阅读说明：本技术 抑制g12c突变型ras蛋白的杂芳基化合物 (Heteroaryl compounds that inhibit G12C mutant RAS proteins ) 是由 J.G.克特尔 S.K.巴加尔 S.博伊德 A.J.伊瑟顿 S.M.菲勒里 G.R.罗布 于 2018-05-08 设计创作，主要内容包括：本说明书涉及具有式(I)的化合物,及其药学上可接受的盐。本说明书还涉及用于制备它们的方法及中间体,包含它们的药物组合物,以及它们在治疗细胞增殖性障碍中的用途。<Image he="418" wi="700" file="DDA0002263792380000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The specification relates to compounds having formula (I), and pharmaceutically acceptable salts thereof. The specification also relates to processes and intermediates for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.)

1. A compound having the formula (I):

wherein:

ring a is selected from aryl, monocyclic heteroaryl and bicyclic heteroaryl;

R¹independently selected from C_1-4Alkyl, halogen, hydroxy, C_1-4Alkoxy radical, C_1-3Fluoroalkyl radical, C_1-3Fluoroalkoxy, cyano, ethynyl, NR⁷R⁸、C(O)NR⁹R¹⁰、CH₂R¹¹、N＝S(O)Me₂S (O) Me and SO₂R¹²；

b is 0, 1, 2 or 3;

w is N or CR¹³；

X is O or NR¹⁴；

Y is CR¹⁵R¹⁶、CR¹⁷R¹⁸CR¹⁹R²⁰C ═ O, or C (O) CR²¹R²²；

R²Is H, cyano, halogen, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-3Fluoroalkyl group, NR²³R²⁴Ethynyl or CH₂OR²⁵；

R³Is H, C_1-3Fluoroalkyl group, OR²⁶、NR²⁷R²⁸、CH₂R²⁹、SR³⁰Or C (O) R³¹；

R⁴Is H or Me;

R⁵is H or Me;

R⁶is H or CH₂NMe₂；

R⁷Is H, C_1-4Alkyl, C (O) C_1-3Alkyl or CO₂C_1-3An alkyl group;

R¹¹is hydroxy, cyano, heterocyclyl, NR³²R³³，C(O)NR³⁴R³⁵Or SO₂C_1-3An alkyl group;

R¹²is C_1-3Alkyl radical, C_1-3Fluoroalkyl or NR³⁶R³⁷；

R¹³Is H, C_1-4Alkyl, halogen, C_1-3Fluoroalkyl or C_1-4An alkoxy group;

R¹⁵、R¹⁶、R¹⁷and R¹⁸Independently selected from H and C_1-3An alkyl group;

R¹⁹、R²⁰、R²¹and R²²Independently selected from H, C_1-3Alkyl, and fluorine;

R²⁶selected from the group consisting of:

-H；

-C optionally substituted with 1 or 2 substituents selected from_1-4Alkyl groups: hydroxy, C_1-3Alkoxy, halogen, NR³⁸R³⁹、C(O)NR⁴⁰R⁴¹、SO₂Me, heteroaryl, C_3-7Cycloalkyl or heterocyclyl, wherein said heteroaryl or C_3-7Cycloalkyl is optionally further substituted by C_1-4Alkyl, hydroxy, halogen, cyano, or C_1-4Alkoxy, and said heterocyclyl is optionally further substituted with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl, heterocyclyl or heteroaryl substituted;

-optionally with C_1-4Alkyl, hydroxy or halogen substituted C_3-7A cycloalkyl group;

-optionally with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl, heterocyclyl or heteroaryl substituted heterocyclyl; and

-optionally with C_1-4Alkyl, hydroxy, halogen, cyano or C_1-4Alkoxy-substituted heteroaryl;

R²⁷selected from the group consisting of:

-H：

-C(O)R⁴²；

-C optionally substituted with 1 or 2 substituents selected from_1-4Alkyl groups: hydroxy, C_1-3Alkoxy, halogen, NR⁴³R⁴⁴、C(O)NR⁴⁵R⁴⁶、SO₂Me, heteroaryl, C_3-7Cycloalkyl or heterocyclyl, wherein said heteroaryl or C_3-7Cycloalkyl is optionally further substituted by C_1-4Alkyl, hydroxy, halogen, cyano, or C_1-4Alkoxy, and said heterocyclyl is optionally further substituted with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl, heterocyclyl or heteroaryl substituted;

-optionally with C_1-4Alkyl, hydroxy or halogen substituted C_3-7A cycloalkyl group;

-optionally with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl radical, CH₂Cyclopropyl, heterocyclyl or heteroaryl substituted heterocyclyl; and

-optionally with C_1-4Alkyl, hydroxy, halogen, cyano or C_1-4Alkoxy-substituted heteroaryl;

R²⁸is H or Me; or

R²⁷And R²⁸Together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered heterocyclic ring, wherein the ring is optionally substituted with C_1-4Alkyl, hydroxy, halogen, C (O) Me, NR⁴⁷R⁴⁸、C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl radical, CH₂Cyclopropyl, heterocyclyl or heteroaryl substitution;

R²⁹selected from the group consisting of:

-H；

-NR⁴⁹R⁵⁰；

-C optionally substituted with 1 or 2 substituents selected from_1-3Alkyl groups: hydroxy, C_1-3Alkoxy, halogen, NR⁵¹R⁵²、C(O)NR⁵³R⁵⁴、SO₂Me, heteroaryl, C_3-7Cycloalkyl or heterocyclyl, wherein said heteroaryl or C_3-7Cycloalkyl is optionally further substituted by C_1-4Alkyl, hydroxy, halogen, cyano, or C_1-4Alkoxy, and said heterocyclyl is optionally further substituted with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl, heterocyclyl or heteroaryl substituted;

-optionally with C_1-4Alkyl, hydroxy or halogen substituted C_3-7A cycloalkyl group;

-optionally with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl radical, CH₂Cyclopropyl, heterocyclyl or heteroaryl substituted heterocyclyl; and

-optionally with C_1-4Alkyl, hydroxy, halogen, cyano or C_1-4Alkoxy-substituted heteroaryl;

R³⁰selected from the group consisting of:

-C optionally substituted with 1 or 2 substituents selected from_1-4Alkyl groups: hydroxy, C_1-3Alkoxy, halogen, NR⁵⁵R⁵⁶、C(O)NR⁵⁷R⁵⁸、SO₂Me, heteroaryl, C_3-7Cycloalkyl or heterocyclyl, wherein said heteroaryl or C_3-7Cycloalkyl is optionally further substituted by C_1-4Alkyl, hydroxy, halogen, cyano, or C_1-4Alkoxy, and said heterocyclyl is optionally further substituted with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl, heterocyclyl or heteroaryl substituted;

-optionally with C_1-4Alkyl, hydroxy or halogen substituted C_3-7A cycloalkyl group;

-optionally with C_1-4Alkyl, hydroxy, halogen, C (O) Me, C_1-3Alkoxy radical, C_1-3Fluoroalkyl radical, C_3-7Cycloalkyl, heterocyclyl or heteroAryl-substituted heterocyclyl; and

-optionally with C_1-4Alkyl, hydroxy, halogen, cyano or C_1-4Alkoxy-substituted heteroaryl;

R³¹is NR⁵⁹R⁶⁰；

R⁴²Is optionally substituted heteroaryl or optionally substituted C_1-4An alkyl group;

R⁴⁹and R⁵¹Independently selected from H, C_1-4Alkyl, heterocyclyl and heteroaryl;

R⁵⁹and R⁶⁰Independently selected from H and C_1-4An alkyl group; or

R⁵⁹And R⁶⁰Together with the nitrogen atom to which they are attached form a 4-, 5-or 6-membered heterocyclic ring, wherein the ring is optionally substituted with C_1-4Alkyl, hydroxy, halogen or C (O) Me;

R⁸、R⁹、R¹⁰、R¹⁴、R²³、R²⁴、R²⁵、R³²、R³³、R³⁴、R³⁵、R³⁶、R³⁷、R³⁸、R³⁹、R⁴⁰、R⁴¹、R⁴³、R⁴⁴、R⁴⁵、R⁴⁶、R⁴⁷、R⁴⁸、R⁵⁰、R⁵²、R⁵³、R⁵⁴、R⁵⁵、R⁵⁶、R⁵⁷and R⁵⁸Independently selected from H and C_1-4An alkyl group;

or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein ring a is a bicyclic heteroaryl selected from the group consisting of:

3. the compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein ring a is phenyl.

4. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein R⁶Is H.

5. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of the preceding claims, wherein X is O and Y is CH₂。

6. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, wherein X is O and Y is CH₂CH₂。

7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein R³Is H.

8. A compound of formula (I) as claimed in any one of the preceding claims or a pharmaceutically acceptable salt thereof for use as a medicament.

9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the prevention or treatment of cancer in a warm-blooded animal such as man.

10. A compound of formula (I) as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by KRAS, NRAS or HRAS G12C mutation.

11. A compound of formula (I) as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in the treatment of non-small cell lung cancer or colorectal cancer.

12. A method for the prevention or treatment of cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.

13. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

14. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament.

15. The compound or pharmaceutically acceptable salt thereof for use according to claim 14, wherein the medicament is for treating a disorder mediated by KRAS, NRAS or HRAS G12C mutation.

16. A combination suitable for use in the treatment of cancer comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6 and another anti-tumour agent.