JPWO2020159980A5 - - Google Patents

Claims (21)

A pharmaceutical composition for treating a brain tumor or brain metastases from another cancer or preventing brain metastases from another cancer in a subject with another cancer, wherein the composition is therapeutically effective Quantity formula (I):

(I)
[In the formula,
R ¹ is hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, R ⁶ C(O)-, or R ⁷ O(CO)-;
R ² and R ³ are each independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₃ -C ₇ cycloalkylmethyl;
^R4 is hydrogen, halogen _, C1 _- C8 alkyl, or C3 _- C7 cycloalkyl _;
R ⁵ is hydrogen or halogen;
R6 is hydrogen _, C1 ^- _C8 alkyl or C3 _- C7 cycloalkyl _; and
^R7 is C1 _{- C8} alkyl or C3 _- C7 cycloalkyl _;
wherein any said alkyl or cycloalkyl is optionally substituted]
or a pharmaceutically acceptable salt, solvate or prodrug thereof . 2. The pharmaceutical composition according to claim ₁ , wherein ^R1 is hydrogen or C1 _- C6 alkyl. 2. The pharmaceutical composition of claim 1, wherein ^R1 is methyl, ethyl, propyl, or isopropyl. The pharmaceutical composition according to any one of claims 1-3, wherein R ² is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, or C ₃ -C ₆ cycloalkylmethyl. The pharmaceutical composition according to any one of claims 1-3, wherein R ² is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclopropylmethyl, or cyclopentylmethyl. A pharmaceutical composition according to any one of claims 1 to 5, wherein R ³ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl. A pharmaceutical composition according to any one of claims 1 to 5, wherein R ³ is methyl, ethyl, propyl, isopropyl or cyclopropyl. A pharmaceutical composition according to any one of claims 1 to 7, wherein R ⁴ is hydrogen or halogen. The pharmaceutical composition according to any one of claims 1-8, wherein R ⁵ is hydrogen or fluoro. R ¹ is hydrogen, methyl, or ethyl; R ² is isopropyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl; R ³ is methyl or ethyl; R ⁴ is hydrogen or fluoro; and R ⁵ is hydrogen or The pharmaceutical composition according to any one of claims 1-9, which is fluoro. 2. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds listed in Table 3. A pharmaceutical composition for treating a brain tumor or brain metastases from another cancer or preventing brain metastases from another cancer in a subject with another cancer, wherein the composition is therapeutically effective Quantity formula:

or

A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt, solvate or prodrug thereof . Pharmaceutical composition according to any one of claims 1 to 12, wherein the brain tumor or another cancer expresses CDK4 and/or CDK6. The pharmaceutical composition according to any one of claims 1 to 13, wherein the brain tumor is glioblastoma. Another cancer is breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC), colorectal cancer, prostate cancer, renal cancer, melanoma, mantle cell lymphoma (MCL), chronic myelogenous leukemia (CML), and acute myeloid leukemia ( AML ). 16. The pharmaceutical composition of any one of claims 1-15, wherein administration is in conjunction with administration of a second therapeutic agent to the subject. 17. The pharmaceutical composition of Claim 16, wherein the second therapeutic agent is another CDK inhibitor, HER2 inhibitor, mTOR inhibitor, or EGFR inhibitor. Formula (I) in the manufacture of a medicament for the treatment of brain tumors or brain metastases from another cancer associated with CDK4 and/or CDK6 activity:

(I)
[In the formula,
R ¹ is hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, R ⁶ C(O)-, or R ⁷ O(CO)-;
R ² and R ³ are each independently hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₇ cycloalkyl, or C ₃ -C ₇ cycloalkylmethyl;
^R4 is hydrogen, halogen _, C1 _- C8 alkyl, or C3 _- C7 cycloalkyl _; and
R ⁵ is hydrogen or halogen;
R6 is hydrogen _, C1 ^- _C8 alkyl or C3 _- C7 cycloalkyl _; and
^R7 is C1 _{- C8} alkyl or C3 _- C7 cycloalkyl _;
wherein any said alkyl or cycloalkyl is optionally substituted]
or a pharmaceutically acceptable salt, solvate or prodrug thereof. Formula for the manufacture of a medicament for the treatment of brain tumors or brain metastases from another cancer, or for the prevention of brain metastases, in a subject with another cancer that is associated with CDK4 and/or CDK6 activity :

or

or a pharmaceutically acceptable salt, solvate or prodrug thereof. 20. Use according to claim 18 or 19, wherein the brain tumor is glioblastoma. Another cancer is breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC), colorectal cancer, prostate cancer, renal cancer, melanoma, mantle cell lymphoma (MCL), chronic myelogenous leukemia (CML), and acute myeloid leukemia (AML).