Patent Application

App. No. 18/661,369

Abstract

Claims (135)

1 . A compound of Formula (I):

or pharmaceutically acceptable salt thereof,

wherein:

Z is N;

R 1 is —H;

Y is —CH 2 —;

R 2 is a member selected from the group consisting of:

A) phenyl substituted with one or two R d members, where each R d is independently selected from the group consisting of: —CN, —CONH 2 , and —CO 2 C 1-3 alkyl;

B) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OC 1-3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and —NH— cyclopropyl;

C) five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of —C 1-3 alkyl, —C 1-3 haloalkyl, —CH 2 OR b , —N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CO 2 N(R b ) 2 , and cyclopropyl; and

R 3 is phenyl substituted with one or two members each independently selected from the group consisting of —Cl, —OC 1-3 alkyl, and —OC 1-3 haloalkyl;

R 4 is —C 1-3 alkyl; and

each R b is independently —H or —CH 3 .

2 . The compound of claim 1 , wherein R 2 is six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OC 1-3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and —NH-cyclopropyl.

3 . The compound of claim 1 , wherein R 2 is a five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of —C 1-3 alkyl, —C 1-3 haloalkyl,

—CH 2 OR b , —N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CO 2 N(R b ) 2 , and cyclopropyl.

4 . The compound of claim 1 , wherein R 2 is 4-phenylamide or 4-phenylcarboxylic acid methyl ester.

5 . The compound of claim 1 , wherein R 2 is

where R d1 is —CONH 2 .

6 . The compound of claim 1 , wherein R 2 is

where R e1 is —OCH 3 , —CONH 2 , —NH 2 , —NHCH 3 , —NHCH 2 CH 2 OH, or —NHcyclopropyl.

7 . The compound of claim 1 , wherein R 2 is

where R f is —NH 2 , or —CH 2 OH.

8 . The compound of claim 1 , wherein R 2 is

where R 9 is —H, —CH 3 , —CH 2 OH, or

—NH 2 .

9 . The chemical entity as in claim 1 , wherein R 2 is

where R h is a member selected from the group consisting of: —H, —CH 3 , —CF 3 , —CH 2 F, —CHF 2 , —OCH 3 , —OCH 2 CH 3 , —CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 CONH 2 , —CONH 2 , —CO 2 CH 3 , and -cyclopropyl.

10 . The compound of claim 1 , selected from the group consisting of:

5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile;

5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide;

5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile;

3-(3-Chlorophenyl)-2-methoxy-5-[(2-methoxypyrimidin-5-yl)methyl]pyrazine;

5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-methylpyrimidin-2-amine;

5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-N-cyclopropylpyrimidin-2-amine;

3-(3-Chlorophenyl)-2-methoxy-5-[(1-methyl-1H-pyrazol-4-yl)methyl]pyrazine;

Methyl 4-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzoate;

4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzonitrile;

5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidin-2-amine;

5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyridine-2-carboxamide;

3-(3-Chlorophenyl)-5-[(dimethyl-1,2-oxazol-4-yl)methyl]-2-methoxypyrazine;

5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carbonitrile;

5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyrimidin-2-amine;

5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidin-2-amine;

5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidin-2-amine;

5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carbonitrile;

5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carbonitrile;

4-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}benzamide;

5-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide;

5-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)pyridine-2-carboxamide;

5-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)pyrimidine-2-carboxamide;

5-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}pyrimidine-2-carboxamide;

Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;

3-(3-Chlorophenyl)-2-methoxy-5-(1H-1,2,4-triazol-1-ylmethyl)pyrazine;

3-(3-Chlorophenyl)-2-methoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine;

3-(3-Chlorophenyl)-5-[(3-cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-2-methoxypyrazine;

3-(3-Chlorophenyl)-2-methoxy-5-[(4-nitro-1H-pyrazol-1-yl)methyl]pyrazine;

3-(3-Chlorophenyl)-2-methoxy-5-(1H-pyrazol-1-ylmethyl)pyrazine;

3-(3-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-2-methoxypyrazine;

3-(3-Chlorophenyl)-2-methoxy-5-[(4-methyl-1H-pyrazol-1-yl)methyl]pyrazine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-[(3-methyl-1H-1,2,4-triazol-1-yl)methyl]pyrazine;

5-[(3-Cyclopropyl-1H-1,2,4-triazol-1-yl)methyl]-3-[3-(difluoromethoxy)phenyl]-2-ethoxypyrazine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[5-(methoxymethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;

Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate;

Methyl 1-((6-(3-(difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-5-carboxylate;

3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine;

3-(3-(Difluoromethoxy)phenyl)-2-ethoxy-5-((5-nitro-1H-1,2,4-triazol-1-yl)methyl)pyrazine;

Methyl 1-{[6-(3-chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-5-carboxylate;

Methyl 1-({6-[3-(difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazole-3-carboxylate;

Methyl 1-{[6-(3-chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazole-3-carboxylate;

(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;

[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;

[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-5-yl]methanol;

(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-5-yl)methanol;

[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,4-triazol-3-yl]methanol;

(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,4-triazol-3-yl)methanol;

1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-pyrazol-4-amine;

1-((6-(3-(Difluoromethoxy)phenyl)-5-ethoxypyrazin-2-yl)methyl)-1H-1,2,4-triazol-3-amine;

3-[3-(Difluoromethoxy)phenyl]-2-ethoxy-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}pyrazine;

3-(3-Chlorophenyl)-5-{[3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl}-2-methoxypyrazine;

[1-({6-[3-(Difluoromethoxy)phenyl]-5-ethoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol;

(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol;

[1-({6-[3-(Difluoromethoxy)phenyl]-5-methoxypyrazin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]methanol;

(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methanol;

1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide;

1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-pyrazole-3-carboxamide;

1-{[6-(3,4-Difluorophenyl)-5-ethoxypyrazin-2-yl]methyl}-1H-imidazole-4-carboxamide;

(1-{[6-(3-Chlorophenyl)-5-methoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;

(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-5-methyl-1H-pyrazol-3-yl)methanol;

(1-{[6-(3-Chlorophenyl)-5-ethoxypyrazin-2-yl]methyl}-2-methyl-1H-imidazol-4-yl)methanol;

3-(3-Chlorophenyl)-5-{[4-(difluoromethyl)-2-methyl-1H-imidazol-1-yl]methyl}-2-ethoxypyrazine; and

pharmaceutically acceptable salts thereof.

11 . A compound of Formula (I):

or pharmaceutically acceptable salt thereof,

wherein:

Z is CH;

R 1 is a member selected from the group consisting of: —H, —C 1-3 alkyl and —C 1-3 haloalkyl;

Y is —C(R a ) 2 —, where each R a is independently selected from the group consisting of: —H, —F, —CH 3 , —OH and —N(R b ) 2 ;

R 2 is a member selected from the group consisting of:

A) six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of: halo, —C 1-3 alkyl, —C 1-3 haloalkyl, —CN, —OH, —C(R b ) 2 OH, —CH 2 NH 2 , —C(R b ) 2 CN, —C(R b ) 2 CONH 2 , —OCH 2 CONH 2 , —OC 1-3 alkyl, —OCH 2 C(R b ) 2 OH, —OCH 2 cyclopropyl, —OC 1-3 haloalkyl, —CO 2 H, —CON(R b ) 2 , —N(R b ) 2 , —NHCH 2 CF 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 N(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHcyclopropyl, —NHCOCH 3 , morpholinyl, pyrrolidin-3-ol, and azetidin-3-ol;

B) five-membered monocyclic heteroaromatic ring containing two, three, or four nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of halo, —C 1-3 alkyl, —C 1-3 haloalkyl, —C(R b ) 2 OH, —N(R b ) 2 , —NO 2 , —CN, —CH 2 CN, —OC 1-3 alkyl, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CONH 2 , —CO 2 C 1-3 alkyl, —CO 2 H, —CONH 2 , —NHCOCH 3 , and cyclopropyl; and

C) five or six-membered ring selected from: 1,2-dihydro-pyridin-2-one, thiazole or 1,2-oxazole unsubstituted or substituted with one or two members each independently selected from the group consisting of —CH 3 , and —NH 2 ;

R 3 is phenyl or pyridine, each substituted with one or two members each independently selected from the group consisting of: -halo, —C 1-3 alkyl, —OC 1-3 alkyl,

—Ocyclopropyl, —O-oxetane, —C 1-3 haloalkyl, —OC 1-3 haloalkyl, —CN, —CH 2 OH,

—SO 2 CH 3 , or —N(CH 3 ) 2 ;

R 4 is a member selected from the group consisting of —C 1-3 alkyl and —C 1-3 haloalkyl; and

each R b is independently selected from —H or —CH 3 ;

12 . The compound of claim 11 , wherein R 2 is six-membered monocyclic heteroaromatic ring containing one or two nitrogen members unsubstituted or substituted with a member selected from the group consisting of: —CN, —OC 1-3 alkyl, —CONH 2 , —NHCH 2 CH 2 OH, —N(R b ) 2 , and

—NH-cyclopropyl.

13 . The compound of claim 11 , wherein R 2 is a five-membered monocyclic heteroaromatic ring containing two or three nitrogen members unsubstituted or substituted with one or two members each independently selected from the group consisting of —C 1-3 alkyl, —C 1-3 haloalkyl,

—CH 2 OR b , —N(R b ) 2 , —NO 2 , —CO 2 CH 3 , —CO 2 N(R b ) 2 , and cyclopropyl.

14 . The compound of claim 11 , selected from the group consisting of:

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[6-(Difluoromethoxy)-5-(3-methoxyphenyl)pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyridin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}pyridin-2-amine;

5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}-N,N-dimethylpyridin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(difluoromethoxy)pyridin-3-yl]methyl}-1,3-thiazol-2-amine;

5-{[5-(3-Fluorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-ethoxypyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[5-(3-Chlorophenyl)-6-(propan-2-yloxy)pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[6-(Difluoromethoxy)-5-[3-(propan-2-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[6-(Difluoromethoxy)-5-[3-(oxetan-3-yloxy)phenyl]pyridin-3-yl]methyl}pyrimidin-2-amine;

5-{[6-(Difluoromethoxy)-5-(2-methoxypyridin-4-yl)pyridin-3-yl]methyl}pyrimidin-2-amine;

5-({5-[2-(Difluoromethoxy)pyridin-4-yl]-6-methoxypyridin-3-yl}methyl)pyrimidin-2-amine; and

pharmaceutically acceptable salts thereof.

15 . A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 ; and a pharmaceutically acceptable excipient.

16 . A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 11 ; and a pharmaceutically acceptable excipient.

17 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by PDE4 enzymatic activity, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1 , wherein the disorder is selected from one or more of the group selected from Alzheimer's Disease, Age Associated Memory Impairment (AAMI), Age Associated Cognitive Decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, an affective disorder, psychotic disorders, neurotic disorders, attention deficit disorder, subdural hematoma, normal-pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities; multiple sclerosis; inflammatory bowel disease; rheumatoid arthritis; COPD, asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases and psoriasis.

18 . A method of treating a disease, disorder, or medical condition mediated by a PDE4 enzyme, comprising administering to an animal in need of such treatment an effective amount of a compound of claim 11 , wherein the disorder is selected from one or more of the group selected from Alzheimer's Disease, Age Associated Memory Impairment (AAMI), Age Associated Cognitive Decline, vascular dementia, delirium, Parkinson's disease, Huntington's disease, Pick's disease, mental retardation, cerebrovascular disease, an affective disorder, psychotic disorders, neurotic disorders, attention deficit disorder, subdural hematoma, normal-pressure hydrocephalus, brain tumor, stroke, cognitive impairment due to sleep deprivation, intellectual and developmental disabilities; multiple sclerosis; inflammatory bowel disease; rheumatoid arthritis; COPD, asthma, allergic rhinitis, pulmonary artery hypertension; renal diseases; allergic skin diseases and psoriasis.

19 . A method of a neurological disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1 .

20 . A method of treating a neurological disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 11 .

Assignments (11)