Fused pyrimidine compound or salt thereof
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, R 2 , and X are as defined in the specification; or a salt thereof.
1. A method for treating a malignant tumor comprising administering a compound represented by Formula (I) below or a salt thereof to a mammal:
wherein in Formula (I), A is
wherein R 1 is selected from the group consisting of
halogen,
cyano,
nitro,
substituted or unsubstituted C1-C6 alkyl,
substituted or unsubstituted C1-C6 alkoxy,
substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C2-C6 alkynyl,
substituted or unsubstituted amino, and
a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,
Y is N or CH, and
n is an integer of 0 to 2,
wherein when n is 2, the two R 1 may be identical or different from each other;
in Formula A2, the group:
forms, together with phenyl or pyridinyl to which this group is bonded, polycyclic C8-C14 aromatic hydrocarbon or an 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur;
R 2 is selected from the group consisting of
substituted or unsubstituted C3-C10 alkyl,
substituted or unsubstituted C3-C7 cycloalkyl,
substituted or unsubstituted C4-C12 bridged cycloalkyl,
substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C3-C7 cycloalkenyl, and
a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,
provided that when each group represented by R 2 has a substituent, the substituent must not be a substituted or unsubstituted saturated heterocyclic group that may have at least one identical or different heteroatom selected from oxygen and sulfur, and has at least one nitrogen atom; and
X is
N or
CR 3 , wherein R 3 is selected from the group consisting of
hydrogen,
halogen,
cyano,
nitro,
substituted or unsubstituted C1-C6 alkyl,
substituted or unsubstituted C1-C6 alkoxy,
substituted or unsubstituted C1-C6 alkylthio,
substituted or unsubstituted C3-C7 cycloalkyl,
substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C2-C6 alkynyl,
substituted or unsubstituted amino,
substituted or unsubstituted carbamoyl,
substituted or unsubstituted C6-C14 aromatic hydrocarbon, and
a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated or unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur.
2. The method according to claim 1 , wherein when A is A1, A1 is
wherein R 1a is selected from the group consisting of
C1-C6 alkyl that is unsubstituted or substituted with C1-C6 alkoxy or C1-C6 alkylthio, wherein hydrogen contained in the alkoxy may be replaced by 1 or more deuterium atoms,
C2-C6 alkenyl,
C2-C6 alkynyl,
amino that may be substituted with 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, or C6-C14 aromatic hydrocarbon, and
a 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur;
R 1b is halogen, C1-C6 alkyl, or C1-C6 alkoxy; and
m is an integer of 0 or 1.
3. The method according to claim 1 , wherein R 2 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 CR 3 , R 3 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 R 4 , wherein R 4 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 R 5 , wherein R 5 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 R 6 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R 6 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 R 7 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R 7 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
wherein R 1a is selected from the group consisting of:
C1-C6 alkyl that is unsubstituted or substituted with C1-C6 alkoxy or C1-C6 alkylthio, wherein hydrogen contained in the alkoxy may be replaced by 1 or more deuterium atoms,
C2-C6 alkenyl,
C2-C6 alkynyl,
amino that may be substituted with one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, or C6-C10 aromatic hydrocarbon, and
a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur;
R 1b is halogen, C1-C6 alkyl, or C1-C6 alkoxy;
m is an integer of 0 or 1;
R 2 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, and
C4-C12 bridged cycloalkyl; and
X is selected from the group consisting of:
N and
CR 3 , wherein R 3 is
hydrogen,
halogen,
cyano,
C1-C4 alkyl,
C1-C6 alkoxy that may be substituted with one or more substituents selected from the group consisting of:
halogen,
C1-C6 alkoxy,
C3-C7 cycloalkyl, and
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-C4 alkenyl that may be substituted with hydroxy,
C2-C6 alkynyl that may be substituted with one or more substituents selected from the group consisting of:
hydroxy,
C1-C4 alkoxy,
amino that may be substituted with R 4 , wherein R 4 is C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or carbamoyl that may be substituted with C3-C5 cycloalkyl,
tri-C1-C6 alkylsilyloxy,
C3-C7 cycloalkyl that may be substituted with hydroxy or oxo,
phenyl that may be substituted with R 5 , wherein R 5 is halogen, methylamino that may be substituted with one or more 4- to 6-membered monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, or C1-C4 alkoxy,
one or more 4- to 6-membered monocyclic saturated heterocyclic groups that may be substituted with R 6 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R 6 is hydroxy, C1-C4 alkyl, C1-C4 alkoxy, or oxo,
one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups that may be substituted with R 7 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R 7 is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, or amino, and
unsaturated heterocyclic oxy that may be substituted with halogen, wherein the unsaturated heterocyclic ring is a 4- to 6-membered monocyclic 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,
phenyl that may be substituted with one or more substituents selected from the group consisting of:
hydroxy,
C1-C4 alkyl that may be substituted with hydroxy,
formyl, and
one or more 4- to 6-membered monocyclic saturated heterocyclic groups that may be substituted with C1-C4 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-C4 alkyl that may be substituted with hydroxy, and
amino that may be substituted with C1-C4 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.
6. The method according to claim 1 , wherein A is
wherein R 1b is halogen;
m is an integer of 0 or 1;
R 2 is selected from the group consisting of branched C3-C6 alkyl that may be substituted with halogen, and C3-C7 cycloalkyl that may be substituted with C1-C4 alkyl or C3-C5 cycloalkyl; and
X is CR 3 , wherein R 3 is selected from the group consisting of
hydrogen,
halogen,
C1-C4 alkoxy that may be substituted with one or more substituents selected from the group consisting of:
C1-C4 alkoxy,
C3-C7 cycloalkyl, and
one or more 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen atom,
C1-C4 alkylthio,
C2-C4 alkenyl,
C2-C6 alkynyl that may be substituted with one or more substituents selected from the group consisting of:
hydroxy,
amino that may be substituted with R 4 , wherein R 4 is C1-C4 alkyl or C1-C4 alkoxy C1-C4 alkyl,
C3-C7 cycloalkyl that may be substituted with hydroxy,
phenyl that may be substituted with R 5 , wherein R 5 is halogen,
one or more 4- to 6-membered monocyclic saturated heterocyclic groups that may be substituted with R 6 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R 6 is hydroxy, C1-C4 alkyl, or oxo, and
one or more 4- to 10-membered monocyclic or bicyclic unsaturated heterocyclic groups that may be substituted with R 7 and contain 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, wherein R 7 is halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, or amino,
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,
phenyl that may be substituted with hydroxy or C1-C4 alkyl that may be substituted with hydroxy, and
a 4- to 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 nitrogen atoms.
7. 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
wherein in Formula (I′), A is
wherein R 1 is selected from the group consisting of
halogen,
cyano,
nitro,
substituted or unsubstituted C1-C6 alkyl,
substituted or unsubstituted C1-C6 alkoxy,
substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C2-C6 alkynyl,
substituted or unsubstituted amino, and
a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,
Y is N or CH, and
n is an integer of 0 to 2,
wherein when n is 2, the two R 1 may be identical or different from each other;
in Formula A2, the group:
forms, together with phenyl or pyridinyl to which this group is bonded, polycyclic C8-C14 aromatic hydrocarbon or an 8- to 14-membered polycyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur;
R 2 is selected from the group consisting of
substituted or unsubstituted C3-C10 alkyl,
substituted or unsubstituted C3-C4 cycloalkyl,
substituted or unsubstituted C4-C12 bridged cycloalkyl,
substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C3-C4 cycloalkenyl, and
a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur,
provided that when each group represented by R 2 has a substituent, the substituent must not be a substituted or unsubstituted saturated heterocyclic group that may have at least one identical or different heteroatom selected from oxygen and sulfur, and has at least one nitrogen atom; and
X is
N or
CR 3 , wherein R 3 is selected from the group consisting of
hydrogen,
halogen,
cyano,
nitro,
substituted or unsubstituted C1-C6 alkyl,
substituted or unsubstituted C1-C6 alkoxy,
substituted or unsubstituted C1-C6 alkylthio,
substituted or unsubstituted C3-C7 cycloalkyl,
substituted or unsubstituted C2-C6 alkenyl,
substituted or unsubstituted C2-C6 alkynyl,
substituted or unsubstituted amino,
substituted or unsubstituted carbamoyl,
substituted or unsubstituted C6-C14 aromatic hydrocarbon, and
a substituted or unsubstituted 4- to 10-membered monocyclic or polycyclic saturated or unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur.