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CN-122029168-A - Methods for preparing KRAS G12C inhibitors

CN122029168ACN 122029168 ACN122029168 ACN 122029168ACN-122029168-A

Abstract

The present disclosure provides compounds that can be used to prepare formula I: A method of and a pharmaceutical composition comprising a compound of formula I, wherein the michael addition impurity is present in an amount of less than 0.3%, as determined by HPLC analysis, and a method of treating cancer using a compound of formula I and a pharmaceutical composition.

Inventors

  • L J Burns
  • K. P. Cole
  • GONG XUEQIAN
  • D. M. Wyman
  • D. P. Keyer
  • R.J. Lindell
  • PENG SHENGBIN
  • SI CHONG

Assignees

  • 伊莱利利公司

Dates

Publication Date
20260512
Application Date
20241009
Priority Date
20231011

Claims (20)

  1. 1. Preparation of a Compound of the formula , A method of making a pharmaceutical composition comprising: combining citrate buffer, acryl group and 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer 。
  2. 2. The method of claim 1, wherein the preparing step is performed in a continuous stirred tank reactor.
  3. 3. The method of claim 1 or 2, wherein the acryl group is acryl chloride, acryl bromide or acryl anhydride.
  4. 4. A process according to any one of claims 1 to 3 wherein the acryloyl group is acryloyl chloride.
  5. 5. The method of any one of claims 1-4, wherein the acryl group is in the range of about 1.05 eq to about 1.35 eq relative to the 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer.
  6. 6. The method of any one of claims 1-5, wherein the acryl group is about 1.25 eq relative to the 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer.
  7. 7. The method of any one of claims 1-6, wherein the citrate buffer is in the range of about 2.0 pH to about 4.0 pH.
  8. 8. The method of any one of claims 1-7, wherein the citrate buffer is about 3.0 pH.
  9. 9. The process of any of claims 2-8, wherein the continuous stirred tank reactor operates in the range of about 300 rpm to about 600 rpm.
  10. 10. The process of any of claims 2-9, wherein the continuous stirred tank reactor is operated at about 450 rpm.
  11. 11. The method of any one of claims 2-10, wherein the citrate buffer is added to the continuous stirred tank reactor at a flow rate of about 3.6 mL/min.
  12. 12. The process of any one of claims 2-11, wherein the acryloyl group is added to the continuous stirred tank reactor at a flow rate of about 0.8 mL/min.
  13. 13. The process of any one of claims 2-12 wherein 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer , Is added to the continuous stirred tank reactor at a flow rate of about 6.6 mL/min.
  14. 14. The process of any one of claims 1-13, wherein michael addition impurity, 4- [ (13 aS) -2- [3- [ (13 aS) -9- (2-amino-3-cyano-7-fluoro-benzothien-4-yl) -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-2-yl ] -3-oxo-propyl ] -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M, M atropisomers , In an amount of less than 0.3% as determined by HPLC analysis.
  15. 15. The method of claim 14, wherein the michael addition impurity is less than 0.15% as determined by HPLC analysis.
  16. 16. Pharmaceutical compositions comprising a compound of the formula , Or a pharmaceutically acceptable salt thereof, wherein the michael addition impurity, 4- [ (13 aS) -2- [3- [ (13 aS) -9- (2-amino-3-cyano-7-fluoro-benzothien-4-yl) -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-2-yl ] -3-oxo-propyl ] -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M, M atropisomers , In an amount of less than 0.3% as determined by HPLC analysis, And a pharmaceutically acceptable carrier, diluent or excipient.
  17. 17. The pharmaceutical composition of claim 16, wherein the michael addition impurity is present in an amount of less than 0.15% as determined by HPLC analysis.
  18. 18. A method of treating cancer in a patient, wherein one or more cells express a KRas G12C mutant protein, comprising administering to the patient in need thereof the pharmaceutical composition of claim 16 or 17, wherein the cancer is selected from lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
  19. 19. A compound of the formula , Or a pharmaceutically acceptable salt thereof, Can be obtained by combining citrate buffer, acryl group and 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer , Wherein the Michael addition impurity, 4- [ (13 aS) -2- [3- [ (13 aS) -9- (2-amino-3-cyano-7-fluoro-benzothien-4-yl) -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-2-yl ] -3-oxo-propyl ] -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M, M atropisomers , In an amount of less than 0.3% as determined by HPLC analysis.
  20. 20. The compound of claim 19, wherein the combining step is performed in a continuous stirred tank reactor.

Description

Methods for preparing KRAS G12C inhibitors The present disclosure relates to processes and pharmaceutical compositions comprising compounds of formula I wherein michael addition impurities are present in an amount of less than 0.3% as determined by HPLC analysis, which can be used to prepare compounds of formula I and pharmaceutically acceptable salts thereof. The compounds and pharmaceutical compositions of formula I may be used for the treatment of cancer. WO 2021/118877 (the' 877 reference below) discloses certain KRas G12C inhibitors or salts thereof, which may be used to treat cancer. Methods of preparing these compounds are also disclosed. The method disclosed in the' 877 reference uses phosphate buffer. These methods produce an amount of impurities that is beyond the desired amount. These impurities include more than the desired amount of Michael addition impurities, namely 4- [ (13 aS) -2- [3- [ (13 aS) -9- (2-amino-3-cyano-7-fluoro-benzothien-4-yl) -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin (benzoxazocin) -2-yl ] -3-oxo-propyl ] -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothien-3-carbonitrile M, M atropisomers , They may be difficult to remove. Thus, there is a need for alternative methods of preparing compounds of formula I. It may be useful to develop new methods that can be used to prepare compounds of formula I that contain fewer impurities, particularly michael addition impurities. SUMMARY Disclosed herein are methods of preparing a compound of formula I or a pharmaceutically acceptable salt thereof. Also disclosed herein are compounds of formula I, or pharmaceutically acceptable salts thereof, which are obtainable by the newly developed methods. In one aspect, disclosed herein is the preparation of a compound of the formula , A method of making a pharmaceutical composition comprising: combining citrate buffer, acryl group and 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer 。 In another aspect, disclosed herein are pharmaceutical compositions comprising a compound of the formula , Or a pharmaceutically acceptable salt thereof, wherein the michael addition impurity 4- [ (13 aS) -2- [3- [ (13 aS) -9- (2-amino-3-cyano-7-fluoro-benzothien-4-yl) -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-2-yl ] -3-oxo-propyl ] -10-chloro-8-fluoro-6-oxo-1, 3,4,12,13 a-hexahydropyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M, M atropisomers , In an amount of less than 0.3% as determined by HPLC analysis, And a pharmaceutically acceptable carrier, diluent or excipient. In one aspect, disclosed herein are compounds of the formula , Or a pharmaceutically acceptable salt thereof, Which is obtainable by combining a citrate buffer, an acryl group and 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer , Wherein the Michael addition impurity is present in an amount of less than 0.3% as determined by HPLC analysis. The present disclosure also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is obtainable by combining a citrate buffer, an acryl group, and a 4- [ (13 aS) -10-chloro-8-fluoro-6-oxo-2, 3,4,12,13 a-hexahydro-1H-pyrazino [2,1-d ] [1,5] benzoxazepin-9-yl ] -2-amino-7-fluoro-benzothiophene-3-carbonitrile M atropisomer, and a pharmaceutically acceptable carrier, diluent, or excipient , Wherein the Michael addition impurity is present in an amount of less than 0.3% as determined by HPLC analysis. The surprising result is that the use of citrate buffer in a base catalyzed reaction reduces the amount of Michael-addition impurities. The present disclosure also provides a method of treating cancer in which one or more cells express a Kras G12C mutant protein, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the michael addition impurity is present in an amount of less than 0.3% as determined by HPLC analysis. In various embodiments, the cancer is lung cancer such as advanced non-small cell lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma (cholangiocarcinoma), or esophageal cancer. In preferred embodiments, the cancer is advanced non-small cell lung cancer, pancreatic cancer or cervical cancer. In still more preferred embodiments, the cancer is non-small cell lung cancer. In yet another form, the present disclos