Heteroaromatic compounds and their use as dopamine D1 ligands

• US 10,421,744 B2
• Filed: 09/06/2018
• Issued: 09/24/2019
• 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:
  US16/123,072
• Publication Number:
  US 20190002439A1
• Time in Patent Office: 383 Days
• Field of Search: 514269, 514274, 51425506, 51425203, 51426203, 544310, 544406, 544239
• 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), and Parkinson'"'"'s disease.

Claims

1. A method for treating a D1-mediated (or D1-associated) disease or disorder in a mammal, which method comprises administering to the mammal a therapeutically effective amount of a compound of Formula I:

2. The method of Claim 1 wherein L¹ is O or S.

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

4. The method of claim 3 wherein:

R¹⁰ is selected from the group consisting of —

CN, C_1-4 alkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R¹⁰ 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 R¹⁰ is optionally substituted with 1, 2, 3, or 4 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;

R^10A is selected from the group consisting of H, C_1-3 alkyl, C_1-3 hydroxylalkyl, C_2-4 alkenyl, —

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; and

R^10B is selected from the group consisting of C_1-4 alkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R^10B 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 R^10B is optionally substituted with 1, 2, 3, or 4 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.

5. The method of claim 2 wherein the compound or a pharmaceutically acceptable salt thereof is a compound of Formula IC-1, IC-2, IC-3, IC-4, IC-5, or IC-6:

6. The method of claim 5 wherein:

each R¹¹ is independently selected from the group consisting of —

CN, C_1-4 alkyl, C_3-4cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R¹¹ 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 R¹¹ is optionally substituted with 1, 2, 3, or 4 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^11A is selected from the group consisting of C_1-4 alkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R¹¹ 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 R^11A is optionally substituted with 1, 2, 3, or 4 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.

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

8. The method of claim 7, wherein:

each R¹² is independently selected from the group consisting of —

CN, C_1-4 alkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R¹² 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 R¹² is optionally substituted with 1, 2, 3, or 4 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^12A is selected from the group consisting of C_1-4 alkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R^12A 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 R^12A is optionally substituted with 1, 2, 3, or 4 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.

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

10. The method of claim 9 wherein:

each R¹³ is independently selected from the group consisting of —

CN, C_1-4 alkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R¹³ 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 R¹³ is optionally substituted with 1, 2, 3, or 4 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^13A is selected from the group consisting of C_1-4 alkyl, C_3-4 cycloalkyl, cyclopropylmethyl, and cyclobutylmethyl, wherein the C_1-4 alkyl of R^13A 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 R^13A is optionally substituted with 1, 2, 3, or 4 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.

11. The method of claim 2 wherein each of R¹ and R² is independently selected from the group consisting of H, halogen, —

CN, C_1-6alkyl, C_1-6 haloalkyl, —

O—

C_1-6 alkyl, C_1-6 haloalkoxy, 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.

12. The method of claim 2 wherein each of R¹ and R² is independently H, methyl, or halogen.

13. The method of claim 2 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 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.

14. The method of claim 2 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.

15. The method of claim 2 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_1-4alkoxy 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_1-4hydroxylalkyl, C_1-4 cyanoalkyl, C_1-4 alkoxy, and C_1-4 haloalkoxy.

16. The method of claim 2 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.

17. The method of claim 2 wherein each of R¹ and R² is H;

R³ is H and R⁴ is methyl;

T¹ is selected from the group consisting of halogen, cyclopropyl, halocyclopropyl, methyl, C₁ haloalkyl, methoxy, and C₁ haloalkoxy; and

T⁴ is H.

18. The method of claim 1 wherein:

the compound or pharmaceutically acceptable salt thereof is a compound of Formula IB-8 or a pharmaceutically acceptable salt thereof;

each of R¹⁰ and R^10B is independently selected from the group consisting of C_1-3 alkyl, C_1-3 haloalkyl, and cyclopropyl;

each of R¹ and R² is independently H, methyl, or halogen;

each of R³ and R⁴ is independently H, F, Cl, CN, 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;

T¹ is selected from the group consisting of halogen, C_1-2 alkyl, C_1-2 haloalkyl, C_1-2 hydroxylalkyl, C_1-2 alkoxy, C_1-2 haloalkoxy, cyclopropyl, and halocyclopropyl;

each of T² and T³ is independently selected from the group consisting of H, halogen, C_1-2 alkyl, C_1-2 haloalkyl, C_1-2 hydroxylalkyl, C_1-2 alkoxy, C_1-2 haloalkoxy, cyclopropyl, and halocyclopropyl; and

T⁴ is H.

19. The method of claim 18 wherein each of R¹⁰ and R^10B is independently selected from the group consisting of C_1-3 alkyl and cyclopropyl;

each of R¹ and R² is H;

R³ is H; and

R⁴ is methyl.

20. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt is a compound selected from the group consisting of:

6-{4-[(3 -cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione;

6-{4-[(3 -chloro-5-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5 -dimethylpyrimidine-2,4(1H,3H)-dione;

6(4-{[3 -(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)-1,5-dimethylpyrimidine-2,4(1H,3H)-dione,

6-{4-[(3 -chloro-5-fluoropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione;

1,5-dimethyl-6-(2-methyl-4-{[3 -(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione; and

6-{4-[(3 -chloropyridin-2-yl)oxy]-2-methylphenyl}-1,5-dimethylpyrimidine-2,4(1H,3H)-dione,

(−

)-6-{4-[(3 -cyclopropylpyridin-2-yl)oxy]-2-methylphenyl}-1, 5 -dimethylpyrimidine-2,4(1H,3H)-dione;

(−

)-6-{4-[(3 -chloro-5 -fluoropyridin-2-yl)oxy]-2-methylphenyl }-1, 5 -dimethylpyrimidine-2,4(1H,3H)-dione;

6-{4-[(3 -chloropyridin-2-yl)oxy]-2-methylphenyl}-5-ethyl-1 -methylpyrimidine-2,4(1H,3H)-dione;

(−

)- 1,5 -dimethyl-6-(2-methyl-4-{[3 -(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrimidine-2,4(1H,3H)-dione;

(−

)-6-{4-[(3 -chloro-5 -methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5 -dimethylpyrimidine-2,4(1H,3H)-dione;

6-{4-[(3 -chloro-4-methylpyridin-2-yl)oxy]phenyl}-1,5 -dimethylpyrimidine-2,4(1H,3H)-dione;

(−

)-6-(4- {[3 -(difluoromethoxy)pyridin-2-yl]oxy}-2-methylphenyl)- 1,5-dimethylpyrimidine-2,4(1H,3H)-dione;

6-{4-[(3 -chloropyridin-2-yl)sulfanyl]-2-methylphenyl}-1,5 -dimethylpyrimidine-2,4(1H,3H)-dione;

(−

)-6-{4-[(3 -chloropyridin-2-yl)oxy]-2-methylphenyl}1,5 -dimethylpyrimidine-2,4(1H,3H)-dione;

6-{4-[(3 -cyclopropylpyridin-2-yl)oxy]phenyl}-1,5 -dimethylpyrimidine-2,4(1H,3H)-dione;

6-{4-[(3 -chloro-4-methylpyridin-2-yl)oxy]-2-methylphenyl}-1,5 -dimethylpyrazin-2(1H)-one;

6-{4-[(3 -chloro-4-methylpyridin-2-yl)oxy]2-methylphenyl }-1,5 -dimethylpyrimidin-2(1H)-one; and

1 -cyclopropyl-6-(4((3-(difluoromethyl)pyridin-2-yl)oxy)-2-methylphenyl)-5-methylpyrimidine-2,4(1H,3H)-dione,

or a pharmaceutically acceptable salt thereof.