Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides

Patent metadata

Field	Value
Publication number	US-11111242-B2
Application number	US-201715446500-A
Country	US
Kind code	B2
Filing date	Mar 1, 2017
Priority date	Dec 5, 2013
Publication date	Sep 7, 2021
Grant date	Sep 7, 2021

Abstract

The present invention provides pharmaceutically active pyrrolo[2,3-d]pyrimidinyl and pyrrolo[2,3-d]pyridinyl acrylam ides and analogues thereof, having the structure:

or a pharmaceutically acceptable salt thereof, as set forth in the Description. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention also is directed to compositions comprising methods for making such compounds, and methods for treating and preventing conditions mediated by JAK.

First claim

The invention claimed is:

1. A method for treating a disorder or condition selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, and ulcerative colitis, comprising the step of administering to a subject an effective amount of a compound having the structure:

or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein
R a , R b , R, and R d are independently selected from hydrogen, C 1 -C 6 linear or branched chain alkyl, C 1-6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)C 1 -C 6 linear or branched chain alkyl, (heteroaryl)C 1 -C 6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C 1 -C 6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C 1 -C 6 linear or branched chain alkyl, (C 1 -C 6 linear or branched chain alkyl)aryl, (C 1 -C 6 linear or branched chain alkyl)heteroaryl, and (C 1 -C 6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF 3 , and C 1 -C 6 cycloalkyl;
R 0 , R 1 , R 4 , and R 6 are independently selected from hydrogen, C 1-6 linear or branched chain alkyl, C 1 -C 6 linear or branched chain perfluoroalkyl, C 1 -C 6 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C 1 -C 6 linear or branched chain alkyl, (heteroaryl)C 1 -C 6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C 1 -C 6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C 1 -C 6 linear or branched chain alkyl, (C 1 -C 6 linear or branched chain alkyl)aryl, (C 1 -C 6 linear or branched chain alkyl)heteroaryl, and (C 1 -C 6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF 3 , and C 1 -C 6 cycloalkyl; where, alternatively, R 0 or R 1 , and/or R 6 , respectively together with either of R 4 , R a , R b , R c or R d , may independently form a bond or a C 1 -C 6 linear alkyl chain; and/or, alternatively, R 4 , respectively together with either of R a , R b , R c or R d , may independently form a bond or a C 1 -C 6 linear alkyl chain; and,
R 8 , R 9 and R 10 are all hydrogen.

2. A method for treating a disorder or condition selected from rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, and ulcerative colitis, comprising the step of administering to a subject an effective amount of a compound selected from the group consisting of:
(R)-1-(3-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one;
1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1-yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-hydroxypiperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one;
1-(5-(7H-pyrrolo[2,3-d]pyri midi n-4-ylamino)-2-(hydroxymethyl)piperidin-1-yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-1-yl)prop-2-en-1-one;
1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-methylpiperidin-1-yl)prop-2-en-1-one;
1-((3S,4R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-fluoropiperidin-1-yl)prop-2-en-1-one;
1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-ethylpiperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(3-chloro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)piperidin-1-yl)prop-2-en-1-one;
1-((2R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(hydroxymethyl)piperidin-1-yl)prop-2-en-1-one;
1-((3R,5R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-fluoropiperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1-yl)prop-2-en-1-one;
1-((2S,5R)-5-(5-(2-methoxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1-yl)prop-2-en-1-one;
1-((3R,5S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylpiperidin-1-yl)prop-2-en-1-one;
1-((3R,4S)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-4-methylpiperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(5-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one;
1-((2S,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methylpiperidin-1-yl)prop-2-en-1-one;
(R)-1-(3-(5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1-one;
(R)-4-(1-acryloylpiperidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile; and,
(3R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-acryloylpiperidine-3-carbonitrile; or, a pharmaceutically acceptable salt thereof.

3. A method for treating inflammatory bowel disease by administering to a mammal in need a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt or solvate thereof, or an enantiomer or diastereomer thereof, and wherein
R a , R b , R c and R d are independently selected from hydrogen, C 1 -C 6 linear or branched chain alkyl, C 1 -C 6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, (aryl)C 1 -C 6 linear or branched chain alkyl, (heteroaryl)C 1 -C 6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C 1 -C 6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C 1 -C 6 linear or branched chain alkyl, (C 1 -C 6 linear or branched chain alkyl)aryl, (C 1 -C 6 linear or branched chain alkyl)heteroaryl, and (C 1 -C 6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF 3 , and C 3 -C 6 cycloalkyl;
R 0 , R 1 , R 4 , and R 6 are independently selected from hydrogen, C 1 -C 6 linear or branched chain alkyl, C 1 -C 6 linear or branched chain perfluoroalkyl, C 6 -C 10 aryl, monocyclic or bicyclic heteroaryl, comprising 5- and/or 6-membered rings, (aryl)C 1 -C 6 linear or branched chain alkyl, (heteroaryl)C 1 -C 6 linear or branched chain alkyl, heteroaryl, halogen, cyano, hydroxyl, C 1 -C 6 linear or branched chain alkoxy, amino, carboxy, aminocarbonyl, (heterocyclic)C 1 -C 6 linear or branched chain alkyl, (C 1 -C 6 linear or branched chain alkyl)aryl, (C 1 -C 6 linear or branched chain alkyl)heteroaryl, and (C 1 -C 6 linear or branched chain alkyl)heterocyclic, where said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, alkylamino, dialkylamino, CF 3 , and C 3 -C 6 cycloalkyl; where, alternatively, R 0 or R 1 , and/or R 6 , respectively together with either of R 4 , R a , R b , R c or R d , may independently form a bond or a C 1 -C 6 linear alkyl chain; and/or, alternatively, R 4 , respectively together with either of R a , R b , R c or R d , may independently form a bond or a C 1 -C 6 linear alkyl chain; and,
R 8 , R 9 and R 10 are all hydrogen.

4. The method of claim 1 , wherein the compound is 1-(2R,5R)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(hydroxymethyl)piperidin-1-yl)prop-2-en-1-one, or, a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the compound is 1-((3R,5R)-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-f

Assignees

• Pfizer

Inventors

• Thorarensen Atli
• Brown Matthew Frank
• Casimiro-Garcia Agustin
• Che Ye
• Coe Jotham Wadsworth
• Flanagan Mark Edward
• Gilbert Adam Matthew
• Hayward Matthew Merrill
• Langille Jonathan David
• Montgomery Justin Ian
• Telliez Jean-Baptiste
• Unwalla Rayomand Jal
• Trujillo John I

Classifications

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P11/08

  Bronchodilators · CPC title