# US 2010/0168077 A1 · Novel Pyridine Derivatives, Processes for Preparing Them, Pharmaceutical Compositions Thereof

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- Number: US 2010/0168077 A1
- Document ID: US20100168077A1
- Status: Published application
- Kind: A1
- Application number: 12/594,313
- Filed: 2008-03-31
- Published: 2010-07-01
- Earliest claimed: 2007-04-04
- Assignees: UCB Pharma S.A.
- Inventors: Duncan Hannah
- Web page: https://patentgrep.com/patent/US20100168077A1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- 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 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- 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

## Abstract

The present invention concerns 2-amino pyridine derivatives of formula 1 processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.

## Claims

### Claim 1

A compound having formula I or pharmaceutically acceptable salts thereof or stereoisomeric forms thereof, and the geometrical isomers, enantiomers, diastereoisomers, and pharmaceutically acceptable salts thereof
* represents the point of attachment to the rest of the molecule
wherein:
B is aryl optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, halogen, C1-3 haloalkyl, hydroxyl, C1-3 alkoxy, C1-3 haloalkoxy, carboxylic acid, ester, C1-3 alkylsulfonyl, amide, sulfonamide, C1-3 dialkylamine, 3-10 member heterocycloalkyl, heteroaryl;
or B is a heteroaryl ring optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, halogen, C1-3 haloalkyl, hydroxyl, C1-3 alkoxy, C1-3 haloalkoxy, carboxylic acid, ester, C1-3 alkylsulfonyl, amide, sulfonamide, C1-3 dialkylamine, 3-10 member heterocycloalkyl, heteroaryl;
or is C1-6 alkyl optionally substituted with a substituent selected from the group consisting of aryl, heteroaryl, 3-10 member cycloalkyl, 3-10 member heterocycloalkyl, hydroxyl, C1-3 alkoxy, C1-3 haloalkoxy, carboxylic acid, ester, C1-3 alkylsulfonyl, amide, sulfonamide, C1-3 dialkylamine;
or B is C2-6 alkenyl optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, aryl, heteroaryl, 3-10 member cycloalkyl, 3-10 member heterocycloalkyl, hydroxyl, C1-3 alkoxy, C1-3 haloalkoxy, carboxylic acid, ester, C1-3 alkylsulfonyl, amide, sulfonamide, C1-3 dialkylamine;
or B is C3-10 cycloalkyl optionally substituted by C1-6 alkyl;
or B is C3-10 cycloalkenyl optionally substituted by C1-6 alkyl;
or B is a group of formula II
wherein
Rb is hydrogen or C1-6 alkyl;
Rc is C3-10 cycloalkyl optionally substituted by C1-3 alkyl;
or Rb and Rc can form together with the nitrogen, a 3-10 member heterocycloalkyl or a heteroaryl optionally substituted by C1-6 alkyl;
D is a group of formula III
wherein
Ra is hydrogen or unsubstituted C1-3 alkyl;
p is 1 or 2 or 3;
Y is a group of formula IV
wherein
Rd is hydrogen or unsubstituted C1-3 alkyl;
Re is hydrogen or unsubstituted C1-3 alkyl;
Rf is hydrogen or unsubstituted C1-3 alkyl;
or Y is a group of formula V
N—Rg formula V
wherein
Rg is hydrogen or unsubstituted C1-3 alkyl;
or D is a group of formula VI
wherein
Rh is hydrogen or unsubstituted C1-3 alkyl;
Ri is hydrogen or unsubstituted C1-3 alkyl;
or D is a group of formula VII
wherein
q is 1 or 2 or 3;
Rk is hydrogen or unsubstituted C1-3 alkyl;
Rl is hydrogen or unsubstituted C1-3 alkyl;
Rm is hydrogen or unsubstituted C1-3 alkyl;
or D is group of formula VIII
wherein
r is 1 or 2;
Rn is hydrogen or unsubstituted C1-3 alkyl;
Ro is hydrogen or unsubstituted C1-3 alkyl;
Rp is hydrogen or unsubstituted C1-3 alkyl;
or D is a group of formula IX
or D is a group of formula X
wherein
Rq is hydrogen or unsubstituted C1-3 alkyl;
or D is a group of formula XI
wherein
Rr is hydrogen or unsubstituted C1-3 alkyl;
Rs is hydrogen or unsubstituted C1-3 alkyl;
s is 1 or 2
t is 1 or 2;
or D is a group of formula XII
wherein
Rt is hydrogen or unsubstituted C1-3 alkyl.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein B is aryl optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, halogen, hydrogen, C1-3 haloalkyl, hydroxyl, C1-3 alkoxy, C1-3 haloalkoxy, carboxylic acid, ester, C1-3 alkylsulfonyl, amide, sulfonamide, C1-3 dialkylamine, 3-10 member heterocycloalkyl, heteroaryl; and D is a group of formula III wherein Ra is C1-3 alkyl, hydrogen; and p is 1 or 2 or 3; and Y is a group of formula IV wherein Rd is hydrogen or C1-3 alkyl; Re is hydrogen or C1-3 alkyl; Rf is hydrogen or C1-3 alkyl.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein B is C3-10 cycloalkyl optionally substituted by C1-6 alkyl; and D is a group of formula III wherein Ra is C1-3 alkyl, hydrogen; and p is 1 or 2 or 3; and Y is a group of formula V wherein Rg is hydrogen or C1-3 alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein B is C3-10 cycloalkenyl optionally substituted by C1-6 alkyl; and D is a group of formula III wherein Ra is C1-3 alkyl, hydrogen; and p is for 2 or 3; and Y is a group of formula IV wherein Rd is hydrogen or C1-3 alkyl; Re is hydrogen or C1-3 alkyl; Rf is hydrogen or C1-3 alkyl.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein B is C3-10 cycloalkenyl optionally substituted by C1-6 alkyl; and D is a group of formula III wherein Ra is C1-3 alkyl, hydrogen; and p is 1 or 2 or 3; and Y is a group of formula V wherein Rg is hydrogen or C1-3 alkyl.

### Claim 6 (depends on 1)

The compound according to claim 1 wherein aryl optionally substituted with a substituent selected from the group consisting of C1-6 alkyl, halogen, hydrogen, C1-3 haloalkyl, hydroxyl, C1-3 alkoxy, C1-3 haloalkoxy, carboxylic acid, ester, C1-3 alkylsulfonyl, amide, sulfonamide, C1-3 dialkylamine, 3-10 member heterocycloalkyl, heteroaryl; and D is a group of formula III wherein Ra is C1-3 alkyl, hydrogen; and p is 1 or 2 or 3; and Y is a group of formula V wherein Rg is hydrogen or C1-3 alkyl.

### Claim 7 (depends on 1)

The compound according to claim 1 wherein B is a group of formula II wherein Rb is hydrogen, C1-6 alkyl; Rc is C3-10 cycloalkyl optionally substituted by C1-3 alkyl; and D is a group of formula III wherein Ra is C1-3 alkyl, hydrogen; and p is 1 or 2 or 3; and Y is a group of formula V wherein Rg is hydrogen or C1-3 alkyl.

### Claim 8 (depends on 1)

The compound according to claim 1 wherein B is a group of formula II wherein Rb and Rc can form together with the nitrogen, a 3-10 member heterocycloalkyl optionally substituted by C1-6 alkyl; and D is a group of formula III wherein Ra is hydrogen; and p is 1; and Y is a group of formula IV wherein Rd is hydrogen; Re is hydrogen; and Rf is C1-3 alkyl.

### Claim 9 (depends on 1)

The compound according to claim 1 wherein B is a group of formula II wherein Rb and Rc can form together with the Nitrogen atom a 3-10 member heterocycloalkyl or heteroaryl optionally substituted by C1-6 alkyl; and D is a group of formula III wherein Ra is C1-3 alkyl, hydrogen; and p is 1 or 2 or 3; and Y is a group of formula IV wherein Rd is hydrogen, C1-3 alkyl; Re is hydrogen, C1-3 alkyl; Rf is hydrogen, C1-3 alkyl.

### Claim 10 (depends on 1)

The compound according to claim 1 wherein B is a group of formula II wherein Rb and Rc can form together with the nitrogen, a 3-10 member heterocycloalkyl optionally substituted by C1-6 alkyl; and D is a group of formula III wherein Ra is hydrogen; and p is 1; and Y is a group of formula IV wherein Rd is hydrogen; Re is hydrogen; and Rf is C1-3 alkyl.

### Claim 11 (depends on 1)

The compound according to claim 1 wherein B is a group of formula II wherein Rb is hydrogen; Rc is C3-10 cycloalkyl; and D is a group of formula III wherein Ra is hydrogen; and p is 2; and Y is a group of formula V wherein Rg is C1-3 alkyl.

### Claim 12 (depends on 1)

The compound according to claim 1 wherein B is an aryl optionally substituted by C1-6 alkyl; and D is a group of formula III wherein Ra is hydrogen; and p is 2; and Y is a group of formula V wherein Rg is C1-3 alkyl.

### Claim 13 (depends on 1)

The compound according to claim 1 wherein B is aryl optionally substituted by halogen; and D is a group of formula III wherein Ra is hydrogen; and p is 1; and Y is a group of formula IV wherein Rd is hydrogen; and Re is hydrogen; and Rf is hydrogen or C1-3 alkyl.

### Claim 14 (depends on 1)

The compound according to claim 1 wherein B is C3-10 cycloalkenyl optionally by C1-6 alkyl group; and D is a group of formula III wherein Ra is hydrogen; and p is 1; and Y is a group of formula IV wherein Rd is hydrogen; and Re is hydrogen; and Rf is C1-3 alkyl.

### Claim 15 (depends on 1)

The compound according to claim 1 selected from the group consisting of:
6-cyclohex-1-en-1-yl-4-[3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine-;
6-(4-chlorophenyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;
6-(4-methylcyclohex-1-en-1-yl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;
6-adamantan-2-yl-4-(4-methylpiperazin-1-yl)pyridin-2-amine;
4-(3-aminopyrrolidin-1-yl)-6-cyclohex-1-en-1-ylpyridin-2-amine;
6-(3-methylphenyl)-4-(4-methylpiperazin-1-yl)pyridin-2-amine;
4-[(3R)-3-aminopyrrolidin-1-yl]-6-(4-chlorophenyl)pyridin-2-amine;
4-(4-methylpiperazin-1-yl)-6-(4-methylpiperidin-1-yl)pyridin-2-amine;
N-cycloheptyl-4-(4-methylpiperazin-1-yl)pyridine-2,6-diamine;
4-[3-(methylamino)pyrrolidin-1-yl]-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine;
4-(4-methylpiperazin-1-yl)-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine;
4-[3-(methylamino)pyrrolidin-1-yl]-6-(4-methylpiperidin-1-yl)pyridin-2-amine;
4-[(3-methylamino)pyrrolidin-1-yl]-6-(4-trifluoromethylphenyl)pyridin-2-amine;
4-[(3-methylamino)pyrrolidin-1-yl]-6-(4-trifluoromethoxyphenyl)pyridin-2-amine;
6-(4-chlorophenyl)-4-[(3-methylamino)pyrrolidin-1-yl)pyridin-2-amine;
4-[(3-methylamino)pyrrolidin-1-yl]-6-(3-methylphenyl)pyridin-2-amine.

### Claim 16 (depends on 1)

The compound according to claim 1 selected from the group consisting of:
N-cycloheptyl-4-(4-methylpiperazin-1-yl)pyridine-2,6-diamine;
4-[3-(methylamino)pyrrolidin-1-yl]-6-(2-methylpyrrolidin-1-yl)pyridin-2-amine;
4-[(3-methylamino)pyrrolidin-1-yl]-6-(3-methylphenyl)pyridin-2-amine.
6-cyclohex-1-en-1-yl-4-[3-(methylamino)pyrrolidin-1-yl]pyridin-2-amine-;
6-(4-chlorophenyl)-4-[(3-methylamino)pyrrolidin-1-yl)pyridin-2-amine.

### Claim 17

Synthesis intermediates selected from a group consisting of:
2,6-difluoro-4-(4-methylpiperazinyl)pyridine;
2-fluoro-4-(4-methylpiperazinyl)-6-(4-methoxybenzylamino)pyridine;
2,6-difluoro-4-((3-N-methyl-N-tertbutoxycarbonylamino)pyrrolidino)-pyridine;
2-(4-methoxybenzylamino)-4-((3-N-methyl-N-tertbutoxycarbonylamino)pyrrolidino)-6-fluoropyridine;
2,6-dibromo-4-((3-tertbutoxycarbonylamino)pyrrolidino)-pyridine;
2-bromo-4-((3-N-methyl,N-tertbutoxycarbonylamino)pyrrolidino)-6-(4-methoxybenzylamino-pyridine;
2,6-dichloro-4-((N-tertbutoxycarbonylamino)pyrrolidino)pyridine;
2-chloro-6-(4-methoxybenzylamino)-4-((N-tertbutoxycarbonylamino)pyrrolidino)pyridine;
2-chloro-4-(4-methylpiperazin-1-yl)-6-(4-methoxybenzylamino)pyridine;
2-(2-adamantyl)-4-(4-methylpiperazin-1-yl)-6-(4-methoxybenzylamino)pyridine.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 19

(canceled)

### Claim 20 (depends on 1)

A method of treating an H4 dependent disease in a subject in need thereof comprising administering a compound or a pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1.

### Claim 21 (depends on 21)

The method of claim 21 wherein the H4 dependent disease is adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion; female and male sexual dysfunction, overactive bladder conditions, urinary incontinence, neurogenic detrusor overactivity, idiopathic detrusor overactivity, benign prostate hyperplasia and lower urinary tract symptoms; dermatological diseases such as dermatitis and psoriasis and treatment of itchy skin; thromboembolic diseases, atherosclerosis, myocardial infarction, angina pectoris, (unstable angina) myocardial ischaemia and arrhythmia, reocclusions and restenosis following angioplasty or coronary bypass, stroke, transitory ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses, hypotension, pulmonary hypertension, malignant hypertension, cardiac insufficiency, heart or kidney failure, stroke and renal dysfunction; diseases of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease, ulcerative colitis; autoimmune diseases including rheumatoid arthritis, multiple sclerosis; cancer; pain; or lymphatic diseases.

### Claim 22 (depends on 21)

The method of claim 21 wherein the H4 dependent disease is adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis, chronic sinusitis, allergy, allergy induced airway responses, allergic rhinitis, viral rhinitis, non-allergic rhinitis, perennial and seasonal rhinitis, nasal congestion, allergic congestion or dermatological diseases such as dermatitis and psoriasis and treatment of itchy skin or diseases of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease, ulcerative colitis, or autoimmune diseases including rheumatoid arthritis, or multiple sclerosis.

### Claim at position 23

-24. (canceled)