Pyrazol-pyridine derivatives

• US 10,457,663 B2
• Filed: 07/30/2018
• Issued: 10/29/2019
• Est. Priority Date: 02/02/2016
• 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): Shameem, Golam M
• Application Number:
  US16/049,469
• Publication Number:
  US 20180339975A1
• Time in Patent Office: 456 Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention relates to compounds of formula I

wherein

• R^1′ is CH₃;
• R¹ is CH₃, 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, CH₃, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropyl-methyl or hydroxy-methyl;
• R³ is hydrogen, Cl, F, CF₃, CH₃, isopropyl, methoxy, cyano or cyclopropyl;
• R⁴ is hydrogen, CH₃, F or Cl;
  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 thereof.

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, which compounds are

N-tert-Butyl-2-(4-chlorophenyl)-6-(2-methyl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(4-fluorophenyl)-6-(2-methyl-pyrazol-3-yl)-pyridine-4-carb oxamide N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-chlorophenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide

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

N-tert-Butyl-2-(4-chlorophenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

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

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

N-tert-Butyl-2-[2-(cyclopropylmethyl)-pyrazol-3-yl]-6-(4-fluorophenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-cyclopropyl-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-cyano-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(3,4-difluoro-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-propan-2-yl-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(3-chloro-4-fluoro-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-methyl-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-methoxy-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-chloro-3-fluoro-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(4-fluoro-3-methyl-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-(3-fluoro-4-methyl-phenyl)-pyridine-4-carboxamide

N-tert-Butyl-2-(2-tert-butyl-pyrazol-3-yl)-6-phenyl-pyridine-4-carboxamide

N-tert-Butyl-2-phenyl-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(4-cyclopropyl-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(4-cyano-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(3,4-difluoro-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(4-propan-2-yl-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

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

N-tert-Butyl-2-(4-methyl-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(4-methoxy-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

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

N-tert-Butyl-2-(4-fluoro-3-methyl-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(4-chlorophenyl)-6-(2-ethyl-pyrazol-3-yl)-pyridine-4-carboxamide

N-tert-Butyl-2-(4-chlorophenyl)-6-[2(cyclopropyl-methyl)-pyrazol-3-yl]-pyridine-4-carboxamide

N-tert-Butyl-2-(2-ethyl-pyrazol-3-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide

N-tert-Butyl-2-[2-(cyclopropylmethyl)-pyrazol-3-yl]-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide or

N-tert-Butyl-2-(2-cyclopropyl-pyrazol-3-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide.

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

5. A compound of formula IB according to claim 4, which compound is

2-(2-tert-Butylpyrazol-3-yl)-6-(4-fluorophenyl)-N-(2-methylbutan-2-yl)-pyridine-4-carboxamide.

6. A compound of formula IC according to claim 1:

7. A compound of formula IC according to claim 6, which compounds are

2-(2-tert-Butyl-pyrazol-3-yl)-6-(4-fluorophenyl)-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-pyridine-4-carboxamide

2-(4-Fluorophenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-pyridine-4-carboxamide

2-(4-Chlorophenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide or

2-(2-tert-Butyl-pyrazol-3 -yl)-6-(4-chlorophenyl)-N-(1,1,1-trifluoro-2-methyl-propan-2-yl)-pyridine-4-carboxamide.

8. A compound of formula ID according to claim 1:

9. A compound of formula ID according to claim 8, which compounds are

2-(2-tert-Butyl-pyrazol-3-yl)-6-(4-fluorophenyl)-N-(1-hydroxy-2-methyl-propan-2-yl)-pyridine-4-carboxamide

2-(4-Fluorophenyl)-N-(1-hydroxy-2-methyl-propan-2-yl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

2-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide or

2-(2-tert-Butyl-pyrazol-3-yl)-6-(4-chlorophenyl)-N-(1-hydroxy-2-methyl-propan-2-yl)-pyridine-4-carboxamide.

10. A compound of formula IE according to claim 1:

11. A compound of formula IE according to claim 10, which compounds are

2-(2-tert-Butyl-pyrazol-3-yl)-N-(2-cyclopropyl-propan-2-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide

N-(2-Cyclopropyl-propan-2-yl)-2-(4-fluorophenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

2-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide or

2-(2-tert-Butyl-pyrazol-3-yl)-6-(4-chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-pyridine-4-carboxamide.

12. A compound of formula IF according to claim 1:

13. A compound of formula IF according to claim 12, which compounds are

2-(2-tert-Butylpyrazol-3-yl)-N-(2-cyano-propan-2-yl)-6-(4-fluoro-phenyl)-pyridine-4-carboxamide

N-(2-Cyanopropan-2-yl)-2-(4-fluorophenyl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide

2-(4-Chlorophenyl)-N-(2-cyanopropan-2-yl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide or

2-(2-tert-Butyl-pyrazol-3-yl)-6-(4-chlorophenyl)-N-(2-cyano-propan-2-yl)-pyridine-4-carboxamide.

14. A compound of formula IG according to claim 1:

15. A compound of formula IG according to claim 14, which compounds are

(RS)-2-(2-tert-Butylpyrazol-3-yl)-6-(4-fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-pyridine-4-carboxamide or

(RS)-2-(4-Fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-6-(2-propan-2-yl-pyrazol-3-yl)-pyridine-4-carboxamide.

16. A process for the manufacture of a compound of formula I as defined in claim 1, which process comprises

a) reacting a compound of formula II

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