Compounds and methods of use

• US 10,501,436 B2
• Filed: 03/23/2018
• Issued: 12/10/2019
• Est. Priority Date: 01/01/2014
• Status: Active Grant

• Current Assignee: Medivation Technologies LLC (Pfizer Inc.)
• Original Assignee: Medivation Technologies LLC (Pfizer Inc.)
• Inventors: Rai, Roopa, Chakravarty, Sarvajit, Pujala, Brahmam, Shinde, Bharat Uttam, Nayak, Anjan Kumar, Chaklan, Naveen, Agarwal, Anil Kumar, Ramachandran, Sreekanth A., Pham, Son Minh
• Primary Examiner(s): Pihonak, Sarah
• Application Number:
  US15/933,532
• Publication Number:
  US 20180208577A1
• Time in Patent Office: 627 Days
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/72 Nitrogen atoms nitro radicals C07D213/61
• CPC Class Codes: C07D 213/73 : Unsubstituted amino or imino radicals
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

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.

Claims

1. 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.

2. The method of claim 1, further comprising administering to the individual a cancer immunotherapy.

3. The method of claim 2, wherein the cancer immunotherapy comprises a therapy selected from the group consisting of a cell-based therapy, an antibody therapy, a cytokine therapy, and an indoleamine 2,3-dioxygenase (IDO) therapy.

4. The method of claim 3, wherein the cancer immunotherapy comprises a cell-based therapy, wherein the cell-based therapy comprises a cell selected from the group consisting of natural killer cell, a lymphokine-activated killer cell, a cytotoxic T cell, a regulatory T cell, and a dendritic T cell.

5. The method of claim 3, wherein the cancer immunotherapy comprises a cell-based therapy, wherein the cell-based therapy comprises sipuleucel-T.

6. The method of claim 3, wherein the cancer immunotherapy comprises an antibody therapy.

7. The method of claim 6, wherein the antibody therapy comprises an antibody to a cell surface receptor, wherein the cell surface receptor is selected from the group consisting of epidermal growth factor and HER2.

8. The method of claim 6, wherein the antibody therapy comprises an antibody to an immune checkpoint molecule, wherein the immune checkpoint molecule is selected from the group consisting of PD-1, PD-L1, and CTLA-4.

9. The method of claim 6, wherein the antibody therapy comprises an antibody selected from the group consisting of Pidilizumab, Alemtuzumab, Bevacizumab, Brentuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, and Trastuzumab.

10. The method of claim 1, comprising administering

11. The method of claim 10, further comprising administering to the individual a cancer immunotherapy.

12. The method of claim 11, wherein the cancer immunotherapy comprises a therapy selected from the group consisting of a cell-based therapy, an antibody therapy, a cytokine therapy, and an indoleamine 2,3-dioxygenase (IDO) therapy.

13. The method of claim 12, wherein the cancer immunotherapy comprises a cell-based therapy, wherein the cell-based therapy comprises a cell selected from the group consisting of natural killer cell, a lymphokine-activated killer cell, a cytotoxic T cell, a regulatory T cell, and a dendritic T cell.

14. The method of claim 12, wherein the cancer immunotherapy comprises a cell-based therapy, wherein the cell-based therapy comprises sipuleucel-T.

15. The method of claim 12, wherein the cancer immunotherapy comprises an antibody therapy.

16. The method of claim 15, wherein the antibody therapy comprises an antibody to a cell surface receptor, wherein the cell surface receptor is selected from the group consisting of epidermal growth factor and HER2.

17. The method of claim 15, wherein the antibody therapy comprises an antibody to an immune checkpoint molecule, wherein the immune checkpoint molecule is selected from the group consisting of PD-1, PD-L1, and CTLA-4.

18. The method of claim 15, wherein the antibody therapy comprises an antibody selected from the group consisting of Pidilizumab, Alemtuzumab, Bevacizumab, Brentuximab vedotin, Cetuximab, Gemtuzumab ozogamicin, Ibritumomab tiuxetan, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tositumomab, and Trastuzumab.

19. The method of claim 1, wherein the individual has a tumor and the tumor is selected from the group consisting of a breast tumor, a prostate tumor, a lung tumor, a skin tumor, a colorectal tumor, a pancreatic tumor, and a brain tumor.

20. The method of claim 19, comprising administering

21. The method of claim 20, wherein the pharmaceutically acceptable salt is a hydrochloride salt.