# US 10,246,469 B2 · Biaryl kinase inhibitors

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- Number: US 10,246,469 B2
- Document ID: US10246469B2
- Status: Granted
- Kind: B2
- Application number: 15/763,281
- Filed: 2016-09-29
- Published: 2019-02-07
- Granted: 2019-04-02
- Earliest claimed: 2015-10-01
- Assignees: Bristol-Myers Squibb Company; Syngene International Limited
- Applicants: Bristol-Myers Squibb Company
- Inventors: Joanne J. Bronson; Ling Chen; Jonathan L. Ditta; Carolyn Diane Dzierba; Prasada Rao Jalagam; Guanglin Luo; John E. Macor; Tarun Kumar Maishal; Susheel Jethanand Nara; Ramkumar Rajamani; Ramesh Kumar Sistla; Soodamani Thangavel
- Web page: https://patentgrep.com/patent/US10246469B2

## CPC

- C07D 513/04: Ortho-condensed systems
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4427: containing further heterocyclic ring systems
- A61K 31/50: Pyridazines; Hydrogenated pyridazines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/51: Thiamines, e.g. vitamin B1
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 213/65: attached in position 3 or 5
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 237/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/36: as doubly bound oxygen atom or as unsubstituted hydroxy radical
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 239/72: Quinazolines; Hydrogenated quinazolines
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: 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

The present disclosure is directed to biaryl compounds of formula (I) which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds and their use for treating e.g. pain, Alzheimer's disease, Parkinson's disease and schizophrenia.

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from
wherein “” denotes the point of attachment to B;
B is selected from
wherein “*” indicates the point of attachment to R5 and “**” indicates the point of attachment to ring A;
R1 is selected from hydrogen, amino, —CO2H, cyclopropyl, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methoxymethyl, methyl, —NHC(O)CH3, —NHCO2CH3, trifluoromethoxy, trifluoromethyl,
wherein Ra is selected from hydrogen, halo and methyl;
R2 is selected from hydrogen, cyano, —CH2OH, halo, and methyl;
R3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, fluoromethyl, halo, hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy, trifluoromethyl, —CH2N(CH3)2, and a five-membered aromatic ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur;
R4 is selected from hydrogen, halo, and methyl;
R5 is selected from
R6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl;
provided that when A is
then B is
R1 is selected from
cyclopropyl, methoxymethyl,
R5 is selected from

### Claim 2 (depends on 1)

A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from

### Claim 3 (depends on 2)

A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein B is selected from

### Claim 4 (depends on 1)

A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from

### Claim 5 (depends on 3)

A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein B is selected from

### Claim 6

A compound selected from
(S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-fluorophenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2,3-dimethylpyrido[2,3-b]pyrazin-8-yl)benzonitrile;
(S)-1-(2-fluoro-4-(pyrido[2,3-b]pyrazin-8-yl)phenoxy)-2,4-dimethylpentan-2-amine
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-amino-3H-imidazo [4,5-b]pyridin-7-yl)benzonitrile;
(S)-7-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)thiazol-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)thiazol-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)thiazole-2-carboxamide;
(S)-7-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)-3H-imidazo [4,5-b]pyridin-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)thiazole-2-carboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)thiazole-2-carboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)-4-methylthiazol-2-amine;
(R)-2,4-dimethyl-1-((3-methyl-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)pentan-2-amine;
(R)-1-((3-chloro-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine;
(R)-1-((5-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-((7-(2-methylpyridin-4-yl)benzo[d]thiazol-4-yl)oxy)pentan-2-amine;
(S)-methyl (4-(4-((2-amino-2,4-dimethylpentyl)oxy)benzo [d]thiazol-7-yl)pyridin-2-yl)carbamate;
(S)-2,4-dimethyl-1-(4-(2-methylthiazolo [5,4-d]pyrimidin-7-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methylthiazolo[5,4-d]pyrimidin-7-yl)benzonitrile;
(S)-1-((3-chloro-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-((3-methyl-5-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-2-yl)oxy)pentan-2-amine;
(S)-1-((2-(fluoromethyl)-6-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine
2-amino-2-(((2′,4-bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)methyl)-4-methylpentan-1-ol;
(S)-1-(4-(imidazo[1,2-b]pyridazin-8-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(imidazo[1,2-b]pyridazin-8-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzonitrile;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(imidazo[1,2-b]pyridazin-8-yl)benzonitrile;
(S)-1-(2-fluoro-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine
2,4-dimethyl-1-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-1-(4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methyl-3H-imidazo [4,5-b]pyridin-7-yl)benzonitrile;
(S)-2,4-dimethyl-1-(2-methyl-4-(2-methyl-3H-imidazo[4,5-b]pyridin-7-yl)phenoxy)pentan-2-amine;
(S)-1-(4-(2-(methoxymethyl)-3H-imidazo [4,5-b]pyridin-7-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(2-(methoxymethyl)-3H-imidazo[4,5-b]pyridin-7-yl)-2-methylphenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-oxo-2,3-dihydro-1H-pyrrolo [2,3-b]pyridin-4-yl)benzonitrile;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one
2-methyl-1-((2-methyl-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)propan-2-amine;
(S)-1-((2-(difluoromethyl)-6-(pyrazolo[1,5-a]pyrimidin-7-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(pyrazolo [,5-a]pyridin-3-yl)phenoxy)-2,4-dimethylpentan-2-amine (S)-2,4-dimethyl-1-(2-methyl-4-(pyrazolo[1,5-a]pyridin-3-yl)phenoxy)pentan-2-amine 4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-N-(3-fluorocyclopentyl)pyridin-2-amine;
(S)-1-(2-fluoro-4-(2-(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine
4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-N-(tetrahydro-2H-pyran-3-yl)pyridin-2-amine
4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-N-(tetrahydro-2H-pyran-3-yl)pyridin-2-amine
4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-N-(tetrahydro-2H-pyran-3-yl)pyridin-2-amine;
(S)-2,4-dimethyl-1-((7-(pyrazolo[1,5-a]pyrimidin-7-yl)benzo [d]thiazol-4-yl)oxy)pentan-2-amine;
(S)-2,4-dimethyl-1-((7-(2-methylpyrimidin-4-yl)benzo [d]thiazol-4-yl)oxy)pentan-2-amine
4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-N-(tetrahydrofuran-3-yl)pyridin-2-amine
4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)-N-(tetrahydrofuran-3-yl)pyridin-2-amine
1-(((3-methyl-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)methyl)cyclobutanamine;
(S)-1-(2-(difluoromethyl)-4-(pyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-(fluoromethyl)-4-(pyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2amine;
(S)-2,4-dimethyl-1-(5-methyl-2-(pyridin-4-yl)thiazol-4-yloxy)pentan-2-amine
6-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-(tetrahydro-2H-pyran-3-yl)pyrimidin-4-amine;
(S)-1-(2-chloro-4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)benzonitrile;
(S)-1-(4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(7-methyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)benzonitrile;
(S)-1-(2-fluoro-4-(7-methyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-(4-(7-methyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyrimidin-2-yl)thiazol-2-amine;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)-N-cyclopropylpyrimidin-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)thiazol-2-amine;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)-4-methylthiazol-2-amine;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-cyclopentylpyrimidin-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-((4-methylthiazol-2-yl)amino)pyrimidin-4-yl)benzonitrile;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyrimidin-2-yl)-4-methylthiazol-2-
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropanecarboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)cyclobutanecarboxamide
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopentanecarboxamide
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-2-cyclopentylacetamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-3-cyclopentylpropanamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-2-cyclohexylacetamide
N-(4-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)tetrahydrofuran-2-carboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-2-cycloheptylacetamide
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)furan-2-carboxamide
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-5-bromofuran-2-carboxamide;
(S)-2-acetamido-N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)thiophene-2-carboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)pyrazine-2-carboxamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-2-methylnicotinamide;
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-1H-1,2,3-triazole-5-carboxamide
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxamide
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-5-methylisoxazole-3-carboxamide
(S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-(pyridin-3-ylmethyl)pyridin-2-amine;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-(furan-2-ylmethyl)pyridin-2-amine;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-(benzo[d][1,3]dioxol-5-yl)pyridin-2-amine;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)-6-methyl-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)benzonitrile;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)benzonitrile;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-6-ethyl-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)-6-ethyl-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-1-(2-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1H-pyrrolo[3,2-b]pyridin-7-yl)benzonitrile;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)benzonitrile;
(S)-1-(4-(1H-pyrrolo[3,2-b]pyridin-7-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-6-methyl-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-2,4-dimethyl-1-(2-methyl-4-(1-methyl-1H-pyrrolo[3,2-b]pyridin-7-yl)phenoxy)pentan-2-amine;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)-6-methyl-6,7-dihydro-5H-pyrrolo [3,4-b]pyridin-5-one;
(S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one
6-(4-(((S)-2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine
6-(6-(((S)-2-amino-2,4-dimethylpentyl)oxy)-5-chloropyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine;
(S)-2,4-dimethyl-1-((2-methyl-6-(2-methylimidazo [1,2-b]pyridazin-8-yl)pyridin-3-yl)oxy)pentan-2-amine;
(S)-1-((2-(difluoromethyl)-6-(2-methylimidazo[1,2-b]pyridazin-8-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine;
(S)-7-(4-((2-amino-2,4-dimethylpentyl)oxy)-2-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;
(S)-1-(2-chloro-4-(pyrazolo [1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-7-(4-((2-amino-2,4-dimethylpentyl) oxy)-3-fluorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine;
(S)-1-(2-chloro-4-(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(pyrazolo[1,5-a]pyrimidin-7-yl)benzonitrile;
(S)-1-(2-fluoro-4-(pyrazolo [1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)—N-(7-(4-((2-amino-2,4-dimethylpentyl) oxy)-3-fluorophenyl) pyrazolo [1,5-a]pyrimidin-5-yl) acetamide;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)benzonitrile;
(S)-2-(2-amino-2,4-dimethylpentyloxy)-5-(2-(piperidin-4-ylamino) pyridin-4-yl) benzonitrile;
(S)-2,4-dimethyl-1-(4-(pyrazolo[1,5-a]pyrimidin-7-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-2-(2-amino-2,4-dimethylpentyloxy)-5-(2-(tetrahydro-2H-pyran-4-ylamino)pyridin-4yl)benzonitrile;
(S)-4-(4-(2-amino-2,4-dimethylpentyloxy)-3-(trifluoromethyl)phenyl)-N-(piperidin-4-yl)pyridin-2-amine;
(S)-1-(4-(6,7-difluoroquinazolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-(2-methyl-4-(pyrazolo [1,5-a]pyrimidin-7-yl)phenoxy)pentan-2-amine;
(S)-2,4-dimethyl-1-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine
4-(4-((5)-2-amino-2,4-dimethylpentyloxy)-3-(trifluoromethyl)phenyl)-N-(tetrahydro-2H-pyran-3-yl)pyridin-2-amine
4-(4-(((5)-2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-(tetrahydro-2H-pyran-3-yl)pyridin-2-amine
4-(4-(((5)-2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-N-(tetrahydro-2H-pyran-3-yl)pyridin-2-amine;
(S)-3-(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methylpyridin-2-yl)pyrazolo [1,5-a]pyrimidine-6-carbonitrile;
(S)-2,4-dimethyl-1-(4-(2-methylthieno [2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-1-(2-chloro-4-(2-cyclopropylpyrazolo [1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(2-Cyclopropylpyrazolo [1,5-a]pyrimidin-7-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-(trifluoromethyl)pyrazolo [1,5-a]pyrimidin-7-yl)benzonitrile;
(S)-5-((2-amino-2,4-dimethylpentyl)oxy)-2-(pyrazolo [1,5-a]pyrimidin-7-yl)isonicotinonitrile;
(S)-2,4-dimethyl-1-((2-methyl-6-(pyrazolo [1,5-a]pyrimidin-7-yl)pyridin-3-yl)oxy)pentan-2-amine;
(S)-1-(2,5-difluoro-4-(pyrazolo[1,5-a]pyrimidin-7-yl)phenoxy)-2,4-dimethylpentan-2-amine
1,1,1-trifluoro-4-methyl-2-(((2-methyl-6-(pyrazolo [1,5-a]pyrimidin-7-yl)pyridin-3-yl)oxy)methyl)pentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methylimidazo [1,2-b]pyridazin-8-yl)benzonitrile
(S)-1-(4-(2-cyclopropylimidazo [1,2-b]pyridazin-8-yl)-2-fluorophenoxy)-2,4-dimethylpentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-8-yl)benzonitrile;
(S)-1-(4-(6-chloro-2-methylimidazo [1,2-b]pyridazin-8-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(4-(6-chloro-2-cyclopropylimidazo [1,2-b]pyridazin-8-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-fluoro-4-(2-methylimidazo[1,2-b]pyridazin-8-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(S)-2,4-dimethyl-1-(4-(2-methylimidazo [1,2-b]pyridazin-8-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine;
(S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-cyclopropylimidazo[1,2-b]pyridazin-8-yl)benzonitrile;
(S)-2,4-dimethyl-1-(2-methyl-4-(2-(trifluoromethyl)imidazo [1,2-b]pyridazin-8-yl)phenoxy)pentan-2-amine;
(S)-2,4-dimethyl-1-(4-(2-(trifluoromethyl)imidazo [1,2-b]pyridazin-8-yl)phenoxy)pentan-2-amine;
(S)-1-(4-(imidazo[1,2-b]pyridazin-3-yl)-2-methylphenoxy)-2,4-dimethylpentan-2-amine;
(S)-1-(2-chloro-4-(imidazo [1,2-b]pyridazin-3-yl)phenoxy)-2,4-dimethylpentan-2-amine;
(R)-2,4-dimethyl-1-((3-methyl-5-(2-(trifluoromethyl)imidazo[1,2-b]pyridazin-8-yl)pyridin-2-yl)oxy)pentan-2-amine; and
(S)-6-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyrimidin-4(3H)-one;
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A composition comprising a pharmaceutically acceptable amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

A method of inhibiting adaptor associated kinase 1 (AAK1) activity, comprising contacting AAK1 with a compound of claim 1, or a pharmaceutically acceptable salt thereof.