# US 10,501,436 B2 · Compounds and methods of use

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- Number: US 10,501,436 B2
- Document ID: US10501436B2
- Status: Granted
- Kind: B2
- Application number: 15/933,532
- Filed: 2018-03-23
- Published: 2018-07-26
- Granted: 2019-12-10
- Earliest claimed: 2014-01-01
- Assignees: Medivation Technologies, Inc.
- Applicants: Medivation Technologies LLC
- Inventors: Roopa Rai; Sarvajit Chakravarty; Brahmam Pujala; Bharat Uttam Shinde; Anjan Kumar Nayak; Naveen Chaklan; Anil Kumar Agarwal; Sreekanth A. Ramachandran; Son Minh Pham
- Web page: https://patentgrep.com/patent/US10501436B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/10: for osteoporosis
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/72: Nitrogen atoms (nitro radicals C07D213/61)
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 213/82: in position 3
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 3)

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.

### Claim 5 (depends on 3)

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

### Claim 6 (depends on 3)

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

### Claim 7 (depends on 6)

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.

### Claim 8 (depends on 6)

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.

### Claim 9 (depends on 6)

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.

### Claim 10 (depends on 1)

The method of claim 1, comprising administering
N-(2-aminoethyl)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)nicotinamide or
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 11)

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.

### Claim 13 (depends on 12)

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.

### Claim 14 (depends on 12)

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

### Claim 15 (depends on 12)

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

### Claim 16 (depends on 15)

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.

### Claim 17 (depends on 15)

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.

### Claim 18 (depends on 15)

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.

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 19)

The method of claim 19, comprising administering
4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide or
a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 20)

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