCM and Et2O and a stream of HCl gas was passed through the solution. 30 mg of the title HCl salt was recovered by filtration as a white solid. Example 509, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-morpholino-1,2,3 HCl ,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 508, but using aldehyde intermediate, I-3. Example 510, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-(1,3-thiazinan- 3-yl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I3) Step 1: tert-Butyl 8-(1,3-thiazinan-3-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0194] A 10 mL screw-cap teflon vial equipped with a magnetic stirrer bar was charged with XPhos precatalyst (29 mg, 0.30 mmol) and XPhos PdG2 (45 mg, 0.30 mmol ) and tert-butyl 8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (1.05 g, 3.0 mmol). The flask was sealed with a teflon screw cap, evacuated and backfilled with N2 3 times. Thiomorpholine (616 µL, 6.00 mmol) was added via syringe, followed by LiHMDS (1 M in THF, 7.2 mL, 7.2 mmol). The reaction mixture was heated at 65 °C overnight. The progress of the reaction was followed by LCMS. After consumption of all starting materials, the reaction mixture was cooled to room temperature and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1N HCl was added to quench the reaction. The last solution was poured into saturated NaHCO 3 solution, diluted with EtOAc and the aqueous layer extracted 3 times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and volatiles removed under reduced pressure. The crude material was purified by flash chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to provide the desired product as a pale yellow solid (510 mg, 46% yield). LC-MS (m/z): [M+H] = 374.2. Step 2: 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-8-(1,3-thiazinan-3 tert-Butyl -yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

[0195] A 100 mL Schlenk flask was charged with tert-butyl 8-thiomorpholine-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (510 mg , 1.365 mmol) and anhydrous THF (10 mL). The resulting suspension was cooled to 0°C with an ice bath and NaH (164 mg, 60% disp, 4.096 mmol) was added in small portions. The gas evolved slowly and the reaction mixture changed from a yellowish-white suspension to a reddish-pink suspension. The ice bath was removed after 2 hours, and the reaction was warmed to room temperature over 10 minutes. Then the mixture was again cooled to 0 °C (ice bath) and 2-chloro-4-(isocyanatomethyl)pyridine (345 mg, 2.048 mmol) in DCM (4.0 mL) was added quickly in one portion. After stirring for 5 minutes at 0 °C, the reaction mixture was carefully quenched with addition of HCl (4 mL, 1.0 M) at 0 °C. The reaction mixture was diluted with water (10 mL) and saturated NaHCO 3 (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude was purified by flash chromatography using EtOAc in Hexanes (0 to 70%) to provide the desired compound as a yellowish amorphous solid (180 mg, 0.33 mmol, 24% yield). LC-MS (m/z): [M+H] = 542.3. Step 3: Preparation of Example 510. In an 8 mL vial, 90 mg of 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-8-(1,3-thiazinan-3-yl)- tert-Butyl 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate was dissolved in 5.0 mL of DCM and 128 µL of TFA was added at room temperature . The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction, volatiles were removed under reduced pressure. The crude was dissolved in 2.0 mL of DCM and 0.2 mL of MeOH after which 70 µL of TEA was added. The resulting solution was cooled to 0 °C and 37 mg of aldehyde intermediate I-3 was added. After stirring for 15 minutes at 0°C, 108 mg of sodium triacetoxyborohydride was added and the resulting solution was stirred for 3 hours. Upon completion of the reaction as monitored by LCMS, 3 mL of saturated NaHCO 3 solution was added and the resulting solution stirred for 1 hour at room temperature. The biphasic solution was passed through a phase separator cartridge and the aqueous layer washed with DCM. The organic volatiles were removed under a stream of N 2 , and the crude material was purified on KP-NH silica using flash chromatography (0 to 100% EtOAc in Hexanes). The crystals were dissolved in DCM and Et2O and a stream of HCl gas was passed through the solution. 45 mg of the title HCl salt was recovered by filtration as a white solid. Example 511, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-8-(1,3-thiazinan-3-HCl) yl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 510, but using aldehyde intermediate, I-39. Example 512, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-8-methoxy-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 167, but using 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3] hydrochloride - b]indole in place of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and the aldehyde intermediate, I-38

[0196] The following compounds were prepared similarly to Example512, but using 8-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride in place of 8- methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and the respective aldehyde intermediate: Example 513, (E)-2-(3-(4-chlorophenyl)allyl )-N-((2-chloropyridin-4-yl)methyl)-8-ethoxy-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I -38) Example 514, (E)-N-((2-chloropyridin-4-yl)methyl)-8-ethoxy-2-(3-(4-fluorophenyl)allyl)-1,2,3,4-tetrahydro -5H-pyrido[4,3-b]indole-5-carboxamide (I-40). Example 515, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-HCl Cyano-N-((2-cyclopropylpyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 1 , but using (2-cyclopropylpyridin-4-yl)methanamine in place of (2-chloropyridin-4-yl)methanamine and aldehyde intermediate (I-3) Example 516, (E)-8-chloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-1,2,3,4,4a,9b -hexahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38) Step 1: 8-Chloro-5-[(2-chloro-4-pyridyl)methylcarbamoyl]-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2-carboxylate tert-butyl

[0197] To a stirred solution of triphosgene (172 mg, 0.56 mmol) in CH2Cl2 (15 mL) at 0 °C was slowly added (Wuxi) 8-chloro-1,3,4,4a,5,9b- commercially available tert-butyl hexahydropyrido[4,3-b]indole-2-carboxylate (500 mg, 1.6 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.5 mmol) as a solution in CH2Cl2 (10 mL). The reaction was warmed to room temperature and stirred for 3 hours. 2-Chloropyridin-4-yl)methanamine (0.37 g, 2.1 mmol) was then added, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with CH2Cl2 (75 mL) and water (75 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo. The crude material was chromatographed (40 g Redi-Sep column) eluting from 100% hexanes to 100% EtOAc to provide the intermediate as a solid. LC-MS (m/z): [M+H-tbutyl] = 421. Step 2: 8-chloro-N-[(2-chloro-4-pyridyl)methyl]-1,2,3,4,4a ,9b-Hexahydropyrido[4,3-b]indole-5-carboxamide.

[0198] The title compound was synthesized following the same procedure as described in Example 145, Step 3, but using 8-chloro-5-[(2-chloro-4-pyridyl)methylcarbamoyl]-3,4,4a,9b tert-butyl-tetrahydro-1H-pyrido[4,3-b]indole-2-carboxylate in place of 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-methyl-3,4- tert-butyl dihydro-1H-pyrido[4,3-b]indole-2-carboxylate. LC-MS (m/z): [M+H] = 377. Step 3: Preparation of Example 516. The title compound was synthesized following the same procedure as for the synthesis of Example 145, Step 4, but using 8- chloro-N-[(2-chloro-4-pyridyl)methyl]-1,2,3,4,4a,9b-hexahydropyrido[4,3-b]indole-5-carboxamide in place of N-[ (2-chloro-4-pyridyl)methyl]-7-methyl-1,2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide and aldehyde intermediate I-38. Example 517, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichlorophenyl)allyl)-1,2,3,4,4a,9b- hexahydro-5H-pyrido[4,3-b]indole-5-carboxamide was prepared similarly to Example 516 with the aldehyde intermediate, I-39. 8-Chloro-N-[(2-chloro-4-pyridyl)methyl]-2-[(E)-3-(3,4-dichlorophenyl)allyl]-3,4,4a,9b-tetrahydro- 1H-pyrido[4,3-b]indole-5-carboxamide was separated into single enantiomers (Prep SFC = Berger Thar MS100, column = AS-H 30 x 250 mm 5 μm, MP A = CO2 MP B = TEA 0, 1% in MeOH, 30% IsocraticB, 100 mL/min, 100 bar, 33 °C) as Peak 1 and Peak 2, respectively.

Biology:

[0199] To identify new parasiticides, compounds were screened for nematicidal activity using in vitro motility assays. The compounds described in this report demonstrated nematocidal activity against Haemonchus contortus (L3) and/or Dirofilaria immitis (microfilariae) as determined by reductions in nematode motility from paralysis or death. The active compounds were subsequently investigated for in vivo efficacy using a jird infection model, whereby clearance of Trichostrongylus colubriformus was determined.

[0200] The biological activity of Haemonchus contortus (L3), Dirofilaria immitis (microfilariae) and effectiveness for jird of the compounds of the invention can be measured using the test methods described below.

In vitro Assay (HcL3) Stage 3 of Haemonchus contortus Larva

[0201] The Haemonchus contortus L3 strain was obtained from the University of Georgia and is a relatively recent resistant multiple field isolate (International Journal for Parasitology 37 (2007) 795 to 804). Compounds were dissolved in DMSO to give an initial concentration of 30 mM. The stock concentration was subsequently titrated in basal medium to provide an eleven-point semi-log concentration curve for testing. After serial dilution, 250 nl of each compound solution was transferred to an assay plate (384 wells), whereby 25 μl of exsheathed worms (~100 larvae/well) were subsequently added. Final compound concentrations in the 384-well plate after worm addition ranged from 0.001 to 100 µM. Assay plates were incubated at 37°C and observed at 96 hours for drug effect. Final data (Table 2, HcL3) are recorded as a Minimum Effective Concentration (MEC) in µM, whereby worm motility is inhibited by approximately 70%.

In vitro Microfilariae Assay (DiMF) Dirofilaria immitis

[0202] The compounds were initially dissolved in DMSO. The stock concentration was subsequently diluted in basal medium and serially diluted to provide a concentration response curve starting at 100 µM (11 total concentrations). After serial dilution, the compound solution was transferred to an assay plate (384 wells) where D.immitis microfilariae (~200/well) that had been purified from canine microfilaremic blood were subsequently added. Assay plates were observed at 72 hours for drug effect. Each compound was evaluated for decrease in microfilariae motility by means of subjective visual assessment and final data were recorded as minimally effective dose (MEC) in µM after the incubation period in Table 2.

Jird Efficiency Model

[0203] The compounds were evaluated for in vivo activity against Trichostrongylus colubriformis (Tc) in a Mongolian gerbil (jird) infection model. Jirds were fed an immunosuppressive diet containing 200 ppm (0.02%) hydrocortisone acetate before being infected by oral gavage with approximately 750 Tc larvae suspended in 0.2 mL of Earles balanced saline. Nine days post-infection, jirds were dosed (4/group) with test compound (10 mg/kg) by subcutaneous administration. Approximately four days after dosing, jirds were euthanized by carbon dioxide asphyxiation and necropsy, whereby the stomach and small intestine were removed for evaluation. Both the stomach and small intestine were dissected to remove contents and placed in 20 mL scintillation vials filled with 15 mL tap water. The flasks were then placed in a 37°C incubator or water bath for approximately four hours before counting the worms. The mean and geometric means were calculated to determine the percentage of effectiveness. A percentage efficacy (Table 2) was calculated against the geometric mean control burden as shown: % Efficacy = 100 x (mean number of worms recovered from the untreated control group - mean number of worms recovered from the treated group) - (mean number of worms recovered from the untreated control group).

Claims (11)

1. Compound CHARACTERIZED by the fact that it has Formula (1.1) or Formula (1.2): wherein: R1a, R1b, R1c and R1d are each independently selected from the group consisting of hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C3C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1 haloalkoxy -C6, -C(O)NRaRb, cyano, -S(O)pR, phenyl, pyridinyl, saturated or partially saturated 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from the group consisting of N, S and O, and wherein said heterocyclic ring, phenyl or pyridinyl moiety are each optionally and independently substituted with at least one substituent selected from the group consisting of oxo, cyano, halo and C1C6 alkyl; or R1a and R1b or R1b and R1c or R1c and R1d together form a tetrahydrofuran ring or phenyl ring; Ra and Rb are each independently selected from the group consisting of H and C1-C6 alkyl; R is H or C1-C6 alkyl; p is the integer 0, 1 or 2; Ring A is phenyl, pyridinyl or thiophene; Ring B is naphthyl, quinolinyl or isoquinolinyl; each of Ring A and Ring B moieties are optionally and independently substituted with at least one R4 substituent selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and -S (O)2CH3; R2 is phenyl, pyridinyl, thiazolyl, pyridazinyl or pyrrolyl, each optionally and independently substituted with at least one R5 substituent selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl and cyclopropyl, n is the integer 0, 1, 2, 3, 4 or 5, and when n is 2 or more, then each R4 can be the same or different from each other; wherein the solid line accompanied by the dotted line “ ” represents a single or double bond, and veterinary acceptable salts thereof. 2. Compound, according to claim 1, CHARACTERIZED by the fact that it has Formula (1.1), in which Ring A is phenyl optionally substituted with at least one substituent R4 selected from halo, cyano, haloalkyl C1-C6, alkoxy C1-C6, C1-C6 alkyl, C1-C6 haloalkoxy and -S(O)2CH3; R2 is pyridinyl or thiazolyl, each optionally and independently substituted with at least one R5 substituent selected from the group consisting of halo, methyl, -CF3, -OCH3, -OCH2CH3, hydroxyl, and cyclopropyl, and veterinary acceptable salts thereof. 3. Compound, according to claim 2, CHARACTERIZED by the fact that R2 is pyridinyl optionally substituted with at least one substituent R5 selected from the group consisting of fluorine, chlorine, bromine, methyl, hydroxyl -CF3, -OCH3, - OCH2CH3 and cyclopropyl and veterinary acceptable salts thereof. 4. Compound, according to claim 1, CHARACTERIZED by the fact that it has Formula (1.2), in which R2 is pyridinyl optionally substituted with at least one substituent R5 selected from the group consisting of fluorine, chlorine, bromine, methyl , -CF3, -OCH3, -OCH2CH3, hydroxyl and cyclopropyl, and veterinary acceptable salts thereof. 5. Compound of Formula (1.1), according to claim 1, CHARACTERIZED by the fact that it presents Formula (1.1a): wherein: R1a, R1b, R1c and R1d are each independently selected from the group consisting of H, chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S (O)2CH3, -C(O)NH2, phenyl, pyridinyl, morpholinyl, azathienyl and pyrrolidinyl; and wherein the phenyl and pyridinyl are optionally substituted with at least one substituent selected from halo, cyano or oxo; or R1a and R1b or R1b and R1c or R1c and R1d together form a phenyl ring or tetrahydrofuran ring; R4a, R4b, R4c, R4d, and R4e are each independently selected from the group consisting of H, fluorine, chlorine, bromine, methyl, -CF3, cyano, -OCF3, -OCH3, and -S(O)2CH3; and R5a and R5b are each independently selected from the group consisting of H, chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3, and -OCH2CH3; and veterinary acceptable salts thereof. 6. Compound of Formula (1.1a), according to claim 5, CHARACTERIZED by the fact that at least two of R1a, R1b, R1c and R1d are H; and wherein one of R5a or R5b is hydrogen and the other is chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3 or -OCH2CH3; and veterinary acceptable salts thereof. 7. Compound of Formula (1.1a), according to claim 6, CHARACTERIZED by the fact that it is selected from the group consisting of: (E)-2-(3-(4-chloro-3,5-difluorophenyl) )allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide ; (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetra- hydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4- tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; (E)-8-cyano-2-(3-(4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H- pyrido[4,3-b]indole-5-carboxamide, and veterinary acceptable salts thereof. 8. Veterinary composition CHARACTERIZED by the fact that it comprises a compound, as defined in any one of claims 1 to 7, and veterinary acceptable salts thereof; and further comprises a veterinary acceptable vehicle, and, optionally, at least one additional antiparasitic agent. 9. Veterinary composition, according to claim 8, CHARACTERIZED by the fact that it further comprises at least one additional antiparasitic agent selected from the group consisting of pyrantel, praziquantel, moxidectin, milbemycin, milbemycin oxime, doramectin, abamectin, ivermectin, selamectin , eprinomectin, levamisole, spinosad, emodepside, albendazole, mebendazole, derquantel or mixtures thereof. 10. Use of a compound having Formula (1.1a): wherein: R1a, R1b, R1c and R1d are each independently selected from the group consisting of H, chlorine, fluorine, bromine, cyano, methyl, -OCH3, -OCH2CH3, -OCF3, -CF3, -SCH3, -S (O)2CH3, -C(O)NH2, phenyl, pyridinyl, morpholinyl, azathienyl and pyrrolidinyl; and wherein the phenyl and pyridinyl are optionally substituted with at least one substituent selected from halo, cyano or oxo; R4a, R4b, R4c, R4d and R4e are each independently selected from the group consisting of H, fluorine, chlorine, bromine, methyl, -CF3, cyano, -OCF3, -OCH3, and -S(O)2CH3; and R5a and R5b are each independently selected from the group consisting of H, chlorine, fluorine, bromine, -CF3, methyl, hydroxyl, cyclopropyl, -OCH3, and -OCH2CH3; and veterinary acceptable salts thereof, CHARACTERIZED in that it is for the preparation of a medicament for treating an endoparasitic infection in an animal, wherein the endoparasitic infection is a gastrointestinal Haemonchus contortus or Trichostrongylus colubriformis infection or a heartworm infection by Dirofilaria immitis. 11. Use, according to claim 10, CHARACTERIZED by the fact that the drug is formulated to be administered orally, topically or parenterally.