IP Library › Granted Patent US 9,045,468

Granted Patent B2

US 9,045,468 · App. 13/211,678 · Granted Jun 2, 2015

2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

Inventors: Peter R. Guzzo (Niskayuna, NY); Shuang Liu (Schenectady, NY); Kristen N. Ryan (Halfmoon, NY); Bruce F. Molino (Slingerlands, NY); Russell DeOrazio (Schenectady, NY); Richard E. Olson (Orange, CT); John E. Macor (Guilford, CT)

Assignees: Albany Molecular Research, Inc.; Bristol-Myers Squibb Company

C07D453/00 C07D519/00

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Quick Facts

Patent No.: US 9,045,468
App. No.: 13/211,678
Granted: Jun 2, 2015
Kind: B2

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Abstract

The compounds of the present invention are represented by the following 2,5-methano- and 2,5-ethano-tetrahydrobenzazepine derivatives having formula (I): where the carbon atom designated * is in the R or S configuration when n is 1 and the substituents X and R 1 -R 7 are as defined herein.

Claims (142)

1. A compound of formula (I) having the following structure:

wherein:

n is 2;

X is phenyl, naphthyl, benzofuranyl, benzothiophenyl, indolyl, or indazolyl, each optionally substituted from 1-4 times with substituents as defined below in R 13 ;

R 1 is H;

R 2 , R 4 , and R 5 are each independently H, halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, —CN, —NH 2 , —NHMe, or —NMe 2 ;

R 3 is H, halogen, —NR 8 R 9 , OR 10 , S(O) p R 11 , —CN, —C(O)R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 4 -C 7 cycloalkylalkyl, where each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 12 ; or

R 3 is a bridged bicyclic ring containing 6-12 carbon atoms and optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the bridged bicyclic ring is optionally substituted from 1 to 3 times with substitutents selected from the group consisting of C 1 -C 3 alkyl, —C(O)R 11 , and —S(O) p R 11 ; or

R 3 is a monocyclic or bicyclic aryl or heteroaryl selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 6-oxopyridazin-1(6H)-yl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, 3-thio-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and other 5- or 6-membered aromatic or non-aromatic monocyclic carbocycles or heterocycles, or [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each optionally substituted from 1 to 4 times with substituents as defined below in R 13 ; or

R 3 is —OR 14 ;

R 6 and R 7 are each independently H, methyl, ethyl, gem-dimethyl, or gem-diethyl,

R 8 and R 9 are each independently selected from the group consisting of H, —C(O)R 11 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, where each of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 10 ; or

R 8 and R 9 are each independently selected from the group consisting of phenyl, benzyl, and other 5- or 6-membered monocyclic heterocycles, where each of the phenyl, benzyl, and 5- or 6-membered monocyclic heterocycle is optionally substituted from 1 to 3 times with substituents as defined below in R 13 ; or

R 8 and R 9 are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or fused bicyclic heterocycle selected from the group consisting of piperidine, pyrrolidine, morpholine, thiomorpholine, [1,2]oxazinane, isoxazolidine, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 3-oxomorpholino, 3-oxothiomorpholino, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine, and other monocyclic or fused bicyclic heterocycles containing 1-4 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the heterocycle is attached to the benzazepine core via the nitrogen atom, and is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OR 10 , —NR 10 R 11 , —S(O) p R 11 , C(O)R 11 , oxo, and C 1 -C 4 alkyl, where each C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 12 ; or

R 8 and R 9 are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperazine, 2-oxopiperazinyl, 2-oxo-1,4-diazepanyl, 5-oxo-1,4-diazepanyl, 1,4-diazepane, and other heterocycles containing at least two nitrogens in the ring, where the heterocycle is optionally substituted on a ring carbon from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OR 10 , —NR 10 R 11 , —S(O) p R 11 , —C(O)R 11 , oxo, and C 1 -C 4 alkyl, or on one or more of the at least two nitrogens in the ring from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of S(O) p R 11 , —C(O)R 11 , C 1 -C 4 alkyl, aryl, and heteroaryl, wherein each C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 12 and wherein each of the aryl or heteroaryl groups is optionally substituted from 1 to 4 times with substituents as defined below in R 13 ; or

R 8 and R 9 are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperazine, 2-oxopiperazinyl, 2-oxo-1,4-diazepanyl, 5-oxo-1,4-diazepanyl, 1,4-diazepane, and other heterocycles containing one additional nitrogen atom in the ring, where the heterocycle is optionally substituted on the additional nitrogen atom with a substituent selected independently at each occurrence thereof from the group consisting of phenyl, benzyl, and 5- or 6-membered aromatic heterocycles containing 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where each of the phenyl, benzyl, and 5- and 6-membered heterocycle is optionally substituted from 1 to 3 times with substituents as defined below in R 13 ; or

when R 3 is —NR 8 R 9 or —C(O)NR 8 R 9 , either R 8 or R 9 is a bridged bicyclic ring containing 6-12 carbon atoms and optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the bridged bicyclic ring is optionally substituted from 1 to 3 times with substituents selected from the group consisting of C 1 -C 3 alkyl, —C(O)R 11 , and —S(O) p R 11 , or either R 8 or R 9 is a C 1 -C 3 alkyl substituted with a bridged bicyclic ring containing 6-12 carbon atoms and optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the bridged bicyclic ring is optionally substituted from 1 to 3 times with substitutents selected from the group consisting of C 1 -C 3 alkyl, —C(O)R 11 , and —S(O) p R 11 ;

R 10 is selected from the group consisting of H, OH, alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, and —C(O)R 11 , where each of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 12 ;

R 11 is selected from the group consisting of —NR 8 R 9 , C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, where each of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 12 ; or

R 10 and R 11 are each independently selected from the group consisting of phenyl, benzyl, pyridazinyl, pyrimidinyl, pyrazinyl, 5- or 6-membered aromatic monocyclic heterocycles, and [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles, the heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, optionally substituted from 1 to 4 times with substituents as defined below in R 13 ; or when R 10 and R 11 are together attached to a nitrogen, R 10 and R 11 are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperidine, pyrrolidine, piperazine, 1,4-diazepane, morpholine, thiomorpholine, and other heterocycles containing 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where the heterocycle is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OR 8 , —S(O) p R 8 , —C(O)R 8 , —C(O)NR 8 R 9 and C 1 -C 4 alkyl, where each of C 1 -C 4 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R′ 2 ;

p is 0, 1, or 2;

R 12 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C(O)R″, C 1 -C 3 alkyl, —OR 10 , —NR 8 R 9 , —S(O) p R 11 , aryl, and heteroaryl, where each of the aryl or heteroaryl groups is optionally substituted from 1 to 4 times with substituents as defined below in R 13 ;

R 13 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —OR 10 , —NR 8 R 9 , —NR 10 C(O) 2 R 11 , —NR 10 C(O)NR 10 R 11 , —S(O) p R 11 , —CN, —C(O)R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, where each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined above in R 12 ; and

R 14 is a 5- or 6-membered aromatic or non-aromatic monocyclic carbocycle or heterocycle, or [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycle or heterocycle containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, optionally substituted from 1 to 4 times with substituents as defined above in R 13 ;

with the proviso that when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are all hydrogen, X cannot be phenyl;

or an oxide thereof, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein X is phenyl optionally substituted from 1-4 times with substituents as defined in R 13 , and R 3 is substituted monocyclic or bicyclic aryl or heteroaryl.

3. The compound according to claim 2 , wherein:

X is phenyl, optionally substituted from 1 to 3 times with chloro or fluoro;

R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are all H;

R 3 is substituted monocyclic or bicyclic aryl or heteroaryl.

4. The compound according to claim 1 , wherein X is phenyl optionally substituted from 1-4 times with substituents as defined in R 13 , and R 3 is H, —NR 8 R 9 , —OR 10 , —OR 14 , —S(O) p R 11 , C(O)R 11 , —CN, halogen, and C 1 -C 6 alkyl, where each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 12 .

5. The compound according to claim 4 , wherein:

X is phenyl, optionally substituted from 1 to 3 times with chloro or fluoro;

R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are all H; and

R 3 is H, —NR 8 R 9 , —OR 10 , —OR 14 , —S(O) p R 11 , C(O)R 11 , —CN, halogen, or C 1 -C 6 alkyl, where each of the C 1 -C 6 alkyl is optionally substituted from 1 to 3 times with substituents as defined above in R 12 .

6. The compound according to claim 1 , wherein

X is phenyl, optionally substituted from 1 to 3 times with chloro or fluoro;

R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are all H; and

R 3 is hydroxy, methoxy, difluoromethoxy, [1,2,4]triazolo[1,5-a]pyridin-6-yl, 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, 2-oxo-pyridin-1-yl, 6-(methoxy)pyridazin-3-yl, 6-(hydroxy)pyridazin-3-yl, 6-(trifluoromethyl)pyridazin-3-yl, 6-(difluoromethoxy)pyridazin-3-yl, 6-(hydroxy)pyridazin-3-yl, 4-cyanophenyl, 3-cyanophenyl, 4-(methylsulfonyl)phenyl, 2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl, pyrimidin-5-yl, pyrazinyl, 5-aminopyrazinyl, quinoxalin-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, morpholinyl, 4-(ethylsulfonyl)piperazin-1-yl, 6-(trifluoromethyl)pyridazin-3-yloxy, pyrazin-2-yloxy, 5-amino-pyrazin-2-yloxy, 3-(pyridin-4-yl)propoxy, 3-(pyridin-3-yl)propoxy, 5-(methylsulfonyl)pyrimidin-2-yl, 6-(methylcarbamoyl)pyridazin-3-yl, 6-carbamoylpyridazin-3-yl, 5-(methylcarbamoyl)pyrimidin-2-yl, or 5-carbamoylpyrimidin-2-yl.

7. The compound according to claim 1 , wherein:

X is phenyl, optionally substituted from 1 to 3 times with chloro or fluoro;

R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are all H; and

R 3 is 6-(1-hydroxyethyl)pyridazin-3-yl, 6-(2-hydroxypropan-2-yl)pyridazin-3-yl, 6-(2,2,2-trifluoro-1-hydroxyethyl)pyridazin-3-yl, 6-(2,2-difluoro-1-hydroxyethyl)pyridazin-3-yl, 2-(1-hydroxyethyl)pyrimidin-5-yl, 2-(2-hydroxypropan-2-yl)pyrimidin-5-yl, 2-(2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-5-yl, or 2-(2,2-difluoro-1-hydroxyethyl)pyrimidin-5-yl.

8. The compound according to claim 1 , wherein the compound is selected from the following group consisting of:

5-(4-chlorophenyl)-8-methoxy-2,5-ethano-2,3,4,5-tetrahydro-1H-2-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-2-benzo[c]azepin-8-ol;

5-(4-chlorophenyl)-8-(6-(difluoromethoxy)pyridazin-3-yl)-2,5-ethano-2,3,4,5-tetrahydro-1H-2-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(pyrimidin-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(pyrazin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyrazin-2-amine;

8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(quinoxalin-2-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

6-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-3,3a-dihydrobenzo[d]oxazol-2(7aH)-one;

2-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one;

1-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridin-2(1H)-one;

2-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-5-methyl-1,3,4-thiadiazole;

5-(4-chlorophenyl)-2,5-ethano-8-(4-(methylsulfonyl)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

3-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)benzonitrile;

4-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)morpholine;

5-(4-chlorophenyl)-8-(4-(ethylsulfonyl)piperazin-1-yl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(pyrazin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxy)pyrazin-2-amine;

5-(4-chlorophenyl)-2,5-ethano-8-(3-(pyridin-4-yl)propoxy)-2,3,4,5-tetrahydro-1H-benzo[c] azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(3-(pyridin-3-yl)propoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3,4-dichlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

6-(5-(3,4-dichlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-3,3a-dihydrobenzo[d]oxazol-2(7aH)-one;

5-(3,4-dichlorophenyl)-8-(6-(difluoromethoxy)pyridazin-3-yl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3,4-dichlorophenyl)-8-(6-methoxypyridazin-3-yl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

6-(5-(3,4-dichlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyridazin-3-ol;

5-(5-(3,4-dichlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)pyrazin-2-amine;

5-(3,4-dichlorophenyl)-2,5-ethano-8-(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3,4-dichlorophenyl)-2,5-ethano-8-(pyrazin-2-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3,4-dichlorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3,4-dichlorophenyl)-2,5-ethano-8-(difluoromethoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3-chloro-4-fluorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chloro-3-fluorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3-chlorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

2,5-ethano-5-(4-(trifluoromethyl)phenyl)-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3,4-difluorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-fluorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yloxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3-chloro-4-fluorophenyl)-2,5-ethano-8-(6-(trifluoromethyl)pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

8-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3-chloro-4-fluorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chlorophenyl)-2,5-ethano-8-(5-(methylsulfonyl)pyrimidin-2-yl)-1,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-fluorophenyl)-2,5-ethano-8-(5-(methylsulfonyl)pyrimidin-2-yl)-1,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3,4-difluorophenyl)-2,5-ethano-8-(5-(methylsulfonyl)pyrimidin-2-yl)-1,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3,4-dichlorophenyl)-2,5-ethano-8-(5-(methylsulfonyl)pyrimidin-2-yl)-1,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(3-chloro-4-fluorophenyl)-2,5-ethano-8-(5-(methylsulfonyl)pyrimidin-2-yl)-1,3,4,5-tetrahydro-1H-benzo[c]azepine;

5-(4-chloro-3-fluorophenyl)-2,5-ethano-8-(5-(methylsulfonyl)pyrimidin-2-yl)-1,3,4,5-tetrahydro-1H-benzo[c]azepine;

6-(5-(4-chlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyridazine-3-carboxamide;

6-(5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyridazine-3-carboxamide;

6-(5-(3,4-difluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyridazine-3-carboxamide;

6-(5-(3,4-dichlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyridazine-3-carboxamide;

6-(5-(4-chloro-3-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyridazine-3-carboxamide;

6-(5-(3-chloro-4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyridazine-3-carboxamide;

6-(5-(4-chlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyridazine-3-carboxamide;

6-(5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyridazine-3-carboxamide;

6-(5-(3,4-difluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyridazine-3-carboxamide;

6-(5-(3,4-dichlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyridazine-3-carboxamide;

6-(5-(4-chloro-3-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyridazine-3-carboxamide;

6-(5-(3-chloro-4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyridazine-3-carboxamide;

2-(5-(4-chlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyrimidine-5-carboxamide;

2-(5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyrimidine-5-carboxamide;

2-(5-(3,4-dichlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyrimidine-5-carboxamide;

2-(5-(3,4-difluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyrimidine-5-carboxamide;

2-(5-(3-chloro-4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyrimidine-5-carboxamide;

2-(5-(4-chloro-3-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-N-methylpyrimidine-5-carboxamide;

2-(5-(4-chlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyrimidine-5-carboxamide;

2-(5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyrimidine-5-carboxamide;

2-(5-(3,4-dichlorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyrimidine-5-carboxamide;

2-(5-(3,4-difluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyrimidine-5-carboxamide;

2-(5-(3-chloro-4-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyrimidine-5-carboxamide; and

2-(5-(4-chloro-3-fluorophenyl)-1,3,4,5-tetrahydro-2,5-ethanobenzo[c]azepin-8-yl)-pyrimidine-5-carboxamide.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1 .

10. A compound of formula (I) having the following structure:

wherein:

n is 2;

X is phenyl, optionally substituted from 1-4 times with substituents as defined below in R 13 ;

R 1 is H;

R 2 , R 4 , and R 5 are each independently H, halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, —CN, —NH 2 , —NHMe, or —NMe 2 ;

R 3 is H, halogen, —NR 8 R 9 , OR 10 , S(O) p R 11 , CN, —C(O)R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 4 -C 7 cycloalkylalkyl, where each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined below in R 12 ;

R 3 is a monocyclic or bicyclic aryl or heteroaryl selected from the group consisting of phenyl, pyridyl, 2-oxo-pyridin-1(2H)-yl, pyrimidinyl, pyridazinyl, 6-oxopyridazin-1(6H)-yl, pyrazinyl, triazinyl, pyranyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indanyl, indenyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo [b][1,4]oxazinyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, 3-thio-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and other 5- or 6-membered aromatic or non-aromatic monocyclic carbocycles or heterocycles, or [5,5]-, [6,5]-, [6,6]-, or [6,7]-fused bicyclic carbocycles or heterocycles containing 1-5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, each optionally substituted from 1 to 4 times with substituents as defined below in R 13 ; or

R 3 is —OR 14 ;

R 6 and R 7 are each independently H, methyl, ethyl, gem-dimethyl, or gem-diethyl;

R 8 and R 9 are taken together with the nitrogen to which they are attached to form a heterocycle selected from the group consisting of piperazine, 2-oxopiperazinyl, 2-oxo-1,4-diazepanyl, 5-oxo-1,4-diazepanyl, 1,4-diazepane, and other heterocycles containing one additional nitrogen atom in the ring, where the heterocycle is optionally substituted on the additional nitrogen atom with a substituent selected independently at each occurrence thereof from the group consisting of phenyl, benzyl, and 5- or 6-membered aromatic heterocycles containing 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur, where each of the phenyl, benzyl, and 5- and 6-membered heterocycle is optionally substituted from 1 to 3 times with substituents as defined below in R 13 ; or

p is 0, 1, or 2;

R 12 is independently selected at each occurrence from a substituent in the group consisting of —CN, halogen, C(O)R 11 , C 1 -C 3 alkyl, —OR 10 , —NR 8 R 9 , —S(O) p R 11 , aryl, and heteroaryl, where each of the aryl or heteroaryl groups is optionally substituted from 1 to 4 times with substituents as defined above in R 13 ;

R 13 is independently selected at each occurrence from a substituent in the group consisting of halogen, —NO 2 , —OR 10 , —NR 8 R 9 , —NR 10 C(O) 2 R 11 , —NR 10 C(O)NR 10 R 11 , S(O) p R 11 , —CN, —C(O)R 11 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl, where each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 3 times with substituents as defined above in R 12 ; and

with the proviso that when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are all hydrogen, X cannot be phenyl;

or an oxide thereof, or a pharmaceutically acceptable salt thereof.

Assignments (14)

ASSIGNMENT OF SECURITY INTEREST IN INTELLECTUAL PROPERTY, RECORDED ON SEPTEMBER 1, 2017, AT REEL/FRAME 043746/0621 Recorded Mar 17, 2025

From: BARCLAYS BANK PLC, AS EXISTING AGENT

To: APOLLO ADMINISTRATIVE AGENCY LLC, AS SUCCESSOR AGENT

Reel/Frame 070531/0279 →

SECURITY INTEREST Recorded Sep 6, 2021

From: CURIA GLOBAL, INC. (FKA ALBANY MOLECULAR RESEARCH, INC.); CURIA MASSACHUSETTS, INC. (FKA AMRI BURLINGTON, INC.); CURIA WISCONSIN, INC. (FKA CEDARBURG PHARMACEUTICALS, INC.); CURIA INDIANA, LLC (FKA AMRI SSCI, LLC); CURIA NEW MEXICO, LLC (FKA OSO BIOPHARMACEUTICALS MANUFACTURING, LLC); CURIA IP HOLDINGS, LLC

To: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS COLLATERAL AGENT

Reel/Frame 057423/0665 →

RELEASE OF SECURITY INTEREST Recorded Oct 29, 2020

From: MORGAN STANLEY SENIOR FUNDING, INC., AS COLLATERAL AGENT

To: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

Reel/Frame 054252/0687 →

CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT PATENT NO. 7541537 PREVIOUSLY RECORDED AT REEL: 034045 FRAME: 0951. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 14, 2018

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 046796/0352 →

FIRST LIEN SECURITY AGREEMENT Recorded Sep 1, 2017

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC-BY ITS SOLE MEMBER: ALO ACQUISITION LLC

To: BARCLAYS BANK, PLC AS COLLATERAL AGENT

Reel/Frame 043746/0621 →

SECOND LIEN SECURITY AGREEMENT Recorded Sep 1, 2017

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING LLC-BY ITS SOLE MEMBER:ALO ACQUISITION LLC

To: MORGAN STANLEY SENIOR FUNDING, INC.

Reel/Frame 043746/0657 →

RELEASE OF SECURITY INTEREST Recorded Aug 31, 2017

From: BARCLAYS BANK PLC, AS COLLATERAL AGENT

To: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC; AMRI SSCI, LLC; EUTICALS INC.

Reel/Frame 043742/0085 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 22, 2016

From: BRISTOL-MYERS SQUIBB COMPANY

To: ALBANY MOLECULAR RESEARCH, INC.

Reel/Frame 039116/0827 →

SECURITY INTEREST Recorded Aug 5, 2015

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI SSCI, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 036257/0914 →

SECURITY INTEREST Recorded Oct 24, 2014

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 034045/0951 →

RELEASE OF SECURITY INTEREST Recorded Jul 9, 2014

From: WELLS FARGO

To: ALBANY MOLECULAR RESEARCH, INC.

Reel/Frame 033283/0357 →

SECURITY AGREEMENT Recorded Apr 20, 2012

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; AMRI BOTHELL RESEARCH CENTER, INC.; AMRI RENESSELAER, INC.

To: WELLS FARGO BANK, NATIONAL ASSOCIATION

Reel/Frame 028078/0227 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 12, 2011

From: OLSON, RICHARD E.; MACOR, JOHN E.