CARBOLINE ANTIPARASITICS

FIELD OF THE INVENTION

This invention relates to carboline derivatives having parasiticidal activity. The compounds of interest are gamma-carboline derivatives. The invention also relates to processes of making said gamma-carboline derivatives, compositions and methods of use thereof.

BACKGROUND

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

Beta-carboline derivatives have been described in publications WO2002/088123 and WO201 1 /038163. These β-derivatives reportedly modulate aminergic G protein- coupled receptors, 5-HT ₆ 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

WO2003/0141 18 generically describes hexahydro- and tetrahydro-1 H-pyrido[4,3- b]indoles as 5-HT ligands capable of treating diseases modulated by 5-HT ₆ , for example, conditions which originate in the central nervous system (pain, dementia, neurodegenerative disorders, hypertension, sleeping, and others). However, this application publication does not describe or exemplify any piperidine substituted derivatives or amide substitutions (urea) of the indole moiety which were shown to impart nematocidal activity to the compounds of the instant invention. Other

antiparasitic indoles have been described in application publication WO2005/061500, WO2005/058897, and WO2013/017678, however, these are all spiroindoline derivatives. The prior art citations do not exemplify the gamma-carboline derivatives of the instant invention, or processes of manufacturing the same, nor does the prior art indicate that such compounds would be useful against a spectrum of parasitic species, particularly endoparasites.

Despite the availability of effective, broad spectrum antiparasitic agents, there remains a need for a safer, convenient, efficacious, and environmentally friendly product(s) that will overcome the ever-present threat of resistance development.

The present invention overcomes one or more of the various disadvantages of, or improves upon, the properties of existing compounds. In particular the present invention develops new gamma-carboline derivatives that demonstrate such

antiparasitic properties.

SUMMARY

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

Thus, according to the invention there is provided a Formula (1 ) compound

(1)

wherein

R ^{1 a} , R ^{1 b} , R ^{1 c} , and R ^{1 d} are each independently selected from the group consisting of hydrogen, halo, d-Cealk l, C2-C6alkenyl, C-3-C6cycloalkyl, d-Cealkoxy, d- C ₆ haloalkyl, d-C ₆ haloalkoxy, -C(0)NR ^a R ^b , cyano, -S(0) _p R, 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 0, 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 C _r C ₆ alkyl; or R ^{1 a} and R ^{1 b} or R ^{1 b} and R ^1c or R ^{1 c} and R ^{1 d} together form a tetrahydrofuran ring or phenyl ring;

R ² is phenyl or a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from the group consisting of N, S, or 0, and wherein said phenyl or heteroaryl ring is optionally and independently substituted with at least one R ⁵ substituent selected from the group consisting of halo, Ci-C6alkyl, d-Cehaloalkyl, hydroxyl, CrC ₆ alkoxy, and C ₃ -C ₆ cycloalkyl;

R ³ is CrC ₄ alkylaryl, CrC ₄ alkylheteroaryl, C ₂ -C ₆ alkenylaryl, or C ₂ - C ₆ alkenylheteroaryl; and wherein each aryl and heteroaryl moiety is optionally and independently substituted with at least one R ⁴ substituent selected from the group consisting of halo, cyano, Ci-C6alkoxy, Ci-Cehaloalkyl, Ci-Cealkyl, Ci-Cehaloalkoxy, and -S(0) _p R; and wherein the alkenyl moiety is optionally substituted with halo;

R ^a and R ^b are each independently selected from the group consisting of H and CrC ₆ alkyl;

R is H or C _r C ₆ alkyl;

p is the integer 0, 1 , or 2; and wherein the solid line accompanied by the dotted line " " represents a single or double bond, and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 ) or Formula (1 .2 compound of Formula (1 )

wherein R ^{1 a} , R ^{1 b} , R ^{1 c} , and R ^{1 d} are each independently selected from the group consisting of hydrogen, halo, CrC ₆ alkyl, C ₂ -C ₆ alkenyl, C3-C ₆ cycloalkyl, CrC ₆ alkoxy, d- C ₆ haloalkyl, CrC ₆ haloalkoxy, -C(0)NR ^a R ^b , cyano, -S(0) _p R, 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 0, 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 C _r C ₆ alkyl; or R ^{1 a} and R ^{1 b} or R ^{1 b} and R ^1c or R ^{1 c} and R ^{1 d} 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 0; and wherein the alkenyl moiety is optionally substituted with halo; Ring B is naphthyl, quinolinyl, or isoquinolinyl; and wherein each of Ring A and Ring B moieties are each optionally and independently substituted with at least one R ⁴ substituent selected from the group consisting of halo, cyano, Ci-C6alkoxy, Ci-Cehaloalkyl, d-Cealkyl, d- C ₆ haloalkoxy, and -S(0) _p R; and R ² is phenyl, pyridinyl, thiazolyl, pyridazinyl, or pyrrolyl, each optionally and independently substituted with at least one R ⁵ substituent selected from the group consisting of halo, d-C ₆ alkyl, d-C ₆ haloalkyl, d-C ₆ 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 R ⁴ 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. The preferred R ^a and R ^b are each independently hydrogen and methyl. The more preferred R ^a and R ^b are each hydrogen. The preferred R is methyl.

In yet another aspect, compounds of the present invention include a Formula (1 .1 ) or Formula (1 .2) compound of Formula (1 ); R ^1a , R ^1b , R ^1c , and R ^{1 d} are each independently selected from the group consisting of hydrogen, halo, d-C6alkyl, C ₂ - C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, d-C ₆ alkoxy, d-C ₆ haloalkyl, d-C ₆ haloalkoxy, -C(0)NR ^a R ^b , cyano, and -S(0) _p R; 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 with at least one R ⁴ substituent selected from halo, cyano, d- C ₆ haloalkyl, d-C ₆ alkyl, d-C ₆ alkoxy, d-C ₆ haloalkoxy, and -S(0) ₂ CH ₃ ; and R ² is phenyl, pyridinyl, thiazolyl, pyridazinyl, or pyrrolyl, each optionally and independently substituted with at least one R ⁵ substituent selected from the group consisting of halo, CrC ₆ alkyl, CrC ₆ haloalkyl, CrC ₆ 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 R ⁴ 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. The preferred R ^a and R ^b are each independently hydrogen and methyl. The more preferred R ^a and R ^b are each hydrogen. The preferred R is methyl.

In yet another aspect, compounds of the present invention include a Formula (1 .1 ) compound of Formula (1 ); R ^1a , R ^{1 b} , R ^{1 c} , and R ^1d are each independently selected from the group consisting of hydrogen, halo, CrC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C _r C ₆ alkoxy, C _r C ₆ haloalkyl, C _r C ₆ haloalkoxy, -C(0)NH ₂ , cyano, -S(0) ₂ CH ₃ ; Ring A is phenyl, pyridinyl, or thiophene; each of which is optionally and independently

substituted with at least one R ⁴ substituent selected from halo, cyano, C _r C ₆ haloalkyl, C-|-C ₆ alkyl, C-|-C ₆ alkoxy, C-|-C ₆ haloalkoxy, and -S(0) ₂ CH ₃ ; and R ² is pyridinyl, thiazolyl, pyridazinyl, or pyrrolyl, each optionally and independently substituted with at least one R ⁵ substituent selected from the group consisting of halo, C-i-Cealkyl, d-Cehaloalkyl, CrC ₆ alkoxy, hydroxyl, and cyclopropyl; and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 ) compound wherein R ^1a , R ^{1 b} , R ^1c , and R ^1d are each independently selected from the group consisting of hydrogen, halo, C-|-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C _r C ₆ alkoxy, C C ₆ haloalkyl, C C ₆ haloalkoxy, -C(0)NH ₂ , cyano, -S(0) ₂ CH ₃ ; Ring A is phenyl optionally substituted with at least one R ⁴ substituent selected from the group consisting of halo, cyano, Ci-C6alkoxy, d-Cehaloalkyl, d-Cealkyl, Ci-Cehaloalkoxy, and -S(0) _p R; and wherein the alkenyl moiety is optionally substituted with halo; and R ² is pyridinyl or thiazolyl, each optionally and independently substituted with at least one R ⁵ substituent selected from the group consisting of halo, methyl, -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , hydroxyl, and cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof. In yet another aspect, compounds of the present invention include a Formula (1 .1 ) compound wherein R ^1a , R ^{1 b} , R ^1c , and R ^1d are each independently selected from the group consisting of hydrogen, halo, CrC ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C _r C ₆ alkoxy, C _r C ₆ haloalkyl, C C ₆ haloalkoxy, -C(0)NH ₂ , cyano, -S(0) ₂ CH ₃ ; Ring A is phenyl substituted with at least one R ⁴ substituent selected from the group consisting of halo, cyano, C Cealkoxy, CrCehaloalkyl, d-Cealkyl, d-Cehaloalkoxy, and -S(0)2CH ₃ ; and wherein the alkenyl moiety is optionally substituted with fluoro; and R ² is pyridinyl substituted with at least one R ⁵ substituent selected from the group consisting of halo, methyl, -CF ₃ , -OCH ₃ , hydroxyl, -OCH ₂ CH ₃ , and cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 a) compound of Formula 1 .1 )

R ^1a , R ^{1 b} , R ^{1 c} , and R ^{1 d} are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -CF ₃ , -SCH ₃ ,

-S(0) ₂ CH ₃ , -C(0)NH ₂ , phenyl, pyridinyl, morpholinyl, azathienyl, and pyrrolidinyl; and wherein the phenyl and pyridinyl is optionally substituted with at least one substituent selected from halo, cyano, or oxo; R ^4a , R ^4b , R ^4c , R ^4d and R ^4e are each independently selected from the group consisting of H, methyl, fluoro, chloro, bromo, -CF ₃ , cyano, -OCF ₃ , -OCH ₃ , and -S(0) ₂ CH ₃ ; and R ^5a and R ^5b are each independently selected from the group consisting of H, chloro, fluoro, bromo, -CF ₃ , methyl, hydroxyl, cyclopropyl, -OCH3, and -OCH2CH3; and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 a) compound wherein R ^1a , R ^{1 b} , R ^1c , and R ^1d are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, -OCH ₃ , -OCH ₂ CH ₃ , - OCF3, -CF ₃ , -SCH3, -S(0) ₂ CH ₃ , and -C(0)NH ₂ ; each of R ^4a , R ^4b , R ^4c , R ^4d and R ^4e are independently selected from the group consisting of H, fluoro, chloro, bromo, -CF ₃ , cyano, -OCF ₃ , -OCH ₃ , methyl, and -S(0) ₂ CH ₃ ; and R ^5a and R ^5b are each independently selected from the group consisting of H, chloro, fluoro, bromo, -CF ₃ , methyl, hydroxyl, cyclopropyl, -OCH ₃ , and -OCH ₂ CH ₃ ; and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 a) compound wherein R ^1a , R ^{1 b} , R ^1c , and R ^1d are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, -OCH3, -OCH ₂ CH ₃ , - OCF3, -CF ₃ , -SCH3, -S(0) ₂ CH ₃ , and -C(0)NH ₂ ; each of R ^4a , R ^4b , R ^4c , R ^4d and R ^4e are independently selected from the group consisting of H, fluoro, chloro, bromo, -CF ₃ , methyl, cyano, -CF ₃ , -OCH ₃ , and -S(0) ₂ CH ₃ ; and one of R ^5a or R ^5b is H and the other is fluoro, chloro, bromo, methyl, -CF ₃ , -OCH3, -OCH ₂ CH ₃ , hydroxyl, or cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 a) compound wherein at least one of R ^1a , R ^{1 b} , R ^{1 c} , and R ^{1 d} is H and the others are each independently selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -CF ₃ , -SCH ₃ , -S(0) ₂ CH ₃ , and -C(0)NH ₂ ; each of R ^4a , R ^4b , R ^4c , R ^4d and R ^4e are independently selected from the group consisting of H, fluoro, chloro, bromo, -CF ₃ , methyl, cyano, -OCF ₃ , -OCH ₃ , and -S(0) ₂ CH ₃ ; and one of R ^5a or R ^5b is H and the other is fluoro, chloro, bromo, methyl, -CF ₃ , -OCH3, -OCH ₂ CH ₃ , hydroxyl, or cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 a) compound wherein at least two of R ^{1 a} , R ^{1 b} , R ^1c , and R ^1d is H and the others are each independently selected from the group consisting of chloro, fluoro, bromo, cyano, methyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -CF ₃ , -SCH ₃ , -S(0) ₂ CH ₃ , and -C(0)NH ₂ ; each of R ^4a , R ^4b , R ^4c , R ^4d and R ^4e are independently selected from the group consisting of H, fluoro, chloro, bromo, -CF ₃ , methyl, cyano, -OCF ₃ , -OCH ₃ , and -S(0) ₂ CH ₃ ; and one of R ^5a or R ^5b is H and the other is fluoro, chloro, bromo, methyl, -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , hydroxyl, or cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 a) compound wherein at least two of R ^{1 a} , R ^{1 b} , R ^1c , and R ^1d is H and the others are each independently selected from the group consisting of chloro, fluoro, cyano, and - CF _3; each of R ^4a , R ^4b , R ^4c , R ^4d and R ^4e are independently selected from the group consisting of H, fluoro, chloro, bromo, -CF ₃ , and cyano; and one of R ^5a or R ^5b is H and the other is fluoro, chloro, bromo, methyl, -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , hydroxyl, or cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 a) compound selected from the group consisting of:

((E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-N-((2-chloropy ridin-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-tri fluorophenyl)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-chloropyr idin-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-f luoropyridin-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-tri fluorophenyl)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-fl uoropyridin-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.

In yet another aspect, compounds of the present invention include a Formula (1 .1 ) compound wherein Ring A is pyridinyl optionally substituted with at least one R ⁴ substituent independently selected from the group consisting of fluoro, chloro, bromo, - CF ₃ , cyano, -OCF ₃ , -OCH ₃ , methyl, and -S(0) ₂ CH ₃ ; R ² is pyridinyl optionally substituted with one or two R ⁵ substituents each independently selected from the group consisting of chloro, fluoro, bromo, -CF ₃ , methyl, hydroxyl, cyclopropyl, -OCH ₃ , -OCH ₂ CH ₃ , and wherein R ^{1 a} , R ^{1 b} , R ^{1 c} , and R ^{1 d} are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -CF ₃ , - SCH ₃ , -S(0) ₂ CH ₃ , and

-C(0)NH ₂ ; and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a Formula (1 .1 ) compound wherein Ring A is thiophene optionally substituted with one or two R ⁴ substituents independently selected from the group consisting of fluoro, chloro, bromo, - CF ₃ , cyano, -OCF ₃ , -OCH ₃ , methyl, and -S(0) ₂ CH ₃ ; R ² is pyridinyl optionally substituted with one or two R ⁵ substituents each independently selected from the group consisting of chloro, fluoro, bromo, -CF ₃ , methyl, hydroxyl, cyclopropyl, -OCH ₃ , -OCH ₂ CH ₃ , and wherein R ^{1 a} , R ^{1 b} , R ^{1 c} , and R ^{1 d} are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -CF ₃ , - SCH ₃ , -S(0) ₂ CH ₃ , and -C(0)NH ₂ ; and veterinary acceptable salts thereof, and stereoisomers thereof.

In yet another aspect, compounds of the present invention include a compound of Formula (1 .2a) of Formula (1 .2)

wherein Ring B is naphthyl, quinolinyl, or isoquinolinyl, each optionally and

independently substituted with at least one R ⁴ substituent selected from the group consisting of H, fluoro, chloro, bromo, -CF ₃ , cyano, -OCF ₃ , -OCH ₃ , methyl, and

-S(0) ₂ CH ₃ ; R ^{1 a} , R ^{1 b} , R ^1c , and R ^1d are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -CF ₃ , -SCH ₃ , -S(0) ₂ CH ₃ , and -C(0)NH ₂ ; and wherein R ^5a and R ^5b are each independently selected from the group consisting of H, chloro, fluoro, bromo, -CF ₃ , methyl, hydroxyl, cyclopropyl, -OCH ₃ , and -OCH ₂ CH ₃ ; and n is the integer 0, 1 , 2, 3, 4, or 5; and when n is 2 or more, then each R ⁴ 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 . In yet another aspect of the invention, Ring B is isoquinolinyl and n is the integer 0 or 1 .

In yet another aspect, compounds of the present invention include a Formula (1 ) compound that is selected from any one of Examples 1 - 517, veterinary acceptable salts thereof, and stereoisomers thereof.

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

In yet another aspect, the invention is a veterinary composition comprising a Formula (1 .1 ) compound, veterinary acceptable salts thereof, and stereoisomers thereof, or a Formula (1 .2) compound, and veterinary acceptable salts thereof. In yet another aspect of the invention is a veterinary composition comprising a Formula (1 .1 ) compound or Formula (1 .2) compound, and further comprising a veterinary acceptable carrier. In yet another aspect of the invention is a veterinary composition comprising a Formula (1 .1 ) or a Formula (1 .2) compound, 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 Formula (1 .1 ) or a Formula (1 .2) compound and further comprising a veterinary acceptable carrier, and at least one additional antiparasitic agent.

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

In yet another aspect, the invention is a veterinary composition comprising a Formula (1 .1 a) compound selected from the group consisting of (E)-2-(3-(4-chloro-3,5- difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cya no-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-tri fluorophenyl)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-chloropyr idin-4-yl)methyl)-7-cyano- 1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide;

(E)-2-(3-(4-chloro-3 _J 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-tri fluorophenyl)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-fl uoropyridin-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-fluoropyrid in-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 antiparsitic agent. In yet another aspect of the invention is a veterinary composition comprising one of these Formula (1 .1 a) compounds and further comprising a veterinary acceptable carrier, and at least one additional antiparsitic agent.

In yet another aspect, the invention is a veterinary composition comprising a Formula (1 ) compound selected from any one of Examples 1 - 517, veterinary

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

In yet another aspect, the invention is a method for treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a Formula (1 ) compound, veterinary acceptable salts thereof, and stereoisomers thereof, to an animal in need thereof. In yet another aspect of the invention is a method for treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a Formula (1 .1 ) or Formula (1 .2) compound to an animal in need thereof. In yet another aspect of the invention is a method for treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a Formula (1 .1 a) compound to an animal in need thereof, and optionally combining a Formula (1 .1 a) compound with at least one additional antiparasitic agent.

In yet another aspect of the invention is a method for treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a Formula (1 .1 a) compound selected from the group consisting of (E)-2-(3-(4-chloro-3,5- difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cya no-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-tri fluorophenyl)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-chloropyr idin-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-tri fluorophenyl)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-fl uoropyridin-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-fluoropyrid in-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 Formula (1 .1 a) compounds with at least one additional antiparasitic agent. In yet another aspect of the invention is a method of treating an animal in need thereof with one of these Formula (1 .1 a) compounds and veterinary acceptable salts thereof, and stereoisomers thereof, combined with at least one additional antiparsitic agent.

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

In yet another aspect, the invention, the animal is a companion animal or livestock and said parasitic infection is an endoparasitic infection, and wherein the Formula (1 ), Formula (1 .1 ), Formula (1 .2), Formula (1 .1 a), or Formula (1 .2a) compound, 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.

In yet another aspect, the invention is the use of a Formula (1 ), Formula (1 .1 ), Formula (1 .2), Formula (1 .1 a), or Formula (1 .2a) compound, veterinary acceptable salts thereof, and stereoisomers thereof, for the manufacture of a medicament for the treatment of a parasitic infection in an animal in need thereof. The medicament can be administered to the animal orally, topically, or parenterally.

DETAILED DESCRIPTION

Definitions

For purposes of the present invention, as described and claimed herein, the following terms and phrases are herein defined:

"Additional antiparasitic agent(s)" as used herein, unless otherwise indicated, refers to other veterinary compounds or products that provide a therapeutically effective amount of said agents that are useful for the treatment of a parasitic infection in an animal, as described herein.

"Alkoxy", as used herein, unless otherwise indicated, refers to an oxygen moiety having a further alkyl substituent. The alkyl portion (i.e., alkyl moiety) of an alkoxy group has the same definition as below. Non-limiting alkoxy examples include: methoxy (-OCH3), ethoxy (-OCH ₂ CH ₃ ), n-propoxy, iso-propoxy, n-butoxy, and the like.

"Alkyl", as used herein, unless otherwise indicated, refers to saturated

monovalent hydrocarbon alkane radicals of the general formula Ο _η Η _2η +1 . The alkane radical may be straight or branched and may be unsubstituted or substituted. For example, the term "C-i-Cealkyl" refers to a monovalent, straight or branched aliphatic group containing 1 to 6 carbon atoms. Non-exclusive examples of CrC ₆ 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 may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Alkyl groups are optionally substituted as described herein. Further when used in compound words such as haloalkyl, said alkyl moiety has the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Non-limiting examples of the compound word, haloalkyl include: difluoromethyl, trifluoromethyl, and the like. Further when used in compound words such as alkylaryl, said alkyl and aryl moieties have the same meaning as herein defined. Non-limiting examples of the compound word, alkylaryl include: benzyl, ethylbenzyl, propylbenzene, iso-butylbenzene, sec-butylbenzene, ethylnaphthalene, propylnaphthylene, 2,2-diphenylethyl, and the like.

"Alkenyl" as used herein, unless otherwise indicated, refers to a straight or branched aliphatic unsaturated hydrocarbon chain having at least one site of olefinic unsaturation (i.e., having at least one moiety 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. Further when used in compound words such as alkenylaryl or alkenylheteroaryl, said alkenyl, aryl, and heteroaryl moieties have the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Non-limiting examples of the compound word, alkenylaryl include: propenylbenzene, ethenylbenzene, butenylbenzene, and the like. Non-limiting examples of the compound word, alkenylheteroaryl include: propenylpyridine, propenylthiazole, butenylpyridine, ethenylimidazole, ethenylpyridine, and the like.

"Animal(s)", as used herein, unless otherwise indicated, refers to an individual animal that is a mammal, bird, or fish. Specifically, mammal refers to a vertebrate animal that is human and non-human, which are members of the taxonomic class Mammalia. Non-exclusive examples of non-human mammals include companion animals and livestock. Non-exclusive examples of a companion animal include: dog, cat, and horse. A preferred companion animal is a dog. Non-exclusive examples of livestock include: swine, camel, rabbits, goat, sheep, deer, elk, and cattle. Preferred livestock is cattle and swine. More preferred is cattle. Specifically, bird refers to a vertebrate animal of the taxonomic class Aves. Birds are feathered, winged, bipedal, endothermic, and egg-laying. Non-exclusive examples of bird include, poultry (e.g., chicken, turkey, duck, and geese), all of which are also referred to herein as fowl.

Specifically, fish refers to the taxonomic class Chondrichthyes (cartilaginous fishes, e.g., sharks and rays) and Osteichthyes (bony fishes) which live in water, have gills or mucus-covered skin for respiration, fins, and may have scales. Non-exclusive examples of fish include shark, salmon, trout, whitefish, catfish, tilapia, sea bass, tuna, halibut, turbot, flounder, sole, striped bass, eel, yellowtail, grouper, and the like.

"Aryl", as used herein, unless otherwise indicated, refers to an aromatic 6- to 10- membered mono- or polycyclic ring containing 6 to 10 carbon atoms, respectively.

Preferred aryls include phenyl and naphthyl. The aryl group may be attached to the chemical moiety by any one of the carbon atoms within the monocyclic or fused ring. Further when used in compound words such as alkylaryl or alkenylaryl, said alkyl, alkenyl, and aryl moieties have the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Non-exclusive examples of alkylaryl include: -C-phenyl, -C-naphthyl, and the like. Nonexclusive examples of alkenylaryl include: -C=C-phenyl, -C-C=C-phenyl, -C-C=C-C- phenyl, and the like. Aryls are optionally substituted as described herein.

"Compounds" and "Compounds of the present invention", as used herein, unless otherwise indicated, refers to a Formula (1 ), Formula (1 .1 ), Formula (1 .1 a), Formula (1 .2), and Formula (1 .2a) compound, stereoisomer thereof, and veterinary acceptable salt thereof.

"Comprise(s)", as used herein, unless otherwise indicated, refers to an inclusive meaning, i.e., that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements. This rationale will also be used when the term "comprised" or "comprising" is used in relation to one or more Steps in a method or process. "CycloalkyI", as used herein, unless otherwise indicated, 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 (C ₃ -C ₆ cycloalkyl) including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may be attached to the chemical moiety by any one of the carbon atoms within the ring. Cycloalkyl groups are optionally substituted with at least one substituent as defined herein. Further when used in compound words such as alkylcycloalkyl, said alkyl and cycloalkyl moiety have the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Examples of C-|-C ₆ alkylC3-C ₆ cycloalkyl include, methylcyclopropane (dalkylC ₃ cycloalkyl or CH ₂ cyclopropane),

ethylcyclopropane (C2alkylC3cycloalkyl or -CH ₂ CH2cyclopropane), methylcyclobutane (CialkylC ₄ cycloalkyl or CH cyclobutane), ethylcyclobutane (C2alkylC ₄ cycloalkyl or CH ₂ CH ₂ cyclobutane), methylcyclohexane (CialkylC ₆ cycloalkyl or CH ₂ cyclohexane), and the like. Cycloalkyl moieties are optionally substituted as described herein

"E/Z Notation" or Έ and Z geometric isomer(s)", as used herein, unless otherwise indicated, refers to the International Union of Pure and Applied Chemistry (lUPAC) preferred method of describing the stereochemistry of double bonds in organic chemistry. It is an extension of cis/trans notation that can be used to describe double bonds having three or four substituents. Following a set of defined rules (Cahn-lngold- Prelog priority rules), each substituent on a double-bond is assigned a priority. If the two groups of higher priority are on opposite sides of the double bond, the bond is assigned the configuration E (from entgegen, the German word for "opposite"). If the two groups of higher priority are on the same side of the double bond, the bond is assigned the configuration Z (from zusammen, the German word for "together").

"Halogen" or "halo", as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine and iodine. Further, when used in compound words such as

"haloalkyl", "haloalkoxy", "haloalkenyl", or "haloalkynyl", said alkyl, alkoxy, alkenyl, and alkynyl may be partially or fully substituted with halogen atoms which may be the same or different and said alkyl, alkoxy, alkenyl, and alkynyl moiety has the same meaning as above and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Examples of "haloalkyi" include F ₃ C-, CICH ₂ -, CF ₃ CH ₂ - and

CF3CCI2-, and the like. The term "haloalkoxy" is defined analogously to the term

"haloalkyi". Examples of "haloalkoxy" include CF ₃ 0-, CCI ₃ CH ₂ 0-, HCF ₂ CH ₂ CH ₂ 0-, CF ₃ CH ₂ 0-, and the like. The term "haloalkenyl is defined analogously to the term "haloalkyi" except that the aliphatic chain contains at least one carbon-carbon double bond. Examples of "haloalkenyl" include CF ₃ C=C-, CCI ₃ C=C-, HCF ₂ C=C-, CF ₃ C=CC-, and the like. The term "haloalkynyl" is defined analogously to the term "haloalkyi" except that the aliphatic chain contains at least one carbon-carbon triple bond. Examples of "haloalkynyl" include F ₃ CC≡C-, CI ₃ CC≡C-, HF ₂ CC≡C-, and the like.

"Heteroaryl" or "Het", as used herein, unless otherwise indicated, refers to a 5- to 6-membered aromatic monocyclic ring or an 8- to 10-membered fused aromatic ring where said monocyclic- and fused-ring moiety contains one or more heteroatoms each independently selected from N, 0, or S, preferably from one to four heteroatoms. Nonexclusive 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 one of the carbon atoms or nitrogen heteroatoms within the monocyclic or fused ring. Further when used in compound words such as alkyl heteroaryl, said alkyl and heteroaryl moiety have the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. Non-exclusive examples of alkylheteroaryl include: d- heteroaryl (e.g., -C-pyridinyl; -C-quinolinyl; -C-isoquinolinyl), ethylpyridine,

ethylpyrimidine, ethylpyridazine, and the like. Heteroaryls are optionally substituted as described herein.

"Heterocycle", as used herein, unless otherwise indicated, refers to a partially saturated or saturated 3- to 7-membered monocyclic ring containing one or more heteroatoms each independently selected from N, 0, or S, preferably from one to four heteroatoms. The heterocyclic ring can be part of a fused ring moiety. Non-exclusive examples of heterocycle include oxirane, thiarane, aziridine, oxetane, azetidine, thiatane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyrane, piperidine, piperazine, tetrahydropyridine, 2H-azirine, 2,3-dihydro-azete, 3,4-dihydro-2H-pyrrole, morpholine, azathiane, and the like. The heterocycle group may be attached to the chemical moiety by any one of the carbon atoms or nitrogen heteroatoms within the ring. Further when used in compound words such as alkylheterocycle, said alkyl and heterocycle moiety have the same meaning as herein defined and may be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. For example, Cialkylheterocycle is C-heterocycle, C ₂ alkylheterocycle is -C-C-heterocycle, and the like. Heterocycles are optionally substituted as described herein.

Optionally substituted", is used herein interchangeably with the phrase substituted or unsubstituted. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. An optionally substituted group also may have no substituents. Therefore, the phrase "optionally substituted with at least one substituent" means that the number of substituents may vary from one up to a number of chemically available positions for substitution.

"Parasite(s)", as used herein, unless otherwise indicated, refers to endoparasites and ectoparasites. Endoparasites are parasites that live within the body of its host and include helminths (e.g., trematodes, cestodes, and nematodes) and protozoa.

Preferred endoparasites are gastrointestinal worms and heart worm. Ectoparasites are organisms of the Arthropoda phylum (e.g., arachnids, insects, and crustaceans (e.g., copepods-sea lice) which feed through or upon the skin of its host. Preferred arachnids are of the order Acarina, e.g., ticks and mites. Preferred insects are midges, fleas, mosquitos, biting flies (stable fly, horn fly, blow fly, horse fly, and the like), bed bugs, 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.

"Protecting group" or "Pg", as used herein, unless otherwise indicated, refers to a substituent that is commonly employed to block or protect an amine on the compound thereby protecting its functionality while allowing for the reaction of other functional groups on the compound. Non-exclusive examples of an amine-protecting group include: acyl groups (e.g., formyl, acetyl, chloroacetyl, trichloro-acetyl, 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-trifluoroethoxy-carbonyl, 2-trimethylsilyl- ethxoycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1 ,1 dimethyl-propynyloxycarbonyl, benzyloxy-carbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, and the like), diphenylmethane, and benzylcarbamates.

"R ⁴ substituent", as used herein, unless otherwise indicated, refers to a substituent that is further defined as R ^4a , R ^4b , R ^4c , R ^4d , and R ^4e , each of which are defined herein, particularly for Formula (1 .1 a) and Formula (1 .2a) compounds.

"R ⁵ substituent" as used herein, unless otherwise indicated, refers to a substituent that is further defined as R ^5a and R ^5b , each of which are defined herein, particularly for Formula (1 .1 a) and Formula (1 .2a) compounds.

"Therapeutically effective amount", as used herein, unless otherwise indicated, refers to a concentration of the active agent in a composition sufficient to elicit the desired biological response to the target parasite(s) after administration of the composition to the animal, as measured by methods known in the art and/or described in the examples herein. In some instances, an "effective amount" of the active agent in the composition will provide an efficacy of at least 70% against the target parasite compared to an untreated control. In other instances, "an effective amount" of the active agent will provide an efficacy of at least 80%, or at least 85% compared to untreated controls. More typically, "an effective amount" of the active agent will provide an efficacy of at least 90%, at least 93%, at least 95% or at least 97% against the target parasite. In certain instances, including the 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 in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint, for example, (i) treat the particular parasitic infection or infestation, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular parasitic infection or infestation, or (iii) prevents or delays the onset of one or more symptoms of the particular parasitic infection or infestation described herein.

"Treatment", "treating", and the like, as used herein, unless otherwise indicated, refers to reversing, alleviating, or inhibiting the parasitic infection, infestation, or condition. As used herein, these terms also encompass, 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 therewith prior to affliction with said infection or infestation. Thus, treatment can refer to administration of the compounds of the present invention to an animal that is not at the time of administration afflicted with the infection or infestation. Treating also encompasses preventing the recurrence of an infection or infestation or of symptoms associated therewith as well as references to "control" (e.g., kill, repel, expel, incapacitate, deter, eliminate, alleviate, minimize, and eradicate). Methods of treatment are synonomous with the use of the compound for treatment and use to prepare a medicament for treatment.

"Veterinary acceptable" as used herein, unless otherwise indicated, indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, composition, and/or the animal being treated therewith.

"Veterinary acceptable salts" as used herein, unless otherwise indicated, are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an animal. A veterinary acceptable salt intends 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. Further examples of veterinary acceptable salts include those listed in Berge et.al., Pharmaceutical Salts, J.Pharm. Sci. (1977), 66(1 ):1 -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 suitable base or acid, respectively, and isolating the salt thus formed during subsequent purification. The present invention provides Formula (1 ) compounds, 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 animals and livestock.

Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein. The 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 e ), 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 for synthesizing compounds of the present invention, and key intermediates. For a more detailed description of the individual reaction Steps, see the Examples section below. A skilled artisan will appreciate that other suitable starting materials, reagents, and synthetic routes may be used to synthesize the compounds of the present invention and a variety of derivatives thereof. Further, 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.

The gamma-carbolines of the present invention described herein, exist in different stereoisomeric forms. Unless specified otherwise, 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 of the Έ" and "Z" isomers of the compounds of Formula (1 ), Formula (1 .1 ), and Formula (1 .1 a) are contemplated.

For illustrative purposes, the reaction schemes depicted below demonstrate potential routes for synthesizing 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 may be used to synthesize the intermediates and compounds of the present invention and a variety of derivatives thereof. Further, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry.

Schemes 1 -4 outline the general procedures useful for the preparation and isolation of compounds of the present invention. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following schemes or modes of preparation. In the preparation of compounds of the present invention, protection of remote functionality of intermediates from undesired reactions can be accomplished with a protecting group. The term "protecting group" or "Pg" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting 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, trichloro-acetyl, 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-trimethylsilylethxoycarbonyl, vinyloxycarbonyl,

allyloxycarbonyl, 1 ,1 -dimethyl-propynyloxycarbonyl, benzyloxy-carbonyl, p- nitrobenzyloxycarbony, 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 readily determined by one 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 .

In the Schemes and Examples below, the following catalysts/reactants and miscellaneous abbreviations include: mobile phase (MP); room temperature (RT);

equivalent (eq); minute (min); hour (h or hr); round bottom flask (RBF); saturated (sat); Ν,Ν-dimethyl formamide (DMF); acetonitrile (ACN, Acn, or MeCN); dichloromethane (DCM); methyl tert-butyl ether (MTBE); triethylamine (TEA or Et ₃ N ); methanol (MeOH), tetrahydrofuran (THF); ethyl acetate (EtOAc); trifluoroacetic acid (TFA); 4- dimethylaminopyridine (DMAP); isopropylmagnesium chloride (iPrMgCI); t- butyloxycarbonyl (BOC, boc); palladium (Pd); isopropyl alcohol (IPA); hydrochloric acid (HCI); dichloromethane (CH ₂ CI ₂ ); diethyl ether (Et ₂ 0); dimethylsulfoxide (DMSO); 1 ,1 '- Bis(diphenylphosphino)ferrocene (Pd(DPPF ₂ )Cl2); zinc cyanide (Zn(CN ₂ )); 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 (Boc ₂ 0); and 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos).

Sche - Fischer Indole Carboline Formation

Scheme 1 describes the Fischer indole synthesis scheme. R ^{1 a} , R ^{1 b} , R ^1c , and R ^1d are as defined herein. The ratio of isomeric products (analogs) varies depending on the aniline or hydrazine starting material. The commercially available aniline (s1 .1 ) is converted to the corresponding hydrazine (s1 .2) by 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 the carboline (s1 .4) is accomplished by the Fischer indole synthesis of the hydrazine (s1 .2) and the commercially available piperidin-4-one (s1 .3) in IPA with hydrochloric acid in dioxane at temperatures up to reflux. The piperidine (s1 .5) moiety is BOC protected using commercially available di-tert-butyl dicarbonate, triethylamine as base in

dichloromethane at 0°C to room temperature.

Scheme 2 - Urea Formation

R ^{1 a} , R ^{1 b} , R ^{1 c} , R ^1d and R ² are as defined herein. The ureas (s2.8) are synthesized first by formation of an intermediate isocyanate (s2.9) from a commercially available methanamine (s2.7) using triphosgene and aqueous potassium carbonate or pyridine as base in dichloromethane as solvent at 0 °C. Carboline (s1 .5) is deprotonated using sodium hydride as base in THF as solvent at 0 °C, followed by subsequent reaction with intermediate isocyanate (s2.9) to provide ureas (s2.8). Alternatively, the ureas (s2.8) can be synthesized by formation of an intermediate carbamoyl chloride (s2.6) using phosgene, triphosgene, or CDI and pyridine or triethylamine as base in dichloromethane or DCE as 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 - Piperidine Substitution

R ^{1 a} , R ^{1 b} , R ^{1 c} , R ^1d , R ² , R ⁴ , n, ring A, and ring B are as defined herein.

Deprotection of the BOC group on (s2.8) is accomplished by treatment with

trifluoroacetic acid in dichloromethane at room temperature. The amine (s3.1 ) was then alkylated using a reductive amination procedure with either a readily prepared or commercially available aldehyde intermediate (s3.2). Mixing of the amine (s3.1 ) and the aldehyde (s3.2) with sodium triacetoxyborohydride and triethylamine in an organic solvent (typically dimethylformamide or dichloromethane) at room temperature affords the substituted piperidine (s3.4). The amine (s3.1 ) can be alternatively alkylated using a reductive alkylation procedure with a commercially available aldehyde (s3.3b) using sodium tnacetoxyborohydride as reducing agent and triethylamine in an organic solvent (typically dimethylformamide or dichloromethane) at room temperature affords the substituted piperidine (s3.5).

Scheme 4 - Alternate S nthesis

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-lndole chemistry, optionally followed by

replacement of the halide X by other substituents (such as nitriles) through conventional palladium cross coupling chemistry.

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

By reversing the order of the reductive amination step and the urea formation, the BOC protecting group can be omitted, thereby reducing the number of synthetic steps. R ⁴ , R ⁵ , and n are as defined herein. The letter "m" is an integer 0, 1 , or 2.

It will be appreciated by those of skill in the art that certain compounds within the compositions of the invention may 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 possess the useful properties described herein.

The compounds within the compositions of 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.

In addition, the compounds within the compositions of the invention may exist as hydrates or solvates, in which a certain stoichiometric amount of water or a solvent is associated with the molecule in the crystalline form. The compositions of the invention may include hydrates and solvates of the active agents.

Also contemplated within the scope of the invention are acid or base salts, where applicable, of the compounds of the invention provided for herein.

The term "acid" contemplates all veterinary acceptable inorganic or organic acids. Inorganic acids include inorganic acids such as hydrobromic acid and

hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid. Organic acids include all veterinary acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, fatty acids and 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, Iinoleic acid, linolenic acid, and phenylsteric acid, gluconic acid, glycoheptonic acid, and lactobionic acid, and the like.

The term "base" contemplates all veterinary acceptable inorganic or organic bases, including hydroxides, carbonates or bicarbonates of alkali metal or alkaline earth metals. Salts formed with such bases include, for example, the alkali metal and alkaline earth metal salts, including, but not limited to, as 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 salts (NH ₄ ), alkyl- and dialkylammonium salts, and salts of cyclic amines such as the morpholine and piperidine salts.

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

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

The present invention includes all veterinary acceptable isotopically-labelled Formula (1 ) compounds wherein 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 ² H and ³ H, carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ¹⁸ F, iodine, such as ¹²³ l and ¹²⁵ l, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ O, ¹⁷ O and ¹⁸ O, and sulphur, such as ³⁵ S. The skilled person will appreciate that the compounds of the present invention could be made by methods other than those herein described as incorporated herein by reference, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group

Transformations", RC Larock, Wiley-VCH (1999 or later editions).

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

The compound of the present invention can be administered alone or in a formulation appropriate to the specific use envisaged, the particular species of host animal being treated and the parasite involved. Generally, it will be administered as a formulation in association with at least one veterinary acceptable carrier. The term "carrier" is used herein to describe any ingredient (e.g., excipient, diluents, and the like) other than the compound of the present invention or any additional veterinary (e.g., antiparasitic) agent. The choice of carrier will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier on solubility and stability, and the nature of the dosage form. In addition to the carrier(s), 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 of the disease, the route and frequency of administration, and thus may vary widely.

In another aspect, the veterinary composition comprises a Formula (1 ) compound with at least one veterinary acceptable carrier. The concentration range will vary depending on the composition (e.g., oral, topical, or injectable). For an oral dose, the range of active (i.e., compound of the present invention) is 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 10mg/kg, and most preferably from about 0.5 to 7 mg/kg or 1 -5 mg/kg. For a topical solution, the range of active is about 0.1 to 1000 mg/mL, and preferably from about 0.5 to 500 mg/mL, and more preferably from about 1 to 250 mg/mL, and even more preferably from about 2 to 200 mg/mL. Depending upon the final volumes of the topical solution(s), the concentration of the active can change from that described above.

Generally, injectable doses tend to be, but not always, lower in concentration.

The formulations can be prepared using conventional dissolution and mixing procedures. Such compositions and methods for their preparation may 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).

A typical formulation is prepared by mixing a Formula (1 ) compound 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 carrier(s) will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to an animal. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or veterinary composition thereof) or aid in the manufacturing of the veterinary product (i.e., medicament). The compound of the present invention will typically be formulated into veterinary dosage forms to provide an easily controllable dosage form for administration.

The methods by which the compound of the present invention may be

administered include oral, topical, and injectable (e.g., parenteral and subcutaneous) administration. The particular route selected by the practitioner depends upon factors such as the physicochemical properties of the therapeutic agent, the condition of the host and economics. In certain cases, it is convenient and efficient to administer veterinary medicines 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.

The compound of the present invention can be administered orally by capsule, bolus, tablet, powders, lozenges, chews, 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 employed as fillers in soft or hard capsules, soft or hard palatable chews, 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, flavorants, and/or suspending agents. Liquid forms include suspensions, solutions, syrups, drenches and elixirs. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. Oral drenches are commonly prepared by dissolving or suspending the compound of the present invention in a suitable medium (e.g. triethylene glycol, benzyl alcohol, and the like). The compound of the present invention can also be formulated with a food substance, e.g., a dietary admixture (food pellets or powder for birds).

The compound of the present invention can be administered topically 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 suited to such formulations, for example liquid forms. Typical

formulations for this purpose include pour-on, spot-on, multi-spot-on, stripe-on, comb- on, roll-on, dip, spray, mousse, shampoo, powder formulation, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and micro emulsions. Liposomes may 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 may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Pour-on or spot-on formulations may 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 encapsulation, to leave a residue of active agent on the surface of the animal, this effect may ensure that the compound of the present invention has increased persistence of action and is more durable, for example it may be more water-fast. Topical formulations contemplated herein can 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, and even more preferably, from 1 mg/kg to 5 mg/kg.

The compounds of the present invention can also be administered topically via a support matrix for example, a synthetic or natural resin, plastic, cloth, leather, or other such polymeric system in the shape of a collar or ear tag. Said collar or ear tag may be coated, impregnated, layered, 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 additional antiparasitic agent, or veterinary acceptable salts thereof. Such formulations are prepared in a conventional manner in accordance with standard medicinal or veterinary practice. Further, these formulations will vary with regard 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. The volume of the applied composition can be from about 0.2 mL/kg to 5 mL/kg and preferably from about 1 mL/kg to 3ml_/kg.

Agents may 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 are applied, for example to improve their persistence on the coat of the animal. It is particularly preferred to include such agents in a formulation which 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. A particular suitable reagent is the trademark reagent "Foraperle" (Redline Products Inc, Texas, USA). Certain topical formulations may include unpalatable additives to minimize oral exposure. The compounds of the present invention can also be administered by injection. Injectable {e.g., subcutaneous and parenteral) formulations may be prepared in the form of a sterile solution, which may contain other substances, for example enough salts or 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 fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrolidin-2-one and glycerol formal. The formulations are prepared by dissolving or suspending 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.

Suitable devices for injectable administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques. Injectable formulations are typically aqueous solutions which may contain excipients such as salts,

carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dry powder form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of injectable formulations under sterile conditions, for example, by lyophilization, may readily be 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 may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility- enhancing agents.

Administration of the compound of the instant invention is contemplated to be once a month. However, an extended duration formulation may allow for dosing once every 2, 3, 4, 5, or 6 months.

Such formulations are prepared in a conventional manner in accordance with standard medicinal or veterinary practice. Further, these formulations will vary with regard 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. The composition of the present invention may be administered alone, as described above, or in combination with at least one other additional antiparasitic agent to form a multi-component parasiticide giving an even broader spectrum of veterinary utility. Thus, the present invention also envisions a combination veterinary composition comprising an effective amount of the compound of the present invention in combination with at least one other additional antiparasitic agent and can further comprise at least one veterinary acceptable carrier.

The following list of additional antiparasitic agents together with which the compound of the present invention can be used is intended to illustrate the possible combinations, but not to impose any limitation. Non-limiting examples of additional antiparasitic agents include: amitraz, aminoacetonitriles, albendazole, cambendazole, fenbendazole, flubendazole, thiabendazole, mebendazole, cyclic octadepsipeptides, oxfendazole, oxibendazole, paraherquamide, parbendazole, piperazines, praziquantel, thiabendazole, tetramisole, triclabendazole, levamisole, pyrantel (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, kinoprene, lufenuron, metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyfen, closantel, clorsulon, novaluron, fluazuron, spinosad, sarolaner ((S)-1 -(5'-(5-(3,5-dichloro-4-fluorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'H-spiro[azetid ine-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-trifl uoroethyl)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-dihy dro-1 ,2-oxazol-3-yl]thiophene- 2-carboxamide); and mixtures thereof. Preferred additional antiparasitic agents include moxidectin, doramectin, selamectin, abamectin, milbemycin, milbemycin oxime, pyrantel, praziquatel, and levamisole. The veterinary composition for application to an animal may be packaged in a variety of ways depending upon the method used for administering the compound of the present invention or combination, thereof. Generally, an article for distribution includes a container having deposited therein the veterinary composition in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

The compounds of the present invention (including the compositions and processes used therein) may also be used in the manufacture of a medicament for the therapeutic applications described herein.

The compounds of the present invention, stereoisomers thereof, and

compositions comprising a therapeutically effective amount of a Formula (1 ) compound and at least one veterinary acceptable carrier are useful as ectoparasiticides for the control and treatment of infections or infestations manifested 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 may, in particular, be used in the fields of veterinary medicine, livestock husbandry and the maintenance of public health:

against acarids, insects, and copepods which are parasitic upon vertebrates, particularly warm-blooded vertebrates, including companion animals, livestock, and fowl and coldblooded vertebrates like fish.

The compounds of the present invention are useful for the treatment of parasitic worms categorized as cestodes (tapeworms), nematodes (roundworms) and

trematodes (flatworms or flukes). The gastrointestinal roundworms include, for example, Ostertagia ostertagi (including inhibited larvae,), 0. 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, 0. dentatum, 0. columbianum, 0. quadrispinulatum, Trichuris spp., and the like. Other parasites include: hookworms (e.g., Ancylostoma caninum, A.tubaeforme, A.braziliense, Uncinaria stenocephala); lungworms (e.g., Dictyocaulus viviparus and Metastrongylus spp); eyeworms (e.g., Thelazia spp.); parasitic stage grubs (e.g., Hypoderma bovis, H. lineatum, Dermatobia hominis); kidneyworms (e.g., Stephanurus dentatus); screw worm (e.g., Cochliomyia hominivorax (larvae); filarial nematodes of the super-family Filarioidea and the

Onchocercidae Family. Non-limiting examples of filarial nematodes within the

Onchocercidae Family include the genus Brugia spp. (i.e., 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. (i.e., D reconditum, D. repens, and the like), Onchocerca spp. (i.e., 0. gibsoni, 0. gutturosa, 0. volvulus, and the Wke), Elaeophora spp. (E.bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri, and the \\ke), Mansonella spp. (i.e., M. ozzardi, M. perstans, and the like J, and Loa spp. (i.e., 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).

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 (e.g., Ixodes spp., {e.g., I. ricinus, I. hexagonus), Rhipicephalus spp., (e.g., 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., D. variabilis, D. andersoni, D. marginatus), Ornithodorus spp., and the like); mites (e.g., Dermanyssus spp., Sarcoptes spp., (e.g., S. scabiei),

Psoroptes spp., (e.g., P/ bovis), Otodectes spp., Chorioptes spp., Demodex spp., (e.g., D. folliculorum, D. canis, and D. brevis) and the like); chewing 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, midges, and mosquitos (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); bed bugs (e.g., insects within the genus Cimex and family Cimicidae); and grubs (e.g.,Hypoderma bovis, H.lineatum); and copepods (e.g., sea lice within the Order Siphonostomatoida, including genera

Lepeophtheirus and Caligus).

The compounds of the present invention and compositions comprising compounds of the present invention in conjunction with at least one other antiparasitic agent are of particular value in the control of ectoparasites and endoparasites which are injurious to, or spread or act as vectors of diseases in companion animals, livestock, birds, and fish. The ectoparasites and endoparasites which can be treated with a combination of a Formula (1 ) compound and an additional antiparasitic agent include those as herein before described.

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 may be administered directly to the animal and/or indirectly by applying it to the local environment in which the animal dwells (such as bedding, enclosures, and the like). Direct administration includes contacting the skin, fur, or feathers of a subject animal with the compound(s), or by feeding or injecting the compounds into the animal.

The Formula (1 ) compound, stereoisomers thereof, veterinary acceptable salts thereof, and combinations with at least one additional antiparasitic agent, as described herein, are of value for the treatment and control of the various lifecycle stages of parasites including egg, nymph, larvae, juvenile and adult stages.

The present invention also relates to a method of 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 parasitic infection or infestation from parasites carried by the animal and to improve the environment in which the animals inhabit. The present invention also relates to a method of 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 poor health comprising the application to said human to reduce or eliminate the potential for human parasitic infection or infestation from parasites carried by the human and to improve the environment in which the human inhabits.

The present invention also relates to a method of 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 to the plant.

The reactions set forth below were done generally under a positive pressure of argon or nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel 60 F 254 precoated plates and eluted with appropriate solvent ratios (v/v). Reactions were assayed by TLC or LCMS and terminated as judged by the consumption of starting material. Visualization of the TLC plates was done with UV light (254 nM wavelength) or with an appropriate TLC visualizing solvent and activated with heat. 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.

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

Certain aspects of the present invention are illustrated by the following

Examples. It is to be understood, however, that the 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 instant disclosure, to one of ordinary skill in the art.

Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include diastereomers, e.g., cis/trans (E/Z) isomers. One 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 stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers.

EXAMPLES

The following examples were prepared according to the Schemes and

preparations as presented herein. Example mass and NMR data is shown in Table 3. Aldehyde Intermediates:

Intermediate 1 : (£)-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

To a solution of 5-bromo-2-chloro-1 ,3-difluoro-benzene (5.0g, 21 mmol) in THF at -40 °C (dry ice/acetonitrile bath) was slowly added Isopropylmagnesium chloride-lithium chloride complex (1 .3 mol/L) in THF (22ml_, 29mmol). The reaction was stirred for 15 minutes. Next, DMF (3.1 mL, 40mmol) was added. The reaction mixture was slowly allowed to warm to -20 °C while stirring over 2 hours. Citric acid was added and the reaction mixture was extracted with EtOAc (2 x 75ml_). The organic phase was washed with brine, dried (Na ₂ S0 ₄ ) and concentrated under vacuum. The crude material was chromatographed (80g Redi-Sep column) eluting from 100% hexanes to 10:90

EtOAc:hexanes to afford the intermediate (3.25g, 70%) as a solid. 1 H NMR (400 MHz, CDCIs) δ: 7.52-7.56 (m, 2 H), 9.95 (t, 1 H).

Step 2: Preparation of Intermediate 1 . To a solution of 4-chloro-3,5-difluoro- benzaldehyde (4.0g, 22.6mmol) in toluene (l OOimL) was added (triphenyl- phosphoranylidene)acetaldehyde (7.7g, 25.3mmol). The reaction mixture was heated to 85 °C for 18 hours. Next, the reaction mixture was cooled and concentrated under vacuum. The crude material was chromatographed (220g Redi-Sep column) eluting from 100% hexanes to 10:90 EtOAc:hexanes to afford the title compound (3.3g, 72%) as a solid. 1 H NMR (400 MHz, CDCI ₃ ) δ: 6.66-6.72 (m, 1 H), 7.19-7.23 (m, 2 H), 7.37 (d, 1 H), 9.75 (d, 1 H).

The following aldehyde intermediates (I-2 to 1-16 and 1-19 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 Journal of Fluorine Chemistry (130 (2009) 175-196).

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

To commercially available 2-bromo-5-trifluoromethylpyridine (295 g, 1 .3 mol) in DCM (4L) at -2°C was added iPr gCI (2M in Et ₂ 0, 750 ml, 1 .5 mol) over 3 minutes then stirred at 0-6 °C for 40 minutes [jacket at 0 °C, mild and gradual exotherm took pot temp to 6 °C maximum after about 15 minutes]. The mixture was cooled to -20 °C then DMF (200ml, 2.6mol) was added in one portion [exotherm to 6 °C]. The mixture was slowly re- cooled to 0°C over 20 minutes then quenched by addition of 1 .5L saturated NaHC0 ₃ in one portion [temperature to 12 °C]. The mixture was stirred at 12 °C for 15 minutes then filtered through a celite pad. The layers were 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 MgS0 ₄ , filtered through a pad of 1 kg silica, washed with 5L DCM and evaporated (bath temp 35 °C). The brown oil was dissolved in 2L hexane and washed with 2 x 1 L 12% brine to remove DMF. The organics were filtered through a pad of MgS0 ₄ and concentrated to low volume. This oil was distilled at 35 °C and 20 inches Hg to remove hexane then at 56 °C and 26 inches Hg to afford the 5- (trifluoromethyl)-picolinaldehyde product (154 g, about 90% purity, 0.79 mol, 61 %) as a pale yellow moist crystal. A solution of 5-(trifluoromethyl)picolinaldehyde (150 g, about 90% purity, 0.77mol) in DCM (1 .5L) 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 (1 OOg) and washed with DCM (400ml). The filtrate was evaporated at 40 °C. The residue was triturated with MTBE (150ml) then diluted with hexane (300ml) and filtered, washing with MTBE/hexane. The filtrate was diluted with DCM to solubilize a small amount of oil that had separated and then chromatographed (3 kg silica, 20-35% MTBE in hexane) to afford the desired product (60.3 g, 0.30 mol, 39%) as a dark red solid,. ¹ H NMR (500 MHz, CDCI ₃ ) δ 9.85 (d, 1 H), 8.95(s, 1 H), 8.02 (dd, 1 H), 7.66 (d, 1 H), 7.55 (d, 1 H), 7.19 (dd, 1 H).

Intermediate 28. (Z)-3-(4-chlorophenyl)-2-fluoroacrylaldehyde

Step 1 : Synthesis of (Z)-1 -etho yl-1 -trimethylsilanyloxy-ethene

In a 250ml_ round bottom flask, to a stirred solution of fluoro-acetic acid ethyl ester (7.5gm, 70.68mmol, 1 eq) and trimethysilyl chloride (19.73ml_, 155.51 mmol, 2.2eq) in dry THF (23mL) at -78 °C was added dropwise a solution of LDA (21 .07ml_,

155.51 mmol, 2.2eq, freshly prepared LDA by using n-BuLi (62.19mL, 155.51 mmol, 2.2eq and diisopropyl amine (21 .8mL, 155.51 mmol, 2.2eq) in dry THF (52.5ml_) at -78 °C under nitrogen atmosphere. Resulting mass was stirred at -78 °C for 2 hours and then allowed to return to room temperature and then diluted with dry hexane (150ml_) and filtered. Filtrate was concentrated under reduced pressure to afford yellow liquid (18gm, crude). Crude was used as such for next step. MW 250.46.

Step 2: Synthesis of (Z)-3-(4-chloro-phenyl)-2-fluoro-acrylic acid ethyl ester

In a 500ml_ round bottom flask to the stirred solution of 4-chloro-benzaldehyde (14gm, 99.595mmol, 1 eq) and tetrabutylammonium acetate (1 .501 gm, 4.98mmol, 0.05eq) in dichloromethane (150ml_) was added (Z)-1 -ethoxy-2-fluoro-2-trimethylsilanyl- 1 -trimethylsilanyloxy-ethene (34.922gm, 139.43mmol, 1 .4eq) at room temperature. Reaction mixture was stirred at room temperature for 1 hour. Progress of reaction was monitored by TLC. After completion of starting material, reaction mixture was quenched with aqueous (1 M) HCI (75ml_) and brine (75ml_). Aqueous layer was extracted with dichloromethane (75ml_ x 2). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford yellow oil as crude compound 20g. Purification was done by combiflash column chromatography (120gm Redisep column). Compound was eluted by 0.5% ethyl acetate in hexane to afford off white solid (17g, 74.66 %). 1 H NMR (400 MHz, CDCI3) δ: 1 .35-1 .38 (m, 3H), 4.31 -4.36 (q, 2H), 6.86 (d, 1 H), 7.34-7.38 (m, 2H), 7.54-7.58 (m, 2H). LC-MS (m/z): Not ionized.

Step 3: Synthesis of (Z)-3-(4- 2-en-1 -ol:

In a 500ml_ round bottom flask to the stirred solution of (Z)-3-(4-chloro-phenyl)-2- fluoro-acrylic acid ethyl ester (9gm, 39.361 mmol, 1 eq) in dichloromethane (100ml_) was added diisobutylaluminium hydride (1 M in THF) (5.598gm, 39.36ml, 39.361 mmol, 1 eq) at -78 °C. After that reaction mixture was stirred at room temperature for 15 hours. Progress of reaction was monitored by TLC. After consumption of starting material, reaction mixture was quenched with aqueous tartarate salt solution (1 OOmL). Aqueous layer was extracted with dichloromethane (100mL x 3). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford yellow semi solid crude compound 10g. 7.2g crude compound of previous batch mixed and purified by combiflash (120gm, Redisep column). Compound was eluted using 8% ethyl acetate in hexane to afford 8g as yellow solid. 1 H NMR (400 MHz, CDCI3) δ: 1 .93 (t, 1 H), 4.24-4.29 (dd, 2H), 5.74 (d, 1 H), 7.21 -7.31 (m, 2H), 7.40-7.44 (m, 2H). LC-MS (m/z): Not ionized.

Step 4: Synthesis of Intermediate 28. In a 100ml_ round bottom flask to a stirred solution of (Z)-3-(4-chloro-phenyl)-2- fluoro-prop-2-en-1 -ol (4gm, 21 .43mmol, 3.0eq) in chloroform (50ml_) was added Mn0 ₂ (9.31 gm, 107.17mmol, 5.0eq). Resulting reaction mixture was heated to 60 ^° C for 5 hours. Progress of reaction was monitored by TLC. TLC showed unreacted starting material on TLC so again Mn0 ₂ (9.31 gm, 107.17mmol, 5.0eq) was added and continued the reaction at 60 ^° C for 15 hours. After maximum consumption of starting material, reaction mass was filtered on Buchner funnel and washed with DCM (50mL x 2). Filtrate was evaporated under reduced pressure to afford yellow oil (5gm, crude). Purification was done by combiflash column chromatography (40gm Redisep column). Compound was eluted by 2% ethyl acetate in hexane to afford off yellow solid (2.2gm, 55.56 %). 1 H NMR (400 MHz, CDCI3) <5: 6.57 (d, 1 H), 7.41 (d, 2H), 7.64 (d, 2H), 9.35 (d, 1 H). LC-MS (m/z): Not ionized.

Commercially available aldehyde intermediates (l-#) were also used for preparing 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 (1-31 ); (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 (1-41 ); (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 (l-46); 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 (1-51 ); (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 (1-58), (E)-3-(4-chloro-3-methyl-phenyl)acrylaldehyde (1-59); and (E)-3-(3-bromo-4-chlorophenyl)acrylaldehyde (1-60).

For the reactions and Examples described herein, 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 T and 9' gamma-carboline isomers. For example, the reaction of (3-bromophenyl)hydrazine and piperidin-4-one hydrochloride will produce 7-bromo-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole and 9- bromo-2,3,4,5-tetrahydro-1 H-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.

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-yl-hydrazine, (4-methylsulfanylphenyl)hydrazine, 2-chloro- 5-hydrazinylbenzonitrile, (4-(methylsulfonyl)phenyl)hydrazine, 4-bromo-3-ethoxy- phenyl)-hydrazine, and the like.

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 phenyl- methanamines, for example (4-fluorophenyl)methanamine, (4-chlorophenyl)- methanamine, and the like, can be used.

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 instead 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 urea's.

Example 1 . (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-N-((2-chloropyr idin-4-yl)methyl)- 7-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI

Step 1 : 7-bromo-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole and 9-bromo-2,3,4,5- tetrahydro-1 H-pyrido[4,3-b indole:

To a solution of (3-bromophenyl)hydrazine (10.Og, 53.5mmol) in IPA (1 OOmL) was added piperidin-4-one HCI (7.9g, 58.8mmol) and HCI (40ml_ of a 4.0M solution in dioxane). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled, filtered and rinsed with I PA to afford the intermediate HCI salt as a mixture of regio-isomers. LC-MS (m/z): [M+H] = 251 , 253.

Step 2: ferf-butyl 7-bromo-1 ,3,4,5 b]indole-2-carboxylate

To a mixture of 7-bromo-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole and 9-bromo-2,3,4,5- tetrahydro-1 H-pyrido[4,3-b]indole (12.5g, 43.5mmol) in CH ₂ CI ₂ (150mL) was added triethylamine (18.4ml_, 130.0mmol) followed by boc anhydride (8.3g, 47.8mmol). 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

(Na ₂ S0 ₄ ), and concentrated under vacuum. The crude mixture was chromatographed (220gRedi-Sep column) eluting from 100% hexanes to 25:75 EtOAc:hexanes, collecting the title compound as first eluting peak. LC-Ms (m/z): [M+H-ibutyl] = 295, 297. The second eluding peak constituted the 9' regio-isomer.

Step 3 : te/t-butyl 7-cyano-1 ,3,4 -tetrahydropyrido[4,3-b]indole-2-carboxylate

To a solution of ferf-butyl 7-bromo-1 ,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (6.4g, 18mmol) in DMF (1 OOmL) was added Zn(CN) ₂ (1 .5g, 13mmol), Zn(OAc) ₂ (670mg, 3.6mmol), Pd(DPPF ₂ )CI ₂ (81 Omg, 1 .1 mmol), and zinc dust (480mg, 7.3mmol). The reaction mixture was purged with nitrogen and heated to 100 °C for 18 hours. The reaction mixture was cooled and poured onto ice water (l OOmL). The resulting precipitate was filtered and washed with additional water. The precipitate was dissolved in CH2CI2 (300ml_) dried (Na2S0 ₄ ), and concentrated under vacuum. The crude material was chromatographed (120g Redi-Sep column) eluting from 100%hexanes to 50:50 EtOAc:hexanes to afford the title compound as a solid. LC-MS (m/z): [M+H-f- butyl] = 242.

Step 4: terf-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-cyano-3,4-dihydro- 1 H- pyrido[4,3-b]indole-2-carboxyla

To a stirred solution of te/t-butyl 7-cyano-1 ,3,4,5-tetrahydropyrido[4,3-b]indole-2- carboxylate (5.0g, 16.8mmol) in THF (75ml) at 0 °C was added sodium hydride (1 .2g, 30.3mmol). The reaction mixture was allowed to warm to room temperature while stirring for 30 minutes. Next, the mixture was cooled back to 0 °C in an ice bath and 2- chloro-4-(isocyanatomethyl)pyridine (3.4g, 20.2mmol) was added. The reaction was kept at 0 °C while stirring for 15 minutes. The reaction was quenched with 5ml_ saturated NH ₄ CI, then ice water was added to the reaction mixture and it was extracted with EtOAc (2 x l OOmL). The combined organic phases were washed with brine, dried (Na ₂ S0 ₄ ), and concentrated under vacuum. The crude product was chromatographed (120g Redi-Sep column) eluting from 25:75 EtOAc:hexanes to 40:60 EtOAc:hexanes to afford title compound as a solid. LC-MS (m/z): [M+H-ibutyl] = 410.

Step 5: A/-[(2-chloro-4-pyridyl)methyl]-7-cyano-1 ,2,3,4-tetrahydropyrido[4,3-b]indole-5- carboxamide.

To a solution of tert-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-cyano-3,4-dihydro- 1 H-pyrido[4,3-b]indole-2-carboxylate (5.2g, 1 1 .0mmol) in DCM (100mL) at O °C was added TFA (8.4mL, 1 10mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours. Toluene (35ml_) was added and the reaction was concentrated under vacuum. The resulting TFA salt was dissolved in EtOAc (175ml_) and saturated NaHC0 ₃ (75ml_) was added. The resulting precipitate was stirred at room temperature for 15 minutes, filtered, and dried under vacuum to afford the title compound as a solid (3.53g, 86%): LC-Ms (m/z): [M+H] = 366.

Step 6: Preparation of Example 1 . To a flask containing N-[(2-chloro-4-pyridyl)methyl]- 7-cyano-1 ,2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide (90mg, 0.25mmol) was added (£)-3-(4-chloro-3,5-difluoro-phenyl)prop-2-enal (Intermediate 1 ) (60mg,

0.30mmol), and CH ₂ CI ₂ (5ml_). The mixture was stirred at room temperature for 15 minutes and sodium triacetoxyborohydride (63mg, 0.30mmol) was added. The reaction mixture was stirred at room temperature for 18 hours; next, diluted with CH ₂ CI ₂ (50ml_), washed with saturated NaHCOs, dried (Na ₂ S0 ₄ ), and concentrated under vacuum. The crude product was chromatographed (24g Redi-Sep column) eluting from 50:50 EtOAc:hexanes to 100% EtOAc. The purified product was subsequently dissolved in CH ₂ CI ₂ (10ml_) and HCI gas was bubbled in slowly until a precipitate formed. The mixture was diluted with diethyl ether (10ml_), stirred for 5 minutes, filtered, washed with with additional diethyl ether, and dried under vacuum to afford the title compound as an HCI salt

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-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide (I-4);

Example 4, (E)-N-((2-chloropyridin-4-yl)methyl)-9-cyano-2-(3-(2,4-dichl orophenyl)allyl)-

1 ,2,3,4-tetrahydro-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-chloropyr idin-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 (1-10);

Example 1 1 , (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 (1-1 1 );

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 (1-12);

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 (1-13);

Example 14, (E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-N-((2-chloropyri din-4-yl)methyl)-

7-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-14);

Example 15, (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyr idin-4-yl)methyl)-

7-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-15);

Example 16, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(perfluoro phenyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-16);

Example 17, (E)-2-(3-(4-chloro-2,3,5,6-tetrafluorophenyl)allyl)-N-((2-ch loropyridin-4- yl)methyl)-7-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-17); Example 18, N-[(2-chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(4-cyano-3-f luoro- phenyl)allyl]-3,4-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide HCI (1-21 );

Example 19, 2-[(E)-3-(5-bromo-2,4-difluoro-phenyl)allyl]-N-[(2-chloro-4- pyridyl)methyl]-

7-cyano-3,4-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide HCI (I-23);

Example 20, N-[(2-chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(3,5-difluor o-4-methoxy- phenyl)allyl]-3,4-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide HCI (I-24);

Example 21 , 2-[(E)-3-(4-chloro-2-fluoro-3-methoxy-phenyl)allyl]-N-[(2-ch loro-4- pyridyl)methyl]-7-cyano-3,4-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide HCI (I-25);

Example 22, N-[(2-chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(3,6-dichlor o-2-fluoro- phenyl)allyl]-3,4-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide HCI (I-26);

Example 23, 2-[(E)-3-(4-bromo-2,5-difluoro-phenyl)allyl]-N-[(2-chloro-4- pyridyl)methyl]-

7-cyano-3,4-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide HCI (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-diflu orophenyl)allyl)-

1 ,2,3,4-tetrahydro-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 (1-31 );

Example 28, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(3,4-diflu orophenyl)allyl)-

1 ,2,3,4-tetrahydro-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-diflu orophenyl)allyl)-

1 ,2,3,4-tetrahydro-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-diflu orophenyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-36); Example 33, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(4-cyanoph enyl)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)met hyl)-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-dichl orophenyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39);

Example 36, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(4-fluorop henyl)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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-41 ); and

Example 38, N-[(2-chloro-4-pyridyl)methyl]-7-cyano-2-[(E)-3-(4-fluoro-3- methoxy- phenyl)allyl]-3,4-dihydro-1 H-pyrido[4,3-b]indole-5-carboxamide HCI (I-53).

Example 39, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((2,6- dichloropyridin-4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, was prepared similarly to Example 1 but using (2,6-dichloropyridin-4- yl)methanamine and aldehyde intermediate, I-3.

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-diflu orophenyl)allyl)- 7-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-1 )

Example 41 , (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chloro-3-fluorop henyl)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-fluorop henyl)allyl)-7- cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, HCI, (I-7);

Example 43, (E)-N-((2-bromopyridin-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 HCI (1-13);

Example 44, (E)-N-((2-bromopyridin-4-yl)methyl)-7-cyano-2-(3-(2,4-difluo rophenyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, HCI (I-30);

Example 45, (E)-N-((2-bromopyridin-4-yl)methyl)-7-cyano-2-(3-(3,4-difluo rophenyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, (I-32);

Example 46, (E)-N-((2-bromopyridin-4-yl)methyl)-7-cyano-2-(3-(3,4,5-trif luorophenyl)- allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, HCI (I-33);

Example 47, (E)-N-((2-bromopyridin-4-yl)methyl)-7-cyano-2-(3-(3,5-difluo rophenyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, (I-34);

Example 48, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chlorophenyl)all yl)-7-cyano-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI. (I-38); and

Example 49, (E)-N-((2-bromopyridin-4-yl)methyl)-7-cyano-2-(3-(4-fluoroph enyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, HCI (I-40).

The following compounds were prepared similarly to Example 1 but using (2- fluoropyridin-4-yl)methanamine and the respective aldehyde intermediate:

Example 50, (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-7-cyano-N-((2-f luoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-1 )

Example 51 , (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-7-cyano-N-((2-fluor opyridin-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-fluor opyridin-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-f luoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-15);

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-tetrahydro-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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI 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-methy lpyridin- 4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI 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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI 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 similarly to Example 1 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-(pyridazi n-4- ylmethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, 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- ro-1 H-pyrrol-3-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI was prepared similarly to Example 1 but using (1 -methyl-1 H-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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI

Step 1 : 8-bromo-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole hydrochloride

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 isopropanol. HCI 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. Progress of the reaction was monitored by 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: tert-butyl 8-bromo-1 _! 3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

In a 500 mL round bottom flask, 8-bromo-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole hydrochloride (13.82 g, 48.06 mmol) was suspended in 200 mL DCM at 0°C, TEA (14.8 mL, 105.72 mmol) was added and the resulting solution was maintained at 0 °C for 15 minutes. Boc ₂ 0 (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. Progress of the reaction was monitored by LCMS. After consumption of all starting materials 200 mL of saturated NaHC0 ₃ was added and the resulting biphasic solution was vigorously stirred 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 MgS0 ₄ and the volatiles removed under reduced pressure. The crude was purified on silica using flash chromatography using 0-50% EtOAc in Hexanes on 340 g column to give the desired product as a pale yellow solid. LC-Ms (m/z): [M+H] = 351 .1 .

For reactions wherein the bromo substitution is to be converted to cyano, the following Step (3) can be performed as described below, or alternatively, similarly to the cyanation step described in Example 1 . If cyanation is not required, for example, to retain the bromo substitution (or other substituted moiety, e.g., CI, F, methyl, methoxy, and the like) then the cyanation step(s) can be bypassed.

Step 3: tert-butyl 8-cyano-1 ,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate

tert-butyl 8-bromo-1 ,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (6.4g, 18mmol) in DMF (1 OOmL) was added Zn(CN) ₂ (1 .5g, 13mmol), Zn(OAc) ₂ (670mg, 3.6mmol), Pd(DPPF ₂ )CI ₂ (810mg, 1 .1 mmol), and zinc dust (480mg, 7.3mmol). The reaction mixture was purged with nitrogen and heated to 100°C for 18 hours. The reaction mixture was cooled and poured onto ice water (100ml_). The resulting precipitate was filtered and washed with additional water. The precipitate was dissolved in CH ₂ CI ₂ (300ml_) dried (Na ₂ S0 ₄ ), and concentrated under vacuum. The crude material was chromatographed (120g Redi-Sep column) eluting from 100%hexanes to 50:50

EtOAc:hexanes to afford the title compound as a solid (This procedure can be used to synthesize subsequent cyano compounds from bromo precursors).

Step 4: tert-butyl 8-cyano-5-(((2-methoxypyridin-4-yl)methyl)carbamoyl)-1 ,3,4,5- tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

A 100ml_ 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 imL). 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 slowly evolves and the reaction mixture turned from an off white suspension to a rose pinkish-red suspension. The ice bath was removed after 2 hours, and the reaction was allowed to warm to room temperature for 10 minutes. Next, the mixture was cooled back 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 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 HCI (10 mL, 1 .0 M) at 0°C. The reaction mixture diluted with water (20mL) and saturated NaHC03 (20 mL) and extracted with EtOAc (2 x 30ml_). The combined organic phases were washed with brine, dried over gS0 ₄ , and concentrated under reduced pressure. The crude was purified by flash chromatography using EtOAc in Hexanes (0 to 70%) to give the desired compound as an amorphous off yellow solid. LC-Ms (m/z): [M+Na] = 484.2.

Step 5: Preparation of Example 63. In a 8 mL vial 1 10 mg of tert-butyl 8-cyano-5-(((2- methoxypyridin-4-yl)methyl)carbamoyl)-1 ,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate was dissolved in 5.0 mL of DCM and 183 il of TFA was added at room temperature. The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction the 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 μί 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. Upon completion of the reaction as monitored by LCMS, 3 mL of saturated NaHCO ₃ solution were 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 flow 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 and washed with cold EtOAc and Et ₂ O and dried under high vacuum. The crystals were dissolved in DCM and Et2O and a stream of HCI gas was passed through the solution to prepare title compound (HCI salt).

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-N-((2-metho xypyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-3);

Example 65, (E)-8-cyano-2-(3-(2,4-dichlorophenyl)allyl)-N-((2-methoxypyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-4);

Example 66, (E)-2-(3-(4-bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-methox ypyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-5); Example 67, (E)-8-cyano-2-(3-(2,4-difluorophenyl)allyl)-N-((2-methoxypyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-30);

Example 68, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-8-cyano-N-((2-metho xypyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-31 ); and Example 69, (E)-8-cyano-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-methoxypyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-39).

Example 70, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-8-cyano-N-((2-ethox ypyridin- 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

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-3,5-difluorophenyl)allyl)-N-((2-chloropyr idin-4-yl)methyl)- 8-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-1 )

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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-5); Example 74, (E)-2-(3-(4-chloro-2,6-difluorophenyl)allyl)-N-((2-chloropyr idin-4-yl)methyl)- 8-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-9); Example 77, (E)-2-(3-(2-bromo-5-fluorophenyl)allyl)-N-((2-chloropyridin- 4-yl)methyl)-8- cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, (1-10);

Example 78, (E)-2-(3-(5-bromo-2-fluorophenyl)allyl)-N-((2-chloropyridin- 4-yl)methyl)-8- cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-1 1 );

Example 79, (E)-2-(3-(3-bromo-4-fluorophenyl)allyl)-N-((2-chloropyridin- 4-yl)methyl)-8- cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-12);

Example 80, (E)-N-((2-chloropyridin-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 HCI (1-13); Example 81 , (E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-N-((2-chloropyri din-4-yl)methyl)- 8-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-14);

Example 82, (E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyr idin-4-yl)methyl)- 8-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI) (1-15);

Example 83, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(perfluoro phenyl)allyl)- 1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-16);

Example 84, (E)-2-(3-(4-chloro-2,3,5,6-tetrafluorophenyl)allyl)-N-((2-ch loropyridin-4- yl)methyl)-8-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-17); Example 85, (E)-2-(3-(4-bromo-3-fluorophenyl)allyl)-N-((2-chloropyridin- 4-yl)methyl)-8- cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-18);

Example 86, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(3-fluoro- 5-(trifluoro- methoxy)phenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-22); 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-diflu orophenyl)allyl)- 1 ,2,3,4-tetrahydro-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-diflu orophenyl)allyl)-

1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34);

Example 91 , (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(4-cyanoph enyl)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)met hyl)-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-dichl orophenyl)allyl)-

1 ,2,3,4-tetrahydro-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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCL (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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-59);

Example 97, (E)-2-(3-(3-bromo-4-chlorophenyl)allyl)-N-((2-chloropyridin- 4-yl)methyl)-8- cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-60); and

Example 98, (E)-N-((2-chloropyridin-4-yl)methyl)-8-cyano-2-(3-(3-cyano-4 - fluorophenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-20).

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-3,5-difluorophenyl)allyl)-8-cyano-N-((2-f luoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-1 )

Example 100, (E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(4-(methyl sulfonyl)- phenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-2);

Example 101 , (E)-8-cyano-2-(3-(2,4-dichlorophenyl)allyl)-N-((2-fluoropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-4);

Example 102, (E)-2-(3-(4-bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-fluoro pyridin-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-f luoropyridin-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-fluor opyridin-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-fluoro pyridin-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-fluoro pyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-10);

Example 108, (E)-2-(3-(5-bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-fluoro pyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-1 1 );

Example 109, (E)-2-(3-(3-bromo-4-fluorophenyl)allyl)-8-cyano-N-((2-fluoro pyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-12);

Example 1 10, (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 HCI (1-13); Example 1 1 1 , (E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-8-cyano-N-((2-fl uoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-14);

Example 1 12, (E)-8-cyano-2-(3-(3,5-dichloro-4-fluorophenyl)allyl)-N-((2-f luoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-19);

Example 1 13, (E)-8-cyano-2-(3-(3-cyano-4-fluorophenyl)allyl)-N-((2-fluoro pyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-20).

Example 1 14, (E)-2-(3-(2-chloro-4-fluorophenyl)allyl)-8-cyano-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29); Example 1 15, (E)-8-cyano-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30);

Example 1 16, (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 1 17, (E)-8-cyano-2-(3-(3,5-difluorophenyl)allyl)-N-((2-fluoropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34);

Example 1 18, (E)-2-(3-(3-chloro-2-fluorophenyl)allyl)-8-cyano-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-35);

Example 1 19, (E)-8-cyano-2-(3-(2,3-difluorophenyl)allyl)-N-((2-fluoropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-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-fluoropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-40);

Example 124, (E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(pyridin-4 -yl)allyl)- 1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-41 );

Example 125, (E)-2-(3-(2-bromo-4-fluorophenyl)allyl)-8-cyano-N-((2-fluoro pyridin-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-fluoropy ridin-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-fluoro pyridin-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]indole-5- carboxamide (I-7)

Example 129, (E)-8-cyano-2-(3-(2,4-difluorophenyl)allyl)-N-((2-(trifluoro methyl)pyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30).

The following compounds were prepared similarly to Example 63 but using (2- bromopyridin-4-yl)methanamine and the respective aldehyd intermediate:

Example 130, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chloro-3,5-diflu orophenyl)- allyl)-8-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-1 )

Example 131 , (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chloro-3-fluorop henyl)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-fluorop henyl)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 (1-13); 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 (1-21 );

Example 135. (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(2-chloro-4-fluorop henyl)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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 137, (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(3-chloro-4-fluorop henyl)allyl)-8- cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCL (1-31 );

Example 138, (E)-N-((2-bromopyridin-4-yl)methyl)-8-cyano-2-(3-(3,4- difluorophenyl)allyl)-1 ,2,3,4-tetrahydro-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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-34); Example 141 , (E)-N-((2-bromopyridin-4-yl)methyl)-2-(3-(4-chlorophenyl)all yl)-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-fluoroph enyl)allyl)- 1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40).

Example 143, (Z)-2-(3-(4-chlorophenyl)-2-fluoroallyl)-8-cyano-N-((2-chlor opyridin- 4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI 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-fluor opyridin- 4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI 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-dichloropheny l)allyl)- 7-methyl-1 ,2,3,4-tetrahydro-5 -pyrido[4,3-b]indole-5-carboxamide (I-39)

Step 1 : fert-butyl 7-methyl-1 ,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate; fert-butyl 9-methyl-1 ,3,4,5-tetrah

To a solution of m-tolylhydrazine (4.0g, 32.7mmol) in IPA (40mL) was added tert-butyl 4-oxopiperidine-1 -carboxylate (6.5g, 32.6mmol) and HCI (9.0ml_ of a 4.0M solution in dioxane). The reaction mixture was heated to reflux for 18 hours. Next, the reaction mixture was cooled and concentrated under vacuum to afford the crude intermediate as a mixture of regio-isomers. The mixture was purified by SFC chromatography (Berger multigram, column = 2-EP 30x250mm 5um, MP A = C0 ₂ MP B = 0.1 %NH ₄ in MeOH, 15%B, l OOmL/minute, 100bar, 40 °C) to afford tert-butyl 7-methyl-1 ,3,4,5- tetrahydropyrido[4,3-b]indole-2-carboxylate (1.53g, 16%) as the first eluting isomer and 9-methyl-1 ,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (1 .9g, 20%) as the second eluting isomer. 1 ^st eluting isomer: LC-Ms (m/z): [M+H-ibutyl] = 231 . 2 ^nd eluting isomer isomer: LC-Ms (m/z): [M+H-ibutyl] = 231 . Step 2: ieri-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-methyl-3,4-dihydro -1 H- pyrido[4,3-b]indole-2-carboxylate

To a stirred solution of 7-methyl-1 ,3 ,4,5-tetrahydropyrido[4,3-b]indole-2-carboxylate (500mg, 1 75mmol) in THF (25ml) at 0 °C was added NaH (21 Omg, 5.2mmol). The reaction mixture was allowed to warm to room temperature while stirring for 1 hour. Next, the mixture was cooled back to 0°C in an ice bath and 2-chloro-4- (isocyanatomethyl)pyridine (590mg, 3.5mmol) was added. The reaction was allowed to warm to room temperature while stirring for an additional 1 hour. Ice water was added and the reaction was extracted with EtOAc (2 x 10OmL). The combined organic phase was washed with brine, dried (Na ₂ S0 ₄ ), and concentrated under vacuum. The crude product was chromatographed (40g Redi-Sep column) eluting from 25:75

EtOAc:hexanes to 50:50 EtOAc:hexanes to afford title compound (341 mg, 43%) as a solid. LC-MS (m/z): [M+H-ibutyl] = 399.

Step 3: A/-[(2-chloro-4-pyridyl)methyl]-7-methyl-1 ,2,3,4-tetrahydropyrido[4,3-b]indole-5- carboxamide

To a solution of fert-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-methyl-3,4-dihydro - 1 H-pyrido[4,3-b]indole-2-carboxylate (330mg, 7.3mmol) in DC (15ml_) at 0 °C was added TFA (1 mL). The reaction was allowed to warm to room temperature and stir for 2 hours. Toluene (35ml_) was added and the reaction was concentrated under vacuum. The resulting TFA salt was dissolved in CH ₂ CI ₂ (1 OOmL) and washed with saturated NaHC0 ₃ (50ml_). The organic phase was separated, dried (Na2S04), and

concentrated under vacuum to afford the free-base intermediate (215mg, 84%) as a solid. LC-Ms (m/z): [M+H] = 355.

Step 4: Preparation of Example 145. To a flask containing A/-[(2-chloro-4- pyridyl)methyl]-7-methyl-1 ,2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide (70mg, 0.19mmol) was added aldehyde intermediate I-39 (40mg, 0.24mmol), and CH2CI2 (5ml_). The mixture was stirred at room temperature for 15 minutes and sodium triacetoxyborohydride (63mg, 0.30mmol) was added. The reaction mixture was stirred at room temperature for 2 hours; next, diluted with CH ₂ CI ₂ (50ml_), washed with saturated NaHC03, dried (Na ₂ S0 ₄ ), and concentrated under vacuum. The crude product was chromatographed (24g Redi-Sep column) eluting from 50:50

EtOAc:hexanes to 90:10 EtOAc:MeOH to afford the title compound (72mg, 67%) as a solid.

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)met hyl)-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)met hyl)-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-dichloropheny l)allyl)-9- methyl-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39);

Example 149, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)al lyl)-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-(thflu oromethyl)- 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 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-tetrah dro-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-fluorop henyl)allyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

Example 154, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluoropheny l)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)all yl)-7- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, (I-37);

Example 156, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-7- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38);

Example 157, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-9- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38);

Example 158, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)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-dichloropheny l)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)al lyl)-7- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40);

Example 161 , (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)al lyl)-9- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-40); 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)meth yl)-7- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37);

Example 165, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)met hyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-38); 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-dichloropheny l)allyl)- 8-fluoro-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39)

Step 1 : teri-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-8-fluoro-3,4-dihydro -1 H- pyrido[4,3-b]indole-2-carboxylate.

To a solution of 8-fluoro-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole HCI (1 .0g, 5.3mmol) in CH ₂ CI ₂ (50mL) was added Ν,Ν-diisopropylamine (2.3ml_, 13.0mmol) followed by BOC anhydride (1 .0g, 5.8mmol). 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 (Na2S0 ₄ ), and concentrated under vacuum. The crude mixture was chromatographed (40gRedi-Sep column) eluting from 100% hexanes to 40:60 EtOAc:hexanes to afford the title compound (1 .49g, 98%) as a solid. LC-Ms (m/z): [M+H-fbutyl] = 235.

Step 2: ferf-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-8-fluoro-3,4-dihydro -1 H- pyrido[4,3-b]indole-2-carboxylate

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

Step 3: A/-[(2-chloro-4-pyridyl)methyl]-8-fluoro-1 ,2,3,4-tetrahydropyrido[4,3-b]indole-5- carboxamide.

The title compound was synthesized following the same procedure as Step 3 of

Example 145 using terf-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-8-fluoro-3,4- dihydro-1 H-pyrido[4,3-b]indole-2-carboxylate in place of terf-butyl 5-[(2-chloro-4- pyridyl)methylcarbamoyl]-7-methyl-3,4-dihydro-1 H-pyrido[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 Step 4 of Example 145 using A/-[(2-chloro-4-pyridyl)methyl]-8-fluoro- 1 ,2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide in place of of A/-[(2-chloro-4- pyridyl)methyl]-7-methyl-1 ,2,3,4-tetrahydropyrido[4,3-b]indole-5-carboxamide.

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)all yl)-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)met hyl)-8-fluoro- 1 ,2,3,4-tetrahydro-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 intermediate, I-38

Example 171 , (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-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, -38

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-tetrahy carboxamide (I-3)

Example 173, (E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(4-cyanoph enyl)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-fluor opyridin-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)met hyl)-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)met hyl)-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

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-chlor opyridin-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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-21 ); Example 181 , (E)-8-bromo-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 182, (E)-8-bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chlor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 183, (E)-8-bromo-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 HCI (I-32); Example 184, (E)-8-bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanoph enyl)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-tetrahydro-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

(I-45).

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-fluor opyridin-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-fluoro pyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

Example 190, (E)-8-bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 191 , (E)-8-bromo-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-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-tetrahydro-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 similarly to Example 145 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 similarly to Example 145 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-chloropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-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-tetrahydro-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-fluor opyridin-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-fluoro pyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

Example 202, (E)-7-bromo-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyri din-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-30);

Example 203, (E)-7-bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-31 ); and Example 204, (E)-7-bromo-2-(3-(3,4-difluorop enyl)allyl)-N-((2-fluoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (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-chlo ropyridin-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-(trifl uoromethyl)- pyridin-2-yl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-18); Example 207, (E)-9-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(5-(trifl uoromethyl)- pyridin-2-yl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-18); 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 (1-21 ); Example 209, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difl uorophenyl)- 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-chlo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 21 1 , (E)-7-chloro-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 212, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanop henyl)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-tetrahydro-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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39);

Example 217, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluoro phenyl)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-fluoro phenyl)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-methox yphenyl)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-methox yphenyl)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-(trifl uoromethoxy)- 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-(trifl uoromethoxy)- 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-(trifl uoromethyl)- 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-fluo ropyridin-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-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

Example 226, (E)-7-chloro-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30);

Example 227, (E)-7-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 228, (E)-7-chloro-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-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-tetrahydro-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 aldehyde intermediate, I-38

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-chlo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3)

Example 233, (£)-8-chloro-2-(3-(4-chloro-2-fluorophenyl)allyl)-A/-((2-ch loropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5/-/-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 (1-21 ); Example 236, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-fluoro -5- (trifluoromethoxy)phenyl)allyl)-1 ,2,3 _! 4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-22);

Example 237, (E)-8-chloro-2-(3-(2-chloro-4-fluorophenyl)allyl)-A/-((2-chl oropyridin-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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-30); Example 239, (E)-8-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chlo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 240, (E)-8-chloro-A/-((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 241 , (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanop henyl)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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 244, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluoro phenyl)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-(trifl uoromethoxy)- 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-(trifl uoromethyl)- 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-chloroquinol in-2- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-48);

Example 248, (£)-8-chloro-A/-((2-chloropyridin-4-yl)methyl)-2-(3-(pyridi n-4-yl)allyl)- 1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-41 );

Example 249, (E)-8-chloro-2-(3-(3-chloro-5-fluorophenyl)allyl)-N-((2-chlo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-52);

Example 250, (E)-8-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-cyano- 5- fluorophenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-54); Example 251 , (E)-8-chloro-2-(3-(3-chloro-5-cyanophenyl)allyl)-N-((2-chlor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamideHCI (I-55);

Example 252, (E)-2-(3-(3-bromo-5-fluorophenyl)allyl)-8-chloro-N-((2-chlor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-56); and Exampe 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-fluo ropyridin-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-fluo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-7);

Example 256, (£)-8-chloro-2-(3-(2-chloro-4-fluorophenyl)allyl)-A/-((2-fl uoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-29);

Example 257, (£)-8-chloro-2-(3-(2,4-difluorophenyl)allyl)-A/-((2-fluorop yridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5/-/-pyrido[4,3-b]indole-5-carboxamide (I-30);

Example 258, ( 5)-8-chloro-2-(3-(3-chloro-4-fluorophenyl)allyl)-A/-((2-fluo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 259, (£)-8-chloro-2-(3-(3,4-difluorophenyl)allyl)-A/-((2-fluorop yridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-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-fluoropyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39);

Example 262, (E)-8-chloro-2-(3-(3-chloro-5-fluorophenyl)allyl)-N-((2-fluo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-52);

Example 263, (E)-8-chloro-2-(3-(3-cyano-5-fluorophenyl)allyl)-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-54);

Example 264, (E)-2-(3-(3-bromo-5-fluorophenyl)allyl)-8-chloro-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-56); and Example 265, (E)-8-chloro-2-(3-(3,5-dichlorophenyl)allyl)-N-((2-fluoropyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-57).

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-(trifl uoromethyl)- pyridin-2-yl)allyl)-1 ,2,3,4-tetrah dro-5H-pyrido[4,3-b]indole-5-carboxamide (1-18)

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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39); Example 269, (E)-6-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluoro phenyl)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-methox yphenyl)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-(trifl uoromethoxy)- 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-(trifl uoromethyl)- 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 aldehyde intermediate, I-38

The following compounds were prepared similarly to Example 145 but using (3,4- dichlorophenyl)hydrazine, and the respective aldehyde interemediate:

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]indole-5-carboxamide (I-3)

Example 275, (E)-7,8-dichloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cy ano-3- fluorophenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

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 (1-31 );

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-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 280, (E)-7,8-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-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-tetrahydro-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-tetrahydro-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-(t rifluoro- methoxy)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-(t rifluoromethyl)- 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 (3,4- dichlorophenyl)hydrazine, (2-fluoropyridin-4-yl)methanamine, and the respective aldehyde interemediate:

Example 286, (E)-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 HCI (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 (1-18);

Example 288, (E)-7,8-dichloro-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-f luoropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-21 );

Example 289, (E)-7,8-dichloro-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-30);

Example 290, (E)-7,8-dichloro-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 HCI (1-31 );

Example 291 , (E)-7,8-dichloro-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-32); Example 292, (E)-7,8-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); and

Example 293, (E)-8,9-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38).

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-chlorothi azol-5- yl)methyl)-1 ,2,3,4-tetrahydr -5H-pyrido[4,3-b]indole-5-carboxamide (I-38)

Example 295, (E)-8,9-dichloro-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothi azol-5- yl)methyl)-1 ,2,3,4-tetrahydro-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 aldehyde intermediate, I-38

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-chlo ropyridin-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-fluoro- phenyl)allyl)-8-fluoro-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 ); Example 299, (E)-7-chloro-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difl uorophenyl)- 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-difl uorophenyl)- 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-difl uorophenyl)- 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-cyanop henyl)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-(trifluoro- methyl)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-carboxami (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 31 1 , (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 (1-21 ); 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 (1-31 ); 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-fluo ropyridin-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-fluo ropyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40).

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)all yl)-7-fluoro-9- (trifluoromethyl)-1 ,2,3,4-tetra -carboxamide (I-37)

Example 321 , (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)all yl)-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)met hyl)-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)met hyl)-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-fluoro phenyl)allyl)-9- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-40); and Example 325, (E)-N-((2-chloropyridin-4-yl)methyl)-9-fluoro-2-(3-(4-fluoro phenyl)allyl)-7- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40).

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-tet e-5-carboxamide (I-38)

; and 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 aldehyde intermediate, I-38

Example 329, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-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 aldehyde intermediate, I-38

Example 330, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-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 aldehyde intermediate, I-38

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)all yl)-8- (trifluoromethyl)-1 ,2,3,4-tetrahyd -5H-pyrido[4,3-b]indole-5-carboxamide (I-37)

Example 332, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-8- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38);

Example 333, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)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)al lyl)-8- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-40); and Example 335, (£)-A/-((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).

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-tetrah dro-5H-pyrido[4,3-b]indole-5-carboxamide (I-3)

Example 337, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-dichloropheny l)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-chloropyr idin-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 (1-18);

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 (1-18);

Example 344, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-cyano-4-fluorop henyl)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-fluorop henyl)allyl)-7- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

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-difluoropheny l)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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 349, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluoropheny l)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)all yl)-7- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 352, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)all yl)-9- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37). Example 353, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-7- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 354, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-9- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 355, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)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)al lyl)-7- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4 _! 3-b]indole-5-carboxamide (I-40); Example 357, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)al lyl)-9- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 358, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)a llyl)-7- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 359, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)a llyl)-9- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 360, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy)-2- (3-(4-(trifluoro- methoxy)phenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); Example 361 , (E)-N-((2-chloropyridin-4-yl)methyl)-9-(trifluoromethoxy)-2- (3-(4-(trifluoro- methoxy)phenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); Example 362,(E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethoxy )-2-(3-(4-(trifluoro- methyl)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-(trifluoro- methyl)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-y l)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)m ethyl)-7- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-50); and Example 368, 2-((6-chloronaphthalen-2-yl)methyl)-N-((2-chloropyridin-4-yl )methyl)-7- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-51 ).

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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 ); 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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 ); 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)met hyl)-7- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 379a, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)met hyl)-9- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-54);

Example 382, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)met hyl)-7- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-38) and Example 383, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)met hyl)-9- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide were prepared similarly to Example 145 but using (3-(trifluoromethoxy)phenyl)hydrazine, (2- chlorothiazol-5-yl)methana -38.

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 (1-18);

Example 386, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorop henyl)allyl)-8- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 ); Example 387, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluoropheny l)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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 ); Example 389, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluoropheny l)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)all yl)-8- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37); Example 391 , (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-8- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38); Example 392, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)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)al lyl)-8- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-40); Example 394, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-methoxyphenyl)a llyl)-8- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-44); Example 395, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-2- (3-(4-(trifluoro- methoxy)phenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); Example 396, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(trifluoromethoxy)-2- (3-(4-(trifluoro- methyl)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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-52); Example 398, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3-cyano-5-fluorop henyl)allyl)-8- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-54); Example 399, (E)-2-(3-(3-chloro-5-cyanophenyl)allyl)-N-((2-chloropyridin- 4-yl)methyl)-8- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b] 5-carboxamide HCI (I-55); and Example 400, (E)-2-(3-(3-bromo-5-fluorophenyl)allyl)-N-((2-chloropyridin- 4-yl)methyl)-8- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-56).

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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-34); and Example 408, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)met hyl)-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)met hyl)-8- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, was prepared similarly to Example 167 but using (4-(trifluoromethoxy)phenyl)hydrazine, (2- chlorothiazol-5-yl)methanami , I-38

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 41 1 , (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyano-3-fluorop henyl)allyl)-8- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

Example 412, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluoropheny l)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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 ); and Example 414, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-difluoropheny l)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)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-21 );

Example 417, (E)-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl )methyl)-8- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-30); Example 418, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin -4-yl)methyl)-8- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

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)meth yl)-8- (trifluoromethyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-37);

Example 421 , (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)met hyl)-8- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-38); 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).

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-4-fluorophenyl)allyl)-N-((2-chloropyridin -4-yl)methyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-31 )

Example 424, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(2,4-difluoropheny l)allyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-30); and

Example 425, (E)-N-((2-chloropyridin-4-yl)methyl)-7-(trifluoromethyl)-2-( 3-(4-(trifluoro- methyl)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 426, (E)-2-(3-(4-cyano-3-fluorophenyl)allyl)-N-((2-fluoropyridin- 4-yl)methyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-21 )

Example 427, (E)-2-(3-(2,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl )methyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-30); Example 428, (E)-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-fluoropyridin -4-yl)methyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-31 ); and

Example 429, (E)-2-(3-(3,4-difluorophenyl)allyl)-N-((2-fluoropyridin-4-yl )methyl)-7- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-32). 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)all yl)-8-methyl- 1 ,2,3,4-tetrahydro-5H-pyrido[ -b]indole-5-carboxamide (I-37)

Example 431 , (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-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-dichloropheny l)allyl)-8- methyl-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-39);

Example 433, (£)-A/-((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-(trifl uoromethoxy)- phenyl)allyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-45); and

Example 435, (f)-A/-((2-chloropyridin-4-yl)methyl)-8-methyl-2-(3-(4-(trif luoromethyl)- 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)me thyl)- 8,9,10,1 1 -tetrahydro-7H-benzo[e]pyrido[4,3-b]indole-7-carboxamide, was prepared similarly to Example 145, but using naphthalen-2-yl-hydrazine and aldehyde intermediate, I-38

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-chlor opyridin-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 (1-21 );

Example 439, (E)-7-bromo-2-(3-(3-chloro-4-fluorophenyl)allyl)-N-((2-chlor opyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-31 );

Example 440, (E)-7-bromo-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 441 , (E)-7-bromo-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanoph enyl)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-cyanoph enyl)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-tetrahydro-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-difluoropheny l)allyl)-8- (methylthio)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-32);

Example 447, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-8- (methylthio)-l ,2,3,4-tetrahydro-5H-pyndo[4,3-b]indole-5-carboxamide (1-38); and Example 448, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)al lyl)-8- (methylthio)-1 ,2,3,4-tetrahydro-5H-pyndo[4,3-b]indole-5-carboxamide (I-40).

Example 449, (E)-8-cyano-2-(3-(3,4-dichlorophenyl)allyl)-N-((2-hydroxypyr idin-4- yl)methyl)-1 ,2,3,4-tetrahydro- -pyrido[4,3-b]indole-5-carboxamide

was prepa

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 M HCI 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 HCI and the no vial was placed in the freezer. The precipitate was collected by filtration. No further purification was required.

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-cyano-N-((2-h ydroxypyridin- 4-yl)methyl)-1 ,2,3,4-tetrahydiO-5H-pyrido[4,3-b]indole-5-carboxamide HCI (1-1 );

Example 451 , (E)-2-(3-(4-bromo-2-fluorophenyl)allyl)-8-cyano-N-((2-hydrox ypyridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI (I-5); and Example 452, (E)-8-cyano-2-(3-(3,5-dichloro-4-fluorophenyl)allyl)-N-((2-h ydroxypyridin- 4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyndo[4,3-b]indole-5-carboxamide HCI (1-19).

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 (Exa

Example 454, (E)-2-(3-(4-cyanophenyl)allyl)-N-((2-hydroxypyridin-4-yl)met hyl)-8- (trifluoromethyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, 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)

in 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-difluoropheny l)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)met hyl)-8- (methylsulfonyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38);

Example 458, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)allyl)-8- (methylsulfonyl)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-39); and Example 459, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)al lyl)-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 accordi

(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(PPh ₃ ) 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 progression of the reaction was monitored by LCMS. After cooling the mixture to room temperature, the crude solution was fitered through a Pd scavenging resin, water was removed and the crude material was purified on a preparatory HPLC to give the title compound as an off white solid after 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 using 2-(4-chlorophenyl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborol

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 using 2-(3-chlorophenyl)-4,4,5,5- tetramethyl-1 ,3,2-dioxabor

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)-N ⁵ -((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 process

In a vial to the mixture of (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)- 7-cyano-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (60mg, 0.1 17 mmol, 1 eq) and TMSCI (0.059mL, 0.466 mmol, 4eq) was added water (0.008ml_, 0.466 mmol, 4eq). After stirring at room temperature for 16 hours, the crude material was purified by preparative HPLC to afford an off white solid. The hydrochloride salt of compound was made by using etheral HCI (2ml_), to afford an off white solid.

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)-N ⁵ -((2-chloropyridin-4-yl)methyl)- 1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5,7-dicarboxamide (I-3); and

Example 466, (E)-N ⁵ -((2-chloropyridin-4-yl)methyl)-2-(3-(4-fluorophenyl)a llyl)-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)-N ⁵ -((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 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-5 -pyrido[4,3-b]indole-5-carboxamide

Step 1 : Synthesis of (4-bro CI salt:

In 250ml_ round bottom flask, to a stirred solution of commercially available 4-bromo-3- ethoxyaniline hydrochloride salt (5.0gm, 23.14mmol, 1 eq) was added concentrated HCI (35mL) at -5 °C to 0°C followed by sodium nitrite (1 .756gm, 25.45mol, 1 .1 eq) pre- dissolved in water (8mL). Reaction mixture was stirred at -5 °C to 0 °C for 1 hour. After that solution of SnCI ₂ .2H ₂ 0 (1 1 .48gm, 50.90mmol, 2.2eq) in concentrated HCI (15mL) was added drop wise. The internal reaction temperature was maintained at -5 °C during the addition. The resulting suspension was stirred at 0°C for 1 hour. Resulting precipitate was filtered, solid was dried under reduced pressure to afford off white solid (6.0gm, HCI salt, crude). Crude was used as such for next Step.LC-MS (m/z): 231 .9

(M+H). Step 2: Synthesis of 8-bromo-7-ethoxy-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole HCI salt:

In a 100ml_ round bottom flask to the stirred solution of (4-bromo-3-ethoxy-phenyl)- hydrazine hydrochloride salt (2.0gm, crude, 7.489mmol, 1 equivalent) in acetic acid (20ml_) and 1 ,4-dioxane HCI (20ml_) was added piperidin-4-one hydrochloride

(1 .204gm, 8.99mmol, 1 .2equivalents) at room temperature. Reaction mixture was heated at 120 °C for 16 hours. Progress of reaction was monitored by LCMS. After completion of starting material, reaction mixture was evaporated under reduced pressure to afford brown solid (3gm, crude). Crude compound was used as such for 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:

In a 100ml_ round bottom flask to the stirred solution of crude 8-bromo-7-ethoxy-2,3,4,5- tetrahydro-1 H-pyrido[4,3-b]indole HCI salt (3.0gm, crude, 9.059mmol, 1 eq)) in THF (30ml_) was added TEA (10.082ml, 72.468mmol, 8eq). After that BOC anhydride (3.291 ml_, 13.588mmol, 1 .5 eq) was added drop wise at room temperature and stirring was continued at room temperature for 1 hour. Progress of reaction was monitored by TLC. After consumption of starting material, reaction mixture was quenched with water (100 ml_). Aqueous layer was extracted with ethyl acetate (100ml_ x 3). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil as crude compound 4g. Crude compound was purified by combiflash (40gm, Redisep column). Compound was eluted using 16% ethyl acetate in hexane to afford 410mg as off-white solid. 1 H 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, 1 H), 7.59 (s, 1 H), 10.87 (s, 1 H). LC-MS (m/z): 393.0 (M-H).

Step 4: Synthesis of 8-bromo-5-[(2-chloro-pyridin-4-ylmethyl)-carbamoyl]-7-ethoxy - 1 ,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester

In a 25ml_ round bottom flask to a stirred solution of NaH (60% in oil) (54.64mg, 2.277mmol, 3.0eq) in THF (3ml_) was added drop wise 8-bromo-7-ethoxy-1 ,3,4,5- tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (300mg, 0.759mmol, 1 .Oeq) in THF (1 .5ml_) at 0 °C. Resulting reaction mixture was allowed to room temperature stirred for 30 minutes. After that added 2-Chloro-4-isocyanatomethyl- pyridine (191 .9mg, 1 .138mmol, 1 .5eq) in THF (1 .5ml_) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 minutes. Progress of reaction was monitored by TLC. Reaction mixture was quenched with cold 6N hydrochloric acid (5ml_) followed by water (15ml_). Aqueous was extracted with ethyl acetate (20ml_ x 3). Combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to get brown oil (400mg, crude). Purification was done by combiflash column chromatography (12gm Redisep column). Compound was eluted by 35% ethyl acetate in hexane to afford off white solid (85mg, 19.86 %). 1 H 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, 1 H), 7.76 (s, 1 H), 8.39 (d, J= 5.08 Hz, 1 H), 8.49 (t, J= 5.60 Hz, 1 H ). LC-MS (m/z): 562.2 (M-H).

Step 5: Synthesis of 8-bromo-7-ethoxy-1 ,2,3,4-tetrahydro-pyrido[4,3-b]indole-5- carboxylic acid (2-chloro-pyridin-4-ylmethyl)-amide TFA salt

In a 10ml_ vial to a stirred solution of 8-Bromo-5-[(2-chloro-pyridin-4-ylmethyl)- carbamoyl]-7-ethoxy-1 ,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (150mg, 0.266mmol, 1 eq) in DCM (2mL) was added trifluoroacetic acid (0.5ml_). Resulting reaction mixture was stirred at room temperature for 1 hour. Progress of reaction was monitored by TLC. After consumption of starting material, reaction mixture was concentrated under reduced pressure to afford 150mg brown mass as TFA salt. Crude was used as such for next Step. LC- S (m/z): 465.2 (M+H).

Step 6: Preparation of Example 468. In a 10ml_ vial to a stirred solution of 8-Bromo-7- ethoxy-1 ,2,3,4-tetrahydro-pyrido[4,3-b]indole-5-carboxylic acid (2-chloro-pyridin-4- ylmethyl)-amide TFA salt (150mg, 0.26mmol, 1 eq) in DMF (1 .5mL) was added TEA (0.181 ml_, 1.298mmol, 5eq) at room temperature. After that added (E)-3-(4-chloro- phenyl)-propenal (51 .90mg, 0.312mmol, 1 .2eq) followed by sodium triacetoxy borohydride (1 10.08mg, 0.519mmol, 2eq). Resulting reaction mixture was stirred at room temperature for 2 hours. Progress of reaction was monitored by TLC and LCMS. After consumption of starting material, reaction mixture was evaporated under reduced pressure to afford brown mass. Purification was done by preparative HPLC using ammonia buffer to afford off white solid (31 mg). HCI salt of compound was made by using etheral HCI (3ml_) to afford off white solid.

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)met hyl)-8-fluoro-7- (trifluoromethoxy)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (I-38) CI

Example 470, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(4-cyanophenyl)all yl)-8-fluoro-7- (trifluoromethoxy)-l ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide (1-37); and Example 471 . (E)-N-((2-chloropyridin-4-yl)methyl)-8-fluoro-2-(3-(4-fluoro phenyl)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 using commercially available 4-fluoro- 3-(trifluoromethoxy)aniline a -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-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-car boxamide HCI (I-3)

Example 474, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(5-(trifluoromethy l)pyridin-2- yl)allyl)-1 ,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-car boxamide (1-18); Example 475, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(4-cyano-3-fluorop henyl)allyl)- 1 ,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-car boxamide HCI (1-21 );

Example 476, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(2,4-difluoropheny l)allyl)- 1 ,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-car boxamide HCI (I-30);

Example 477, (E)-8-(3-(3-chloro-4-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-car boxamide, HCI (1-31 );

Example 478, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(3,4-difluoropheny l)allyl)- 1 ,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-car boxamide HCI ((I-32);

Example 479, (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(4-cyanophenyl)all yl)-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)met hyl)- 1 ,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-car boxamide (I-38);

Example 481 , (E)-N-((2-chloropyridin-4-yl)methyl)-8-(3-(4-fluorophenyl)al lyl)-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-(trifluoromethy l)phenyl)allyl)- 1 ,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-car boxamide (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 respective aldehyde intermediate:

Example 483, (E)-8-(3-(4-chlorophenyl)allyl)-N-((2-fluoropyridin-4-yl)met hyl)-1 ,3,6,7,8,9- hexahydro-5H-furo[3,4-f]pyrid -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-car boxamide (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-car boxamide (1-21 );

Example 486, (E)-8-(3-(2,4-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-car boxamide HCI (I-30); Example 487, (E)-8-(3-(3-chloro-4-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-car boxamide HCI (1-31 ); 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-car boxamide (I-32).

Example 489, (E)-8-(3-(4-chlorophenyl)allyl)-N-((2-chlorothiazol-5-yl)met hyl)- 1 ,3,6,7,8,9-hexahydro-5H-furo[3,4-f]pyrido[4,3-b]indole-5-car boxamide, was prepared similarly to Example 468 but using commercially available 1 ,3-dihydroisobenzofuran-5- amine and (2-chlorothiazol-5-y

Example 490, (E)-9-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)- 1 ,3,7,8,9,10-hexahydro-6H-furo[3,4-e]pyrido[4,3-b]indole-6-ca rboxamide 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)met hyl)-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)met hyl)-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 commercially available 5-amino-2- methoxybenzonitrile

Example 494, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-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 commercially available 3-methyl-4- (trifluoromethoxy)aniline

Example 495, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-7- fluoro-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-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-

was prepared similarly to Example 468 but using commercially available 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)met hyl)-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 commercially available 1 -(4- aminophenyl)pyridin-2(1 H)-one

Example 501 , (E)-2-(3-(4-chlorophenyl)allyl)-8-cyclopropyl-N-((2-fluoropy ridin-4- yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, was prepared similarly to Example 468 but 4-cyclopropylaniline

Example 502, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-7- cyano-8-(trifluoromet oxy)-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)benzonitr

Example 503, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-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 CI

Example 504, (E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin -4- yl)methyl)-8-morpholino-1 ,2, -tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI

Step 1 : tert-butyl 8-morpholino-1 -tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

A teflon screw-cap 10 mL vial, equipped with a magnetic stir bar, was charged with XPhos (144 mg, 0.30 mmol) and XPhos Pd G2 precatalyst (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 vial was sealed with a teflon screw-cap, evacuated and backfilled with N ₂ 3 times. Morpholine (315 μί, 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 down to RT and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1 N HCI was added to quench the reaction. The latter solution was poured into a saturated NaHCO ₃ solution, diluted with EtOAc and the aq. layer extracted 3 times with EtOAc. The org layers were combined, dried over MgSO ₄ , filtered and the volatiles removed under reduced pressure. The crude material was purified by flash chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to give the desired product as a pale yellow solid (632 mg, 71 % yield). LC-Ms (m/z): [M+H] = 358.2

Step 2: tert-butyl 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-8-morpholino-1 ,3,4,5- tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

A 10 mL Teflon cap vial 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 μί, 1 .50 mmol). The resulting suspension was heated to 65 °C for 30 minutes. The progress of the reaction was monitored by LCMS. After cooling the reaction mixture to room temperature, the crude material was transferred into a separatory funnel, diluted with 50 mL DCM and 50 mL 15% citric acid in H ₂ 0 and the layers were separated. The aqueous layer was extracted with DCM, the organic layers were combined, dried over MgS0 ₄ 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 give the desired product as an amorphous white solid (198 mg, 0.652 mmol, 75%). LC-Ms (m/z): [M+H] = 526.2.

Step 3: Preparation of Example 504. In a 8 mL vial 98 mg of tert-butyl 5-(((2- chloropyridin-4-yl)methyl)carbamoyl)-8-morpholino-1 ,3,4,5-tetrahydro-2H-pyrido[4 _! 3- b]indole-2-carboxylate was dissolved in 5.0 mL of DCM and 284 μΐ of TFA was added at room temperature. The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction the 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 μΐ of TEA was added. The resulting solution was cooled to 0°C and 41 mg of aldehyde intermediate 1-3 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 NaHC0 ₃ solution were 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 flow of N ₂ , and the crude material was purified on KP-NH silica using flash

chromatography (EtOAc in Hexanes from 0 to 100%). The crystals were dissolved in DCM and Et20 and a stream of HCI gas was passed through the solution. 32 mg of the title HCI salt were retrieved by filtration as a white solid.

Example 505, (E)-2-(3-(4-chlorophenyl)allyl)-N-((2-chloropyridin-4-yl)met hyl)-8- morpholino-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, 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)- -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

A teflon screw-cap 10 ml_ vial, equipped with a magnetic stir bar, was charged with XPhos (144 mg, 0.30 mmol) and XPhos Pd G2 precatalyst (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 vial was sealed with a teflon screw-cap, evacuated and backfilled with N ₂ 3 times. Pyrrolidine (347 μΙ_, 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 down to room temperature and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1 N HCI was added to quench the reaction. The latter solution was poured into a saturated NaHC0 ₃ solution, diluted with EtOAc and the aqueous layer extracted 3 times with EtOAc. The org layers were combined, dried over MgS0 ₄ , filtered and the volatiles removed under reduced pressure. The crude material was purified by flash

chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to give the desired product as a pale yellow solid (890 mg, 87% yield). LC-Ms (m/z): [M+H] = 342.3.

Step 2: tert-butyl 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-8-(pyrrolidin-1 -yl)-1 ,3,4,5- tetrahydro-2H-pyrido[4,3-b]ind

A 10 mL Teflon cap vial was charged with tert-butyl 8-(pyrrolidin-1 -yl)-1 ,3,4,5- tetrahydro-2H-pyrido[4,3-b]indole-2-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 .1 1 mL, 7.953 mmol). The resulting suspension was heated to 65 °C for 30 minutes. The progress of the reaction was monitored by LCMS. After cooling the reaction mixture to room temperature, the crude material was transferred into a separatory funnel, diluted with 50 mL DCM and 50 mL 15% citric acid in H ₂ O and the layers were separated. The aq. layer was extracted with DCM, the organic layers were combined, dried over MgSO ₄ 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 give the desired product as an amorphous white solid (314 mg, 0.616 mmol, 23%). LC-Ms (m/z): [M+H] = 510.2 Step 3: Preparation of Example 506. In a 8 mL vial 105 mg of tert-butyl 5-(((2- chloropyridin-4-yl)methyl)carbarrioyl)-8-(pyrrolidin-1 -yl)-1 ,3,4,5-tetrahydro-2H-pyrido[4,3- b]indole-2-carboxylate was dissolved in 5.0 mL of DCM and 157 \iL of TFA was added at room temperature. The resulting solution was stirred at room temperature for two hours. Upon completion of the reaction the 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 il 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 were 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 flow of N2, and the crude material was purified on KP-NH silica using flash

chromatography (EtOAc in Hexanes from 0 to 100%) to give the title compound as a free amine as an off-white solid.

Example 507, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)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, (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)allyl)- 7-morpholino-1 ,2,3,4-tetrahy rboxamide HCI (I-39)

Step 1 : tert-butyl 7-morpholino-1 ,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

A teflon screw-cap 10 mL vial, equipped with a magnetic stir bar, was charged with SPhos (45 mg, 0.30 mmol) and SPhos Pd G2 precatalyst (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 vial was sealed with a teflon screw-cap, evacuated and backfilled with N ₂ 3 times. Morpholine (315 μΙ_, 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 LC S. After consumption of all starting materials the reaction mixture was cooled down to RT and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1 N HCI was added to quench the reaction. The latter solution was poured into a saturated NaHC0 ₃ solution, diluted with EtOAc and the aq. layer extracted 3 times with EtOAc. The org layers were combined, dried over MgSO ₄ , filtered and the volatiles removed under reduced pressure. The crude material was purified by flash chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to give the desired product as a pale yellow solid (570 mg, 53% yield). LC-Ms (m/z): [M+H] = 358.2

Step 2: tert-butyl 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-7-morpholino-1 ,3,4,5- tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

A 100mL 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. Gas slowly evolves and the reaction mixture turned from an off white suspension to a rose pinkish-red suspension. The ice bath was removed after 2 hours, and the reaction was allowed to warm to RT for 10 minutes. Next, the mixture was cooled back to 0 °C (ice bath) and 2-chloro-4- (isocyanatomethyl)pyridine (255 mg, 1 .50 mmol) in DCM (3.0 mL) was added quickly in one portion. After stirring for 5 minutes at 0 °C, the reaction mixture was carefully quenched with addition of HCI (3 ml_, 1 .0 M) at 0 °C. The reaction mixture diluted with water (10ml_) and saturated NaHC0 ₃ (10 mL) and extracted with EtOAc (2 x 15ml_). The combined organic phases were washed with brine, dried over MgS0 ₄ , and concentrated under reduced pressure. The crude was purified by flash chromatography using EtOAc in Hexanes (0 to 70%) to give the desired compound as an amorphous off yellow solid (180 mg, 0.34 mmol, 34% yield). LC-Ms (m/z): [M+H] = 526.2.

Step 3: Preparation of Example 508. In a 8 mL vial 90 mg of tert-butyl 5-(((2- chloropyridin-4-yl)methyl)carbamoyl)-7-morpholino-1 ,3,4,5-tetrahydro-2H-pyrido[4,3- b]indole-2-carboxylate was dissolved in 5.0 mL of DCM and 131 μΐ of TFA was added at RT. The resulting solution was stirred at RT for two hours. Upon completion of the reaction the 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 μΐ 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, 1 1 1 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 NaHC0 ₃ solution were added and the resulting solution stirred for 1 hour at RT. The biphasic solution was passed through a phase separator cartridge and the aqueous layer washed with DCM. The organic volatiles were removed under a flow of N ₂ , and the crude material was purified on KP- NH silica using flash chromatography (EtOAc in Hexanes from 0 to 100%). The crystals were dissolved in DCM and Et ₂ O and a stream of HCI gas was passed through the solution. 30 mg of the title HCI salt were retrieved 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 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, HCI 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, HCI (I-3)

Step 1 : tert-butyl 8-(1 ,3-thiazinan-3-yl)-1 ,3 A5-tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate

A teflon screw-cap 10 mL vial, equipped with a magnetic stir bar, was charged with XPhos (29 mg, 0.30 mmol) and XPhos Pd G2 precatalyst (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 vial was sealed with a teflon screw-cap, evacuated and backfilled with N ₂ 3 times. Thiomorpholine (616 μΙ_, 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 LC S. After consumption of all starting materials the reaction mixture was cooled down to RT and the crude mixture was diluted with 10 mL of EtOAc, then 5 mL of 1 N HCI was added to quench the reaction. The latter solution was poured into a saturated NaHC0 ₃ solution, diluted with EtOAc and the aq. layer extracted 3 times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and the volatiles removed under reduced pressure. The crude material was purified by flash chromatography on silica using EtOAc in Hexanes (from 0 to 50%) to give the desired product as a pale yellow solid (510 mg, 46% yield). LC-Ms (m/z): [M+H] = 374.2

Step 2: tert-butyl 5-(((2-chloropyridin-4-yl)methyl)carbamoyl)-8-(1 ,3-thiazinan-3-yl)- 1 ,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate

A 100ml_ Schlenk flask was charged with tert-butyl 8-thiomorpholino-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. Gas slowly evolves and the reaction mixture turned from an off white suspension to a rose pinkish-red suspension. The ice bath was removed after 2 hours, and the reaction was allowed to warm to RT for 10 minutes. Next, the mixture was cooled back 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 HCI (4 mL, 1 .0 M) at 0 °C. The reaction mixture diluted with water (10mL) and saturated NaHC0 ₃ (10 mL) and extracted with EtOAc (2 x 15mL). The combined organic phases were washed with brine, dried over MgS0 ₄ , and concentrated under reduced pressure. The crude was purified by flash chromatography using EtOAc in Hexanes (0 to 70%) to give the desired compound as an amorphous off yellow solid (180 mg, 0.33 mmol, 24% yield). LC-Ms (m/z): [M+H] = 542.3.

Step 3: Preparation of Example 510. In a 8 mL vial 90 mg of tert-butyl 5-(((2- chloropyridin-4-yl)methyl)carbamoyl)-8-(1 ,3-thiazinan-3-yl)-1 ,3,4,5-tetrahydro-2H- pyrido[4,3-b]indole-2-carboxylate was dissolved in 5.0 mL of DCM and 128 μΐ of TFA was added at RT. The resulting solution was stirred at RT for two hours. Upon completion of the reaction the 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 μΐ 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 were added and the resulting solution stirred for 1 hour at RT. The biphasic solution was passed through a phase separator cartridge and the aqueous layer washed with DCM. The organic volatiles were removed under a flow of N ₂ , and the crude material was purified on KP-NH silica using flash chromatography (EtOAc in Hexanes from 0 to 100%). The crystals were dissolved in DCM and Et ₂ 0 and a stream of HCI gas was passed through the solution. 45 mg of the title HCI salt were retrieved by filtration as a white solid.

Example 51 1 , (E)-N-((2-chloropyridin-4-yl)methyl)-2-(3-(3,4-dichloropheny l)allyl)- 8-(1 ,3-thiazinan-3-yl)-1 ^^^-tetrahydro-SH-pyrido^^-bjindole-S-carboxamide, HCI, 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)met hyl)-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-1 H-pyrido[4,3-b]indole hydrochloride in place of 8-fluoro-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole and the aldehyde intermediate, I-38

The following compounds were prepared similarly to Example 512 but using 8- ethoxy-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole hydrochloride in place of 8-methoxy- 2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole hydrochloride and the respective aldehyde intermediate:

Example 513, (£)-2-(3-(4-chlorophenyl)allyl)-A/-((2-chloropyridin-4-yl)m ethyl)-8-ethoxy- 1 ,2,3,4-tetrahydro-5H-pyri -b]indole-5-carboxamide (I-38)

Example 514, (£)-A/-((2-chloropyridin-4-yl)methyl)-8-ethoxy-2-(3-(4-fluo rophenyl)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-cyano-N-((2- cyclopropylpyridin-4-yl)methyl)-1 ,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide HCI, 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 : terf-butyl 8-chloro-5-[(2-chloro-4-pyridyl)methylcarbamoyl]-3,4,4a,9b-t etrahydro- 1 H-pyrido[4,3-b]indole-2-carboxylate.

To a stirred solution of triphosgene (172mg, 0.56 mmol) in CH2CI2 (15mL) at 0 °C was slowly added commercially available (Wuxi) tert-butyl 8-chloro-1 ,3,4,4a,5,9b- hexahydropyrido[4,3-b]indole-2-carboxylate (500mg, 1 .6mmol) and N,N- diisopropylethylamine (1 .2ml_, 6.5mmol) as a solution in CH2CI2 (1 OmL). The reaction was allowed to warm to room temperature and stirred for 3 hours. 2-chloropyridin-4- yl)methanamine (0.37g, 2.1 mmol) was next added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with CH ₂ Cl2 (75ml_) and water (75ml_). The organic phase was separated, dried (Na ₂ S0 ₄ ), and concentrated under vacuum. The crude material was chromatographed (40g Redi-Sep column) eluting from 100 hexanes to 100% EtOAc to afford the intermediate as a solid. LC-Ms (m/z): [M+H-ibutyl] = 421 .

Step 2: 8-chloro-N-[(2-chloro-4-pyridyl)methyl]-1 ,2,3,4,4a,9b-hexahydropyrido[4,3- b]indole-5-carboxamide.

The title compound was synthesized following the same procedure as described in Example 145, Step-3, but using te/t-butyl 8-chloro-5-[(2-chloro-4- pyridyl)methylcarbamoyl]-3,4,4a,9b-tetrahydro-1 H-pyrido[4,3-b]indole-2-carboxylate in place of terf-butyl 5-[(2-chloro-4-pyridyl)methylcarbamoyl]-7-methyl-3,4-dihydro -1 H- 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 of A/-[(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 ^^^^a^b-hexahydro-SH-pyrido^^-bjindole-S-carboxamide was prepared similarly to Example 516 with the aldehyde intermediate, I-39. The 8- chloro-N-[(2-chloro-4-pyridyl)methyl]-2-[(£)-3-(3,4-dichlor ophenyl)allyl]-3,4,4a,9b- tetrahydro-1 H-pyrido[4,3-b]indole-5-carboxamide was separated into single enantiomers (Prep SFC = Berger Thar MS100, column = AS-H 30x250mm 5um, MP A = C0 ₂ MP B = 0.1 %TEA in MeOH, Isocratic 30%B, 100mL/min,100bar, 33 °C) as Peak 1 and Peak 2, respectively.

Biology:

To identify novel parasiticides, compounds were screened for nematocidal activity using in vitro motility assays. The compounds described herein have

demonstrated nematocidal activity against either Haemonchus contortus (L3) and/or Dirofilaria immitis (microfilariae) as determined by reductions in nematode motility either by paralysis or death. Active compounds were then subsequently investigated for in vivo efficacy using a jird infection model whereby clearance of Trichostrongylus colubriformus was determined.

The biological activity Haemonchus contortus (L3), Dirofilaria immitis

(microfilariae) and jird efficacy of the compounds of the invention can be measured using the test methods described below.

Haemonchus contortus. Larvae Stage 3 (HcL3) In vitro Assay

The Haemonchus contortus L3 strain was obtained from the University of Georgia and is a relatively recent multiple-resistant field isolate (International Journal for Parasitology 37 (2007) 795-804). Compounds were dissolved in DMSO to give an initial concentration of 30mM. The stock concentration was subsequently titrated in basal media to give an eleven point half-log concentration curve for testing. Following the serial dilution, 250nl of each compound solution was transferred to an assay plate (384- well) whereby 25μΙ_ of exsheathed worms (-100 larvae/well) were subsequently added. The final compound concentrations in the 384-well plate following worm addition ranged from 0.001 -100μΜ. Assay plates were incubated at 37 ^Q C and observed at 96 hours for drug effect. Endpoint data (Table 2, HcL3) are recorded as a Minimal Effective

Concentration (MEC) in μΜ, whereby worm motility is inhibited by approximately 70%. Dirofilaria immitis. Microfilariae (D/MF) In vitro Assay

Compounds were initially dissolved in DMSO. The stock concentration was subsequently diluted in basal media and serially diluted to give a concentration response curve starting at 100μΜ (1 1 total concentrations). Following the serial dilution, compound solution was transferred to an assay plate (384-well) where D.immitis microfilariae (~200/well) that have been purified from microfilaremic canine blood were subsequently added. Assay plates were observed at 72 hours for drug effect. Each compound was evaluated for decrease in microfilariae motility by subjective visual assessment and endpoint data were recorded as minimally effective dose (MEC) in μΜ following the incubation period in Table 2.

Jird Efficacy Model

Compounds were evaluated for in vivo activity against Trichostrongylus colubriformis {T.c.) in a Mongolian gerbil (jird) infection model. Jirds were fed an immunosuppression diet containing 200ppm (0.02%) hydrocortisone acetate before being infected by oral gavage with approximately 750 T.c. larvae suspended in 0.2ml_ Earles balanced salt solution. Nine days post-infection, jirds were dosed (4/group) with test compound (10mg/kg) by subcutaneous route of administration. Approximately four days after dosing, jirds were euthanized by carbon dioxide asphyxiation and necropsied whereby stomach and small intestine were removed for evaluation. Both stomach and small intestine were dissected to remove contents and placed in 20ml_ scintillation vials filled with 15ml_ tap water. Vials were then placed in a 37 °C incubator or water bath for approximately four hours before worms were counted. The mean and geometric means were calculated to determine percentage efficacy. A percentage efficacy (Table 2) was calculated against the geometric mean control burden as shown:

% Efficacy = 100 x (mean number of worms recovered from control untreated group - mean number of worms recovered from treated group) ÷ (mean number of worms recovered from control untreated group). Table 2. Biological Data

104 3.2 0.1 162 10.0 >100

105 >100 0.3 163 5.7 1.8 100

106 >100 0.3 164 10.0 3.3 100

107 1.8 0.5 165 3.3 3.3 100

108 3.2 2.4 100 166 5.7 10.0

109 18.2 1.22 99 167 33.0 0.3

110 >100 0.3 168 10.0 0.5

111 >100 0.3 169 18.2 0.1

112 >100 0.5 170 1.0 >100

113 >100 1.3 171 10.0 0.5

114 10.0 0.1 172 >100 10.0

115 3.3 0.1 100 173 >100 18.2

116 1.3 0.1 174 >100 57.4

117 1.8 0.2 175 10.0 1.8

118 5.7 1.8 176 3.3 0.2

119 18.2 3.3 177 5.7 0.3

120 >100 0.5 178 >100 0.3

121 10.0 0.3 179 75.8 0.5

122 18.2 1.0 100 180 >100 0.5

123 10.0 0.3 100 181 32.3 0.2

124 33 100 182 >100 1.0

125 >100 0.3 183 18.2 0.5

126 >100 >100 184 57.4 1.0 100

128 0.7 0.1 100 185 7.7 0.7 100

129 3.5 0.05 186 >100 1.0

145 33.0 1.0 187 >100 1.3

146 10.0 0.4 188 3.3 0.3

147 10.0 2.8 189 10.4 0.3

148 10.0 5.7 190 5.7 1.0

149 10.0 4.4 191 10.0 0.3

150 10.0 3.3 192 11.5 0.7

151 13.5 >100 193 75.8 1.0

152 3.3 1.0 99 194 5.7 0.4

153 7.6 1.3 195 5.7 0.5

155 22.6 1.0 100 196 5.7 0.3

156 33.0 0.5 99 197 4.4 0.4

157 11.9 3.8 198 5.7 1.0

158 16.8 2.2 199 24.5 5.7

159 10.0 18.2 205 18.2 1.0

160 10.0 1.8 206 3.3 0.2

161 10.0 2.1 207 10.0 0.3 208 >100 1.8 255 18.2 0.3

209 33.0 >100 256 10.0 0.2

210 10.0 3.3 257 5.7 0.2

211 10.0 1.0 100 258 100 10

212 >100 1.0 259 3.3 0.1

213 3.3 0.3 260 10.0 0.4

214 18.2 0.5 261 10.0 1.0

215 10.0 0.5 266 18.2 >100

216 18.2 1.0 267 10.0 >100

217 3.3 1.8 268 10.0 >100

218 10.0 1.0 269 3.3 >100

219 3.3 0.5 270 10.0 >100

220 10.0 3.3 271 5.7 >100

221 3.3 >100 272 10.0 >100

222 10.0 >100 273 18.2 >100

223 3.3 10.0 274 33.0 1.8

224 3.3 1.8 275 >100 0.3

225 3.3 1.8 276 18.2 0.3

226 1.8 >100 277 >100 1.0

227 1.8 5.7 278 18.2 1.8

228 3.3 1.8 98 279 >100 1.8

229 10.0 3.3 100 280 >100 0.3

230 10.0 1.8 100 281 >100 1.0

231 13.5 3.3 282 3.3 0.3 100

232 10.0 1.0 283 3.3 0.5

233 1.8 0.01 284 10.0 >100

234 3.3 0.1 285 10.0 >100

235 >100 0.1 287 3.3 0.2

237 1.8 0.03 292 5.7 3.3

238 5.7 1.0 100 293 5.7 3.3

239 3.3 0.3 98 294 10.0 >100

240 3.3 0.2 98 295 18.2 >100

241 13.5 0.4 296 >100 1.0

242 10.0 0.7 297 >100 0.3

243 10.0 1.3 298 >100 1.8

244 10.0 0.7 299 1.8 0.4

245 11.9 3.3 300 10.0 0.5

246 10.0 3.3 301 18.2 0.2

247 1.8 1.0 302 5.7 0.3

248 0.5 0.4 303 57.4 1.0

254 100 3.3 304 18.2 0.3 305 16.5 0.9 346 1.8 0.5

306 2.7 0.5 98 347 2.4 2.4

307 3.3 0.5 100 348 24.5 1.0

308 32.1 10.3 349 10.0 1.0 99

309 1.8 0.3 350 1.3 0.2

310 24.5 1.3 351 32.3 0.7

311 5.7 0.5 352 5.7 33.0

312 1.0 0.1 353 18.2 1.0

313 3.3 0.5 354 18.2 57.4

314 3.3 1.0 100 355 69.1 1.0

315 5.7 1.0 356 3.8 0.6 100

316 5.7 >100 357 3.3 10.0

317 18.2 1.0 100 358 7.6 1.3

318 5.7 3.3 359 3.3 3.3

319 10.0 10.0 360 13.6 7.7

320 18.2 3.3 361 57.4 >100

321 5.7 2.4 100 362 31.5 >100

322 10.0 5.7 363 33.0 >100

323 7.6 >100 364 1.8 >100

324 10.0 3.3 365 4.4 >100

325 7.6 3.3 366 2.4 >100

326 10.0 7.6 367 >100 10.0

327 10.0 >100 368 43.5 >100

328 33.0 0.3 369 10.0 1.0

329 1.8 0.3 370 33.0 3.3

330 >100 0.5 371 24.5 1.3

331 24.0 0.7 372 5.7 0.5

332 13.5 1.0 373 10.0 1.8

333 >100 1.8 374 5.7 5.7 72

334 10.0 1.0 375 18.2 1.8

335 24.0 10.0 376 10.0 0.5

336 33.0 1.0 377 5.7 0.3 99

337 18.2 1.0 378 10.0 1.8

338 10.0 0.3 379 5.7 1.0 100

339 0.5 0.5 379a 3.3 >100

340 5.7 0.3 380 33.0 >100

341 5.7 3.3 382 10.0 3.3

342 10.0 1.8 383 5.7 >100

343 3.3 33.0 384 18.2 1.0

344 10.0 0.5 100 385 47.8 0.5

345 18.2 0.5 386 3.3 0.2 387 3.3 0.2 438 18.2 >100

388 >100 1.8 439 18.2 1.8

389 10.0 0.5 440 10.0 1.8

390 18.2 0.5 100 441 4.4 >100

391 32.1 1.0 100 442 10.0 10.0

392 22.2 1.0 443 3.3 0.5

393 1.5 0.4 444 2.4 0.7 100

394 6.9 1.0 445 33.0 0.5

395 22.2 3.3 446 3.3 0.5

396 1.0 3.3 447 3.3 0.5

401 18.2 0.5 448 3.3 1.3

402 5.7 0.3 449 >100 >100

403 18.2 0.3 450 100.0 0.5

404 18.2 1.0 451 3.3 >100

405 5.7 0.3 452 >100 >100

406 13.5 0.4 453 10.0 >100

407 5.7 1.0 454 >100 >100

408 10.0 1.0 455 5.7 0.7

409 10.0 1.0 456 10.0 1.3

410 10.0 1.8 457 10.0 1.0

411 1.8 0.03 458 3.3 5.7

412 10.0 1.8 459 5.7 1.0 92

413 >100 1.8 460 57.4 >100

414 10.0 1.0 461 >100 33.0

415 12.4 2.7 462 >100 >100

416 57.4 1.8 463 >100 >100

417 10.0 5.7 100 464 7.6 3.3

418 18.2 3.3 95 465 10.0 3.3

419 10.0 1.0 100 466 3.3 >100

420 14.1 2.8 100 467 1.0 >100

421 12.7 3.3 100 468 1.8 0.2

422 18.2 10.0 469 >100 1.0

425 15.8 >100 470 13.5 1.0 100

430 >100 1.0 471 10.0 0.3

431 3.3 1.0 472 10.0 1.0

432 57.4 1.0 474 10.0 0.2

433 5.7 0.5 479 >100 1.0

434 5.7 3.3 480 3.3 0.3

435 5.7 5.7 481 3.3 0.3 99

436 18.2 >100 482 3.3 1.8

437 10.0 1.0 483 3.3 0.5 100 489 3.3 3.3 100 504 10.0 5.7 100

490 10.0 0.2 505 13.5 10.0 100

491 18.2 1.0 506 >100 7.6

492 0.5 1.8 507 13.5 10.0

493 5.7 1.0 508 9.0 1.6

494 >100 1.0 509 18.2 1.0

495 10.0 1.0 510 >100 >100

496 5.7 1.0 511 >100 >100

497 5.7 1.0 512 10.0 1.0

498 5.7 1.8 513 3.3 7.6

499 >100 1.8 514 5.7 5.7

500 5.7 >100 515 13.5 1.8

501 18.2 3.3 516 10.0 0.3

502 >100 18.2 517 10.0 0.5

503 3.3 33.0

Table 3. Example Mass and NMR Data

7.73-7.78(m,2H), 8.25-8.28(m,lH), 8.38-8.41(m,lH), 9.13(t,lH), 11.50(bs,lH)

536 3.34-3.51(m,3H), 3.74-3.81(m,lH), 4.09-4.24(m,2H), 4.35-4.40(m,lH), 4.59-4.67(m,3H), 6.64-6.72(m,lH), 6.86(d,lH), 7.29-7.36(m,2H), 7.47(dd,lH), 7.57(s,lH), 7.63(dd,lH), 7.79(d,lH), 8.24-8.27(m,lH), 8.38-8.41(m,lH), 9.13(t,lH), 11.66(bs,lH)

580 3.35-3.54(m,3H), 3.78-3.84(m,lH), 4.14-4.26(m,2H), 4.40-4.45(m,lH), 4.60(d,2H),

4.73(d,lH), 6.60-6.67(m,lH), 7.11(d,lH), 7.18-7.23(m,lH), 7.47(dd,lH), 7.57(s,lH), 7.63(dd,lH), 7.69-7J8(m,3H), 8.25-8.28(m,lH), 8.38-8.41(m,lH), 9.13(t,lH),

11.58(bs,lH)

580 3.35-3.54(m,3H), 3.77-3.85(m,lH), 4.11-4.23(m,2H), 4.39-4.44(m,lH), 4.60(d,2H),

4.70(d,lH), 6.67-6.74(m,lH), 7.00(d,lH), 7.25-7.30(m,lH), 7.47(dd,lH), 7.57-7.64(m, 4 H), 7.78(d,lH), 7.94(dd,lH), 8.25-8.28(m,lH), 8.38-8.42(m,lH), 9.13(t,lH), 11.54(bs,lH)

580 3.34-3.54(m,3H), 3.75-3.83(m,lH), 4.05-4.14(m,2H), 4.38-4.43(m,lH), 4.59(d,2H),

4.69(d,lH), 6.53-6.61(m,lH), 6.90(d,lH), 7.40-7.48(m,2H), 7.57-7.64(m,3H), 7.78(d,lH), 7.93(dd,lH), 8.25-8.28(m,lH), 8.38-8.42(m,lH), 9.14(t,lH), 11.53(bs,lH)

536 3.36-3.52(m,3H), 3.75-3.83(m,lH), 4.11-4.22(m,2H), 4.37-4.43(m,lH), 4.59(d,2H),

4.68(d,lH), 6.64-6.71(m,lH), 7.01(d,lH), 7.37-7.45(m,lH), 7.47(dd,lH), 7.54- 7.65(m,3H), 7.78(d,lH), 8.24-8.27(m,lH), 8.38-8.42(m,lH), 9.15(t,lH), 11.71(bs,lH)

596,5 3.36-3.53(m,3H), 3.75-3.83(m,lH), 4.13-4.22(m,2H), 4.38-4.43(m,lH), 4.59(d,2H), 98 4.69(d,lH), 6.71-6.78(m,lH), 7.02(d,lH), 7.47-7.64(m,5H), 7.78(d,lH), 8.25-8.27(m,lH), 8.38-8.42(m,lH), 9.14(t,lH), 11.70(bs,lH)

552 3.35-3.52(m,3H), 3.76-3.84(m,lH), 4.13-4.24(m,2H), 4.36-4.45(m,lH), 4.60(d,2H), 4.66- 4.73(m,lH), 6.68-6.78(m,lH), 7.03(d,lH), 7.46-7.65(m, 5 H), 7.78(d,lH), 8.25- 8.28(m,lH), 8.38-8.42(m,lH), 9.13(t,lH), 11.59(bs,lH)

572 3.35-3.52(m,3H), 3.72-3.83(m,lH), 4.16-4.30(m,2H), 4.35-4.44(m,lH), 4.56-4.70(m,3H ), 6.76-6.95(m,2H), 7.47(dd,lH), 7.57-7.65(m,2H), 7.77(d,lH), 8.25-8.28(m,lH), 8.38- 8.42(m,lH), 9.15(t,lH), 11.90(bs,lH)

588 3.35-3.53 (m,3H), 3.73-3.83 (m,lH), 4.17-4.32 (m,2H), 4.35-4.44 (m,lH), 4.56-4.71

(m,3H), 6.82-6.99 (m,2H), 7.47 (dd,lH), 7.57-7.65 (m,2H), 7.77 (d,lH), 8.25-8.28 (m,lH), 8.38-8.42 (m,lH), 9.14 (t,lH), 11.85 (bs,lH).

584 11.82(br s,lH), 9.18(m,lH), 8.40(d,lH), 8.26(s,lH), 7.91-8.03(m,lH), 7.72-7.80(m,2H), 7.63(m,lH), 7.57(m,2H), 7.48(d,lH), 6.96-7.05(m,lH), 6.78-6.92(m,lH), 4.71(br d,lH), 4.60(br d,2H), 4.37-4.48(m,lH), 4.16(br s,2H), 3.80(br s,lH), 3.39-3.54(m,3H).

598 11.87(br s,lH), 9.20(m,lH), 8.40(d,lH), 8.26(s,lH), 8.12(m,lH), 7.77(d,lH), 7.62(m,lH), 7.53-7.61(m,2H), 7.48(d,lH), 6.97(d,lH), 6.64-6.76(m,lH), 4.69(br d,lH), 4.56- 4.64(m,2H), 4.35-4.47(m,lH), 4.08-4.20(m,2H), 3.73-3.82(m,lH), 3.34-3.55(m,3H).

548 11.69(br s,lH), 9.18(m,lH), 8.40(d,lH), 8.26(s,lH), 7.77(d,lH), 7.63(d,lH), 7.57(s,lH), 7.48(m,lH), 7.33-7.41(m,2H), 6.84(d,lH), 6.52-6.63(m,lH), 4.68(br d,lH), 4.56- 4.64(m,2H), 4.40(br m,lH), 4.05-4.17(m,2H), 3.93-4.00(m,3H), 3.77(br s,lH), 3.36- 3.54(m,3H).

564 11.80(br s,lH), 9.17(m,lH), 8.40(d,lH), 8.26(s,lH), 7.78(d,lH), 7.53-7.67(m,2H), 7.36- 7.53(m,3H), 7.02(d,lH), 6.63-6.73(m,lH), 4.68(br d,lH), 4.55-4.63(m,2H), 4.41(br s,lH), 4.13-4.21(m,2H), 3.84-3.96(m,3H), 3.78(br s,lH), 3.35-3.53(m,3H).

570 11.94(br s,lH), 9.16(m,lH), 8.40(d,lH), 8.26(s,lH), 7.77(d,lH), 7.56-7.67(m,3H), 7.43- 7.52(m,2H), 6.97(d,lH), 6.68-6.80(m,lH), 4.66(br d,lH), 4.60(d,2H), 4.40(br m,lH), 4.20- 4.31(m,2H), 3.78(br s,lH), 3.37-3.54(m,3H).

598 11.85(br s,lH), 9.19(m,lH), 8.39(d,lH), 8.25(s,lH), 7.72-7.87(m,3H), 7.55-7.66(m,2H), 7.48(d,lH), 6.98(d,lH), 6.70-6.83(m,lH), 4.69(br d,lH), 4.55-4.64(m,2H), 4.35- 4.46(m,lH), 4.10-4.21(m,2H), 3.73-3.82(m,lH), 3.39-3.54(m,3H).

534 3.36-3.54(m,3H), 3.77-3.83(m,lH), 4.12-4.23(m,2H), 4.38-4.44(m,lH), 4.59(d,2H),

4.70(d,lH), 6.53-6.61(m,lH), 7.16(d,lH), 7.30-7.35(m,lH), 7.47(dd,lH), 7.52(dd,lH), 3.37-3.54(m,3H).

568 3.45-3.47(m,3H), 3.80-3.83(m,lH), 4.10-4.13(m,2H), 4.39-4.42(m,lH), 4.61(d,2H),

4.73(d,lH), 6.56-6.64(m ,lH), 6.90(d,lH), 7.41(d,lH), 7.61-7.69(m,5H), 7.76(d,lH), 8.30(s,lH), 9.05(bs,lH), 10.86(bs,lH),

596 3.32-3.42(m,2H), 3.46-3.50(m,lH), 3.80-3.89(m,lH), 4.11-4.13(m,2H), 4.38-4.44(dd,lH), 4.58(d,2H), 4.72(d,lH), 6.66-6.73(m,lH), 6.89(d,lH), 7.49-7.50(dd,lH), 7.58(d,2H), 7.63- 7.65(dd,lH), 7.70(s,lH), 7.76(d,lH), 8.27(s,lH), 8.37(d,lH), 9.11(t,lH), 11.24(bs,lH).

578 3.38(bs,2H), 3.51(bs,lH), 3.80-3.83(m,lH), 4.12-4.13(m ,2H), 4.39-4.44(m,lH),

4.58(d,2H), 4.72(d,lH), 6.57-6.65(m,lH), 6.90(d,lH), 7.39-7.42(dd,lH), 7.49(d,lH), 7.61- 7.70(m, 4H), 7.77(d,lH), 7.27(s,lH), 8.37(d,lH), 9.09(t,lH), 11.02(bs,lH)

578 3.47-3.49(m,3H), 3.80-3.83(m,lH), 4.14-4.17(m,2H), 4.38-4.43(m,lH), 4.58(d,2H),

4.72(d,lH), 6.57-6.64(m,lH), 7.0(d,lH), 7.36-7.39(m,lH), 7.49-7.56(m,2H), 7.62- 7.64(m,lH), 7.70-7.79(m,3H), 8.27(s,lH), 8.37(d,lH), 9.08(t,lH), 10.89(bs,lH).

580 3.34-3.48(m,3H), 3.79-3.81(m,lH), 4.14-4.17(m,2H), 4.37-4.42(dd,lH), 4.58(d,2H), 4.70(d,lH), 6.60-6.68(m,lH), 7.00(d,lH), 7.38-7.44(m,lH), 7.50(d,lH), 7.55-7.59(m,lH), 7.62-7.64(m,lH), 7.70(s,lH), 7.78(d,lH), 8.27(s,lH), 8.37(d,lH), 9.11(t,lH),

11.33(bs,lH).

562 3.34-3.48(m,3H), 3.77-3.80(m,lH), 4.13-4.16(m,2H), 4.37-4.43(m,lH), 4.58(d,2H),

4.70(d,lH), 6.52-6.60(m,lH), 6.99(d,lH), 7.16-7.21(m,lH), 7.31-7.37(m,lH), 7.49(d,lH), 7.62-7.64(m,lH), 7.70(s,lH), 7.75-7.81(m,2H), 8.27(s,lH), 8.37(d,lH), 9.10(t,lH), 11.10(bs,lH)

562 3.44-3.49(m,3H), 3.79-3.81(m,lH), 4.09-4.12(m,2H), 4.40-4.42(m,lH), 4.58(d,2H),

4.72(d,lH), 6.48-6.56(m,lH), 6.88(d,lH), 7.38-7.40(m,lH), 7.45-7.52(m,2H), 7.64(d,lH), 7.68-7.78(m,3H), 8.27(s,lH), 8.37(d,lH), 9.09(bs,lH), 10.92(bs,lH).

580 3.38-3.49(m,3H), 3.77-3.80(m,lH), 4.11-4.12(m,2H), 4.38-4.43(m,lH), 4.58(d,2H),

4.71(d,lH), 6.57-6.65(m,lH), 6.85(d,lH), 7.50(d,lH), 7.56-7.60(m,2H), 7.63-7.65(m,lH), 7.70(s,lH), 7.76(d,lH), 8.27(s,lH), 8.37(d,lH), 9.12(t,lH), 11.21(bs,lH).

562 3.38-3.40(m,2H), 3.49-3.52(m,lH), 3.81-3.83(m,lH), 4.11-4.14(m,2H), 4.39-4.45(m,lH), 4.58(d,2H), 4.73(d,lH), 6.61-6.69(m,lH), 6.90(d,lH), 7.22-7.27(m,lH), 7.33- 7.7.34(m,2H), 7.50(d,lH), 7.63-7.65(m,lH), 7.70(s,lH), 7.77(d,lH), 8.27(s,lH),

8.37(d,lH), 9.09(t,lH), 10.99(bs,lH).

560 3.36-3.39(m,2H), 3.48-3.52(m,lH), 3J9-3.81(m,lH), 4.09-4.12(m,2H), 4.38-4.43(m,lH), 4.58(d,2H), 4.71(d,lH), 6.49-6.57(m,lH), 6.91(d,lH), 7.47-7.50(m,3H), 7.57(d,2H), 7.62- 7.64(dd,lH), 7.70(s,lH), 7.78(d,lH), 8.27(s,lH), 8.37(d,lH), 9.09(t,lH), 11.00(bs,lH).

544 3.42-3.45(m,3H), 3.78-3.79(m,lH), 4.07-4.10(m,2H), 4.39-4.42(m,lH), 4.57(d,2H), 4.66- 4.69(m,lH), 6.42-6.49(m,lH), 6.90(d,lH), 7.24(t,lH), 7.46-7.50(m,2H), 7.57-7.63(m,3H), 7.70(s,lH), 7.77(d,lH), 8.26(s,lH), 8.37(d,lH), 9.09(bs,lH), 11.12(bs,lH).

536 3.38-3.52(m,3H), 3.76-3.84(m,lH), 4.07-4.18(m,2H), 4.37-4.46(m,lH), 4.63(d,2H),

4.71(d,lH), 6.67-6.76(m,lH), 6.91(d,lH), 7.22(s,lH), 7.39-7.44(m,lH), 7.54-7.66(m,3H), 7.77(d,lH), 8.21-8.28(m,2H), 9.16(t,lH), 11.56(bs,lH)

518 3.39-3.53(m,3H), 3.77-3.84(m,lH), 4.08-4.16(m,2H), 4.38-4.46(m,lH), 4.63(d,2H),

4.70(d,lH), 6.60-6.69(m,lH), 6.92(d,lH), 7.22(s,lH), 7.38-7.44(m,2H), 7.60-7.67(m,3H), 7.77(d,lH), 8.22-8.28(m,2H), 9.14(t,lH), 11.46(bs,lH)

518 3.38-3.52(m,3H), 3.76-3.83(m,lH), 4.10-4.18(m,2H), 4.38-4.46(m,lH), 4.63(d,2H),

4.69(d,lH), 6.60-6.69(m,lH), 7.00(d,lH), 7.22(s,lH), 7.35-7.44(m,2H), 7.52(dd,lH), 7.62(dd,lH), 7.73-7.80(m,2H), 8.22-8.28(m,2H), 9.14(t,lH), 11.50(bs,lH)

536 .35-3.52(m,3H), 3.75-3.86(m,lH), 4.11-4.24(m,2H), 4.36-4.46(m,lH), 4.60-4.73(m,3H), 6.67-6.77(m,lH), 7.03(d,lH), 7.22(s,lH), 7.39-7.43(m,lH), 7.49-7.65(m,3H), 7.78(d,lH), 8.21-8.29(m,2H), 9.12(t,lH), 11.45(bs,lH)

568 3.37-3.50(m,3H), 3.80(bs,lH), 4.03-4.24(m,2H), 4.37-4.44(m,lH), 4.62(d,2H), 4.72(d,lH), 544 I.29(t, 3H), 3.36(bs,2H), 3.52(bs,lH), 3.74-3.84(m,lH), 4.09-4.14(m,2H), 4.29(q,2H), 4.36-4.42(dd,lH), 4.51(d,2H), 4.70(d, , 1H), 6.56-6.63(m,lH), 6.78(s,lH), 6.91(d,lH), 7.01(d,lH), 7.41(d,lH), 7.62-7.72(m,3H), 7.91(d,lH), 8.13(d,lH), 8.19(s,lH), 9.11(t,lH),

I I.06(bs,lH).

552 3.41(m,2H), 3.51(br dd,lH), 3.74(br s,lH), 4.14(br d,2H), 4.39(m,lH), 4.57 (d,2H) 4.67 (br d,lH) 6.72 (m,lH) 6.92 (d,lH) 7.46 (dd,lH) 7.55 (d,2H) 7.56 (m,lH) 7.69 (dd,lH) 7.93 (d,lH) 8.17 (d,lH) 8.39 (d,lH) 9.28 (t, 1H) 11.77 (br s, 1H)

534 3.33 - 3.45(m,3H) 3.77(br s,lH) 4.04 - 4.20(m,2H) 4.39(br dd,lH) 4.58(br d,2H) 4.67(br d,lH) 6.65(dt,lH) 6.94(br d,lH) 7.40(br d,lH) 7.47(br d,lH) 7.56(s,lH) 7.60 - 7.67(m,2H) 7.70(dd,lH) 7.94(d,lH) 8.19(s,lH) 8.40(d,lH) 9.26(br t,lH) 11.72(br s,lH).

578 3.41(m,2H) 3.49(m,lH) 3.77(m,lH) 4.16(m,2H), 4.37(br dd,lH) 4.57(d,2H) 4.64(br d,lH) 6.68(m,lH) 7.00(d,lH) 7.47(dd,lH) 7.49(m,lH) 7.55(d,lH), 7.66(m,3H) 7.93(d,lH) 8.19(d,lH), 8.39(d,lH) 9.27(t,lH) 11.85 (br s,lH)

552 3.42 (m,2H), 3.48(br s,lH), 3.76(br d,lH) 4.17(m,2H), 4.36(br dd,lH) 4.57 (br d,2H), 4.60(m,lH), 6.78(m,lH), 6.89(m,lH), 7.48(m,3H), 7.56(s,lH) 7.69 (dd,lH) 7.93 (d,lH) 8.21 (d,lH) 8.40 (d,lH) 9.30 (t,lH) 12.03 (br s,lH)

534 3.40-3.50(m,3H), 3.80(bs,lH), 4.14-4.25(m,2H), 4.40(bs,lH), 4.58(d, 2H), 4.69(d,lH), 6.59-6.64(m,lH), 7.00(d,lH), 7.38(d,lH), 7.46(d,lH ), 7.51-7.55(m,2H), 7.70-7.77(m,2H), 7.94(d,lH ), 8.20(s,lH ), 8.40(d,lH ), 9.14(bs,lH ), 11.03(bs,lH),

536 3.42 (m,3H) 3.77 (br d,lH) 4.23 (m,2H) 4.36 (br dd,lH) 4.58 (d,2H) 4.63 (br d,lH) 6.71 (m,lH) 6.87 (m,lH) 7.32 (m,2H) 7.47 (dd,lH) 7.56 (d,lH) 7.70 (dd,lH) 7.94 (dd,lH) 8.22 (d,lH) 8.40 (dd,lH) 9.25 (t, 1H) 11.84 (br s, 1H)

578 3.42 (m,2H) 3.53 (m,lH) 3.80 (m,lH) 4.19 (m,2H) 4.40 (br dd,lH) 4.58 (br s, 2H) 4.69 (br d,lH) 6.64 (m,lH) 7.11 (d,lH) 7.20 (td,lH) 7.47 (dd,lH) 7.56 (d,lH) 7.70 (m,3H) 7.94 (d,lH) 8.18 (d,lH) 8.39 (d,lH) 9.27 (t, 1H) 11.83 (br s, 1H)

578 3.42 (m,2H) 3.50 (m,lH) 3.78 (m,lH) 4.15 (m,2H) 4.34 (m,lH) 4.57 (d,2H), 4.66(br

d,lH), 6.71(m,lH), 7.00(d,lH), 7.27(dd,lH), 7.47(dd,lH), 7.55(d,lH), 7.58(m,lH), 7.69 (dd,lH), 7.93 (m,2H), 8.19(d,lH), 8.39(d,lH) 9.27 (t, 1H) 11.84 (br s, 1H)

578 3.52 (m,3H) 3.80 (m,lH) 4.11 (m,2H) 4.40 (br s, 1H) 4.58 (br s, 2H) 4.67 (br d,lH) 6.56 (m,lH) 6.91 (br d,lH) 7.46 (br s, 2H) 7.55 (br s, 2H) 7.70 (br d,lH) 7.94 (m,2H) 8.19 (br s, 1H) 8.40 (br s, 1H) 9.21 (br s, 1H) 11.48 (m,lH)

536 3.42 (m,2H) 3.50 (m,lH) 3.78 (m,lH) 4.17 (m,2H) 4.44 (m,lH) 4.58 (d,2H) 4.66 (br d,lH) 6.69 (m,lH) 7.02 (d,lH) 7.41 (m,lH) 7.47 (dd,lH) 7.57 (m,2H) 7.70 (dd,lH) 7.94 (d,lH) 8.20 (d,lH) 8.40 (d,lH) 9.28 (t, 1H) 11.88 (br s, 1H)

596 3.42 (m,2H) 3.50 (m,lH) 3.78 (m,lH) 4.18 (m,2H) 4.38 (br s, 1H) 4.58 (d,2H) 4.66 (br d,lH) 6.76 (m,lH) 7.04 (d,lH) 7.47 (dd,lH) 7.51 (ddd,lH) 7.56 (d,lH) 7.61 (m,lH) 7.70 (m,lH) 7.94 (d,lH) 8.19 (d,lH) 8.40 (d,lH) 9.29 (t, 1H) 11.93 (br dJH)

552 3.41 (m,2H) 3.49 (br d,lH) 3.78 (m,lH) 4.17 (m,2H) 4.38 (br dd,lH) 4.57 (d,2H) 4.65 (br d,lH) 6.75 (m,lH) 7.03 (d,lH) 7.47 (dd,lH) 7.51 (m,lH) 7.55 (m,2H) 7.69 (dd,lH) 7.93 (d,lH) 8.19 (d,lH) 8.39 (d,lH) 9.27 (t, 1H) 11.89 (br s, 1H)

572 3.44 (br s, 2H) 3.49 (m,lH) 3.76 (br d,lH) 4.20 (m,lH) 4.27 (m,lH) 4.37 (br dd,lH) 4.57 (d,2H) 4.63 (br d,lH) 6.85 (m,lH) 6.92 (m,lH) 7.47 (dd,lH) 7.56 (s, 1H) 7.70 (dd,lH) 7.94 (d,lH) 8.20 (d,lH) 8.39 (d,lH), 9.29(t,lH), 12.10(br s,lH)

588 3.44 (br s,2H), 3.48 (br s,lH), 3.76(br d,lH), 4.23(m,2H), 4.36(br s,lH), 4.57(d,2H),

4.62(br d,lH), 6.90(m,lH), 6.96(m,lH), 7.47(dd,lH), 7.55(d,lH), 7.69(dd,lH), 7.93(d,lH), 8.19(d,lH), 8.39(d,lH), 9.30(t,lH), 12.15(br s,lH)

578 3.41(m,2H), 3.51(br dd,lH), 3.77(m,lH), 4.11(m,2H), 4.39(br dd,lH) 4.57 (d,2H), 4.66 (br d,lH), 6.67(m,lH), 6.93(d,lH), 7.33(dd,lH), 7.47(dd,lH), 7.55(d,lH), 7.59(dd,lH), 7.69(dd,lH), 7.74(t,lH), 7.93(d,lH), 8.18(d,lH) 8.39 (d,lH) 9.28 (t, 1H) 11.81 (br s, 1H)

584 3.37-3.50(m,3H), 3.80-3.83(m,lH), 4.10-4.15(m,2H), 4.37-4.43(m,lH), 4.57(d,2H), 4.70(d,lH), 6.65-6.72(m,lH), 6.95(d,lH), 7.39-7.47(m,3H), 7.54-7.55(m,2H), 7.70- 7.73(dd,lH), 7.94(d,lH), 8.19(s,lH), 8.39(d,lH), 9.18(t,lH), 11.22(bs,lH).

87 534 3.34-3.51(m,3H), 3.80(bs,lH), 4.09-4.12(m,2H), 4.40(bs,lH), 4.58(d,2H), 4.69(d,lH),

6.49-6.57(m,lH), 6.89(d,lH ), 7.45-7.49(m,2H), 7.55-7.58(m,2H), 7.71(d,lH ), 7.82- 7.84(dd,lH ), 7.94(d,lH ), 8.19(s,lH ), 8.40(d,lH ), 9.16(bs,lH ), l l.l l(bs,lH),

88 516 3.37-3.38(m,2H), 3.45(bs,lH), 3.79-3.82(m,lH), 4.10-4.17(m,2H), 4.35-4.40(m,lH),

4.58(d,2H), 4.67(d,lH), 6.52-6.60(m,lH), 6.99(d,lH), 7.16-7.21(m,lH), 7.31-7.37(m,lH), 7.45-7.47(dd,lH), 7.55(s,lH), 7.69-7.72(dd,lH), 7.74-7.80(m,lH), 7.94(d,lH), 8.20(s,lH), 8.40(d,lH), 9.17(t,lH), 11.25(bs,lH)

89 536 3.40-3.51(m,3H), 3.80-3.83(m,lH), 4.10-4.14(m,2H), 4.40(bs,lH ), 4.58(d,2H),

4.70(d,lH), 6.54-6.62(m,lH), 6.86(d,lH ), 7.46(d,lH), 7.55-7.60(m,3H ), 7.72(d,lH ), 7.94(d,lH ), 8.18(s,lH), 8.40(d,lH ), 9.15(bs,lH ), 11.03(bs,lH).

90 518 3.38-3.54(m,3H), 3.79-3.82(m,lH), 4.09-4.15(m,2H), 4.36-4.42(dd,lH), 4.58(d,2H),

4.70(d,lH), 6.61-6.69(m,lH), 6.91(d,lH ), 7.21-7.26(m,lH), 7.31-7.34(m,lH ), 7.45- 7.47(m,lH), 7.55(s,lH), 7.70-7.72(dd,lH), 7.94(d,lH ), 8.19(d,lH), 8.40(d,lH ),

9.18(t,lH), 11.30(bs,lH)

91 507 3.33 - 3.44(m,3H) 3.80(br s,lH) 4.08 - 4.22(m,2H) 4.40(br dd,lH) 4.58(d,2H) 4.69(br d,lH) 6.73(dt,lH) 7.01(d,lH) 7.47(dd,lH) 7.55(d,lH) 7.68 - 7.73(m,lH) 7.74(d,2H) 7.89(d.2H) 7.94(d,lH) 8.19(d,lH) 8.40(d,lH) 9.19(t,lH) 11.44(br s,lH).

92 516 3.41(br s,2H) 3.50(br s,lH) 3.77(br s,2H) 4.13(br s,lH) 4.38(br dd,lH) 4.57(d,2H) 4.67(br d,lH) 6.56(dt,lH) 6.93(d,lH) 7.44 - 7.50(m,3H) 7.55(s,2H) 7.58(s,lH) 7.70(dd,lH) 7.94(d.lH) 8.20(d,lH) 8.40(d,lH) 9.22(br t,lH), 11.55(br s,lH)

93 550 3.36 - 3.46(m,2H) 3.47 - 3.56(m,lH) 3.75 - 3.82(m,lH) 4.03 - 4.19(m,2H) 4.39(br dd,lH)

4.58(d,2H) 4.67(br d,lH) 6.65(dt,lH) 6.92(d,lH) 7.47(dd,lH) 7.53(dd,lH) 7.55(d,lH) 7.68(d,lH) 7.70(dd,lH) 7.84(d,lH) 7.94(dd,lH) 8.19(d,lH), 8.40(dd,lH), 9.24(t,lH), 11.66(br s,lH)

94 578 3.42 (m,2H) 3.51 (m,lH) 3.78 (m,lH) 4.17 (m,2H) 4.39 (br dd,lH) 4.57 (br d,2H) 4.66 (br d,lH) 6.54 (m,lH) 7.10 (d,lH) 7.36 (td,lH) 7.47 (dd,lH) 7.55 (d,lH) 7.66 (dd,lH) 7.69 (dd,lH) 7.83 (dd,lH) 7.93 (d,lH), 8.19(d,lH), 8.39(d,lH), 9.28 (t,lH), 11.89 (br s,lH)

95 541 3.35-3.43(m,2H), 3.51-3.55(m,lH), 3.79-3.82(m,lH), 4.08-4.19(m,2H), 4.37-4.42(dd,lH),

4.58(d,2H), 4.69(d,lH), 6J2-6.79(m,lH), 6.94(d,lH), 7.46-7.47(dd,lH), 7.55(s,lH), 7.69- 7.72(dd,lH), 7.94(d,lH), 8.00-8.02(m,2H), 8.05(s,lH), 8.18(d,lH), 8.40(d,lH), 9.23(t,lH), 11.62(bs,lH).

96 530 2.35 (s, 3H) 3.41 (m,2H) 3.49 (m,lH) 3.76 (mJH) 4.10 (m,2H) 4.31 (mJH) 4.57 (d,2H)

4.64 (br d,lH) 6.55 (m,lH) 6.90 (d,lH) 7.38 (m,lH) 7.44 (m,lH) 7.47 (dd,lH) 7.51 (d,lH) 7.56 (d,lH) 7.69 (dd,lH) 7.93 (d,lH) 8.19 (d,lH) 8.39 (d,lH) 9.28 (t, 1H) 11.79 (br s, 1H)

97 594 3.41 (m,2H) 3.51 (br dd,lH) 3.79 (br dd,lH) 4.11 (m,2H) 4.39 (br dd,lH) 4.57 (d,2H) 4.67

(br d,lH) 6.64 (m,lH) 6.92 (d,lH) 7.47 (dd,lH) 7.56 (m,2H) 7.66 (d,lH) 7.70 (dd.lH) 7.93 (d,lH) 7.96 (d,lH) 8.18 (d,lH) 8.40 (d,lH) 9.25 (t, 1H) 11.72 (br s, 1H)

98 525 3.42 (m,2H) 3.52 (br dd,lH) 3.79 (m,lH) 4.11 (m,2H) 4.39 (br dd,lH) 4.58 (d,2H) 4.67 (br d,lH) 6.65 (m,lH) 6.96 (d,lH) 7.47 (dd,lH) 7.56 (d,lH) 7.59 (t, 1H) 7.70 (dd,lH) 7.95 (m,2H) 8.15 (dd,lH) 8.18 (d,lH) 8.40 (d,lH) 9.28 (t, 1H) 11.79 (br s, 1H)

99 536 3.52 - 3.64(m,3H) 3.79(br s,lH) 4.13(br d,2H) 4.42(br s,lH) 4.62(br d,2H) 4.69(br s,lH)

6.56 - 6J4(m,lH) 6.90(br d,lH) 7.20(s,lH) 7.40(br d,lH) 7.57(d,2H) 7.71(dd,lH) 7.95(d.lH) 8.17(d,lH) 8.23(d,lH) 9.16(br s,lH) 11.00(br s,lH)

100 544 3.23 (s, 3H) 3.43 (m,2H) 3.53 (m,lH) 3.80 (mJH) 4.17 (m,2H) 4.41 (br dd,lH) 4.62

(d,2H) 4.68 (br d,lH) 6.75 (dt, 1H) 7.05 (d,lH) 7.21 (s, 1H) 7.41 (dt, 1H) 7.70 (dd,lH) 7.80 (d,2H) 7.96 (m,3H) 8.20 (d,lH) 8.23 (d,lH) 9.26 (t. 1H) 11.74 (br s, 1H)

101 534 3.39-3.42(m,2H), 3.47-3.53(m,lH), 4.14-4.21(m,2H), 4.36-4.42(dd,lH ), 4.61(d,2H),

4.69(d,lH), 6.58-6.65(m,lH), 7.14-7.20(m,2H), 7.41(d,lH ), 7.51-7.53(dd,lH ), 7.70- 7.72(m,2H), 7.83(d,lH ), 7.94(d,lH ), 8.19-8.23(m,2H ), 9.20(t,lH ), 11.41(bs,lH).

102 562 3.38 - 3.46(m,2H) 3.49(br d,lH) 3.78(br s,lH) 4.15(br dd,2H) 4.33 - 4.40(m,lH)

4.61(d,2H) 4.66(br d,lH) 6.67(dt,lH) 7.00(d,lH) 7.21(s,lH) 7.41(dt,lH) 7.50(dd,lH) 7.63(dd,lH) 7.67(t,lH) 7.70(dd,lH) 7.94(dd,lH) 8.20(d,lH) 8.23(d,lH) 9.23(t,lH) 11.62(br s,lH)

103 536 3.41(br d,2H) 3.46(br s,lH) 3.78(br s,lH) 4.16(br d,lH) 4.21(br d,lH) 4.29 - 4.43(m,lH)

4.61(br d,2H) 4.65(br s,lH) 6.74(dt,lH) 6.88(d,lH) 7.20(s,lH) 7.40(br d,lH) 7.48(d,2H) 7.70(dd,lH) 7.94(d,lH) 8.21(d,lH) 8.23(d,lH) 9.22(br t,lH) 11.67(br s,lH).

104 518 3.37-3.52(m,3H), 3.74-3.82(m,lH), 4.13-4.18(m,2H), 4.35-4.41(dd,lH ), 4.61(d,2H),

4.68(d,lH), 6.58-6.65(m,lH), 7.00(d,lH ), 7.20(s,lH), 7.36-7.40(m,2H ), 7.51-7.54(dd,lH ), 7.70-7.77(m,2H), 7.94(d,lH ), 8.20-8.23(m,2H), 9.17(t,lH ), 11.15(bs,lH)

105 562 3.43(br s,2H) 3.48 - 3.57(m,lH) 3.72 - 3.82(m,lH) 4.01 - 4.20(m,2H) 4.39(br dd,lH)

4.60(d.2H) 4.66(br d,lH) 6.67(dt,lH) 6.93(d,lH) 7.21(s,lH) 7.33(dd,lH) 7.38 - 7.43(m,lH) 7.59(dd,lH) 7.67 - 7.71(m,lH) 7.74(dd,lH) 7.94(dd,lH) 8.18(d,lH)

8.22(d,lH) 9.31(t,lH) 11.86(br s,lH).

106 520 3.34 - 3.44(m,2H) 3.45 - 3.53(m,lH) 3.62(br s,lH) 4.07 - 4.18(m,lH) 4.18 - 4.28(m,lH)

4.36(br dd,lH) 4.61(d,2H) 4.65(br s,lH) 6.68(dt,lH) 6.86(d,lH) 7.20(s,lH) 7.32(t,2H) 7.38 - 7.43(m,lH) 7.70(dd,lH) 7.94(dd,lH) 8.21(d,lH) 8.23(d,lH) 9.22(t,lH) 11.64(br s,lH).

107 562 3.40 - 3.48(m,2H) 3.48 - 3.58(m,lH) 3.76 - 3.84(m,lH) 4.10 - 4.28(m,2H) 4.41(br dd,lH)

4.61(d,2H) 4.70(br d,lH) 6.64(dt,lH) 7.11(d,lH) 7.16 - 7.24(m,2H) 7.38 - 7.44(m,lH) 7.66 - 7.72(m,2H) 7.74(d,lH) 7.95(dd,lH) 8.18(d,lH) 8.23(d,lH) 9.25(t,lH) 11.70(br s,lH).

108 562 3.42 - 3.47(m,2H) 3.48 - 3.57(m,lH) 3.79(br s,lH) 4.07 - 4.25(m,2H) 4.39(br dd,lH)

4.61(d,2H) 4.68(br d,lH) 6.70(dt,lH) 7.00(d,lH) 7.21(s,lH) 7.27(dd,lH) 7.41(dt,lH) 7.58(ddd,lH) 7.70(dd,lH) 7.91 - 7.94(m,lH) 7.94(d,lH) 8.19(d,lH) 8.23(d,lH) 9.24(t,lH) 11.65(br s,lH)

109 562 3.43 (m,2H) 3.51 (m,lH) 3.79 (m,lH) 4.10 (m,2H) 4.39 (br dd,lH) 4.61 (d,2H) 4.67 (br d,lH) 6.57 (dt, 1H) 6.92 (d,lH) 7.21 (s, 1H) 7.42 (dd,lH) 7.43 (t, 1H) 7.59 (ddd,lH) 7.70 (dd,lH) 7.93 (m,2H) 8.19 (d,lH) 8.23 (d,lH) 9.27 (t, 1H) 11.68 (br s, 1H)

110 520 3.43(br dd,2H) 3.47 - 3.55(m,lH) 3.74 - 3.83(m,lH) 4.08 - 4.25(m,2H) 4.38(br dd,lH)

4.61(d,2H) 4.65(br d,lH) 6.68(dt,lH) 7.01(d,lH) 7.21(s,lH) 7.36 - 7.45(m,2H) 7.52 - 7.61(m,lH) 7.69(dd,lH) 7.94(d,lH) 8.19(d,lH) 8.23(d,lH) 9.27(t,lH) 11.81(br s,lH).

111 580 3.35 - 3.44(m,2H) 3.49 - 3.55(m,lH) 3.74 - 3.84(m,lH) 4.08 - 4.27(m,2H) 4.39(br dd,lH)

4.61(d,2H) 4.67(br d,lH) 6.74(dt,lH) 7.03(d,lH) 7.21(s,lH) 7.39 - 7.43(m,lH) 7.48 - 7.55(m,lH) 7.62(ddd,lH) 7.70(dd,lH) 7.95(d,lH) 8.20(d,lH) 8.23(d,lH) 9.24(t,lH) 11.71(br s,lH).

112 552 3.41(br s,2H) 3.47 - 3.52(m,lH) 3.80(br d,lH) 4.01 - 4.20(m,2H) 4.39(br dd,lH)

4.61(d,2H) 4.68(br d,lH) 6.65(dt,lH) 6.88(d,lH) 7.21(s,lH) 7.41(dt,lH) 7.70(dd,lH) 7.81(d,2H) 7.94(dd,lH) 8.18(d,lH) 8.23(d,lH) 9.24(t,lH) 11.63(br s,lH)

113 509 3.42(br s,2H) 3.48 - 3.57(m,lH) 3.72 - 3.83(m,lH) 4.10(br s,2H) 4.39(br dd,lH)

4.61(d,2H) 4.67(br d,lH) 6.59 - 6.70(m,lH) 6.96(d,lH) 7.21(s,lH) 7.37 - 7.43(m,lH) 7.59(t,lH) 7.70(dd,lH) 7.94(d,lH) 7.94 - 7.97(m,lH) 8.15(dd,lH) 8.18(d,lH) 8.23(d,lH) 9.29(t,lH) 11.79(br s,lH).

114 518 3.38-3.39(m,3H), 3.80-3.83(m,lH), 4.13-4.20(m,2H), 4.37-4.42(dd,lH ), 4.61(d,2H),

4.70(d,lH), 6.53-6.57(m,lH), 7.13-7.20(m,2H), 7.31-7.36(m,lH), 7.41(d,lH ), 7.52- 7.55(dd,lH ), 7.70-7.72(dd,lH ), 7.85-7.89(m,lH ), 7.95(d,lH ), 8.20-8.23(m,2H ), 9.18(t,lH ), 11.21(bs,lH)

115 500 3.33(s,lH), 3.45-3.50(m,2H), 3.79-3.82(m,lH), 4.11-4.17(m,2H), 4.35-4.41(m,lH),

4.61(d,2H), 4.68(d,lH), 6.52-6.59(m,lH), 6.99(d,lH), 7.16-7.20(m,2H), 7.31-7.37(m,lH), 7.40(d,lH), 7.70-7.72(dd,lH), 7.74-7.8 l(m,lH ), 7.94(d,lH ), 8.20-8.22(m,2H ),

9.18(t,lH), 11.16(bs,lH)

116 520 3.39(bs,2H), 3.47-3.53(m,lH), 3.78-3.81(m,lH), 4.09-4.13(m,2H), 4.36-4.41(dd,lH ),

4.61(d,2H), 4.68(d,lH), 6.57-6.64(m,lH), 6.87(d,lH ), 7.20(s,lH), 7.41(d,lH ), 7.55- 7.59(m,2H), 7.70-7.72(dd,lH ), 7.94(d,lH ), 8.18(d,lH ), 8.23(d,lH ), 9.23(t,lH ), 11.44(bs,lH).

117 502 3.38 - 3.48(m,2H) 3.47 - 3.58(m,lH) 3.74 - 3.85(m,lH) 4.12(br dd,2H) 4.39(d,lH)

4.61(d,2H) 4.68(br d,lH) 6.68(dt,lH) 6.92(d,lH) 7.21(s,lH) 7.22 - 7.27(m,lH) 7.27 - 7.35(m,2H) 7.41(dt,lH) 7.70(dd,lH) 7.94(dd,lH) 8.19(d,lH) 8.23(d,lH) 9.24(t,lH) 11.60(br s,lH).

118 518 3.40(br s,2H) 3.49(br s,lH) 3.79(br s,lH) 4.16(br s,2H) 4.40(br s,lH) 4.61(d,2H) 4.67(br s,lH) 6.63 - 6.75(m,lH) 7.05(d,lH) 7.20(s,lH) 7.29(t,lH) 7.38 - 7.43(m,lH) 7.54 - 7.62(m,lH) 7.65 - 7.70(m,lH) 7.70(dd,lH) 7.94(dd,lH) 8.20(d,lH) 8.23(d,lH) 9.22(br t,lH) 11.64(br s,lH).

119 502 3.39 - 3.47(m,2H) 3.47 - 3.54(m,lH) 3.74 - 3.83(m,lH) 4.07 - 4.18(m,2H) 4.38(br dd,lH)

4.61(d,2H) 4.66(br d,lH) 6.71(dt,lH) 7.06(d,lH) 7.21(s,lH) 7.24 - 7.31(m,lH) 7.38 - 7.47(m,2H) 7.48 - 7.54(m,lH) 7.70(dd,lH) 7.94(dd,lH) 8.20(d,lH) 8.23(d,lH) 9.27(t,lH) 11.81(br s,lH).

120 491 3.42(br s,2H) 3.47 - 3.57(m,lH) 3.78(br s,lH) 4.09 - 4.15(m,2H) 4.41(br d,lH) 4.61(br d,2H) 4.68(br d,lH) 6.70 - 6.80(m,lH) 7.02(d,lH) 7.21(s,lH) 7.41(br d,lH) 7.51(d,lH) 7.74(d,2H) 7.89(d,2H) 7.92 - 7.97(m,lH) 8.20(s,lH) 8.23(d,lH) 9.17(br t,lH) 11.74(br s,lH).

121 500 3.44(br d,2H) 3.48 - 3.55(m,lH) 3.75(br s,lH) 4.10(br dd,2H) 4.38(br dd,lH) 4.60(br d,2H) 4.64(br d,lH) 6.52 - 6.73(m,lH) 6.94(d,lH) 7.21(s,lH) 7.41(br d,lH) 7.44 - 7.50(m,2H) 7.52 - 7.60(m,2H) 7.67 - 7.73(m,lH) 7.88 - 7.96(m,lH) 8.19(d,lH) 8.22(d,lH) 9.31(t,lH) 11.84(br s,lH).

122 534 3.34 - 3.46(m,2H) 3.51(br dd,lH) 3.78(br s,lH) 4.03 - 4.20(m,2H) 4.35 - 4.43(m,lH)

4.61(br d,2H) 4.67(br d,lH) 6.65(dt,lH) 6.92(d,lH) 7.21(s,lH) 7.39 - 7.43(m,lH) 7.53(dd,lH) 7.68(d,lH) 7.71(d,lH) 7.84(d,lH) 7.94(d,lH) 8.19(d,lH) 8.23(d,lH) 9.25(t,lH) 11.68(br s,lH).

123 484 3.33 - 3.44(m,2H) 3.44 - 3.54(m,lH) 3.74 - 3.78(m,lH) 4.09(br dd,2H) 4.39(br dd,lH)

4.61(br d,2H) 4.67(br d,lH) 6.41 - 6.53(m,lH) 6.92(d,lH) 7.16 - 7.21(m,lH) 7.21 - 7.32(m,2H) 7.40(br d,lH) 7.60(dd,2H) 7.71(dd,lH) 7.94(d,lH) 8.20(d,lH) 8.23(d,lH) 9.20(t,lH) 11.33(br s,lH)

124 467 3.47 (br s, 2H) 3.59 (br s, 1H) 3.80 (br d,lH) 4.27 (br s, 2H) 4.40 (br d,lH) 4.61 (d,2H)

4.70 (br s, 1H) 7.21 (d,2H) 7.26 (m,lH) 7.42 (br d,lH) 7.70 (dd,lH) 7.94 (m,lH) 8.15 (s, 1H) 8.17 (s, 2H) 8.23 (d,lH) 8.93 (d,2H) 9.36 (t, 1H) 12.28 (br s, 1H)

125 562 3.39 - 3.47(m,2H) 3.47 - 3.56(m,lH) 3.76 - 3.84(m,lH) 4.15 - 4.22(m,2H) 4.39(br dd,lH)

4.61(d,2H) 4.68(br d,lH) 6.53(dt,lH) 7.10(d,lH) 7.21(s,lH) 7.37(td,lH) 7.41(br d,lH) 7.66(dd,lH) 7.70(dd,lH) 7.84(dd,lH) 7.94(d,lH) 8.19(d,lH) 8.23(d,lH) 9.25(t,lH) 11.76(br s,lH).

126 550 3.40(br d,2H) 3.46(br s,lH) 3.75(br s,lH) 4.08(br dd,2H) 4.36(br d,lH) 4.61(d,2H) 4.65(br s,lH) 6.34(dt,lH) 7.06(d,lH) 7.21(s,lH) 7.29(d,lH) 7.38 - 7.43(m,lH) 7.68(d,lH) 7.70(dd,lH) 7.94(dd,lH) 8.21(d,lH) 8.23(d,lH) 9.23(br t,lH) 11.60(br s,lH)

127 509 3.38(bs,2H), 3.51-3.58(m,lH), 3.80-3.83(m,lH), 4.09-4.17(m,2H), 4.37-4.42(m,lH),

4.61(d,2H), 4.69(d,lH), 6J0-6.77(m,lH), 6.94(d,lH), 7.21(s,lH), 7.40(d,lH), 7.70- 7.73(dd,lH), 7.83-7.86(m,2H), 7.94(d,2H), 8.18(bs,lH), 8.23(d,lH), 9.21(bs,lH), 11.32(bs,lH).

128 567

129 551 130 596 3.36-3.52 )m,3H), 3.80 )bs,lH), 4.11-4.15 (m,2H), 4.40-4.42 (m,lH), 4.56 (d,2H), 4.70 (d,lH), 6.64-6.71 (m,lH), 6.90 (d,lH), 7.48 (d,lH), 7.58 (d,2H), 6.69-7.73 (m,2H), 7.93 (d,lH), 8.18 (bs,lH), 8.38 (d,lH), 9.16 (t,lH) 11.15 (bs,lH)

131 578 1H NMR(400 MHz, DMSO-d6) δ: 3.38-3.40(m,2H), 3.46-3.53(m,lH), 3.79-3.82(m,lH),

4.08- 4.14(m,2H), 4.36-4.41(m,lH), 4.56(d,2H), 4.68(d,lH), 6.57-6.64(m ,1H),

6.91(d,lH), 7.41(dd,lH), 7.48(dd,lH), 7.62-7.92(m, 4H), 7.93(d,lH), 8.19(d,lH), 8.37(d,lH), 9.17(t,lH), 11.21(bs,lH),

132 578 3.37-3.54(m,3H), 3.80-3.83(m,lH), 4.13- 4.19(m,2H), 4.36-4.41(m,lH), 4.56(d,2H),

4.68(d,lH), 6.57-6.64(m ,lH), 7.0(d,lH), 7.38(dd,lH), 7.48-7.54(m,2H), 7.68-7.77(m,3H), 7.93(d,lH), 8.20(d,lH), 8.38(d,lH), 9.13(t,lH), 11.02(bs,lH),

133 580 3.36-3.48(m,3H), 3.80-3.83(m,lH), 4.13- 4.22(m,2H), 4.35-4.41(m,lH), 4.56(d,2H),

4.68(d,lH), 6.58-6.66(m ,1H), 7.0(d,lH), 7.39-7.45(m,lH), 7.49(d,lH), 7.55-7.61(m,lH), 7.69-7.73(m,2H), 7.94(d,lH), 8.2(d,lH), 8.39(d,lH), 9.15(t,lH), 11.17(bs,lH),

134 569 3.36-3.40(m,2H), 3.51-3.53(m,lH), 3.80-3.83(m,lH), 4.11- 4.16(m,2H), 4.37-4.42(m,lH),

4.56(d,2H), 4.70(d,lH), 6.75-6.83(m ,1H), 6.99(d,lH), 7.49(d,lH), 7.58(d,lH), 7.69- 7.72(m,2H), 7.76(d,lH), 7.93(d,lH), 7.98(t,lH), 8.18(s,lH), 8.37(d,lH), 9.19(t,lH), 11.41(bs,lH),

135 578 3.33-3.52(m,3H), 3.82(bs,lH), 4.16- 4.20(m,2H), 4.39-4.43(m,lH), 4.57(d,2H),

4.71(d.lH), 6.47-6.55(m ,lH), 7.16(d,lH), 7.32-7.36(m,lH), 7.48-7.55(m,2H), 7.68- 7.73(m,2H), 7.86-7.95(m,2H), 8.19(s,lH), 8.38(d,lH), 9.11(bs,lH), 10.87(bs,lH),

136 562 .33-3.37(m,2H), 3.45-3.50(m,lH), 3.79-3.81(m,lH), 4.11-4.18(m,2H), 4.35-4.40(m,lH),

4.56(d.2H), 4.68(d,lH), 6.54-6.60(m ,1H), 6.99(d,lH), 7.16- 7.21(m,lH), 7.31- 7.37(m,lH), 7.48(dd,lH), 7.69-7.72(m,2H), 7.74-7.80(m,lH), 7.93(d,lH), 8.21(d,lH), 8.37(d,lH), 9.17(t,lH), 11.28(bs,lH)

137 578 3.34-3.54(m,3H), 3.80-3.84(m,lH), 4.05- 4.16(m,2H), 4.39-4.45(m,lH), 4.56(d,2H),

4.71(d,lH), 6.48-6.55(m,lH), 6.90(d,lH), 7.45-7.49(m,2H), 7.55-7.58(m,lH), 7.68- 7.73(m,2H), 7.84(d,lH), 7.94(d,lH), 8.19(s,lH), 8.38(d,lH), 9.12(bs,lH), 10.79(bs,lH).

138 562 3.35-3.37(m,2H), 3.49-3.52(m,lH), 3.80-3.82(m,lH), 4.10-4.17(m,2H), 4.39-4.42(m,lH),

4.56(d,2H), 4.71(d,lH), 6.46-6.53(m ,1H), 6.88(d,lH), 7.39- 7.41(m,lH), 7.46- 7.52(m,2H), 7.68-7.73(m,3H), 7.94(d,lH), 8.19(s,lH), 8.38(d,lH), 9.13(bs,lH),

10.79(bs,lH),

139 580 3.36-3.40(m,2H), 3.46-3.53(m,lH), 3.78-3.81(m,lH), 4.06- 4.13(m,2H), 4.36-4.41(m,lH),

4.56(d,2H), 4.70(d,lH), 6.56-6.63(m ,1H), 6.86(d,lH), 7.48(dd,lH), 7.56-7.60(m,2H), 7.69-7.73(m,2H), 7.94(d,lH), 8.18(d,lH), 8.37(d,lH), 9.18(t,lH), 11.25(bs,lH),

140 562 3.33-3.38(m,2H), 3.50-3.54(m,lH), 3J9-3.82(m,lH), 4.09-4.16(m,2H), 4.36-4.42(m,lH),

4.56(d,2H), 4.69(dlH), 6.61-6.69(m ,1H), 6.91(d,lH), 7.21- 7.27(m,lH), 7.30-7.35(m,2H), 7.49(dd,lH), 7.69-7.72(m,2H), 7.93(d,lH), 8.19(d,lH), 8.37(d,lH), 9.19(t,lH),

11.33(bs,lH),

141 560 3.34-3.51(m,3H), 3.78-3.82(m,lH), 4.05- 4.15(m,2H), 4.37-4.41(m,lH), 4.56(d,2H),

4.70(d,lH), 6.47-6.55(m,lH), 6.91(d,lH), 7.47-7.49(m,3H), 7.58(d,2H), 7.68-7.72(m,2H), 7.93(d,lH), 8.20(bs,lH), 8.38(d,lH), 9.13(bs,lH), 10.09(bs,lH),

142 544 3.37-3.52(m,3H), 3.80-3.83(m,lH), 4.07- 4.13(m,2H), 4.36-4.41(m,lH), 4.56(d,2H),

4.70(d,lH), 6.39-6.47(m ,lH), 6.91(d,lH), 7.24-7.28(m,2H), 7.49(d,lH), 7.59-7.62(m,2H), 7.69-7.73(m,2H), 7.94(d,lH), 8.21(bs,lH), 8.38(d,lH), 9.13(t,lH), 10.87(bs,lH),

143 534 3.38-3.44(m,2H), 3.50-3.58(m,2H), 4.39- 4.44(m,3H), 4.57(d,2H), 4.64-4.68(m,lH),

6.42(d,lH), 7.46(d,lH), 7.50-7.55(m,3H), 7.60(d,2H), 7.71(d,lH), 7.93(d,lH),

8.23(bs,lH), 8.40(d,lH), 9.21(bs,lH), 11.45(bs,lH).

144 518 3.36-3.47(m,3H), 3.85-3.89(m,lH), 4.30- 4.48(m,3H), 4.60-4.65(m,3H), 6.40(d,lH),

7.20(s,lH), 7.39(d,lH), 7.51(d,2H), 7.60(d,2H), 7.70(d,lH), 7.94(d,lH), 8.23(d,2H), 9.19(bs,lH), 11.31(bs,lH). 145 539 2.40(s, 3H), 2.82(t,2H), 2.96-3.03(m,2H), 3.38(d,2H), 3.62(s,2H), 4.53(d,2H), 6.52- 6.68(m,2H), 6.97(d,lH), 7.29(d,lH), 7.43(dd,lH), 7.48-7.53(m,2H) 7.57-7.61(m,2H), 7.78(d,lH), 8.38-8.41(m,lH), 8.47(t,lH).

146 505 2.40(s, 3H), 2.81(t,2H), 2.97-3.04(m,2H), 3.38(d,2H), 3.61(s,2H), 4.52(d,2H), 6.41- 6.50(m,lH), 6.63(d,lH), 6.97(d,lH), 7.29(d,lH), 7.37-7.43(m,3H), 7.49-7.53(m,3H) 7.59(s,lH), 8.38-8.41(m,lH), 8.46(t,lH).

147 505 2.50(s, 3H), 2.78(t,2H), 2.99(t,2H), 3.40(d,2H), 3.92(s,2H), 4.52(d,2H), 6.42-6.47(m,lH),

6.64(d,lH), 6.87(d,lH), 7.05(t,lH), 7.38-7.43(m,3H), 7.50-7.53(m,3H), 7.57(d,lH), 8.38- 8.41(m,lH), 8.53(t,lH)

148 399 1.45(s, 9 H), 2.51(s, 3H), 2.97(t,2H), 3.64(t,2H), 4.52(d,2H), 4.80(s,2H), 6.91(d,lH),

7.09(t,lH), 7.42(d,lH), 7.50(s,lH), 7.58(d,lH), 8.39,(d,lH), 8.55(t,lH).

149 489 2.50(s, 3H), 2.78(t,2H), 2.99(t,2H), 3.39(d,2H), 3.92(s,2H), 4.52(d,2H), 6.33-6.42(m,lH),

6.64(d,lH), 6.87(d,lH), 7.05(t,lH), 7.14-7.18(m,2H), 7.48(d,lH) 7.51-7.59(m, 4 H), 8.38- 8.41(m,lH), 8.53(t,lH).

150 539 2.40(s, 3H), 2.83(t,2H), 2.98-3.05(m,2H), 3.42(d,2H), 3.63(s,2H), 4.53(d,2H), 6.57- 6.65(m,lH), 6.74(d,lH), 6.97(d,lH), 7.29(d,lH), 7.41-7.61(m,3H), 7.69-7.76(m, 4 H), 8.38-8.41(m,lH), 8.47(t,lH).

151 603 3.23(s, 3H), 3.40-3.55(m,3H), 3.80-3.86(m,lH), 4.13-4.21(m,2H), 4.41-4.47(m,lH),

4.60(d,2H), 4.72(d,lH), 6.72-6.80(m,lH), 7.05(d,lH), 7.47(dd,lH), 7.55-7.59(m,2H), 7.78- 7.83(m,3H), 7.96(d,2H), 8.10(s,lH), 8.40(d,lH), 9.14(t,lH), 11.50(bs,lH).

152 577 2.86(t,2H), 3.09(t,2H), 3.41(d,2H), 3.70(s,2H), 4.57(d,2H), 6.51-6.58(m,lH), 6.65(d,lH),

7.29(dd,lH), 7.43-7.48(m,2H) 7.52-7.66(m, 4 H), 8.07(s,lH), 8.38-8.41(m,lH), 8.70(t,lH).

153 568 3.37-3.56(m,3H), 3.77-3.86(m,lH), 4.07-4.19(m,2H), 4.41-4.47(m,lH), 4.60(d,2H),

4.74(d,lH), 6.79-6.87(m,lH), 7.01(d,lH), 7.47(dd,lH), 7.55-7.61(m,3H), 7.75- 7.82(m,2H), 7.96-8.00(m,lH), 8.10(s,lH), 8.40(d,lH), 9.14(t,lH), 11.51(bs,lH).

154 561 3.33-3.51 (m,3H), 3.83 (bs, 1H), 4.12 (bs, 2H), 4.43-4.44 (m,lH), 4.60 (d,2H), 4.74 (d,lH),

6.48-6.55 (m,lH), 6.89 (d,lH), 7.40-7.58 (m, 5H), 7.70-7.81 (m,2H), 8.09 (bs, 1H), 8.40 (d,lH), 9.08 (bs, 1H), 10.66 (bs, 1H).

155 550 2.93-2.95(m,2H), 3.12-3.14(m,2H), 3.48(d,2H), 3.72(s,2H), 4.67(d,2H), 5.94(t,lH), 6.45- 6.52(m,lH), 6.65(d,lH), 7.22-7.23(m,lH), 7.33(s,lH), 7.45-7.48(m, 4H), 7.60(d,2H), 8.12(s,lH), 8.38(d,lH).

156 559 2.86(t,2H), 3.09(t,2H), 3.40(d,2H), 3.70(s,2H), 4.56(d,2H), 6.40-6.48(m,lH), 6.65(d,lH),

7.38-7.54(m, 7 H) 7.66(d,lH), 8.07(s,lH), 8.38-8.41(m,lH), 8.69(t,lH).

157 559 2.85(t,2H), 3.07(t,2H), 3.39(d,2H), 3.67(s,2H), 4.57(d,2H), 6.37-6.46(m,lH), 6.63(d,lH),

7.33-7.41(m,3H), 7.44(d,lH), 7.48-7.55(m, 4 H), 8.04(d,lH), 8.40(d,lH), 8.88(t,lH).

158 593 2.86(t,2H), 3.09(t,2H), 3.42(d,2H), 3.70(s,2H), 4.57(d,2H), 6.52-6.66(m,2H), 7.44- 7.51(m,3H) 7.54 (s,lH), 7.59(d,lH), 7.68(d,lH), 7.78(d,lH), 8.07(s,lH), 8.38-8.41(m,lH), 8.70(t,lH).

159 593 2.85(t,2H), 3.07(t,2H), 3.39(d,2H), 3.68(s,2H), 4.57(d,2H), 6.48-6.57(m,lH), 6.63(d,lH),

7.35(t,lH), 7.44-7.60(m, 5 H), 7.76(d,lH), 8.04(d,lH), 8.41(d,lH), 8.88(t,lH).

160 543 2.86(t,2H), 3.09(t,2H), 3.41(d,2H), 3.69(s,2H), 4.56(d,2H), 6.32-6.43(m,lH), 6.64(d,lH),

7.14-7.17(m,2H) 7.42-7.55 (m, 5 H), 7.66(d,lH), 8.07(s,lH), 8.38-8.41(m,lH), 8.69(t,lH).

161 543 2.85(t,2H), 3.07(t,2H), 3.38(d,2H), 3.67(s,2H), 4.57(d,2H), 6.30-6.39(m,lH), 6.63(d,lH),

7.13-7.18(m,2H), 7.36(t,lH), 7.44(d,lH), 7.49-7.55(m, 4 H), 8.04(d,lH), 8.40(d,lH), 8.88(t,lH).

162 593 2.87(t,2H), 3.08(t,2H), 3.43(d,2H), 3.69(s,2H), 4.57(d,2H), 6.53-6.62(m,lH), 6.74(d,lH),

7.36(t,lH), 7.44(d,lH), 7.52-7.56(m,2H), 7.69(s, 4 H), 8.04(d,lH), 8.40(d,lH), 8.88(t,lH).

163 561 2.86(t,2H), 3.10(t,2H), 3.41(d,2H), 3.70(s,2H), 4.60(d,2H), 6.50-6.58(m,lH), 6.65(d,lH),

7.19(s,lH), 7.32-7.42(m,2H), 7.45(d,lH), 7.52-7.66(m,3H), 8.08(s,lH), 8.23(d,lH), 8.71(t,lH). 164 534 2.87(t,2H), 3.11(t,2H), 3.45(d,2H), 3.71(s,2H), 4.60(d,2H), 6.62-6.77(m,2H), 7.19(s,lH), 7.37-7.41(m,lH), 7.45(dd,lH), 7.64-7.70(m,3H), 7.77-7.82(m,2H), 8.08(s,lH), 8.23(d,lH), 8.71(t,lH).

165 543 2.86(t,2H), 3.10(t,2H), 3.40(d,2H), 3.70(s,2H), 4.60(d,2H), 6.40-6.48(m,lH), 6.65(d,lH),

7.19(s,lH), 7.38-7.52(m, 6 H), 7.65(d,lH), 8.08(s,lH), 8.23(d,lH), 8.70(t,lH).

166 577 2.86(t,2H), 3.10(t,2H), 3.41(d,2H), 3.70(s,2H), 4.60(d,2H), 6.52-6.60(m,lH), 6.65(d,lH),

7.19(s,lH), 7.38(d,lH), 7.43-7.52(m,2H), 7.59(d,lH), 7.64(d,lH), 7.78(d,lH), 8.08(s,lH), 8.23(d,lH), 8.71(t,lH).

167 543 2.83(t,2H), 3.04(t,2H), 3.38(d,2H), 3.63(s,2H), 4.52(d,2H), 6.52-6.66(m,2H), 7.01- 7.06(m,lH), 7.22-7.26(m,lH), 7.42-7.44(m,lH), 7.47-7.52(m,2H), 7.59(d,lH), 7.75- 7.79(m,2H), 8.38(d,lH), 8.51(t,lH).

168 500 3.35-3.40(m,3H), 3.80-3.83(m,lH), 4.12-4.20(m,2H), 4.33-4.38(m ,1H), 4.55(d,2H),

4.65(d.lH), 6.65-6.73(m,lH), 7.01(d,lH), 7.15-7.20(m,lH), 7.42-7.45(m,2H), 7.53(s,lH), 7.74(d,2H), 7.78-7.82(m,lH), 7.89(d,2H), 8.39(d,lH), 8.90(t,lH), 10.88(bs,lH).

169 509 2.83(t,2H), 3.04(t,2H), 3.39(d,2H), 3.62(s,2H), 4.52(d,2H), 6.40-6.48(m,lH), 6.64(d,lH),

6.99-7.04(m,lH), 7.22-7.27(m,lH), 7.37-7.42(m,3H), 7.49-7.53(m,3H), 7.75-7.79(m,lH), 8.38(d,lH), 8.50(t,lH).

170 492 2.9(2H, t), 3.1(2H, bs), 3.45(2H, d), 3.7(2H, s), 4.1(2H, d), 5.8(lh, bt), 6.35(1H, dt),

6.6(1H, d), 6.95(1H, dt), 7.0-7.15(3H, m), 7.25-7.45(6H, m), 7.75(1H, d).

171 584 3.35-3.43(m,3H), 3.50-3.53(m,lH), 3.83(bs,lH), 4.10-4.17(m,2H), 4.41-4.45(m,lH),

4.61(d,2H), 4.76(d,lH), 6.47-6.54(m,lH), 6.92(d,lH), 7.47-7.50(m,3H), 7.57-7.60(m,3H), 8.26(s,lH), 8.41(d,lH), 8.55(s,lH), 9.34(bs,lH), 11.12(bs,lH),

172 552 3.40(bs,2H), 3.51(bs,lH), 3J4-3.79(m,lH), 4.10-4.12(m,2H), 4.33-4.37(m,lH),

4.59(d,2H), 4.66(d,lH), 6.55-6.63(m,lH), 6.90(d,lH), 7.39-7.41(dd,lH), 7.46-7.47(m,lH), 7.57(s,lH), 7.62-7.67(m,2H), 7.77(d,lH), 8.33(d,lH), 8.40(d,lH), 9.12(t,lH), 11.15(bs,lH).

173 525 3.40-3.48(m,2H), 3.79(bs,lH), 4.11-4.16(m,3H), 4.33-4.38(dd,lH), 4.59(d,2H),

4.64(d,lH), 6.68-6.76(m,lH), 6.99(d,lH), 7.47(d,lH), 7.57(s,lH), 7.71-7.79(m,3H), 7.88(d,2H), 8.32(d,lH), 8.39(d,lH), 9.16(t,lH), 11.59(bs,lH).

174 518 3.39(bs,2H), 3.47-3.49(m,lH), 3.80(bs,lH), 4.09-4.1 l(m,2H), 4.35-4.37(m,lH), 4.61- 4.68(m,3H), 6.46-6.53(m,lH), 6.90(d,lH), 7.21(s,lH), 7.41(d,lH), 7.48(d,2H), 7.57(d,2H), 7.78 (d,lH), 8.23(d,lH), 8.33(d,lH), 9.11(bs,lH), 10.90(bs,lH)

175 518 3.40(bs,2H), 3.46-3.49(m,lH), 3.79(bs,lH), 4.06-4.1 l(m,2H), 4.33-4.38(dd,lH),

4.59(d,2H), 4.65(d,lH), 6.39-6.46(m,lH), 6.90(d,lH), 7.25(t,2H), 7.47(d,lH), 7.56- 7.61(m,3H), 7.79(d,lH), 8.33(d,lH), 8.40(d,lH), 9.09-9.10(m,lH), 10.96(bs,lH).

176 528 2.54(s, 3H), 3.34-3.48(m,3H), 3.78(bs,lH), 4.05-4. l l(m,2H), 4.33-4.38(m,lH),

4.58(d,2H), 4.64(d,lH), 6.52-6.58(m,lH), 6.91(d,lH), 7.45-7.49(m,3H), 7.58-7.61(m,3H), 7.63(s,lH), 8.19(s,lH), 8.39(d,lH ), 9.02(t,lH ), 11.23(bs,lH)

177 550 3.49(bs,2H), 3.82(bs,lH), 4.07-4.14(m,3H), 4.39(bs,lH), 4.59(d,2H), 4.70(d,lH), 6.43- 6.51(m ,1H), 6.91(d,lH), 7.45-7.49(m,3H), 7.56-7.58(m,3H), 8.07(s,lH), 8.35(s,lH), 8.40(d,lH), 9.16(bs,lH), 10.63(bs,lH).

178 534 3.50(bs, 3H), 3.80(m,lH), 4.07-4.15(m,2H), 4.39(m,lH), 4.57(d,2H), 4.68(d,lH), 6.46- 6.54(m ,1H), 6.92(d,lH), 7.45-7.49(m,3H), 7.56-7.58(m,3H), 7.89(d,lH), 8.26(d,lH), 8.40(d,lH), 9.11(bs,lH), 10.71(bs,lH).

179 589 3.38(bs,2H), 3.49-3.52(bs,lH), 3.79-3.81(bs,lH), 4.10-4.13(m,2H), 4.34-4.36(m,lH),

4.56(d,2H), 4.69(d,lH), 6.56-6.62(m,lH), 6.90(d,lH), 7.40-7.46(m,3H), 7.53(s,lH), 7.65(q,2H), 7.75(d,lH), 7.83(s,lH), 8.39(d,lH), 8.93(s,lH), 10.72(bs,lH)

180 580 3.40(bs,2H), 3.51(bs,lH), 3.80(bs,lH), 4.14-4.17(m,2H), 4.33-4.37(m,lH), 4.56(d,2H),

4.69(d,lH), 6.72-6.80(m,lH), 6.96(d,lH), 7.44-7.47(m, 2H), 7.53(s,lH), 7.57-7.59(d,lH), 7.74-7.82(m,3H), 7.98(t,lH), 8.39(d,lH), 8.95(bs,lH), 10.89(bs,lH), 181 573 3.48-3.49(m,2H), 3.78(bs,lH), 4.10-4.16(m,2H), 4.31-4.36(m,lH), 4.55(d,2H), 4.67(d,lH), 6.50-6.57(m,lH), 6.99(d,lH), 7.19(t,lH), 7.31(t,lH), 7.44-7.46(m,2H), 7.53(s,lH), 7.74- 7.82(m,2H), 7.85(s,lH), 8.39(d,lH), 8.94(bs,lH), 10.80(bs,lH),

182 587 3.30(bs,lH), 3.37(bs,lH), 3.45-3.49(m,lH), 3.79-3.81(m,lH), 4.06-4.1 l(m,2H), 4.32- 4.38(m,lH), 4.56(d,2H), 4.68(d,lH), 6.49-6.56(m,lH), 6.89(d,lH), 7.44-7.49(m,3H), 7.53(s,lH), 7.54-7.58(m,lH), 7.75(d,lH), 7.83-7.85(m,2H), 8.39(d,lH), 8.94(t,lH),

183 571 3.38(bs,2H), 3.49(bs,lH), 3.78(bs,lH), 4.06-4.1 l(m,2H), 4.32-4.37(m,lH), 4.56(d,2H),

4.68(d,lH), 6.47-6.54(m,lH), 6.88(d,lH), 7.38-7.44(m,lH), 7.45-7.50(m,3H), 7.53(s,lH), 7.68-7.73(m,lH), 7.75(d,lH), 7.84(d,lH), 8.39(d,lH), 8.94(t,lH), 10.78(bs,lH)

184 560 2.92(t,2H), 3.11(t,2H), 3.46(d,2H), 3.66(s,2H), 4.64(d,2H), 5.90(t,lH), 6.44-6.51(m,lH),

6.63(d,lH), 7.22(dd,lH), 7.31-7.33(m,lH), 7.34(d,lH), 7.46-7.50(m,3H), 7.60(d,2H), 7.67(d,lH), 8.37(d,lH).

185 569 2.93(t,2H) 3.12(t,2H) 3.44(dd,2H) 3.66(s,2H) 4.63(d,2H) 6.20(s.lH) 6.33(dt,lH)

6.59(d,lH) 7.20 - 7.23(m,lH) 7.28 - 7.36(m, 6 H) 7.49(d,lH) 7.69(d,lH) 8.36(dd,lH).

186 603 2.88(t,2H) 3.07(t,2H) 3.40(dd,2H) 3.60(s,2H) 4.60(d,2H) 6.29(dt,lH) 6.35(t,lH)

6.52(d,lH) 7.18(dd,lH) 7.21(dd,lH) 7.25 - 7.31(m,2H) 7.38(d,lH) 7.46(t,2H) 7.64(d,lH) 8.31(dd,lH).

187 619 2.87(t,2H) 3.06(t,2H) 3.40(dd,2H) 3.58(s,2H) 4.58(d,2H) 6.30(dt,2H) 6.59(d,lH) 7.14 - 7.17(m,2H) 7.18(s,lH) 7.24 - 7.29(m,2H) 7.38 - 7.42(m,2H) 7.44(d,lH) 7.62(d,lH) 8.29(dd,lH).

188 571 3.36-3.37(m,2H), 3.47(m,lH), 3.78-3.80(m,lH), 4.07-4.12(m,2H), 4.32-4.37(m,lH),

4.59(d,2H), 4.66(d,lH), 6.57-6.64(m,lH), 6.91(d,lH), 7.18(s,lH), 7.38-7.46(m,3H), 7.61- 7.68(m,2H), 7.76(d,lH), 7.83(d,lH), 8.22(d,lH), 8.98(t,lH), 11.05(s,lH).

189 562 3.36(m,2H), 3.51(bs,lH), 3.80(bs,lH), 4.14-4.17(m,2H), 4.35-4.39(m,lH), 4.59(d,2H),

4.69(d,lH), 6.72-6.80(m,lH), 6.98(d,lH), 7.18(s,lH), 7.39(d,lH), 7.44-7.47(dd,lH), 7.59(d,lH), 7.75-7.82(m,3H), 7.98(t,lH), 8.22(d,lH), 8.96(s,lH), 10.88(s,lH).

190 571 3.36(bs,2H), 3.49(m,lH), 3.78-3.81(m,lH), 4.06-4.11 (m,2H), 4.32-4.37(m,lH), 4.58- 4.68(m,3H), 6.50-6.57(m,lH), 6.89(d,lH), 7.18(s,lH), 7.39(d,lH), 7.44-7.49(m,2H), 7.54- 7.58(m,lH), 7.76(d,lH), 7.82-7.84(m,2H), 8.22 (d,lH), 8.98(t,lH), 11.0(s,lH).

191 555 3.43-3.49(m,3H), 3.79-3.82(m,lH), 4.08-4.10(m,2H), 4.34-4.37(m,lH), 4.59(d,2H),

4.68(d,lH), 6.46-6.53(m,lH), 6.88(d,lH), 7.18(s,lH), 7.39-7.50(m, 4H), 7.69-7.77(m, 2H), 7.84(s,lH), 8.22(d,lH), 8.94(s,lH), 10.63(s,lH).

192 553 2.90 - 2.97(m,2H) 3.13(br t,2H) 3.44(dd.2H) 3.67(s,2H) 4.69(d,2H) 6.04(br t,lH)

6.34(dt,lH) 6.59(d,lH) 6.93(dd,lH) 7.18(dt,lH) 7.29 - 7.34(m, 4 H) 7.34 - 7.36(m,lH) 7.51(d,lH) 7.70(d,lH) 8.21(d,lH).

193 576 2.81(t,2H), 2.98(s,2H), 3.36(d,2H), 3.61(s,2H), 4.61(d,2H), 6.39-6.47(m,lH), 6.62(d,lH),

7.32-7.34(dd,lH), 7.38(d,2H), 7.50(d,2H), 7.62-7.69(m,3H), 8.67(t,lH).

194 583 2.46(s, 3H), 3.32(bs,2H), 3.44-3.48(m,lH), 3.76-3.79(m,lH), 4.05-4.12(m,2H), 4.31- 4.35(m,lH), 4.56(d,2H), 4.64(d,lH), 6.50-6.55(m,lH), 6.90(d,lH), 7.44-7.49(m,3H), 7.54- 7.58(m,3H), 7.79(s,lH), 7.87(s,lH), 8.39(d,lH), 8.92(t,lH), 10.92(s,lH).

195 599 3.31(bs,2H), 3.39(m,lH), 3.77-3.80(m,lH), 3.87(s, 3H), 4.06-4.12(m,2H), 4.32- 4.34(m,lH), 4.57-4.65(m,3H), 6.46-6.54(m,lH), 6.90(d,lH), 7.44-7.49(m, 4H), 7.57- 7.59(m,3H), 7.86(s,lH), 8.40(d,lH), 8.90(t,lH), 10.68(bs,lH).

196 603 3.55(bs,2H), 3.46-3.47(m,lH), 3.77(bs,lH), 4.07-4.12(m,2H), 4.31-4.34(m,lH),

4.57(d,2H), 4.66(d,lH), 6.47-6.55(m,lH), 6.90(d,lH), 7.44-7.49(m,3H), 7.55-7.58(m,3H), 8.02(s,lH), 8.07(s,lH), 8.39(d,lH), 9.01(t,lH), 10.98(s,lH).

197 587 3.34(bs,2H), 3.48(s,lH), 3.80(m.lH), 4.06-4.12(m,2H), 4.31-4.36(m,lH), 4.56(d,2H),

4.65(d,lH), 6.47-6.54(m,lH), 6.91(d,lH), 7.44-7.49(m,3H), 7.56(m,3H), 7.79(d,lH), 7.99(d,lH), 8.39(d,lH), 8.94(t,lH), 10.92(s,lH).

198 650 3.36(bs,2H), 3.48(bs,lH), 3.78-3.81(m,lH), 4.06-4.12(m,2H), 4.31-4.34(m,lH), 4.57(d,2H), 4.67(d,lH), 6.48-6.53(m,lH), 6.90(d,lH), 7.44-7.49(m,3H), 7.55-7.58(m,3H), 8.07(s,lH), 8.14(s,lH), 8.39(d,lH ), 9.00(bs,lH ), 10.82(bs,lH).

199 573

200 573 3.30 (bs, 2H), 3.47 (bs, 1H), 3.79 (bs, 1H), 4.12 (bs, 2H), 4.39 (bs, 1H), 4.60 (d,2H), 4.67

(d,lH), 6.56-6.64 (m,lH), 6.90 (d,lH), 7.19 (s, 1H), 7.38-7.42 (m,3H), 7.54 (d,lH), 7.61- 7.69 (m,2H), 7.97 (d,lH), 8.23 (d,lH), 8.99 (bs, 1H), 10.86 (bs, 1H),

201 563 3.31 (bs, 2H), 3.47-3.49 (m,lH), 3.80-3.83 (m,lH), 4.17 (bs, 2H), 4.40 (bs, 1H), 4.60

(d,2H), 4.69 (d,lH), 6.73-6.81 (m,lH), 6.97 (d,lH), 7.19 (s, 1H), 7.38-7.42 (m,2H), 7.52- 7.59 (m,2H), 7.78 (d,lH), 7.96-8.00 (m,2H), 8.23 (d,lH), 8.98 (bs, 1H), 10.80 (bs, 1H),

202 551 3.29 (bs, 2H), 3.45 (bs, 1H), 3.78 (bs, 1H), 4.14 (bs, 1H), 4.38 (bs, 2H), 4.59-4.68 (m,3H),

6.51-6.58 (m,lH), 6.98 (d,lH), 7.16-7.19 (m,2H), 7.31-7.41 (m,3H), 7.55 (d,lH), 7.78 (q, 1H), 7.97 (d,lH), 8.22 (d,lH), 8.98 (bs, 1H), 10.84 (bs, 1H),

203 573 3.30-3.33 (m,2H), 3.43-3.47 (m,lH), 3.78-3.81 (m,lH), 4.05-4.13 (m,2H), 4.35-4.43

(m,lH), 4.60 (d,2H), 4.68 (d,lH), 6.49-6.56 (m,lH), 6.88 (dJH), 7.19 (s, 1H), 7.38-7.58 (m, 5H), 7.84 (d,lH), 7.97 (d,lH), 8.23 (d,lH) 8.98 (t, 5 Hz, 1H), 10.66 (bs, 1H).

204 555 3.30-3.33 (m,2H), 3.43-3.47 (m,lH), 3.78-3.81 (m,lH), 4.05-4.13 (m,2H), 4.35-4.40

(m,lH), 4.60 (d,2H), 4.68 (d,lH), 6.48-6.55 (m,lH), 6.89 (dJH), 7.19 (s, 1H), 7.38-7.73 (m, 5 H), 7.68-7.73 (m,lH), 7.97 (d,lH), 8.23 (d,lH), 8.97 (t, 5 Hz, 1H), 10.81 (bs, 1H).

205 543 3.33-3.37(m,2H), 3.49(bs,lH), 3.77-3.80(m,lH), 4.09-4.12(m,2H), 4.35-4.40(dd,lH),

4.57(d,2H), 4.66(dlH), 6.58-6.66(m,lH), 6.90(d,lH), 7.28-7.30(dd,lH), 7.40-7.42(dd,lH), 7.44-7.46(dd,lH), 7.55(s,lH), 7.59(d,lH), 7.61-7.68(m,2H), 7.83(d,lH), 8.39(d,lH), 8.99(t,lH), 11.10(bs,lH)

206 560 2.84(t,2H), 3.04(bs,2H), 3.48(d2H), 3.66(s,2H), 4.54(d,2H), 6.84(d,lH), 6.99-7.06(m,lH),

7.16-7.18(dd,lH), 7.42-7.46(m,2H), 7.52(s,lH), 7.72(d,lH), 7.79(d,lH), 8.15- 8.17(dd,lH), 8.39(d,lH), 8.58(t,lH), 8.89(s,lH)

207 560 2.89(t, 2H), 3.09(t, 2H), 3.52(d,2H), 4.07(s,2H), 4.64(d, 2H), 6.03(t, 1H), 6.78(d,lH),

6.94-7.01(m,lH), 7.10-7.15(m,2H), 7.20-7.22(dd,lH), 7.31(s,lH), 7.41(d, 1H),

7.68(dd,lH), 7.85(ddlH), 8.37(d,lH), 8.80(s,lH)

208 534 3.32-3.41(m,3H), 3.79-3.82(m,lH), 4.15-4.17(m,2H), 4.36-4.41(dd,lH), 4.57(d,2H),

4.68(d,lH), 6.75-6.82(m,lH), 6.98(d,lH), 7.28-7.30(dd,lH), 7.44-7.45(dd,lH), 7.54- 7.60(m,3H), 7.78(d,lH), 7.83(d,lH), 7.98(t,lH), 8.40(d,lH), 8.97(t,lH), 11.04(bs,lH).

209 527 3.32(m,2H), 3.47-3.48(m,lH), 3.78-3.81(m,lH), 4.14-4.15(m,2H), 4.34-4.39(m,lH),

4.57(d,2H), 4.66(d,lH), 6.51-6.58(m,lH), 6.99(d,lH), 7.15-7.20(m,lH), 7.30-7.36(m,2H), 7.45(d,lH), 7.54(s,lH), 7.60(d,lH), 7.75-7.81(m,lH), 7.83(d,lH), 8.40(d,lH), 8.96(t,lH), 10.86(s,lH).

210 543 3.32-3.36(m,2H), 3.41-3.48(m,lH), 3.78-3.81(m,lH), 4.08-4.11 (m,2H), 4.35-4.40(dd,lH),

4.57(d,2H), 4.67(d,lH), 6.50-6.58(m,lH), 6.89(d,lH), 7.28-7.30(dd,lH), 7.44-7.49(m,2H), 7.54-7.61(m,3H), 7.83-7.85(m,2H), 8.40(d,lH), 8.97(t,lH), 10.93(bs,lH).

211 527 3.33-3.36(m,2H), 3.42-3.48(m,lH), 3J7-3.80(m,lH), 4.07-4.10(m,2H), 4.34-4.39(dd,lH),

4.57(d,2H), 4.65(d,lH), 6.50-6.57(m,lH), 6.89(d,lH), 7.28-7.30(dd,lH), 7.37-7.40(m,lH), 7.44-7.52(m,2H), 7.55(s,lH), 7.60(d,lH), 7.67-7.72(m,lH), 8.39(d,lH), 9.00(t,lH), 11.10(bs,lH).

212 516 2.92(t,2H), 3.10(t,2H), 3.46(d,2H), 3.68(s,2H), 4.65(d,2H), 5.91(t,lH), 6.44-6.51(m,lH),

6.64(d,lH), 7.16-7.18(dd,lH), 7.21-7.22(dd,lH), 7.24-7.32(m,2H), 7.46(d,2H), 7.60(d,2H), 7.84(d,lH), 8.37(d,lH).

213 525 2.82-2.83(m,2H), 3.02(bs,2H), 3.38(d,2H), 3.63(s,2H), 4.53(d,2H), 6.40-6.47(m,lH),

6.63(d,lH), 7.15-7.17(dd,lH), 7.37-7.45(m, 4H), 7.50(d,3H), 7.79(s,lH), 8.38(d,lH), 8.57(t,lH).

214 525 2.86(t,2H), 3.07(t,2H), 3.43(d,2H), 4.04(s,2H), 4.63(t,2H), 5.98(t,lH), 6.29-6.36(m,lH),

6.57(d,lH), 7.13-7.14(m,2H), 7.20(d,lH), 7.27-7.33(m,5H), 7.66-7.68(ddlH), 8.37(d,lH) 232 543 11.69(br s,lH), 9.06(m,lH), 8.39(d,lH), 7.81(d,lH), 7.70(d,lH), 7.60-7.68(m,2H), 7.54(s,lH), 7.36-7.48(m,2H), 7.33(m,lH), 6.93(d,lH), 6.61-6.71(m,lH), 4.63(br d,lH), 4.53-4.59(m,2H), 4.26-4.42(m,lH), 4.00-4.20(m,2H), 3.69-3.82(m,lH), 3.44-3.55(m,lH), 3.34-3.44(m,2H).

233 543 11.78(br s,lH), 9.06(m,lH), 8.39(d,lH), 7.69-7.85(m,3H), 7.44-7.56(m,3H), 7.37(br

m,lH), 7.32(d,lH), 7.01(d,lH), 6.62-6.76(m,lH), 4.62(br d,lH), 4.56(d,2H), 4.33(br m,lH), 4.06-4.24(m,2H), 3.66-3.85(m,lH), 3.32-3.53(m,3H).

234 534 11.63(br s,lH), 9.04(m,lH), 8.39(d,lH), 8.16(m,lH), 7.90-8.01(m,lH), 7.81(d,lH),

7.69(d,lH), 7.52-7.63(m,2H), 7.46(m,lH), 7.29-7.38(m,lH), 6.95(d,lH), 6.59-6.71(m,lH), 4.64(br d,lH), 4.52-4.60(m,2H), 4.20-4.45(m,lH), 4.01-4.20(m,2H), 3.71-3.83(m,lH), 3.34-3.54(m,3H).

235 534 11.82(br s,lH), 9.07(m,lH), 8.39(d,lH), 7.97(m,lH), 7.68-7.83(m,3H), 7.51-7.61(m,lH),

7.51-7.61(m,lH), 7.46(d,lH), 7.33(d,lH), 6.97-7.05(m,lH), 6.77-6.91(m,lH), 4.65(br d,lH), 4.52-4.60(m,2H), 4.30-4.43(m,lH), 4.04-4.24(m,2H), 3.71-3.84(m,lH), 3.33- 3.55(m,3H)

236 593 3.37-3.52(m,3H), 3.76-3.79(m,lH), 4.08-4.14(m,2H), 4.32-4.38(dd,lH), 4.55(d,2H),

4.65(d,lH), 6.67-6.75(m,lH), 6.95(d,lH), 7.31-4.34(dd,lH), 7.38(dlH), 7.44-7.46(m,2H), 7.52-7.55(m,2H), 7.70(d,lH), 7.80(d,lH), 8.39(d,lH), 9.01(t,lH), 11.48(bs,lH).

237 543 11.72(br s,lH), 9.04(m,lH), 8.39(d,lH), 7.86(m,lH), 7.81(d,lH), 7.70(d,lH), 7.48- 7.58(m,2H), 7.46(m,lH), 7.26-7.40(m,2H), 7.15(d,lH), 6.53-6.65(m,lH), 4.64(br d,lH), 4.51-4.59(m,2H), 4.35(br m,lH), 4.07-4.14(m,2H), 3.69-3.84(m,lH), 3.33-3.54(m,3H).

238 527 11.72(br s,lH), 9.05(m,lH), 8.39(d,lH), 7.68-7.84(m,3H), 7.54(s,lH), 7.46(m,lH), 7.26- 7.39(m,2H), 7.18(m,lH), 7.00(d,lH), 6.55-6.65(m,lH), 4.50-4.65(m,3H), 4.26- 4.50(m,lH), 4.02-4.23(m,2H), 3.66-3.85(m,lH), 3.32-3.52(m,3H).

239 543 11.69(br s,lH), 9.06(m,lH), 8.39(d,lH), 7.79-7.85(m,2H), 7.70(d,lH), 7.51-7.60(m,2H),

7.44-7.51(m,2H), 7.33(d,lH), 6.92(d,lH), 6.54-6.64(m,lH), 4.63(br d,lH), 4.56(d,2H), 4.33(br d,lH), 3.96-4.22(m,2H), 3.67-3.84(m,lH), 3.33-3.54(m,3H).

240 527 11.69(br s,lH), 9.07(m,lH), 8.39(d,lH), 7.80(d,lH), 7.64-7.73(m,2H), 7.44-7.59(m,3H),

7.25-7.44(m,2H), 6.93(s,lH), 6.52-6.67(m,lH), 4.63(br d,lH), 4.56(d,2H), 4.26- 4.51(m,lH), 4.00-4.18(m,2H), 3.66-3.84(m,lH), 3.33-3.53(m,3H).

241 516 2.91(t,2H) 3.09(t,2H) 3.45(dd,2H) 3.64(s,2H) 4.60(d,2H) 6.31(t,lH) 6.47(dt,lH)

6.64(d,lH) 7.15(dd,lH) 7.18(dd,lH) 7.30(dd,2H) 7.46(d,2H) 7.58(d,2H) 7.69(d,lH) 8.31(d,lH).

242 525 2.97(t,2H) 3.15(br t,2H) 3.47(dd,2H) 3.70(s,2H) 4.65(d,2H) 6.07(br t,lH) 6.34(dt,lH)

6.60(d,lH) 7.18 - 7.24(m,2H) 7.29 - 7.37(m, 6 H) 7J4(dd,lH) 8.38(dd,lH).

243 559 2.83(br t,2H) 3.03(br t,2H) 3.38(br d,2H) 3.64(s,2H) 4.53(d,2H) 6.54(dt,lH) 6.62(d,lH)

7.21(dd,lH) 7.42(dd,lH) 7.47 - 7.50(m,lH) 7.50(d,2H) 7.58(d,lH) 7.76(d,lH) 7.77(s,lH) 8.39(d,lH) 8.55(t,lH).

244 509 2.83(br t,2H) 3.03(br s,2H) 3.37(br d,2H) 3.63(s,2H) 4.53(d,2H) 6.36(dt,lH) 6.63(d,lH)

7.16(t,2H) 7.21(dd,lH) 7.42(dd,lH) 7.51(d,2H) 7.52 - 7.56(m,2H) 7.76(d,lH) 8.38(dd,lH) 8.55(t,lH).

245 575 2.92(t,2H) 3.11(t,2H) 3.44(dd,2H) 3.65(s,2H) 4.63(d,2H) 6.13(br t,lH) 6.33(dt,lH)

6.62(d,lH) 7.16 - 7.22(m, 4 H) 7.31(dd,lH) 7.33(d,lH) 7.40 - 7.44(m,2H) 7.72(dd,lH) 8.35(dd,lH).

246 559 2.95(t,2H) 3.14(br t,2H) 3.48(dd,2H) 3.69(s,2H) 4.66(d,2H) 5.99(br t,lH) 6.47(dt,lH)

6.68(d,lH) 7.19 - 7.24(m,2H) 7.33(dd,lH) 7.36(d,lH) 7.51(d,2H) 7.59(d,2H) 7.74(d,lH) 8.38(dd,lH).

247 550 11.59(br s,lH), 9.12(m,lH), 8.52(d,lH), 8.39(d,lH), 8.24(d,lH), 8.12(d,lH), 7.94(d,lH),

7.87(m,lH), 7.81(d,lH), 7.66(d,lH), 7.55(s,lH), 7.47(m,lH), 7.31(m,lH), 4.91(s,2H), 4.61(br s,2H), 4.56(d,2H), 3.78(br s,2H), 3.37-3.54(m,2H) . 248 492 12.26(br s,lH), 9.14(br m,lH), 8.92(d,2H), 8.39(d,lH), 8.15(d,2H), 7.81(d,lH),

7.68(d,lH), 7.55(s,lH), 7.43-7.50(m,lH), 7.15-7.38(m,3H), 4.66(br s,lH), 4.49- 4.61(m,2H), 4.41(br s,lH), 4.19-4.33(m,2H), 3.78(br s,lH), 3.56(br s,lH), 3.45(br s,2H).

249 543 3.31(bs,2H), 3.50(bs,lH), 3.79(bs,lH), 4.10-4.14(m,2H), 4.33-4.37(m,lH), 4.55(d,2H),

4.68(d,lH), 6.61-6.69(m,lH), 6.89(d,lH), 7.35(dd,lH), 7.42-7.47(m,3H), 7.53(s,2H), 7.70(s,lH), 7.80(d,lH), 8.39(d,lH), 8.95(bs,lH), 10.92(brs,lH),

250 534 3.36(bs,2H), 3.50-3.52(m,lH), 3.79-3.82(m,lH), 4.08-4.15(m,2H), 4.33-4.38(m,lH),

4.55(d,2H), 4.69(d,lH), 6J0-6.77(m,lH), 6.93(d,lH), 7.34(dd,lH), 7.45(d,lH),

7.54(s,lH), 7.69(d,lH), 7.79-7.85(m,3H), 7.95(s,lH), 8.39(d,lH), 8.98(t,lH), 11.19(bs,lH)

251 550 3.37-3.52(m,3H), 3.77-3.80(m,lH), 4.07-4.15(m,2H), 4.32-4.38(dd,lH), 4.55(d,2H),

4.66(d,lH), 6.72-6.79(m,lH), 6.93(d,lH), 7.32-4.34(dd,lH), 7.44-7.46(dd,lH), 7.54(s,lH), 7.69(d,lH), 7.80 (d,lH), 8.01-8.05(m,3H), 8.39(d,lH), 9.01(t,lH), 11.52(bs,lH).

252 589 3.35(bs,2H), 3.50(bs,lH), 3.78-3.81(m,lH), 4.06-4.12(m,2H), 4.32-4.38(m,lH),

4.55(d,2H), 4.66(d,lH), 6.61-6.69(m,lH), 6.89(d,lH), 7.33(dd,lH), 7.44-7.49(m,2H), 7.53- 7.55(m,2H), 7.65(s,lH), 7.69(d,lH), 7.80(d,lH), 8.39(d,lH), 8.97(t,lH), 11.13(bs,lH),

253 559 3.35(bs,2H), 3.50(bs,lH), 3.78-3.81(m,lH), 4.07-4.12(m,2H), 4.33-4.38(m,lH),

4.55(d,2H), 4.67(d,lH), 6.63-6.71(m,lH), 6.88(d,lH), 7.33(dd,lH), 7.45(d,lH),

7.53(s,lH), 7.59(bs,lH), 7.65(d,2H), 7.69(d,lH), 7.80(d,lH), 8.40(d,lH), 8.97(bs,lH), 11.09(bs,lH)

254 527 11.54(br s,lH), 9.04(m,lH), 8.23(d,lH), 7.81(d,lH), 7.70(d,lH), 7.57-7.68(m,2H), 7.37- 7.46(m,2H), 7.33(m,lH), 7.19(s,lH), 6.92(d,lH), 6.59-6.72(m,lH), 4.53-4.69(m,3H), 4.35(br d,lH), 4.11(br s,2H), 3.76(br s,lH), 3.47(br d,3H).

255 527 11.66(br s,lH), 9.05(m,lH), 8.22(d,lH), 7.81(d,lH), 7.67-7.78(m,2H), 7.51(m,lH), 7.30- 7.45(m,3H), 7.19(s,lH), 7.01(d,lH), 6.61-6.74(m,lH), 4.54-4.68(m,3H), 4.24-4.49(m,lH), 3.99-4.24(m,2H), 3.75(br s,lH), 3.33-3.53(m,3H).

256 527 11.63(br s,lH), 9.04(m,lH), 8.23(d,lH), 7.87(m,lH), 7.78-7.84(m,lH), 7.67-7.73(m,lH),

7.52(m,lH), 7.40(br d,lH), 7.29-7.37(m,2H), 7.11-7.22(m,2H), 6.51-6.66(m,lH), 4.54- 4.68(m,3H), 4.35(br m,lH), 4.10-4.29(m,2H), 3.73-3.82(m,lH), 3.36-3.53(m,3H).

257 511 11.69(br s,lH), 9.06(m,lH), 8.22(d,lH), 7.69-7.84(m,3H), 7.40(br d,lH), 7.26-7.37(m,2H),

7.13-7.25(m,2H), 7.00(d,lH), 6.56-6.66(m,lH), 4.55-4.67(m,3H), 4.33(br m,lH), 4.04- 4.20(m,2H), 3.75(br s,lH), 3.33-3.52(m,3H).

258 527 11.63(br s,lH), 9.06(m,lH), 8.23(d,lH), 7.81(d,2H), 7.70(d,lH), 7.55(m,lH), 7.43- 7.50(m,lH), 7.37-7.42(m,lH), 7.33(d,lH), 7.19(s,lH), 6.91(d,lH), 6.53-6.64(m,lH), 4.55- 4.68(m,3H), 4.35(br m,lH), 4.02-4.10(m,2H), 3.72-3.82(m,lH), 3.34-3.54(m,3H).

259 511 11.50(br s,lH), 9.04(m,lH), 8.23(d,lH), 7.81(d,lH), 7.62-7.75(m,2H), 7.48(m,lH), 7.36- 7.42(m,2H), 7.33(m,lH), 7.19(s,lH), 6.91(d,lH), 6.49-6.63(m,lH), 4.56-4.67(m,3H), 4.35(br m,lH), 3.98-4.17(m,2H), 3.76(br s,lH), 3.33-3.46(m,3H).

260 509 2.83(t,2H), 3.04(t,2H), 3.38(d,2H), 3.64(s,2H), 4.56(d,2H), 6.39-6.47(m,lH), 6.64(d,lH),

7.16(s,lH), 7.22(d,lH), 7.36-7.41(m,3H), 7.48-7.53(m,3H), 7.77(d,lH), 8.22(d,lH), 8.57(t,lH).

261 543 2.83(t,2H), 3.04(t,2H), 3.38(d,2H), 3.64(s,2H), 4.56(d,2H), 6.50-6.65(m,2H), 7.16(s,lH),

7.22(d,lH), 7.36-7.39(m,lH), 7.47-7.53(m,2H), 7.59(d,lH), 7.75-7.79(m,2H), 8.22(d,lH), 8.57(t,lH).

262 527 3.35-3.50(m,3H), 3.79(bs,lH), 4.09-4.13(m,2H), 4.34-4.38(m,lH), 4.59(d,2H), 4.67(d,lH),

6.62-6.69(m,lH), 6.89(d,lH), 7.19(s,lH), 7.32-7.35(dd,lH), 7.38-7.46(m,3H), 7.53(s,lH), 7.70(d,lH), 7.81(d,lH), 8.23(d,lH), 8.98(t,lH), 11.05(bs,lH).

263 518 3.41-3.50(m,3H), 3.79(bs,lH), 4.11-4.15(m,2H), 4.33-4.37(m,lH), 4.59(d,2H), 4.67(d,lH),

6.70-6.77(m,lH), 6.93(d,lH), 7.19(s,lH), 7.32-7.35(dd,lH), 7.39(d,lH), 7.69(d,lH), 7.80- 7.85(m,3H), 7.95(s,lH), 8.23(d,lH), 9.00(t,lH), 11.19(bs,lH).

264 571 3.40-3.50(m,3H), 3.78-3.81(m,lH), 4.09-4. l l(m,2H), 4.33-4.36(m,lH), 4.59(d,2H), 286 561 3.33-3.37 (m,2H), 3.5 (bs, IH), 3.79 (bs, IH), 4.09-4.13 (m,2H), 4.33-4.35 (m,lH), 4.60 (d,2H), 4.65-4.69 (m,lH), 6.54-6.62 (m,lH), 6.90 (d,lH), 7.20 (s, IH), 7.38-7.42 (m,2H), 7.62-7.68 (m,2H), 7.93 (s, IH), 8.02 (s, IH), 8.23 (d,lH), 9.02 (bs, IH), 10.92 (bs, IH).

287 594 2.84(t,2H), 3.05(bs,2H), 3.47(d,2H), 3.66(s,2H), 4.54(d,2H), 6.84(d,lH), 6.98-7.05(m,lH),

7.43(dd,lH), 7.52(s,lH), 7.72(d,lH), 7.75(s,lH), 7.96(s,lH), 8.16(dd,lH), 8.39(d,lH), 8.62(t,lH), 8.89(s,lH).

288 552 3.30-3.32 (m,2H), 3.45-3.50 (m,lH), 3.78-3.80 (m,lH), 4.10-4.18 (m,2H), 4.35-4.43

(m,lH), 4.60 (d,2H), 4.68 (d,lH), 6.72-6.80 (m,lH), 6.98 (d,lH), 7.20 (s, IH), 7.39 (d,lH), 7.58 (d,lH), 7.77 (d,lH), 7.93 (s, IH), 7.96 (t, IH), 8.02 (s, IH), 8.23 (d,lH), 9.03 (t, IH), 11.06 (bs, IH).

289 545 3.33-3.48 (m,3H), 3.78-3.80 (m,lH), 4.05-4.18 (m,2H), 4.35-4.43 (m,lH), 4.60 (d,2H),

4.69 (d,lH), 6.48-6.55 (m,lH), 6.99 (d,lH), 7.17-7.40 (m, 4H), 7.75-7.81 (m,lH), 7.95 (s, IH), 8.02 (s, IH), 8.23 (d,lH), 9.00 (t, IH), 10.75 (bs, IH).

290 561 3.35-3.38 (m,2H), 3.47 (bs, IH), 3.78 (bs, IH), 4.06-4.11 (m,2H), 4.33-4.35 (m,lH), 4.60

(d,2H), 4.64-4.68 (m,lH), 6.49-6.56 (m,lH), 6.88 (d,lH), 7.20 (s, IH), 7.39 (d,lH), 7.47 (t, IH), 7.54-7.58 (m,lH), 7.82-7.84 (dd,lH), 7.94 (s, IH), 8.02 (s, IH), 8.22 (d,lH), 9.1 (bs, IH), 11.06 (bs, IH).

291 545 3.35-3.40 (m,2H), 3.40-3.50 (m,lH), 3.78-3.80 (m,lH), 4.05-4.18 (m,2H), 4.35-4.43

(m,lH), 4.60 (d,2H), 4.69 (d,lH), 6.45-6.52 (m,lH), 6.89 (d.lH), 7.20 (s, IH), 7.38-7.52 (m,3H), 7.68-7.73 (m,lH), 7.94 (s, IH), 8.02 (s, IH), 8.23 (d,lH), 9.01 (t, IH), 10.72 (bs, IH).

292 543 2.82-2.83(m,2H), 3.04(bs,2H), 3.39(m,2H), 3.63(s,2H), 4.56(d,2H), 6.40-6.46(m,lH),

6.63(d,lH), 7.17(s,lH), 7.36-7.39(m,3H), 7.50(d,2H), 7.75(s,lH), 7.96(s,lH), 8.22(d,lH), 8.62(t,lH).

293 543 2.80(bs,2H), 3.03(bs,2H), 3.40(d,2H), 3.94(s,2H), 4.56(d,2H), 6.41-6.45(m,lH), 6.63(d,

H), 7.16(s,lH), 7.36-7.39(m, 4H), 7.50(d,2H), 7.71(dlH) 8.21(d, IH), 8.78(t,lH).

294 565 2.80-2.81(m,2H), 2.98(bs,2H), 3.36(d,2H), 3.61(s,2H), 4.62(d,2H), 6.38-6.46(m,lH),

6.62(d,lH), 7.38(d,2H), 7.49(d,2H), 7.66(s,lH), 7.74(s,lH), 7.94 ,1H), 8.72(t,lH).

295 565 2.78-2.79(m,2H), 2.97(bs,2H), 3.39(d,2H), 3.92(s,2H), 4.62(d,2H), 6.41-6.46(m,lH),

6.63(d,lH ), 7.37-7.39(m,3H), 7.50(d,2H), 7.66-7.69(m,2H), 8.88(t,lH),

296 550

297 561 3.35(bs,2H), 3.41-3.49(m,lH), 3.80(bs,lH), 4.12(bs,2H), 4.35(bs,lH), 4.57(d,2H),

4.64(d,lH), 6.53-6.61(m,lH), 6.90(d,lH), 7.40-7.45(m,2H), 7.55(s,lH), 7.62-7.69(m,3H), 7.96(d,lH), 8.40(d,lH), 8.95(bs,lH), 10.72(bs,lH).

298 552 3.37-3.40(m,2H), 3.45-3.50(m,lH), 3.77-3.80(m,lH), 4.11-4.16(m,2H), 4.31-4.36(m,lH),

4.55-4.64(m,3H), 6.73-6.83(m,lH), 6.99(d,lH), 7.46(d,lH), 7.55-7.58(m,2H), 7.68(d,lH), 7.76(d,lH), 7.95-7.99(m,2H), 8.39(d,lH), 9.02(t,lH), 11.52(s,lH).

299 545 3.35(m,2H), 3.5(m,lH), 3J9(m,lH), 4.13-4.15(m,2H), 4.32-4.34(m,2H), 4.56-4.64(m,3H),

6.50-6.56(m,lH), 6.98(d,lH), 7.13-7.21(m,lH), 7.31-7.36(m,lH), 7.44-7.45(dd,lH), 7.55(s,lH), 7.70(d,lH), 7.75-7.81(m,lH), 7.96(d,lH), 8.39(d,lH), 8.95(m,lH),

10.83(s,lH).

300 545 : 3.33-3.39(m,2H), 3.48(bs,lH), 3.80(bs,lH), 4.10(bs,2H), 4.36(bs,lH), 4.57(d,2H),

4.63(d,lH), 6.45-6.53(m,lH), 6.88(d,lH), 7.38(d,lH), 7.44-7.52(m,2H), 7.55(s,lH), 7.67- 7.72(m,2H), 7.96(d,lH), 8.40(d,lH), 8.96(bs,lH), 10.78(bs,lH).

301 563 3.31-3.34(m,2H), 3.41-3.51(m,lH), 3.78-3.81(m,lH), 4.08-4.11 (m,2H), 4.31-4.36(dd,lH ),

4.57(d,2H), 4.63(d,lH), 6.54-6.62(m,lH), 6.85(d,lH), 7.44-7.46(m,lH), 7.55-7.60(m,3H), 7.68(d,lH), 7.96(d,lH), 8.40(d,lH ), 8.98(t,lH ), 11.03(bs,lH).

302 545 3.35-3.50(m,3H), 3.78(bs,lH), 4.10-4.12(m,2H), 4.31-4.37(dd,lH), 4.56-4.65(m,3H), 6.64- 6.67(m,lH), 6.90(d,lH), 7.21-7.26(m,lH), 7.31-7.34(m,2H), 7.44-7.46(dd,lH), 7.55(s,lH), 7.68(d,lH), 7.96(d,lH), 8.40(d,lH), 8.98(t,lH), 11.12(bs,lH), 303 534 2.87(t,2H), 3.08(t,2H), 3.47(d,2H), 4.05(s,2H), 4.63(d,2H), 5.92(t,lH), 6.45-6.51(m,lH), 6.64(d,lH), 7.02(t,lH), 7.19-7.21(dd,lH), 7.30(s,lH), 7.46(d,2H), 7.60(d,2H), 7.66- 7.69(dd,lH), 8.38(d,lH).

304 543 2.82(t,2H), 3.03(s,2H), 3.37(d,2H), 3.61(s,2H), 4.53(d,2H), 6.39-6.46(m,lH), 6.63(d,3H),

7.38(d,2H), 7.42(d,lH), 7.51(d, 4H), 7.89(d,lH), 8.38(d,2H), 8.57(t,lH).

305 543 2.87(t,2H), 3.06(t,2H), 3.43(d,2H), 4.04(s,2H), 4.63(d,2H), 5.91(t,lH), 6.27-6.35(m,lH),

6.57(d,lH), 7.01(t,lH), 7.20(dd,lH), 7.27-7.33(m,5H), 7.67-7.71(dd,lH), 8.37(d,lH).

306 527 2.82(t,2H), 3.03(s,2H), 3.36(d,2H), 3.61(s,2H), 4.53(d,2H), 6.31-6.39(m,lH), 6.62(d,lH),

7.16(t,2H), 7.42(d,lH), 7.50-7.54(m, 4H), 7.89(d,lH), 8.38(d,lH), 8.57(t,lH).

307 527 2.87(t,2H), 3.06(t,2H), 3.43(d,2H), 4.03(s,2H), 4.62(d,2H), 5.96(t,lH), 6.21-6.28(m,lH),

6.58(d,lH), 6.98-7.03(m,3H), 7.20(dd,lH), 7.30(s,lH), 7.34-7.37(m,2H), 7.67- 7.70(dd,lH), 8.37(d,lH).

308 577 2.88(t,2H), 3.08(t,2H), 3.47(d,2H), 4.05(s,2H), 4.63(d,2H), 5.90(t,lH), 6.40-6.48(m,lH),

6.66(d,lH), 7.02(t,lH), 7.21(d,lH), 7.30(s,lH), 7.48(d,2H), 7.57(d,2H), 7.67-7.70(dd,lH), 8.38(d,lH).

309 545 3.33(s,2H), 3.48(bs,lH), 3.79(bs,lH), 4.10-4.11(m,2H), 4.33-4.35(m,lH), 4.60(d,2H),

4.65(s,lH), 6.55-6.62(m,lH), 6.90(d,lH), 7.19(s,lH), 7.38-7.42(m,2H), 7.61-7.69(m,3H), 7.96(d,lH), 8.22(d,lH), 8.98(s,lH), 10.94(s,lH).

310 543 3.30-3.35(m,2H), 3.43-3.47(m,lH), 3.78(bs,lH), 4.12-4.16(m,2H), 4.30-4.35(dd,lH ),

4.59-4.63(m,3H), 6.57-6.65(m,lH), 6.99(d,lH), 7.20(s,lH), 7.36-7.40(m,2H), 7.51- 7.54(dd,lH ), 7.70(d,lH ), 7.75(t,lH ), 7.96(d,lH ), 8.23(d,lH ), 8.99(t,lH), l l.l l(bs,lH).

311 536 3.35(bs, 3H), 3.81(m,lH), 4.15-4.16(m,2H), 4.36(m,lH), 4.59-4.67(m,3H), 6.73- 6.78(m,lH), 6.98(d,lH), 7.19(s,lH), 7.39(d,lH), 7.58(d,lH), 7.68(d,lH), 7.78(d,lH), 7.96- 8.00(m,2H), 8.23(d,lH), 8.98(d,lH), 10.80(bs,lH).

312 529 3.46-3.49(m,2H), 3.78(bs,lH), 4.13-4.15(m,2H), 4.32-4.33(m,lH), 4.59-4.63(m,3H), 6.49- 6.57(m,lH), 6.98(d,lH), 7.16-7.19(m,2H), 7.31-7.39(m,2H), 7.70(d,lH), 7.77-7.80(m,lH), 7.97(d,lH), 8.23(d,lH), 10.91(bs,lH),

313 545 3.35-3.42(3, 3H), 3.78-3.80(m,lH), 4.06-4.10(m,2H), 4.31-4.35(m,lH), 4.59-4.64(m,3H),

6.53-6.56(m,lH), 6.88(d,lH), 7.20(s,lH), 7.39(d,lH), 7.47(t,lH), 7.54-7.57(m,lH), 7.69(d.lH), 7.81-7.84(dd,lH), 7.96(d,lH), 8.22(d,lH). 9.00(t,lH), 11.06(s,lH).

314 529 3.51(bs, 3H), 3.79(bs,lH), 4.10(bs,2H), 4.35(bs,lH), 4.59-4.64(m,3H), 6.48-6.54(m,lH),

6.88(d,lH), 7.20(s,lH), 7.39(bs,2H), 7.45-7.52(q,lH), 7.67-7.72(m,2H), 7.97(d,lH), 8.23(d.lH), 8.98(s,lH), 10.88(bs,lH)

315 547 3.36-3.49(m,3H), 3.77-3.80(m,lH), 4.07-4.10(m,2H), 4.31-4.36(dd,lH), 4.59-4.64(m,3H),

6.55-6.63(m,lH), 6.85(d,lH), 7.20(s,lH), 7.39(d,lH ), 7.55-7.59(m,2H), 7.68(d,lH ), 7.96(d,lH), 8.23(d,lH ), 9.00(t,lH), 11.04(bs,lH).

316 529 3.45-3.49(m,3H), 3.78(bs,lH), 4.12(bs,2H), 4.35(bs, 1H), 4.59-4.64(m,3H), 6.60- 6.67(m,lH), 6.90(d,lH), 7.18-7.26(m,2H), 7.31-7.33(m,2H), 7.39(d,lH), 7.68(d,lH ), 7.96(d,lH), 8.23(d,lH ), 8.99(t,lH), 11.14(bs,lH),

317 527 2.82(t,2H), 3.04(bs,2H), 3.37(d,2H), 3.61(s,2H), 4.56(d,2H), 6.41-6.47(m,lH), 6.63(d,lH),

7.17(s,lH), 7.36-7.39(m,3H), 7.49-7.52(m,3H), 7.90(d,lH), 8.21(d,lH), 8.58(t,lH).

318 527 2.87(t,2H), 3.07(t,2H), 3.43(d,2H), 4.04(s,2H), 4.67(d,2H), 5.92(t,lH), 6.27-6.35(m,lH),

6.57(d,lH), 6.90(s,lH), 7.02(t,lH), 7.16(d,lH), 7.29-7.33(m, 4H), 7.68-7.71(dd,lH), 8.21(d,lH).

319 511 3.35-3.40(m,2H), 3.45-3.49(m,lH), 3.77-3.80(m,lH), 4.05-4.12(m,2H), 4.30-4.36(m ,1H),

4.59-4.63(m,3H), 6.40-6.48(m,lH), 6.90(d,lH), 7.20(s,lH), 7.25(t,2H), 7.39(d,lH), 7.57- 7.61(m,2H), 7.70(d,lH), 7.96(d,lH), 8.22(d,lH), 8.99(t,lH), 11.03(bs,lH)

320 568 3.30-3.32(m,lH), 3.50(bs,2H), 3.82(bs,lH), 4.20-4.24(m,2H), 4.41(bs,lH), 4.49(d,lH ),

4.59(d2H ), 6.64-6.71(m,lH), 6.99(d,lH), 7.46(d,lH), 7.56(s,lH), 7.61(d,lH), 7.72(d,2H), 7.88(d,2H), 7.99(d,lH), 8.40(d,lH), 9.25(bs,lH), 10.90(bs,lH). 321 568 3.34-3.45(m,2H), 3.49(bs,lH), 3.80(bs,lH), 4.19(bs,2H), 4.59-4.60(m,3H), 4.76(d,lH), 6.70-6.78(m ,1H), 6.99-7.03(d,lH), 7.46-7.50(m,2H), 7.57(s,lH), 7.75(d,2H), 7.88(d,2H), 7.95(s,lH), 8.40(d,lH), 9.24(t,lH), 11.21(bs,lH)

322 577 3.32-3.34(m,lH), 3.46-3.50(m,2H), 3.82(bs,lH), 4.12-4.20(m,2H), 4.34-4.37(m,lH),

4.48(d,lH ), 4.59(d,2H ), 6.44-6.51(m,lH), 6.90(d,lH), 7.46-7.49(m,3H), 7.55- 7.57(m,3H), 7.62(d,lH), 7.99(d,lH), 8.41(d,lH), 9.23(bs,lH), 10.68(bs,lH).

323 577 3.35-3.37(m,2H), 3.41-3.47(m,lH), 3.80(bs,lH), 4.15(bs,2H), 4.56-4.60(m,3H),

4.76(d,lH), 6.51-6.58(m ,lH), 6.92(d,lH), 7.46-7.48(m, 4H), 7.57-7.59(m,3H), 7.95(s,lH), 8.41(d,lH), 9.22(t,lH), 10.94(bs,lH),

324 561 3.37(bs,2H), 3.48-3.50(m,lH), 3.81-3.84(m,lH), 4.13-4.18(m,2H), 4.37(bs,lH), 4.48(d,lH

), 4.59(d,2H ), 6.37-6.45(m,lH), 6.90(d,lH), 7.25(t,2H), 7.46(d,lH), 7.56-7.63(m, 4H), 7.97-8.00(dd,lH), 8.41(d,lH), 9.25(d,lH), 10.82(bs,lH)

325 561 3.35-3.41(m,lH), 3.47(bs,2H), 3.79(bs,lH), 4.13(bs,2H), 4.53-4.60(m,3H), 4.74(d,lH),

6.44-6.51(m ,1H), 6.93(d,lH), 7.25(t,2H), 7.46-7.50(m,2H), 7.57-7.62(m,3H), 7.95(s,lH), 8.40(d,lH), 9.22(t,lH), 11.07(bs,lH).

326 561 3.28-3.30(m,lH), 3.44-3.51(m,2H), 3.82-3.85(m,lH), 4.15-4.20(m,2H), 4.35-4.38(m,lH),

4.50(d,lH ), 4.63(d,2H ), 6.45-6.51(m,lH), 6.90(d,lH), 7.21(s,lH), 7.40(d,lH),

7.48(d,2H), 8.54(d,2H), 8.62(d,lH), 8.00(d,lH), 8.24(d,lH), 9.24(bs,lH), 10.57(bs,lH).

327 561 3.32(bs,2H), 3.47(bs,lH), 3.77(bs,lH), 4.12(bs,2H), 4.55-4.61(m,3H), 4.74(d,lH), 6.48- 6.55(m ,1H), 6.89(d,lH), 7.19(s,lH), 7.38(d,lH), 7.44(d,3H), 7.55(d,2H), 7.93(s,lH), 8.20(d,lH), 9.22(bs,lH), 10.89(bs,lH).

328 593 3.39(bs,2H), 3.50(bs,lH), 3.82(m,lH), 4.10(bs,2H), 4.39(bs,lH), 4.59(d,2H), 4J2(d,lH),

6.49-6.54(m ,1H), 6.91(d,lH), 7.44-7.49(m,3H), 7.56-7.59(m,3H), 8.02(s,lH), 8.18(s,lH), 8.41(d,lH), 9.12(bs,lH), 10.75(bs,lH).

329 589 3.50-3.53(m,2H), 3.82(bs,2H), 3.90(s, 3H), 4.11-4.14(m,2H), 4.35-4.40(m,lH),

4.57(d,2H), 4.67(d,lH), 6.49-6.56(m,lH), 6.92(d,lH), 7.41(s,lH), 7.44-7.49(m,3H), 7.55- 7.59(m,3H), 8.00(s,lH), 8.39(d,lH ), 8.96(t,lH), 10.78(bs,lH).

330 573 2.49(s, 3H), 3.42-3.50(m,3H), 3.82-3.85(m,lH), 4.11-4.14(m,2H), 4.30-4.39(m,lH),

4.59(bs,2H), 4.69(d,lH), 6.47-6.55(m ,1H), 6.91(d,lH), 7.45-7.49(m,3H), 7.56-7.62(m, 4H), 8.06(s,lH), 8.40(d,lH), 9.01(bs,lH), 10.64(bs,lH).

331 550 3.36-3.52(m,3H), 3.74-3.84(m,lH), 4.05-4.18(m,2H), 4.39-4.44(m,lH), 4.60(d,2H),

4.70(d,lH), 6.61-6.69(m,lH), 6.92(d,lH), 7.40(dd,lH), 7.47(dd,lH), 7.57(s,lH), 7.61- 7.66(m,3H), 7.77(d,lH), 8.25-8.27(m,lH), 8.38-8.41(m,lH), 9.15(t,lH), 11.60(bs,lH).

332 559 3.04(br t,2H) 3.22(br s,2H) 3.54(br d,2H) 3.83(s,2H) 4.67(d,2H) 6.20(br s,lH) 6.38(dt,lH)

6.64(d,lH) 7.25(dd,lH) 7.29 - 7.38(m, 5 H) 7.52(dd,lH) 7.66(s,lH) 7.93(d,lH)

8.40(dd,lH).

333 593 8.71(s,lH), 8.40(d,lH), 7.94(d,lH), 7.84(s,lH), 7.78(d,lH), 7.48-7.60(m, 4H), 7.44(d,lH),

6.52-6.68(m,2H), 4.56(d,2H), 3.73(s,2H), 3.41(br d,2H), 3.06(br s,2H), 2.86(br s,2H).

334 543 8.71(m,lH), 8.40(d,lH), 7.94(d,lH), 7.81-7.88(m,lH), 7.48-7.58(m, 4H), 7.44(m,lH),

7.12-7.23(m,2H), 6.64(d,lH), 6.38(m,lH), 4.56(d,2H), 3.72(s,2H), 3.39(br d,2H), 3.06(br s,2H), 2.85(br m,2H)

335 609 8.72(m,lH), 8.40(d,lH), 7.94(d,lH), 7.85(s,lH), 7.61(d,2H), 7.49-7.56(m,2H), 7.44(d,lH),

7.33(d,2H), 6.69(d,lH), 6.47(m,lH), 4.56(d,2H), 3.72(s,2H), 3.41(br d,2H), 3.07(br s,2H), 2.86(br m,2H).

336 593 3.37(bs,2H), 3.49(bs,lH), 3.79-3.82(m,lH), 4.12(bs,2H), 4.39-4.41(m,lH), 4.58(d,2H),

4.68(d,lH), 6.57-6.65(m,lH), 6.91(d,lH), 7.26(d,lH), 7.40-7.45(m,2H), 7.54(s,lH), 7.61- 7.68(m,3H), 7.75(s,lH), 8.39(d,lH), 8.96-8.97(m,lH), 10.89(bs,lH).

337 611 3.35-3.53(m,3H), 3.75-3.82(m,lH), 4.14-4.23(m,2H), 4.37-4.42(m,lH), 4.58(d,2H),

4.67(m,lH), 6.62-6.69(m,lH), 7.17(d,lH), 7.22-7.27(m,lH), 7.45(dd,lH), 7.50- 7.56(m,2H), 7.67-7.70(m,2H), 7.74-7.77(m,lH), 7.83(d,lH), 8.38-8.41(m,lH), 9.03(t,lH), 11.65(bs,lH).

338 637, 3.35-3.52(m,3H), 3.74-3.81(m,lH), 4.10-4.20(m,2H), 4.35-4.41(m,lH), 4.57(d,2H),

639 4.65(d,lH), 6.64-6.72(m,lH), 7.00(d,lH), 7.22-7.27(m,lH), 7.44-7.52(m,2H), 7.55(s,lH), 7.62-7.71(m,3H), 7.73-7.77(m,lH), 8.38-8.41(m,lH), 9.03(t,lH), 11.56(bs,lH).

339 611 3.37-3.50(m,3H), 3.74-3.81(m,lH), 4.15-4.23(m,2H), 4.33-4.38(m,lH), 4.57-4.66(m,3H),

6.70-6.79(m,lH), 6.88(d,lH), 7.22-7.26(m,lH), 7.45-7.52(m,3H), 7.54-7.56(m,lH), 7.69(d,lH), 7.74-7.77(m,lH), 8.38-8.42(m,lH), 9.02(t,lH), 11.67(bs,lH).

340 593 3.34-3.52(m,3H), 3.75-3.81(m,lH), 4.12-4.20(m,2H), 4.35-4.41(m,lH), 4.57(d,2H),

4.65(d,lH), 6.63-6.71(m,lH), 7.01(d,lH), 7.22-7.27(m,lH), 7.37(dd,lH), 7.46(dd,lH), 7.50-7.56(m,2H), 7.67-7.79(m,3H), 8.38-8.41(m,lH), 9.03(t,lH), 11.57(bs,lH).

341 595 3.34-3.51(m,3H), 3.73-3.81(m,lH), 4.11-4.24(m,2H), 4.33-4.38(m,lH), 4.55-4.66(m,3H),

6.65-6.73(m,lH), 6.87(d,lH), 7.21-7.36(m,3H), 7.46(dd,lH), 7.54-7.56(m,lH), 7.67- 7.77(m,2H), 8.38-8.41(m,lH), 9.02(t,lH), 11.64(bs,lH).

342 610 3.35-3.40(m,2H), 3.46-3.50(m,lH), 3.78-3.81(m,lH), 4.18-4.23(m,2H), 4.37-4.43(dd,lH),

4.58(d,2H), 4.67(d,lH), 7.11-7.13(m,2H), 7.24(d,lH), 7.46(d,lH), 7.54(s,lH), 7.69(d,lH), 7.75-7.79(m,2H), 8.26-8.28(dd,lH), 8.39(d,lH), 8.98-9.01(m,2H), 11.38(bs,lH)

343 610 2.91(t,2H), 3.09-3.10(m,2H), 3.51(d,2H), 3.89(s,2H), 4.65(d,2H), 5.96(t,lH), 6J8(d,lH),

6.93-6.98(m,lH), 7.05-7.07(dd,lH), 7.19-7.22(m,2H), 7.32(s,lH), 7.40(d,lH), 7.72(d,lH), 7.84-7.87(dd,lH), 8.37(d,lH), 8.81(s,lH).

344 584 3.36-3.55(m,3H), 3.74-3.82(m,lH), 4.07-4.17(m,2H), 4.37-4.42(m,lH), 4.57(d,2H),

4.66(d,lH), 6.62-6.70(m,lH), 6.95(d,lH), 7.23-7.28(m,lH), 7.46(dd,lH), 7.55- 7.61(m,2H), 7.67(d,lH), 7.74-7.77(m,lH), 7.93-7.97(m,lH), 8.15-8.19(m,lH), 8.38- 8.42(m,lH), 9.06(t,lH), 11.65(bs,lH).

345 584 3.38(bs,2H), 3.48-3.50(m,lH), 3.80-3.82(m,lH), 4.16(bs,2H), 4.38-4.42(m,lH),

4.58(d,2H), 4.70(d,lH), 6J6-6.84(m,lH), 6.99(d,lH), 7.26(d,lH), 7.45(d,lH), 7.54- 7.59(m,2H), 7.67(d,lH), 7.75-7.79(m,2H), 7.98(t,lH), 8.39(d,lH), 8.98(t,lH),

11.16(bs,lH).

346 593 3.37-3.52(m,3H), 3.75-3.81(m,lH), 4.14-4.22(m,2H), 4.37-4.42(m,lH), 4.58(d,2H),

4.67(m,lH), 6.55-6.63(m,lH), 7.16(d,lH), 7.22-7.27(m,lH), 7.29-7.36(m,lH),

7.46(dd,lH), 7.51-7.56(m,2H), 7.68(d,lH), 7.74-7.77(m,lH), 7.84-7.88(m,lH), 8.38- 8.41(m,lH), 9.04(t,lH), 11.64(bs,lH).

347 577 3.35(bs,2H), 3.80(bs,2H), 4.16-4.17(m,2H), 4.41(hump, 1H), 4.58(d,2H), 4.70(d,lH), 6.50- 6.57(m,lH), 6.99(d,lH), 7.15-7.21(m,lH), 7.26(d,lH), 7.31-7.37(m,lH), 7.45(d,lH), 7.54(s,lH), 7.69(d,lH), 7.75-7.82(m,2H), 8.39(d,lH), 9.82-8.94(m,lH), 10.61(s,lH).

348 593 3.37-3.38(m,2H), 3.50(bs,lH), 3.78-3.81(m,lH), 4.08-4.1 l(m,2H), 4.37-4.42(dd,lH),

4.58(d,2H), 4.68(d,lH), 6.52-6.60(m,lH), 6.89(d,lH), 7.24-7.26(dd,lH), 7.44-7.49(m,2H), 7.54-7.58(m,2H), 7.68(d,lH), 7.75(s,lH), 7.82-7.84(dd,lH), 8.39(d,lH), 8.98(t,lH), 11.10(bs,lH).

349 577 3.35(bs,2H), 3.38-3.49(m,lH), 3.79-3.82(m,lH), 4.11(bs,2H), 4.37-4.41(m,lH),

4.58(d,2H), 4.68(d,lH), 6.49-6.57(m,lH), 6.89(d,lH), 7.26(d,lH), 7.37-7.40(m,lH), 7.44- 7.52(m,2H) 7.54(s,lH), 7.67-7.75(m,3H), 8.39(d,lH), 8.97(t,lH), 10.90(bs,lH).

350 595 3.37-3.52(m,3H), 3.74-3.82(m,lH), 4.07-4.16(m,2H), 4.37-4.42(m,lH), 4.57(d,2H),

4.67(d,lH), 6.62-6.68(m,lH), 6.88(d,lH), 7.23-7.28(m,lH), 7.45(dd,lH), 7.53- 7.61(m,3H), 7.67(d,lH), 7.74-7.77(m,lH), 8.38-8.42(m,lH), 9.05(t,lH), 11.56(bs,lH)

351 566 2.92(t,2H), 3.10(t,2H), 3.47(d,2H), 3.70(s,2H), 4.65(d,2H), 5.88(brs,lH), 6.46-6.51(m,lH),

6.64(d,lH), 7.09(d,lH), 7.21-7.22(m,lH), 7.32-7.35(m,2H), 7.47(d,2H), 7.60(d,2H), 7.77(s,lH), 8.38(d,lH)

352 566 2.90(t,2H), 3.09-3.1 l(m,2H), 3.45(d,2H), 3.86(s,2H), 4.65(d2H), 5.95(t,lH), 6.45- 6.50(m,lH), 6.64(d,lH), 7.05-7.07(dd,lH), 7.19-7.22(m,2H), 7.32(s,lH), 7.46(d,2H), 7.60(d,2H), 7.70(d,lH), 8.37(d,lH). 7.75(m, 4H), 8.23(d,lH), 8.99(bs,lH), 10.99(bs,lH).

370 593 3.35-3.49(m,3H), 3.80(bs,lH), 4.19(bs,2H), 4.38-4.42(m,lH), 4.61(d,2H), 4.71(d,lH),

6.56-6.64(m,lH), 7.14-7.19(m,2H), 7.26(d,lH), 7.40(d, 1H ), 7.51-7.53(dd,lH ), 7.66- 7.70(m,2H), 7.76(s,lH), 7.85(d,lH), 8.23(d,lH ), 8.97(bs,lH ), 10.90(bs,lH),

371 575 3.35-3.48(m,3H), 3.78(bs,lH), 4.16(bs,2H), 4.38-4.40(m,lH), 4.61(d,2H), 4.67(d,lH),

6.60-6.67(m,lH), 7.00(d,lH), 7.19(s,lH), 7.25(d,lH), 7.36-7.40(m,2H), 7.50-7.54(dd,lH ), 7.68(d,lH), 7.73-7.77(m,2H), 8.23(d,lH ), 8.99(bs,lH ), 11.46(bs,lH).

372 566 3.27(bs,lH), 3.51(bs,2H), 3.80(bs,lH), 4.17(bs,2H), 4.40-4.42(m,lH), 4.62(d,2H),

4.71(d,lH), 6.75-6.83(m,lH), 6.98(d,lH), 7.19(s,lH), 7.26(d,lH), 7.40(d,lH), 7.58(d,lH), 7.67(d,lH), 7.75-7.79(m,2H), 7.98(t,lH), 8.23(d,lH), 8.99(s,lH), 11.03(bs,lH).

373 577 3.39-3.41(m,3H), 3.78-3.79(m,lH), 4.15-4.18(m,2H), 4.40-4.42(m, 1H), 4.60-4.69(m,3H),

6.57-6.60(m,lH), 7.13-7.19(m,2H), 7.23-7.26(dd,lH), 7.30-7.35(m,lH), 7.40(d,lH ), 7.51- 7.54(dd,lH ), 7.68(d,lH ), 7.75(s,lH), 7.85-7.88(m,lH), 8.23(d,lH ), 9.02(t,lH),

11.40(bs,lH),

374 559 3.30(bs,lH), 3.42-3.48(m,2H), 3.79(bs,lH), 4.15(bs,2H), 4.38-4.41(m,lH), 4.62(d,2H),

4.68(d,lH), 6.51-6.59(m,lH), 6.99(d,lH), 7.16-7.19(m,2H), 7.25(d,lH), 7.31-7.39(m,2H), 7.68(d,lH), 7.75-7.81(m,2H), 8.23(d,lH), 8.97(bs,lH), 10.84(bs,lH).

375 575 3.31(bs,lH), 3.45-3.49(m,2H), 3.79(bs,lH), 4.10(bs,2H), 4.39-4.41(m,lH), 4.62(d,2H),

4.69(d,lH), 6.51-6.59(m,lH), 6.89(dlH), 7.19(s,lH), 7.26(d,lH), 7.39(d,lH), 7.47(t,lH), 7.54-7.58(m,lH), 7.68(d,lH), 7.75(s,lH), 7.83-7.85(dd,lH), 8.23(d,lH), 897-8.98(m,lH), 10.95(bs,lH).

376 561 3.28(bs,lH), 3.49(bs,2H), 3.79(bs,lH), 4.11(bs,2H), 4.39-4.41(m,lH), 4.62(d,2H),

4.69(d,lH), 6.49-6.56(m,lH), 6.89(d,lH), 7.19-7.27(m,2H), 7.35-7.40(m,2H), 7.45- 7.56(m,lH), 7.66-7.75(m,3H), 8.23(d,lH), 8.98(s,lH), 10.88(bs,lH).

377 579 3.47-3.52(m,3H), 3.78(m,lH), 4.11(bs,2H), 4.40-4.42(m,lH), 4.60-4.70(m,3H), 6.59- 6.65(m,lH), 6.86(d,lH), 7.19(s,lH), 7.26(d,lH), 7.40(d,lH), 7.56-7.60(m,2H), 7.67(d,lH), 7.75(s,lH), 8.23 (d,lH), 9.00(t,lH), l l.l l(bs,lH).

378 561 3.34-3.50(m,3H), 3.81(bs,lH), 4.14(bs,2H), 4.40-4.42(m, 1H), 4.61(d,2H), 4.71(d,lH),

6.63-6.68(m,lH), 6.90(dlH), 7.19(s,lH), 7.21-7.27(m,2H), 7.33(d,2H ), 7.40(d,lH ), 7.67(d,lH), 7.75(s,lH), 8.23(d,lH ), 8.97(bs,lH), 10.82(bs,lH).

379 559 2.92(t,2H), 3.10(t,2H), 3.42-3.44(m,2H), 3.69(s,2H), 4.69(d,2H), 5.89(t,lH), 6.28- 6.35(m,lH), 6.57(d,lH), 6.91(s,lH), 7.09(dd,lH), 7.17(d,lH), 7.26-7.35(m,5H),

7.79(s,lH), 8.21(d,lH).

379a 559 2.90(t,2H), 3.10-3.1 l(m,2H), 3.42(d,2H), 3.87(s,2H), 4.68(d,2H), 5.96(brs,lH), 6.29- 6.34(m,lH), 6.57(d,lH), 6.92(s,lH), 7.05-7.07(m,lH), 7.16-7.24(m,2H), 7.25-7.50(m, 4H), 7.72(d,lH), 8.21(d,lH).

380 577 3.37-3.50(m,3H), 3.78(bs,lH), 4.12(bs,2H), 4.39-4.42(m,lH), 4.61(d,2H), 4.68(d,lH),

6.65-6.72(m,lH), 6.90(d,lH), 7.19(s,lH), 7.25(d,lH), 7.39-7.46(m,3H), 7.52(s,lH), 7.67(d,lH), 7.75(s,lH), 8.23(d,lH), 9.00(bs,lH), 11.26(bs,lH),

381 568 3.44-3.50 (m,3H), 3.81 (bs, 1H), 4.15 (bs, 2H), 4.35-4.40 (m,lH), 4.60 (d,2H), 4.71 (d, J =

14.76 Hz, 1H), 6.70-6.77 (m,lH), 6.93 (d,lH), 7.19 (s, 1H), 7.31-7.40 (m,2H), 7.63 (s, 1H), 7.83-7.90 (m,3H), 7.96 (s, 1H), 8.23 (d,lH), 9.02 (s, 1H), 10.95 (bs, 1H).

382 581 2.90-2.94(m,2H), 3.06(t,2H), 3.40-3.42(dd,2H), 3.67(s,2H), 4.73(d,2H), 5.81(t,lH), 6.28- 6.35(m,lH), 6.57(d,lH), 7.08(dd,lH), 7.26-7.33(m,5H), 7.48(s,lH), 7.77(s,lH).

383 581 2.87(t,2H), 3.07(t,2H), 3.40(d,2H), 3.83(s,2H), 4.73(d,2H), 5.92(t,lH), 6.26-6.34(m,lH),

6.56(d,lH), 7.03-7.05(dd,lH), 7.21(t,lH), 7.26-7.32(m, 4H), 7.48(s,lH), 7.69(d,lH).

384 593 3.36(bs,2H), 3.46-3.51(m,lH), 3.80-3.83(m,lH), 4.09-4.12(m,2H), 4.35-4.41(dd,lH),

4.57(d,2H), 4.68(d,lH), 6.57-6.64(m,lH), 6.91(d,lH), 7.32(d,lH), 7.40-7.42(dd,lH), 7.46(d,lH), 7.54(s,lH), 7.62-7.69(m,3H), 7.88(d,lH), 8.40(d,lH), 9.00(t,lH),

10.91(bs,lH). 385 610 2.85(bs,2H), 3.06(bs,2H), 3.48-3.49(m,2H), 3.68(s,2H), 4.54(d, H), 6.85(d,lH), 7.00- 7.07(m,lH), 7.19(d,lH), 7.43(d,lH), 7.46(s,lH), 7.51(s,lH), 7.73(d,lH), 7.83(d,lH), 8.16(d,lH), 8.39(d,lH), 8.62(bs,lH), 8.90(s,lH).

386 584 3.31(m,lH), 3.38-3.50(m,2H), 3.80-3.82(m,lH), 4.14-4.16(m,2H), 4.36-4.41(dd,lH),

4.57(d,2H), 4.69(d,lH), 6.76-6.83(m,lH), 6.99(d,lH), 7.32(d,lH), 7.44-7.46(ddlH), 7.54(s,lH), 7.57-7.59(dd,lH), 7.64(s,lH), 7.76-7.79(dd,lH), 7.88(d,lH ), 7.98(t,lH ), 8.40(d,lH ), 9.01(t,lH ), 11.17(bs,lH),

387 577 3.35(bs,2H), 3.52(bs,lH), 3.79-3.82(m,lH), 4.13-4.15(m,2H), 4.34-4.40(m,lH),

4.56(d,2H), 4.68(d,lH), 6.51-6.58(m,lH), 6.73-6.77(m,lH), 6.99(d,lH), 7.13-7.21(m,lH), 7.30-7.36(m,lH), 7.45(d,lH), 7.54(s,lH), 7.67(s,lH), 7J5-7.81(m,lH), 7.88(d,lH), 8.39(d,lH), 8.98(t,lH), 10.84(s,lH)

388 593 3.34-3.39(m,2H), 3.50(bs,lH), 3.81(bs,lH), 4.08-4.1 l(m,2H), 4.38-4.40(m,lH),

4.56(d,2H), 4.70(d,lH), 6.50-6.54(m,lH), 6.89(d,lH), 7.32(d,lH), 7.44-7.49(m,2H), 7.54- 7.57(m,2H), 7.65(s,lH), 7.84-7.89(m,2H), 8.39(d,lH), 8.98(bs,lH), 10.59(bs,lH).

389 577 3.30-3.39(m,2H), 3.49(bs,lH), 3.81-3.83(m,lH), 4.10-4.1 l(m,2H), 4.38-4.40(m,lH),

4.56(d,2H), 4.70(d,lH), 6.46-6.54(m,lH), 6.89(d,lH), 7.32(d,lH), 7.40(bs,lH), 7.44- 7.50(m,2H), 7.54(s,lH), 7.65(s,lH), 7.69-7.74(m,lH), 7.88(d,lH), 8.40(d,lH), 8.96- 8.98(m,lH), 10.57(bs,lH).

390 566 2.92(t,2H), 3.12(bs,2H), 3.46(d,2H), 3.68(s,2H), 4.65(d,2H), 5.91(t,lH), 6.44-6.52(m,lH),

6.65(d,lH), 7.12(d,lH), 7.22-7.24(m,2H), 7.31(s,lH), 7.47(d,2H), 7.60(d,2H), 7.81(d,lH), 8.37(d,lH).

391 575 2.80-2.8 l(m, 2H), 3.01(bs,2H), 3.35(d,2H), 3.62(s,2H), 4.50(d,2H), 6.38-6.45(m,lH),

6.61(d,lH), 7.15(d,lH), 7.36(d,2H), 7.35-7.42(m, 2H), 7.47-7.49(m, 3H), 7.80(d,lH), 8.35(d,lH), 8.59(t,lH).

392 609 2.83(t,2H), 3.04(m,2H), 3.39(d,2H), 3.65(s,2H), 4.53(d,2H), 6.51-6.55(m,2H), 7.18(d,lH),

7.42-7.44(m,2H), 7.47-7.51(m,2H), 7.58(d,lH), 7.78(d,lH), 7.83(d,lH), 8.39(d,lH), 8.62(t,lH).

393 559 2.83(t,2H), 3.03(bs,2H), 3.33-3.38(m,2H), 3.65(s,2H), 4.53(d,2H), 6.33-6.40(m,lH),

6.63(d,lH), 7.14-7.19(m,3H), 7.42-7.45(m,2H), 7.51-7.54(m,3H), 7.83(d,lH), 8.39(d,lH), 8.61(t,lH).

394 571 2.82(t,2H), 3.03(bs,2H), 3.33-3.36(m,2H), 3.64(s,2H), 3.75(s, 3H), 4.53(d,2H), 6.21- 6.28(m,lH), 6.56(d,lH), 6.90(d,2H), 7.18(d,lH), 7.39-7.44(m, 4H), 7.51(s,lH),

7.83(d,lH), 8.39(d,lH), 8.61(t,lH).

395 625 2.83(t,2H), 3.04(bs,2H), 3.40(d,2H), 3.65(s,2H), 4.53(d,2H), 6.42-6.49(m,lH), 6.67(d,lH),

7.17-7.19(dd,lH), 7.32(d,2H), 7.42-7.44(m,2H), 7.51(s,lH), 7.61(d,2H), 7.83(d,lH), 8.39(d,lH), 8.62(t,lH).

396 609 2.83-2.86(m,2H), 3.05(bs,2H), 3.43(d,2H), 3.67(s,2H), 4.53(d,2H), 6.58-6.64(m,lH),

6.75(d,lH), 7.19(d,lH), 7.42-7.45(m,2H), 7.51(s,lH), 7.67-7.72(m, 4H), 7.83(d,lH), 8.39(d,lH), 8.62(t,lH).

397 593 3.34-3.40 (m,2H), 3.50 (bs, 1H), 3.80-3.83 (mJH), 4.09-4.14 (m,2H), 4.36-4.41 (m,lH),

4.56 (d,2H), 4.69 (d,lH), 6.62-6.70 (m,lH), 6.89 (d,lH), 7.32 (d,lH), 7.42-7.47 (m,3H), 7.54 (s, 2H), 7.65 (bs, 1H), 7.88 (d,lH), 8.39 (d,lH), 9.01 (t, lH), 10.93 (bs, 1H).

398 584 3.38 (bs, 2H), 3.50 (bs, 1H), 3.81 (bs, 1H), 4.15 (bs, 2H), 4.40.4.42 (m,lH), 4.56 (d,2H),

4.70 (d,lH), 6.69-6.76 (m,lH), 6.93 (d,lH), 7.32 (d,lH), 7.45 (d,lH), 7.54 (s, 1H), 7.64 (bs, 1H), 7.84-7.89 (m,3H), 7.96 (bs. 1H), 8.39 (d,lH), 9.00 (bs, 1H), 10.87 (bs, 1H).

399 600 3.32-3.40 (m,2H), 3.49-3.51 (m,lH), 3.81-3.83 (m,lH), 4.11-4.14 (m,2H), 4.36-4.42

(dd,lH), 4.57 (d,2H), 4.70 (d,lH), 6.71-6.78 (m,lH), 6.92 (d,lH), 7.30-7.33 (m,lH), 7.45- 7.46 (dd,lH), 7.54 (s, 1H), 7.63 (s, 1H), 7.88 (d,lH), 8.03 (d,2H), 8.07 (d,lH), 8.40 (d,lH), 9.01 (t, 1H), 11.04 (bs, 1H).

400 637 3.40 (bs, 2H), 3.50 (bs, 1H), 3.80-3.83 (m,lH), 4.11-4.12 (m,2H), 4.36-4.41 (m,lH), 4.56 (d,2H), 4.70 (d,lH), 6.61-6.69 (m,lH), 6.88 (d,lH), 7.32 (d,lH), 7.45 (d,lH), 7.49 (d,lH), 7.54-7.56 (m,2H), 7.65-7.66 (m,2H), 7.88 (d,lH), 8.39 (d,lH), 9.01 (bs, 1H), 10.89 (bs, 1H).

401 575 3.29(s,lH), 3.49(hump, 2H), 3.81-3.84(m,lH), 4.13(bs,2H), 4.40-4.42(m,lH), 4.60(d,2H),

4.71(d,lH), 6.55-6.62(m,lH), 6.91(d,lH), 7.19(s,lH), 7.32(d,lH), 7.39-7.43(m,2H), 7.62- 7.69(m,3H), 7.89(d,lH ), 8.23(d,lH ), 9.00(bs,lH ), 10.60(bs,lH).

402 566 3.40-3.50(m,2H), 3.72-3.84(m,2H), 4.17(bs,2H), 4.35-4.41(m,lH), 4.60(d,2H), 4.71(d,lH),

6.75-6.80(m,lH), 6.98(d,lH), 7.19(s,lH), 7.32(d,lH), 7.40(d,lH ), 7.59(d,lH ), 7.64(s,lH), 7.79(d,lH ), 7.89(d,lH ), 7.98(t,lH ), 8.23(d,lH ), 9.00(bs,lH ), 10J7(bs,lH).

403 559 3.49(bs,lH), 3.83(bs,2H), 4.16(bs, 3H), 4.40(bs,lH), 4.60(d,2H), 4.70(dlH), 6.48- 6.53(m,lH), 6.99(d,lH), 7.18(bs,2H), 7.33(d,2H), 7.39(d,lH ), 7.67(s,lH), 7.77- 7.81(m,lH), 7.89(d,lH), 8.23(d,lH ), 8.98(bs,lH ), 10.39(bs,lH).

404 577 3.49(bs,2H), 3.84(bs,2H), 4.12(bs,2H), 4.40(bs,lH), 4.60(d,2H), 4.71(d,lH), 6.50- 6.54(m,lH), 6.89(d,lH), 7.19(s,lH), 7.32(d,lH), 7.40(d,lH), 7.47(t,lH), 7.57(bs,lH), 7.65(s,lH), 7.85(d,lH ), 7.89(d,lH), 8.23(d,lH ), 8.99(bs,lH ), 10.52(bs,lH),

405 559 3.42-3.48(m,2H), 3.84(bs,2H), 4.11(bs,2H), 4.35-4.40(m,lH), 4.60(d,2H), 4.70(d,lH),

6.46-6.54(m,lH), 6.89(d,lH), 7.19(s,lH), 7.32(d,lH), 7.40(d,2H ), 7.46-7.52(q,lH), 7.65(s,lH), 7.71(t,lH ), 7.89(d,lH ), 8.23(d,lH ), 9.00(bs,lH ), 10.57(bs,lH).

406 579 3.34-3.49(m,3H), 3.78-3.80(m,lH), 4.08-4.11(m,2H), 4.35-4.40(dd,lH ), 4.60(d,2H),

4.68(d,lH), 6.57-6.65(m,lH), 6.86(d,lH ), 7.19(s,lH), 7.30-7.33(dd,lH), 7.40(d,lH), 7.56- 7.63(m,3H), 7.89(d,lH ), 8.23(d,lH ), 9.04(t,lH), 11.21(bs,lH).

407 561 3.29(bs,lH), 3.45-3.49(m,2H), 3.79(bs,lH), 4.12(bs,2H), 4.38-4.41(m,lH), 4.59(d,2H),

4.69(d,lH), 6.61-6.69(m,lH), 6.90(d,lH), 7.19-7.26(m,2H), 7.30-7.34(m,3H), 7.40(d,lH), 7.64(s,lH), 7.89(d,lH), 8.19(s,lH), 8.23 (d,lH), 9.02(bs,lH), 10.99(bs,lH).

408 559 2.81-2.84(m, 2H), 3.03-3.06(m,2H), 3.39(d,2H), 3.65(s,2H), 4.57(d,2H), 6.41- 6.49(m,lH), 6.63(d,lH), 7.16-7.19(m,2H), 7.36-7.40(m,3H), 7.45(s,lH), 7.51(d,2H), 7.83(d,lH), 8.22(d,lH), 8.63(t,lH).

409 581 2.81(t,2H), 2.98-3.01(m,2H), 3.38(d,2H), 3.63(s,2H), 4.63(d,2H), 6.40-6.47(m,lH),

6.63(d,lH), 7.19(d,lH), 7.39(d,2H), 7.43(s,lH), 7.51(d,2H), 7.66(s,lH), 7.80(d,lH), 8.71(t,lH),

410 577 3.37(bs,2H), 3.46(bs,lH), 3.81-3.84(m,lH), 4.06-4.15(m,2H), 4.40-4.46(m,lH),

4.59(d,2H), 4.77(d,lH), 6.57-6.64(m,lH), 6.91(d,lH), 7.42(d,lH), 7.47(d,lH), 7.55(s,lH), 7.62-7.70(m,3H), 7.98(d,lH), 8.04(s,lH), 8.41(d,lH), 9.09(t,lH), 10.83(bs,lH).

411 566 3.30(bs,lH), 3.53-3.57(m,2H), 3.82(bs,lH), 4.15-4.19(m,2H), 4.42-4.45(m,lH),

4.58(d,2H), 4.79(d,lH), 6.74-6.82(m,lH), 7.99(d,lH), 7.46(d,lH), 7.55-7.66(m,3H), 7.78(d,lH), 7.97-8.03(m,3H ), 8.40(d,lH ), 9.09(bs,lH ), 10.99(bs,lH),

412 559 3.28(bs,lH), 3.50-3.51(m,2H), 3.82-3.85(m,lH), 4.14-4.18(m,2H), 4.40-4.45(m,lH),

4.59(d,2H), 4.78(d,lH), 6.50-6.57(m,lH), 7.00(d,lH), 7.19(t,lH), 7.34(m,lH), 7.46(d,2H), 7.55(s,lH), 7.64(d,lH ), 7.77-7.83(m,lH ), 7.98(d,lH ), 8.06(s,lH), 8.40(d,lH),

10.64(bs,lH).

413 577 3.37(bs,2H), 3.47-3.55(bs,lH), 3.80-3.83(m,lH), 4.06-4.13(m,2H), 4.40-4.45(dd,lH),

4.58(d,2H), 4.77(d,lH), 6.51-6.59(m,lH), 6.90(d,lH), 7.45-7.49(m,2H), 7.55-7.59(m,2H), 7.63-7.65(m,lH), 7.83-7.85(dd,lH), 7.98(d,lH), 8.05(s,lH), 8.41(d,lH), 9.11(t,lH), 10.97(bs,lH).

414 561 3.38(bs,2H), 3.46-3.53(m,lH), 3.80-3.83(m,lH), 4.09-4.14(m,2H), 4.39-4.45(dd,lH),

4.58(d,2H), 4.75(d,lH), 6.50-6.57(m,lH), 6.90(d,lH), 7.37-7.41(m,lH), 7.45-7.52(m,2H), 7.55(s,lH), 7.63-7.65(m,lH), 7.68-7.73(m,lH), 7.98(d,lH), 8.05(s,lH), 8.41(d,lH), 9.12(t,lH), 11.07(bs,lH).

415 561 2.90(t,2H) 3.10(t,2H) 3.42(dd,2H) 3.67(s,2H) 4.66(d,2H) 6.33(dt,lH) 6.47(t,lH)

6.55(d,lH) 6.90(s,lH) 7.10(dd,lH) 7.13 - 7.19(m,2H) 7.33(t,lH) 7.44(dd,lH) 7.61(d,lH) 7.87(d,lH) 8.13(d,lH).

416 552 3.35(bs,2H), 3.53(bs,lH), 3.82(bs,lH), 4.15-4.19(m,2H), 4.44(bs,lH), 4.61(d,2H),

4.78(d,lH), 6.76-6.83(m,lH), 6.99(d,lH), 7.20(s,lH), 7.40(d,lH), 7.57-7.65(m,2H), 7.78(d,lH), 7.96-8.03(m,3H), 8.23(d,lH), 9.13(s,lH), 11.16(bs,lH).

417 545 3.38 - 3.45(m,2H) 3.47(br s,lH) 3.80(br dd,lH) 4.05 - 4.24(m,2H) 4.41(br dd,lH)

4.62(d,2H) 4.73(br d,lH) 6.60(dt,lH) 7.00(d,lH) 7.18(dd,lH) 7.21(s,lH) 7.33(ddd,lH) 7.38 - 7.44(m,lH) 7.63(dd,lH) 7.78(td,lH) 7.98(d,lH) 8.06(s,lH) 8.23(d,lH) 9.16(t,lH) 11.43(br s,lH).

418 561 3.38(bs,2H), 3.51(bs,lH), 3.81(bs,lH), 4.08-4.13(bs,2H), 4.40-4.43(m,lH), 4.62(d,2H),

4.78(d,lH), 6.51-6.58(m,lH), 6.89(d,lH), 7.20(s,lH), 7.40-7.41(m,lH), 7.47(t,lH), 7.55- 7.59(m,lH), 7.64(d,lH), 7.84(dd,lH), 7.98(d,lH), 8.04(s,lH), 8.23(d,lH), 9.12(bs,lH), 10.94(bs,lH).

419 545 3.38(bs,2H), 3.51(bs,lH), 3.82(bs,lH), 4.09-4.13(bs,2H), 4.40-4.44(m,lH), 4.62(d,2H),

4.78(d,lH), 6.50-6.56(m,lH), 6.92(d,lH), 7.20(s,lH), 7.40-7.41(m,2H), 7.45-7.52(m,lH), 7.64(d,lH), 7.71(m,lH), 7.98(d,lH), 8.04(s,lH), 8.23(d,lH), 9.10(bs,lH), 10.88(bs,lH).

420 534 2.92(br t,2H) 3.08 - 3.15(m,2H) 3.47(dd,2H) 3.70(s,2H) 4.67(d,2H) 6.44 - 6.49(m,lH) 6.50

- 6.57(m,lH) 6.65(d,lH) 6.91(s,lH) 7.16(dt,lH) 7.42 - 7.50(m,3H) 7.54 - 7.59(m,2H) 7.62(s,lH) 7.88(d,lH) 8.14(d,lH)

421 543 2.90(t,2H) 3.04 - 3.13(m,2H) 3.38 - 3.46(m,2H) 3.64(s,2H) 4.66(d,2H) 6.31(dt,lH) 6.50 - 6.62(m,2H) 6.90(s,lH) 7.15(dt,lH) 7.27 - 7.35(m, 4 H) 7.44(dd,lH) 7.60(s,lH) 7.87(d,lH) 8.14(d,lH).

422 577 2.91(t,2H) 3.07 - 3.14(m,2H) 3.43(dd,2H) 3.68(s,2H) 4.67(d,2H) 6.34(dt,lH) 6.46(br t,lH)

6.54(d,lH) 6.91(d,lH) 7.16(dt,lH) 7.22(dd,lH) 7.38(d,lH) 7.45(dd,lH) 7.47(d,lH) 7.62(s,lH) 7.88(d,lH) 8.15(d,lH).

423 577 3.34-3.39 (m,2H), 3.50 (bs, IH), 3.83 (bs, IH), 4.12 (bs, 2H), 4.39-4.44 (m,lH), 4.60

(d,2H), 4.74 (d,lH), 6.51-6.58 (m,lH), 6.89 (d,lH), 7.45-7.49 (m,2H), 7.55-7.57 (m,3H), 7.80 (d,lH), 7.85 (d,lH), 8.09 (s, IH), 8.41 (d,lH), 9.09 (bs, IH), 10.81 (bs, IH).

424 561 3.38-3.45 (m,3H), 3.81 (bs, IH), 4.14-4.17 (bs, 2H), 4.39-4.45 (dd,lH), 4.60 (d,2H), 4.72

(d,lH), 6.53-6.60 (m,lH), 7.00 (d,lH), 7.16-7.21 (m,lH), 7.31-7.37 (m,lH), 7.47 (d,lH), 7.55-7.57 (m,2H), 7.76-7.82 (m,2H), 8.09 (s, IH), 8.41 (d,lH), 9.11 (t, IH), 11.04 (bs, IH).

425 593 2.87 (t, 2H), 3.10 (t, 2H), 3.44 (d,2H), 3.72 (s, 2H), 4.57 (d,2H), 6.57-6.66 (m,lH), 6.76

(d,lH), 7.42-7.47 (m,2H) 7.54 (s, IH), 7.63-7.73 (m, 5 H), 8.07 (s, IH), 8.38-8.41 (m,lH), 8.70 (t, IH).

426 552 3.37-3.41 (m,2H), 3.48-3.52 (m,lH), 3.83 (bs, IH), 4.17 (bs, 2H), 4.45 (bs, IH), 4.63

(d,2H), 4.75 (d,lH), 6.76-6.84 (m,lH), 6.99 (d,lH), 7.22 (s, IH), 7.41 (d,lH), 7.55-7.60 (m,2H), 7.77-7.80 (m,2H), 7.98 (t, IH), 8.10 (s, IH), 8.24 (d,lH), 9.12 (bs, IH), 11.12 (bs, IH).

427 545 3.35-3.46 (m,3H), 3.81 (bs, IH), 4.16 (bs, 2H), 4.42-4.43 (m,lH), 4.63 (d,2H), 4.73 (d,lH),

6.52-6.60 (m,lH), 6.99 (d,lH), 7.17-7.22 (m,2H), 7.31-7.37 (m,lH), 7.41 (d,lH), 7.55 (d,lH), 7.76-7.81 (m,2H), 8.10 (s, IH), 8.24 (d,lH), 9.11 (bs, IH), 10.96 (bs, IH).

428 561 .36-3.40 (m,2H), 3.47-3.51 (m,lH), 3.81 (bs, IH), 4.12 (bs, 2H), 4.41-4.46 (dd,lH), 4.63

(d,2H), 4.73 (d,lH), 6.52-6.60 (m,lH), 6.89 (d,lH), 7.22 (s, IH), 7.41 (d,lH), 7.47 (t,lH), 7.55-7.58 (m,2H), 7.80 (d,lH), 7.83-7.86 (dd,lH), 8.10 (s, IH), 8.24 (d,lH), 9.12 (t, IH), 11.02 (bs, IH).

429 545 3.35-3.40 (m,2H), 3.45-3.50 (m,lH), 3.82 (bs, IH), 4.12 (bs, 2H), 4.44 (bs, IH), 4.63

(d,2H), 4.73 (d,lH), 6.50-6.57 (m,lH), 6.89 (d,lH), 7.22 (s, IH), 7.40-7.41 (m,2H), 7.45- 7.52 (m,lH), 7.56 (d,lH), 7.69-7.74 (m,lH), 7.80 (d,lH), 8.10 (s, IH), 8.24 (d,lH), 9.11 (bs, IH), 10.92 (bs, IH).

430 496 8.33-8.46(m,2H), 7.79(d,2H), 7.67(m,3H), 7.50(s,lH), 7.42(d,lH), 7.19(s,lH),

7.02(m,lH), 6.61-6.78(m,2H), 4.52(d,2H), 3.55-3.66(m,2H), 3.42(d,2H), 3.02(br s,2H), 2.75-2.90(m,2H), 2.32-2.41(m,3H).

431 505 8.35-8.44(m,2H), 7.66(d,lH), 7.51(d,3H), 7.37-7.49(m,3H), 7.19(s,lH), 7.02(d,lH), 6.59- 6.68(m,lH), 6.45(m,lH), 4.52(d,2H), 3.61(s,2H), 3.38(br d,2H), 2.98-3.05(m,2H), 2.77- 2.89(m,2H), 2.32-2.40(m,3H).

432 539 8.36-8.43(m,2H), 7.78(d,lH), 7.66(d,lH), 7.55-7.61(m,lH), 7.46-7.53(m,2H), 7.42(m,lH),

7.19(s,lH), 7.02(m,lH), 6.52-6.67(m,2H), 4.52(d,2H), 3.61(s,2H), 3.38(d,2H), 3.02(br s,2H), 2.75-2.88(m,2H), 2.31-2.41(m,3H).

433 489 8.33-8.45(m,2H), 7.66(d,lH), 7.47-7.57(m,3H), 7.32-7.47(m,lH), 7.12-7.24(m,3H), 6.96- 7.12(m,lH), 6.63(d,lH), 6.29-6.44(m,lH), 4.52(d,2H), 3.61(s,2H), 3.37(br d,2H), 3.01(br s,2H), 2.72-2.92(m,2H), 2.30-2.42(m,3H).

434 555 8.35-8.44(m,2H), 7.58-7.68(m,3H), 7.50(s,lH), 7.42(m,lH), 7.32(d,2H), 7.20(s,lH),

7.02(m,lH), 6.68(d,lH), 6.46(m,lH), 4.52(d,2H), 3.61(s,2H), 3.39(br d,2H), 3.02(br s,2H), 2.74-2.91 (m,2H), 2.32-2.41 (m,3H).

435 539 8.36-8.44(m,2H), 7.63-7.75(m,5H), 7.50(s,lH), 7.42(m,lH), 7.20(s,lH), 7.02(m,lH), 6.70- 6.78(m,lH), 6.56-6.67(m,lH), 4.52(d,2H), 3.63(s,2H), 3.42(br d,2H), 3.03(br s,2H), 2.77- 2.91(m,2H), 2.32-2.41(m,3H).

436 541 3.39(bs,lH), 3.47-3.49(m,2H), 3.83(bs,lH), 4.21-4.27(m,2H), 4.61(d,2H), 4.87- 4.89(m,lH), 5.16(d,lH), 6.62-6.68(m,lH), 6.90-6.99(m,lH), 7.47-7.49(m,3H), 7.52- 7.54(m,lH), 7.56(s,lH), 7.61(d,2H), 7.64-7.66(m,lH), 7.78-7.83(m,lH), 7.98(d,lH), 8.03- 8.10(m,2H ), 8.42(d,lH), 9.17(bs,lH), 10.68(bs,lH).

437 589 3.28-3.37(m,2H), 3.42-3.47(m,lH), 3.77-3.81(m,lH), 4.08-4.11 (m,2H), 4.34-4.40(m,lH),

4.57(d,2H), 4.65(d,lH), 6.59-6.66(m,lH), 6.90(d,lH), 7.39-7.45(m,3H), 7.53-7.55(m,2H), 7.61-7.67(m,2H), 7.96(d,lH), 8.39(d,lH), 9.00(t,lH), 11.23(bs,lH).

438 580 3.28-3.46(m,3H), 3.79-3.82(m,lH), 4.15-4.20(m,2H), 4.36-4.41(dd,lH), 4.57(d,2H),

4.68(d,lH), 6.75-6.82(m,lH), 6.98(d,lH), 7.39-7.45(m,2H), 7.53-7.59(m,3H), 7.78(d,lH), 7.96-7.99(m,2H), 8.40(d,lH), 8.98(t,lH), 11.07(bs,lH).

439 588 3.36-3.39(m,2H), 3.45-3.51(m,lH), 3.77-3.80(m,lH), 4.07-4.10(m,2H), 4.34-4.40(dd,lH),

4.57(d,2H), 4.66(d,lH ), 6.51-6.59(m,lH), 6.89(d,lH), 7.39-7.41(dd,lH), 7.44-7.49(m,2H), 7.53-7.57(m,3H), 7.82-7.84(dd,lH), 7.97(d,lH), 8.40(d,lH), 8.98(t,lH), 11.12(bs,lH).

440 571 3.28-3.32(m,2H), 3.40-3.52(m,lH), 3.77-3.80(m,lH), 4.07-4.11 (m,2H), 4.34-4.39(dd,lH),

4.57(d,2H), 4.66(d,lH), 6.50-6.57(m,lH), 6.89(d,lH), 7.36-7.41(m,2H), 7.44-7.55(m, 4H), 7.67-7.72(m,lH), 7.97(d,lH), 8.40(d,lH), 8.99(t,lH), 11.08(bs,lH).

441 560 3.31-3.36(m,2H), 3.47-3.49(m,lH), 3.77-3.82(m,lH), 4.12-4.16(m,2H), 4.35-4.41(dd,lH),

4.56(d,2H), 4.67(d,lH), 6.67-6.74(m,lH), 6.99(d,lH), 7.39-7.41(dd,lH), 7.44-7.45(m,lH), 7.53-7.55(m,2H), 7.74(d,2H), 7.89(d,2H), 7.97(d,lH), 8.40(d,lH), 8.99(t,lH),

10.99(bs,lH),

442 560 3.32-3.38(m,2H), 3.40-3.44(m,lH), 3.76-3.79(m,lH), 4.18-4.23(m,2H), 4.56(d,2H), 4.63- 4.68(dd,lH), 4.93(d,lH), 6.70-6.78(m,lH), 7.01(d,lH), 7.24(t,lH), 7.41-7.45(m,2H), 7.53(s,lH), 7.74(d,2H), 7.8(d,lH), 7.88(d,2H), 8.39(d,lH), 9.14(t,lH), 11.24(bs,lH),

443 569 3.32-3.36(m,lH), 3.42-3.47(m,lH), 3.76-3.79(m,2H), 4.08-4.11 (m,2H), 4.34-4.39(m,lH),

4.56(d,2H), 4.65(d,lH), 6.52-6.57(m,lH), 6.91(d,lH), 7.38-7.41(dd,lH), 7.44-7.45(m, 1), 7.47(d,2H), 7.54-7.58(m, 4H), 7.96(d,lH), 8.40(d,lH), 8.99(t,lH), 11.06(bs,lH)

444 569 3.32-3.35(m,2H), 3.40-3.42(m,lH), 3.74-3.76(m,lH), 4.12-4.16(m,2H), 4.56(d,2H),

4.64(dd,lH), 6.53-6.59(m,lH), 6.93(d,lH), 7.22(t,lH), 7.41-7.48(m, 4H), 7.56(t, 3H), 7.80(d,2H), 8.40(d,lH), 9.14(t,lH), 11.16(bs,lH),

445 555 2.50(s, 3H), 3.31-3.50(m,3H), 3.74-3.81(m,lH), 4.05-4.15(m,2H), 4.33-4.38(m,lH),

4.55(d,2H), 4.64(d,lH), 6.62-6.69(m,lH), 6.92(d,lH), 7.26(dd,lH), 7.38-7.47(m,2H), 7.50- 7.55(m,2H), 7.61-7.68(m,2H), 7.75(d,lH), 8.38-8.41(m,lH), 8.91(t,lH), 11.43(bs,lH).

446 539 2.49(s, 3H), 3.31-3.50(m,3H), 3.72-3.80(m,lH), 4.03-4.15(m,2H), 4.32-4.38(m,lH),

4.55(d,2H), 4.65(d,lH), 6.53-6.61(m,lH), 6.90(d,lH), 7.25(dd,lH), 7.38-7.54(m, 5 H), 7.65-7.75(m,2H), 8.38-8.42(m,lH), 8.91(t,lH), 11.39(bs,lH).

447 537 2.49(s, 3H), 3.31-3.49(m,3H), 3.73-3.80(m,lH), 4.04-4.14(m,2H), 4.32-4.37(m,lH),

4.55(d,2H), 4.63(d,lH), 6.54-6.62(m,lH), 6.92(d,lH), 7.25(dd,lH), 7.44-7.58(m, 7 H), 7.75(d,lH), 8.38-8.41(m,lH), 8.91(t,lH), 11.43(bs,lH).

448 521 2.49(s, 3H), 3.34-3.51(m,3H), 3.75-3.80(m,lH), 4.03-4.13(m,2H), 4.32-4.38(m,lH),

4.55(d,2H), 4.64(d,lH), 6.46-6.54(m,lH), 6.92(d,lH), 7.22-7.28(m,3H), 7.45(dd,lH), 7.51- 7.53(m,2H), 7.57-7.63(m,2H), 7.75(d,lH), 8.38-8.41(m,lH), 8.90(t,lH), 11.33(bs,lH).

449 532 3.39(br s under H20 peak, 2H) 3.53(br s,lH) 3.79(br s,lH) 4.11(br dd,2H) 4.35(br d,2H)

4.41(br s,lH) 4.68(br d,lH) 6.22(dd,lH) 6.28(d,lH) 6.58 - 6.71(m,lH) 6.91(d,lH) 7.36(d,lH) 7.54(dd,lH) 7.68(d,lH) 7.70(dd,lH) 7.85(d,lH) 7.90(d,lH) 8.19(d,lH) 9.10(t,lH) 11.53(br s,lH) 11.57(br s,lH).

450 534 3.39(br s,2H) 3.49 - 3.62(m,lH) 3.79(br s,lH) 4.03 - 4.23(m,2H) 4.35(br d,2H) 4.41(br s,lH) 4.63 - 4.76(m,lH) 6.22(dd,lH) 6.28(d,lH) 6.70(dt,lH) 6.91(d,lH) 7.36(dd,lH) 7.53 - 7.59(m,2H) 7.70(dd,lH) 7.90(dd,lH) 8.17(d,lH) 9.10(t,lH) 11.52(br s,lH) 11.58(br s,lH).

451 560 3.43 - 3.48(m,2H) 3.50 - 3.57(m,lH) 3.71 - 3.86(m,lH) 4.15(br dd,2H) 4.35(br d,2H)

4.39(br s,lH) 4.66(br d,lH) 6.23(dd,lH) 6.29(s,lH) 6.66(dt,lH) 6.99(br dJH) 7.36(d,lH) 7.50(dd,lH) 7.63(dd,lH) 7.67(br t,lH) 7.70(dd,lH) 7.90(d,lH) 8.20(d,lH) 9.10(br t,lH) 11.59(br s,2H).

452 550 3.45 - 3.48(m,lH) 3.53(br s,2H) 3.80(br s,lH) 4.00 - 4.20(m,2H) 4.35(br d,2H) 4.41(br s,lH) 4.69(br d,lH) 6.24(dd,lH) 6.29(s,lH) 6.59 - 6.71(m,lH) 6.88(br d,lH) 7.37(d,lH) 7.71(dd,lH) 7.82(d,2H) 7.90(d,lH) 8.18(s,lH) 9.11(br t,lH) 11.61(br s,2H).

453 543 3.38 - 3.40(m,lH) 3.43 - 3.58(m,2H) 3.80(br d,lH) 4.14(br dd,2H) 4.35(br d,2H) 4.42(br s,lH) 4.73(br d,lH) 6.23(dd,lH) 6.28(s,lH) 6.60(dt,lH) 6.99(d,lH) 7.18(td,lH) 7.28 - 7.35(m,lH) 7.36(d,lH) 7.62(dd,lH) 7.78(td,lH) 7.94(d,lH) 8.05(s,lH) 9.03(br t,lH) 11.50(br s,2H).

454 532 3.41(br s,2H) 3.48 - 3.56(m,lH) 3.78 - 3.87(m,lH) 4.07 - 4.25(m,2H) 4.35(br d,2H)

4.43(br dd,lH) 4.76(br d,lH) 6.23(dd,lH) 6.29(d,lH) 6.74(dt,lH) 7.01(d,lH) 7.36(d,lH) 7.63(dd,lH) 7.72 - 7.77(m,2H) 7.86 - 7.91(m,2H) 7.94(d,lH) 8.05(s,lH) 9.01(t,lH) 11.33(br s,lH) 11.53(br s,lH).

455 587 3.21(s, 3H), 3.35-3.55(m,3H), 3.78-3.84(m,lH), 4.07-4.20(m,2H), 4.42-4.47(m,lH),

4.59(d,2H), 4.76(d,lH), 6.62-6.70(m,lH), 6.94(d,lH), 7.40-7.49(m,2H), 7.54-7.58(m,lH), 7.62-7.68(m,2H), 7.84(dd,lH), 8.00(d,lH), 8.21-8.24(m,lH), 8.38-8.42(m,lH), 9.22(t,lH), 11.49(bs,lH).

456 571 3.21(s, 3H), 3.35-3.54(m,3H), 3.76-3.84(m,lH), 4.08-4.22(m,2H), 4.40-4.46(m,lH),

4.58(d,2H), 4.75(d,lH), 6.57-6.65(m,lH), 7.01(d,lH), 7.15-7.22(m,lH), 7.29-7.35(m,lH), 7.47(dd,lH), 7.54-7.58(m,lH), 7.75-7.85(m,2H), 8.00(d,lH), 8.21-8.25(m,lH), 8.38- 8.42(m,lH), 9.23(t,lH), 11.56(bs,lH).

457 569 3.21(s, 3H), 3.34-3.54(m,3H), 3.74-3.84(m,lH), 4.04-4.19(m,2H), 4.41-4.46(m,lH),

4.58(d,2H), 4.74(d,lH), 6.55-6.63(m,lH), 6.95(d,lH), 7.45-7.51(m,3H), 7.54-7.59(m,3H), 7.84(dd,lH), 8.00(d,lH), 8.21-8.24(m,lH), 8.38-8.42(m,lH), 9.24(t,lH), 11.58(bs,lH).

458 605 3.21(s, 3H), 3.35-3.56(m,3H), 3.77-3.84(m,lH), 4.06-4.18(m,2H), 4.41-4.47(m,lH),

4.58(d,2H), 4.76(d,lH), 6.64-6.71(m,lH), 6.93(d,lH), 7.47(dd,lH), 7.52-7.57(m,2H), 7.68(d,lH), 7.83-7.87(m,2H), 8.00(d,lH), 8.21-8.24(m,lH), 8.38-8.42(m,lH), 9.24(t,lH), 11.62(bs,lH)

459 553 3.21(s, 3H), 3.36-3.52(m,3H), 3.76-3.82(m,lH), 4.01-4.17(m,2H), 4.41-4.46(m,lH),

4.58(d,2H), 4.75(d,lH), 6.47-6.55(m,lH), 6.94(d,lH), 7.22-7.28(m,2H), 7.46(dd,lH), 7.53- 7.66(m,3H), 7.84(dd,lH), 8.00(d,lH), 8.21-8.25(m,lH), 8.38-8.42(m,lH), 9.23(t,lH), 11.51(bs,lH).

460 577 3.45(br t, 2H) 3.68(br s,2H) 4.11(br d,2H) 4.55(br s,2H) 4.71(s,2H) 6.50(dt,lH) 6.96(br d,lH) 7.14(s,lH) 7.36 - 7.44(m, 4 H) 7.54(d,3H) 7.72(dd,lH) 7.93 - 8.00(m,2H)

8.20(d,lH) 8.30(dd,lH) 9.06(d,lH).

461 585 2.67(q,2H) 2.91(t, 2H) 3.18(br t, 2H) 3.68(s,2H) 4.68(d,2H) 6.34(dt,lH) 6.58(d,lH)

6.98(s,lH) 7.02(t, 1H) 7.22(dt,lH) 7.28 - 7.38(m, 6 H) 7.40(dd,lH) 7.47(d,lH) 7.49 - 7.53(m,2H) 7.87(dd,lH) 8.16(d,lH).

462 585 3.37(br s,2H) 3.44(br s,2H) 3.86(br d,2H) 4.26(br s,2H) 4.67(d,2H) 6.33(dt,lH) 6.73(d,lH)

6.98(s,lH) 7.23(br d,lH) 7.30 - 7.40(m, 7 H) 7.42 - 7.49(m,2H) 7.51(dd,lH) 7.55(t,lH) 7.84(d,lH) 8.19(d,lH).

463 569 3.04(br t,2H) 3.22(br s,2H) 3.54(br d,2H) 3.83(br s,2H) 4.70(d,2H) 6.36(dt,lH) 6.41(br s,lH) 6.62(d,lH) 6.96(s,lH) 7.12(t,2H) 7.21(br d,lH) 7.33(q, 4 H) 7.44(dd,lH) 7.49(d,lH) 7.51 - 7.58(m,2H) 7.83(d,lH) 8.21(d,lH)

464 534 3.34(m,2H), 3.51(m,lH), 3.80-3.83(m,lH), 4.12(bs,2H), 4.38-4.34(m,lH), 4.60(d,2H),

4.69(d,lH), 6.49-6.56(m,lH), 6.91(d,lH), 7.38(s,lH), 7.46-7.49(m,3H), 7.56-7.62(m, 4H), 7.75-7.78(dd,lH), 8.03(s,lH), 8.35(s,lH), 8.39(d,2H), 9.02(t,lH), 10.69(s,lH).

465 550 3.34(m,2H), 3.42-3.49(m,lH), 3.80-3.83(m,lH), 4.12-4.14(m,2H), 4.37-4.43(m,lH),

4.60(d,2H), 4.69(d,lH), 6.58-6.66(m,lH), 6.91(d,lH), 7.38-7.47(m,3H), 7.56(s,lH), 7.59- 7.65(m,2H), 7.66-7.69(m,lH), 7.77(d,lH), 8.04(s,lH), 8.35-8.40(m,2H), 9.05(t,lH), 10.92(s,lH).

466 518 3.34-3.41(m,2H), 3.49-3.50(m,lH), 3.79-3.82(m,lH), 4.11(m,2H), 4.37-4.42(m,lH),

4.60(d,2H), 4.68(d,lH), 6.42-6.49(m,lH), 6.91(d,lH), 7.25(t,2H), 7.38(s,lH), 7.47(d,lH), 7.56(s,lH), 7.59-7.62(m,3H), 7.76(d,lH), 8.04(s,lH), 8.35(s,lH), 8.39(d,lH), 9.04(t,lH), 10.77(s,lH).

467 552 3.33-3.42(m,2H), 3.50-3.53(m,lH), 3.80-3.82(m,lH), 4.13-4.16(m, 2H), 4.40-4.44(m,lH),

4.58(d,2H), 4.73(d,lH), 6.57-6.65(m,lH), 6.91(d,lH), 7.33(s,lH), 7.42-7.46(m,2H), 7.54(s,lH), 7.62-7.7 l(m,2H), 7.80-7.88(m, 2H), 7.97(s,lH), 8.15(s,lH), 8.40(d,lH), 8.97(t,lH), 10.62(s,lH).

468 613 1.38(t, 3H), 3.31(bs,2H), 3.45(d,lH), 3.76-3.79(m,lH), 4.07-4.12(m, 4H), 4.32(bs,lH),

4.56-4.65(m,3H), 6.47-6.54(m,lH), 6.90(d,lH), 7.42(s,lH), 7.46-7.49(m, 3H), 7.56- 7.59(m, 3H), 7.85(s,lH), 8.40(d,lH), 8.89(t,lH), 10.79(s,lH).

469 593 3.43-3.50(m,3H), 3.75-3.76(m,lH), 4.04-4.12(m,2H), 4.31-4.36(m,lH), 4.55-4.61(m,3H),

6.54-6.59(m,lH), 6.92(d,lH), 7.45-7.48(m,3H), 7.54-7.57(m, 3H), 7.78(d,lH),

7.89(d,lH), 8.39(d,lH), 9.08(t,lH), 11.61(bs,lH).

470 584 3.41(bs,2H), 3.47-3.51(m,lH), 3.77-3.79(m,lH), 4.11-4.16(m,2H), 4.32-4.38(m,lH),

4.57(d,2H), 4.62(d,lH), 6.70-6.76(m,lH), 7.00(d,lH), 7.45(d,lH), 7.55(s,lH), 7.72- 7.78(m,3H), 7.89(d,3H ), 8.39(d,lH), 9.05(t,lH ), 11.51(bs,lH).

471 577 3.38-3.41(m,3H), 3.76(bs,lH), 4.05-4.12(m,2H), 4.35-4.37(m,lH), 4.56-4.62(m,3H), 6.43- 6.50(m,lH), 6.91(d,lH), 7.25(t,2H), 7.45-7.46(d,lH), 7.55-7.60(m,3H), 7.78(d,lH), 7.89(d,lH ), 8.39(d,lH ), 9.04(t,lH), 11.36(bs,lH).

472 577 3.41(bs,2H), 3.51(bs,lH), 3.78(bs,lH), 4.09-4.12(m,2H), 4.34-4.36(m,lH), 4.60- 4.65(m,3H), 6.50-6.55(m ,1H), 6.91(d,lH), 7.20(s,lH), 7.39(d,lH), 7.48(d,2H),

7.57(d,2H), 7.77(d,lH), 7.90(d,lH), 8.22(d,lH), 9.00(bs,lH), 11.03(bs,lH).

473 551

474 568 2.85(d,2H), 3.04(s,2H), 3.48(d,2H), 3.65(s,2H), 4.52(d,2H), 5.03(d, 4H), 6.85(d,lH),

7.00-7.07(m,lH), 7.30(s,lH), 7.42(d,lH), 7.50(s,lH), 7.69-7.73(m,2H), 8.16(dd,lH), 8.38(d,lH), 8.49(t,lH), 8.89(s,lH).

475 542 3.34-3.50(m,3H), 3.77-3.80(m,lH), 4.13-4.16(m,2H), 4.34-4.39(m,lH), 4.54(d,2H),

4.64(d,lH), 5.07(d, 4H), 6.79-6.85(m,lH), 6.99(d,lH), 7.44-7.45(m,2H), 7.53(s,lH), 7.56- 7.59(m,lH), 7.74(s,lH), 7.76-7.81(m,lH), 7.97(t,lH), 8.39(d,lH), 8.92(t,lH),

11.35(bs,lH).

476 535 3.37-3.50(m,3H), 3.75-3.78(m,lH), 4.11-4.16(m,2H), 4.31-4.36(m,lH), 4.54(d,2H), 4.59(d,lH), 5.07(d, 4H), 6.59-6.63(m,lH), 6.98(d,lH), 7.15-7.20(m,lH), 7.30-7.36(m,lH), 7.45(bs,2H), 7.53(s,lH), 7.73-7.80(m,2H), 8.38(d,lH), 8.92(t,lH), 11.40(bs,lH),

477 551 3.32-3.33(m,2H), 3.43-3.50(m,lH), 3.76-3.79(m,lH), 4.07-4.12(m,2H), 4.32-4.41(m,lH),

4.54(d,2H), 4.62(d,lH), 5.06(d, 4H), 6.53-6.60(m,lH), 6.89(d,lH), 7.44-7.48(m,3H), 7.53- 7.57(m,2H), 7.74(s,lH), 7.82(dd,lH), 8.39(d,lH), 8.91(t,lH), 11.23(bs,lH),

478 535 3.32-3.36(m,2H), 3.48(bs,lH), 3.78-3.81(m,lH), 4.08-4.1 l(m,2H), 4.33-4.39(m,lH),

4.55(d,2H), 4.64(d,lH), 5.07(d, 4H), 6.49-6.57(m,lH), 6.89(d,lH), 7.38-7.53(m,5H), 7.68- 7.74(m,2H), 8.38(d,lH), 8.89(t,lH), 10.92(bs,lH),

479 524 2.93(t,2H), 3.12(t,2H), 3.46(d,2H), 3.69(s,2H), 4.64(d,2H), 5.14(d,4H), 5.91(t,lH), 6.45- 6.53(m,lH), 6.64(d,lH), 7.19(s,lH), 7.21(dd,lH), 7.31(d,lH), 7.47(d,2H), 7.60(d,2H), 7.69(s,lH), 8.37(d,lH).

480 533 2.82(t,2H), 3.02(s,2H), 3.38(d,2H), 3.62(s,2H), 4.52(d,2H), 5.03(d, 4H), 6.40-6.48(m,lH),

6.63(d.lH), 7.29(s,lH), 7.37-7.42(m,3H), 7.51(d,3H), 7.69(s,lH), 8.38(d,lH), 8.48(t,lH).

481 517 2.82(s,2H), 3.02(s,2H), 3.37(d,2H), 3.62(s,2H), 4.52(d,2H), 5.03(d, 4H), 6.32-6.40(m,lH),

6.63(d,lH), 7.16(t,2H), 7.29(s,lH), 7.42(d,lH), 7.50-7.54(m,3H), 7.69(s,lH), 8.38(d,lH), 8.48(t,lH).

482 567 2.85(d,2H), 3.03(s,2H), 3.42(d,2H), 3.64(s,2H), 4.52(d,2H), 5.03(d, 4H), 6.56- 6.64(m,lH), 6.74(d,lH), 7.29(s,lH), 7.42(d,lH), 7.50(s,lH), 7.67-7.74(m,5H),

8.38(d,lH), 8.50(t,lH).

483 517 2.82(t,2H), 3.03(s,2H), 3.38(d,2H), 3.62(s,2H), 4.55(d,2H), 5.03(d, 4H), 6.41-6.48(m,lH),

6.63(d,lH), 7.15(s,lH), 7.29(s,lH), 7.35-7.39(m,3H), 7.51(d,2H), 7.69(s,lH), 8.21(d,lH), 8.49(t,lH).

484 535 3.31-3.33(m,2H), 3.46-3.48(m,lH), 3J9-3.81(m,lH), 4.12-4.13(m,2H), 4.34-4.39(m,lH),

4.58(d,2H), 4.64(d,lH), 5.07(d, 4H), 6.57-6.64(m,lH), 6.90(d,lH), 7.17(s,lH), 7.38- 7.42(m,2H), 7. 45(s,lH), 7.62(d,lH), 7.65-7.70(m,lH), 7.75(s,lH), 8.22(d,lH), 8.89(t,lH), 10.82(bs,lH).

485 526 3.33-3.36(m,2H), 3.50-3.52(m,lH), 3.79-3.82(m,lH), 4.16-4.19(m,2H), 4.37-4.38(m,lH),

4.58(d,2H), 4.66(d,lH), 5.07(d, 4H), 6.75-6.82(m,lH), 6.98(d,lH), 7.17(s,lH), 7.38(d,lH), 7.44(s,lH), 7.58(d,lH), 7.75(s,lH), 7.78(d,lH), 7.98(t,lH), 8.22(d,lH), 8.90(bs,lH), 10.95(bs,lH).

486 519 3.32-3.35(m,2H), 3.42-3.45(m,lH), 3.75-3.78(m,lH), 4.13-4.16(m,2H), 4.32-4.35(m,lH),

4.58(d,2H), 4.61-4.63(m,lH), 5.07(d, 4H), 6.57-6.61(m,lH), 6.98(d,lH), 7.16-7.20(m,2H), 7.30-7.39(m,2H), 7.45(s,lH), 7.74(s,lH), 7.77-7.81(m,lH), 8.22(d,lH), 8.91(t,lH), 11.16(bs,lH).

487 535 3.33-3.39(m,2H), 3.41-3.49(m,lH), 3.79-3.81(m,lH), 4.11-4.12(m,2H), 4.34-4.39(m,lH),

4.58(d,2H), 4.65(d,lH), 5.07(d, 4H), 6.50-6.58(m,lH), 6.88(d,lH), 7.17(s,lH), 7.38(d,lH), 7.45 -7.49(m,2H), 7.56-7.58(m,lH), 7.74(s,lH), 7.83-7.86(dd,lH), 8.22(d,lH), 8.89(t,lH), 10.82(bs,lH).

488 519 3.33-3.37(m,2H), 3.46-3.349(m,lH), 3.78-3.81(m,lH), 4.10-4.11(m,2H), 4.34-4.39(m,lH),

4.58(d,2H), 4.64(d,lH), 5.07(d, 4H), 6.49-6.56(m,lH), 6.88(d,lH), 7.17(s,lH), 7.38(d,2H), 7.45 -7.52(m,2H), 7.69-7.75(m,2H), 8.22(d,lH), 8.90(t,lH), 10.86(bs,lH).

489 539 2.78(t,2H), 2.95(s,2H), 3.34(d,2H), 3.57(s,2H), 4.57(d,2H), 4.98(s,2H), 5.03(s,2H), 6.37- 6.44(m,lH), 6.60(d,lH), 7.25(s,lH), 7.36(d,2H), 7.48(d,2H), 7.63(d,2H), 8.54(t,lH).

490 533 2.78(t,2H), 3.01(bs,2H), 3.36(d,2H), 3.70(s,2H), 4.52(d,2H), 5.05(s,2H), 5.25(s,2H), 6.40- 6.47(m,lH), 6.63(d,lH), 7.12(d,lH), 7.38(d,2H), 7.42(d,lH), 7.51(d,3H), 7.69(d,lH), 8.38(d,lH), 8.55(t,lH).

491 562 2.61(s, 3H), 3.36(s,2H), 3.48(bs,lH), 3.79(bs,lH), 4.11(bs,2H), 4.39(bs,lH), 4.58(d,2H),

4.70(d,lH), 6.50-6.57(m,lH), 6.91(d,lH), 7.43-7.49(m,3H), 7.56-7.58(m,3H), 7.71(s,lH), 8.24(s,lH), 8.39(d,lH), 9.03(bs,lH), l l.l l(bs,lH).

492 653 3.39-3.50(m,3H), 3.78(bs,lH), 4.06-4.12(m,2H), 4.33-4.38(m,lH), 4.56-4.57(m,2H), 4.67(d,lH), 6.48-6.55(m,lH), 6.91(d,lH), 7.45-7.49(m,3H), 7.55-7.58(m,3H), 7.88(s,lH), 8.10(s,lH), 8.39(d,lH), 9.02(t,lH), 11.04(s,lH).

493 546 3.37-3.43(m,3H), 3.77(bs,lH), 3.92(s, 3H), 4.11(bs,2H), 4.31-4.36(m,lH), 4.56- 4.65(m,3H), 6.52-6.60(m,lH), 6.91(d,lH), 7.39(s,lH), 7.45-7.48(m,3H), 7.55-7.58(m,3H), 8.13(s,lH), 8.38(d,lH), 8.96(t,lH), 11.39(s,lH).

494 589 2.39(s, 3H), 3.32-3.48(m,3H), 3.77-3.80(m,lH), 4.07-4.10(m,2H), 4.33-4.39(m,lH),

4.56(d,2H), 4.66(d,lH), 6.49-6.57(m,lH), 6.93(d,lH), 7.45-7.49(m,3H), 7.53-7.60(m, 4H), 7.78(s,lH), 8.39(d,lH ), 8.97(t,lH ), 10.92(bs,lH).

495 593 3.31(bs,lH), 3.47(bs,2H), 3.78-3.81(m,lH), 4.07-4.12(m,2H), 4.34-4.39(m,lH),

4.56(d,2H), 4.67(d,lH), 6.49-6.55(m,lH), 6.91(d,lH), 7.44-7.49(m,3H), 7.55-7.58(m,3H), 7.88-7.90(m,2H), 8.39(d,lH ), 8.99-9.00(m,lH ), 10.87(bs,lH).

496 609 3.35(bs,2H), 3.48(bs,lH), 3.79-3.82(m,lH), 4.09-4.11 (m,2H), 4.35-4.40(m,lH),

4.55(d.2H), 4.70(d,lH), 6.49-6.54(m,lH), 6.91(d,lH), 7.44-7.49(m,3H), 7.55-7.58(m,3H), 7.89(s,lH), 8.04(s,lH), 8.40(d,lH ), 9.04(bs,lH ), 10.76(bs,lH).

497 653 3.29(bs,lH), 3.45-3.49(m,2H), 3.79(bs,lH), 4.11(bs,2H), 4.35-4.39(m,lH), 4.57(d,2H),

4.70(d,lH), 6.49-6.54(m,lH), 6.91(d,lH), 7.45-7.49(m,3H), 7.55-7.58(m,3H), 7.86(s,lH), 8.15(s,lH), 8.40(d,lH ), 9.04(bs,lH ), 10.75(bs,lH).

498 637 3.40(bs,2H), 3.50(bs,lH), 3.81(bs,lH), 4.09-4.13(m,2H), 4.33-4.39(m,lH), 4.60(d,2H),

4.73(d,lH), 6.46-6.54(m,lH), 6.91(d,lH), 7.46-7.49(m,3H), 7.57-7.59(m,3H), 8.19(s,2H), 8.41(d,lH), 9.13(bs,lH ), 10.82(bs,lH).

499 609 3.39-3.50(m,3H), 3.78(bs,lH), 4.08-4.12(m,2H), 4.34-4.37(m,lH), 4.56-4.58(m,2H),

4.66(d,lH), 6.48-6.56(m,lH), 6.91(d,lH), 7.45-7.49(m,3H), 7.55-7.58(m,3H), 7.90(s,lH), 7.98(s,lH), 8.40(d,lH), 9.04(bs,lH ), 11.15(bs,lH).

500 584 3.38-3.40(m,2H), 3.46-3.50(m,lH), 3.78-3.79(m,lH), 4.06-4.14(m,2H), 4.31-4.36(m,lH),

4.57(d,2H), 4.62(s,lH), 6.31-6.33(m,lH), 6.48(d,lH), 6.53-6.57(m,lH), 6.91(d,lH), 7.30- 7.32(dd,lH), 7.45-7.47(m,3H), 7.50-7.53(m,lH), 7.54-7.57(m,3H), 7.64-7.66(m,2H), 7.87(d,lH), 8.40(d,lH), 9.06(t,lH), 11.36(bs,lH).

501 515

502 600

503 600

504 595 3.17(br s, 4 H) 3.26 - 3.41(m,3H) 3.76(br s,lH) 3.81(br s, 4 H) 4.11(br s,2H) 4.32(br

dd,lH) 4.54(br d,2H) 4.59(br d,lH) 6.66(dt,lH) 6.92(br d,lH) 7.16(br s,2H) 7.41(dd,lH) 7.44(d,lH) 7.52(s,lH) 7.63(br t,lH) 7.66(dd,lH) 7.72(br d,lH) 8.39(d,lH) 8.78(br t,lH) 11.35(br s,lH).

505 576 3.40(br s, 4 H) 3.41 - 3.61(m,3H) 3.77(br d,lH) 3.97(br s, 4 H) 4.07 - 4.18(m,2H) 4.34(br ddJH) 4.55(br d,2H) 4.58(br s,lH) 6.60(dt,lH) 6.93(d,lH) 7.43 - 7.50(m,3H) 7.54(d,lH) 7.55 - 7.59(m,2H) 7.68(br s,lH) 7.82(br d,lH) 8.39(d,lH) 8.97(br s,lH) 11.67(br s,lH).

506 578 2.00 - 2.03(m, 4 H) 2.86 - 2.92(m,2H) 3.12(br t,2H) 3.27 - 3.31(m, 4 H) 3.42(dd,2H)

3.65(s,2H) 4.58(d,2H) 6.15 - 6.19(m,lH) 6.32 - 6.41(m,lH) 6.42(d,lH) 6.53(s,lH) 6.53 - 6.57(m,lH) 7.09 - 7.13(m,lH) 7.17 - 7.21(m,2H) 7.28 - 7.30(m,lH) 7.33(t,lH) 7.57(d,lH) 8.32(d,lH).

507 578 2.02(dt, 4 H) 2.88 - 2.93(m,2H) 3.13(br t,2H) 3.30(br t, 4 H) 3.44(br dd,2H) 3.66(s,2H)

4.61(d,2H) 6.11(t,lH) 6.34 - 6.41(m,lH) 6.43(d,lH) 6.52(s,lH) 6.54 - 6.58(m,lH) 7.19 - 7.22(m,lH) 7.24(dd,lH) 7.31(dd,lH) 7.39(d,lH) 7.48(d,lH) 7.57(d,lH) 8.34(dd,lH).

508 610 3.32 - 3.40(m,2H) 3.45(br s, 4 H) 3.48 - 3.57(m,lH) 3.72 - 3.79(m,lH) 3.99(br s, 4 H) 4.06

- 4.14(m,2H) 4.32 - 4.40(m,lH) 4.57(br d,2H) 4.63(br s,lH) 6.67(dt,lH) 6.92(d,lH) 7.43 - 7.49(m,lH) 7.49 - 7.54(m,2H) 7.59(d,lH) 7.61(br d,lH) 7.67(d,lH) 7.84(d,lH) 7.92(br s,lH) 8.40(dd,lH) 9.16(br t,lH) 11.74(br s,lH)

509 594 3.32 - 3.38(m, 4 H) 3.41 - 3.49(m,lH) 3.71 - 3.79(m,lH) 3.92(br s, 4 H) 4.08 - 4.14(m,2H)

4.25(br dd,2H) 4.35(br dd,lH) 4.57(br d,2H) 4.60 - 4.65(m,lH) 6.66(dt,lH) 6.92(d,lH) 7.28 - 7.34(m,lH) 7.40(dd,lH) 7.49(dd,lH) 7.55(br d,lH) 7.58(d,lH) 7.63(br t,lH) 7.65(br dd,lH) 7.68 - 7.74(m,lH) 8.40(dd,lH) 9.05(br t,lH) 11.54(br s,lH).

510 610 3.13 - 3.22(m,2H) 3.39 - 3.44(m,2H) 3.46 - 3.53(m,2H) 3.73(br s, 6 H, under H20 peak)

4.14(br s,2H) 4.37(br dd,lH) 4.57(br d,2H) 4.60(br s,lH) 6.63 - 6.74(m,lH) 6.94(d,lH) 7.46(dd,lH) 7.51 - 7.56(m,2H) 7.68(d,lH) 7.71 - 7.78(m,lH) 7.83 - 7.91(m,2H) 7.98(br d,lH) 8.40(dd,lH) 9.08(br t,lH) 11.81(br s,lH).

511 626 2.95 - 3.04(m,lH) 3.28(br dd,lH) 3.35 - 3.45(m,2H) 3.46 - 3.52(m,lH) 3.61(br d,lH)

3.75(br s, 3H) 3.88 - 3.98(m,lH) 4.14(br s,2H) 4.31 - 4.42(m,2H) 4.52 - 4.63(m, 4 H) 6.61 - 6.75(m,lH) 6.89 - 7.00(m,lH) 7.40(dd,lH) 7.44 - 7.48(m,lH) 7.52 - 7.56(m,lH) 7.60 - 7.67(m,2H) 7.80(br d,lH) 7.89(d,lH) 7.99 - 8.11(m,lH) 8.40(d,lH) 9.12(br t,lH) 11.87(br s,lH).

512 521 2.91(t,2H) 3.12(br t,2H) 3.43(dd,2H) 3.65(s,2H) 3.83(s, 3H) 4.62(d,2H) 6.10-6.17(m,lH)

6.35(dt,lH) 6.58(d,lH) 6.81(d,lH) 6.84(dd,lH) 7.18 - 7.22(m,lH) 7.28 - 7.36(m, 5 H) 7.66(d,lH) 8.34(dd,lH).

513 535 8.32-8.43(m,2H), 7.67(d,lH), 7.46-7.55(m,3H), 7.36-7.44(m,3H), 6.91(d,lH), 6.80(m,lH),

6.60-6.69(m,lH), 6.37-6.52(m,lH), 4.51(d,2H), 3.98-4.06(m,2H), 3.61(br s,2H), 3.39(br d,2H), 3.02(br s,2H), 2.74-2.89(m,2H), 1.32(m,3H).

514 519 8.31-8.43(m,2H), 7.67(d,lH), 7.47-7.56(m,3H), 7.42(m,lH), 7.10-7.22(m,2H), 6.91(d,lH),

6.80(m,lH), 6.63(d,lH), 6.37(m.lH), 4.51(d,2H), 4.02(m,2H), 3.61(s,2H), 3.37(br d,2H), 3.02(br s,2H), 2.72-2.90(m,2H), 1.32(m,3H).

515 540 1.08 (bs, 2H), 1.14-1.23 (m,2H), 2.32 (bs, 1H), 3.40-3.49 (m,3H), 3.80 (bs, 1H), 4.12 (bs,

2H), 4.41-4.43(m,lH), 4.64-4.74 (m,3H), 6.54-6.66 (m,lH), 6.92 (d,lH), 7.41 (d,lH), 7.55-7.68 (m, 5H), 7.78 (d, Hz, 1H), 8.27 (s, 1H), 8.53 (bs, 1H), 9.16 (bs, 1H). 11.22 (bs, 1H).

516 527 1.21-1.36(m,lH), 1.89(t,lH), 2.09-2.18(m,lH), 2.35-2.44(m,lH), 2.72-2.81(m,lH), 3.03- 3.10(m,lH), 3.17-3.25(m,lH), 3.46-3.55(m,2H), 4.33-4.46(m,3H), 6.31-6.39(m,lH), 6.55(d,lH), 7.14(dd,lH), 7.25(s,lH), 7.31-7.42(m, 4 H), 7.46-7.57(m,3H), 7.78(d,lH), 8.34(d,lH).

517 563 Peak 1: 1.22-1.37(m,lH), 1.89(t,lH), 2.10-2.19(m,lH), 2.36-2.45(m,lH), 2.72-2.80(m,lH),

3.04-3.11(m,lH), 3.17-3.25(m,lH), 3.46-3.55(m,2H), 4.34-4.47(m,3H), 6.42-6.56(m,2H), 7.14(dd,lH), 7.26(s,lH), 7.31-7.34(m,lH), 7.40(s,lH), 7.44-7.49(m,lH), 7.52-7.58(m,2H), 7.73-7.80(m,2H), 8.34(d,lH).

517 563 Peak 2: 1.22-1.37(m,lH), 1.89(t,lH), 2.10-2.19(m,lH), 2.36-2.45(m,lH), 2.72-2.80(m,lH),

3.04-3.11(m,lH), 3.17-3.25(m,lH), 3.46-3.55(m,2H), 4.34-4.47(m,3H), 6.42-6.56(m,2H), 7.14(dd,lH), 7.26(s,lH), 7.31-7.34(m,lH), 7.40(s,lH), 7.44-7.49(m,lH), 7.52-7.58(m,2H), 7.73-7.80(m,2H), 8.34(d,lH).