Heteroaromatic compounds and their use as dopamine D1 ligands

• US 9,822,097 B2
• Filed: 11/11/2016
• Issued: 11/21/2017
• Est. Priority Date: 06/27/2013
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Brodney, Michael Aaron, Davoren, Jennifer Elizabeth, Dounay, Amy Beth, Efremov, Ivan Viktorovich, Gray, David Lawrence Firman, Green, Michael Eric, Henderson, Jaclyn Louise, Lee, Chewah, Mente, Scot Richard, O'Neil, Steven Victor, Rogers, Bruce Nelsen, Zhang, Lei
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US15/349,075
• Publication Number:
  US 20170057947A1
• Time in Patent Office: 375 Days
• Field of Search: 544310, 544239, 544406, 514269, 514274, 51425203, 51425506
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: 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
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings

Abstract

The present invention provides, in part, compounds of Formula I:

and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), age-related cognitive decline, dementia, and Parkinson'"'"'s disease.

Claims

1. A compound of Formula IA-1:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L¹ is O or S.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula IA-1 is a compound of Formula IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IA-8, IA-9, or IA-10:

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:

each R⁹ is independently selected from the group consisting of —

CN, C_1-4 alkyl, C_1-4 haloalkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R⁹ is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —

OH, —

CN, C_1-4 alkoxy, and C_1-4 haloalkoxy; and

wherein each of the C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl of R⁹ is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —

OH, —

CN, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 hydroxylalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy; and

R^9A is selected from the group consisting of H, C_1-3 alkyl, C_1-3 hydroxylalkyl, allyl, —

S(═

O)₂N(R⁵)(R⁶), —

C(═

O)—

N(R⁵)(R⁶), —

C(═

O)—

R⁸, —

C(═

O)—

OR⁸, —

C(R¹⁴)₂—

OH, —

C(R¹⁴)₂—

OS(═

O)₂H, —

C(R¹⁴)₂—

OP(═

O)(OH)₂, —

C(R¹⁴)₂—

OR¹⁵, and —

C(R¹⁴)₂—

OC(═

O)—

R¹⁵.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein each R⁹ is independently selected from the group consisting of C_1-3 alkyl and cyclopropyl.

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each R⁹ is independently methyl or ethyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R¹ and R² is independently selected from the group consisting of H, halogen, —

CN, C_1-6 alkyl, C_1-6 haloalkyl, —

O—

_1-6 alkyl, C_1-6haloalkoxy, C_3-6 cycloalkyl, —

C(═

O)—

(C_1-4 alkyl), and C(═

O)—

O—

(C_1-4 alkyl), wherein each of the C_1-6 alkyl and C_3-6 cycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —

OH, —

CN, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R¹ and R² is independently H, methyl, or halogen.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R³ and R⁴ is independently selected from the group consisting of H, halogen, —

CN, —

C_1-4 alkyl, —

O—

C_1-4 alkyl, and C_3-4 cycloalkyl, wherein each of the C_1-4 alkyl and —

O—

C_1-4 alkyl of R³ and R⁴ is optionally substituted with 1, 2, or 3, or substituents each independently selected from the group consisting of halogen, —

OH, C_1-4 alkoxy, and C_1-4 haloalkoxy; and

wherein the C_3-4 cycloalkyl of R³ and R⁴ is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —

OH, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is H;

and R⁴ is H, halogen, or methyl, wherein the methyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —

OH, and C_1-4 alkoxy.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of T¹, T², T³, and T⁴ is independently selected from the group consisting of H, halogen, —

CN, C_1-4 alkyl, C_1-4 haloalkyl, C_2-4 alkenyl, C_1-4 alkoxy, C_1-4 haloalkoxy, and C_3-4 cycloalkyl, wherein each of the C_1-4 alkyl, C_2-4 alkenyl, and C_1-4 alkoxy of T¹, T², T³, and T⁴ is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —

OH, —

CN, C_1-4 alkoxy, and C_1-4 haloalkoxy; and

wherein the C_3-4 cycloalkyl of T¹, T², T³, and T⁴ is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —

OH, —

CN, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 hydroxylalkyl, C_1-4 cyanoalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein each of T¹, T², T³, and T⁴ is independently selected from the group consisting of H, halogen, C_1-4 alkyl, C_1-4 hydroxylalkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_3-4 cycloalkyl, and C_3-4 halocycloalkyl.

13. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A compound selected from:

(+)-5-(4-{[3-(difluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-32H)-one;

5-{4-[(3-chloro-4-methylpyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridazin-3(2H)-one;

5-{4-[(3-cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridazin-3(2H) -one;

5-{4-[(3-iodopyridin-2-yl)oxy]-2-methylphenyl}-4,6-dimethylpyridazin-3(2H)-one;

5-{4-[(3-chloropyridin-2-yl)oxy]-2-methylphenyl -}1-4,6-dimethylpyridazin-3(2I-1)-one;

5-(4-{[3-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one;

5-(4-{[4-methoxy-3(trifluoromethyl)pyridin-2-yl]oxy}-2-methylphenyl)-4,6-dimethylpyridazin-3(2H)-one; and

(+)-4,6-dimethyl-5-(2-methyl-4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyridazin-3(2H)-one,

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to claim 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.