Combination therapy of KRAS inhibitors and ATR inhibitors for cancer treatment

Abstract

The present invention relates to a method for treating cancer in a subject, and to the subject, The present invention provides a method comprising administering (a) a KRAS inhibitor and (b) an ataxia telangiectasia and Rad-3-related (ATR) inhibitor. Compositions and kits comprising (a) a KRAS inhibitor and (b) an ATR inhibitor are also disclosed.

Description

[Technical Field]

[0001] This specification asserts the rights of U.S. Provisional Application No. 63 / 496,040, filed on April 14, 2023, the contents of which are incorporated herein by reference in their entirety for any purpose.

[0002] (Field of invention) This disclosure provides a method for treating cancer in a subject, comprising administering to the subject (a) a KRAS inhibitor and (b) an ataxia telangiectasia and Rad-3-related (ATR) inhibitor. Compositions and kits comprising (a) the KRAS inhibitor and (b) the ATR inhibitor are also disclosed. [Background technology]

[0003] KRAS is a small GTPase protein that cycles between GDP-binding inactive and GTP-binding active states, regulating the cellular signaling cascade and promoting cell proliferation and survival. KRAS frequently mutates in cancers with hotspots, such as gain-of-function missense mutations clustering at codons 12, 13, and 61. Oncogenic mutations at these residues can disrupt endogenous and GAP-mediated GTP hydrolysis, increasing levels of GTP-binding KRAS and thereby leading to inappropriate activation of the cellular signaling cascade that can drive cancer progression.

[0004] Historically, KRAS has been considered a troublesome target due to the lack of a drug-drugable pocket and its high affinity binding to nucleotides. However, several small molecules with improved potency and pharmacological properties have been developed that covalently bind to mutant cysteine ​​residues in KRAS, capture them in a GDP-inactive state, and drive antitumor activity in preclinical models of KRAS, such as sotrasib and adagrasib. However, not all patients with KRAS-mutated tumors respond strongly to treatment.

[0005] Ataxia telangiectasia and Rad3-related (ATR) are serine / threonine protein kinases, apical kinases involved in modulating DNA damage responses induced by cell cycle checkpoints and DNA replication stress. Inhibition of ATR has been explored as a potential treatment for cancer, initially focusing on targeting tumor-specific mechanisms that exhibit enhanced sensitivity to ATR inhibition due to missing double-strand break (DSB) repair mechanisms. Several ATR inhibitors are known, including AZD6738 (ceraracertib, (Foote KM., et al., J Med Chem. 2018; 61(22): 9889-907)), M6620 / VX970 (belzocertib, (Gorecki L, et al., Pharmacol Ther. 2020; 210: 107518)), and BAY-1895344 (elimsertib, (Lucking U, et al., J Med Chem. 2020; 63(13): 7293-325)). [Overview of the project]

[0006] In some embodiments, the present disclosure provides a method for treating cancer in a subject, comprising administering to the subject (a) a KRAS inhibitor and (b) a telangiectasia and Rad-3-related (ATR) inhibitor.

[0007] In some embodiments, this disclosure provides KRAS inhibitors for use in the treatment of cancer in a subject, and the treatment is a. KRAS inhibitors, b. ATR inhibitors and This includes administering the drug to the target group separately, sequentially, or simultaneously.

[0008] In some embodiments, this disclosure provides ATR inhibitors for use in the treatment of cancer in a subject, and the treatment is a. KRAS inhibitors, b. ATR inhibitors and This includes administering the drug to the target group separately, sequentially, or simultaneously.

[0009] In some embodiments, the disclosure provides the use of a KRAS inhibitor or an ATR inhibitor in the manufacture of a pharmaceutical product for the combined administration of a KRAS inhibitor and an ATR inhibitor for the treatment of cancer in a subject.

[0010] In some embodiments, the KRAS inhibitor is an antibody. In some embodiments, the antibody is ELI-002, KRAS-EphA-2-CAR-DC, anti-KRAS G12V mTCR PBL, anti-KRAS G12D mTCR PBL, siG12D-LODER, or KRAS G12D siRNA. In some embodiments, the KRAS inhibitor is a small molecule KRAS inhibitor. In some embodiments, the small molecule KRAS inhibitor is sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, MRTX1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, or QTX3046.

[0011] In some embodiments, the small molecule KRAS inhibitor is a compound of formula (I) as defined herein.

[0012] [ka] In some embodiments, the small molecule KRAS inhibitor has the following structure as defined herein.

[0013] [ka] It has. In some embodiments, ring A is

[0014] [ka] It is selected from the group consisting of the following.

[0015] In some embodiments, ring A, as listed above, is bonded to the rest of the compound of formula (I) at any point on the ring listed above.

[0016] In some embodiments, R 4 H is H. In some embodiments, R 6 is H. In some embodiments, Y is CH2. In some embodiments, Y is CH2CH2. In some embodiments, R 2 is Cl. In some embodiments, R 3 F is F. In some embodiments, R 4 H is R 5 is Me. In some embodiments, the small molecule KRAS inhibitor is 7-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindole-1-one, 1-[(8aS,11S)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 1-[(8aS,11R)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 5-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]isoquinoline-1(2H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazole-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinoline-1(2H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl)propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl)propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinoline-1(2H)-one, (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 8-[3-chloro-1-fluoro-8-(propa-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-2-yl]-7-methylisoquinoline-1(2H)-one, 1-[(6aS,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aR,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aS,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(8aS)-4-chloro-6-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 8-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinoline-1(2H)-one, (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, and Selected from (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the small molecule KRAS inhibitor is a compound of formula (II)

[0018]

Chemical formula

[0019] In some embodiments, the small molecule KRAS inhibitor is a compound of formula (III) as defined herein

[0020]

Chemical formula

[0021] In some embodiments of formula (III), i) X 1 is CR 17 and Y 1 is CR 18 or ii) X 1 is N and Y 1 is CR 18 or iii) X 1 is CR 17 and Y 1 is N. In some embodiments of formula (III), Z 1 is O. In some embodiments of formula (III), R 13a and R 13b are H. In some embodiments of formula (III), R 14 is H. In some embodiments of formula (III), R 16 is H. In some embodiments of formula (III), A 1 is phenyl. In some embodiments, the small molecule KRAS inhibitor is (12aS)-2-acryloyl-10-chloro-9-(5-methyl-1H-indazole-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-6-one, 1-((12aS)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, (12aR)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-((12aR)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazole-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-7-carbonitrile, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazole-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 8-[(12aR)-10-chloro-8-fluoro-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-9-yl]-7-methylisoquinoline-1(2H)-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aS)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aS)-10-chloro-11-methyl-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one, 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-hydroxy-6-methylphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, (12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(propa-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-1-one, 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(propa-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-1-one, 1-[(8aR)-6-chloro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydro-14H-pyrazino[2,1-c][1,2,4]triazolo[4',3':1,2]pyrido[3,4-f][1,4]oxazepine-10(8H)-yl]propa-2-en-1-one, 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazole-9(7H)-yl]propa-2-en-1-one, and 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazole-9(7H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-10-chloro-8-ethynyl-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(7aR)-5-chloro-4-(2-chloro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydroimidazo[4,5-g]pyrazino[2,1-c][1,4]benzoxazepine-9(7H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropyloxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)propa-1-in-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridine-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidine-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2 H3)methyloxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, and 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-7-[2-(dimethylamino)ethoxy]-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(propa-1-in-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, and Selected from 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl)propa-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the small molecule KRAS inhibitor is a compound of formula (IV).

[0023] [ka] That is the case. The compound of formula (IV) is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the ATR inhibitor is an antibody. In some embodiments, the ATR inhibitor is a small molecule ATR inhibitor. In some embodiments, the small molecule ATR inhibitor is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-5597, or IMP9064. In some embodiments, the small molecule ATR inhibitor is a compound of formula (V) as defined herein.

[0025] [ka] That is the case.

[0026] In some embodiments, R 24 and R 25 together with the atoms to which they are attached form ring A 2 and ring A 2 is a C 3-6 cycloalkyl, or a saturated 4- to 6-membered heterocyclic ring containing one heteroatom selected from O and N. In some embodiments, ring A 2 is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. In some embodiments, R 22A is hydrogen, R 22B is hydrogen, R 22C is hydrogen, R 22D is hydrogen, R 22E is hydrogen, R 22F is hydrogen. In some embodiments, R 21 is morpholin-4-yl. In some embodiments, R 21 is 3-methylmorpholin-4-yl. In some embodiments, the compound of formula (V) is a compound of formula (Va)

[0027]

Chemical formula

[0028] In some embodiments, the small molecule ATR inhibitor is a compound of formula (VI) (ceraracertib),

[0029] [ka] That is the case. The compound of formula (VI) is 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, (i) a KRAS inhibitor and (ii) an ATR inhibitor are one of the combinations shown in Table 4. In some embodiments, (i) the KRAS inhibitor is a compound of formula (II) and (ii) the ATR inhibitor is seracertib. In some embodiments, (i) the KRAS inhibitor is a compound of formula (IV) and (ii) the ATR inhibitor is seracertib.

[0031] In some embodiments, the subject has a KRAS, NRAS, or HRAS mutation. In some embodiments, the subject has a KRAS mutation. In some embodiments, the KRAS mutation is a mutation at codon 12, codon 13, and / or codon 61. In some embodiments, the KRAS mutation is a mutation at codon 12. In some embodiments, the KRAS mutation is a G12C mutation. In some embodiments, the subject has lung cancer, colorectal cancer, pancreatic cancer, or a combination thereof. In some embodiments, the subject is a human subject. In some embodiments, the subject has lung cancer, colorectal cancer, pancreatic cancer, esophageal and gastric cancer, endometrial cancer, bile duct cancer, or a combination thereof.

[0032] In some embodiments, the Disclosure provides a method for modulating an adaptive immune response in a subject, comprising administering a composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, the Disclosure provides a method for reducing the volume of a cancerous tumor in a subject, comprising administering a composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, the Disclosure provides a method for treating a subject in need of treatment, comprising administering a composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor, wherein the subject has a disorder mediated by a KRAS, NRAS, or HRAS G12C mutation.

[0033] This disclosure also provides compositions comprising (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, the KRAS inhibitor is sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, MRTX 1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV). In some embodiments, the ATR inhibitor is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-5597, or IMP9064, a compound of formula (V), or a compound of formula (VI).

[0034] In some embodiments, the composition is a liquid. In some embodiments, the composition is a solid. In some embodiments, the composition is a solid oral dosage form. In some embodiments, the composition further comprises pharmaceutically acceptable excipients, diluents, or carriers.

[0035] This disclosure also provides the use of the compositions described herein for the manufacture of pharmaceuticals, optionally for the treatment of cancer.

[0036] In some embodiments, the Disclosure provides a kit comprising (a) a first container containing a first composition comprising a KRAS inhibitor, and (b) a second container containing a second composition comprising an ATR inhibitor. In some embodiments, the KRAS inhibitor in the kit is sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, M RTX1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV). In some embodiments, the ATR inhibitor in the kit is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-5597, or IMP9064, a compound of formula (V), or a compound of formula (VI).

[0037] In some embodiments, the first composition, the second composition, or both the first and second compositions are liquids. In some embodiments, the first composition, the second composition, or both the first and second compositions are solids. In some embodiments, the first composition, the second composition, or both the first and second compositions are solid oral dosage forms. In some embodiments, the first composition, the second composition, or both the first and second compositions further comprise a pharmaceutically acceptable excipient, diluent, or carrier.

Brief Description of the Drawings

[0038] [Figure 1] Inhibition of KRAS and ATR drives tumor regression in the KRAS G12C mutant model. Figure 1A: Schematic showing the dosing schedules of AZD4625 (compound of formula II) and AZD6738 (ceralasertib) used in the study. Tumor growth (Figure 1B) or body weight change (Figure 1C) in individual animals dosed with AZD4625 or AZD6738, either alone or in combination, or a control. [Figure 2] Combined activity expected for all allosteric G12C inhibitors. Figure 2A: Schematic showing the dosing schedules of AZD4625, the compound of formula IV, and AZD6738 used in the study. Figure 2B: Tumor growth in individual animals dosed with AZD4625, the compound of formula IV, or AZD6738, either alone or in combination, or a control. [Figure 3] KRAS and ATR inhibition provides long-term antitumor protection. Figure 3A: Schematic of the rechallenge study design. Figure 3B: Individual CT26 G12C tumor growth in the left flank of untreated mice or mice rechallenged after a complete antitumor response to the compound of formula IV and AZD6738. [Figure 4]A sustained antitumor response is achieved in preclinical models with intact immune systems. Comparison of monotherapy and combination responses with KRASG12C inhibitors (either AZD4625 or a compound of formula (IV)) and AZD6738 in immunodeficient nude mice and immunocompetent BALB / c mice for tumor growth (Figure 4A) or time to endpoint (Figure 4B) during a 4-week drug treatment period. The gray bars in Figure 4A indicate the treatment period for AZD6738. The gray bars in Figure 4B indicate the drug administration period for all treatments. [Figure 5] A sustained antitumor response is achieved in a preclinical model with an intact immune system. Comparison of monotherapy and combination therapy responses with KRASG12C inhibitors (either adaglasib or sotrasib) and AZD6738 in immunocompetent BALB / c mice for tumor growth (Figure 5A), time to endpoint (Figure 5B), and percentage change in body weight (Figure 5C) during a 4-week drug treatment period. The gray bars in Figures 5A and 5C indicate the duration of AZD6738 treatment. The gray bars in Figure 5B indicate the duration of drug administration for all treatments. [Modes for carrying out the invention]

[0039] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meanings generally understood by those skilled in the art.

[0040] Furthermore, unless otherwise specifically required by the context, singular terms shall include the plural form, and plural terms shall include the singular form. As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising," the words "a" or "an" may mean one or more. As used herein, "another" or "further" may mean at least a second or more.

[0041] The use of the term “or” in the claims is used to mean “and / or” unless it is expressly indicated that it refers only to substitutes, or that the substitutes are not mutually exclusive; however, this disclosure supports the definitions that refer only to substitutes and “and / or.”

[0042] As used herein, “comprising” (and any variations or forms of “comprising,” such as “comprise” and “comprises”), “having” (and any variations or forms of “having,” such as “have” and “has”), “including” (and any variations or forms of “including,” such as “includes” and “include”), or “containing” (and any variations or forms of “containing,” such as “contains” and “contain”) are comprehensive or non-restrictive and do not exclude additional unlisted elements or steps of methods.

[0043] Throughout this application, the term “approximately” is used to indicate that a value includes inherent variations in the error of the method / apparatus used to determine the value, or variations present among the subjects of study. Typically, the term “approximately” means, depending on the context, to include variations of less than or greater than approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% (either “greater” or “less” than the indicated value). In embodiments, those skilled in the art will understand the level of variability indicated by the term “approximately” from the context in which it is used herein. It should also be understood that the use of the term “approximately” also includes the values ​​specifically listed.

[0044] The use of the term “for example” and its corresponding abbreviation “eg” (whether italicized or not) means that the specific terms described are representative examples and embodiments of the disclosure, and are not intended to be limited to the specific examples referenced or cited unless otherwise expressly stated.

[0045] The ranges provided herein are of any kind and include all values ​​within a given range and values ​​relating to the endpoints of a given range. Where used herein, “between” refers to a range that includes both ends of the range. For example, the numbers between x and y explicitly include the numbers x and y, as well as any numbers that fall within x and y.

[0046] The terms “to treat” or “to cure” refer to administering a compound or pharmaceutical composition to an animal in order to bring about a change or improvement in a disease, disorder, or condition of the animal. In some embodiments, “to treat” or “to cure” is provided to a subject suffering from a condition suitable for treatment with the combination described herein. In some embodiments, “to treat” or “to cure” is provided to a subject at high risk of suffering from a KRAS and / or ATR-dependent condition, as described herein, even before any clinical signs of such a condition become apparent in the subject.

[0047] The terms "administer" or "to administer" refer to a route through which a compound or composition provided herein is introduced into an individual in order to perform an intended function. Examples of possible administration routes include, but are not limited to, parenteral administration such as subcutaneous, intravenous, or intramuscular injection or infusion, or oral administration using, for example, a solid oral dosage form.

[0048] The term “subject” means any subject, in particular mammalian subjects, that requires treatment with the KRAS inhibitors / ATR inhibitors described herein. Mammalian subjects include humans or non-human animals. In some embodiments, the term “subject” refers to human subjects. In some embodiments, the term “subject” refers to female subjects. In some embodiments, the term “subject” refers to male subjects. In some embodiments, human subjects are 12 years of age or older, 14 years of age or older, 4–17 years of age or older, or 18 years of age or older. Non-human animals include, but are not limited to, pigs, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, apes, monkeys, orangutans and chimpanzees, etc.

[0049] As used herein, “subjects requiring it” refers to subjects for whom treatment is desirable, for example, subjects having cancer and / or KRAS mutations as described herein. In some embodiments, the term “subjects requiring it” may refer to subjects at high risk of developing cancer and / or KRAS mutations as described herein, regardless of whether the subject has physical signs of such a condition.

[0050] A “pharmaceutically acceptable salt” refers to a salt of a compound that is physiologically and pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound, and includes salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases. “Pharmaceutically acceptable salts” of the compounds described herein can be prepared by methods well known in the art. For an overview of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0051] This disclosure relates to a method for treating cancer in a subject, comprising administering to the subject (a) a KRAS inhibitor and (b) a telangiectasia and Rad-3-related (ATR) inhibitor.

[0052] This disclosure also relates to KRAS inhibitors for use in the treatment of cancer in the subject, and the treatment is a. KRAS inhibitors, b. ATR inhibitors and This includes administering the drug to the target group separately, sequentially, or simultaneously.

[0053] This disclosure also relates to ATR inhibitors for use in the treatment of cancer in the subject, and the treatment is a. KRAS inhibitors, b. ATR inhibitors and This includes administering the drug to the target group separately, sequentially, or simultaneously.

[0054] This disclosure also covers the use of a KRAS inhibitor or an ATR inhibitor in the manufacture of a pharmaceutical product for the combined administration of a KRAS inhibitor and an ATR inhibitor for the treatment of cancer in the subject.

[0055] The term KRAS refers to the Kirsten rat sarcoma 2-vial oncogene homolog (annotated by the U.S. government's National Center for Biotechnology Information (NCBI) Genbank (http: / / www.ncbi.nlm.nih.gov / ) gene ID number 3845), a small GTPase class of proteins that are well-studied in the art. The terms “KRAS,” “the KRAS,” and “KRAS protein” are used interchangeably herein. Alternative RNA splicing of the KRAS transcript results in two known KRAS isoforms, KRAS4A and KRAS4B, which differ in their C-terminal regions. The amino acid sequence of the human wild-type KRAS4A isoform may be as annotated by Genbank acceptance number NP_203524.1 or Swissprot / Uniprot (http: / / www.uniprot.org / ) acceptance number: P01116-1(v1), the NP_203524.1 sequence reproduced in Table 1.

[0056] [Table 1]

[0057] The amino acid sequence of the human wild-type KRAS4B isoform may be as annotated by Genbank acceptance number: NP_004976.2 or Swissprot / Uniprot acceptance number: P01116-2(v1), and the NP_004976.2 sequence is reproduced herein in Table 2.

[0058] [Table 2]

[0059] In some embodiments, KRAS may include other related Ras proteins, such as NRAS or HRAS, which are essentially identical at positions 1-86, including the regions surrounding G12 and G13, and therefore, the same molecule can be used to target mutant human KRAS, NRAS, and HRAS proteins at G12 or G13. The human wild-type HRAS amino acid sequence may be as annotated by Genbank acceptance number: NP_005334.1 or Swissprot / Uniprot acceptance number: P01112(v1), and the NP_005334.1 sequence is reproduced herein in Table 3 below.

[0060] [Table 3]

[0061] In human cancers, KRAS is primarily a mutated RAS isoform (85%). In particular, the amino acid sequences of human KRAS, NRAS, and HRAS are essentially identical from positions 1 to 86, including the regions surrounding G12 and G13. Therefore, the same molecule can be used to mark G12 or G13 mutant human KRAS, NRAS, and HRAS proteins.

[0062] In some embodiments, KRAS inhibitors can inhibit human KRAS. The modifier “human” as used herein in relation to KRAS proteins may, in some interpretation, refer to the amino acid sequence of a KRAS protein. For example, a KRAS protein having the amino acid sequence as found in humans may also be obtained by technical means, for example, recombinant expression, cell-free translation, or abiological peptide synthesis. Since this molecule is intended to therapeutically target mutant KRAS proteins in humans, in some particular other interpretation, the modifier “human” may more specifically refer to a KRAS protein found or present in humans, whether the KRAS protein forms part of a human subject, organ, cell, or tissue, or is at least partially isolated therefrom. Those skilled in the art will understand that the amino acid sequences of a given native protein, such as a KRAS protein, may differ between or within different individuals of the same species due to normal genetic diversity (allelemic variation, polymorphism) within that species and / or due to differences in post-transcriptional or post-translational modifications. Any such variant or isoform of a natural protein is included by reference to or designation of the protein.

[0063] Various compounds that inhibit KRAS are known in the art and may include antibodies that specifically bind to KRAS. In some embodiments, the KRAS inhibitor is an antibody or other therapeutic protein that can selectively bind to KRAS, i.e., an anti-KRAS antibody.

[0064] As used herein, the term “antibody” refers to a polypeptide or group of polypeptides comprising at least one binding domain formed from the folding of a polypeptide chain having a three-dimensional binding space having an internal surface shape and charge distribution complementary to the characteristics of the antigenic determinant of the antigen. Antibodies typically have a tetrameric form with two pairs of polypeptide chains, each pair having one “light” chain and one “heavy” chain, and the variable region of each light / heavy chain pair forms the antibody binding site. Typically, each light chain is linked to the heavy chain by one covalent disulfide bond, while the number of disulfide bonds differs between heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide crosslinks. Typically, each heavy chain has a variable domain (VH) at one end followed by several constant domains (CH), and each light chain has a variable domain (VL) at one end and a constant domain (CL) at the other end, with the constant domains of the light chain aligned with the first constant domain of the heavy chain, and the variable domains of the light chain aligned with the variable domains of the heavy chain.

[0065] As used herein, the terms “antibody,” “antibodies,” and “immunoglobulin” encompass monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two different epitope-binding fragments, CDR-transplanted human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, single-chain Fv (scFv), single-chain antibodies, single-domain antibodies, Fab fragments, Fab' fragments, F(ab')2 fragments, antibody fragments exhibiting desired biological activity (e.g., antigen-binding moieties), disulfide-linked Fv (dsFv), and anti-idiotypic (anti-Id) antibodies, intracellular antibodies, and any of the epitope-binding fragments or derivatives described above. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules containing at least one antigen-binding site. Immunoglobulin molecules may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), subisotype (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or allotype (e.g., Gm, e.g., G1m(f, z, a, or x), G2m(n), G3m(g, b, or c), Am, Em, and Km(1, 2, or 3)). Antibodies may be derived from any mammalian species, including but not limited to humans, monkeys, pigs, horses, rabbits, dogs, cats, and mice, or from other animals such as birds, including but not limited to chickens. Antibodies may be fused to heterologous polypeptide sequences, for example, tags to facilitate purification.

[0066] Antibodies can be modified in the Fc region to provide desired effector function or serum half-life. As will be discussed in more detail in the following sections, with an appropriate Fc region, a naked antibody bound to the cell surface can induce cytotoxicity by antibody-dependent cellular cytotoxicity (ADCC), by recruiting complement in complement-dependent cytotoxicity (CDC), by recruiting nonspecific cytotoxic cells that recognize the bound antibody on influenza A virus and subsequently cause cellular phagocytosis in antibody-dependent cell-mediated phagocytosis (ADCP), or by several other mechanisms. Alternatively, if it is desirable to eliminate or reduce effector function to reduce side effects or therapeutic complications, for example, a modified Fc region can be used to increase binding affinity to FcRn and increase serum half-life. Alternatively, the Fc region can be conjugated to a portion such as PEG or albumin to increase serum half-life.

[0067] As used herein, the term “variant” refers to an antibody whose amino acid sequence differs from that of the “parent” antibody due to the addition, deletion, and / or substitution of one or more amino acid residues in the parent antibody sequence. A variant antibody may include one or more substitutions, deletions including internal deletions, additions including additions that result in a fusion protein, or conservative substitutions of amino acid residues of the parent antibody.

[0068] In some embodiments, the KRAS inhibitor is an antibody such as ELI-002, KRAS-EphA-2-CAR-DC, anti-KRAS G12V mTCR PBL, anti-KRAS G12D mTCR PBL, siG12D-LODER, or KRAS G12D siRNA. In some embodiments, the anti-KRAS antibody is a monoclonal antibody.

[0069] In some embodiments, the KRAS inhibitor is a small molecule KRAS inhibitor. As used herein, the term “small molecule” inhibitor refers to non-peptide-based and non-nucleic acid-based chemical compounds that reduce the activity of KRAS. In some embodiments, the small molecule KRAS inhibitor reduces the activity of KRAS. In some embodiments, the small molecule KRAS inhibitor increases the degradation of KRAS, thereby reducing the activity of KRAS function. In some embodiments, the small molecule inhibitor has a molecular weight of less than 1.5 kDa, less than 1.0 kDa, or less than 700 kDa. In some embodiments, the small molecule KRAS inhibitor binds to KRAS. In some embodiments, small molecule KRAS inhibitors have an IC50 of less than about 1 mM, less than about 100 μM, less than about 50 μM, less than about 25 μM, 10 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 2.5 nM. In some embodiments, small molecule KRAS inhibitors have an IC50 of less than about 2 nM or less than about 1 nM. In some embodiments, small molecule KRAS inhibitors have an IC50 of about 0.05 nM to about 50 nM, about 0.1 nM to about 10 nM, about 0.1 nM to about 25 nM, or about 0.5 nM to about 10 nM. In some embodiments, small molecule KRAS inhibitors have an IC50 of about 0.5 nM to about 5 nM, or about 0.5 nM to about 2 nM.

[0070] In some embodiments, the small molecule KRAS inhibitor may include small molecules known to those skilled in the art. For example, in some embodiments, the small molecule KRAS inhibitor is Sotrasib (AMG-510, Amgen, Formula L)

[0071] [ka] Adagrasib (MRTX849, Mirati Therapeutics, Inc., formula M)

[0072] [ka] Ly3537982 (Lilly, formula N)

[0073] [ka] Divalasib (GDC-6036, Genetech, Formula O)

[0074] [ka] Galsolacib (D-1553, InventisBio, Co., Ltd., Formula P)

[0075] [ka] Opnuracive (JDQ443, Novartis, formula Q)

[0076] [ka] Fluzerasib (IBI351, GFH925, Innovent Biologics, formula R)

[0077] [ka] These include BI1823911, D35-001, glesilassib (JAB-21822, Jacobio), HBI-2438, YL-15293, GEC255, RMC-6291, MK-1084, MRTX1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, or QTX3046. In some embodiments, the KRAS inhibitor may include combinations of small molecule KRAS inhibitors described herein.

[0078] Small molecule KRAS inhibitors of formula (I) are described in International Publication No. 2019215203, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the small molecule KRAS inhibitor is a compound of formula (I).

[0079] [ka] (In the formula, Ring A is selected from phenyl and bicyclic heteroaryl compounds. R 1 In each occurrence, independently, C 1-4 Alkyl, halo, hydroxy, C 1-4 Alkoxy, C 1-3 Fluoroalkyl, C 1-3 Selected from fluoroalkoxy, cyano, and acetylenyl, b is 0, 1, 2, or 3. Y is either CH2 or CH2CH2. R 2 cyano, halo, C 1-4 Alkyl, C 1-4 Alkoxy, or C 1-3 It is a fluoroalkyl, R 3 is F, Me, Et, MeO, or C 1-2 It is a fluoroalkyl, R 4 is either H or Me, R 5 is either H or Me, R 6 (This is H or CH2NMe2), or a pharmaceutically acceptable salt thereof, provided that Y is CH2 and R 2 Cl is and R 3 is F, ring A is phenyl, b is 2, R 1 The groups are F and OH, and each is ortho relative to the biaryl bond, and R 4 and R 6 If both are H, then R 5 This is conditional on it being Me.

[0080] In some embodiments of formula (I), the small molecule KRAS inhibitor has the following structure:

[0081] [ka]

[0082] Various bicyclic aryl rings can be used for ring A in formula (I). In some embodiments, ring A in the compound of formula (I) is selected from phenyl and bicyclic heteroaryls. As used herein, a bicyclic heteroaryl refers to an aromatic group comprising two fused rings and containing 1, 2, 3, or 4 N atoms, or 1 O atom, or 1 S atom, or 1 N atom and 1 S atom, or 1 N atom and 1 O atom, or 2 N atoms and 1 S atom, or 2 N atoms and 1 O atom. A bicyclic heteroaryl group includes a group in which both fused rings are aromatic, or in which one fused ring is aromatic and the other fused ring is partially or completely saturated. A partially saturated or fully saturated fused ring may contain a carbonyl group. At least one heteroatom in the bicyclic heteroaryl group may be present in the aromatic ring or the saturated ring. The bicyclic heteroaryl group A of the compound of formula (I) is a [6,6] or [6,5] ring system, and suitable examples of bicyclic heteroaryl groups include indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, azaindolyl, azindazolyl, pyrrolo[1,2-b]pyridazinyl and pyrrolo[2,3-b]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, sinnolinyl, phthalazinyl, quinoxalinyl and naphthilidinyl, and their partially saturated derivatives.

[0083] In some embodiments, the ring A of formula (I) is

[0084] [ka] It is selected from the group consisting of the following.

[0085] In some embodiments, ring A, as listed above, is bonded to the rest of the compound of formula (I) at any point on the ring listed above. In some embodiments, ring A, as listed above, is bonded to the rest of the compound of formula (I) at a carbon on the ring. In some embodiments, ring A, as listed above, is bonded to the rest of the compound of formula (I) at a heteroatom on the ring. In some embodiments, ring A, as listed above, is bonded to the rest of the compound of formula (I) at position 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the ring.

[0086] In some embodiments, (R 1 ) b It is joined to ring A listed above at any point on the ring listed above. In some embodiments, (R 1 ) b It is bonded to the carbon atoms on the ring A listed above. In some embodiments, (R 1 ) b It is bonded to the ring A listed above at the heteroatom on the ring. In some embodiments, (R 1 ) b It is bonded to ring A listed above at position 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the ring.

[0087] In some embodiments, R 1 In each occurrence, independently, C 1-4 Alkyl, halo, hydroxy, C 1-4 Alkoxy, C 1-3 Fluoroalkyl, C 1-3 Selected from fluoroalkoxy, cyano, and acetylenyl. To avoid misunderstanding, C 1-4 Alkyl refers to a linear or branched alkyl group containing 1 to 4 carbon atoms, and throughout this specification, the use of subscripts for alkoxy, fluoroalkyl, and fluoroalkoxy groups is consistent with this usage.

[0088] As used herein, the term halo refers to an atom selected from F, Cl, Br, or I. In embodiments herein, the halo group in the compound of formula (I), in particular the group R 2 and R 1 For this, F and Cl are preferred halo groups.

[0089] base R 2 cyano, halo, C 1-4 Alkyl, C 1-4 Alkoxy, or C 1-3 Selected from fluoroalkyl groups. Preferred R 2 Examples of the group include Cl, methyl, and cyano, for example, Cl. 3 is F, Me, Et, MeO, or C 1-2 A fluoroalkyl group is selected, for example, from F, Me, or MeO.

[0090] To avoid misunderstanding, if multiple substituents are independently selected from a given group, the selected substituents may include the same or different substituents from within the given group. As just one example, if ring A of formula (I) is (R 1 ) b If phenyl is substituted with and b is 2, then there are two R 1 The groups may be the same, for example, both may be fluoro, or they may be different, for example, one may be fluoro and the other hydroxy.

[0091] To avoid further misunderstanding, the formulas in this specification

[0092] [ka] The use of indicates a bond point between different groups.

[0093] As described above, in some embodiments, the small molecule KRAS inhibitor is a compound of formula (I).

[0094] [ka] (wherein ring A is selected from phenyl and bicyclic heteroaryl, R 1 is, in each occurrence, independently, C 1-4 alkyl, halo, hydroxy, C 1-4 alkoxy, C 1-3 fluoroalkyl, C 1-3 fluoroalkoxy, cyano, and acetylenyl, b is 0, 1, 2, or 3, Y is CH2 or CH2CH2, R 2 is cyano, halo, C 1-4 alkyl, C 1-4 alkoxy, or C 1-3 fluoroalkyl, R 3 is F, Me, Et, MeO, or C 1-2 fluoroalkyl, R 4 is H or Me, R 5 is H or Me, R 6 is H or CH2NMe2), or a pharmaceutical composition thereof, provided that when Y is CH2, R 2 is Cl, R 3 is F, A is phenyl, b is 2, the R 1 groups are F and OH, each ortho to the biaryl bond, and R 4 and R 6 are both H, then R 5 is Me.

[0095] In one embodiment, the small molecule KRAS inhibitor is a compound of formula (I) as defined above.

[0096] In one embodiment, the small molecule KRAS inhibitor is a pharmaceutically acceptable salt of a compound of formula (I).

[0097] In this embodiment, the compound of formula (I) is the compound of formula (Ia), where Y is CH2.

[0098] In this embodiment, the compound of formula (I) is the compound of formula (Ib), where Y is CH2CH2.

[0099] In this embodiment, the compound of formula (I), (Ia), or (Ib) is R 2 However, it is a compound of formula (Ic) selected from Cl, Me, or CN (cyano). In the embodiment, the compound of formula (Ic) is R 2 It is a compound of formula (Id) where Cl is present.

[0100] In the embodiment, the compound of formula (I), (Ia), (Ib), (Ic), or (Id) is R 3 However, it is a compound of formula (Ie) selected from F, Me, or MeO. In the embodiment, the compound of formula (Ie) is R 3 It is a compound of formula (If) where F is.

[0101] In the embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) are R 4 It is a compound of formula (Ig) where H is present.

[0102] In the embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) are R 5 It is a compound of formula (Ih) where is H. In the embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) are R 5 It is a compound of formula (Ii) where Me is present.

[0103] In the embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) are R 6 It is a compound of formula (Ij) where H is present.

[0104] In the embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij) are compounds of formula (Ik) in which ring A is phenyl.

[0105] In the embodiment, the compound of formula (Ik) is such that the integer b is 2 or 3, and at least one R 1 The compound of formula (Il) has an OH group. In embodiments, the compound of formula (Ik) or (Il) has at least two R 1 It is a compound of formula (Im) in which the group is ortho relative to the biaryl bond.

[0106] In this embodiment, the compound of formula (Ik) is A(R 1 ) b but

[0107] [ka] And, at will, R 1 is a compound of formula (In) selected from Me, F, Cl, and CN (cyano). In the embodiment, R in the compound of formula (In) 1 This is selected from Me, Cl, and CN.

[0108] In this embodiment, the compound of formula (Ik) is A(R 1 ) b but

[0109] [ka] It is a compound of formula (Io).

[0110] In the embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij) are compounds of formula (Ip), wherein ring A is a bicyclic heteroaryl compound.

[0111] In this embodiment, the compound of formula (Ip) is the compound of formula (Iq), wherein the bicyclic heteroaryl group of ring A is selected from the group consisting of .

[0112] [ka]

[0113] In some embodiments, the bicyclic heteroaryl group of ring A, as listed above, is bonded to the remainder of the compound of formula (Ip) at any point on the ring listed above. In some embodiments, the bicyclic heteroaryl group of ring A, as listed above, is bonded to the remainder of the compound of formula (Ip) at a carbon on the ring. In some embodiments, the bicyclic heteroaryl group of ring A, as listed above, is bonded to the remainder of the compound of formula (Ip) at a heteroatom on the ring. In some embodiments, the bicyclic heteroaryl group of ring A, as listed above, is bonded to the remainder of the compound of formula (Ip) at position 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the ring.

[0114] In some embodiments, (R 1 ) b It is joined to the ring A listed above at any point on the ring listed above for formula (Ip). In some embodiments, (R 1 ) b It is bonded to the carbon on the ring of formula (Ip) as listed above, ring A. In some embodiments, (R 1 ) b In the heteroatoms on the ring of formula (Ip), the elements are bonded to ring A listed above. In some embodiments, (R 1 ) b It is bonded to the ring A listed above at position 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the ring of formula (Ip).

[0115] In this embodiment, the compound of formula (Ip) is a compound of formula (Ir) in which the bicyclic heteroaryl group is selected from the group consisting of .

[0116] [ka]

[0117] In this embodiment, the compound of formula (Ip) is a compound of formula (Is) selected from the group consisting of a bicyclic heteroaryl group.

[0118] [ka]

[0119] In this embodiment, the compound of formula (Ip) is the compound of formula (It), wherein the bicyclic heteroaryl group is selected from the group consisting of .

[0120] [ka]

[0121] In the embodiment, the compound of formula (I), i.e., any of the compounds of formula (I), (Ia), (Ib) to (It), is the compound of formula (Iu) or (Iv), whose stereochemistry is as shown below.

[0122] [ka] That is the case.

[0123] In the embodiment, the compound of formula (Iu) is the compound of formula (Iui), where Y=CH2. In the embodiment, the compound of formula (Iv) is the compound of formula (Ivi), where Y=CH2CH2.

[0124] In this embodiment, the compound of formula (I), i.e., any of the compounds of formula (I), (Ia), (Ib) to (Ivi), is R 4 H is R 5 It is a compound of formula (Iw) where Me is present.

[0125] In this embodiment, the compound of formula (I) is as follows: 7-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindole-1-one, 1-[(8aS,11S)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 1-[(8aS,11R)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 5-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]isoquinoline-1(2H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazole-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinoline-1(2H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl)propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl)propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinoline-1(2H)-one, (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 8-[3-chloro-1-fluoro-8-(propa-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-2-yl]-7-methylisoquinoline-1(2H)-one, 1-[(6aS,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aR,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aS,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(8aS)-4-chloro-6-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]propa-2-en-1-one, 8-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinoline-1(2H)-one, (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, and Selected from each enantiomer and atropisomer of (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the small molecule KRAS inhibitor is a compound of formula (II),

[0127] [ka] The compound is 1-[(6aS,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0128] A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further optionally comprises, together with a pharmaceutically acceptable excipient, one or more other stereoisomers of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in the composition at a diastereomer excess of ≥90% (%de).

[0129] A pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further optionally comprises, together with a pharmaceutically acceptable excipient, one or more other stereoisomers of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomer excess of ≥90% (%ee) and a diastereomer excess of ≥90% (%de).

[0130] Compounds of formula (I) and their pharmaceutically acceptable salts may be prepared, used, or supplied in amorphous, crystalline, or semicrystalline form, and any given compound of formula (I) or its pharmaceutically acceptable salt may be formed into two or more crystalline / polymorphic forms, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric forms of hydrate) and / or solvated forms. It should be understood that this specification encompasses any and all such solid forms of compounds of formula (I), as well as their pharmaceutically acceptable salts.

[0131] A small molecule KRAS inhibitor of formula (A) is described in International Publication No. 2020178282, the contents of which are incorporated herein by reference in their entirety. In one embodiment, the small molecule KRAS inhibitor is a compound of formula (A).

[0132] [ka] (In the formula, A 1 is a phenyl or bicyclic heteroaryl group, X 1 and Y 1It is joined by a double bond, i)X 1 CR 17 Y 1 CR 18 ii) X 1 is N, and Y 1 CR 18 or iii)X 1 CR 17 Y 1 is N, or X 1 and Y 1 Together, C(O)NR 19 is, or X 1 and Y 1 However, Z 1 An adjacent ring atom of an optionally substituted 5-membered or 6-membered N-heterocyclic ring fused to an aromatic ring that is substituted with X 1 and Y 1 However, both are C, or C and N. Z 1 is O, NH, or NMe, R 10 These are independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl, and C1-C3 fluoroalkyl. n is 0, 1, 2, or 3. R 12 These are H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt. R 13a and R 13b Together, they equal O, or R 13a and R 13b H is H, R 14 is either H or Me, R 15 is either H or Me, R 16 It is H or CH2NMe2, R 17 R 18These are independently selected from H, F, Cl, CCH, CC(C1-C3 alkyl), CCCH2NMe2, CCCH2O(C1-C3 alkyl), CN, Me, C1-C6 alkyl, OH, OMe, O(C1-C3 alkyl), O(C1-C3 deuteroalkyl), O(C1-C3 fluoroalkyl), O(C3-C6 cycloalkyl), C1-C3 fluoroalkyl, OCH2CH2NMe2, OCH2CH2OMe, CH2OMe, OCH2CH2N(CH2CH2)2CH, OCH2CH2N(CH2CH2)2O, OCH2CH2(2-pyridyl), or optionally substituted 3, 4, 5, or 6-membered carbocyclic or heterocyclic rings, or R 17 and R 18 These together form a 5-membered or 6-membered carbon ring or heterocycle with optional substitutions. R 19 (Selected from H, Me, Et, C3H7, and C1-C3 fluoroalkyl), or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment, the compound of formula A) is the compound of formula (III)

[0134] [ka] (In the formula, A 1 is a phenyl or bicyclic heteroaryl group, X 1 and Y 1 It is joined by a double bond, i)X 1 CR 17 Y 1 CR 18 ii) X 1 is N, and Y 1 CR 18 or iii)X 1 CR 17 Y 1 is N, or X 1 and Y 1 Together, C(O)NR19 is, or X 1 and Y 1 However, Z 1 An adjacent ring atom of an optionally substituted 5-membered or 6-membered N-heterocyclic ring fused to an aromatic ring that is substituted with X 1 and Y 1 However, both are C, or C and N. Z 1 is O, NH, or NMe, R 10 These are independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl, and C1-C3 fluoroalkyl. n is 0, 1, 2, or 3. R 12 These are H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt. R 13a and R 13b Together, they equal O, or R 13a and R 13b H is H, R 14 is either H or Me, R 15 is either H or Me, R 16 It is H or CH2NMe2, R 17 and R 18 is selected from H, F, Cl, CCH, CN, Me, OH, OMe, O(C1-C3 alkyl), C1-C3 fluoroalkyl, or a 5-membered or 6-membered carbocyclic or heterocyclic ring that is optionally substituted, R 17 and R 18 These together form a 5-membered or 6-membered carbon ring or heterocycle with optional substitutions. R 19 (Selected from H, Me, Et, C3H7, and C1-C3 fluoroalkyl), or a pharmaceutically acceptable salt thereof.

[0135] A compound of formula (A), for example, a compound of formula (III), has the group X 1 and Y 1 The aromatic ring containing 1,4-diazepane (Z 1 =N) or 1,4-oxazepane (Z 1 It is characterized by a [6,7,6]-tricyclic core linked to piperazine by an =O) motif. Furthermore, it is characterized by a group A selected from phenyl and bicyclic heteroaryls. 1 The group X is formed via a biaryl bond. 1 and Y 1 It is linked to an aromatic ring containing the base R. 10 , R 12 , and X 1 Due to its properties, rotation around the biaryl bond is restricted, and the compound of formula (III) can consequently exist in a stable atropisomer form. The acrylamide motif is bonded to the tricyclic core via a non-bridgehead piperazine nitrogen.

[0136] As used herein, the term "alkyl" refers to both linear and branched saturated hydrocarbon radicals having a specific number of carbon atoms. As used herein, the term "deuteroalkyl" refers to one or more alkyl groups in which all hydrogen atoms are optionally replaced by deuterium atoms. The term "cycloalkyl" refers to a saturated carbon ring.

[0137] The term acetylenyl refers to the ethynyl radical, or -CCH group.

[0138] In this specification, "C" is defined as a case where x and y are integers. x -C y When used in terms such as "alkyl," the prefix C x -C yThe value indicates the numerical range of carbon atoms present in the group. For example, C1-C4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t-butyl, while examples of C1-C3 alkyl groups include methyl, ethyl, n-propyl, and i-propyl. C1-C4 alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, and t-butoxy. Examples of C1-C3 alkoxy groups include methoxy, ethoxy, n-propoxy, and i-propoxy. Examples of C1-C3 fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, and 2,2,2-trifluoroethyl. Examples of C1-C3 fluoroalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy. -O(C1-C3 deuteroalkyl) groups are partially or completely deuterated O-methyl, O-ethyl, or On-propyl or Oi-propyl groups. C3-C6 cycloalkyl groups mean cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. 2-Pyridyl groups are pyridine rings bonded to the pyridine N atom by a meta bond, i.e., groups

[0139] [ka] That is the case.

[0140] Unless otherwise specified, the bonding of atoms or groups may be any suitable atom of that group. For example, propyl includes propa-1-yl and propa-2-yl.

[0141] Unless otherwise specified, halos are selected from Cl, F, Br, and I, generally from Cl, F, or Br, or from Cl and F.

[0142] As mentioned above, A 1This may be a phenyl group or a bicyclic heteroaryl group. In this context, a bicyclic heteroaryl group refers to an aromatic group containing two fused rings and containing 1, 2, 3, or 4 nitrogen atoms, or 1 oxygen atom, or 1 sulfur atom, or 1 nitrogen atom and 1 sulfur atom, or 1 nitrogen atom and 1 oxygen atom, or 2 nitrogen atoms and 1 sulfur atom, or 2 nitrogen atoms and 1 oxygen atom. A bicyclic heteroaryl group includes groups in which both fused rings are aromatic, or in which one fused ring is aromatic and the other fused ring is partially or completely saturated. A partially saturated or completely saturated fused ring may contain a carbonyl group. Suitable examples of bicyclic heteroaryl groups include indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, azaindolyl, azindazolyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, sinnolinyl, phthalazinyl, quinoxalinyl, and naphthilidinyl.

[0143] As described above, X in the compound of formula (III) 1 and Y 1 is, Z 1 The adjacent ring atoms of a 5-membered or 6-membered N-heterocycle fused to an aromatic ring substituted with are either both C or C and N. The term 5-membered or 6-membered N-heterocycle refers to a saturated or unsaturated, for example, aromatic 5-membered or 6-membered ring containing at least one nitrogen atom and up to two further heteroatoms selected from O, N, and S. 1 The five-membered N-heterocycle fused to the aromatic ring substituted with can be selected from pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, oxadiazole, thiazole, and isothiazole, as well as their partially saturated equivalents. 1The six-membered N-heterocycle condensed to the aromatic ring substituted with can be selected from pyridine, pyridazine, pyrimidine, and pyrazine. The five-membered or six-membered N-heterocycle may be optionally substituted with one or two substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, Cl, F, CN, OH, OMe, OEt, NH2, NHMe, NMe2, and C1-C3 alkyl optionally substituted with OH, OMe, NH2, NHMe, or NMe2.

[0144] As described above, R in the compound of formula (III) 17 and R 18 The ring may be a five- or six-membered carbocyclic or heterocyclic ring that is optionally substituted. The term optionally substituted five- or six-membered carbocyclic or heterocyclic ring refers to a saturated or unsaturated, for example, aromatic ring containing up to three heteroatoms selected from O, N, and S. Five-membered heterocyclic rings may be selected from pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, 1,2,3-oxadiazole, thiazole, isothiazole, and their partially or fully saturated equivalents. Six-membered heterocyclic rings may be selected from pyridine, pyridazine, pyrimidine, and pyrazine. The five-membered or six-membered carbocyclic or heterocyclic ring may be optionally substituted with one or two substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, Cl, F, CN, OH, OMe, OEt, NH2, NHMe, NMe2, and C1-C3 alkyl which are optionally substituted with OH, OMe, NH2, NHMe, or NMe2.

[0145] As mentioned above, R 17 and R 18 If both are present in a compound of formula (A), for example, in a compound of formula (III), then together they become Z 1A optionally substituted five- or six-membered carbocyclic or heterocyclic ring can be formed by condensation with the aromatic ring substituted with . The optionally substituted five- or six-membered carbocyclic or heterocyclic ring may be saturated or unsaturated. The five- or six-membered carbocyclic or heterocyclic ring may be optionally substituted with one or two substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, Cl, F, CN, OH, OMe, OEt, NH2, NHMe, NMe2, and C1-C3 alkyl which is optionally substituted with OH, OMe, NH2, NHMe, or NMe2. 17 and R 18 When they come together to form a five-membered ring, they can together represent a C3, C2O, COC, C2N, CNC, CNO, NCO, CNS, or NCS chain. 17 and R 18 When they come together to form a 6-membered ring, they can together represent a C4, C3O, COC2, OC2O, C3N, C2NC, NCNC, CNNC, or NCCN chain. 17 and R 18 The chains are covalently bonded and substituted with hydrogen or optionally substituted substituents to satisfy their normal valencies.

[0146] To avoid misunderstanding, when multiple substituents are independently selected from a given group, the selected substituents may include the same or different substituents from within the given group. As just one example, A 1 However, (R 10 ) n If phenyl is substituted with and n is 2, then there are two R 10 The substituents may be the same, for example, both may be fluoro, or they may be different, for example, one may be fluoro and the other hydroxyl.

[0147] To avoid further misunderstanding, the formulas in this specification

[0148] [ka] The use of indicates a bond point between different groups.

[0149] If any embodiment within this specification includes a group referred to as "optionally substituted," further embodiments include embodiments in which the group is unsubstituted.

[0150] In one embodiment, the small molecule KRAS inhibitor is a compound of formula (A).

[0151] [ka] (In the formula, A 1 is a phenyl or bicyclic heteroaryl group, X 1 and Y 1 It is joined by a double bond, i)X 1 CR 17 Y 1 CR 18 ii) X 1 is N, and Y 1 CR 18 or iii)X 1 CR 17 Y 1 is N, or X 1 and Y 1 Together, C(O)NR 19 is, or X 1 and Y 1 However, Z 1 An adjacent ring atom of an optionally substituted 5-membered or 6-membered N-heterocyclic ring fused to an aromatic ring that is substituted with X 1 and Y 1 However, both are C, or C and N. Z 1 is O, NH, or NMe, R 10 These are independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl, and C1-C3 fluoroalkyl. n is 0, 1, 2, or 3. R12 These are H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt. R 13a and R 13b Together, they equal O, or R 13a and R 13b H is H, R 14 is either H or Me, R 15 is either H or Me, R 16 It is H or CH2NMe2, R 17 R 18 These are independently selected from H, F, Cl, CCH, CC(C1-C3 alkyl), CCCH2Nme2, CCCH2O(C1-C3 alkyl), CN, Me, C1-C6 alkyl, OH, OMe, O(C1-C3 alkyl), O(C1-C3 deuteroalkyl), O(C1-C3 fluoroalkyl), O(C3-C6 cycloalkyl), C1-C3 fluoroalkyl, OCH2CH2Nme2, OCH2CH2Ome, CH2OMe, OCH2CH2N(CH2CH2)2CH, OCH2CH2N(CH2CH2)2O, OCH2CH2(2-pyridyl), or optionally substituted 3, 4, 5, or 6-membered carbocyclic or heterocyclic rings, or R 17 and R 18 These together form a 5-membered or 6-membered carbon ring or heterocycle with optional substitutions. R 19 (Selected from H, Me, Et, C3H7, and C1-C3 fluoroalkyl), or a pharmaceutically acceptable salt thereof.

[0152] In this embodiment, the compound of formula (A) is R 16 It is a compound of formula (Aa) where H is present.

[0153] In the embodiment, the compound of formula (A) or (Aa) is R 15 It is a compound of formula (Ab) where H is present.

[0154] In the embodiment, the compound of formula (A), (Aa), or (Ab) is R 14 It is a compound of formula (Ac) where H is present.

[0155] In the embodiment, the compound of formula (A), (Aa), (Ab), or (Ac) is the compound of formula (Ad), where A is phenyl.

[0156] In this embodiment, the compound of formula (A) is the compound of formula (Ae)

[0157] [ka] That is the case.

[0158] In this embodiment, the compound of formula (Ae) is R 15 It is a compound of formula (Af) where H is present.

[0159] In the embodiment, the compound of formula (Ae) or (Af) is R 13a and R 13b It is a compound of formula (Ag) where H is present.

[0160] In the embodiment, the compound of formula (Ae) or (Af) is R 13a and R 13b It is a compound of formula (Ah) where the two atoms combine to equal 0.

[0161] In the embodiment, the compound of formula (Ae), (Af), (Ag), or (Ah) is Z 1 It is a compound of formula (Ai) where O is present.

[0162] In the embodiment, the compound of formula (Ae), (Af), (Ag), (Ah), or (Ai) is R 12 It is a compound of formula (Aj) in which is selected from F or Cl.

[0163] In embodiments, the compounds of formula (Ae), (Af), (Ag), (Ah), (Ai), or (Aj) have n = 2 or 3 and at least two R10 It is a compound of formula (Ak) in which the group is ortho relative to the biaryl bond.

[0164] In the embodiment, the compounds of formula (Ae), (Af), (Ag), (Ah), (Ai), (Aj), or (Ak) are at least one R 10 It is a compound with the formula (Al) whose group is OH.

[0165] In the embodiment, compounds of formula (A), (Ae), (Af), (Ag), (Ai), (Aj), (Ak), or (Al) are defined as compounds of formula (Am).

[0166] [ka] That is the case.

[0167] In the embodiment, compounds of formula (A), (Ae), (Af), (Ag), (Ah), (Ai), (Aj), (Ak), or (Al) are defined as compounds of formula (An) or (Ao).

[0168] [ka] That is the case.

[0169] In the embodiment, compounds of formula (A), (Ae), (Af), (Ag), (Ah), (Ai), (Aj), (Ak), or (Al) are X 1 and Y 1 C(O)NR 19 It is a compound of formula (Ap).

[0170] In the embodiment, the compound of formula (A), (Ae), (Af), (Ag), (Ah), (Ai), (Aj), (Ak), or (Al) is the compound of formula (Aq), where X 1 and Y 1is an adjacent ring atom of pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, 1,2,3-oxadiazole, thiazole, or isothiazole, which is optionally substituted.

[0171] In this embodiment, the compound of formula (Aq) is X 1 and Y 1 The compound is of formula (Ar), wherein an optional substituent on the five-membered ring containing is selected from C1-C3 alkyl, OC1-C2 alkyl, OMe, OH, F, and Cl.

[0172] In the embodiment, compounds of formula (A), (Aa) to (Ar) are as follows:

[0173] [ka] It has the stereochemistry shown in [image / diagram].

[0174] As described above, in some embodiments, the small molecule KRAS inhibitor is a compound of formula (III).

[0175] [ka] (In the formula, A 1 is a phenyl or bicyclic heteroaryl group, X 1 and Y 1 It is joined by a double bond, i)X 1 CR 17 Y 1 CR 18 ii) X 1 is N, and Y 1 CR 18 or iii)X 1 CR 17 Y 1 is N, or X 1 and Y 1 Together, C(O)NR19 is, or X 1 and Y 1 However, Z 1 An adjacent ring atom of an optionally substituted 5-membered or 6-membered N-heterocyclic ring fused to an aromatic ring that is substituted with X 1 and Y 1 However, both are C, or C and N. Z 1 is O, NH, or NMe, R 10 These are independently selected from F, Cl, Br, OH, CH2OH, OMe, CH2OMe, C1-C3 alkyl, and C1-C3 fluoroalkyl. n is 0, 1, 2, or 3. R 12 These are H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe, or OEt. R 13a and R 13b Together, they equal O, or R 13a and R 13b H is H, R 14 is either H or Me, R 15 is either H or Me, R 16 It is H or CH2NMe2, R 17 and R 18 is selected from H, F, Cl, CCH, CN, Me, OH, OMe, O(C1-C3 alkyl), C1-C3 fluoroalkyl, or a 5-membered or 6-membered carbocyclic or heterocyclic ring that is optionally substituted, R 17 and R 18 These together form a 5-membered or 6-membered carbon ring or heterocycle with optional substitutions. R 19 (Selected from H, Me, Et, C3H7, and C1-C3 fluoroalkyl), or a pharmaceutically acceptable salt thereof.

[0176] In this embodiment, the compound of formula (III) is R 16 It is a compound of formula (IIIa) where H is present.

[0177] In the embodiment, the compound of formula (III) or (IIIa) is R 15 It is a compound of formula (IIIb) where H is present.

[0178] In the embodiment, the compound of formula (III), (IIIa), or (IIIb) is R 14 It is a compound of formula (IIIc) where H is present.

[0179] In the embodiment, the compound of formula (III), (IIIa), (IIIb), or (IIIc) is A 1 It is a compound of formula (IIId) in which phenyl is present.

[0180] In the embodiment, the compound of formula (III) is the compound of formula (IIIe)

[0181] [ka] That is the case.

[0182] In this embodiment, the compound of formula (IIIe) is R 15 It is a compound of formula (IIIf) where H is present.

[0183] In the embodiment, the compound of formula (IIIe) or (IIIf) is R 13a and R 13b It is a compound of formula (IIIg) where H is present.

[0184] In the embodiment, the compound of formula (IIIe) or (IIIf) is R 13a and R 13b It is a compound of formula (IIIh) where the two atoms combine to equal O.

[0185] In the embodiment, the compound of formula (IIIe), (IIIf), (IIIg), or (IIIh) is Z 1It is a compound of formula (IIIi) where O is present.

[0186] In the embodiment, the compound of formula (IIIe), (IIIf), (IIIg), (IIIh), or (IIIi) is R 12 It is a compound of formula (IIIj), in which is selected from F or Cl.

[0187] In embodiments, the compounds of formula (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), or (IIIj) have n = 2 or 3 and at least two R 10 It is a compound of formula (IIIk) in which the group is ortho relative to the biaryl bond.

[0188] In the embodiment, the compounds of formula (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), or (IIIk) are at least one R 10 It is a compound of formula (IIIl) whose group is OH.

[0189] In the embodiment, the compounds of formula (III), (IIIe), (IIIf), (IIIg), (IIIi), (IIIj), (IIIk), or (IIIl) are the compounds of formula (IIIm).

[0190] [ka] That is the case.

[0191] In the embodiment, the compounds of formula (III), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), or (IIIl) are compounds of formula (IIIn) or (IIIo).

[0192] [ka] That is the case.

[0193] In the embodiment, the compound of formula (III), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), or (IIIl) is X 1 and Y 1 C(O)NR 19 It is a compound of formula (IIIp).

[0194] In the embodiment, the compound of formula (III), (IIIe), (IIIf), (IIIg), (IIIh), (IIIi), (IIIj), (IIIk), or (IIIl) is the compound of formula (IIIq), where X 1 and Y 1 is an adjacent ring atom of pyrrole, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, 1,2,3-oxadiazole, thiazole, or isothiazole, which is optionally substituted.

[0195] In this embodiment, the compound of formula (IIIq) is X 1 and Y 1 The compound is of formula (IIIr), wherein an optional substituent on the five-membered ring containing is selected from C1-C3 alkyl, OC1-C2 alkyl, OMe, OH, F, and Cl.

[0196] In the embodiment, the compounds of formulas (III), (IIIa) to (IIIr) are as follows:

[0197] [ka] It has the stereochemistry shown in [image / diagram].

[0198] In this embodiment, the compound of formula (A) is (12aS)-2-acryloyl-10-chloro-9-(5-methyl-1H-indazole-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-6-one, 1-((12aS)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, (12aR)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-((12aR)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazole-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-7-carbonitrile, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazole-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 8-[(12aR)-10-chloro-8-fluoro-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-9-yl]-7-methylisoquinoline-1(2H)-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aS)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aS)-10-chloro-11-methyl-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one, 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-hydroxy-6-methylphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, (12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(propa-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-1-one, 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(propa-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-1-one, 1-[(8aR)-6-chloro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydro-14H-pyrazino[2,1-c][1,2,4]triazolo[4',3':1,2]pyrido[3,4-f][1,4]oxazepine-10(8H)-yl]propa-2-en-1-one, 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazole-9(7H)-yl]propa-2-en-1-one, 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazole-9(7H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, and 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-10-chloro-8-ethynyl-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(7aR)-5-chloro-4-(2-chloro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydroimidazo[4,5-g]pyrazino[2,1-c][1,4]benzoxazepine-9(7H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropyloxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)propa-1-in-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridine-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidine-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2 H3)methyloxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, and 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-7-[2-(dimethylamino)ethoxy]-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(propa-1-in-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, and Selected from 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl)propa-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0199] As will be understood by those skilled in the art, the compound of formula (A) is A 1 And, X 1 and Y 1 It contains a biaryl bond between the ring containing the biaryl bond.

[0200] The following descriptions relating to compounds of formula (III) in this specification should be interpreted as applying equally to compounds of formula (A).

[0201] Compounds of formula (A), for example, compound (III), include, for example, piperazine to which acrylamide is bonded and Z 1 It is recognized that compounds of formula (A), e.g., compounds of formula (III), having one or more chiral centers at the bridgehead carbon between the ring containing and , can be prepared, isolated, and / or supplied with or without the presence of one or more other possible stereoisomers of the compound of formula (A) in any relative proportion. The preparation of stereoenriched / stereopure compounds can be carried out by standard techniques of organic chemistry well known in the art, e.g., by synthesis from stereoenriched or stereopure starting materials, by appropriately using a stereoenriched or stereopure catalyst during synthesis, and / or by splitting a racemic or partially enriched mixture of stereoisomers via chiral chromatography, e.g., by chiral chromatography. In preferred embodiments, the compounds herein are as shown below, Z 1 If O, then it is an (R)-stereoconfiguration.

[0202] [ka]

[0203] In particular, the compound of formula (III) is A 1 and X 1 and Y 1Because rotation around the biaryl bond with the ring containing is restricted, it can have axial chirality and therefore can exist as a mixture of atropisomers with an enantiomer excess of about 0% to >98%ee. When the compound is a pure atropisomer, the stereochemistry at each chiral center can be identified by either aR or aS. Such a designation may also be used for a mixture rich in one atropisomer. As a mere example, the following part exhibits atropisomerism and can be separated into aR and aS atropisomers by chiral chromatography. For illustrative purposes, A 1 The two atropisomers of the compound of formula (III), which is 2-F,6-hydroxyphenyl, are shown below (R 13 , R 14 , R 15 , and R 16 (These are omitted for clarity.)

[0204] [ka]

[0205] Further explanations of atropisomerism and axial chirality, as well as rules for stereochemistry assignment, can be found in Eliel, EL & Wilen, SH'Stereochemistry of Organic Compounds, John Wiley and Sons, Inc., 1994. In the compounds herein, the group R 10 , R 12 , and X 1 This can be selected to eliminate or substantially reduce interconversion between (aR) and (aS) atropisomers.

[0206] For more details, see Basic A 1 (R 10 ) n and substituent R 12 and / or X 1 The interaction between ring A 1 and X 1 The rotation around the bond with the ring containing the substituent R can be advantageously restricted.12 and ring A 1 and / or substituent R thereon 10 The interaction between the two can, as a result, be used to stabilize the atropisomer of the compound according to this specification. This, in turn, may advantageously allow for the isolation of a stable atropisomer that exhibits higher activity as an inhibitor of the G12C mutant Ras than the second atropisomer. It is understood that the more active atropisomer is a preferred embodiment.

[0207] Group X 1 In embodiments of the compound of formula (III) in which R is substituted, the substituent is R 12 As described herein, it may be possible to stabilize the atropisomers of the compounds.

[0208] A pharmaceutical composition comprising the compound of formula (III) or a pharmaceutically acceptable salt thereof further optionally comprises, together with a pharmaceutically acceptable excipient, one or more other stereoisomers of the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (III) or a pharmaceutically acceptable salt thereof is present in the composition at a diastereomer excess of ≥90% (%de.).

[0209] A pharmaceutical composition comprising the compound of formula (III) or a pharmaceutically acceptable salt thereof further optionally comprises, together with a pharmaceutically acceptable excipient, one or more other stereoisomers of the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (III) or a pharmaceutically acceptable salt thereof is present in the composition in an enantiomer excess of ≥90% (%ee) and a diastereomer excess of ≥90% (%de).

[0210] Compounds of formula (III) and their pharmaceutically acceptable salts may be prepared, used, or supplied in amorphous, crystalline, or semicrystalline form, and any given compound of formula (III) or its pharmaceutically acceptable salt may be formed into two or more crystalline / polymorphic forms, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric forms of hydrate) and / or solvated forms. It should be understood that this specification encompasses any and all such solid forms of compounds of formula (III), as well as their pharmaceutically acceptable salts.

[0211] In some embodiments, the small molecule KRAS inhibitor is a compound of formula (IV),

[0212] [ka] The compound is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, or a pharmaceutically acceptable salt thereof.

[0213] Ataxia telangiectasia mutations and RAD-3-related protein kinases, namely ATR protein kinases (also known as FRAP-related protein 1; FRP1; MEC1; SCKL; SECKL1), are members of the PI3-kinase-like kinase (PIKK) family of proteins involved in genome repair, maintenance, and stability (as outlined in Cimprich KA and Cortez D. 2008, Nature Rev. Mol. Cell Biol. 9:616-627). This disclosure provides the administration of ATR inhibitors.

[0214] In some embodiments, ATR inhibitors can inhibit human ATR. As previously stated, when used herein in relation to ATR proteins, the modifier "human" may, in one interpretation, refer to the amino acid sequence of ATR proteins, but also include ATR proteins found in humans obtained by other technical means, for example, recombinant expression, cell-free translation, or non-biological peptide synthesis.

[0215] Various compounds that inhibit ATR are known in the art and may include antibodies that specifically bind to ATR. In some embodiments, the ATR inhibitor is an antibody or other therapeutic protein that can selectively bind to ATR. In some embodiments, the ATR inhibitor is an antibody.

[0216] In some embodiments, the ATR inhibitor is a small molecule ATR inhibitor. As used herein, the term “small molecule” ATR inhibitor refers to non-peptide-based and non-nucleic acid-based chemical compounds that reduce the activity of ATR. In some embodiments, the small molecule ATR inhibitor reduces the activity of ATR. In some embodiments, the small molecule ATR inhibitor increases the degradation of ATR, thereby reducing the activity of ATR function. In some embodiments, the small molecule ATR inhibitor has a molecular weight of less than 1.5 kDa, less than 1.0 kDa, or less than 700 kDa. In some embodiments, the small molecule ATR inhibitor binds to ATR. In some embodiments, the small molecule ATR inhibitor has an IC50 of less than about 1 mM, less than about 100 μM, less than about 50 μM, less than about 25 μM, 10 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM, less than about 5 nM, or less than about 2.5 nM. In some embodiments, the small molecule ATR inhibitor has an IC50 of less than about 2 nM or less than about 1 nM. In some embodiments, the small molecule ATR inhibitor has an IC50 of about 0.05 nM to about 50 nM, about 0.1 nM to about 10 nM, about 0.1 nM to about 25 nM, or about 0.5 nM to about 10 nM. In some embodiments, the small molecule ATR inhibitor has an IC50 of about 0.5 nM to about 5 nM, or about 0.5 nM to about 2 nM.

[0217] For example, in some embodiments, the small molecule ATR inhibitor is M6620 / VX970 (belzocertib; Merck KGaA, formula B),

[0218] [ka] BAY-1895344 (Elimsertib, Bayer KGaA, Formula C)

[0219] [ka] RP-3500 (Camon Selcib, Roche, Formula D)

[0220] [ka] ATRN-119 (Aprea Therapeutics), SC0245 (Shijiazhuang Sagacity New Drug Development Co Ltd / WuXi AppTec Co), ATRN-212 (Aprea Therapeutics), LR-02 (Laevoroc Oncology AG), M4344 (Gultisertib. Merck KGaA Formula E),

[0221] [ka] M1774 (Tubular cellulose, Merck KGaA, Formula F)

[0222] [ka] ATG-018 (Antengene Corp Ltd), ART-0380 (Artios), BG-129 (Celator Pharmaceuticals), JS-123 (Shanghai Junshi Biosciences Co Ltd; Wigen Biomedicine Technology (Shanghai) Co Ltd), BKT-300 (Biokine Therapeutics Ltd, Formula G)

[0223] [ka] AZ-20 (AstraZeneca, formula H)

[0224] [ka] VE-821 (University of Oxford, Formula J)

[0225] [ka] AZD-5597(The University of Newcastle Upon Tyne, Formula K)

[0226] [ka] Alternatively, it is IMP-9064 (Impact Therapeutics).

[0227] The small molecule ATR compounds of formula (V) are described in International Publication No. 2011154737, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the small molecule ATR inhibitor is a compound of formula (V).

[0228] [ka] (In the formula, R 21 It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, R 22 teeth,

[0229] [ka] And, n is either 0 or 1. R 22A , R 22C , R 22E , and R 22F Each is independently either hydrogen or methyl, R 22B and R 22D Each is independently either hydrogen or methyl, R 22G -NHR 27 and -NHCOR 28 Selected from, R 22H It is fluoro, R 23 It is methyl, R 24 and R 25Each is independently either hydrogen or methyl, or R 24 and R 25 However, together with the atoms to which they are bonded, they form ring A 2 Forming, Ring A 2 C 3-6 A saturated 4-6 membered heterocyclic ring containing a cycloalkyl or one heteroatom selected from O and N, R 26 It is hydrogen, R 27 is hydrogen or methyl, R 28 (It is methyl), or a pharmaceutically acceptable salt thereof.

[0230] According to further aspects of this disclosure, small molecule ATR inhibitors are compounds of formula (V).

[0231] [ka] (In the formula, R 21 It is 3-methylmorpholine-4-yl, R 22 teeth,

[0232] [ka] And, n is either 0 or 1. R 22A , R 22C , R 22E , and R 22F Each is independently either hydrogen or methyl, R 22B and R 22D Each is independently either hydrogen or methyl, R 22G The -NH2, -NHMe, and -NHCOMe options are selected. R 22H It is fluoro, R 23 It is methyl, R 24 and R 25 Each is independently either hydrogen or methyl, or R 24 and R 25 However, together with the atoms to which they are bonded, they form ring A 2 Forming, Ring A 2 C 3-6 A saturated 4-6 membered heterocyclic ring containing a cycloalkyl or one heteroatom selected from O and N, R 26 (is hydrogen), or a pharmaceutically acceptable salt thereof.

[0233] Certain compounds of formula (V) can exist in the form of stereoisomers. It is understood that this disclosure encompasses all geometric and optical isomers of compounds of formula (V), as well as mixtures thereof, including racemates. Tautomers and mixtures thereof also form aspects of this disclosure. Solvates and mixtures thereof also form aspects of this disclosure. For example, preferred solvates of compounds of formula (V) may be hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates, or in amounts equivalent thereto.

[0234] To the extent that certain compounds of formula (V) as defined above can exist in an optically active or racemic form due to one or more chiral carbon atoms or sulfur atoms, this disclosure should be understood to include, in its definition, any such optically active or racemic form having the above activity. This disclosure encompasses all such stereoisomers having the activity as defined herein. Furthermore, in the names of chiral compounds, (R,S) indicates any scalmic or racemic mixture, while (R) and (S) indicate enantiomers. Where (R,S), (R), or (S) are not present in the name, the name refers to any scalmic or racemic mixture, where a scalmic mixture contains R and S enantiomers in any relative ratio, and a racemic mixture contains R and S enantiomers in a 50:50 ratio. Synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example, by synthesis from optically active starting materials, or by the division of racemic forms. Racemic mixtures can be separated into individual enantiomers using known procedures (see, for example, Advanced Organic Chemistry: 3rd Edition: author J March, pp. 104-107). A preferred procedure involves the formation of diastereomer derivatives by reaction of the racemic material with a chiral auxiliary agent, followed by separation of the diastereomers by, for example, chromatography, and then cleavage of the auxiliary species. Similarly, the above activities can be evaluated using standard laboratory techniques mentioned below.

[0235] It is understood that this disclosure encompasses compounds having one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 It may be any isotopic form containing H(T). C is 12 C, 13 C, and 14 It may be any isotopic form containing C. O is 16 O and 18 It may be any isotopic form, including O, etc.

[0236] This disclosure relates to compounds of formula (V) as defined herein and salts thereof. Salts for use in pharmaceutical compositions are pharmaceutically acceptable salts, but other salts may also be useful in the production of compounds of formula (V) and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of this disclosure may include, for example, acid addition salts of compounds of formula (V) as defined herein that are sufficiently basic to form such salts. Such acid addition salts include, but are not limited to, salts formed with fumarates, methanesulfonates, hydrochlorides, hydrobroms, citrates and maleates, as well as salts formed with phosphoric acid and sulfuric acid. In addition, if the compound of formula (V) is sufficiently acidic, the salt is a basic salt, and examples include, but are not limited to, alkali metal salts, e.g., sodium or potassium, alkaline earth metal salts, e.g., calcium or magnesium, or organic amine salts, e.g., amino acids such as triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, or lysine.

[0237] Compounds of formula (V) may be provided as in vivo hydrolyzable esters. In vivo hydrolyzable esters of compounds of formula (V) containing a carboxyl or hydroxyl group are, for example, pharmaceutically acceptable esters that are cleaved in the body of a human or animal to produce a hydrophilic acid or an alcohol. Such esters may be identified, for example, by intravenously administering the compound under test to a test animal and subsequently examining the body fluids of the test animal.

[0238] Suitable pharmaceutically acceptable esters for carboxy include C 1-6 Alkoxymethyl esters, for example, methoxymethyl, C 1-6 Alkanoyloxymethyl esters, for example, pivaloyloxymethyl, phthalidyl esters, C 3-8 Cycloalkoxycarbonyloxy C 1-6Alkyl esters, for example, 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolene-2-onylmethyl esters, for example, 5-methyl-1,3-dioxolene-2-onylmethyl, and C 1-6 This includes alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl, which can be formed with any carboxyl group in the compounds of this disclosure.

[0239] Suitable pharmaceutically acceptable esters for hydroxyl include inorganic esters such as phosphate esters (including phosphoramidocyclic esters) and α-acyloxyalkyl ethers, as well as related compounds that decompose as a result of in vivo hydrolysis of esters to yield a hydroxyl group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. For the selection of ester-forming groups that can be hydrolyzed in vivo for hydroxyl, C1- 10 Alkanoyls, e.g., formyl, acetyl, benzoyl, phenylacetyl, substituted benzoyl, and phenylacetyl; C1- 10 Alkoxycarbonyls (resulting in alkyl carbonates), e.g., ethoxycarbonyl; di-C1-4 alkylcarbamoyl and N-(di-C1-4 alkylaminoethyl)-N-C1-4 alkylcarbamoyl (resulting in carbamates); di-C1-4 alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, C 1-4 Examples include alkylaminomethyl and di-C1-4 alkyl)aminomethyl, as well as morpholino or piperazino linked from a ring nitrogen atom to the 3rd or 4th position of the benzoyl ring via a methylene linking group. Other interesting in vivo hydrolyzable esters include, for example, R A C(O)OC 1-6 Alkyl-CO- is one example, and in the formula, R AFor example, these are benzyloxy-C1-4 alkyl or phenyl. Preferred substituents on the phenyl group in such esters include, for example, 4-C1-4 piperazino-C1-4 alkyl, piperazino-C1-4 alkyl, and morpholino-C1-4 alkyl.

[0240] The compound of formula (V) can be administered in the form of a prodrug, which is broken down in the human or animal body to yield the compound of formula (V). Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see below. a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985). b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", H. Bundgaard p.113-191 (1991), c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988), and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

[0241] Ring A 2 n (if related to equation (V)), R 21 , R 22 , R 24 , R 25 , R 26 , R 27 , and R 28The specific values ​​of are as follows. Such values ​​may be used individually or, where appropriate, in combination, in connection with any aspect or part thereof of this disclosure and with any of the definitions, claims, or embodiments defined herein.

[0242] n: In one embodiment, n is 0. In another embodiment, n is 1.

[0243] R 21 In one aspect, R 21 R is selected from morpholine-4-yl and 3-methylmorpholine-4-yl. In a further embodiment, R 21 is 3-methylmorpholine-4-yl. In a further embodiment, R 21 teeth,

[0244] [ka] In a further embodiment, R 21 teeth,

[0245] [ka] That is the case.

[0246] R 22 In one aspect, R 22 teeth,

[0247] [ka] In one aspect, R 22 teeth,

[0248] [ka] In one aspect, R 22 teeth,

[0249] [ka] In one aspect, R22 teeth,

[0250] [ka] That is the case.

[0251] R 22A In one aspect, R 22A It is hydrogen.

[0252] R 22B In one aspect, R 22B It is hydrogen.

[0253] R 22C In one aspect, R 22C It is hydrogen.

[0254] R 22D In one aspect, R 22D It is hydrogen.

[0255] R 22E In one aspect, R 22E It is hydrogen.

[0256] R 22F In one aspect, R 22F It is hydrogen.

[0257] R 22G In one aspect of this disclosure, R 22G -NHR 27 and -NHCOR 28 Selected from. In one aspect of this disclosure, R 22G -NHR 27 In one aspect of this disclosure, R 22G is -NHCOR 28 In one aspect of this disclosure, R 22G R is selected from -NH2, -NHMe, and -NHCOMe. In one aspect of this disclosure, R 22G is -NH2. In one aspect of this disclosure, R 22G is -NHMe. In one aspect of this disclosure, R 22G It is -NHCOMe.

[0258] R 24 and R 25 In one aspect of this disclosure, R 24 and R 25 is hydrogen. In one aspect of this disclosure, R 24 and R 25 R is methyl. In one aspect of this disclosure, R 24 and R 25 Together with the atoms to which they are bonded, they form ring A 2 It forms.

[0259] Ring A 2 In one aspect of this disclosure, Ring A 2 C 3-6 A saturated 4-6 heterocyclic ring containing a cycloalkyl or one heteroatom selected from O and N. In another embodiment, ring A 2 is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl ring. In another embodiment, ring A 2 is a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, or piperidinyl ring. In another embodiment, ring A 2 is a cyclopropyl, cyclopentyl, tetrahydropyranyl, or piperidinyl ring. In another embodiment, ring A 2 is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. In another embodiment, ring A 2 is a cyclopropyl or tetrahydropyranyl ring. In another embodiment, ring A 2 is a piperidinyl ring. In another embodiment, ring A 2 This is a tetrahydropyranyl ring. In another embodiment, ring A 2 It is a cyclopropyl ring.

[0260] R 26 In one aspect, R 26 It is hydrogen.

[0261] R 27 In one aspect, R 27is hydrogen or methyl. In one embodiment, R 27 is methyl. In one embodiment, R 27 It is hydrogen.

[0262] R 28 In one aspect, R 28 It is methyl.

[0263] In one embodiment, the small molecule ATR inhibitor is a compound of formula (V) or a pharmaceutically acceptable salt thereof, where R 21 n is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is 0 or 1, and R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22D is hydrogen, and R 22E is hydrogen, and R 22F is hydrogen, and R 22G -NHR 27 and -NHCOR 28 Selected from, R 22H is fluoro, and R 23 It is methyl, and R 24 and R 25 Together with the atoms to which they are bonded, they form ring A 2 Forms ring A 2 C 3-6 A cycloalkyl or saturated 4-6 heterocyclic ring containing one heteroatom selected from O and N, R 26 is hydrogen, and R 27 is hydrogen or methyl, and R 28 It is methyl.

[0264] In another embodiment, the small molecule ATR inhibitor is a compound of formula (V) or a pharmaceutically acceptable salt thereof, where R 21 n is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is 0 or 1, and R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22D is hydrogen, and R22E is hydrogen, and R 22F is hydrogen, and R 22G It is selected from -NH2, -NHMe, and -NHCOMe, R 22H is fluoro, and R 23 It is methyl, and R 24 and R 25 Together with the atoms to which they are bonded, they form ring A 2 Forms ring A 2 C 3-6 A cycloalkyl or saturated 4-6 heterocyclic ring containing one heteroatom selected from O and N, R 26 It is hydrogen.

[0265] In another embodiment, the small molecule ATR inhibitor is a compound of formula (V) or a pharmaceutically acceptable salt thereof, where R 21 n is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is 0 or 1, and R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22D is hydrogen, and R 22E is hydrogen, and R 22F is hydrogen, and R 22G -NHR 27 and -NHCOR 28 Selected from, R 22H is fluoro, and R 23 It is methyl, and R 24 and R 25 Together with the atoms to which they are bonded, they form ring A 2 Forms ring A 2 R is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl ring, 26 is hydrogen, and R 27 is hydrogen or methyl, and R 28 It is methyl.

[0266] In another embodiment, the small molecule ATR inhibitor is a compound of formula (V) or a pharmaceutically acceptable salt thereof, where R 21 n is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, n is 0 or 1, and R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22D is hydrogen, and R 22E is hydrogen, and R 22F is hydrogen, and R 22G It is selected from -NH2, -NHMe, and -NHCOMe, R 22H is fluoro, and R 23 It is methyl, and R 24 and R 5 Together with the atoms to which they are bonded, they form ring A 2 Forms ring A 2 R is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl ring, 26 It is hydrogen.

[0267] In another embodiment, the small molecule ATR inhibitor is a compound of formula (Va),

[0268] [ka] or a pharmaceutically acceptable salt thereof, in the formula, Ring A 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring, R 22 teeth,

[0269] [ka] And, n is either 0 or 1, R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22Dis hydrogen, and R 22E is hydrogen, and R 22F is hydrogen, and R 22G -NHR 27 and -NHCOR 28 Selected from, R 22H is fluoro, and R 23 is a methyl group, R 26 is hydrogen, and R 27 is hydrogen or methyl, and R 28 It is methyl.

[0270] In another embodiment, the small molecule ATR inhibitor is a compound of formula (Va),

[0271] [ka] or a pharmaceutically acceptable salt thereof, in the formula, Ring A 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring, R 22 teeth,

[0272] [ka] And, n is either 0 or 1, R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22D is hydrogen, and R 22E is hydrogen, and R 22F is hydrogen, and R 22G It is selected from -NH2, -NHMe, and -NHCOMe, R 22H is fluoro, and R 23 is a methyl group, R 26 It is hydrogen.

[0273] In another embodiment, the small molecule ATR inhibitor is a compound of formula (Va),

[0274] [ka] or a pharmaceutically acceptable salt thereof, in the formula, Ring A 2 It is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring, R 22 teeth,

[0275] [ka] And, n is either 0 or 1, R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22D is hydrogen, and R 22E is hydrogen, and R 22F is hydrogen, and R 22G -NHR 27 And R 22H is fluoro, and R 23 is a methyl group, R 26 is hydrogen, and R 27 It is hydrogen.

[0276] In another embodiment, the small molecule ATR inhibitor is a compound of formula (Va),

[0277] [ka] or a pharmaceutically acceptable salt thereof, in the formula, Ring A 2 It is a cyclopropyl ring, R 22 teeth,

[0278] [ka] And, n is 0, and R 22A is hydrogen, and R 22B is hydrogen, and R 22C is hydrogen, and R 22D is hydrogen, and R22E is hydrogen, and R 22F is hydrogen, and R 22G -NHR 27 And R 22H is fluoro, and R 23 is a methyl group, R 26 is hydrogen, and R 27 It is methyl.

[0279] In another embodiment, small molecule ATR inhibitors are 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[((R)-S-methylsulfonimidoyl)methyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzimidazole-2-amine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzimidazole-2-amine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-indole, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-indole, 1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-c]pyridine, N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidine-2-yl}-1H-benzimidazole-2-amine, N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidine-2-yl}-1H-benzimidazole-2-amine, N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidine-2-yl}-1H-benzimidazole-2-amine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[4-((R)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidine-2-yl}-1H-benzimidazole-2-amine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[4-((S)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidine-2-yl}-1H-indole, 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, and A compound selected from any one of the following: 6-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzimidazole-2-amine or a pharmaceutically acceptable salt thereof.

[0280] In another embodiment, small molecule ATR inhibitors are 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[(R)-S-methylsulfonimidoyl)methyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-(R)-(S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzimidazole-2-amine, and A compound selected from any one of the following: N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-(S)-(S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzimidazole-2-amine or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the small molecule ATR inhibitor is a compound of formula (VI) (ceraracertib),

[0282] [ka] The compound is 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine or a pharmaceutically acceptable salt thereof.

[0283] Various combinations of KRAS inhibitors and ATR inhibitors are envisioned in this disclosure. For example, in some embodiments, the combination of a KRAS inhibitor and an ATR inhibitor may include one of the following combinations shown in Table 4.

[0284] [Table 4-1]

[0285] [Table 4-2]

[0286] [Table 4-3]

[0287] [Table 4-4]

[0288] In some embodiments, (i) a KRAS inhibitor and (ii) an ATR inhibitor are 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, 91-100, 101-110, 111-120, 121-130, 131-140, 141-150, 151-160, 161 The combination is one of the following: ~170, 171~180, 181~190, 191~200, 201~210, 211~220, 221~230, 231~240, 241~250, 251~260, 261~270, 271~280, 281~290, 291~300, 301~310, 311~320, or 321~330. In some embodiments, (i) the KRAS inhibitor is a compound of formula (I), and (ii) the ATR inhibitor is seracertib. In some embodiments, (i) the KRAS inhibitor is a compound of formula (II), and (ii) the ATR inhibitor is seracertib. In some embodiments, (i) the KRAS inhibitor is a compound of formula (III), and (ii) the ATR inhibitor is seracertib. In some embodiments, (i) the KRAS inhibitor is a compound of formula (IV), and (ii) the ATR inhibitor is ceraracertib.

[0289] In some embodiments, the subject has KRAS, NRAS, or HRAS mutations. In some embodiments, the subject has KRAS mutations. In some embodiments, the KRAS inhibitors described herein, e.g., antibodies or small molecule KRAS inhibitors, selectively target mutations at codon 12, codon 13, and / or codon 61. In some embodiments, mutations at codon 12 or codon 13 result in downregulation through induction of intermolecular beta sheet formation, but do not substantially alter the amount or biological activity of wild-type RAS. From this perspective, the term “wild-type” can refer to the conventional meaning of KRAS variants encoded by the alleles of each KRAS gene that are most commonly observed in human populations.

[0290] In some embodiments, the subject has a "G12 mutant human KRAS" in which the glycine residue at position 12 (G12) is mutated. In some embodiments, the subject has a KRAS protein in which G12 is deleted, i.e., a deletion mutant. In some embodiments, the subject has a KRAS protein in which an additional amino acid is encoded upstream or downstream of G12, i.e., an insertion mutant. In some embodiments, the subject has a KRAS protein in which G12 is replaced by exactly one amino acid other than glycine (G12 missense mutant KRAS). Missense mutations in which G12 of human RAS is replaced by substantially any other amino acid, including missense mutations of G12A, G12D, G12F, G12L, G12P, G12S, G12V, G12Y, G12C, G12E, G121, G12N, G12R, G12T, and G12W, have been demonstrated in disease. Misssense mutations in G12Q, G12H, G12K, and G12M are also possible.

[0291] In some embodiments, "G13 mutant human KRAS" is characterized by a mutation in the glycine residue at position 13 (G13). Of particular interest is the mutant KRAS protein in which G13 is replaced by exactly one amino acid other than glycine (G13 missense mutant KRAS). Missense mutations in which G13 of human RAS is replaced by substantially any other amino acid, including missense mutations of G13A, G13D, G13F, G13M, G13P, G13S, G13Y, G13C, G13E, G131, G13N, G13R, and G13V, have been demonstrated in disease. Missense mutations of G13L, G13W, G13H, G13K, G13Q, and G13T are also conceivable.

[0292] In some embodiments, "Q61 mutant human KRAS" has a mutation in the glutamine residue (Q61) at position 61. Of particular interest is the mutant KRAS protein in which Q61 is replaced by exactly one amino acid other than glutamine (Q61 missense mutant KRAS). Missense mutations that replace Q61 in human KRAS may include missense mutations of Q61A, Q61D, Q61F, Q61M, Q61P, Q61S, Q61Y, Q61C, Q61E, Q611, Q61N, Q61R, and Q61V. Missense mutations of Q61L, Q61W, Q61H, Q61K, Q61G, and Q61T are also possible.

[0293] In some embodiments, G12, G13, or Q61 mutant human KRAS proteins, particularly G12 or G13 missense mutants, may cause or be associated with proliferative or neoplastic diseases and / or result in a constitutively active KRAS, more specifically a KRAS lacking GAP-mediated GTP hydrolysis.

[0294] In some embodiments, the methods described herein can be used when the amino acid at positions 12, 13, or 61 is replaced from the wild type to an uncharged amino acid. In some embodiments, the mutants at positions 12, 13, or 61 of the human KRAS protein may be those in which the amino acid at positions 12, 13, or 61 is replaced by a hydrophobic amino acid other than proline, such as glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), phenylalanine (F), methionine (M), and tryptophan (W). In some embodiments, the mutant amino acid at positions 12, 13, or 61 of the human KRAS protein may be those in which the amino acid at positions 12, 13, or 61 is replaced by a polar amino acid, such as serine (S), threonine (T), cysteine ​​(C), asparagine (N), glutamine (Q), or tyrosine (Y). In some embodiments, the mutant amino acid at position 12 or 13 of the human KRAS protein may be a G12V, G12C, G12A, or G12S mutant human KRAS protein, NRAS, or HRAS protein, such as a G12V, G12C, G12A, or G12S mutant human KRAS protein. In a particularly preferred embodiment, the G12 mutant human KRAS protein may be a G12V mutant human KRAS protein, such as a G12V mutant human KRAS protein. In some embodiments, the G13 mutant human KRAS protein may be a G13V, G13C, or G13S mutant human KRAS protein. In some embodiments, the KRAS mutation is a mutation at codon 12, codon 13, and / or codon 61. In some embodiments, the KRAS mutation is a mutation at codon 12. In some embodiments, the KRAS mutation is a G12C mutation.

[0295] In some embodiments, mutations at codon 12, codon 13, and / or codon 61 may result in proliferative or neoplastic disease in a subject, for example, a human subject. In some embodiments, the subject has lung cancer, colorectal cancer, pancreatic cancer, or a combination thereof. In some embodiments, the subject has mutations at codon 12, codon 13, and / or codon 61 and has been diagnosed with lung cancer, colorectal cancer, pancreatic cancer, or a combination thereof. In some embodiments, the subject has lung cancer, colorectal cancer, pancreatic cancer, esophageal and gastric cancer, endometrial cancer, bile duct cancer, or a combination thereof. In some embodiments, the subject is human.

[0296] In some embodiments, the methods described herein may be administered to modulate an adaptive immune response. In some embodiments, modulating an adaptive immune response provides deep, sustained antitumor activity, causing the subject to develop a long-term immunogenic memory response against the tumor. In some embodiments, tumor growth after discontinuation of administration of KRAS inhibitors and ATR inhibitors continues to decrease and / or be eliminated and / or reduced. Accordingly, in some embodiments, the methods and compositions described herein provide a method for modulating an adaptive immune response in a subject, comprising administering a composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor.

[0297] In some embodiments, the methods and compositions described herein can reduce the size of a tumor in a subject. In some embodiments, the methods and compositions described herein are intended to reduce the volume of a cancerous tumor in a subject, and the method comprises administering a composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor.

[0298] In some embodiments, the methods and compositions described herein can treat subjects in need of treatment, the method comprising administering a composition comprising (a) a KRAS inhibitor and (b) an ATR inhibitor, the subject having a disorder mediated by a KRAS, NRAS, or HRAS G12C mutation.

[0299] In some embodiments, this disclosure provides compositions comprising (a) a KRAS inhibitor and (b) an ATR inhibitor. In some embodiments, the compositions are in oral dosage forms, e.g., liquids, capsules, tablets, or chewable tablets; injectable dosage forms (e.g., intramuscular or intravenous dosage forms, sublingual or transmucosal dosage forms, nasal dosage forms, inhalable dosage forms, or cutaneous dosage forms; those skilled in the art will be able to incorporate appropriate excipients, diluents, binders, etc., according to the mode of administration, and such may be added to the compositions described herein. In some embodiments, compositions comprising (a) a KRAS inhibitor and (b) an ATR inhibitor are pharmaceutically acceptable. When used herein, compositions comprising a KRAS inhibitor / ATR inhibitor will be described. For the purposes of this definition, “pharmaceutically acceptable” means that it is approved by a federal or state regulatory authority or is listed in the United States Pharmacopeia, the European Pharmacopeia, or any other generally recognized pharmacopoeia for use in animals, more specifically in humans. In some embodiments, the term “pharmaceutically acceptable” means a composition and / or dosage form containing a KRAS inhibitor / ATR inhibitor that, within reasonable medical judgment, is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic response, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0300] Various combinations of (a) KRAS inhibitors and (b) ATR inhibitors can be used in this disclosure. In some embodiments, the KRAS inhibitor is sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, MRTX 1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV). In some embodiments, the ATR inhibitor is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-559, or IMP9064, a compound of formula (V), or a compound of formula (VI).

[0301] In some embodiments, the composition includes a combination of (i) a KRAS inhibitor and (ii) an ATR inhibitor, as shown in Table 4. In some embodiments, the composition includes 1-10, 11-20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, 81-90, 91-100, 101-110, 111-120, 121-130, 131-140, 141-150, 151-160, 161-170, 171-180, 181-1 This includes combinations of (i) a KRAS inhibitor and (ii) an ATR inhibitor, as seen in combinations of 90, 191-200, 201-210, 211-220, 221-230, 231-240, 241-250, 251-260, 261-270, 271-280, 281-290, 291-300, 301-310, 311-320, or 321-330. In some embodiments, the composition comprises (i) a KRAS inhibitor compound of formula (I) and (ii) seracertib. In some embodiments, the composition comprises (i) a KRAS inhibitor of formula (II) and (ii) seracertib. In some embodiments, the composition comprises (i) a KRAS inhibitor of formula (III) and (ii) seracertib. In some embodiments, the composition comprises (i) a KRAS inhibitor of formula (IV) and (ii) ceraracertib.

[0302] In some embodiments, the composition comprising a KRAS inhibitor and an ATR inhibitor may be in a physical state suitable for an appropriate mode of administration. In some embodiments, the composition is a liquid. In some embodiments, the composition is a solid. In some embodiments, the composition is a solid oral dosage form. In some embodiments, the composition further comprises pharmaceutically acceptable excipients, diluents, or carriers.

[0303] In some embodiments, this disclosure provides the use of the compositions described herein for the manufacture of pharmaceuticals, for example, pharmaceuticals for the treatment of cancer.

[0304] This disclosure describes how the administration of both KRAS inhibitors and ATR inhibitors may be used to treat cancer. In some embodiments, both KRAS inhibitors and ATR inhibitors are in the same composition. However, in some embodiments, the KRAS inhibitors and ATR inhibitors are in separate compositions, but both KRAS inhibitors and ATR inhibitors are in a kit so that they may be administered to the same subject for a condition, e.g., cancer. In some embodiments, the kit includes (a) a first container containing a first composition comprising a KRAS inhibitor, and (b) a second container containing a second composition comprising an ATR inhibitor. In some embodiments, the kit further includes instructions for administering the KRAS inhibitors and ATR inhibitors, including the mode of administration, dosage, and administration regimen.

[0305] In some embodiments, the KRAS inhibitors in the kit are sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, M RTX1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV). In some embodiments, the ATR inhibitor in the kit is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-559, or IMP9064, a compound of formula (V), or a compound of formula (VI).

[0306] In some embodiments, the dosage forms in the kit may be the same, for example, both the KRAS inhibitor and the ATR inhibitor may be in oral dosage form. In some embodiments, the dosage forms in the kit may be different, for example, the KRAS inhibitor may be in oral dosage form and the ATR inhibitor may be in intravenous dosage form. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first and second compositions of the kit may be liquids. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first and second compositions of the kit may be solids. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first and second compositions of the kit may be solid oral dosage forms. In some embodiments, the first composition of the kit, the second composition of the kit, or both the first and second compositions of the kit may further comprise pharmaceutically acceptable excipients, diluents, or carriers.

[0307] All references cited herein, including patents, patent applications, papers, textbooks, etc., and references cited within them, are incorporated herein by reference in their entirety, unless they have not yet been cited. [Examples]

[0308] The completely pathogen-free animals used in the following study were housed in a controlled pathogen-free environment under the following conditions: temperature (19–23°C), humidity 55% ± 10%, photoperiod (12-hour light / dark cycle), and air exchange. The animals were housed in individually ventilated cages and given free access to food and water.

[0309] The following test materials were used in the following preclinical in vivo studies: vehicle (0.5% HPMC / 0.1% Tween 80), AZD4625 (0.5% HPMC / 0.1% Tween 80), compound of formula IV (0.5% HPMC / 0.1% Tween 80), and AZD6738 (10% DMSO / 40% PG / 50% WFI). For monotherapy, the vehicle and the inhibitor were administered orally at a volume of 0.05–0.1 mL / 10 g. For combination therapy, AZD4625 or compound of formula IV was administered 4 or 2 hours after the AM administration of AZD6738.

[0310] Tumors were measured three times a week using a calipas, and their volume was calculated using the elliptic equation (π / 6 × width × width × length). Animal body weight and tumor status were also recorded throughout the study period. For anti-tumor studies, the target mice had a tumor size of 1.5 cm. 3 Regarding the second-chance study, 0.7cm 3 The study continued until clinical signs were observed or until the end of the study period.

[0311] Example 1 Antitumor activity by dual inhibition of KRAS and ATR in KRAS-mutated cancers G12C This was determined in a preclinical in vivo study using ATR inhibitors. The KRAS used was also determined. G12C And ATR inhibitors include AZD4625 (KRAS G12C These were a covalent allosteric inhibitor and AZD6738 (ceraracertib, an ATP-competitive ATR inhibitor).

[0312] For research purposes, KRAS G12C CT26 manipulated to express mutations G12C Mouse colon cancer cells were grown subcutaneously in BALB / c mice with an intact immune system. 5 × 10⁶ mice were used to prepare the control mice. 5 pieces and 5 × 10 4 CT26 G12C(G12C clone P5E6) cells were subcutaneously transplanted into the right flank of female BALB / c mice (Envigo UK, strain ID: HSD-162) or female nude Foxn1nu mice (Envigo UK, strain ID: HSD-069), respectively. The average volume was approximately 0.2 cm³. 3 Once tumors formed, the mice were randomized to either a treatment group or a control group and treated for 4 weeks with vehicle control, AZD4625, or AZD6738 monotherapy, or in combination therapy. AZD4625 was administered daily, and AZD6738 was administered twice daily during the treatment period, on a schedule of 7 days of administration followed by 7 days of rest (Figure 1A). Tumor growth and body weight of the animals were monitored during and after treatment. The mice had a tumor size of 1.5 cm. 3 The study continued until clinical signs were observed or until the end of the study (day 54).

[0313] Results: Treatment groups treated with AZD4625 or AZD6738 monotherapy initially showed delayed tumor growth and extended survival compared to the control group, but most tumors eventually regressed (Figure 1B, "Vehicle", "AZD4625", and "AZD6738"). In contrast, treatment groups treated with combination therapy of AZD4625 and AZD6738 showed complete tumor regression, and the response persisted without drug, with 9 out of 10 animals maintaining complete tumor regression throughout the study period even after drug discontinuation (Figure 1Bm, "AZD4625 + AZD6738"). All treatments were well-tolerated and had minimal impact on body weight (Figure 1C).

[0314] Example 2 Antitumor activity by dual inhibition of KRAS and ATR in KRAS-mutated cancers G12C This was determined in a second in vivo study using ATR inhibitors. G12C And ATR inhibitors include AZD4625 (KRAS G12C (a covalent allosteric inhibitor), compound of formula IV (a second chemically different allosteric covalent KRAS) G12CThe drugs were an inhibitor, and AZD6738 (ceraracertib, an ATP competitive ATR inhibitor).

[0315] For research purposes, KRAS G12C CT26 manipulated to express mutations G12C Mouse colon cancer cells were grown subcutaneously in BALB / c mice with an intact immune system. 5 × 10⁶ mice were used to prepare the control mice. 5 pieces and 5 × 10 4 CT26 G12C (G12C clone P5E6) cells were subcutaneously transplanted into the right flank of female BALB / c mice (Envigo UK, strain ID: HSD-162) or female nude Foxn1nu mice (Envigo UK, strain ID: HSD-069), respectively. The average volume was approximately 0.2 cm³. 3 Once tumors formed, the mice were randomized to either a treatment group or a control group and treated for 4 weeks with either vehicle control, AZD4625, compound IV, or AZD6738 monotherapy, or combination therapy with AZD4625 and AZD6738, or compound IV and AZD6738. AZD4625 and compound IV were administered daily, while AZD6738 was administered twice daily during the treatment period, on a 7-day administration-7-day rest schedule (Figure 2A). Tumor growth and body weight were monitored during and after treatment. The mice had a tumor size of 1.5 cm. 3 The study continued until clinical signs were observed or until the end of the study. Mice in the AZD4625 monotherapy and combination therapy groups were monitored up to 65 days post-transplant, while mice in the monotherapy and combination therapy groups of the compound of formula IV were monitored up to 119 days post-transplant.

[0316] Results: The treatment group treated with the compound of formula IV as monotherapy initially showed similar tumor regression to the AZD4625 monotherapy group, but 8 out of 9 tumors returned after drug discontinuation (Figure 2B, "Vehicle", "AZD4625", "Compound of formula IV", "AZD6738"). In contrast, the treatment group treated with the compound of formula IV and AZD6738 as combination therapy showed complete tumor regression, the response persisted without drug, and all 9 animals maintained tumor regression levels even after drug discontinuation and over the subsequent 90-day monitoring period (Figure 2B, "Compound of formula IV + AZD6738"). In the AZD6738 and AZD4625 groups, 7 out of 9 mice showed a complete response, which persisted in 5 mice when drug treatment was discontinued (Figure 2B, "AZD4625 + AZD6738").

[0317] Example 3 Long-term antitumor activity by dual inhibition of KRAS and ATR in KRAS-mutated cancers G12C This was determined in a follow-up in vivo study (re-challenge study) using ATR inhibitors. The KRAS used was also determined. G12C The ATR inhibitors were the compound of formula IV and AZD6738.

[0318] For the second attempt research, 5 x 10 5 CT26 G12C (G12C clone P5E6) cells were subcutaneously transplanted into the left flank of five mice that showed a complete antitumor response to combination therapy with compound IV and AZD6738. For the control group, 5 × 10⁶ cells were transplanted. 5 CT26 G12C (G12C clone P5E6) cells were transplanted into the left flank of untreated female BALB / c mice (Figure 3A). Tumor engraftment and growth were monitored for 4 weeks without drug treatment.

[0319] Result: CT26 G12CTumor growth was observed as expected in untreated control mice, but no tumor growth was observed in any of the flanks of the re-challenge mice (Figure 3B). In one mouse in the re-challenge group, a lesion was observed in the non-transplant site (lymph node), but the origin of this tumor was the transplanted CT26 G12C It could not be confirmed that it was a cell. This data is from KRAS. G12C This suggests that mice treated with combination therapy including ATR inhibitors may have developed long-term antitumor immunity.

[0320] Example 4 The role of the adaptive immune system in driving antitumor activity in dual inhibition of KRAS and ATR in KRAS-mutated cancers was investigated in nude mice lacking a thymus and therefore unable to produce mature T cells in CT26. G12C This was determined using xenograft studies.

[0321] Results: CT26 in nude mice G12C Transient regression of tumors is KRAS G12C While observed with inhibitor monotherapy, the depth and duration of the antitumor response were not as robust as in immunoqualified BALB / c mice (Figure 4A). In nude mice, KRAS G12C The antitumor response to combination therapy with inhibitors and AZD6738 is KRAS G12C The results were slightly better than inhibitor monotherapy (Figure 4A). However, CT26 observed in immunocompetent BALB / c mice G12C In contrast to deep and persistent tumor regression, there were no complete responders to combination therapy in nude mice (Figure 4A).

[0322] Lower antitumor activity in nude mice translated to lower overall survival rates, and all subjects discontinued the study within 2 days of the treatment period due to tumor volume or clinical signs (Figure 4B). Therefore, this data is not relevant to KRAS. G12C The deep, sustained antitumor activity observed with the inhibitor and AZD6738 suggests that it is mediated through an adaptive immune response.

[0323] KRAS G12C Combination therapy with inhibitors and AZD6738 is effective in treating KRAS in mice with intact immune systems. G12C The combination therapy exhibits both unexpected and robust antitumor activity against preclinical models of mutated cancer. Complete tumor regression was observed with the combination therapy, and this regression persisted even after discontinuation of drug treatment. Mouse subjects showing a complete antitumor response to the combination therapy were also protected from tumor rechallenge, suggesting that a long-term memory response to the tumor was induced. This data is from KRAS. G12C This is consistent with the hypothesis that the deep and sustained antitumor activity of combination therapy with inhibitors and AZD6738 is mediated through adaptive immune responses.

[0324] Example 5 Additional antitumor studies using the KRAS inhibitor adagrasib (MTRX849) or sotrasib (AMG510) in combination with the ATR inhibitor AZD6738 (ceraracertib) are being conducted in vivo at CT26 G12C This was conducted using xenograft studies.

[0325] CT26 G12C Mouse colon cancer cells were grown subcutaneously in intact immune system BALB / c mice as described in Examples 1 and 2. The mice were randomized to either a treatment group or a control group and treated for 4 weeks with vehicle control, adaglacib, sotracib, or AZD6738 monotherapy or in combination therapy. Adaglaciv or sotracib was administered daily, and AZD6738 was administered twice daily at the indicated dose over the treatment period, on a schedule of 7 days of administration followed by 7 days of rest (Figure 5). Tumor growth and body weight were monitored during and after treatment. The target mice had a tumor size of 1.5 cm. 3 The study continued until clinical signs were observed or until the study was completed.

[0326] Results: Compared to the vehicle control group, the groups treated with adaglacib or sotracib monotherapy showed delayed early tumor growth (Figure 5A) and increased survival rate (Figure 5B), although most tumors reverted after drug discontinuation, with 0-10% of mice remaining at the end of the study. AZD6738 monotherapy showed no or weak activity compared to the vehicle control group. In contrast, both the adaglacib and AZD6738, or the sotracib and AZD6738 combination therapy groups showed the same KRAS G12C Compared to the inhibitor monotherapy group, the treatment demonstrated improved and more sustained tumor growth inhibition (Figure 5A), further extended survival rates (Figure 5B), and 30–50% of mice remained at the end of the study. All treatments were well-tolerated compared to the vehicle control group and had minimal impact on body weight (Figure 5C).

Claims

1. A method for treating cancer in a subject, wherein the subject a. KRAS inhibitors and b. A method comprising administering ataxia telangiectasia and a Rad-3 related (ATR) inhibitor.

2. A KRAS inhibitor for use in the treatment of cancer in the subject, a. The KRAS inhibitor and, b. ATR inhibitors and A KRAS inhibitor, comprising administering to the aforementioned subjects separately, sequentially, or simultaneously.

3. ATR inhibitors for use in the treatment of cancer in the subject, a. KRAS inhibitors and b. The ATR inhibitor and An ATR inhibitor, comprising administering to the aforementioned subjects separately, sequentially, or simultaneously.

4. The use of the KRAS inhibitor or the ATR inhibitor in the manufacture of a pharmaceutical product for the combined administration of a KRAS inhibitor and an ATR inhibitor for the treatment of cancer in a target population.

5. The method according to claim 1, the inhibitor for use according to claim 2 or 3, or the use according to claim 4, wherein the KRAS inhibitor is an antibody.

6. The method, inhibitor for use, or use according to claim 5, wherein the antibody is ELI-002, KRAS-EphA-2-CAR-DC, anti-KRAS G12V mTCR PBL, anti-KRAS G12D mTCR PBL, siG12D-LODER, or KRAS G12D siRNA.

7. The method, inhibitor for use, or use according to any one of claims 1 to 5, wherein the KRAS inhibitor is a small molecule KRAS inhibitor.

8. The aforementioned small molecule KRAS inhibitors include sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, An inhibitor for use, or use according to claim 7, wherein the inhibitor is MRTX1133, HRS-4642, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, or QTX3046.

9. The aforementioned small molecule KRAS inhibitor is a compound of formula (I). 【Chemistry 1】 (In the formula, Ring A is selected from phenyl and bicyclic heteroaryl compounds. R １ In each occurrence, independently, C １－４ Alkyl, halo, hydroxy, C １－４ Alkoxy, C １－３ Fluoroalkyl, C １－３ Selected from fluoroalkoxy, cyano, and acetylenyl, b is 0, 1, 2, or 3. Y is CH ２ or CH ２ CH ２ And, R ２ is cyano, halo, C １－４ alkyl, C １－４ alkoxy, or C １－３ fluoroalkyl, and R ３ is F, Me, Et, MeO, or C １－２ It is a fluoroalkyl, R ４ is H or Me, R ５ is H or Me, R ６ is H or CH ２ NMe ２ (It is) or a pharmaceutically acceptable salt thereof, provided that Y is CH ２ And R ２ Cl is and R ３ is F, ring A is phenyl, b is 2, R １ The groups are F and OH, and each is ortho relative to the biaryl bond, and R ４ and R ６ If both are H, then R ５ The method according to claim 7, an inhibitor for use, or use, provided that is Me.

10. The small molecule KRAS inhibitor having the structure: an inhibitor for use, or for use according to claim 9. 【Chemistry 2】

11. The aforementioned ring A is 【Transformation 3】 Selected from the group consisting of, The method according to claim 10, an inhibitor for use, or use, wherein the ring A is bonded to the rest of the compound of formula (I) at any point on the ring listed above.

12. R ４ However, H is the method according to any one of claims 9 to 11, an inhibitor for use, or a use.

13. R ６ However, H is the method according to any one of claims 9 to 12, an inhibitor for use, or use.

14. Y is CH ２ The method according to claim 9, an inhibitor for use, or use.

15. Y is CH ２ CH ２ The method according to claim 9, an inhibitor for use, or use.

16. R ２ However, the method according to any one of claims 9 to 15, an inhibitor for use, or use, wherein the method is Cl.

17. R ３ However, F is the method, inhibitor for use, or use according to any one of claims 9 to 16.

18. R ４ H is R ５ A method, inhibitor for use, or use according to any one of claims 9 to 17, wherein is Me.

19. The aforementioned small molecule KRAS inhibitor 7-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindole-1-one, 1-[(8aS,11S)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 1-[(8aS,11R)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 5-[(8aS)-10-acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]isoquinoline-1(2H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazole-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinoline-1(2H)-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzotriazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl)propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl)propa-2-en-1-one, 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzotriazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 8-[(8aS)-6-chloro-4-fluoro-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinoline-1(2H)-one, (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 8-[3-chloro-1-fluoro-8-(propa-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-2-yl]-7-methylisoquinoline-1(2H)-one, 1-[(6aS,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aR,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(6aS,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazosino[4,3,2-de]quinazolin-8-yl]propa-2-en-1-one, 1-[(8aS)-4-chloro-6-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]propa-2-en-1-one, 8-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-10-(propa-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinoline-1(2H)-one, (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, and Selected from (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-indazole-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-yl]-4-(dimethylamino)buta-2-en-1-one, The method according to claim 9, an inhibitor for use, or a use thereof, which is a pharmaceutically acceptable salt thereof.

20. The aforementioned small molecule KRAS inhibitor is a compound of formula (II). 【Chemistry 4】 The method according to claim 7, an inhibitor for use, or use.

21. The aforementioned small molecule KRAS inhibitor is a compound of formula III. 【Transformation 5】 (In the formula, A １ is a phenyl or bicyclic heteroaryl group, X １ and Y １ It is joined by a double bond, i) X １ CR １７ Y １ CR １８ Is it, or ii) X １ is N, Y １ CR １８ or iii) X １ CR １７ Y １ Is N, or X １ and Y １ They come together as C(O)NR １９ is, or X １ and Y １ However, Z １ An adjacent ring atom of an optionally substituted 5-membered or 6-membered N-heterogeneous ring condensed with an aromatic ring that is substituted with X １ and Y １ However, both are C, or C and N. Z １ is O, NH, or NMe, R １０ These are independently F, Cl, Br, OH, CH ２ OH, OMe, CH ２ OMe, C １ -C ３ Alkyl and C １ -C ３ Selected from fluoroalkyl groups, n is 0, 1, 2, or 3. R １２ are H, F, Cl, CCH, CCMe, CN, Br, C １ -C ３ Alkyl, C １ -C ３ It is a fluoroalkyl, OMe, or OEt, R １３ａ and R １３ｂ Together, they equal O, or R １３ａ and R １３ｂ H is, R １４ is H or Me, R １５ is H or Me, R １６ is H or CH ２ NMe ２ And, R １７ and R １８ These are independently H, F, Cl, CCH, CC(C １ -C ３ Alkyl), CCCH ２ Nme ２ 、CCCH ２ O(C １ -C ３ alkyl), CN, Me, C １ -C ６ alkyl, OH, OMe, O(C １ -C ３ alkyl), O(C １ -C ３ dideuterioalkyl), O(C １ -C ３ fluoroalkyl), O(C ３ -C ６ cycloalkyl), C １ -C ３ fluoroalkyl, OCH ２ CH ２ NMe ２ 、OCH ２ CH ２ OMe、CH ２ OMe、OCH ２ CH ２ N(CH ２ CH ２ ) ２ CH、OCH ２ CH ２ N(CH ２ CH ２ ) ２ O、OCH ２ CH ２ (2-pyridyl), or selected from optionally substituted 3-, 4-, 5-, or 6-membered carbocyclic or heterocyclic rings, or R １７ and R １８ These together form a five- or six-membered carbon ring or heterocycle which is optionally substituted. R １９ is H, Me, Et, C ３ H ７ , and C １ -C ３ (Selected from fluoroalkyls), The method, inhibitor for use, or use according to claim 7, or a pharmaceutically acceptable salt thereof.

22. i) X １ CR １７ Y １ CR １８ Is it, or ii) X １ N is Y １ CR １８ or iii) X １ CR １７ Y １ The method according to claim 21, an inhibitor for use, or use, wherein N is N.

23. Z １ The method according to claim 21 or 22, an inhibitor for use, or a use, wherein O is present.

24. R １３ａ and R １３ｂ The method according to any one of claims 21 to 23, an inhibitor for use, or a use, wherein H is present.

25. R １４ The method according to any one of claims 21 to 24, an inhibitor for use, or use, wherein H is present.

26. R １６ The method, inhibitor for use, or use according to any one of claims 21 to 25, wherein H is present.

27. A １ The method according to any one of claims 21 to 26, an inhibitor for use, or a use, wherein the inhibitor is phenyl.

28. The aforementioned small molecule KRAS inhibitor (12aS)-2-acryloyl-10-chloro-9-(5-methyl-1H-indazole-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-6-one, 1-((12aS)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, (12aR)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-((12aR)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazole-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-7-carbonitrile, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazole-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazole-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-6-one, 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 8-[(12aR)-10-chloro-8-fluoro-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-9-yl]-7-methylisoquinoline-1(2H)-one, 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aS)-10-chloro-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aS)-10-chloro-11-methyl-9-(5-methyl-1H-indazole-4-yl)-2-(propa-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepine-6(2H)-one, 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-10-chloro-9-(2-hydroxy-6-methylphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, (12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-2-(propa-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile, 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(propa-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-1-one, 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(propa-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-1-one, 1-[(8aR)-6-chloro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydro-14H-pyrazino[2,1-c][1,2,4]triazolo[4',3':1,2]pyrido[3,4-f][1,4]oxazepine-10(8H)-yl]propa-2-en-1-one, 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazole-9(7H)-yl]propa-2-en-1-one, and 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazole-9(7H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-10-chloro-8-ethynyl-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(7aR)-5-chloro-4-(2-chloro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydroimidazo[4,5-g]pyrazino[2,1-c][1,4]benzoxazepine-9(7H)-yl]propa-2-en-1-one, 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropyloxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)propa-1-in-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepine-2(1H)-yl)propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridine-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidine-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(propa-1-in-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( ２ H ３ )methyloxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-7-[2-(dimethylamino)ethoxy]-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-2(1H)-yl]propa-2-en-1-one, 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(propa-1-in-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl]propa-2-en-1-one, and Selected from 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepine-8(6H)-yl)propa-2-en-1-one, The method, inhibitor for use, or use according to claim 21, or a pharmaceutically acceptable salt thereof.

29. The small molecule KRAS inhibitor is a compound of formula (IV). 【Transformation 6】 The method according to claim 7, an inhibitor for use, or use.

30. The method according to any one of claims 1 to 29, an inhibitor for use, or use, wherein the ATR inhibitor is an antibody.

31. The method according to any one of claims 1 to 29, an inhibitor for use, or use, wherein the ATR inhibitor is a small molecule ATR inhibitor.

32. The method according to claim 31, an inhibitor for use, or use, wherein the small molecule ATR inhibitor is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-559, or IMP9064.

33. The small molecule ATR inhibitor is a compound of formula (V). 【Transformation 7】 (In the formula, R ２１ It is selected from morpholine-4-yl and 3-methylmorpholine-4-yl, R ２２ teeth, 【Transformation 8】 And, n is either 0 or 1, R ２２Ａ , R ２２Ｃ , R ２２Ｅ , and R ２２Ｆ Each is independently either hydrogen or methyl, R ２２Ｂ and R ２２Ｄ Each is independently either hydrogen or methyl, R ２２Ｇ -NHR ２７ and -NHCOR ２８ Selected from, R ２２Ｈ It is fluoro, R ２３ It is methyl, R ２４ and R ２５ Each is independently either hydrogen or methyl, or R ２４ and R ２５ but, Together with the atoms to which they are bonded, they form ring A ２ Forming, Ring A ２ C ３－６ A saturated 4-6 membered heterocyclic ring containing a cycloalkyl or one heteroatom selected from O and N, R ２６ It is hydrogen, R ２７ is hydrogen or methyl, R ２８ (It is methyl.) The method, inhibitor for use, or use according to claim 31, or a pharmaceutically acceptable salt thereof.

34. R ２４ and R ２５ However, together with the atoms to which they are bonded, they form ring A ２ Forms ring A ２ However, C ３－６ The method according to claim 33, an inhibitor for use, or use, wherein the method is a cycloalkyl or a saturated 4-6 heterocyclic ring containing one heteroatom selected from O and N.

35. Ring A ２ The method according to claim 33 or 34, an inhibitor for use, or a use, wherein the ring is cyclopropyl, tetrahydropyranil, or piperidinil.

36. R ２２Ａ However, it is hydrogen, R ２２Ｂ However, it is hydrogen, R ２２Ｃ However, it is hydrogen, R ２２Ｄ However, it is hydrogen, R ２２Ｅ However, it is hydrogen, R ２２Ｆ The method according to any one of claims 33 to 35, an inhibitor for use, or a use, wherein the inhibitor is hydrogen.

37. R ２１ The method according to any one of claims 33 to 36, an inhibitor for use, or a use, wherein the inhibitor is morpholin-4-yl.

38. R ２１ The method according to any one of claims 33 to 36, an inhibitor for use, or a use, wherein the inhibitor is 3-methylmorpholine-4-yl.

39. The compound of formula (V) is the compound of formula (Va), 【Chemistry 9】 The method, inhibitor for use, or use according to claim 33, or a pharmaceutically acceptable salt thereof.

40. Ring A ２ However, it is a cyclopropyl ring, R ２２ but, 【Chemistry 10】 And, n is 0 or 1, R ２２Ａ However, it is hydrogen, R ２２Ｂ However, it is hydrogen, R ２２Ｃ However, it is hydrogen, R ２２Ｄ However, it is hydrogen, R ２２Ｅ However, it is hydrogen, R ２２Ｆ However, it is hydrogen, R ２２Ｇ However, -NHR ２７ And, R ２２Ｈ However, it is fluoro, R ２３ However, it is methyl, R ２６ However, it is hydrogen, R ２７ However, it is hydrogen or methyl, The method, inhibitor for use, or use according to claim 39, or a pharmaceutically acceptable salt thereof.

41. The aforementioned small molecule ATR inhibitor 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[((R)-S-methylsulfonimidoyl)methyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-b]pyridine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-indole, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-indole, 1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-pyrrolo[2,3-c]pyridine, N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[4-((S)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[4-((R)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-{4-[(3R)-3-methylmorpholine-4-yl]-6-[4-((S)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidine-2-yl}-1H-indole, 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholine-4-yl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzoimidazole-2-amine, and One of the following is selected: 6-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholine-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidine-2-yl}-1H-benzimidazole-2-amine The method, inhibitor for use, or use according to claim 31, or a pharmaceutically acceptable salt thereof.

42. The aforementioned small molecule ATR inhibitor is a compound of formula (VI) (ceraracertib), 【Chemistry 11】 The method, inhibitor for use, or use according to claim 31, or a pharmaceutically acceptable salt thereof.

43. The above (i) KRAS inhibitor and (ii) ATR inhibitor are used in the following combinations: Table 1-1 Table 1-2 Table 1-3 One of these is the method according to claim 1, the inhibitor for use according to claim 2 or 3, or the use according to claim 4.

44. The method according to claim 1, the inhibitor for use according to claim 2 or 3, or the use according to claim 4, wherein (i) the KRAS inhibitor is a compound of formula (II) and (ii) the ATR inhibitor is ceraracertib.

45. The method according to claim 1, the inhibitor for use according to claim 2 or 3, or the use according to claim 4, wherein (i) the KRAS inhibitor is a compound of formula (IV) and (ii) the ATR inhibitor is ceraracertib.

46. The method, inhibitor for use, or use according to any one of claims 1 to 45, wherein the subject has a KRAS, NRAS, or HRAS mutation.

47. The method, inhibitor for use, or use according to any one of claims 1 to 45, wherein the subject has a KRAS mutation.

48. The method according to claim 47, an inhibitor for use, or use, wherein the KRAS mutation is a mutation at codon 12, codon 13, and / or codon 61.

49. The method according to claim 47, an inhibitor for use, or use, wherein the KRAS mutation is a mutation at codon 12.

50. The method according to claim 47, an inhibitor for use, or use, wherein the KRAS mutation is a G12C mutation.

51. The method, inhibitor for use, or use according to any one of claims 1 to 50, wherein the subject is lung cancer, colorectal cancer, pancreatic cancer, esophageal and gastric cancer, endometrial cancer, bile duct cancer, or a combination thereof.

52. The method, inhibitor for use, or use according to any one of claims 1 to 51, wherein the subject is a human subject.

53. The method, inhibitor for use, or use according to any one of claims 1 to 52, wherein the subject is lung cancer, colorectal cancer, pancreatic cancer, or a combination thereof.

54. A method for modulating the adaptive immune response in a subject, a. KRAS inhibitors and b. A method comprising administering a composition comprising an ATR inhibitor.

55. A method for reducing the volume of cancerous tumors in a subject, a. KRAS inhibitors and b. A method comprising administering a composition comprising an ATR inhibitor.

56. A method of treating a subject that requires treatment, a. KRAS inhibitors and b. The treatment involves administering a composition comprising an ATR inhibitor, A method wherein the subject has a disorder mediated by the KRAS, NRAS, or HRAS G12C mutation.

57. a. KRAS inhibitors and b. A composition comprising an ATR inhibitor.

58. The KRAS inhibitors mentioned above are sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, MRTX1133, and HRS-46. The composition according to claim 57, wherein 42, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV).

59. The composition according to claim 57 or 58, wherein the ATR inhibitor is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-5597, or IMP9064, a compound of formula (V), or a compound of formula (VI).

60. The composition according to any one of claims 57 to 59, wherein the composition is a liquid.

61. The composition according to any one of claims 57 to 59, wherein the composition is solid.

62. The composition according to any one of claims 57 to 59, wherein the composition is in the form of a solid oral dosage.

63. The composition according to any one of claims 57 to 62, wherein the composition further comprises a pharmaceutically acceptable excipient, diluent, or carrier.

64. Use of a composition according to any one of claims 57 to 63 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the optional treatment of cancer.

65. It's a kit, a. A first container containing a first composition comprising a KRAS inhibitor, b. A kit comprising a second container containing a second composition comprising an ATR inhibitor.

66. The KRAS inhibitors mentioned above are sotrasib, adagrasib, Ly3537982, GDC-6036, D-1553, JDQ443, BI1823911, GFH925, D35-001, JAB-21822, HBI-2438, YL-15293, GEC255, IBI351, RMC-6291, MK-1084, MRTX1133, and HRS-46. 42, RMC-9805, JAB-2200, Vrtx153, ERAS-4, ASP3082, RMC-0708, RMC-8839, RMC-6291, JAB-23400, TEB-17231, QTX3046, a compound of formula (I), a compound of formula (II), a compound of formula (III), or a compound of formula (IV), according to claim 65.

67. The kit according to claim 65 or 66, wherein the ATR inhibitor is M6620 / VX970 (belzocertib), BAY-1895344 (elimsertib), RP-3500 (camoncertib), ATRN-119, SC0245, ATRN-212, LR-02, M4344 (galticertib), M1774, ATG-018, ART0380, BG-129, JS-123, BKT-300, AZ-20, VE-821, AZD-5597, or IMP9064, a compound of formula (V), or a compound of formula (VI).

68. The kit according to any one of claims 65 to 67, wherein the first composition, the second composition, or both the first composition and the second composition are liquids.

69. The kit according to any one of claims 65 to 67, wherein the first composition, the second composition, or both the first composition and the second composition are solid.

70. The kit according to any one of claims 65 to 67, wherein the first composition, the second composition, or both the first composition and the second composition are in solid oral dosage form.

71. The kit according to any one of claims 65 to 70, wherein the first composition, the second composition, or both the first and second compositions further comprises a pharmaceutically acceptable excipient, diluent, or carrier.

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