NOVEL FUSED PYRIMIDINE COMPOUND OR SALT THEREOF

• US 20190330214A1
• Filed: 11/01/2018
• Published: 10/31/2019
• Est. Priority Date: 02/23/2016
• Status: Active Grant

• Current Assignee: Taiho Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Taiho Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Inventors: MIYAZAKI, Isao, SHIMAMURA, Tadashi, KATO, Masanori, FUJITA, Hidenori, IGUCHI, Satoru
• Granted Patent: US 10,807,986 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The problem to be solved by the present invention is to provide a novel compound having RET inhibitory activity. The present invention also provides a pharmaceutical preparation that is useful for the prevention and/or treatment of RET-related diseases, particularly cancer, based on RET inhibitory activity. The present invention provides a compound represented by Formula (I):

wherein A, R², and X are as defined in the specification; or a salt thereof.

Claims

1. A method of inhibiting RET comprising administering a compound represented by Formula (I) below or a salt thereof to a mammal:

2. The method according to claim 1, wherein when A is A1, A1 is

3. The method according to claim 1, wherein R² is selected from the group consisting of:

C3-C10 alkyl that may be substituted with halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,

C3-C7 cycloalkyl that may be substituted with C1-C6 alkyl, C3-C7 cycloalkyl, or halogeno C1-C6 alkyl,

C4-C12 bridged cycloalkyl, and

C3-C7 cycloalkenyl.

4. The method according to claim 1, wherein when X is CR³, R³ is selected from the group consisting of:

hydrogen,

halogen,

cyano,

C1-C4 alkyl that may be substituted with hydroxy or oxo,

C1-C6 alkoxy that may be substituted with halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic saturated heterocyclic groups that may be substituted with oxo and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C6 alkenyl that may be substituted with hydroxy,

C2-C6 alkynyl that may be substituted with a substitutent selected from the group consisting of;

hydroxy,

C1-C6 alkoxy,

amino that may be substituted with R⁴, wherein R⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl that may be substituted with C3-C7 cycloalkyl,

C1-C6 alkylsilyloxy,

C3-C7 cycloalkyl that may be substituted with hydroxy or oxo,

C6-C14 aromatic hydrocarbon that may be substituted with R⁵, wherein R⁵ is halogen, C1-C4 alkylamino that may be substituted with one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, or C1-C6 alkoxy,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups that may be substituted with R⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups that may be substituted with R⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or amino, and

unsaturated heterocyclic oxy that may be substituted with halogen, wherein the unsaturated heterocyclic ring is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein the position of the triple bond of the C2-C6 alkynyl is disposed between the carbon atom bonded to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and a carbon atom adjacent to the carbon atom,

C6-C14 aromatic hydrocarbon that is unsubstituted or substituted with one or more substituents selected from the group consisting of

hydroxy,

C1-C6 alkyl that may be substituted with hydroxy,

formyl, and

one or more 4- to 10-membered monocyclic saturated heterocyclic groups that may be substituted with C1-C6 alkyl and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, and

a 4- to 6-membered monocyclic unsaturated heterocyclic group that may be substituted with one or more substituents selected from the group consisting of

halogen,

C1-C6 alkyl that may be substituted with hydroxy, and

amino that may be substituted with C1-C6 alkyl(carbonyl),

wherein said 4- to 6-membered monocyclic unsaturated heterocyclic group contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur.

5. The method according to claim 1, wherein A is

6. The method according to claim 1, wherein A is

14. The method according to claim 1, comprising administering to a mammal in need of such treatment, a composition comprising a compound or a salt thereof according to Formula (I′

) as an active ingredient

7. A method for preventing or treating a malignant tumor comprising administering a compound represented by Formula (I) below or a salt thereof to a mammal:

8. The method according to claim 7, wherein when A is A1, A1 is

9. The method according to claim 7, wherein R² is selected from the group consisting of:

C3-C10 alkyl that may be substituted with halogen, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,

C3-C7 cycloalkyl that may be substituted with C1-C6 alkyl, C3-C7 cycloalkyl, or halogeno C1-C6 alkyl,

C4-C12 bridged cycloalkyl, and

C3-C7 cycloalkenyl.

10. The method according to claim 7, wherein when X is CR³, R³ is selected from the group consisting of:

hydrogen,

halogen,

cyano,

C1-C4 alkyl that may be substituted with hydroxy or oxo,

C1-C6 alkoxy that may be substituted with halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, or one or more 4- to 10-membered monocyclic saturated heterocyclic groups that may be substituted with oxo and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,

C1-C4 alkylthio,

C3-C5 cycloalkyl,

C2-C6 alkenyl that may be substituted with hydroxy,

C2-C6 alkynyl that is unsubstituted or substituted with a substitutent selected from the group consisting of;

hydroxy,

C1-C6 alkoxy,

amino that may be substituted with R⁴, wherein R⁴ is C1-C6 alkyl, C1-C4 alkoxy C1-C6 alkyl, or carbamoyl that may be substituted with C3-C7 cycloalkyl,

C1-C6 alkylsilyloxy,

C3-C7 cycloalkyl that may be substituted with hydroxy or oxo,

C6-C14 aromatic hydrocarbon that may be substituted with R⁵, wherein R⁵ is halogen, C1-C4 alkylamino that may be substituted with one or more 4- to 10-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, or C1-C6 alkoxy,

one or more 4- to 10-membered monocyclic saturated heterocyclic groups that may be substituted with R⁶ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R⁶ is hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or oxo,

one or more 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups that may be substituted with R⁷ and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R⁷ is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or amino, and

unsaturated heterocyclic oxy that may be substituted with halogen, wherein the unsaturated heterocyclic ring is a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic ring containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein the position of the triple bond of the C2-C6 alkynyl is disposed between the carbon atom bonded to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and a carbon atom adjacent to the carbon atom,

C6-C14 aromatic hydrocarbon that is unsubstituted or substituted with one or more substituents selected from the group consisting of

hydroxy,

C1-C6 alkyl that may be substituted with hydroxy,

formyl, and

one or more 4- to 10-membered monocyclic saturated heterocyclic groups that may be substituted with C1-C6 alkyl and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, and

a 4- to 6-membered monocyclic unsaturated heterocyclic group that may be substituted with one or more substituents selected from the group consisting of

halogen,

C1-C6 alkyl that may be substituted with hydroxy, and

amino that may be substituted with C1-C6 alkyl(carbonyl),

wherein said 4- to 6-membered monocyclic unsaturated heterocyclic group contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur.

11. The method according to claim 7, wherein A is

12. The method according to claim 7, wherein A is

13. The method according to claim 7, comprising administering to a mammal in need of such treatment, a composition comprising a compound or a salt thereof according to Formula (I′

) as an active ingredient