US 10,501,436 B2Granted

Compounds and methods of use

AssigneeMedivation Technologies, Inc.

InventorsRoopa Rai, Sarvajit Chakravarty, Brahmam Pujala, Bharat Uttam Shinde, Anjan Kumar Nayak, Naveen Chaklan, Anil Kumar Agarwal, Sreekanth A. Ramachandran, Son Minh Pham

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Abstract

This disclosure provides compounds and compositions and methods of using those compounds and compositions to treat diseases and disorders associated with excessive transforming growth factor-beta (TGFβ) activity. This disclosure also provides methods of using the compounds in combination with one or more cancer immunotherapies.

Claims21

Dependent claims

A method of inhibiting SMAD-2 or ALK1-5 in an individual, comprising administering to the individual an effective amount of a compound or a pharmaceutically acceptable salt of the compound, wherein the compound is selected from the group consisting of:

4-(5-bromo-2-(5-chloro-2-fluorophenyl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide;
1-((4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)methylamino)propan-2-ol;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxy-2-methylpropan-2-yl)nicotinamide;
(4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone;
4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide;
4-(2-(5-chloro-2-fluorophenyl)-5-methoxypyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
N-(2-acetamidoethyl)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)nicotinamide;
N-(2-amino-2-oxoethyl)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(2-methoxypropan-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-(methylsulfonamido)ethyl)nicotinamide;
N-(2-aminoethyl)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)nicotinamide;
3-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide;
3-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide;
4-(2-amino-6-(5-chloro-2-fluorophenyl)-3-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxybutan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxy-3-methylbutan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxyethyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-cyclopropylnicotinamide;
N-(2-hydroxypropyl)-4-(5-isopropyl-2-phenylpyridin-4-ylamino)nicotinamide;
N-(3′-fluoro-5-isopropyl-2,2′-bipyridin-4-yl)-1H-pyrrolo [2,3-b]pyridin-4-amine;
N-(3′-fluoro-5-isopropyl-2,2′-bipyridin-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine;
4-(2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
N-(2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-yl)-1H-pyrrolo [2,3-b]pyridin-4-amine;
4-(2-(5-chloro-2-fluorophenyl)-5-(pyrrolidin-1-yl)pyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide;
(4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)pyridin-3-yl)(pyrrolidin-1-yl)methanone;
N-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine;
N-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-yl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine;
4-(2-(2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(4-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(3-chlorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
N-(2-hydroxypropyl)-4-(5-(prop-1-en-2-yl)-2-(3-(trifluoromethyl)phenyl)pyridin-4-ylamino)nicotinamide;
N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-4-amine;
N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-5-amine;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxybutan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide;
4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxolan-3-yl)pyridine-3-carboxamide;
4-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide;
N-[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]quinolin-4-amine;
N4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl)-N2-methylpyridine-2,4-diamine;
4-(2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(2,5-difluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
and
4-(2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide.

52 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/933,532Filed 23 Mar 2018 · continuation
Priority: IN 6/DEL/20141 Jan 2014
Published: US 2018/0208577 A126 Jul 2018
Granted: 10 Dec 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Family

PCT/US2014/072922Parent of this continuation · filed 31 Dec 2014
US 2018/0208577 A1Pre-grant publication · published 26 Jul 2018
Application15/109,013Parent of this continuation
US 10,030,004 B2Parent of this continuation
US 2016/0326137 A1Published application
US 10,501,436 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

4-(5-bromo-2-(5-chloro-2-fluorophenyl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide;
1-((4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)methylamino)propan-2-ol;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxy-2-methylpropan-2-yl)nicotinamide;
(4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)(4-hydroxypiperidin-1-yl)methanone;
4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide;
4-(2-(5-chloro-2-fluorophenyl)-5-methoxypyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
N-(2-acetamidoethyl)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)nicotinamide;
N-(2-amino-2-oxoethyl)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(2-methoxypropan-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-(methylsulfonamido)ethyl)nicotinamide;
N-(2-aminoethyl)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)nicotinamide;
3-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide;
3-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide;
4-(2-amino-6-(5-chloro-2-fluorophenyl)-3-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxybutan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxy-3-methylbutan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxyethyl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-cyclopropylnicotinamide;
N-(2-hydroxypropyl)-4-(5-isopropyl-2-phenylpyridin-4-ylamino)nicotinamide;
N-(3′-fluoro-5-isopropyl-2,2′-bipyridin-4-yl)-1H-pyrrolo [2,3-b]pyridin-4-amine;
N-(3′-fluoro-5-isopropyl-2,2′-bipyridin-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine;
4-(2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
N-(2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-yl)-1H-pyrrolo [2,3-b]pyridin-4-amine;
4-(2-(5-chloro-2-fluorophenyl)-5-(pyrrolidin-1-yl)pyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide;
(4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)pyridin-3-yl)(pyrrolidin-1-yl)methanone;
N-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-yl)-7H-pyrrolo [2,3-d]pyrimidin-4-amine;
N-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-yl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine;
4-(2-(2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(4-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(3-chlorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
N-(2-hydroxypropyl)-4-(5-(prop-1-en-2-yl)-2-(3-(trifluoromethyl)phenyl)pyridin-4-ylamino)nicotinamide;
N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-4-amine;
N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-5-amine;
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxybutan-2-yl)nicotinamide;
4-(2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide;
4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxolan-3-yl)pyridine-3-carboxamide;
4-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide;
N-[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]quinolin-4-amine;
N4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl)-N2-methylpyridine-2,4-diamine;
4-(2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(2,5-difluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
4-(2-(2-fluoro-5-(trifluoromethyl)phenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide;
and
4-(2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide.

52 more elements

Facts

Application

15/933,532Filed 23 Mar 2018 · continuation

Priority

IN 6/DEL/20141 Jan 2014

Published

US 2018/0208577 A126 Jul 2018

Granted

10 Dec 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification31 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/4439
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Family

PCT/US2014/072922Parent of this continuation · filed 31 Dec 2014

US 2018/0208577 A1Pre-grant publication · published 26 Jul 2018

Application15/109,013Parent of this continuation

US 10,030,004 B2Parent of this continuation

US 2016/0326137 A1Published application

US 10,501,436 B2This patent

From the US filing history. Foreign family members aren’t listed.