Pyrimidine compound as axl inhibitor
AssigneeNanjing Chia Tai Tianqing Pharmaceutical Co., Ltd.
InventorsChangyou MA, Linlin ZHANG, Dongdong LI, Youzhi WU, Haiwei FENG, Qiuhua ZHOU, Junjie PEI, Jian WU, Dan XU, Chunxia ZHU, Zhoushan TIAN
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Abstract
A pyrimidine compound as an AXL inhibitor is provided. The structure of the pyrimidine compound is as shown in general formula I, and the definition of each substituent is as described in the description. The present invention further provides a preparation method for the pyrimidine compound. The pyrimidine compound of the present invention has significant AXL inhibitory activity, and can be used as an AXL inhibitor.
Claims19
A compound of Formula I or a pharmaceutically acceptable salt of the compound,
- wherein X is CH or N;
- R1 is a 5-12 membered saturated heterocyclic ring or a 5-8 membered saturated carbocyclic ring optionally substituted by one or more C1-6 alkyl, C1-6 alkoxyl, halogen, cyano, deuterium, or hydroxyl, and
- R1 is not
- R2 is halogen;
- ring A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, and 9-12 membered benzoheterocyclyl, wherein the phenyl and the 5-6 membered heteroaryl are optionally substituted by one or more R3, and the 9-12 membered benzoheterocyclyl is optionally substituted by
- or one or more R3;
- R3 is selected from the group consisting of deuterium, halogen, C1-6 alkyl, C1-6 alkox 1, C3-10 cycloalkyloxyl,
- and
- wherein the C1-6 alkyl or the C1-6 alkoxyl is optionally substituted by hydroxyl, halogen, cyano, C1-3 alkoxyl, or 4-7 membered heterocycloalkyl;
- R4 and R5 are independently selected from the group consisting of C1-6 alkyl, hydroxyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, and C3-10 cycloalkyl, wherein the C1-6 alkyl is optionally substituted by deuterium, hydroxyl, halogen, cyano, or C1-3 alkoxyl;
- or R4 and R5 is configured to form a 3-6 membered phosphorus-containing saturated monocyclic ring together with adjacent P atom;
- R6 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, and 5-7 membered heteroaryl;
- R7 and R8 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 alkoxyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, and 5-7 membered heteroaryl, wherein the C1-6 alkyl is optionally substituted by hydroxyl, halogen, cyano, or C1-3 alkoxyl;
- or R7 and R8 form a 3-6 membered nitrogen-containing saturated monocyclic ring together with their adjacent N atom;
- R9 and R10 are independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl;
- R11 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, and 5-7 membered heteroaryl;
- and
- R12 is selected from the group consisting of C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, and 5-7 membered heteroaryl, the C3-10 cycloalkyl, the 4-7 membered heterocycloalkyl, or the 5-7 membered heteroaryl is optionally substituted by one or more hydroxyl, halogen, cyano, C1-6 alkyl, or 3-7 membered heterocycloalkyl.
A compound of Formula II or a pharmaceutically acceptable salt of the compound,
- wherein definitions of X, R1, R2, and R3 are consistent with those defined in the compound of the Formula I;
- n is an integer from 0 to 4;
- Ra is deuterium, halogen, C1-6 alkyl, C1-6 alkoxyl, C3-10 cycloalkyloxyl,
- wherein the C1-6 alkyl or the C1-6 alkoxyl is optionally substituted by one or more deuterium, methoxyl, hydroxyl, halogen, or cyano;
- wherein definitions of R4, R5, R7, R8, and R12 are consistent with those defined in the compound of the Formula I;
- preferably, the compound of the Formula II has a structure shown in the following Formula II-1,
- wherein definitions of R1, R2, R3, Ra, and n are consistent with those defined in the compound of the Formula II.
A compound of Formula IV or a pharmaceutically acceptable salt of the compound,
- wherein definitions of X, R1 and R2 are consistent with those defined in the compound of Formula I;
- n is an integer from 0 to 4;
- ring B is selected from the group consisting of phenyl 5-6 membered heteroaryl, and 9-12 membered benzoheterocyclyl optionally substituted by
- Rb is deuterium, halogen C1-6 alkyl, C1-6 alkoxyl, C3-10 cycloalkyloxyl,
- wherein the C1-6 alkyl or the C1-6 alkoxyl is optionally substituted by one or more methoxyl, hydroxyl, deuterium, halogen, or cyano;
- wherein definitions of R4, R5, R7, R8, and R12 are consistent with those defined in the compound of the Formula I;
- preferably, the compound of the Formula IV has a structure shown in the following Formula IV-1:
- wherein definitions of R1, R2, Rb, n, and ring B are consistent with those defined in the compound of the Formula IV;
- preferably, the compound of the Formula IV has a structure shown in the following Formula V:
- wherein definitions of X, R1, R2, Rb and n are consistent with those defined in the compound of the Formula IV;
- preferably, the compound of the Formula IV has a structure shown in the following Formula VI, or a pharmaceutically acceptable salt of the compound:
- wherein definitions of X, R1, R2, and Rb are consistent with those defined in the compound of the Formula IV.
A compound selected from the group consisting of the following formulars or a pharmaceutically acceptable salt of the compound:
A method for preparing a compound of Formula I, comprising the following step:
- synthesis scheme 1:
- wherein definitions of R1, R2, X, and ring A are consistent with those defined in the Formula I;
- and
- a compound of the Formula H-1-3 is prepared from a compound of the Formula H-1-1 and a compound of the Formula H-1-2 in the presence of a first solvent and an alkaline, and the compound of the Formula I is prepared from a compound of the formula H-1-3 and a compound of the Formula H-1-4 in the presence of a second solvent and an acid.
A method for preparing a compound of Formula I-1, II-1, III-1 or IV-1, comprising the following step:
- synthesis scheme 2:
- wherein definitions of R2 and ring A are consistent with those defined in the Formula I-1, and definition of R1 is consistent with that defined in the Formula I;
- a compound of the Formula H-2-3 is prepared from a compound of the Formula H-2-1 and a compound of the Formula H-2-2 in the presence of a third solvent and an alkaline, a compound of the Formula H-2-5 is prepared by a reaction of a compound of the Formula H-2-3 and a compound of the Formula H-2-4 in the presence of a fourth solvent and an acid, and a compound of the Formula H-2-6 is obtained by reacting a compound of the Formula H-2-5 with R1H or an acid addition salt thereof in the presence of a fifth solvent and a reducing agent;
- and optionally, an optically pure target product is prepared by a chiral resolution.
A pharmaceutical composition, comprising a therapeutically effective amount of the compound of Formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI, or a pharmaceutically acceptable salt of the compound, wherein preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers;
- preferably, the pharmaceutical composition is administered orally, for example, the pharmaceutical composition is in a form of tablets, capsules, or a solution;
- and preferably, the pharmaceutical composition is administered parenterally in a form of a sterile aqueous solution, a suspension, or a lyophilized powder.
A method of a use of a compound of Formula I, I-1, I-2, II, II-1, III, III-1, IV, IV-1, V, or VI, or a pharmaceutically acceptable salt of the compound in a preparation of a drug for preventing and/or treating diseases or disease conditions mediated by AXL protein kinase;
- and preferably, the diseases or disease conditions mediated by the AXL protein kinase comprise autoimmune diseases.
Dependencies are inferred from the claim text.