Pyridine or pyrimidine derivatives

• US 10,155,741 B2
• Filed: 04/17/2018
• Issued: 12/18/2018
• Est. Priority Date: 10/28/2015
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Hoener, Marius, Wichmann, Juergen
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US15/954,964
• Publication Number:
  US 20180258066A1
• Time in Patent Office: 245 Days
• Field of Search: 544333, 546257, 514256, 514333, 514332
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 211/80 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 239/24 having three or more double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

The present invention relates to compounds of formula I

wherein

• R^1′ is methyl;
• R¹ is methyl, ethyl, CF₃, CH₂OH, cyclopropyl or cyano, or R^1′ and R¹ may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;
• R² is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl;
• R³ is Cl, F, CF₃, methyl, methoxy, or cyclopropyl;
• R⁴ is hydrogen, methyl, F or Cl;
• X is N or CH;
• Y is N or CH;
  • with the proviso that X and Y are not simultaneously CH;
    or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer.

The compounds of formula I may be used in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.

Claims

1. A compound of formula I:

2. A compound of formula IA according to claim 1:

3. A compound of formula IA according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-propan-2-yl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(3,4-difluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluoro-3-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chloro-3-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-cyclopropyl-phenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

2-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

2-(4-Chlorophenyl)-N-(2-cyanopropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

2-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

2-(4-Chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-methoxyphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(3-fluoro-4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

(RS)-2-(4-Fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carb oxamide;

2-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-ethyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyrimidin-5-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-cyclopropylpyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-tert-butylpyrimidin-5-yl)-6-(4-chlorophenyl)-pyridine-4-carboxamide; and

N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide.

4. A compound of formula IB according to claim 1:

5. A compound of formula IB according to claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-propan-2-yl-pyridin-3-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;

N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide; and

N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide.

6. A process for the manufacture of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1, which process comprises:

a) reacting a compound of formula

7. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

8. A method for the treatment of schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder in a mammal, which method comprises administering an effective amount of a compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, to the mammal.