# US 2014/0155390 A1 · Novel selective androgen receptor modulators

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- Number: US 2014/0155390 A1
- Document ID: US20140155390A1
- Status: Published application
- Kind: A1
- Application number: 14/093,812
- Filed: 2013-12-02
- Published: 2014-06-05
- Earliest claimed: 2012-12-03
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: James Thomas Anderson; Eugene Lvovich Piatnitski Chekler; Edmund L. Ellsworth; Bruce Kipp Erickson; Adam Matthew Gilbert; Anthony P. Ricketts; David P. Thompson; Rayomand Jal Unwalla; Patrick Robert Verhoest
- Web page: https://patentgrep.com/patent/US20140155390A1

## CPC

- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 5/26: Androgens
- A61P 5/28: Antiandrogens
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 255/58: containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C 255/59: the carbon skeleton being further substituted by singly-bound oxygen atoms
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D 211/22: by oxygen atoms
- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 285/10: 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to a compound of Formula 1, 2 or 3: wherein A is N or —CR0—, where R0 is hydrogen, C1-C6 linear or branched chain alkyl, etc., Z is —CRe—, or, —N—, where Re is hydrogen, C1-C6 linear or branched chain alkyl,etc.; R1 is hydrogen, C1-C6 linear or branched chain alkyl, etc.; R2 are independently hydrogen or C1-C6 linear or branched chain alkyl; R3 and R4 are independently hydrogen, C1-C6 linear or branched chain alkyl, etc.;. R5 and R6 are independently hydrogen or C1-C6 linear or branched chain alkyl, etc.; R8 is hydrogen, C1-C6 linear or branched chain alkyl, etc.; R9 and R10 are independently hydrogen or C1-C6 linear or branched chain alkyl, etc.; Q is —CO—, —(CH2)q—, —(CHRs)q—, or (CRsRt)q—, where Rs and Rt are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where q is 0, 1, 2, or 3; and, where n is 0, 1, 2, 3, 4 or 5; or, a pharmaceutically acceptable salt thereof, to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly, those affected or mediated by the androgen receptor.

## Claims

### Claim 1

A compound of Formula 1, 2 or 3:
wherein A is N or —CR0—, where R0 is hydrogen, C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, perfluoroaryl, alkylaryl, heteroaryl; or, alkylheteroaryl
X and Y are independently —CH2—, —CHRa—, or, —CRaRb—, where Ra and Rb are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or, alkylheteroaryl; or, Ra and Rb together form a chain comprising —(CH2)j—, —(CHRc)j—, or —(CRcRd)j—, where Rc and Rd are independently C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where j is 2; 3, 4 or 5
Z is −CR3—, or, —N—, where Re is hydrogen, C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, heteroaryl or, alkylheteroaryl;
R1 is hydrogen, C1-C6 linear or branched chain alkyl, aryl, C1-C6 linear or branched chain perfluoroalkyl, alkylaryl, heteroaryl, alkylheteroaryl, C1-C6 linear or branched chain alkoxylcarbonyl, C1-C6 linear or branched chain alkylamino-carbonylamino, C6 linear or branched chain alkyloxycarbonylamino, C1-C6 linear or branched chain alkylcarbonylamino, or, C1-C6 linear or branched chain alkylaminocarbonyl;
R2 are independently hydrogen or C1-C6 linear or branched chain alkyl;
R3 and R4 are independently hydrogen, C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, C1-C6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, hydroxyl, aryl, heteroaryl, C1-C6 linear or branched chain alkoxylcarbonyl, C1-C6 linear or branched chain alkylamino-carbonylamino, or, C1-C6 linear or branched chain alkylaminocarbonyl;
R5 and R6 are independently hydrogen or C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, cyano, hydroxyl, amino, carboxy, hydroxyl, aryl, heteroaryl, or, R5 and R6 together form a chain comprising —(CH2)k—, —(CHR7)k—, or (CR7aR7b)k—, where R7, R7a, and R7b are independently C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where k is 2; 3, 4 or 5;
R8 is hydrogen, C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, aryl, aryl substituted with one, two or three fluorine atoms, perfluoroaryl, alkylaryl, heteroaryl; or, alkylheteroaryl; or, R1 and R8 together form a chain comprising —(CH2)m—, —(CHRf)m—, or —(CRfRg)m—, where Rf and Rg are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where m is 2; 3, 4 or 5;
R9 and R10 are independently hydrogen or C1-C6 linear or branched chain alkyl, C1-C6 linear or branched chain perfluoroalkyl, cyano, hydroxyl, amino, carboxy, hydroxyl, aryl, heteroaryl, or, R9 and R10 together form a chain comprising —(CH2)p—, —(CHRh)p—, or —(CRhRi)p—, where Rh and Ri are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where p is 2; 3, 4 or 5;
Q is —CO—, —(CH2)q—, —(CHRs)q—, or —(CRsRt)q—, where Rs and Rt are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where q is 0, 1, 2, or 3; and, where n is 0, 1, 2, 3, 4 or 5; or, a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 having Formula 1 wherein R1 and R2 are independently C1-C6 linear or branched chain alkyl; and, R3 and R4 are both hydrogen.

### Claim 3 (depends on 2)

The compound of claim 2 wherein R1 and R2 are independently methyl, ethyl or propyl.

### Claim 4 (depends on 1)

The compound of claim 1 having Formula 2 wherein Q is —(CH2)q—, —(CHRs)q—, or (CRsRt)q—, where Rs and Rt are independently C1-C6 linear or branched chain alkyl; and, q is 1 or 2.

### Claim 5 (depends on 4)

The compound of claim 4 wherein Q is CO—.

### Claim 6 (depends on 1)

The compound of claim 1 having Formula 3 wherein X and Y are independently —CH2—, —CHRa—, or, —CRal Rb—, where Ra and Rb are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or, alkylheteroaryl.

### Claim 7 (depends on 6)

The compound of claim 6 wherein X and Y are independently —CH2—, —CHRa—, or, —CRaRb—, where Ra and Rb are independently methyl, ethyl.

### Claim 8 (depends on 1)

The compound of claim 1 selected from the group consisting of:
6-[(3S)-3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile;
6-[(3S)-3-ethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile
6-[(3R)-1,1-dioxido-3-(2,2,2-trifluoroethyl)-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile;
6-[(3R)-1,1-dioxido-3-(2-phenylethyl)-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile;
6-[1-methyl-(3S)-3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile;
6-{(3R)-1,1-dioxido-3-[3-(trifluoromethyl)phenyl]-1,2,5-thiadiazolidin-2-yl}isoquinoline-1-carbonitrile;
6-[(3S)-3-(4-chlorophenyl)-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile;
6-[(3S)-3-methyl-1,1-dioxido-1,2-thiazolidin-2-yl]isoquinoline-1-carbonitrile;
6-[(3S)-3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]naphthalene-1-carbonitrile;
6-[(4R)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile;
6-[(4S)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile;
6-{(3R)-1,1-dioxido-3-(3-phenyl)-1,2,5-thiadiazolidin-2-yl}isoquinoline-1-carbonitrile;
6-(4,4-dimethyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl}isoquinoline-1-carbonitrile;
6-(6,6-dioxido-6-thia-5,7-diazaspiro[2.5]oct-5-yl)isoquinoline-1-carbonitrile;
6-[(4R)-4-(3-methylbenzyl)-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile;
6-[(4R)-6-ethyl-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile;
6-(5-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)isoquinoline-1-carbonitrile;
6-[(4S)-4-(4-methylphenyl)-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile;
6-[(4R)-4-(4-methylphenyl)-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile;
6-[(4S)-4-(3-methylphenyl)-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile;
6-[(4S)-4-ethyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile; and,
6-(1,1-dioxido-4-propyl-1,2,6-thiadiazinan-2-yl)isoquinoline-1-carbonitrile,
6-{[(2R,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl]amino}isoquinoline-1-carbonitrile;
6-{(2R)-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]azetidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2S)-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]azetidin-1-yl}isoquinoline-1-carbonitrile;
6-{methyl-[(2R,3R)-4,4,4-trifluoro-3-hydroxybutan-2-yl]amino}isoquinoline-1-carbonitrile;
6-{methyl-[(2R,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl]amino}isoquinoline-1-carbonitrile;
6-{(2R)-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]piperidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2R)-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]piperidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2R,5R)-2-methyl-5-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2R,5R)-2-[(1R)-1-hydroxyethyl]-5-methylpyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(5R)-2-oxo-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(5S)-2-oxo-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2R)-2-[(1R)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2R)-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2S)-2-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2S)-2-[(1 R)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2S,5S)-2-methyl-5-[(1S)-2,2,2-trifluoro-1-hydroxyethyl]pyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-{(2R,5R)-2-[(1S)-1-hydroxyethyl]-5-methylpyrrolidin-1-yl}isoquinoline-1-carbonitrile;
6-((2R,3S)-4,4,4-trifluoro-3-hydroxybutan-2-ylamino)-1-naphthonitrile;
6-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)azetidin-1-yl)-1-naphthonitrile;
6-((S)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)azetidin-1-yl)-1-naphthonitrile
6-(methyl((2R,3R)-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-1-naphthonitrile;
6-(methyl((2R,3S)-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-1-naphthonitrile;
6-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)-1-naphthonitrile;
6-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)piperidin-1-yl)-1-naphthonitrile;
6-((2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile;
6-((2R,5R)-2-((R)-1-hydroxyethyl)-5-methylpyrrolidin-1-yl)-1-naphthonitrile;
6-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile;
6-((S)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile;
6-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile;
6-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile;
6-((S)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile;
6-((S)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile;
6-((2S,5S)-2-methyl-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-1-naphthonitrile; and,
6-((2R,5R)-2-((S)-1-hydroxyethyl)-5-methylpyrrolidin-1-yl)-1-naphthonitrile, or, a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1 comprising 6-[(3R)-3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1 comprising 6-[(3S)-3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]isoquinoline-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1 comprising 6-[(4R)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1 comprising 6-[(4S)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1 comprising 6-(methyl-((2R,3R)-4,4,4-trifluoro-3-hydroxybutan-2-yl)amino)-1-naphthonitrile, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A method for modulating an activity of an androgen receptor in a subject in need thereof, comprising contacting said androgen receptor with an effective amount of a compound of claim 1, thereby modulating the activity of said androgen receptor.

### Claim 15 (depends on 1)

A method for treating a disorder or condition in a subject, wherein the disorder or condition is selected from among anemia; anorexia; arthritis; bone disease; musculoskeletal impairment; cachexia; frailty; age-related functional decline in the elderly; growth hormone deficiency; hematopoietic disorders; hormone replacement; loss of muscle strength and/or function; muscular dystrophies; muscle loss following surgery; muscular atrophy; neurodegenerative diseases; neuromuscular disease; obesity; osteoporosis; and, muscle wasting, comprising administering to said subject an effective amount of a compound of claim 1, thereby treating said disease or condition.